Document BRZ5bRjVKnYrJorwDDQVmeDNX

4 FOR IMMEDIATE RELEASE FOR FURTHER I'.'FORMAT Contact: Ji- Har.sen Phone: 517-636-3205 Midland, Michigan March 17, 1970 DOW RESEARCH ON 2,4,5-T BLAMES BIRTH DEFECTS ON IMPURITY The Dow Chemical Company scientists presented detailed evidence today showing that a contaminant rather than the compound 2,4,5-T was probably the cause of birth abnormalities reported in test animals in a recent study. 2,4,5-T herbicides produced by several companies are widely used throughout the world for brush control purposes on agricultural lands and are used for weed control in a few 'food crops. The material in combination with 2,4-D, another herbicide, has also been used in Vietnam as a defoliant. . 2,4,5-T has been under fire since October of last year when it was announced that a study conducted by Bionetics Laboratories, Inc., under contract to the National Cancer Institute, indicated higher than normal rates of birth defects in test animals treated with massive doses of 2,4,5-T. Examination of data from the Bionetics testssuggested to scientists at Dow that rather than 2,4,5-T, the real culprit might have been a toxic contaminant that has from time to time been a problem in the manufacture of the material. The Bionetics sample material was analyzed and found to contain approximately 27 parts per million of the contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin. Production standards for the more 5994 MiiTitis a tra ir iit tic a a* c i t m e i i coitili iiaiois. mici i - 2- Page 2 herbicide as produced by Dow require that 2,4,5-T contain less than one part per million of the dioxin. Dow established this specification in 1965 to assure safety in the production of the 'material. In papers presented today at the meeting of the Society of Toxicology in Atlanta, V. K. Rowe and Dr. J. L. Emerson cited detailed studies just completed that indicate no fetal abnormalities are produced by the herbicide when the Dow standard for dioxin content is met. The animal studies involved the feeding of rats with 2,4,5-T containing less than one PPM of the dioxin contaminant at levels comparable to those used in the earlier studies. Results indicated very clearly that the herbicide containing less than one part per million of the dioxin had no effect on either mothers or fetuses. In addition, another group of test animals was given the cioxir. alone at levels comparable to those in the impure sample used in the Bionetics work. Results in the test with the pure dioxin indicated a high level of maternal and fetal toxicity of the material. Abnormalities observed in these tests were similar to those reported by Bionetics Laboratories. In a comment on the test work, V. K. Rowe, toxicologist at Dow and principal investigator in one of the studies, said, "We simply proved again what we already knew. 2,4,5-T is a material of low toxicity while the dioxin is highly toxic. That is precisely why we set a rigid production standard for our products many years \go.M }' #I* i Page 3 ABSTRACT Teratogenic Study of 2,4,5-Trichlorophenoxy acetic acid in the Rat. J. L. Emerson, D. J. Thompson, C. G. Gerbig and V. B. Robinson, The Dow Chemical Company, Zionsville, Indiana. A study to determine the embryotoxicity or teratogenicity of 2 ,4,5-trichlorophenoxyacetic acid containing less than one part per million of 2,3,7,8-tetrachlorodibenzo-pdioxin has been completed in Sprague-Dawley derived rats. Five treatment groups, each consisting of 25 females were administered 1, 3, 6, 12 or 24 mg/kg/day of the compound via gavage in 0.25% 1IETH0CEL on days 6 through 15 of gestation. A single group of 50 females received the suspending vehicle and served as controls. The following parameters were examined: clinical observations, maternal body weights (prebreeding and day 20), number and position of fetuses and resorptions, number of corpora lutea, pup weight and sex, gross external examination of pups, and macroscopic examination for intestinal hemorrhage in pups. Two-thirds of each litter were fixed in Bouin's solution and one-third was prepared for alizarin red-S staining and skeletal examination. Examination of Wilson sections under the dissection microscope or of alizarin stained skeletons of all fetuses from the 24 mg/kg/day group and an equal number of control fetuses was performed. Repre sentative stained histologic sections through the head, thorax, and abdomen of 10 control and 10 high level fetuses were studied for histopathologic changes. 2cciBii <o F 7oxt0>Y A y \A & c .tJ 17 5996 Page 3 ABSTRACT Teratogenic Study of 2,4,5-Trichlorophenoxy acetic acid in the Rat. J. L. Emerson, D. J. Thompson, C. G. Gerbig and V. B. Robinson, The Dow Chemical Company, Zionsville, Indiana. A study to determine the embryotoxicity or teratogenicity of 2 ,4,5-trichlorophenoxyacetic acid containing less than one part per million of 2,3,7,8-tetrachlorodibenzo-pdioxin has been completed in Sprague-Dawley derived rats. Five treatment groups, each consisting of 25 females were administered 1, 3, 6, 12 or 24 mg/kg/day of the compound via gavage in 0.25% METHOCEL on days 6 through 15 of gestation. A single group of 50 females received the suspending vehicle and served as controls. The following parameters were examined: clinical observations, maternal body weights (prebreeding and day 20), number and position of fetuses and resorptions, number of corpora lutea, pup weight and sex, gross external examination of pups, and macroscopic examination for intestinal hemorrhage in pups. Two-thirds of each litter were fixed in Bouin's solution and one-third was prepared for alizarin red-S staining and skeletal examination. Examination of Wilson sections under the dissection microscope or of alizarin stained skeletons of all fetuses from the 24 mg/kg/day group and an equal number of control fetuses was performed. Repre sentative stained histologic sections through the head, thorax, and abdomen of 10 control and 10 high level fetuses were studied for histopathologic changes. Soct7y Io F lAAfccF P j l ^ 70 5997 Page 3 ABSTRACT Teratogenic Study of 2,4,5-Trichlorophenoxy acetic acid in the Rat. J. L. Emerson, D. J. Thompson, C. G. Gerbig and V. B. Robinson, The Dow Chemical Company, Zionsville, Indiana. A study to determine the embryotoxicity or teratogenicity of 2,4,5-trichlorophenoxyacetic acid containing less than one part per million of 2,3,7,8-tetrachlorodibenzo-pdioxin has been completed in Sprague-Dawley derived rats. Five treatment groups, each consisting of 25 females were administered 1, 3, 6, 12 or 24 mg/kg/day of the compound via gavage in 0.25% LIETHOCEL on days 6 through 15 of gestation. A single group of 50 females received the suspending vehicle and served as controls. The following parameters were examined: clinical observations, maternal body weights (prebreeding and day 20), number and position of fetuses and resorptions, number of corpora lutea, pup weight and sex, gross external examination of pups, and macroscopic examination for intestinal hemorrhage in pups. Two-thirds of each litter were fixed in Bouin's solution and one-third was prepared for alizarin red-S staining and skeletal examination. Examination of Wilson sections under the dissection microscope or of alizarin stained skeletons of all fetuses from the 24 mg/kg/day group and an equal number of control fetuses was performed. Repre sentative stained histologic sections through the head, thorax, and abdomen of 10 control and 10 high level fetuses were studied for histopathologic changes. 17 j / 9 7 ^ 5998 2- - EXHIBIT B Page 4 No clinical or gross pathologic signs of ad-,erso chemical effect were observed in treated dams during the period of treatment or gestation. Similarly, litter size, number of fetal resorptions, birth weights and sex ratio of pups appeared to be unaffected by chemical treatment. Skeletal and visceral examination of high level and control fetuses as well as histopathologic examination of certain fetuses failed to reveal any teratogenic or embryotoxic effects. The results of this study fail to s u b s t a n t i a l the findings reported recently (unpublished data: Bionetics Research Laboratories, Bethesda, Maryland) of serious effects in fetuses obtained from dams given comparable daily doses of 2,4,5-T containing approximately 27 parts per million of the contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin. / 5999 e x :;:b :t b Page 5 ABSTRACT Teratogenic Study of 2,3,7, 8-Tetrachlorodibenzo-p-dioxin in the Rat. G. L. Sparschu, F. L. Dunn and V. K. Rowe, The Dow Chemical Company, Midland, Michigan. 2,3,7,8-Tetrachlorodibenzo-p-dioxin has been found to occur in small amounts as a contaminant in some commer cially manufactured samples of 2,4,5-trichlorophenoxy acetic acid. The purpose of this study was to learn whether.the presence of this impurity possibly could account for the fetal abnormalities in test animals reported in a recent study (unpublished data: Bionetics Research Laboratories, Bethesda, Maryland). The dioxin was administered by gavage in 9:1 corn oil T* acetone solution in doses of 0 (control), 0.03, 0.125, 0.5, 2.0 and 8.0 micrograms per kilogram body weight per day to groups of 24 (control) and 12 (treatment) pregnant female Sprague-Dawley derived rats on days 6 through 15 of gestation. On day 20 of gestation, each dam was sacrificed and a cesarean section performed. The number of viable and dead fetuses and early and late resorptions was recorded. Each fetus was examined for any gross abnormalities. Two-thirds of each litter were fixed in Bouin's solution, Wilson sections were examined under the dissection micro scope, and tissues were studied for histopathology. One-third of each litter were fixed in alcohol and exam ined for skeletal abnormalities by alizarin red-S stainin Soe/STY o f EXHIBIT 3 - 2- P a g e 6 No differences were observed in the fetuses taken from dams treated at the dosage of 0.03 ^g/kg/day and those taken from dams that received the solvent vehicle only. At the 0.125 ^ig/kg/day dosage, all parameters studied were within normal limits except for a very slight decrease in average weight, and the occurrence of intestinal hemorrhage (18/127) and subcutaneous edema (22/80) in the fetuses from dams that received this treatment. At the 0 . 5 ^ug/kg/day level, the number of fetuses was reduced and the number of resorptions and fetal deaths was increased. The average weight of the viable fetuses was very slightly decreased. The inci dence of intestinal hemorrhage (36/99) and subcutaneous edema (31/65) was markedly increased over that seen in the 0.125^ig/kg/day treatment. At the 2.0 ^g/kg/day level, only 7 viable fetuses were obtained. These w e r e 'from 4 of the 11 litters examined. Resorptions were numerous, intestinal hemorrhage was frequent (4/7), and subcutaneous edema was present in all of the 4 fetuses examined by Wilson section. One fetus from this treatment level was found to have a kinked tail and two of its feet were somewhat misshapen. Skeletal examination, however, revealed no evidence of bone abnormalities. The 8.0 ^ig/kg/day dosage level proved to be toxic to the dams. There were no viable fetuses in the dams which were examined on day 20 of gestation. All resorptions occurred early and no evidence of fetal tissue was found. / Page 7 Skeletal examinations revealed delayed ossification of some sternebrae and skull bones. This occurred generally throughout the various groups, including controls, and is not considered to be of practical significance. The results of this study indicate a high level of maternal and fetal toxicity to be associated with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Its presence in the sample tested in the Bionetics Laboratories study could well have accounted for the observations reported and attributed to 2,4,5-trichlorophenoxy acetic acid. 8002 n I7 ........... ^ 5 - -- 0 ^ ^ * .-J* '** *t "'2*` * It. * DEPOSITION { EXHIBIT Vs 8 * F -j v Kli. j& 9 m in c o h *oixatbo ,,/( ex CC: Dr. R. 3 . S c o tt - K .O .S y n . tr . C. L. Dunn - H .O .iyn. Dr. J . F. va l k e r / B l d g . 8 1 Kr. A. Z. Conner/jlldg. 8100 Dr. A. E. Sldw ell -Jacksonville Kj rch 19, 1970 TO: DR. M. A. TAVES, SYNTHETICS RESEARCH DIVISION MOM: J . J . FORD, ANALYTICAL DIVISION ANALYSIS OF 2 , h , 5 - T ACID FOR "DIOXIN" CC1.TENT A aurn-ary o f th e a n a l y t i c a l i a t o obtained f e r tha "dioxin" content of Hercules 2 ,^ ,5 -T Acid la given in the attached t a b le . A t o t a l o f 13 samples have no been an alysed by our modified a n a ly tic a l procedure. This series Includes seven samples representing 2 , b , 5 - T produced between 1967 and 1970 and s i x samples o f 2 , ,5 - T produced In 1965. The l a t t e r s a b l e s were retained from our previous work ( 1963) on t h is problem. No s i g n i f i c a n t amounts o f "dlexln" errte sdie t e c t e d lr. any o f t h e 2 , 4 , 5 - T r e p r e s e n t in g t h e 1967 t o 1970 p r o d u cttliaonn. Based on r e c o v e r y data from "add back" ex p e r im e n ts, t h e "dioxin** con ten t o f t h e s e samples i s l e s s than 0.2 ppm. ^ The samples o f 2 , ^ , 5 - T r e p r e s e n t in g I965 p rod u ction y ie ld e d d io x in " ve lu e a in th e range o f 1 . 3 t o J.5 ppm. These values agree wall with tha resu lts previously reported for these samples. (See l e t t e r Ford t o T aves, 0/ 26/ 65) Ve now f e e l we have an adequate a n a l y t i c a l procedura fo r the a n r ' y s l s o f 2 ,b ,5 * T f o r " d io x in " c o n te n t. Scb F is h e r , a chem ist a t the J a c k s o n v ille p la n t v i s i t e d v th us during the week o f March 2nd to le a r n t n i a method. J a c k s o n v i l l e Lab i s p r e s e n t ly " t o o lin g up* t o apply t h l a procedure. JJF/paw Attach. S v *1cL 1 r.w *> V & : ft4 -eeA#'Afj i** *rr ?i * V`ij.ty]*-v, ,0 I b y i DEFENDANT'S i EXHIBIT /(W 7 `y.T&v.i:-*i. 1. - sSr*a..?O:T..V::.*-" Sr*- -. - V-- 'tiieii'-i-.-.-. SMpl# D m lrnutlon X1739"- 2 1 - l -21-2 . --*211--3 n -21.5 - 21-6 ' -?l-7 XH67-2-AI -2-A2 -2-AJ -2-A4 -2-A5 -A6 -- ? ,ln " Coot.nt of g . t . ^ r . Pecrlptlon Cmpoilte 10/12 1960 Compos 1 te U / l i + 11/A 160 Composlt 12/6 l ?/7 1968 Campos ( U 1/16 1/1 9 I96g T ots Bln 2 /2 1 /7 0 Campos 11 S /fi/60 Comooslt 5/29 b /30 1967 Lot L 71965 5 /1 5 /6 5 Lot H 71965 6/ 1/65 Lot N 71065 6/ 15/65 ' p )t P 71965 7/1/65 Lot Q 71965 7/19/65 Current 7/ 7/65 y*ftrenc Beferene Aeferanc Iteferencs A B C L tter T relsbsck to Lo 2 /2 1 /7 0 . S sn p les tfellvareil bjr Bob P lsh er. U t t * r S ld w ell to T*ves 7/ I 9/ 65. *t>ioxin" 2,37,8-T trchlorodiberjto-p-dloxln. t. i i o M 2. :j'i c* cru> -M,.-til l i vra Oloiln* <0.2 p p .. .< 0.2 pp, <0.2 ppa. < 0 .2 ppm. <0.2 pp, < 0 .2 ppm. < 0 .2 ppm. I8 I I if 'J I a HERCl/Lr.S 4 n a t io n a l A g r ic u l t u r a l C h em ic a ls a s s o c ia t io n mi im Kj r c h 2 4 , 1970 l,, fi ^ K r. J . O. K ing Diamond Sham rock C hem ical C o. 300 U nion Commerce b u ild in g C le v e la n d , O hio 4411b D ear Jim : Thanks fo r y o u r l e t t e r o f K arch 2 regarding p o s s ib le industry p u b lic r e la tio n s value in p u b lic iz in g the f u ll c io x in 'sto ry . When t h e F e d e r a l d i o x i n t e s t l n q p ro g ra m v a s f i r s t a n n o u n c e d , 1 'ta lk e d w ith some o f o u r em ber com panies a b o u t i t , esp e c ia l ly th o s e m ost c lo s e ly in v o lv e d ! - Ihe co n cen su s was th a t th e se com panies could handle th e v a tte r ore a p p ro p ria te ly and e x p e d itio u s ly them selves, a t le a s t during th a t early a ta g e w hich re q u ir e d quick a c tio n and re s p o n s iv e f l e x i b i l i t y on tn e ir p a r t S in c e t h a t t i e , X h av e d le c u a e e d t h e m a t te r w i t h o u r own p u b lic r e la tio n e people and X w ill bring i t up ag ain to tha nurbera o f th e Phenoxy h e rb ic id e Task Force when th ey g e t to g eth er a g a in . Ii Tours very t r u l y 9 # UXiftt facet Mr /C h a r l e a Duna irm eth K. K rao ach e r ir a cto r o f Tacim i c a l S erv ices +i4 i H 01503 i 6008 ct G O VERNM ENT 0000629 Government steps up pressure on pesticides Recent joint action restricting use of 2,4,5-T herbicide portends changes in pesticide regulations and testing $ When Sen. Philip A. Hart (D.-Mich.) opened a Congressional inquiry into the hazards of 2,4,5-T earlier this month, he cautiously suggested that questions on the widely used herbi cide's safety "might in the end appear to be much ado about very little in deed" or portend "the most horrible tragedy ever known to mankind." The hearings fell short of proving the latter. But they did provide new evidence that catalyzed government suspension and cancellation of con sumer and food crop uses of 2,4,5-T and a halt to its use in Vietnam. What's more, pesticide producers and formulators were again put on notice that Congress intends to scrutinize other products and that pesticide reg ulations an'd testing will likely change. The multipronged action suspended use of liquid formulations containing 2,4,5-T around the home, near lakes and ponds, and on ditch banks and canceled use of nonliquid formula tions around the home and on apples, blueberries, barley, com, oats, rye, rice, and sugar cane. Not restricted are uses for weed and brush control on range, pasture, forest, rights-of-way, and nonagricultural land. But defoli ation in Vietnam with a 2,4,5-T and 2,4-D mixture ("agent orange" ) will be suspended; use of a 2,4-D and picloram mixture ("agent white") will continue. Of the two steps against U.S. uses, suspension is the more drastic; It halts interstate sales immediately. Cancellation provides for a 30-day pe riod for industry comment. Appeals are possible for both steps, and if a company appeals, only suspension pre vents marketing during the appeal process. Dow Chemical, a major pro ducer of the herbicide had not an nounced what action it would take, if any, at press time. Some 10/'c o-f total 2;4,5-T"sales are affected by the orders, Dow estimates. Production of the herbicide in 1968, the latest yearfor which figures are available, was 17.5 million pounds. With the home gardening season now in full swing, 2,4,5-T formulations are already on retailers' shelves. Although these products may continue to be sold, one industry source suggests that state agencies may be under pressure not to buy and may ride out the year M C & E N A P R IL 27. 1970 without new purchases for those uses said that HEW judged that an "imini-, still registered. nent hazard" existed and that the sus- <- New evidence. For some time 2,4,- pension action was taken to protect* 5-T has been under attack for its use women of child-bearing age. But hs in Vietnam defoliation and because of stressed that HEW was "not aware of research findings by Bionetics Re any reliable evidence that 2,4,5-T, in-'5 search Laboratories that it caused deed any of the pesticidal chemicals, birth defects in laboratory animals. has resulted in human birth abnormaiy?' Dow, one of three current producers t, ies.t* t. along with Monsanto and Hercules, Further scientific evidence against ; had contested these findings, however. 2,4,5-T was presented by Dr. M. Jac- " The company contended that the tera queline Verrett of the Food and Drug ? f-togenic (fetus deforming) effects were Administration. She testified that due to. dioxin contaminants in a Dia ; mond Alkali (now Diamond Sham rock) sample taken in 1965. (Dia mond Shamrock no longer makes 2,4,- 5-T. Various estimates of that sample place one contaminant, 2,3,7,8-tetra- chlorodibenzo-p-dioxin, at from 16 to 27 p.p.m.) And Agriculture wit nesses, testifying before the Hart (Com merce Subcommittee, early this month judged the evidence insufficient to recommend any new restrictions (C&EN, April 13, page 21). But fu rth e r research by the Na tional Institute of Environmental Health Sciences (NIEHS) overturned the Agriculture position. The data were analyzed April 11 and 12, pre sented to HEW, federal regulatory of- . ficials, and Cabinet members on April 13, and disclosed by Surgeon General Jesse Steinfeld on April 15 to the Hart subcommittee. The joint Agriculture- In terior-HEW announcement for tak ing the action states that "2,4,5,-T, as well as its contaminant dioxines, may produce abnormal development in un born* animals. Nearly pure 2,4,5-T was reported to cause birth defects chick embryo -studies and preliminary when injected at high doses into . . . hamster data indicate that current pro-J pregnant mice, but not in rats. No duction 2,4,5-T with 0.5 p.p.m. of tbt*J data on humans are available." tetradioxin "is teratogenic and embryo- I A summary of NIEHS data indi toxic." Surgeon General Steinfeld.^ cates that the 2,4,5-T, comparable to however, expressed concern over the^i that available commercially from Dow, tests' "degree of reliance" and said | Monsanto, and Hercules, was admin that "they do not clarify the uncer-1 istered subcutaneously in dimethyl sul tainties as to the significance for man.' -' foxide solution to three strains of Climate of pressure. Confronted mice--random bred Charles River, - with the Government's ban, Dr. Julius C57B1/6, and D13A/2. Charles River E. Johnson, Dow vice president andd>', rats received an orally administered rector of research, told Sen. Hart that sucrose suspension of 2,4,5-T. Dioxin he could not agree with the decisk* was also administered to both mice "as far-as [2,4,o-T] is an imminent: \ and rats-. hazard" but that he would have to i Under questioning by the.subcom agree "in the climate.of pressure to- | mittee, Dr. Steinfeld' professed his day." Dr. Johnson argued that: . A "surprise"' at-the research results and , Low mammalian toxicity of 2,L-1 '6009 ' f ..."r'?i ^5-T and absence of reports of in- -'creased incidence of birth defects in Seattle or sheep grazing rangelands ^sprayed with 2,4,5-T make it "difficult .,,-to believe that any practical hazard V,existed" from registered uses, j-'b Tests with Sprague-Dawley rats `administered both regular production^vgrade 2,4,5-T and 2,3,7,8-tetrachlorovdibenzo-p-dioxin, at dosages bracket- mg those given in the Bionetics studv, 'did not cause birth defects in the case ref- 2,4,5-T, but did indicate a high level of maternal and fetal toxicity ^from the dioxin. Dr. Ian Mitchell of National Cancer Institute told JsDow that the rat tests, according to -Ur. Johnson, would be superior to ^ tests with ice. 'Production of 2,4,5-T under specifications requiring less than 1 p.p.m. inst' of the tetradioxin "presents no practi- hazard when used in accordance good agricultural practices. : *a 130-pound (60 kg.) person Sen. Philip A. Hart Safe or unsafe? * .cer- that issop Ots 3.3 pounds (1.5 kg.) of food ^daily and all of this food contains 0.2 jfpqun. 2,4,5-T (a proposed negligible :: residue tolerance), the total amount of 2,1,5-T ingested per day would be 300 :|jmcrograms. If the 2,4,5-T contained 1 p.p.m. of the tetradioxin, the food would contain 300 picogranis. If a person ingested this amount of dioxin ..each day for 100 yeans, the total ^amount ingested would be only 11 .aerograms . . . which represents a 6000-fold safety factor over the amount required to cause embryonic .effects in rats. (By contrast, FDA onitored 5300 food samples for 2,4,5-T, found 25 samples with trace resi- es, and only two with 0.19 and 0.29 (jLp.m. 2,4,5-T") Support for the NIEIIS and FDA studies came from Dr. Samuel S. Ep.stein, cochairman of the teratogenicity panel of HEW 's Commission on Pes-` ticides. Dr. Epstein testified that these studies "clearly confirm" 2,4,5-T's teratogenicity. Although Dr. Epstein says that the teratogenic data on 2,4-D is "far less conclusive" than that for 2,4,5-T, he suggested, under questioning,- that there is a "strong presumption" for suspending phenoxy herbicides "under any circumstances in the environ ment." He raises questions about re stricting captan, carbaryl, organomercuiy compounds, and PCNB (pentachloronitrobenzene). And he con cludes that there is an "urgent need" for restricting human exposure to di oxins--particularly in light of the lack of toxicology data--and that similar restrictions should extend to polychlorophenols, polychlorophenoliccontaining compounds, and their com bustion products. Scientific challenge. W hat effect the 2,4,5-T hearings will have on other pesticides isn't immediately clear. But Dr. Steinfeld promises that HEW will, "in the very near future," set up a, clearinghouse for information on all types of pesticides. On the related question of exchanging scientific infor mation, Dow's Johnson strongly urges that research results be subject to open discussion and scientific challenge. The Bionetics results were leaked to the press and to Capitol Hill, but chemical company officials as well as members of the Mrak Commission (Secretary's Commission on Pesticides and Their Relationship to Environ mental Health) had difficulty in ob taining the results. Dr. Lee A. Dubridge, President Nixon's science adviser, in a state ment submitted for the record, indi cated that more federal funds might have to be spent on the "background research relating to health and other effects of environmental agents, includ ing pesticides."* He also pointed out that the Administration is considering a series of proposed amendments to federal laws regulating pesticides. One, not alluded to by Dr. DuBridge, would require Agriculture to inspect plants making pesticides. This is currently blocked, .however, by the Bureau of the Budget. Another may involve what Dr. DuBridge called the lack of a mechanism for Government to "exercise prudent and unequivo cally effective restraint temporarily on new, unexpected information and while awaiting more definitive results." Meanwhile, an industry spokesman tells C&EN, "Everyone is looking at their costs and companies are e'ither cutting back or combining their re search efforts." If you're interested in this section of the periodic table, you've come to the right p lace.. DAVISON CHEMICAL This is also the group which is a specialty of our Rare Earth Depart ment. If you haven't yet evaluated Grace/Davison's rare earth chem icals, take a moment to fill out and mail the coupon below to express your specific needs. It may well put more profit and performance in your products! i------------------------------------------------------- W. R. GRACE & CO. i DAVISON CHEMICAL DIVISION ! 4000 N. Hawthorne Street J Chattanooga, Tenn. 37406 { Please send me technical data on: Rare Earth Chloride 1 Rare Earth Fluoride Rare Earth Carbonate Rare Earth Oxide Cerium Oxide Cerium Hydrate Lanthanum Saltp Didymium Salts Thorium Salts High Purity Rare Earths Specific information regarding rare earths________________ | | J } ' < i j J | | \ NAME P O S IT IO N COMPANY AODPS CITY S T A T E /Z tP ni o A P R IL 27. 1970 C A E N (1 I 20 'F - "v 5 ./ C! W i Ci '.I.OttODsISUNZO-p-D'OX v. Survey of Polychlorodiben/.o-/; dioxin Content in Selected Pesticides . Edwin A. Woolxon,* Ronald F. Thomas,1and Peter D. J. Ensor . Onc-hundrcd-twenty-ninc samples of 17 different pesticides derived from chtorophcnuls were cx- amined for polyehlorinuted dibenZo/z-dioxins by electron capture gas chromatography (cc-gc). The method of cleanup ititolvcd a concentrated sulfuric acid extraction of impurities from hexane and a mild nitration of the chlorophenol extracts. Seventy-six percent of the samples analyzed contained less than 0.1 /ig/g of 2,f,7,K-teliachh)rodil>eii/.o-/j-dioxin (TCDD) in the technical material, wheteas 7% conlaincd between 0.1 to 1.0 /rg/g, and 9% contained greater than 10 /*g/g TCDD. No TCDD was dctcctcd in the 20 tri-. tetra-. or pcr.tachloropheaol ; samples examined. However, tugii levels of dioxins were found. All samples which 'contained' more than 1.0 ag/g of dioxin by -sc'w ere confinnC*! . by gas chromatography using a ftiKye ionization . lector (fid-gc), a microcoutoiueiric detector (mc-ge).' p values, uv irradiation, and/or gas chromatography/ 7 ' mass spectromeliy (gc-msj. Samples of phrnosy herbicides from current production contained less t h a n 0 .5/rg/gTCDD. , 'X '. ' ; ;. ' .' fra amide. ivalcnt cquiy J with .its, line ive I .mum onses ively, canty con- t,154 1971 olychlorodibenzo-p-dioxins may be contaminants in chloroplicnols or in pesticides which use ehlorophenols in the manufacturing process. Chlorinated dibenzo- p-dioxins arc hazardous materials and m ay cause skin erup tions, teratogencsis, and are toxic to animals at low levels. The dioxins are formed usually when the reaction tempera ture for making o-chlorbphcnol by hydiolysis exceeds 160C under pressure. The icaction may be an alkaline hydiolysis of poJychlorobenzene or a chlorination of phenol to form a 4 po'ychlorophenol. _ 'N 2,3,7,8-TctrachIorodibenzo://dioxin (iC 'DD, Figure .1) i is the dioxin that may be formed when the reaction tempera i1 ture for making 2,4,5-frichlorophcnol from tctrachlorobcnzene exceeds 160'C (Schultz., 1968). Jn chlorinating pheaol ii to make tetra- or pentaclilurophcnoi, heat must be supplied to the reaction mixture in order 1o maintain the mix ns n ntrlt. If loo much heat is supplied, hcxii-, hepta-, and/or octa- chlorodibenzo-p-dioxins may be furnied. Since little or no heat is required to form di- and triehloropheuols by chlorina tion, there is little likelihood that di-, tri-, or telrachlorodi- Jjehzo-p-dioxms will be formed in this pt oicss. Interest in dioxins originated in 1957 from outbreaks of 4 "chick edema (CE) disease." The disease was characterized by hydroparicardium in chickens. In 1958 a toxic substance, isolated from an unsaponifiable fraction of feed fats which caused CE, was identified (Cantrell et id., 1969) by single crystal X-ray crystallography as 1,2,3,7,8,9 hexachlorodi- benzo-p-dioxin (HCDD). In 1970, 2,4,5 trichlorophenoxy- acctic acid (2,4,5-T) was implicated as a potential teratogen in pregnant rats (Courtney et id., 1970). Later tests indi cated that the teratogencsis may have beep caused by 27 8 ppm of TCDD present as contaminant in the 2,4,5-T. a In order to assess possible environmental contamination with TCDD or higher chlorinated dioxins through pcsticidal materials, samples of 17 pesticides based on use of chloio- phenols in their manufacturing process were collected from U.S. Department of Agriculture's foimer Pesticide Regula tion Division (PRD) laboratories**- Additionally, samples of 2,4,5-T from one manufacturer, covering a 3-year petiod, were collected. A method was developed for the analysis Plant Science Research Division, Agriculture Research Service, U.S. Department of Agrieultuie, Deltsville, Maryland 20705. 1Present uddiess:1^ Pesticide Regulation Divison, Environ mental Protection Agency, Ucltsvillc,Maryland 20705. of dioxins in the 17 different pesticides. The method dcvcL. oped and results of the survey arc reported, in (his paper.; PROCEDURE Materials. No nt tempt should be made to analyze for ; dioxins without proper safety procedures. The following. : solvents were distilled in glass or were of pesticide grade quality: hexane, methanol, xdroiemn ether, acetonitfd^. benzene, and diethyl ether. \ The following apparatuses were required: chroma'bg- raphy columns (45CNX 19 mm i.d.) with Teflon stc-.vrock. gas chromatogrr.pl; (gs), preferably equipped wit;: a NiS! .. detector (flame ionization or microcouloinotric d-.-liTfors, also desirable for confirmali*':i steps), glass ge colum ns/!.S3- y m X 4-nim), a sun lamp with maximum output at 310 nnv. and thin-!:iycrchrcmsiography(<'c)appai;:lus. The following compounds were examined for polvchlqro- ; dibenz.o-/vdioxi:is: (2,4-d:iti]<;rophciisykicc(ic acid, 2,4-T>; 4-(2,4-dichlorophcnoxy)bu;yris ' add, 2,4-DR: 2-(2,4-di- ; chlorophenoxy)propionic acid. 2,4-DP; "phenoxy)acctic, 2,4,5-T; 2-(2,4.5-trieh!o: ophenoxy)nrr- pionic acid, silver:; 2-(2,4 d;ch!cropheroxy)e*.h>d "sodium sulfate, sesone; 3,6-dichloio-o anisic acid, dicamba: pen-.',, tachlorophcnol, PCP; telracblorophcxol; triclitorrphcnoi; ' 2,4-dichlorophcnyl p-nitropheny! ether, nilrofen; 0 (2,4- dichlorophcnyl) O-methyl isopiopylphosphoramidpthioatc,:. DMPA; 2-(2,4,5-trich!orcphcr.oxy)etliyl 2,2-dichloroprop>on-,y * ate, erbon; tris[2-(2,4-dieh.lorophenoxy)cthyIlphospluVc, 2,4-/ ;; DEP; O.O-dimctb.yl 0-2,4,5-lrichlorophenyl phosphorothion- _y ate, ronncl; 2,4,5,4'-tetrach!orodiphcny! sulfone, tetradifon; and O-2,4-dich!orophcny! 0,0-diethy! pnosphorolhioaic. VC- 13, Nentacide. The cleanup procedure consisted of three steps which were dependent on the nature cf impurities found in and the com plexity of the sample. Step A. T echnical Salts and A cids of Piienony Arms. One-hundred milliliters cf McOIl was ndded to 3.00 g of herbicide and 10 ml of 5,Ar KOH contained in a tPOO-mt sepdratery funnel. Two-hundred milliliters of H:0 and 100 ml of hcxnnc were added after 20 min and shaken. The aqueous phase was rccxtractc.d with 100 mi of hexane and the ' extracts were combined. The hexane extracts weir washed twice with 100 ml -of 1 fi NaOH, twice with 1 V HCi, and twice with 100 ml of 1l.O. The extracts were dried over anhydrous Nads9<, transferred to a 250-ml beaker. m d cr ap- orated to ca. 10 ml. Tire sample was transferred to a pre- c\? cc J. AGR. FOOD CHEM., VOL. 20. NO. 2, !977 3 3 t -SON, THOMAS, ENSOR f ' Table I. Relative Retention Tiiaes of Several Chlorinated Hydrocarbon Insecticides and Polyehlorodibcn/o-p-dioxiiis on Five Gas Chromatography Columns" I ) -- Aldrin p,p'-DDE p,p'-TDE p ,p '-d d t Endrin Endrin, A keto 2,7-CDD* 2,3,7-CDD tri-CDD tctra-CDDr tctra-CDD( 2,3,7,8-CDD penta-CDD hexa-CDD () fcexa-CDD (2) hcxa-CDD (3) hcpta-CDD (1) .hcpta-CDD (1) octa-CDD 5% OV-225 1.00 (2.17)* 2.63 . \ -5-84 : \ 5.62 3.69 15.76 1.29 1.94 2.30 2.86 3.27 4.?3 8.29 11.61 13.13 16.45 23.32 26.96 " j 46.31 ( lUlauvc rcK-udon thw.-A on columns 1.5%OV-l7 + " " 2 0% QF-1 (HI) 5% OV-17 5% UCW-OS 1.00 (1.80) 2.50 - 3.62 . 4.17 2.78 6.89 1.00 1.67 1.83 2 50 2.52 3.44 6.56 9 28 10.56 12.44 18.39 21.17 36.28 1.00 (0.91) 1.98 3.19 d 3.08 8.57 - 1.21 1 2.09 7.10 2.31 2.33 3.41 7.18 8.24 11.10 13.19 15.82 23.41 1.00 (1.26) t .67 2.14 2.70 1.90 3.25 0.83 1.51 1.57 2.22 2.24 2.85 5.08 7 . Co 7.94 9.97 13.09 14. C3 24.52 " is% ot-'-i jr ' 10% UC-HK (1; 1) 1.00 (4.2) 1.90 2.64 3.14 2.64 5.48 V 1.02 1.64 1.83 2.38 2.52 3.19 5.48 7.26 8.09 9.45 13.26 14. S3 24.05 Column conditions: length, 1.8-m X 4-inm glass; solid support, Chromosutb W, 80-100 mesh: injector, NOV:; crlttmtt. - 2QC; detector, Nt'*, 310'C; (low rate, 80-100 ml/min. k l % . eTime in minutes in parentheses. * Not resolved from TDE. Chlorodihc-.tio-p.-dioxtn CDD. t More than one isomer was present in the tri-, tetru-, hexa-, and heptachlorodibeuxo-p-dioxins. Known isomers have the positions nuav bered. -*J' . 22?<?.. V COD-, i\: pernii"-; f min : vS; anal) :i ; Ihren rev 2% Q. -i chlorirv"- pics wit.k cicnlhi ?'s1 P V.!'.! four spi.-v chtorod;' mixtures area or ( in aceto.; 0.02. r from front m be tarier stay on tow sos-j tri a ! V light stroyed iratijtii Suspici o n i Uv shaken for 1 min, washed with IJ.O, and the hexane was of cbto 2 drained through a NallCOj-Na.-SO column. The volume -.iiii'.n, was adjusted for analysis, f at etvv Quantitation was made or. a 5% OV-225 column usinj *A io 3 electron-capture gas chromatography tec -gc). Analysis war | |-.(po made with temperature programming from 2'0 to 260T t Figure 1. Structure of dibemo-p-dioxin. Chlorines may be at tached at the 1,2,3,4,6,7,8, and/or 9 positions to yield clilorudibeu/.o- p-djoxir.s ._ 4C/m in and a 16-min hold at the l;r.a; temperature. | ' .osng'.i Confirmation Techniques for Dioxins. If a positive f u j sponsc was found by cc-gc, the p value was determined for J ' foAn-.l. the dioxin between hexane and acetonitrile on a Dortion of | _ . ^ . Tt c <* the extract. The p value equals fir.r.i concent; ation in hex.-.n: j -4so-o initial concentration in hc.xane (Dcroza and Bowman, 1965). \ prCv.i Another portion of the extract was irradiated for 16 hr nadir } . (970 washed (petroleum etiier) 15-g AhO t column (450 X 19 mm i.d.) and eluted with 100 ml of petroleum ether followed by 50 ml of 5% (v/v) diethyl ether in petroleum ether, which were discarded. One-hundred milliliters of 50% (v/v) di ethyl ether in petroleum ether was collected, evaporated just to dryness, and adjusted to volume with hexane. The amount of each dioxin present was determined. Step B. Low O rganic M a fil r Soils, I'hlnol-Basi.u I nsecticides, O il, and Osier F okmulajrofls of P hlnoxy H erbicides. The following steps were jjerfonned prior to me AUGj column in Slep A. The extract Xvas shaken with concentrated H3SO< until the acid was clear (not yellow or cloudy after standing ca. 10 min), washed with ILO, and passed through a NaHCOj-NniSO, column (I cm of each layered in a 19 mm i.d. column). The <4uant was evaporated to ca. 10 ml and conlinued with the ALO) column in Slep A. S te p C. C hlorglhenols, H igh O rganic M ai ilk Soils, and O ther Samples D ifficult to C lfan U i\ After com pleting parts A and B of the cleanup procedure, the eluant from the AI:Oj column was evaporated just to dryness, cooled to ca. 0C on an ice Lath, and 10 ml of 1:1 (v/v) HNOjiHj50 mixture was added. Them ix Was giadually warmed to a sun lamp (maximum output, 310 nm) at a distance *>f IB f. " Th em since TCDD and the lower dioxins arc destroyed under sent.- these conditions. | reetn The remainder of the extract was condensed for confirms- ] ' sm-p tion on different gc columns using different detectors. Tht ! .ySs.^ 1columns preferred were 1:1 (w/w) mix of 1.5% OV-I7 plus \ 2.0% QF-1 and 5% UCW-93, both, on Chromosorb W, 30- I V^cUU 100 mesh. Flame ionization and microcoulomctric detec tion were with these detectors. The ultimate confirina(ic!> i was provided by a Perkin-Outer Model 270 gc-mnss . spectrometer (gc-ms). There was very little fragmcnt.tiwn since the parent peak (mjc 322) was the parent ion and ni i 257 and 194 were the only fragments over 20% in relative h abundance for the tetradioxin. ; Two-dimensional tic was use;! for cleanup and partial fkniuiion occasionally. The plate was developed fust n acetonitrile followed by bcnr.enc. The spots were visv. !l;s-d under a uv lamp and were scraped off, cxtraetc 'nd assayed by gc if desired. Infrared spectrometry was also used confirm the identity of various chlorodioxins. 6013 RESULTS AND DISCUSSION* room temperature and added to 50 ml of ice water in a sep Relative retention times of 13 dioxin isonur: and a k'r aratory funnel after 15 inin. The beaker was rinsed with selected chlorinated hydrocarbon insecticides are preser.:.'- 5 X 10 ml of hexane. The combined hexane rinses were in Table I. The values were determined isothermal:)' j: 220CC. Because of the large value (rt. = 46.31) for the octa- CDD, the 5% OV-225 column was normally used with tem perature programming from 230 to 26(JC at a rate of 4C/ min and a final temperature hold. Under these conditions, analysis was completed in about 40 min. The use of the three recommended columns (5% OV-225, 1.5% OV-17 plus 2% QF-1, and 5% UCW-98) prevented confusion of some chlorinated hydrocarbon insecticides in environmental sam ples with dioxins because relative retention times were sulli- ciently different. * ^ \- c p Values for dioxins are presented in Table II. Values for four specific isomers (2,7-, 3,3,7-, 2,3,7,8-, and l,j>,3,4.6.7.8.9- chlorodibcnzo-p-dioxiris) ar eiven. ^Olhcr valued are'for mixtures of isomers and wete determined using total peak area or peak height. Jit values for all dioxin isomers by tic in acetonitrile were 0.82 0.08 and in benzene were 0.80 0.02. The di-, tri-, tetra-, and hexadioxin wete not separated from each other under our test conditions, but were separated from most interfering impurities in formulations. Care must be taken not to overload the spots or the material appears to stay on the origin. This behavior is presumably due to the low solubility of dioxins in most solvents. In a further confirmatory step, dioxins were destroyed by uv light. The lower isomers (<4 Cl) were completely de stroyed in 16 hr by irradiation (Crosby etui., 1971) at concen trations less than 0.2 ppm in hexane. Nondcsti uetion of the suspected di-, tri-, or tetrachlorodioxin is sullieient evidence that the peak is not a chloroilioxin. The higher the degree of chlorination, the more resistant the dioxins were to irradi ation. Only 20% of the octa-CDD was destroyed in 16 hr at concentrado ns ofabout 0.3 ppm. A total o f 129 pesticide samples were analysed for dioxins. Table III presents the occurrence and content of the dioxins in all samples. TCDD (tetra-) was found primarily in 2,4,5-T samples. Only one sample of silvex contained moie-vthan 0.5 ppm o f TCDD. Detectable amounts of Rexa-CDD were found in four 2,4,5-T samples, one 2,4-D, and two other sam ples other than the chlorophenols. Heuta- and octa-CDD also occurred in four other samples apiece in addition to their presence in chlorophenols. Most samples were made before 1970 and may not represent current production materials. The TCDD concentration in selected pesticides is also pre sented in Table III. Twenty-two of 42 2,4,5-T samples col lected contained less than 0.5 ppm Of TCD1). O f the 20 samples containing more than 0.5 ppm of TCDD, 15 were obtained for the yearly survey of one manufacturer. The jamplcs were from 1966-1970, with four samples usually collected each year. There was a tenfold drop in TCDD FOLVC;;LOV-Opr''!N'70 P-rs\:N Table II. (v/vj A cetonitrile:tH cxar.c Solvent System " Isom er p Value std dev 2,7-C D D 2,3,7-C D D 2,3,7,8-C D D hcxa-CD D hcpta-C D D octa-C D D 0.76 0 .8 6 0.51 0 .9 4 0 .9 0 0 .9 0 : .-til.03 0 .0 3 0 .0 6 0 .0 3 0 .0 5 0 .0 5 ...,: hexane-saturated acetonitrile to peak height in hexane after equilibra tion. ' ''x ---1___ s,, i ,; ....:..__i .KTACLCRCCE T fXIn 4 . ^ .1 1i ___ _i _ i zzl; 1 , . ii `I . ..i -------,,--ra\ --: i - v i -ftKIACll KPH8 ;i kt?j . _.JL_d!_..__._ ------\t j. -- - 4 20CO 1800 rwav0Eu:? i\o*O.oj JXX> VX0 80S *C0 - Figure 2. Infrared^ spectra cf authentic oetnehiornditea/o-p- -dioxin and a cleancd-itp pcataeldci/oplict:-;! c.:tract. The.material, was incorporated in KUr and the spectra made on a IVrVii-l'.trrer 625 infrared spectrometer L: content by this manfnclurer between 1968 and 19!. How ever, their technical 2,4,5-T sliil contained 2-3 ppm of TCDD, in 1970. Four of the five remaining samples containing over 0.5 ppm of TCDD also came from this same. nmmUacituer and were received from the PRD laboratories. Reams (t9?il) samples from anotltcr manufacturer contained <0.5 ppm ot TCDD. No other samples tested had over O j ppm of TCDD. Any sample could contain one or more difTircn' chlorodioxins. N . ` :i- The higher polychlorodibenzo-p-dtoxin content of the -same selected pesticides is also presented in Table 111. Four sam ples of 2,4,5-T contained greater than 0.5 ppm of the hexp isomers. No higher dioxins were found in silvex or riicamoa - Pesticide > - Table 111. Number and Content of I*olyeiiloro(lil>cnzo-/>-dioxi Eclcctc Pesticides * tetra - <10 <100 <10 ppm "f chlurodibczo-/>dioxir! hexa hepta <100 <1000 <10 <100 <1900 <10 octa <too <1000 No. of ToMt ' samples no. of contam- samples ; anted tested 2,4,5-T Silvex --2,4-D (-DB.-DP) Dicamba 7* 1 ND ND 13^ 3 0 ND ... 1 , ND 1 0 ND* ND ND ___ Nl5 0 0 ND ND ND ... ND Chlorophenol trj- tetrapentaOthers ND / ND ND ND ... 4 1 0 1 0 0 -1 0 02 1 01 2 0 1' 7 0 0 *4 6 0 0 1 3 -.0 1 3 *Any sample may outain one or mor 1diiicicnt dioxins. ` ND = <0.5 ppin of any one chlorodioxin. ... ' ... . . 00 20 46 10 23 42 t 71 2S 0 8 46 33 10 1 7 24 6014 J. AGIt. FOOD CHHM.. VOL. 20, NO. 2. !9?2 353 v4 uchI r , o l in and only one sample of 2,4-D contained measurable amounts the hexa isomers. The hexa isomers present presumably C ..ere';there because of tetrachlorophenol impurities which condensed with each others Higher dioxins were found in some samples of several other pesticides, including erbon, tetradifon, ronnel, sesone, and DM BA. The dioxin content of the 20 chlorophenol samples is also presented in Table III. No TCDD was detected in any sam ple at levels above 0.5 ppm. -However, the higher dioxins were plentiful. Trichlorophchol contained only small amounts of hexachlorodibenzo-p-dioxin and no sample con tained over 10 ppm. Tetrachlorophenol contained less than 100 ppm of hexa-, hcpla-, and octachlorudibcnzo-yz-dioxins, while six of 20 pentachlorophenol samples contained over 100 ppm of the hepta- and octachlorodiben/u-/;-dio.\iii iso mers. An infrared spectrum of a pentachlorophenol ex tract is presented in Figure 2. It is quite obvious that the extract contains octachlorudiben/o-p-dioxin when the spec trum is compared to the standard oetachlorodibeiizo-p-dioxin spectrum. Analysis by cc-gc indicated both hepta- and octachlorodioxins were present in the sample, 'lhis may account for the peak broadening. The reason for the high amounts of dioxin in chlorophenol is probably due to heat treatment during synthesis. As chloiinaiion of phenol pro ceeds past the dichloropl.enol stage, heat must be supplied in order to keep the reaction inixtuie in a melt condition. Since heat is being supplied in the presence of chlorophcnols, the formation of higher chlorinated dibenzo-p-dioxins might be expected. The rate and time of melt heating probably governs the formation ar.d amounts of the various dioxin isomers. If the chlorination tempera lure is raised too hijh, too quickly, the lower chlorinated dioxins may be formed since the lower chlorophcnols would be present and available for reaction with each ether. If the temperature is raised too high after nearly all chlorophenol is in the penta form, oc(a- : chlorodibcnzo-p-dioxin would be the prodominant impurity formed. - - In conclusion, TCDD has been present at levels above fl.5 ppm in the past, but was less that: 0.5 pprn in the current pro duction samples examined. Higher chloroclioxins are pres ent predominantly in chlorophcnols with, the highest amounts present in pentachlorophenol. Thirty-eight percent of all samples examined contained at least one chlorodioxin. with many containing more than one. LITERATURE CITED Bcroza, M., Bowman, M. C., /. Ass. Oijlc. Att-.d. Chan. is. 35$ (1965). Cantrell, J. S., Webb, N. C., Mabis, A. J., Acta Crystallogr. U33, 150(1969). Courtney, K. D ,, G aylor, D. W .. H orcr.. Vi. D., Falk, H. L.. Bates, R. R., Mitchell, I.. Science IOC, o54 (1970). Crosby, D. G ., Worn, A. 3., Bummer, J. R., V/oolson. E. A.. Science 173, 743 (.1971). Sehultz, K. H., Arbaismcdizin-SociuUnediz'n-ArbcHshvgia:? 3. 25(196$). Receivedfo r review August 9 ^ 9 7 1 . Accepted November 15, 1971. c The Insecticidal and the Anticholinesterase Activity of /ta-Acylnmidophcnyl and/nefa-Thioureidophenyl/V-Methylcarbamates R. M. Sacher* and J. F. Olin Fifty-nine new AAmethyl and A./VdimclhyTcarba- mates were synthesized and tested as insecticides and as inhibitors of ily and bovine cholinesterases. In spite of the high anticholinesterase aetivily ex hibited by many of these compounds, only few chemicals have shown insecticidal activity. Fur thermore, these compounds could mol be syner- gized effectively by 2,3-tncthyle*re;'ioxynaphthalene. Structure-activity correlation revealed that maximal anticholinesterase activity is associated with a definite size of the alkyl substituent on the amid': or the thiourea grouping. In all series tested, alkyl substituent with, four to' six carbon atoms produced the most potent cholinesterase inhibiters. ST 09 T he insecticidal properties of A-methyl and N,Ndimethylearbainic esters of various alcohols and phenols have been demonstrated^by several investi gators (Gysin, 1954; Kolbezen et til., 1954). A systematic evaluation of the structure-activity correlation of various aromatic carbamates was published in a series of papers by Metcalf, Fukuto, and voworkers (e.g., Metcalf et al., 19o0, 1962; Metcalf and Fukuto, lvo!:). This paper presents a discussion of two new groups of iuseslicivt.il c.iihamaies, the /wfii-acylamidophcnyl a n d : the metu thiouicklophcuyl /V-mcthylcarbamates. ^ Agricultural Division, Monsanto Comp.my, St. l.ouis. MATERIALS AND METHODS Chemicals. The nirrc-acyLir.il!`phenyl iV-mcthylearhamates were prepared according to T..cuckart (l$93) by tv:3ting the corresponding mc.'c-liyxiroxyacylar.ilidc with mv...yl isocyanate. Anhydrous aicch.ol-frc: etl.-yl acetate wax stituted for toluene as solvent, and tricthylaniine was used as a catalyst. The mrta-thiourcidophcnyl Af-rr.clhylcarbamnter. were prc* paied ciu mem-hydroxypivenyl -oti.iocyniiuh:; ilie latte; '-v.m synthesized by the procedure r f Dyson and George i l l>- *' It is noteworthy that this hydroxyphenyl isothiocyarcwr reacts exothermically with, ir.elhj i isocyanate in the absence e-f a catalyst, a behavior which, had nut been previously <vob4 . ........ it ..i: .1 ., t * ; j; ; Vl .7: * VV( d_ 6016 r TRANSVAAL, INC. P. O. Box 69 / Marshall Road Jacksonville. Arkansas 72076 Phone 501-982-2132 TECHNICAL 2,4-D ACID EESCKEPTICN: Off-whita to white, coarse, crystalline solid. SOLUBILITY: Relatively insoluble in water; soluble in alcohol and aromatic solvents. BULK DENSITY: 52 lbs./cu. ft. packed LOSS CN DRYING: DICHLOFPHENGL: 0.4% (w/w), maximum 0.4% (w/V) tmaximum ' SODIUM OEIORIEE: 0.5% (w/V), maximum ACID EQUIPMENT:* 99% (w/w) - A.O.A.C., Tenth Edition PACKAGING: Bags; Fiber Drums (200 lbs. net.) If requested, certified analysis supplied cn materials shipped. Name: Chemical Formula: Formula Weight: Acid Equivalent: 2,4-Dichlorcphenoxyacetic CI2C5H3O OE 2COCH 221.04 100% (w/W) Acid(2,4-D) EPA Peg. No. 11687-29 Prod. Code No. AC Spec. Sheet 11/72 . 6017 TRANSVAAL, INC. P. O. Box 69 / Marshall Road Jacksonville, Arkansas 72076 Phone 501-982-2132 TECHNICAL 2,4,5-T ACID EESCRIPTICN: Off-white to tan, granular solid. SOLUBILITY: Insoluble in water; soluble in alcohol and aromatic solvents. BULK DENSITY: 48 lbs./cu. ft. packed LOSS CN DRYING: 0.4% (w/w), maximum , TRECHLORCPHENCL: 0.05% (w/V), maximum SODItM CHLORIDE:: 1.0% (w/Vr), maximum ACID EQUIVAUNT:* 98% (w/w) - A.O.A.C., Tenth Edition TCDD CONTENT: Less than 0.50 ppm. PACKAGING: Bags; Fiber Drums (200 lbs. net.) If requested, certified analysis supplied on materials shipped. *Name: 2,4,5-Trichlorophenoxyaoetic Acid (2,4,5-T) Chemical Formula: CI3CH2OCH2OOCH Formula Weight: 255.49 Acid Equivalent: 100% (w/W) EPA Rag. No. U687-30 Prod. OrJe No. AD , Spec. Sheet 11/72 6018 TRANSVAAL, INC. P. O. Box 69 / Marshall Road Jacksonville, Arkansas 72076 Phone 501-982-2132 TECHNICAL 2,4,5-TP ACID DESCRIPTION: Off-white to tan, granular solid. SCGUBILnY: insoluble in water; soluble in alcohol and arenatic solvents. BULK DENSITY: 48 lbs./cu. ft. packed LOSS CN DRYING: 0.4% (wA*), maximum , TRIOELORCPHENQL: 0.06% (w/w), maximum SODIUM CHLORIDE: 1.0% (wA*), maximum ACID EQUIVALENT:* 97% (wA*) - A.O.A.C., Tenth Edition PACKAGING: Bags; Fiber Drums (200 lbs. net.) If requested, certified analysis supplied cn materials shipped. *Name: Chemical Formila: Formula Weight: Acid Equivalent; 2-(2,4,5-Trichlorophenoxy) Propicnic Acid (2,4,5-TP) CI3C6H2OCH (Oi3)ODCH 269.52 100% (w/V;) EPA Reg. No. 11687-38 Prod. Code No. jAL Spec. Sheet 11/72 6019 r TRANSVAAL, INC. P. O. Box 69 / Marshall Road Jacksonville, Arkansas 72076 Phone 501-982-2132 TECHNICAL BUTYL ESTER OF 2,4-D EESCRIPnCN: Amber colored, oily liquid. SOLUBILITY: Insoluble in water; soluble in alcohol, aromatic and aliphatic solvents. SPECIFIC GRAVITY: 1.24 at 20C., Average WEIGHT PER GAIIN: 10.3 lbs. at 20*C., Average ACTIVE INGREDIENT * (INTENT: 98.0% (w/w), Minimum ACID EQUIVAIZNT: 78.2% (w/to), Minimum - A.O.A.C., Tenth Edition PASSAGING: 1, 5, 30, and 55 gal. containers If requested, certified analysis supplied on materials shipped. Name: Chemical Formula: Formula Weight: Acid Equivalent: Butyl 2,4-Dichlorophenaxyaoetate CI2C6H3O OE 2GOO (C4H9) 277.15 79.76% (w/w) as 2,4-D EPA Reg No. 11687-36 Prod. Code No. AJ t Spec. Sheet 11/72 6020 TRANSVAAL, INC. P. O. Box 69 / Marshall Road Jacksonville, Arkansas 72076 Phone 501-982-2132 TECHNICAL 2-E1HYIHEXYL ESTER OF 2,4-D DESCREPTICN: Straw to amber colored oily liquid. SOTJBTT.TTYt Insoluble in water; soluble in alcohol aromatic and aliphatic solvents. SPECIFIC GRAVITY 1.155 at 20C., Average WEIGHT PER GALLON: 9.62 lbs. at 20C. Average ACTIVE INGEEDIEWT * CENTEUT: 98.0% (wAO , Minimum ACID EQUIVALENT: 65.0% (w/to) Minimum - A.O.A.C. Tenth Edition PACKAGING: 1 5 30 and 55 gal. containers If requested certified analysis supplied on materials shipped. Name: Chemical Formula: Formula Weight: Acid Equivalent: 2-Ethylhexyl 2,4-Dichlorophenaxyaaetate a 2C6H3O OE 2COO (CH2CH (C2Hs )OE 2OE2CH2CH3) 333.27 66.32% (w/w) as 2,4-D EPA Reg. No. 11687-32 Prod. Code No. AF > Spec. Sheet 11/72 TRANSVAAL, INC. P. O. Box 69 / Marshall Road Jacksonville. Arkansas 72076 Phone 501-982-2132 TECHNICAL BUTYL ESTER OF 2,4,5-T EESCRIPTTCN: Amber colored oily liquid. SOLUBILITY: Insoluble in water; soluble in alcohol, aromatic and aliphatic solvents. SPECIFIC GRAVITY: 1.330 at 20#C., Average WEIOiT PER GALLCN: 11.08 lbs. at 20C., Average ACTIVE INGFEDIENT* CONTENT: ACID EQUIVAIZNT: 96.0% (w/w), Minimum 78.7% (w/w), Minimart - A.O.A.C,, Tenth Edition PACKAGING: 1, 5, 30, and 55 gal. containers If requested, certified analysis supplied on materials shipped. *Name: Chemical Formula: Formula Weight: Acid Equivalent: Butyl 2,4,5-TricilorcphencKyaoetate CI3C6H2 OCB2COO (C4H9) 311.6 82.0% (w/w) as 2,4,5-T EPA Reg. No. 11687-31 Prod. Code No. AE / > Spec. Sheet 11/72 6022 TRANSVAAL, INC. P. O. Box 69 / Marshall Road Jacksonville, Arkansas 72076 Phone 501-982-2132 TECHNICAL 2-ETHYLHEXYL ESTER OF 2,4,5-T EESCREPTICN: Amber color, light to dark, oily liquid. SOLUBILITY: Insoluble in water; soluble in alcohol, arcnatic and aliphatic solvents. SPECIFIC GRAVITY: 1.210 at 20C., Average WEK2T PER GALLCN: 10.08 lbs. at 20C., Average ACTIVE INGTODIENT * CCNTENT: ACID EQUIVALENT: 96.0% '(w/vr), Minijruin 66.7% (w/w), Minimum - A.O.A.C., Tenth Edition PACKAGING: 1, 5, 30, and 55 gal. containers If requested, certified analysis supplied cn materials shipped. *Name: Chemical Formula: Formula Weight: Acid Equivalent: 2-Ethylhexyl 2,4,5-Trichlorophenoocyacetate CI3C6H2O OE 2COO (CH2CH (C2H5)OE 2CH2OE 2CH3) 367.71 69.48% (w/W) as 2,4,5-T EPA Req. No. 11687-33 Prod. Code No. AG Spec. Sheet 11/72 TRANSVAAL, INC. P. O. Box 69 / Marshall Road Jacksonville. Arkansas 72076 Phone 501-982-2132 TECHNICAL 2-EIHYLHEXYL ESTER OF 2,4,5-TP EESCRIPTICN: Dark arrtier-oolored oily liquid. SOLUBILITY: Insoluble in water; soluble in alcohol, aromatic and aliphatic solvents. SPECIFIC GRAVITY: 1.196 at 20C., Average WEIGHT PER GALLCN: ACTIVE INGREDIENT* CGNTENT: 9.96 lbs. at 20C., Average t 95.0% (w/V) Minimum ACID EQUIVALENT: 67.1% (w/w) Minimum - A.O.A.C., Tenth Edition PACKAGING: 1, 5, 30, and 55 gal. ocntainers If requested, certified analysis supplied on materials shipped. Name: Chemical Formula: Formula Weight: Acid Equivalent: 2-Ethylhexyl 2(2,4,5-Trichlarophencocy)prcpicnate C ^ C ^ C X l ^ ( C H 3)OCX)ICH2CH(C2H5)CH2CH2CH2CH3] 381.74 70.6% (w/V) as 2,4,5-TP EPA Reg. No. 11687-34 Prod. Cede No. '`Spec. Sheet 11/72 Z 2~ cc < < A. C O N - O - G R A M K R f T E - D O HOT TYPE P(4Mw4 OAT G ?V i - T0: D . v A y<L K-.H'J "' 9 ! p / vr;- - -/? - - 7 7 yy~ i f f v i < if /L iA -J y ^ jc -J ix j / j i j tX/z, . " /.C J i. s T /, J2 sU i~ 4 A / JL-- ~ Z 2-JL V - y g ^ Z Z l -gag -.. 7 X /7/-<-V y/~ / /) y -r* 1 />L Cy<^/;s-ir,\ /?sv . A ~ A ^. tS tz y A i ~J. " 7 "~P ~ ; ^ \ i c /L'r-f'J _ * / jy is i________/ W r-, / ' / # 'iJ 'C .' ^ -d sL ^ '/s ir .. '; / < ? v T f y.'SL . S?~-Mr T 1^ - T-^T-~: a .> - r . Yy^U >.. /- 7 7 ? D /P - j. -><-<-?____ //;~ A' ~i^/-~ s - / * /V r / y f/fA A ^ t f / J y L s / / ' - / / i> //' --,- /* -V ~ / ? / * - / / : < y :-t\ > V- /.<'' i ^ y . -> . y L0* ^ 0 En v e l o p e PEOU(KED \ 'Of. o* V"r - * ^ -/ y.-y-rr ' ,/ / PLAINTIFF'S o o H o w o ^ i ! F1^ ,, , b IT 25--- O f i O P I n o c- **' t/j cvcRje j/oe fo* *f* ' 6026 6027  *1 TRAM -V/AAI,, INC. I V !< M.'i-ImI! i . k '"in ir!.. Aik.wivis rii..,,.' r>fi i I i TECHNICAL 2-ETHYLHEXYL ESTER OF 2,4,5-TP DESCRIPTION: Dark amber-colored oily liquid SOLUBILITY: Insoluble in water; soluble in alcohol, aromatic and aliphatic solvents. \ ! ! v ;: : ; skciFC GRAVITY: 7 . \ 1.190 at 20 C., Average * if WEIGHT PER GALLON: 9.91 lbs. at 20 C., Average ACTIVE INGREDIENT* CONTENT: 95.0% (w/w) Minimum ACID EQUIVALENT: 67.1% (w/w) Minimum - A.O.A.C., 12th Edition TRICHLOROPHENOL: 0.5%, Maximum WATER: 0.2%., Maximum FREE HERBICIDE ACID: 2.0%, Maximum TCDD CONTENT: (2,3,7,8-Tetrachloro- dibenzoparadioxin) < 0.1 ppm. PACKAGING: 1, 5, 30, and 55 gallon containers and bulk I * \ ' i'f requested, certified analysis supplied on materials shipped f ' l *Name: 2-Ethylhexyl 2(2,4,5-Trichlorophenoxy)propionate Chemical Formula: Cl3CcH20CH2(CH3)C00[CH2CH(C2H5)CH2CH2CH2CH3] Formula Weight: 381./4 Acid Equivalent: 70.6% (w/w) as 2,4,5-TP EPA.-R_eg.jHa. l.l/687-,34 iProd. .Coae:No. :AH * ,-n h : I 11/76 6028 TECHNICAL ISOOCTYL ESTER OF 2,4,5-T DESCRIPTION: Amber color, light to dark, oily liquid. SOLUBILITY: Insoluble in water; soluble in alcohol, aromatic and aliphatic solvents. SPECIFIC GRAVITY: 1.222 at 20 C., Average WEIGHT PER GALLON: ACTIVE INGREDIENT*' CONTENT: ' 10.18 lbs. at 20:C., Average .i . M / 96.0% (w/w), Minimum ACID EQUIVALENT: 66.7% (w/w), Minimum - A.O.A.C., 12th Edition, 1975 TRICHLOROPHENOL: 0.4% maximum WATER: '0.2% maximum FREE HERBICIDE ACID: 2.0% maximum TCDD CONTENT: Less than 0.1 ppm. PACKAGING: 1, 5, 30, and 55 gallon containers and bulk If requested, certified analysis supplied on materials shipped. *Name: ' Chemical Formula: Formula Weight: Acid Equivalent: Isooctyl 2,4,5-Trichlorophenoxyacetate a ^ H 20CH2C00(c8Hi7) 69.48?; (w/w) as 2,4,5-T EPA Regv No. 11687-33 Prod. Code No. AG t * * > Spec. Sheet 9/76 . . 3i 6029 :1 T U A 1! A A i. l!'. WEED-RHAP A-6-MCPA DESCRIPTION: Amber-colored liquid with slight ammoniacal odor. SOLUBILITY: Forms stable solutions, in 1710 ppm hard water. SPECIFIC GRAVITY: 1.172 at 20 C., Average WEIGHT PER GALLON: 9.76 pounds at 20 C., Average ACTIVE INGREDIENT* CONTENT: 75.0% (w/w) Dimethylamine Salt of 2-Methyl-4-Chlorophenoxyacetic Acid ACID EQUIVALENT: 61 v2% (w/w) or 6 pounds per gallon A.O.A.C., 11th Edition PACKAGING: 1, 5, 30, and 55 gallon containers and bulk If requested, certified analysis supplied on materials shipped. *Name: Chemical Formula: Formula Weight: Acid Equivalent: Dimethylamine Salt of 2-Methyl-4Chlorophenoxyacetic Acid CH3C1C6H30CH2C00H'HN c h 3^2 245.7 81.65% (w/w) as MCPA EPA Reg. No. 11687-52 Prod. Code No. AZ Spec. Sheet 6/76 6030 TRANSVAAL. JNC______________ P O. Box (>9 ' M .if'l' >li Ko.ul l.icksonvillc. Ark.mv.K Phone r) 0 l fij< : ; i \?. TECHNICAL 2,4,5-T ACID DESCRIPTION: ` 0ff-wh1te to tan, granular solid. SOLUBILITY: Insoluble 1n water; soluble in alcohol and aromatic solvents. BULK DENSITY: 48 Ibs./cu. ft. packed LOSS ON DRYING: TRICHL0R0PHEN0L: 0.4% (w/w), maximum 0.5% maximum SODIUM CHLORIDE: 0.5% (w/w), maximum ACID EQUIVALENT:* 98% (w/w), - A.O.A.C., 12th Edition, 1975 TCDD CONTENT: Less than 0.1 ppm. PACKAGING: Bags; Fiber Drums (200 lbs. net) If requested, certified analysis supplied on materials shipped. *Name: Chemical Formula: Formula Weight: Acid Equivalent: 2,4,5-TrichioropRenoxyacet1c Acid (2,4,5-T) CljjCjjH20CH2C00H 100% (w/w) EPA Reg: No. 11687-30 Prod. Code No. AD 5 Spec. Sheet 9/76 6031 sto :irarr fei-- p * * 1 T ] [A i-':'-V . T., r p . - TECHNICAL BUTYL ESTER OF 2,4,5-T DESCRIPTION: Amber colored oily liquid. SOLUBILITY: Insoluble in water; soluble in alcohol, aromatic and aliphatic solvents. SPECIFIC GRAVITY: 1.330 at 20 C., Average WEIGHT PER GALLON: 11.08 lbs. at 20 C., Average ACTIVE INGREDIENT* CONTENT: 96.0% (w/w), Minimum ACID EQUIVALENT: 78.7% (w/w), Minimum - A.O.A.C., ^ 12th Edition PHENOL: 0.5%, Maximum WATER: 0.2%, Maximum FREE ACID: 2.0%, Maximum PACKAGING: 1, 5, 30, and 55 gallon containers and bulk If requested, certified analysis supplied on materials shipped. *Name: Chemical Formula: Formula Weight: Acid Equivalent: Butyl 2,4,5-Trichlorophenoxyacetate C13C6H2 OCH2COO (C4H9) 311.6 82.0% (w/w) as 2,4,5-T EPA Reg. No. 11687-31 Product Code/ No. AE Spec. Sheet 10/76 f 6032 6033 2,4,5-T, Agent Oran' Tetrachlorodibenzo-p-cix-.. Evolution of the problem / "\ 7 / 0 Marion Moses, M.D. Presentation - Recent Advances in Occupational Medicine, Environmental Sciences Laboratory, Mount Sinai School of Medicine of The City University of Mew York October 15, 1979. ENV IRO NM ENTA L SCIENCES LABORATORY M O U N T SINAI S C H O O L OF M EDICINE OF THE CITY U NIV ERSITY OF NEW YORK ooe Tj 6034 ? Use of 2,4,5-T in the United States in 1974 Purpose Maintenance of right of way Rangeland Rice Forestry Other Pounds Used 3,960,000 1,980,000 220,000 48,400 990,000 if I 8035 2,4,5-T (2,4,5-trichlorophenoxy)acetic acid a SILVEX 2-(2,4,5-trichlorophenoxy)propionic acid 2,4-D (2,4-dichlorophenoxy)acetic acid \/ CHi--COOII a MCPA [(4-chloro-o-tolyl)oxy] aceric acid (2*methyl-4-chlorophenoxyacetic acid) l 6036 Possible Number.of Isomers - Polychlorinated Dibenzodioxins OOvlONl4MJtoH Chlorine Atoms Number of Isomers 2 10 14 22 14 10 2 1 < 6037 Cl OH sodium pentachlorophenate Heat Cl y Cl I 2 ,3 ,7 ,8-tetrachlorodibenzodioxin 6038 I 2,3,7,8-_tetrachlorodibenzod_ioxin (TCDD) Most toxic synthetic compound known Persistent in the environment Concentrates mainly in the liver and fat Lesser concentrations in thymus, spleen, liy^r Crosses the placenta (pregnant rat) Excreted unmetabolized in breast milk Metabolism in humans unknown I 6039 Comparative T o x ic ity o f Various Toxic Substances Substance Minimum Lethal Dose us/kt; Botulinus Toxin A Tetanus Toxin Diphtheria Toxin 2,3,7,8-Tetrachlorodibenzobioxin Saxitoxin Tetrodotoxin Bufotoxin Curare Strychnine Muscarin Diisopropylflurophosphate Sodium Cyanide 0.00003 0.0001 0.3 1.0 i* 9.0 8-20 390 500 500 1100 3100 10,000 ? LD^g of 2,3,7,8-TCDD in Laboratory Animals Guinea Pig 1 yg/kg Rat (male) 22 yg/kg Rat (female) 45 yg/kg Monkey >70 yg/kg Rabbit 115 yg/kg Mouse 100-250 yg/kg Dog >300 yg/kg it l Age Dependent Toxicity in Mice Fed 25pg/kg of TCDD Weekly For Four Doses Age 4 months 2 months 1 month Mortality (%) 0 17 44 Source: Vos Moore, Zinkl 1974 2 , 3 , 7 , 8 -_ tetra ch lo ro d ib en zo d io x in (TCDD) Most toxic synthetic compound known Persistent in the environment lipophilic Concentrates mainly in the liver and fat Lesser concentrations in thymus, spleen, liygr Crosses the placenta (pregnant rat) Excreted unmetabolized in breast milk Metabolism in humans unknown I Comparative T o x ic ity o f Various Toxic Substances Substance Minimum' Lethal Dose ue;/k? Botulinus Toxin A Tetanus Toxin Diphtheria Toxin 2,3,7,8-Tetrachlorodibenzobioxin . Saxitoxin Tetrodotoxin Bufotoxin Curare Strychnine Muscarin Diisopropylflurophosphate Sodium Cyanide 0.00003 0.0001 0.3 1.0 i> 9.0 8-20 390 500 500 1100 3100 10,000 I LD^q in Selected PCDD Isomers in ppb 2,3,7,8-tetra 1,2,3,7,8-penta 1,2,4,7,8-penta 1,2,3,4,7,8-hexa 1,2,3,6,7,8-hexa GP 2. 3.1 1125 72.5 70-100 Mouse 283.7 337.5 5000 825 1250 2,8-di 30,000 Source: McConnell et al (1978) i' 6045 2 , 3 , 7 , 8-_tetrach lorod ib en z o d io x in (TCDD) Most toxic synthetic compound known Persistent In the environment lipophilic Concentrates mainly in the liver and fat Lesser concentrations in thymus, spleen, liy^r Crosses the placenta (pregnant rat) Excreted unmetabolized in breast milk Metabolism in humans unknown f* 6046 H erbicides used in Vietnam Name Agent Purple Composition Pounds used (Active ingredient) n-butyl ester 2,4-D 50% n-butyl ester 2,4,5-T 30% isobutyl ester 2,4.,5-T 20% 1,180,300 Years used 1962-1964 Agent Pink ^sobutvDester 2,4,5-T 40% f^buty} ester 2,4,5-T 60% 1,001,980 1962-1964 Agent Green n-butyl ester 2,4,5-T 100% 66,980 1962-1964 Agent Orange Cn-butvOester 2,4-D 50% n-butyl ester 2,4,5-T 50% * Agent Blue Cacodylic acid 4.7% Sodium cacodylate 26.4% 99,172,750 3,548,710 1965-1971 1962-1971 Agent White . Picloram 10% 2,4-D 40% 22,531,616 1965-1971 Source: Young, Alvin L. et al. Tbe Toxicology, Environmental Fate, and Human Risk of Herbicide Orange and its Associated Dioxin. USAF, 1978. 2,3,7,8-TCDD Contamination o f H erb icid es Used in Vietnam Agent Purple Agent Pink Agent Green Agent Orange 17 to 47 ppm 65 ppm 1 to 50 ppm !> I 6048 Estimation, of the Amount of 2,3,7,8-TCDD Released into the Environment in Vietnam and in Seveso Vietnam Seveso 368 pounds 5 pounds % 604 Industrial Accidents or Overexposures to TCDD Resulting in Human Illness 1949 1952 1953 1960 1963 1964 1964 1968 1976 USA - Monsanto Germany - Boehringer '*-Germany - BASF USA - Diamond Sham-Rock Holland - Philips Duphar Czechoslovakia - Spolana USA - Dow England - Coalite Italy - Givaudan 6050 2,3,7,8-TCDD Contamination o f H erb icid es Used in Vietnam Agent Purple Agent Pink Agent Green Agent Orange 17 to 47 ppm 65 ppm 1 to 50 ppm > 6051 Sources of Human Environmental Exposure to Chlorinated . _ .. Dibenzodioxins Living in the household of an exposed worker Pyrolysis products in the air from municipal waste incineration, burning of contaminated wood, etc. Living in the vicinity of an industrial facility (e.g. Midland, Michigan ; Jacksonville, Arkansas) Drift from herbicide applications to forests, rights of way etc. Herbicide defoliant sppays used in Vietnam Living near a site where toxic wastes are^buried (e.g. Love Canal) Living in the vicinity where an industrial accident has occurred (e.g. Seveso, Italy) Etc. * I 6052 i E ffe c ts on th e Skin and Mucous Membranes . in Humans Exposed to TCDD Chloracne Hyperpigmentation Hypertrichosis Edema and erythema Blepharoconj unctivitis Conjunctival cysts Sties \ \\ Chloracne Chronology 1897 Von Bettman first described in workers manufacturing Hydrochloric acid 1901 Herxheimer describes in same workers - ascribes effects to chlorinated aromatic hydrocarbons WWI Chlorinated naphthalenes and chlorinated diphenyls used as halogenated waxes by Germans in manufacture of gas masks - chloracne seen in the workers 1912 First cases seen in US related to synthetic wax manufacture 1920's Many cases reported in workers in the electronics and 1930's radio industry using Halowax for electrical wiring 1936 Schwartz published the first case in the US WW II Post War Shipyard workers affected who were putting synthetic wax on ship to deter German magnetic mines t Most exposures have been related to the manufacture of the chlor-fnrifrd r^ri?fT^~i especially 2,4,5-T and Pentachlorophenol manufacture 1957 Kimming and Schulz indentified 2,3,7,8-tetrachlorodibenzodioxin as the acneigen in 2,4,5-trichlorophenol 1972 Cases still being reported in Us (New York State) in workers exposed to synthetic waxes I 6054 E f f e c t s on th e Nervous System in Humans Exposed to TCDD Headache Lower extremity weakness Difficulty in walking Ataxia Paresis Hearing loss Loss of sense of taste, odor Lack of vigor, drive Easy fatigability Insomnia Hyp ersomnolence Personality change Emotional instability Depression Diminished ability ^to learn Memory deficits Decreased libido Impotence Abnormalities in psychological tests 'Abnormalities in tests of motor and sensory peripheral nerve function Abnormalities in nerve biopsy E ffe c ts on the L iver in Humans Exposed to TCDD Clinical Findings Hepatomegaly Right upper quadrant tenderness, pain Hepatitis Hepatic porphyria Increased excretion uroprophyrins Porphyria Cutanea Tarda Liver function test abnormalities Alkaline phosphatase, SGOT,SGPT Bilirubin, BromosulfophthaJLein Liver Biopsy Findings Mild steatosis Periportal fibrosis Chronic venostatis with Kupffer cell activation Red fluoresence E f f e c t s on th e G a s t r o in t e s t in a l System in Humans Exposed to TCDD Weight loss Anorexia Abdominal pain Post Prandial) flatulence Nausea/vomiting Gastritis E ffe c ts on the C ardiovascular System in Humans Exposed to TCDD Excess cardiovascular death (myocardial infarction) in accident clean-up crew Case report of rapidly progressive athero sclerosis in 2,4,5- TCP worker Abnormalities in blood lipids (Increased cholesterol and/or triglycerides) with as yet unknown possible effects on heart and blood vessels O i E ffe c ts on the C ardiovascular System in Humans Exposed to TCDD Excess cardiovascular death (myocardial infarction) in accident clean-up crew Case report of rapidly progressive athero sclerosis in 2,4,5- TCP worker Abnormalities in blood lipids (increased cholesterol and/or triglycerides) with as yet unknown possible effects on heart and blood vessels 6059 Reported Effects on Reproduction in Vietmanese Veterans Increase in neural tube defects reported in offspring of soldiers from the north who had fought in the south as compared to soldiers who had remained in the north. > Chromosomal Changes in Human_PgripbaL Lymphocytes in P otential or Actual tn Dioxin { Herbicide workers increased aberrations reported Seveso populations no differences from controls reported 2,4,5-TCP workers with chloracne no differences from controls reported / y j Vietnamese populations insufficient data available to draw any conclusions I E f f e c t s o f TCDD on th e IIntteeggummeeint in Experimental An:idSIIs Rabbit Acneigen (ear) Rat, Mouse, Guinea Pig .No effect Monkey Periorbital and facial edema Alopecia"(including eyelashes) Dry, crusty skin BYTl*iVrVpgarO*;'t palms, soles Loss fingernails, toen--'''Squamous metaplasia se Palpebral and scleral with purulent exudare E f f e c t s o f TCDD on th e L iver in Experim ental Animals Rat Multiple foci hepatocellular degeneration, necrosis Fibrosis with periportal inflammation Cytomegaly Fatty metamorphosis Bile duct hyperplasia Cytoplasmic vacuolization Increased basophilia Multinucleated hepatocytes Increased RER with distortion and fragmentation Increased lysosomal activity Hyperplastic nodules (females) Hepatocellular carcinoma (females) Mouse Centrilobular degeneration and necrosis Cellular infiltration Extensive lipid accumulation Bile duct hyperplasia Guinea pig Minimal change Monkey Few scattered necrotic hepatocytes Distended, thickened bile ducts Im m unological E f f e c t s o f TCDD in E xperim ental Animals Reduction in Peripheral Lymphocytes Mouse, guinea pig, but not in rat Decreased Resistance to Salmonella berae infection Mouse Humoral Antibody Response No difference between treated and control in re sponse to BGG (T dependent antigen - helper cells) Mouse Delayed Type Hypersensitivity Response Decreased in guinea pig and rats exposed prenatally (still present 1 2 0 days post exposure with normal thymus size and histology) No change in.adult rats Lymphocyte Response to Mitogen Stimulation Decreased response spleen and thymus cells to PHA and Con A in rats exposed pre and post natally Thymus Atrophy Rat, mouse, guinea pig / I Hem atopoetic E f f e c t s o f TCDD in E xperim ental Animals Decreased hemoglobin, hematocrit Rat, monkey Decreased hemoglobin Mouse Lymphopenia, pancytopenia, hypocellular bone marrow Monkey 1 Gi E f f e c t s o f TCDD on th e G a s t r o in t e s t in a l System in Experimental Animals Monkey Microcystic dilitation crypts Loss of parietal cells with replacement by mucous secreting cells Gastric ulceration Degranulation of cells of exocrine pancreas Hemorrhage Edema Mouse Submucosal edema of stomach, intestine Increased cellularity lamina propria Rats Minimal change E f f e c t s o f TCDD on the Kidney and Urinary Tract in Experim ental Animals Hyperplasia renal pelvis (monkey, guinea pig, rat) Hyperplasia urinary tract (guinea pig) Dilatation convoluted tubules (mouse) Adenocarcinoma of kidney (rat) it * I Immunological E f f e c t s o f TCDD in Experim ental Animals Reduction in Peripheral Lymphocytes Mouse, guinea pig, but not in rat Decreased Resistance to Salmonella b e m e infection Mouse Humoral Antibody Response No difference between treated and control in re sponse to BGG (T dependent antigen - helper cells) Mouse Delayed Type Hypersensitivity Response Decreased in guinea pig and rats exposed prenatally (still present 1 2 0 days post exposure with normal thymus size and histology) h No change in.adult rats Lymphocyte Response to Mitogen Stimulation Decreased response spleen and thymus cells to PHA and Con A in rats exposed pre and post natally Thymus Atrophy Rat, mouse, guinea pig 6068 I Hematopoetic Effects of TCDD in Experimental Animals Decreased hemoglobin, hematocrit Rat, monkey Decreased hemoglobin Mouse Lymphopenia, pancytopenia, hypocellular bone marrow Monkey *i Effects of TCDD on the Cardiovascular System of Rats Fed 0.1 yg/kg [2200ppt] daily for 2 years Brain hemorrhage (female) Mesenteric/thoracic periarteritis with thrombosis and hematoma (male, female) Myocardial degenerative changes (female) Periarteritis with thrombosis of testicular and/or thoracic mediastinal vessels Source: Rociba et al., 1978 6070 Effects of TCDD on the Respiratory System in the Rat Increase in focal alveolar hyperplasia Accumulation of alveolar macrophages Focal interstitial inflammation and fibrosis Pulmonary edema Squamous metaplasia Squamous cell carcinoma of lung Effect of a Single Dose of 25 pg/kg TCDD on Thyroid Function in Rats_________ increased biliary excretion of Increased biliary clearance of T4 increased ^ l j uptake increased thyroid gland weight increased serum TSH increased serum T3 decreased serum T4 Source: Bastomsky 1977 > I Concentrations at Necropsy in Rats Fed TCDD for Two Years Tissue O.lug/kg ( 2 2 0 0 ppt) O.Olug/kg ( 2 2 0 ppt) O.OOlug/kg (22 ppt) f Liver 24,000ppt 5100ppt 540ppt Fat 8 ,1 0 0 ppt 1700ppt 5A0ppt Source: Kociba, 1978 1 r'A1*t-*^n vf; *?i R eproductive E f f e c t s o f TCDD in E xperim ental Animals Decreased size of testicles and degeneration of seminiferous components - guinea pig Decreased spermatogenesis - Sprague-Dawley rats Decrease in rate of synthesis of testicular DNA - mice Decreased progesterone and estradiol levels, inability to carry infant to term and changes in menstrual cycle with increased bleeding - monkey I 6074 I Embryotoxic Effects of TCDD in the Rat Effect Decreased fetal weight Subcutaneous edema Intestinal hemorrhage Fetal death *" Dose .125 ug/kg .125 ug/kg .1 2 5 -.5 ug/kg 2.0 ug/kg ./ > 6075 Species Teratogenic E ffect of 2,4,5-T and i t ' s A sso cia ted D ioxin Effect Compound and dose Mice Rat Cleft palate Cystic kidney Cystic kidney Skeletal abnormalities Hamster Absence of eyelid Delayed head ossifi cation Exencephaly 3 pg/kg TCDD 1 pg/kg TCDD 113 mg/kg 2,4,5-T with 30 ppm TCDD 100 mg/kg 2,4,5-T with < .5 ppm TCDD i* 100 mg/kg 2,4,5-T with < .5 ppm TCDD I 6076 Embryotoxic Effects of TCDD In the Rat Effect Decreased fetal weight Subcutaneous edema Intestinal hemorrhage Fetal death Dose .125 ug/kg .125 ug/kg .125-.5 ug/kg 2 . 0 ug/kg / 6077 Mutagenic E ffe c ts o f D ioxin Salmonella Typhimurium 2,3,7,8-TCDD OCDD Unsubstituted TA1530 TA1532 TA1531 TA1534 TA1535 TA1537 TA1538 .. ++ ++ - - ? - -- Dominant Lethal No effect demonstrated in 20 Wistar rats fed 4,8,12 yg/kg daily for 7 days. Chromosome Chanees in Rat Bone Marrow 2,7-DDD OCDD 2,3,7,8-TCDD negative negative positive (weak) I 6078 f Reproductive Effects of TCDD in Experimental Animals Decreased size of testicles and degeneration of seminiferous components - guinea pig Decreased spermatogenesis - Sprague-Dawley rats Decrease in rate of synthesis of testicular DSA - mice Decreased progesterone and estradiol levels, inability to carry infant to term and changes in menstrual cycle with increased bleeding - monkey it Neoplastic Changes in Rats Fed 2,3,7,8-TCDD for 78 Weeks Tumor Carcinoma of the ear duct Lymphocytic Leukemia Adenocarcinoma of Kidney Malignant Histiocytoma Angiosarcoma of Skin Leydig Cell Adenoma of Testes Sclerosing Seminoma of Testes Carcinoma of the Skin Cholangiosarcoma of the Liver Glioblastoma (brain) Squamous Cell Lung Tumors Neoplastic Liver Nodules Source: Van Miller et al. 1977 V / 5ppt 1 1 1 1 1 1 Dosage 500ppt lppb 5ppb 2 4_ 4 I 6080 f Carcinogenic Effect in Rats Fed 2,3,7,8-TCDD for 2 Years Squamous Cell Carcinoma Hard Palate Squamous Cell Carcinoma Tongue Hepatocellular Carcinoma Hyperplastic Liver Nodules Squamous Cell Carcinoma of Lung Source: Kociba et al. 1978 F, M M F F F O.lyg/kg (2200ppt) O.lyg/kg O.lug/kg O.Olyg/kg (220ppt) O.lug/kg > 6031 TCDD E f f e c t s on Enzyme In d u ctio n in Chick Embryo L iver 30,000 times more potent as inducer of Aryl hydrocarbon hydroxylase than methylcholanthrene 1 0 0 0 times more potent as Inducer of delta-aminolevulinic acid synthetase than any other chemical tested Effect of induction persists over a long period of time Potency as inducer correlates with toxicity 6082 TCDD E f f e c t s on Enzyme In d u ctio n in Mammalian L iv er Affects P448 mediated enzymes, e.g. Aryl hydrocarbon hydroxylase Biphenyl 2-and4-hydroxylase UDP-glucuronyltransferase No effect on ALA in rat, guinea pig, mouse Effect still present 2 to 3 months after dosing Potency as inducer correlates with toxicity Selected Bibliography on Dioxin. 1/4 Allen, J.R., D.A. Barsotti, J.P. Van Miller et al; Morphological Changes in Monkeys Consuming a Diet Containing Low Levels of 2,3,7,8-Tetrachlorodibenzo-p-dioxin, Fd Cos Tox 15:401-10, 1977 Allen, J.R., Van Miller, J.P., Norba<zk,D.H.; Tissue Distribution, Excretion, and Biological Effects of [l^C]Tetrachlorodibenzo-p-dioxin in Rats, Fd Cos Tox 13:501-5, 1975 Barsotti, D.A., Abrahamson, L.J., Allen, J.R.; Hormonal. Alterations in Female Monkeys Fed a Diet Containing 2,3,7,8-Tetrachlorodibenzo-p-dioxin, Bull Env Cont Tox 21:463-9, 1979 Bastomsky, C.H., Enhanced Thyroxine Metabolism and High Uptake Goiter in Rats after a Single Dose of 2,3,7,8-Tetrachlorodibenzo-p-dioxin, Endocrinology 101:292-6, 1977 Bleiberg, Jacob, Wallen, Marven, and Brodkin, Roger; Industrially Acquired Prop'nyria, Arch Derm 89:793-7, 1964 Boeri, R., Bordo, B., Crenna, P., et al; Preliminary Results of a Neurological Investigation of the Population Exposed to TCDD in the Seveso Region; Riv. Pat Nerv Ment 99:111-128, 1978 Collins, T.F. X. Williams, C.H.; Teratogenic Studies with 2,4,5-T and 2,4,-D in the Hamster, Bull Env Cont Tox 6:559-67, 1971 Crow, K.D.; Chloracne, Trans St. Johns Hosp Derm Assoc 56:79-99, 1970 Crow, K.D.; Chloracne- An Up to Date Assessment, Ann Occup Hyg 21:297-8,1978 Courtney, K.Diane, Gaylor, D. W . , Hogan, M.D. et al; Teratogenic Evaluation of 2,4,5-T, Science 168:864-6, 1970 Courtney, K.Diane, Moore, John A.; Teratology Studies with 2,4,5-Trichlorophenoxvacetic Acid and 2,3,7,8-Tetrachlorodibenzo-p-dioxin, Tox Appl Pharm 20:396-403, 1971 Dost, Frank N.; Toxicology of Phenoxy Herbicides and 2,3,7,8-Tetrachlorodibenzop-dioxin, Report of Task Force - Dept, of Agric Chem and Env Hlth Sci Center Oregon State Univ Feb 1978 EPA, Rebuttable Presumtion Against Registration and Continued Registration of Pesticide Products Containing 2,4,5-T, Federal Register 43(78)17116 - 17157 April 21, 1978 / Hay, Alastair W.M.; Tetrachlorodibenzo-p-dioxin Release at Seveso, Disasters 1:289-308, 1977 I 1 2/4 Homberger, E., Reggianl, G . , Sambeth, J. et al; The Seveso Accident: Its Nature, Extent and Consequences, Report by Givaudan Research Company, F. Hoffman-La Roche Company and ICMESA, Undated Draft IARC, Some Fumigants, the Herbicides 2,4,-D and 2,4,5-T, Chlorinated Dibenzodioxins and Dibenzofurans, Volume 15, pp 273-300 and 41-102 August, 1977 Jensen, N.E.; Chloracne: Three Cases, Proc Roy Soc Med 65:687-8, 1972 Jirasek, L., Klanesky, J., Kubec, K. et al; Acne Chlorina, Porphyria Cutanes and Other Manifestations of General Intoxication During Manufac turing of Herbicides, II, Ceskoslovenska Dermatologie 49:145-57, 1974 Jones, Glenys, Butler, W.H.; A Morphological Study of the Liver Lesion Induced by 2,3,7,8 -Tetrachlorodlbenzo-p-dioxin in Rats, J Path 112:93-7, 1974 Jones, Glenys; A Histochemical Study of the Liver Lesion Induced by 2,3,7,8-Tetrachlorodibenzo-p-dioxin (Dioxin) in Rats, J Path 116:101-5, 1975 Kitchin, KirkT., Woods, James S.; 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Effects on Hepatic Microsomal Cytoohrome P-448-Mediated Enzyme Activities, Tox Appl Pharm 47:537-46, 1979 Kimbrough, Renate; The Toxicology of Polychlorinated Polycyclic Compounds and Related Chemicals; CRC Crit Rev Tox 2:445-98, 1974 Kimbrough, Renate, Carter, Coleman, Liddle, John A. et al; Epidemiology and Pathology of a Tetrachlorodibenzodioxin Poisoning Episode, Arch Env Hlth, Mar/Apr: 77-86, 1977 Kociba, R.J., Keyes, D.G., Beyer, J.E. et al; Results of a Two-Year Chronic Toxicity and Oncogenicity Study of 2,3 ,7,8 -Tetrachlorodibenzo-p-dioxin in Rats, Tox Appl Pharm 46:229-303, 1978 McConnell, E.E., Moore, J.A. , Dalgard, D.W., Toxicity of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in Rhesus Monkeys (Macaca mulatta) Following a Single Oral Dose, Tox Appl Pharm 43:175-187, 1978 McConnell, E.E., Moore, J.A., Haseman, J.K., et al; The Comparative Toxicity of Chlorinated Dibenzo-p-dioxins in Mice and Guinea Pigs, Tox Appl Pharm 44:335-56, 1978 May, George; Chloracne From Accidental Production of Tetrachlorodibenzo-pdioxin, Brit J Ind Med 30:276-83, 1973 Moore, J.A., Gupta, B.N., Zinkl, J.G, et al: -Postnatal Effects of Maternal Exposure to 2,3,7,8 -Tetrachlorodibenzo-p-dioxin (TCDD), Env Hlth Persp 5:81-5, 1973 I 3/4 Neubert, D., A Survey of Embryotoxic Effects of Tetracnlorodibenzo-p-dioxin in Mammalian Species, Env Hlth Persp 5:67-79, 1973 NIEHS/IARC; Long-Term Hazards of Polychlorinated Dibenzodioxins and Poly chlorinated Dibenzofurans; A Working Group Report, IARC, Lyon, June, 1978 Oliver, R.M.; Toxic Effects of Tetrachlorodibenzo-p-dioxin in Laboratory Workers, Brit J Ind Med 32:49-53, 1975 Pazderova, J., Lukas, E., Nemcova, M. et al; Chronic Intoxication by Chlorinated Hydrocarbon Produced During the Manufacture of Sodium 2,4,5-Trichlorophenate, Prac Lek 26:332-9, 1974 Poland, Alan P., Smith, Donald, Metter, Gerald et al; A Health Survey of Workers in a 2,4-D and 2,4,5-T Plant, Arch Env Hlth 22:316-327, 1971 Poland, Alan, Glover, Edward; Chlorinated Dibenzo-p-dioxins: Potent Inducers of delta Aminolevulinic acid Synthetase and Aryl Hydrocarbon Hydroxylase, Mol Pharm 9:736-47, 1973 Poland, Alan, Glover, Edward; Comparison of 2,3,7,8-Tetrachlorodibenzo-pdioxin, a Potent Inducer of Aryl Hydrocarbon Hydroxylase, with 3-Methylcholanthrene, Mol Pharm 10:349-59 , 1974 Poland, Alan, Kende, Andrew; 2,3,7,8-Tetrachlorodibenzo-p-dioxin: Environ mental Contaminent and Molecular Probe', Fed Proced 35:2404-11, 1976 Rappe, Christoffer, Marklund, Stellan; Formation of Polychlorinated Dibenzo dioxins and Dibenzofurans by Burning or Heating Chlorophenates, Chemosphere 3:269-81, 1978 Rose, J.Q., Ramsey, J.C., Wentzler, T.H. et al; The Fate of 2,3,7,8-Tetrachlorodibenzo-p-dioxin Following Single and Repeated Oral Doses to the Rat, Tox Appl Pharm 36:209-226, 1976 Seiler, J.P., Phenoxyacids as Inhibitors of Testicular DNA Synthesis in Male Mice, Bull Env Cont Tox 21:89-92, .1979 Taylor, James S.; Chloracne-- A Continuing Problem, Cutis 13:585-91, 1974 Van Miller, J.P., Calich, J.J., Allen, J.R.; Increased Incidence of Neoplasms In Rats Exposed to Low Levels of 2,3,7,8-Tetrachlorodibenzo-p-dioxin, Chemosphere 9:537-44, 1977 Vos, J.G., Moore, J.A., Zinkl, J.G.; Effect of 2,3,7,8-Tetrachlorodibenzo-pdioxin on the Immune System of Laboratory Animals, Env Hlth Persp 5:148-62, 1973 Vos, J.G.; Immunosuppresion as Related to Toxicology, CRC Crit Rev Toxic May : 67-101^ 1977 4- Vos, J.G., Moore, J.A., Zinkl, J.G.; Toxicity of 2,3,7,8-Tetrachlorodibenzo-pdioxin (T C D D ) in C57B1/6 Mice, Tox Appl Pharm 29:229-41, 1974 4. f 6086 ? 4/4 Wassom, J.S., Huff, J.E., Loprieno, N.; A Review of the Genetic Toxicology of Chlorinated Dibenzo-p-dioxins, Mut Res 47:141-160, 1^77/1978 Young, Alvin L., Calcagni, John A., Thalken, Charles E. et al; The Toxicology, Environmental Fate, and Human Risk of Herbicide Orange and its Associated Dioxin, United States Air Force OEHL Technical Report Number TR-78-92, October 1978 I* * PROTOCOL: o?, V -T " T -------- *------------ 7------ P - oit' O X J O O t z a - v q ^ c^-n d tu r' d u n o o /S 1 / ^ a . c h l o t t e d ^ c- p ^ / a - U , K>^) # /"/ 0 - f - 1 C ;0 )L T / u t . 0 C 'H ' k i g. /H G C ; Y / HH ec tiAt .- )r>;4+-' 55>;' n Ct. -e C *. r L , UL C C e 0 fi P C K.g ' - 6 /^ ` 6 -<-P 1 1 o c | 5 | ^^ ^ ' (p> ,7JiU - t ^ {rTa D H ' ' X ^ ^ f g. c L / a< CONTACT PEOPLE: f'/Ci.ZiCf-j H oze H . T- ^ n / i c c - n H c U ^ > U T 'J l ' I Q ^ 3 i > l C G 0 t.7 p / - c ci(; L.G <. C / G t L f 1/Cl/LvL c. C g O /L* t - c c J3 (J. / d & - &>/ 7 y ;C G ^ JKDED ET: A ahzcak SCHOOLS INVOLVED: DATE OF STUDY: Co:'`-V'O L 0 'G 1 /e?' / ? 7 / ( 25 6089 Revised 12/15/79 Section 9, G Page 1 DETERMINATION OF TCDD RESIDUES IN HUMAN MILK, BEEF LIVER, FISH, WATER, AND SEDIMENT I. INTRODUCTION The highly toxic compound 2,3,7,8-tetrachlorodibenzo-j^-dioxin (TCDD) may be formed as a by-product in manufacturing processes utilizing tetrachlorobenzene to produce trichlorophenol. Under very basic, high temperature, high pressure conditions, 1 ,2,4,5-tetrachlorobenzene is hydrolyzed to the 2,4,5-trichlorophenate. Acidifi cation yields the phenol. Unfortunately, a condensation can take place in this reaction resulting in formation of TCDD. Herbicides containing esters of 2,4,5-trichlophenoxyacetic acid (2,4,5-T) manufactured from trichlorophenol have been found to contain trace amounts of TCDD. TCDD has been recognized as an extremely toxic (oral LD50 0.6 mg/kg, guinea pig), teratogenic compound that is stable in biological systems. The toxicological properties of TCDD have been well documented. Because of its toxicity and occurrence as a trace contaminate in chemical products, it is necessary to analyze for TCDD at pi cogram/ gram (low and sub-parts per trillion, ppt) levels, which are below the usual limits of detection for pesticide residue analysis. The analysis of human, biological, and environmental samples for possible TCDD contamination in the ppt concentration range is complicated by the presence of many interfering components ranging from naturally occurring compounds to industrial pollutants, such as PCBs, and the agricultural chemicals DDT, DDE, etc. An extremely efficient and specific analytical cleanup procedure is a prerequisite for ppt TCDD analysis specifying GLC MS detection techniques. The GLC MS detection technique must be ultra sensitive and also highly specific because of the required low ppt detection limits. High resolution glass capillary column GLC interfaced with high resolution MS multiple ion selection analysis provides the required GLC resolution, MS sensitivity, and specificity for TCDD analysis in the 0.02-100 ppt concentration range. Described below are the sample preparation procedures and capillary column GLC HRMS techniques developed and currently applied by EPA laboratories for isolation, detection, quantification, and confirmation of TCDD residues in human milk, beef liver, fish, water, and sediment extracts. The results of quality assurance samples and samples with unusual contamination are also discussed. Revised 12/15/79 REFERENCE: Section 9, G Page 2 Sample Preparation Procedures and Gas Chromatography/Mass Spectroscopic Methods of Analysis for TCDD, Harless, R. L., Oswald, E. 0., and Wilkinson, M. K., Analytical Chemistry Branch, U.S. EPA, HERL, ETD, Research Triangle Park, NC 27711. Submitted for publication to Anal. Chem. II. PRINCIPLE: Tissue, milk, water, soil, and sediment samples are subjected to an "acid-base" sample preparation procedure involving saponification with hot caustic followed by extraction with hexane, washing with concentrated sulfuric acid, cleanup by alumina column chromatography, and capillary column GLC/high resolution mass spectrometric multiple ion selection (GLC HRMS) analysis for TCDD residues. Fish tissue is subjected to a "neutral" cleanup procedure that is similar except that extraction is carried out with acetonitrile, and cleanup by solvent partitioning and Florisil column chromatography precedes the alumina column cleanup. 37C1-TCDD is added to all samples as an internal standard or marker to monitor and determine the analytical cleanup procedure efficiency. III. SAFETY PRECAUTIONS: TCDD is toxic and can pose grave health hazards if used improper ly. Techniques for handling radioactive and infectious materials are applicable to TCDD. Only qualified individuals who are trained in laboratory procedures and familiar with the dangers of TCDD should handle this substance. Females of childbearing age should not work with this material. A good laboratory practice involves routine physical examinations and blood checks of employees working with TCDD. Also, facial photographs using oblique photoflood lighting should be periodically taken to detect chloroacne, which is an early sign of overexposure. IV. EQUIPMENT: 1. Gas chromatograph, Varian Model 2700, equipped with an SE-30 WCOT glass capillary column, 30 m x 0.25 mm, i.d. The capillary column yielded an efficiency of 113,000 effective plates measured at the 35C1-TCDD peak. Splitless injection incorporating n-tetradecane was employed. 2. Mass spectrometer, Varian 311A, interfaced to the chromatograph so as to ensure maximum transfer efficiency. ^The spectrometer was equipped with a turbo-molecular vacuum pumping system, combination chemical ionization (Cl) and electron impact (EL) Revised 12/15/79 Section 9, G Page 3 ion source, and a Varian eight channel hardware (manual control) multiple ion selection (MIS) device. This vacuum system easily acconmodated the 5 ml/minute helium flow from the GLC MS inter face and did not contribute detectable background contamination. The MIS device was operated in the normal coupled electric mode (jumping the acceleration voltage). Each MIS channel was equipped with individual controls for selecting the acceleration voltage, measuring range, output signal bandwidth, compensation for background contamination, and integration rate. The intensities of the selected masses were monitored in a time division multiplex system, setting alternately to each of the selected masses and recording their intensities simultaneously on an eight channel Soltec recorder. The adjustable integration rate, 0.01 second to 1 second was sufficient to accurately reproduce capillary column peaks two seconds wide at half height. Alternative Instrumentation: Current MS instrumentation used by other laboratories (EPA contract laboratories) for TCDD analysis include (1) AEI MS-30, (2) AEI MS-50, and (3) Varian CH-5DF. These instruments are interfaced with a packed column gas chro matograph and use high resolution MS double ion monitoring techniques. The general requirements for the GLS MS instrumentation are: (1) Packed or preferably capillary column GLC introduction L of the sample. (2) High resolution (10,000 minimum) MS mass analysis. (3) Ultra high sensitivity (1 to 50 pg TCDD quantification standards). 3. Pasteur pipets, 5.75 inches (14.6 cm) x 0.5 cm i.d. 4. Glass column, 50 cm x 11 mm, equipped with a Teflon stopcock and removal glass tip. 5. Desiccator, equipped with Drierite, which can accommodate adsorbent-packed Pasteur pipets. I 6. Reflux condenser, water cooled, equipped with 100 ml boiling flasks. 7. Separatory funnels, 250 ml. 8. Evaporation apparatus including a 12 ml distillation receiver, micro-Sqyder column Kontes K-569251, and steam bath. y LI t 6092 M ,-i1; 0! I: ;|! i-l*i Revised 12/15/79 9. Filter funnel. Section 9, G Page 4 10. Filter tube, glass, 16 cm x 42 mm. 11. Glass column, 39 cm x 11 mm i.d., with a 125 ml reservoir and Teflon stopcock. 12. Kuderna-Danish (K-D) evaporative concentrator, 250 ml. 13. Chromaflex sample tube, 2 ml, graduated, Kontes K-422560. 14. Glass tubing, 7 cm x 3 mm i.d. 15. Blender, Waring, or equivalent. 16. Magnetic stirrer. 17. Hotplate, explosion proof. 18. Mills type concentrator tube, Kontes K-570050. V. REAGENTS: 1. 2,3,7,8-Tetrachlorodibenzo--dioxin (TCDD), 37C labeled, isotopic purity >98% 37C1, Eco-Control, Inc., 71 Rogers St., Cambridge, MA 02142. 2. TCDD analytical standard, Dow Chemical Co., Midland, MI; ITT Research Institute, Chicago, IL; and Eco-Control, Inc. 3. Hexane, acetone, benzene, methylene chloride, ethyl alcohol, acetonitrile, Mallinckrodt Nanograde. 4. Carbon tetrachloride, Fisher ACS grade, 0.01% water maximum; a greater water content can cause TCDD to elute in the incorrect fraction. 5. Alumina, neutral, activity grade 1, Woelm. 6. Florisil, 60-120 mesh, suitable for pesticide residue analysis by the criteria in Section 3,D, activated at 225C for 24 hours before use. 1 7. Sodium carbonate, sodium sulfate, and ammonium chloride, . Mallinckrodt AR grade, Soxhlet extracted overnight with methylene chloride and dried at 2000.: - 8. Potassium hydroxide and sulfuric acid, Mallinckrodt AR grade 6093 Revised 12/15/79 Section 9, G Page 5 C 9. Glass wool, pre-extracted with methylene chloride. 10. Water, passed through a column of activated carbon and distilled. 11. Nitrogen for solvent evaporation, Zero Grade, Liquid Air, Inc., NewJDrleans, rLA. ;;, _____ ..... 12. Dry ice. VI. PREPARATION OF CHROMATOGRAPHIC CLEANUP COLUMNS: 1. Alumina a. Prewash and dry a disposable Pasteur pipet and plug the tip with glass wool. b. Pack the pipet with 4.5 cm of neutral alumina and top the column with 0.5 cm of anhydrous, granular sodium sulfate. c. Wash the column with 4 ml of methylene chloride and force the residual solvent from the column with a stream of dry nitrogen. d. Store the prepared columns in an oven at 225C at least 24 hours. c e. Before use, equilibrate the oven-activated columns to room temperature in a desiccator over Drierite. 2. Florisil a. Pack a 500 x 11 mm glass column with 15 grams of activated Florisil. b. Pack a 2.5 cm layer of anhydrous sodium sulfate on top of the Florisil. c. Hold at 225C until ready for use (a minimum of 24 hours). d. Cool the column to near room temperature and prewash with 100 ml of hexane. VII. SAMPLE PREPARATION AND CLEANUP - ACID-BASE PROCEDURE: 1. Lean Tissue a. Grind tissue samples to obtain a homogeneous sample. - > CI 3 3f if it AI* Revised 12/15/79 Section 9, G Page 6 b. Weigh a 10-20 gram sample into a 100 ml boiling flask and add 20 ml of ethyl alcohol and 40 ml of 45% K0H solution. c. Add 5-10 ng of 37C1-TCDD standard solution. d. Attach the flask to a water cooled reflux condenser and heat under reflux with stirring for 2.5 hours. e. Cool and transfer the solution to a 250 ml separatory funnel. f. Rinse the boiling flask with 10 ml of ethyl alcohol followed by 20 ml of hexane, and add to the separatory funnel. g. Extract the solution with four 25 ml portions of hexane and combine the hexane extracts. 2. Adipose Tissue a. Grind or render adipose samples, if necessary, to obtain a representative sample free of connective or other tissue. b. Add 5-10 ng of 37C1-TCDD to 10 grams of sample. c. Add 15 ml of distilled,,water to the sample. Extract and continue as described in Subsection 1, b-g, for lean tissue. 3. Milk a. Add 2.5 ng of 37C1-TCDD standard solution to 10-20 grams of milk. b. Extract the sample as described in Subsection 1, b-g, for lean tissue. 4. Water a. Fortify one kilogram of a well mixed water sample (including particulate matter, if present) with 2.5 ng of 37C1-TCDD standard solution. b. Extract the sample with three 100 ml portions of methylene chloride. c. Evaporate the combined extracts to near dryness in a K-D concentrator with an attached Snyder column utilizing a steam bath. Complete the.evaporation to dryness by placing the tube in a warm water bath under a gentle stream of dry ~ nitrogen. .' f 6095 Revised 12/15/79 Section 9, G Page 7 d. Transfer the residue to a separatory funnel with several rinsings of hexane totaling 100 ml. e. Wash the hexane solution with 50 ml of 1 N KOH solution followed by concentrated H2S0i* as described in Subsection 6 _ on cleanup. 5. Soil and Sediment a. Fortify 10-20 grams of well mixed sample with 2.5 ng of 37C1-TCDD. b. Extract as described in Subsection 1, b-g, for lean tissue. c. After refluxing and cooling, decant the solution into a separatory funnel through a filter funnel packed with glass wool. d. Rinse the boiling flask and filter funnel with two 10 ml portions of ethyl alcohol followed by 20 ml of hexane. e. Extract the combined solution with four 25 ml portions of hexane that had previously been used to rinse the boiling flask and filter funnel. 6. Cleanup a. Wash the combined hexane extracts, obtained as describe above in Subsections 1-5, with 25 ml of 1 N KOH solution followed by four 50 ml portions of concentrated HzSOi*. b. Add 25 ml of water and shake. Neutralize the water and hexane layers by addition of powered Na2C03 in small portions with mixing until C02 evolution ceases. c. Discard the aqueous layer, and dry the hexane layer by passage through the 39 cm x 11 mm i.d. glass column contain ing 10 cm of anhydrous powered Na2C03. d. Transfer the hexane concentrate to an alumina column, prepared as described in Subsection VI, 1, that was prewetted with one ml of hexane. e. Wash the column with 6 ml of CCl^ and discard the wash. f. Elute the column with 4 ml of methylene chloride and collect in a 21 ml distillation receiver. I Revised 12/15/79 Section 9, G Page 8 g. Cap the distillation receiver with a micro-Snyder column and evaporate the methylene chloride just to dryness on a hot water or steam bath. h. Add two separate 2 ml portions of hexane to the distillation receiver and evaporate each just to dryness. i. Dissolve the residue in 3 ml of hexane and chromatograph on a second alumina column as just described. j. Evaporate the methylene chloride eluate from the second column just to dryness. k. Add 2 ml of benzene to the receiver and concentrate to ca 100 yl. l. Transfer the benzene solution quantitatively to a 2 ml graduated Chromaflex sample tube. m. Carefully concentrate the benzene ca 100 yl under a gentle stream of dry nitrogen. Quantitatively transfer with two 25 yl benzene rinses to a glass tube (7 cm x 3 mm i.d.) that is sealed at one end. 4 n . Carefully concentrate the extract to 60 yl and flame seal the tube. Store below 0C until analysis by GLC MS. VIII. SAMPLE PREPARATION AND CLEANUP - NEUTRAL PROCEDURE: 1. Extraction of Fish Tissue a. Grind fish tissue to obtain a homogeneous sample. b. Place a 15 gram sample and 150 grams of anhydrous granular sodium sulfate in a blender jar and blend for one minute. c. Blend next with 50 gram portions of dry ice until the sample is thoroughly powered. d. Transfer the powder to an Erlenmeyer flask and add 10 ng of 37C1-TCDD directly onto the powder. e. Rinse the blender jar with acetonitrile. f. Add the rinsings plus enough additional acetonitrile to the flask to make a total of exactly 150 ml. g. Mix vigorously on a magnetic stirrer for 2 hours. 6097 Revised 12/15/79 Section 9, G Page 9 h. Filter the mixture through a glass filter tube containing 30 grams of anhydrous granular sodium sulfate. 2. Cleanup a. Partition exactly a 100 ml aliquot of the acetonitrile extract, representing 10 grams of the original sample, with 50 ml hexane that is saturated with acetonitrile. Draw the acetonitrile (bottom) layer into a 500 ml separatory funnel. b. Partition the hexane layer with two 100 ml portions of acetonitrile saturated with hexane followed by one 50 ml portion of the same solvent and combine with the above acetonitrile (350 ml total volume). c. Partition the combined acetonitrile layers with 10 ml of hexane saturated with acetonitrile. d. Draw the acetonitrile layer into a 500 ml flat bottom 20/40 5 Florence flask and concentrate to ca 10 ml under a Snyder column on an explosion-proof hotplate. e. Transfer the concentrate by repeated rinsings with a total of 200 ml of hexane to a K-D apparatus with a 10 ml Mills tube attached. Concentrate each of 5-10 ml on a hot water or steam bath. f. Transfer the hexane concentrate to a Florisil column, prepared as described in Section VI,2, using three 5 ml portions of hexane. g. Elute the column with 100 ml of hexane-methylene chloride (90:10 v/v) and discard this eluate. h. Elute with 100 ml of hexane-methylene chloride (75:25 v/v) and collect in a Kuderna-Danish evaporator equipped with a 100 ml Mills tube. i. Concentrate to ca 3 ml on a hot water or steam bath. j. Dissolve the concentrate in 100 ml of hexane and again evaporate to ca 3 m l . k. Transfer the concentrate to an alumina column and proceed with chromatography as described in the acid/base procedure (Subsection VII,6), but use only one alumina column. I 8098 Revised 12/15/79 Section 9, G Page 10 IX. CAPILLARY COLUMN GC/HRMS MULTIPLE ION SELECTION ANALYSIS: 1. Tune the magnet current to perfluorokerosene (PFK) m/e 318.9793 and adjust the spectrometer from 5000 to 9000 mass resolution. 2. Monitor the ESA voltage and use in calculating the exact acceleration voltage required for the masses m/e 327.8847 Ci2Hit0237Cl4 , m/e 321.8936 C12Hit0235Cl 337C1, and m/e 319.8965 Ci2H*0235C V 3. Introduce the calculated values of MIS channels 2, 3, and 4. 4. Inject 2 ul of TCDD quantification standard, 500 pg/yl 37C1-TCDD (labeled 2,3,7,8-tetrachlorodibenzo--dioxin, 37C1, isotopic purity greater than 98%) and one pg/yl TDCC, and 0.5 yl of iv-tetradecane (keeper) into the capillary column (on-column splitless injection) maintained at 80C. 5. Rapidly turn the GLC oven manual temperature control to 265C exactly 6 minutes after injection of the sample; the manual control provides an accurate and rapid heating rate of 34C/ minute. 6. Close the solvent vent valv exactly 14 minutes after injection of the sample. 7. Optimize the MS sensitivity for the source operating pressure, 6 x 10-6 Toor, using PFK m/e 318.9793. 8. Initiate the MIS analysis 16 minutes after injection of the sample. 9. Adhering to a strict (stopwatch) time schedule of events, the GLC HRMS experimental retention time for TCDD was 23 minutes + 15 seconds with the following GLC and MS parameters: 30 m SE-30 WC0T glass capillary column injection port temperature, 260C GLC transfer line into the MS ion source, 255C ion source temperature, 240C variable acceleration voltage 3 kV maximum electron energy, 70 eV filament emission, 1 mA mass resolution 5,000-10,000 multiplier gain, greater than 106' I 6099 Revised 12/15/79 X. C0C1 LOSS ANALYSIS: Section 9, G Page 11 1. Tune the magnet current to PFK m/e 254.9856. 2. Introduce the exact acceleration voltages required for TCDD masses m/e 256.9327, m/e 258.9298, m/e 319.8965, m/e 321.8936, : and m/e327.8847 into respective MIS channels (M+-- C0C1 peak, : -m/e .258.9298,- is. used to confirm TCDD structure). 3. Perform the analysis, adhering to the previously described time schedule of events. 4. Observe the GLC HRMS five channel simultaneous response for 37C1-TCDD and TCDD and record at the correct GLC retention time for TCDD. XI. ELEMENTAL COMPOSITION ANALYSIS: 1. Adjust the mass spectrometer for 10,000 mass resolution using PFK m/e 318.9793 as reference. 2. Initiate the peak matching analysis, adhering to the exact time schedule of events utilized in the GLC HRMS MIS analyses. 3. Display alternately the reference mass and the exact mass range of interest and view simultaneously on the MS oscilloscope. XII. DETECTION AND RECOVERY RESULTS AND DISCUSSION OF METHODS: 1. Glass capillary columns enhanced the GLC HRMS method of analysis because (a) they provided the required resolution of complex mixtures into individual components before they entered the mass spectrometer; (b) the narrow band width of the TCDD component enhanced MS sensitivity; (c) direct coupling of the capillary column to the mass spectrometer ensured maximum transfer effi ciency; (d) capillary column bleed rate was low, therefore background contamination was minimized and MS sensitivity was enhanced. 2. The requirements imposed on the mass spectrometer used as a GLC detector in these analyses were (a) extremely stable electronic, circuits; (b) ultra high sensitivity; (c) specific mass detection. The requirements were satisfied by optimizing all components that influenced sensitivity, noise, and mass resolution. The MIS response for a quantification standard, 37C1-TCDD and TCDD, is shown in Figure 1. / 6100 } Revised 12/15/79 Section 9, G Page 12 3. Precision and Accuracy of GLC HRMS Technique When adjusted for 7500 mass resolution and used as a GLC detec tor in MIS analyses, the mass spectrometer will give positive responses for those components eluting from the gas chromato graph that yield a molecular or fragment ion in the range + 30 millimass units of TCDD masses m/e 319.8955, m/e 321.8936, and m/e 327.8847. This minimizes the interference from contaminating components, thus yielding responses that are reproducible and linear relative to the amount of TCDD injected. Two concentration ranges, 0.2-2 pg and 2-10 pg, were used to provide the most efficient and accurate quantification of TCDD because of the extremely high sensitivity and manual control attenuation used in these analyses. Sample extracts should be diluted or concentrated as required for quantification purposes. The reproducibility of peak height response for TCDD standards, 1 pg/yl or 5 pg/yl, during daily operation was +20%. The TCDD m/e 320 and m/e 322 chlorine isotope ratio ranged from 0.75-0.95 to 1. The variation from the theoretical chlorine ratio, 0.8 to 1.0, was attributed to the MIS integration rate, very narrow capillary column GLC peaks, and the small amount of TCDD being analyzed. The GLC HRMS peak matching accuracy for known elemental composi tions was determined to be t 2 millimass units at 9500 mass resolution with PFK as reference. The reference mass and TCDD mass were observed to be exactly superimposed on the mass spectrometer oscilloscope at the exact GLC HRMS retention time of TCDD. 4. Recovery of 37C1-TCDD and Measurement of TCDD The MIS simultaneous peak height responses (m/e 328, m/e 322, and m/e 320) of sample and sample fortified with a known amount of 37C1-TCDD and TCDD were used to determine the sample prepara tion procedure efficiency (percentage recovery), TCDD residue level, and limit of detection. The criteria utilized for confirmation of TCDD are shown in Table 1. The percentage recovery experimental value was used to correct the TCDD residue level and limit of detection for 37C1-TCDD recovery losses. A minimum acceptable percentage recovery (50%) was established for reporting TCDD analyses. The infrequent analyses exhibiting less than 50% recovery were discarded. TCDD results were not corrected for recovery values greater than 100%. Recovery values between 100 and 135% were attributed^to interference fi^om PCBs and unidentified contamination. ..Due to the widespread (tistribution of PCBs, the accuracy of 37Cl-TCDf) determination primarily depends on the sample preparation procedure efficiency and specificity, and the capillary column GLC resolution o'f 1 6101 'z&z'rjTj. Revised 12/15/79 Section 9, G Patje 13 components. The MS mass resolution, ca 45000, required to separate 37C1-TCDD m/e 327.8847 and PCB m/e 327.8758 is not feasible owing to MS limitations. For occasional and highly contaminated sample extracts, the 37C1-TCDD m/e 328 peak height was determined utilizing the PCB m/e 326 peak height to calculate the PCB contribution to the m/e 328, a mixture of 37C1-TCDD and PCB. Limit of Detection The limit of detection was defined as the quantity of TCDD that would provide a signal to noise ratio greater than 2.5:1 with clearly defined peak shapes (m/e 320 and m/e 322) in the proper isotopic ratio. The limit of detection varied from sample to sample because of percentage recovery, sample size, matrix effects, and electronic noise present in the time frame of measurements. 6. Isotopic Purity of 37C1-TCDD Fortification Standard The 37C1-TCDD standard, 1 ng/yl in benzene, was subjected to MIS analyses for determination of purity and possible interferences for sub-ppt TCDD analyses prior to human milk studies. A TCDD isomer was detected at 1 pg/ng 37C1-TCDD. The GLC HRMS peak matching technique with PFK as reference was used to confirm the elemental composition of m/e 319.8965 and 321.8936, both corresponding to TCDD, in a concentrated solution of 37C1-TCDD standard. The elemental^compositions, the m/e 320/322 Cl ratio, and the GLC retention time of 37C1-TCDD fortified with 2,3,7,8TCDD were criteria used to confirm the presence of a TCDD isomer in 37C1-TCDD standard that satisfies the analytical criteria for 2,3,7,8-TCDD. These results indicated that 10 ng 37C1-TCDD foritification levels in 10 gram samples would produce 1 ppt TCDD analyses. This was confirmed experimentally. The fortifi cation level was reduced from 10 to 2.5 ng 37C1-TCDD per sample to avoid false positive results in 0 to 2 ppt TCDD analyses. 7. Human Milk Studies EPA has initiated a study to determine the possible presence of TCDD in human milk. Sample locations were selected based on the aerial application of 2,4,5-T for conifer release as part of a forestry management program. The samples were subjected to the described acid-base extraction and cleanup procedure prior to GLC HRMS MIS analysis. The 60 yl human milk extracts were quantitatively concentrated to 7-20 yl using dry nitrogen gas for.sub-ppt TCDD analysis. The MIS analysis sequence was sample, sample fortified with I 6102 } Revised 12/15/79 Section 9, G Page 14 37C1-TCDD, and TCDD. A typical analysis for TCDD residues in a QC sample of human mother's milk is shown in Figure 2. The corrected experimental results indicated the sample contained 1.2 ppt TCDD residue. This 10 gram sample had been fortified with 10 pg of TCDD, which corresponds to 1 ppt TCDD. The total TCDD analyses, analytical cleanup efficiency, TCDD residue level, and limit of detection were performed on injections of a sample and fortified sample. Duplicate analyses were usually performed on each sample to establish precision values. The results of a quality assurance study incorporating human milk fortified with 2.5 ng 37C1-TCDD and 0-5 ppt TCDD are shown in Table 2. Evaluation of the experimental results and theoret ical results after completion of study indicate: (a) the analyt ical cleanup procedure and MIS method of analysis provided reasonably accurate TCDD analysis in the 0.2-5 ppt concentration range; (b) false positive results were not detected; (c) 2.5 ng 37C1-TCDD fortification levels were adequate for recovery purposes; (d) the small amount, (2.5 pg) of TCDD, in adverse effects in 0-5 ppt TCDD analyses, with a 0.2 ppt detection limit. A representative number of positive results generated at this level of detection should be confirmed with supplemental tech niques such as C0C1 loss, peak matching analyses, etc. Contamination was a constant problem in 0-5 ppt TCDD analysis. A very efficient and optimized capillary column was required to resolve TCDD from contamination, and its effectiveness could be destroyed in the presence of high amounts of contamination. In general, PCBs were the contaminants of major concern. The mass resolutions 12,476 and 45,539 required to separate PCB masses 321.8677 and 327.8758 from TCDD masses 321.8935 and 327.8847 could not be used in 0-5 ppt TCDD analysis because of instrument design and sensitivity. The PCB interference to TCDD analysis was observed to have the following effects: (a) recovery of 37C1-TCDD became greater than 100% and (b) the TCDD m/e 320/322 chlorine isotope ratio was destroyed. Mass resolution of 5,000 to 8,000 was sufficient to resolve TCDD from other contamination present. 8. Fish Analysis Edible portions (2.5 to 10 grams) of fish samples were fortified with 2.5 to 10 ng 37C1-TCDD and subjected to the described acid/ base extraction and cleanup procedures. An MIS analysis is shown in Figure 3, for sample .and fortified sample. Unusual and high concentrations of contaminate masses were detected at m/e ^ 320 and m/e 322 in fish collected from polluted waters. The 'contamination was not detected in analyses of ocean perch, fish from specific locations, and beef liver during the analysis l 6103 Revised 12/15/79 Section 9, G Page 15 sequence, the high concentration of co-extractable components in fish caused serious problems (capillary column overload, co-elution of components, and decreased ns sensitivity). To minimize or cancel these effects, very high MS sensitivity (4-9 pg quantification standard) and small sample size (0.5 to 3 pl~ from 55 yl equivalent to a 10 gram sample) were used in analysis of fish. A small number of highly contaminated fish extracts were subjected to additional GLC HRMS analyses and to a "neutral" cleanup procedure to confirm the presence of TCDD: (a) MIS simultaneous response for the molecular ion cluster m/e 320, m/e 322, and m/e 324 to confirm the tetrachloro isotope ratio. (b) MIS simultaneous response for m/e 320, m/e 322, m/e 257, and m/e 259 to confirm the M+-C0C1 loss indicative of the TCDD structure. (c) GLC HRMS peak matching analysis to confirm the elemental composition of the TCDD molecular ion, m/e 319.8965. Two exact masses corresponding to TCDD isomers were observed eluting before and after TCDD. Contaminant masses, differing from the exact mass of TCDD, were also observed during the time frame of the analysis. Highly contaminated fish samples were subjected to a "neutral" cleanup procedure described in Section 9G. Capillary column GLC HRMS MIS analysis yielded positive 37C1-TCDD and TCDD responses essentially free of contamination. The quality assurance sample results utilized in these studies are shown in Table 3. 9. Water and Sediment Analysis Water and sediment samples were collected from specific areas of the United States and subjected to the described analytical extraction and cleanup procedures prior to MIS analysis. The analytical results for quality assurance samples incorporated in these studies are shown in Table 4. Evaluation of the results shown in Table 4 indicates that the analytical extraction and cleanup procedure and MIS technique provided reasonably accurate analysis for 10-1000 parts per quadrillion (10-15) TCDD in water and 0-35 ppt TCDD in sediment. Water extracts were very clean. Significant amounts of contam ination differing from the exact mass of TCDD were detected in specific sediment samples but did not interfere with TCDD analysis. I 6104 Revised 12/15/79 10. TCDD Isomers Section 9, G Page 16 The toxicological properties of TCDD isomers are known to be significantly different. The mass spectra of known TCDD isomers are identical except in the low mass range, and this minor difference would not be of significant value in ppt analy sis of environmental or biological extracts. Therefore, it is extremely important that the gas chromatograph be equipped with high resolution capillary columns to resolve TCDD isomers before they enter the mass spectrometer. The 2,3,7,8-, 2,3,6,8-, and 1 ,2,3,4-TCDDs and a mixture consisting of 70% 1,3,6,8-TCDD and 30% of an unknown TCDD isomer have been separated in this laboratory using glass capillary column GLC HRMS. The SE-30 WCOT glass capillary column resolution of TCDD isomers and order of elution were similar to separations reported in the literature on an 0V-101 glass capillary column. The 2,3,6,8-TCDD isomer was only partially resolved from 1 ,2,3,4-TCDD. Several TCDD isomers have been detected and confirmed in environ mental, biological, and chemical formulation samples using the described capillary column GLC HRMS techniques and coinjection of specific TCDD isomers. Preliminary studies using the acid-base cleanup procedure and nanogram quantities of hexa-, hepta-, and octa-substituted dioxins (analytical standards) suggest that tetrachlorodioxin isomers are not formed from the degradation of higher chlorin ated dioxins by acid-base sample preparation conditions. Nanogram quantities of 2,4,5-trichlorophenol showed no evidence of condensation to 2,3,7,8-TCDD under the same acid-base conditions. XIII. ANALYTICAL QUALITY CONTROL: The analytical cleanup laboratory should assign identification numbers to all samples. The samples and QC samples are fortified with 2.5-10 ng of 37C1-TCDD. The QC samples are fortified with 0 to 1, 250 pg (p to 125 ppt) of TCDD before extraction and cleanup. A method blank is included as part of the QC sample package. All sample extracts and quantification standards, 37C1-TCDD and TCDD, are submitted to the GLC MS laboratory in a blind fashion, i.e., there should be no way to distinguish QC and actual samples. The efficiency, accuracy, precision, and validity of ppt TCDD analyses depend on an incorporated quality assurance program. The supplemental and conclusive GLC HRMS validation techniques involving analyses for Mf-COCl loss and GLC HRMS peak matching analysis (real time)* can not easily be applied to 0-30 ppt TCDD analyses at this, date, using the described procedures. Based on the incorporated Revised 12/15/79 Section 9, G Page 17 quality assurance program, analytical criteria, GLC HRMS techniques, and multiple laboratory participation, the described methodologies have been shown to be effective for isolation, detection, and quantification of 0.02-100 ppt levels of TCDD in specific types of samples. Samples containing high ppt or part per billing (ppb) levels of TCDD can cause serious contamination problems in the sample preparation laboratories, which result in erroneous low ppt TCDD analysis of the sample next in the series. Extreme care and very clean laboratory practices are mandatory for low ppt TCDD analyses. Results of some quality assurance studies are presented in Subsection XII. TABLE 1. CRITERIA USED FOR CONFIRMATION OF 2,3,7,8-TCDD RESIDUES IN HUMAN, ENVIRONMENTAL AND FISH SAMPLES 1. Capillary column GLC HRMS retention time of 2,3,7,8-TCDD. 2. Co-injection of sample fortified with 37C1-TCDD and TCDD standard. 3. Molecular ion chlorine isotope ratio (m/e 320 and m/e 322). 4. Capillary column GLC HRMS multipie ion monitoring response for TCDD masses (simultaneous response for elemental composition of m/e 320, m/e 322, and m/e 328, 37C1-TCDD). 5. Response of m/e 320 and m/e 322 greater than 2.5 times the noise level. CI 6106 Revised 12/15/79 Section 9, G Page 18 TABLE 2. ANALYTICAL RESULTS FOR 2,3,7,8-TCDD RESIDUES IN QUALITY ASSURANCE SAMPLES OF HUMAN MILK Experimental Results 37C1-TCDD % Recovery TCDD Detection Limit* (ppt) TCDD Detected* (PPt) TCDD Fortification Level (pg) (ppt) 50 72 68 64 68 84 64 51 73 52 72 - 100 50** 0.3 1.9 0.2 0.6 0.1 0.2 0.3 ND 0.4 0.9 0.2 1.4 0.2 0.4 0.2. ND 0.4 0.6 0.3 1.4 0.5 3.0 0.5 4.0 0.2 ND 10 3 1 0 9 20 5 2 7.5 6.5 30 50 0 1.0 0.3 0.1 0 0.9 2.0 0.5 0.2 0.75 0.65 3.0 5.0 0 Each 10 gram sample was fortified with 2.5 ng 37C1-TCDD. * Corrected for recovery. ** Method blank. ND = Not detected. ppt = Parts per trillion. Revised 12/15/79 Section 9, G Page 19 TABLE 3. SUMMARY OF ANALYTICAL RESULTS FOR QUALITY ASSURANCE SAMPLES (OCEAN PERCH, LAKE TROUT, BEEF LIVER) GEN- " .. v r .: ERATED DURING ANALYSIS. OF FISH FOR TCDD RESIDUES Experimental Results Sample Weight (gram) 37C1-TCDD Fortifica tion Level (ng) 37C1-TCDD % Recovery 35C1-TCDD TCDD TCDD Fortifica ( p g ) ( p p t )Detection - Detected Limit (ppt)* (ppt)* tion Level 5 (1) 5 (1) 5 (1) 5 (4) 5 (3) 5 (3) 5 (3) 5 (1) 5 (1) 10 (1) 10 (1) 10 (2) 10 (2) in (l) 10 (4) 10 (1) 10 (1) 5 5 5 5 5 5 5 5 5 10 10 10 10 10 10 5 10 62 52 82 100 54 100 78 92 97 100+ 100+ 100+ 100+ 100+ 67 93 84 2 20 110 22 4 34 185 35 3 ND 0 0 3 ND 0 0 1 19 70 14 2 ND 0 0 2 ND 0 0 2 19 55 11 5 45 240 48 1" 8 130 13 4 43 600 60 7 ND 0 0 3 ND 0 0 4 76 1250 125 1 ND 0 0 3 56 650 65 4 73 620 62 * Corrected for recovery (1) ocean perch (2) lake trout (.3) beef li ver (4) method blank ND = Not detected. > Revised 12/15/79 Sample Type Sample Weight (gram) Section 9, G F ) 20 TABLE 4. SUMMARY OF ANALYTICAL RESULTS FOR OUALITY ASSURANCE SAMPLES GENERATED DURING ANALYSIS OF WATER AND SEDIMENT FOR 2,3,7,8-TCDD RESIDUES Experimental Results 37C1-TCDD Fortification Level (ng) 37C1-TCDD % Recovery Detection Limit* TCDD Detected* TCDD Fortification Level water water water water water water water sediment sediment sediment sediment sediment sediment sediment 1000 1000 1000 1000 1000 1000 1000 50 * 50 10 10 10 n1o0 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5: ppqd = Parts per quadrillion (10~15). ppt = Parts per trillion (10"12). * Corrected for recovery, ND = Not detected. 73 90 66 95 78 78 100+ 69 100+ 100+ 96 100+ 68 100 15 ppqd ` 50 " 14 " 10 " 15 " 15 " 41 " 0.13 ppt 0.14 " 0.6 " 0.5 " 2.0 " 4.0 " 0.7 " 85 ppqd 730 " ND 50 " 116 " 28 " 422 " 1.0 ppt 1.0 " 2.5 " 3.3 " 23.0 " 30.0 " ND 75 ppqd 1000 " 10 " 50 " 100 " 25 " 500 " 1.0 ppt 1.4 " 1.6 - " 4.6 " 17.0 " 35.0 " 0 V-,v .J, OE> O CO Revised 12/15/79 Section 9, G Page 21 FIGURE 1. GLC/HRMS multiple ion selection response for 1 ng 37C1-TCDD * and 2 pg "Cl-TCDD. I 6110 rw w ij,> ii.n ,fi wmm iw ^ w a w a g g a g c ! 1 Revised 12/15/79 Section 9, G Page 22 FIGURE 2. GLC/HRMS MIS monitoring analysis for TCDD residues in a human milk QA sample. (A) 2 pi of sample (fortified with 1 ppt TCDD). (B) 1 ul of sample fortified with 500 pg ^Cl-TCDD and 1 pg 35ci-TCDD. I Revised 12/15/79 Section 9, 6 Page 23 TIME (min) FIGURE 3. GLC/HRMS MIS monitoring analysis of a fish extract. (A) Sample 1 1 from 50 yl; (B) Fortified sample, 0.5 yl from 50 1 plus quantification standard. ; I 6112 2 . fe > Bll 3 Dow Chemical U.S.A. Agricultural Products Dept., Box 1706, Midland, Ml 48640 137-1274-80 It TTFNDA^r^,,,,, | EXHIBIT 1 yw? ' \ J V \ J X v V/ CD PUBLIC CONCERNS ABOUT 2,4,5-T Wendell R. Mulllson, Ph.D. A pril, 1980 Subject INDEX Page No. Miscarriages and Birth Defects: B ackg ro u n d .................................... 1 Miscarriages and Birth Defects: 2,4,5-T Scientific Facts .............. 2 Cancer Assessment .................................................................................. 4 Diseases and Illnesses.............................................................................. 6 TCDD Toxicity: A n im als............................................................................ 6 TCDD Toxicity: Humans .......................................................................... 7 Dispute Resolution Conference ................................ 8 Genetic C o n c e rn s ..................................................................................... 9 * Ecological Concerns ....... 9 2,4,5-T Use H is to ry .................................................................................... 10 Independent Risk Assessment of 2 ,4 ,5 -T ............................................ 11 Conclusions ................................................................................................ 12 B ibliograp h y................................................................................................ 13 The author is a former employee of Dow Chemical U.S.A. and is now retired after 32 years of experience in agricultural research, development and registration. He is now a consultant on agricultural pesticides, particularly herbicides. He is a charter member of the Weed Science Society of America, a life member of the American Society of Plant Physiologists and the Botanical Society of America. He was chairman of the committee that revised the Herbicide Handbook which was published as the fourth edition in 1979 by the Weed Science Society of America. Wendell Mullison earned a doctoral degree in botany from the University of Chicago. 6115 PUBLIC CONCERNS ABOUT 2,4,5-T Wendell R. Mullison* There appears to be considerable apprehension among certain sectors of the public about the use of the herbicide 2,4,5-T (2,4,5-trichlorophenoxyacetic acid) which is used in many herbicidal formulations. These concerns are usually based upon inaccurate and often outright misstatements of fact that are frequently cited in the news media. This paper discusses certain public concerns about 2,4,5-T. The 2,4,5-T discussed in this paper contains the trace contaminant TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin). The legal limit for TCDD in 2,4,5-T acid in Denmark, Australia, New Zealand, and many other countries is'0.1 p p m 1. Recent production runs of Dow products contain significantly less TCDD (0.02-0.04 ppm). There has been a great deal of unfavorable publicity in the news media about the toxicity of 2,4,5-T. According to many accounts this herbicide is a harbinger of doom. The allegations are that 2,4,5-T causes tremendous human health hazards. However, the . . . overwhelming scientific data clearly show that 2,4,5-T with its trace contaminant TCDD does not cause human health problems. These alleged health problems have been grouped in the following classifications: 1. Miscarriages and birth defects 2. Cancer 3. Diseases or illnesses possible from a multiplicity of causes 4. Rare diseases with an unknown or obscure etiology MISCARRIAGES AND BIRTH DEFECTS: BACKGROUND The worldwide rate of spontaneous abortions or miscarriages has been estimated to be 15 to 20% according to the World Health Organization.2 This estimate is probably low. Other authoritieequote higher figures. A recent Great Britain report said 25% of all pregnancies result in miscafriagiir One s c ie n tis t says "a pregnancy x wastage of between 30 and 50% seems to afflict laboratory and wild animals, domestic breeds and man." It is generally recognized that the majority of the miscarriages result from chromosomal or developmental abnormalities in the fertilized egg or the developing fetus. Thus, a miscarriage is Nature's way of handling a rrstake.' *This paper wa s presented at the 33rd Meeting, Western Society ot Weed Science March 18-20, I960, Salt Lake City. Utah. 1 Sirth detects also are far more common than is usually realized. In the United States4 it has been estimated that 7% of all live babies born each year have a serious birth defect. The U.S. Department of Health, Education and Welfare in a recent article5 surveyed the incidence of 16 selected birth defects in the United States in 1970 and 1971 as well as in 1976-1977. They said, "There is no evidence for an overall increase or decrease in malformation rates (birth defects) since 1970." This same study indicated the rate of encephaly declined 5.4% while spina bifida declined by 6.7%. The etiology of birth defects is not easily characterized although viral infections such as German measles are known to be a common cause. Based on surveys and case reports in medical literature, the following causes of birth defects and their frequency are: genetics -- 20%; chromosomal aberration -- 3-5% ; radiation less than 1%; . disease -- 2-3%; maternal metabolic imbalance -- 1-2%; drugs and environmental chemicals -- 4-5% ; and unknown causes -- 65-70%. It is noteworthy that 65% to 70% of birth defects still have an unknown cause today. Thus, even with our modern medical knowledge this is still every poorly understood field. The importance of the figures previously cited is that they show the chances of a woman having a miscarriage or a child with a birth defect are far greater than ordinarily realized. In fact, such problems really are not uncommon. These problems of birth defects and miscarriages have been with mankind since prehistoric times, long before 2,4,5-T was manufactured. It therefore seems quite unreasonable to assume that 2.4.5- T is necessarily implicated as a cause of these problems, particularly when the charges are based on anecdotal reports. This is especially true when there is a large body of scientific evidence that indicates the use of 2,4,5-T does not cause human birth defects or miscarriages. MISCARRIAGES AND BIRTH DEFECTS: 2,4,5-T SCIENTIFIC FACTS 2.4.5- T has been carefully studied in scientific experiments on seven species of mammals to determine whether it would cause birth defects. In six species of animals tested (monkeys, rats, rabbits, hamsters, sheep, and reindeer)7 i4. 2,4,5-T has been found to cause no birth defects and no spontaneous abortions or miscarriages (or the animal equivalent thereof). However, 2,4,5-T has been found to cause the birth defect of cleft palate in mice. Mice, however, are so highly susceptible to cleft palate that this defect can be caused by an experimental stimulus as mild as an airplane ride during pregnancy. Since this defect is so easily caused, its occurrence in mice is not a reliable indicator of hazard to humans. 6116 2 Governmental committees in Australia and New Zealand, after studying the question of whether human birth defects are caused by 2.4.5- T, have found these allegations to be unfounded and have given a clean bill of health to 2,4,5-T. Dr. Donald P. Morgan, a physician in the Environmental Toxicology Division at the University of Iowa, reviewed the Australian report for EPA. Hp stated15: "The calculations confirm what one would expect on the grounds of common sense alone, i.e., that absorption of sufficient amounts of these agents to cause reproductive morbidity is extremely unlikely, if not impossible. Dr. Morgan made some additional observations that are of interest: "Sim ilar reviews of the same literature must have been completed by at least a hundred government agencies in the last five years. A study by the government of New Zealand in June, 1977, arrived at the same conclusions, using essentially the same investigative m e th o d s___ Interest in this aspect of human health (reproductive morbidity and congenital defects) will probably increase in the years ahead,'and the public will be inclined to fasten on one or another agent as causative xxf birth defects, according to the fashion of the times." Any discussion of alleged human miscarriages being caused by 2.4.5- T must include the Alsea II Oregon Study conducted for EPA. This came about as a result of a well-written letter to EPA and subsequent media publicity concerning eight women in the Alsea, Oregon area who had suffered 10 miscarriages16. The Alsea II Study is important because EPA said, in a press conference of March 1, 1979, when announcing the emergency suspension action to halt the use of 2,4,5-T and silvex: "We are taking emergency action today to halt the spring spraying of the herbicide 2,4,5-T on the basis of new information indicating its potential link to human miscarriages . . . . We have just received the results of a study which show a high probability that the herbicide is linked to actual human miscarriages in an area where 2,4,5-T is used regularly. New studies in the Alsea basin area of Oregon show a high - miscarriage rate shortly after the spraying of 2,4,5-T in the forests." , According to EPA's press conference statement this Alsea II report was instrumental in prompting the Agency's emergency suspension action against 2,4,5-T and silvex. Unfortunately, this Alsea II report is seriously flawed scientifically. The following common-sense points indicate why this report is considered to be invalid: (1) There is no exposure data in the report that show the affected women ever came in contact with the herbicide. For instance, only 3 Sirth defects also are far more common than is usually realized. In the United States4 it has been estimated that 7% of all live babies born each year have a serious birth defect. The U.S. Department of Health, Education and Welfare in a recent article5 surveyed the incidence of 16 selected birth defects in the United States in 1970 and 1971 as well as in 1976-1977. They said, "There is no evidence for an overall increase or decrease in malformation rates (birth defects) since 1970." This same study indicated the rate of encephaly declined 5.4% while spina bifida declined by 6.7%. The etiology of birth defects is not easily characterized although viral infections such as German measles are known to be a common cause. Based on surveys and case reports in medical literature, the following causes of birth defects and their frequency are: genetics -- 20%; chromosomal aberration -- 3-5% ; radiation less than 1%; . disease -- 2-3%; maternal metabolic imbalance -- 1-2%; drugs and environmental chemicals -- 4-5% ; and unknown causes -- 65-70% .6 It is noteworthy that 65% to 70% of birth defects still have an unknown cause today. Thus, even with our modern medical knowledge this is still a very poorly understood field. The importance of the figures previously cited is that they show the chances of a woman having a miscarriage or a child with a birth defect are far greater than ordinarily realized. In fact, such problems really are not uncommon. These problems of birth defects and miscarriages have been with mankind since prehistoric times, long before 2,4,5-T was manufactured. It therefore seems quite unreasonable to assume that 2.4.5- T is necessarily implicated as a cause of these problems, particularly when the charges are based on anecdotal reports. This is especially true when there is a large body of scientific evidence that indicates the use of 2,4,5-T does not cause human birth defects or miscarriages. MISCARRIAGES AND BIRTH DEFECTS: 2,4,5-T SCIENTIFIC FACTS 2.4.5- T has been carefully studied in scientific experiments on seven species of mammals to determine whether it would cause birth defects. In six species of animals tested (monkeys, rats, rabbits, hamsters, sheep, and reindeer) 7-u, 2,4,5-T has been found to cause no birth defects and no spontaneous abortions or miscarriages (or the animal equivalent thereof). However, 2,4,5-T has been found to cause the birth defect of cleft palate in mice. Mice, however, are so highly susceptible to cleft palate that this defect can be caused by an experimental stimulus as mild as an airplane ride during pregnancy. Since this defect is so easily caused, its occurrence in mice is not a reliable indicator of hazard to humans. 2 8117 Governmental committees in Australia and New Zealand, after studying the question of whether human birth defects are caused by 2.4.5 - T, have found these allegations to be unfounded and have given a clean bill of health to 2,4,5-T. Dr. Donald P. Morgan, a physician in the Environmental Toxicology Division at the University of Iowa, reviewed the Australian report for EPA. Hp stated15: "The calculations confirm what one would expect on the grounds of common sense alone, i.e., that absorption of sufficient amounts of these agents to cause reproductive morbidity is extremely unlikely, if not impossible.'1 Dr. Morgan made some additional observations that are of interest: "Sim ilar reviews of the same literature must have been completed by at least a hundred government agencies in the last five years. A study by the government of New Zealand in June, 1977, arrived at the same conclusions, using essentially the same investigative methods . . . . Interest in this aspect of human health (reproductive morbidity and congenital defects) will probably increase in the years ahead,'and the public will be inclined to fasten on one or another agent as causative of birth defects, according to the fashion of the times." Any discussion of alleged human miscarriages being caused by 2.4.5 - T must include the Alsea II Oregon Study conducted for EPA. This came about as a result of a well-written letter to EPA and subsequent media publicity concerning eight women in the Alsea, Oregon area who had suffered 10 miscarriages16. The Alsea II Study is important because EPA said, in a press conference of March 1, 1979, when announcing the emergency suspension action to halt the use of 2,4,5 -T and silvex: "W e are taking emergency action today to halt the spring spraying of the herbicide 2,4,5 -T on the basis of new information indicating its potential link to human miscarriages ------We have just received the results of a study which shovy a high probability that the herbicide is linked to actual human miscarriages in an area where 2,4,5 -T is used regularly. New studies in the Alsea basin area of Oregon show a high miscarriage rate shortly after the spraying of 2,4,5-T in the ,forests." According to EPA's press conference statement this Alsea II report was instrumental in prompting the Agency's emergency suspension action against 2,4,5-T and silvex. Unfortunately, this Alsea II report is seriously flawed scientifically. The following common-sense points indicate why this report is considered to be invalid: (1) There is no exposure data in the report that show the affected women ever came in contact with the herbicide. For instance, only 3 '3 % of the basin was sprayed and in addition this was a forest area with the majority of people living elsewhere. (2) There was no dose response effect; that is, when 2,4.5-T was applied to the forests at twice the dosage there was not a corresponding substantial increase of miscarriages. The Environmental Health Sciences Center of Oregon State University has published a 93-page report with a 21-page supplement entitled "A Scientific Critique of the EPA Alsea II Study and Report with November 16, 1979 Supplement." This Oregon State University evaluation points out in detail the many inaccuracies and erroneous assumptions of EPA's Alsea II Report. The critique states that due to the many flaws in the study methodology the conclusions of EPA's Alsea II Report are wrong. The Oregon State University study is merely the latest criticism. The Alsea II data and report have been critically analyzed by highly respected statisticians, physicians, and other scientists from foreign countries including Canada, Great Britain, Australia, and New Zealand. Their scientists could find no justification for the claims stated in the Alsea II Report. The Alsea II report was also carefully studied by the Scientific Dispute Resolution Conference on 2,4,5-T ' 7: "The miscarriages reported in this study were not demonstrated to result from the spraying of the forests with 2,4,5-T." "The group found no evidence for an abortifacient (causing abortion) effect of TCDD in the human." It is seldom indeed that a scientific report has received such detailed and universal criticism. T h e L a n c e t ' 8, the leading medical journal of Great Britain, and one of the most influential in the world, characterized the Alsea II Report in this manner: "Independent statisticians have been unable to find any evidence in the data of a link between abortion and 2,4,5-T; and, the EPA, it seems, is now having second thoughts." T h e L a n c e t 2,4,5-T article concluded: "To reduce the risks of chemical accidents, we need an inspectorate which is skilled, properly trained, and adequately paid. Getting the technology right is important, too. But it is a waste of effort, resources, and credibility to cry `w o lf about - 2,4,5-T when there is no wolf." CANCER ASSESSMENT OD . Human cancer generally develops slowly over a latency period of ^ many years and usually is a disease of old age. Thus, in studying 0 0 possible causative agents, especially at low levels of exposure, it is 4 necessary to go back approximately 20 years or itk befpre there is proper human data to study. Since 2,4,5-T has been a commercial product for more than 30 years, there has been sufficient time for a possible carcinogenic effect to have been identified in humans. During the Vietnam war and subsequently, a physician from North Vietnam, Dr. Ton That Tung, has alleged that there has been an increase in liver cancer from spraying of Herbicide Orange* for defoliation in Vietnam. Research19 by Dr. Tung on.this matter was presented at a scientific meeting in France. In the discussion that followed, Dr. R. Favre made the following comments: "I have no opinion whatsoever concerning the role of defoliants promoting the appearance of primary cancer of the liver since my stay in Indochina goes back to 1949-T52 (prior-to the Vietnam war). On the other hand, I was able to verify at this time, with astonishment, the extraordinary frequency of cancer of the liver with respect to its frequency in Europe. One should discuss the difference in diagnosis with am oebic hepatitis, especially since more frequently primary cancer of the liver in Vietnam is a febrile form accompanied by a localized and painful hepatomegalia." T Thus, Dr. Tung's allegation as to the cause of the high frequency of liver cancer in Vietnam is invalid since historically there has been a high incidence of this disease there. Tung also did not take into account other possible confusing causative factors such as aflatoxin. Aflatoxin is a common very poisonous mold that causes liver cancer.20 Aflatoxin in spoiled grain could certainly have increased in Vietnam under wartime conditions. Another criticism of Tung's paper is that enough time had not elapsed to draw such conclusions about the increased incidence of liver cancer. It is not surprising, therefore, that reviews by both the World Health Organization and the Cancer Assessment Group of EPA concluded that Tung's data was inadequate and did not prove Herbicide Orange caused an increase of liver cancer in Vietnam. There have been nine long-term carcinogenic studies with rats and mice. The two most recent studies, reported last year, were done with rats; these were lifetime studies that usea the latest and best technology available.u j One of these studies was done in Germany, the other in the United States. The authors in both cases concluded that 2,4,5-T was not a carcinogen. * Herbicide Orange was the code-name ol a 50:50 mixture of the n-butyl esters of 2.4-D and 2,4,5-T. It contained 4.21 lb. of 2.4-C and 4.41 lb. 2,4,5-T acid equivalent per gallon. 5  T.iese rat data are confirmed by seven long-term carcinogenic experiments with mice.23 Review of these studies of 2,4,5-T with varying quantities of TCDD confirm each other and clearly show that 2,4,5-T does not cause cancer. Medical surveillance of the workers engaged in the manufacture of Dow's 2,4,5-T has been carried out and is continuing. A recent published report24 of some of these studies shows that among these workers there was no excess mortality from cancer caused by exposure to 2,4,5-T. The number of individuals studied is relatively small, due to the small work force involved. However, the results strongly indicate that 2,4,5-T is not carcinogenic. Since this chemical has been in production and use for over 30 years, there has been ample time for cancer to appear if it were a problem. Thus, the limited human data available are in agreement with the extensive animal data as to the non-carcinogenic effects of 2,4,5-T. DISEASES AND ILLNESSES 1 Human illnesses mistakenly associated with 2,4,5-T are those with symptoms such as nervousness, chronic tiredness, and mental illness. Such symptoms.are very common and are associated with many every day ailments having a multiplicity of causes such as normal menstrual difficulties, respiratory problems, flu. overwork, stress, and psychological factors. There are also obscure and rare medical problems that may arise with an unknown or poorly understood etiology. However, there is no scientific evidence that indicates 2,4,5-T causes such disorders. The question of the toxicity of 2,4,5-T and whether it causes human health problems has been complicated by the trace contaminant TCDD which is an extremely toxic material. TCDD TOXICITY: ANIMALS Most of the toxicological investigations have been done with 2,4,5-T that contained various amounts of TCDD. However, in carefully controlled animal experiments with rats using only TCDD in both lifetime feeding studies38 and three-generation reproduction studies31, no-effect levels for TCDD have been found. These results were confirmed upon review by the Scientific Advisory Panel.37 A no-effect level has been demonstrated in chronic feeding studies21 in rats using 2,4,5-T containing 0.05 ppm of TCDD. Such results support the findings from the experiments using TCDD alone. These studies clearly show that TCDD is not a practical hazard at the very low levels at which it is. present as a trace contaminant in the herbicide 2.4,5-T. The Council for Agricultural Science and Technology (CAST) ^ reported that 200 to 2,000 toxic doses of 2,4,5-T would have to be administered, depending on the species, before a single toxic dose ^r"n"L of TCDD would be received based on the trace amounts of TCDD 6 present in 2,4,5-T.25 This same report concludes, "T>. j , the current level of TCDD in 2,4,5-T does not contribute significantly to the toxicity of herbicidal preparations of 2,4,5-T." To further illustrate the negligible practical hazard from this trace contaminant in 2,4,5-T, CAST also said that if you assume a grazing animal about the size of a sheep or deer (175 lb or 80 kg and also the average weight of many a human) with the sensitivity of the most sensitive species known, the guinea pig, this animal would have to consume all the treated vegetation on more than nine acres of land to get a lethal dose. This assumes all the material is on the vegetation and that none of it decomposes. As a practical matter, TCDD on leaf surfaces is rapidly decomposed by sunlight. TCDD contacting the soil is immobilized immediately and gradually decomposes. ( TCDD TOXICITY: HUMANS There is some toxicological data on the effects of TCDD on humans that has been documented from industrial accidents. This information strongly suggests that the trace contam inant TCDD in 2,4,5-T does not constitute a problem to human health. Trichtorophenol is used in the manufacture of 2,4,5-T and it is during this process that the impurity TCDD is forpied. Subsequently, this impurity becomes the trace contaminant in 2,4,5-T. Data from industrial accidents indicate that chloracne is the first visible symptom of human over-exposure to TCDD. At Nitro, West Virginia there was an accident on March 8, 1949 at a plant manufacturing trichlorophenol. Workers in this plant were exposed to TCDD. All of the 121 workers who developed chloracne were studied. Recently a medical evaluation of this 30-year history on the Nitro episode26 has been published: "it is important that no apparent excess in total mortality or in deaths from malignant neoplasms or diseases of the circulatory system were observed in a group of workers with a high peak exposure to tetrachlorodibenzodioxin who were followed over a period of nearly 30 years." They also note the small number of deaths observed. Unfortunately these results, as the authors acknowledge, are not conclusive because of the small number of Objects available to be studied. To further put this trace contaminant TCDD in perspective, the incident at Seveso, Italy is summarized. As a result of an industrial accident on July 10, 1976 at Seveso, approximately 37,000 people living in an area of about 6 square miles were exposed to varying amounts of TCDD.27-Estimates of the total quantity of TCDD that was released into the atmosphere vary, from 1.5 to 3.7 pounds. CAST estimated there is only one ounce of TCDD in all the 2,4,5-T used each year in the entire United States. This unfortunate incident at 7 Seveso was unrelated to 2,4,5-T or its manufacture but this accident continues to provide useful information on the toxicity of TCDD to humans. ' It is important to consider that the people of Seveso were exposed to thousands of times more TCDD than would ever be encountered from an accidental exposure to an application of 2,4,5-T for an agricultural use. Seveso and the entire region has been under medical surveillance since the accident. Technical specialists in many fields including statisticians, sociologists, epidemiologists, biochemists, pathologists, pediatricians, dermatologists, obstetricians, and neurologists, have been involved in studying possible health effects on this population. From such industrial accidents it appears that TCDD is less toxic to humans than would be expected from the animal toxicological data. Although the people at Seveso were exposed to extremely high concentrations of TCDD, no serious medical problems have beerF identified except the skin disorder, chloracne. A report27, approximately three years after the accident, states that nearly all the chloracne has healed. No spontaneous abortions, fetal malformations, neurological or psychological changes, unfavorable immunoresponses, or other various problems have been attributed to TCDD. This information is strong evidence that TCDD when present as a trace contaminant in 2,4,5-T presents no unreasonable hazard to human health. DISPUTE RESOLUTION CONFERENCE Another group of scientists carefully studied the scientific data known about 2,4,5-T and its trace contaminant TCDD at the Dispute Resolution Conference28 in Arlington, Virginia near Washington, DC in 1979. These experts came to several conclusions which address the potential effect of 2,4,5-T on human health. Some of their conclusions are: "2,4,5-T is not a carcinogen nor mutagen in animal test systems studied to date." " Phenoxy herbicides containing TCDD have not been shown to be carcinogenic in humans in retrospective epidemiologic studies to date." "In studies conducted in rats and monkeys, the apparent no-effect level in rats (for TCDD) was 0.001 /ig /kg /d ay; a level 10 times below the demonstrated no-effect level in Rhesus monkeys." This means rats are ten times more sensitive to TCDD than monkeys. "Analysis of the available data* leads this group to the conclusion that no adverse effects on human reproduction have yet been demonstrated after exposure to'2,4,5-T or TCDD." 6120 Data from the United States. Sweden, New Zealand, Australia, Vietnam and Italy were studied. 8 GENETIC CONCERNS Data from in v iv o mammalian tests for possible germ cell mutations are best for predicting genetic risk to humans. Such tests to date show there have been no mutagenic effects of 2.4,5-T in mammals. Chromosomal studies29 have been made in humans at Seveso, Italy who had been exposed to high concentrations of TCDD. This exposure was thousands of times higher than the actual exposure from herbicidal applications as used in the United States. The Seveso population have'shown no evidence of chromosome abnormalities due to TCDD exposure. Three-generation reproduction studies with 2,4,5 -T 30 as well as with TCDD alone have shown that these chemicals are not mutagenic in mammals.31 In addition, a chromosomal study32 done on the workers at one 2,4,5-T manufacturing plant ii\ the United States showed no chromosomal abnormalities in the exposed'work force. This is strong evidence as to its nontoxicity from a genetic viewpoint. K ECOLOGICAL CONCERNS A unique one square mile (640 acres) test site at the Eglin Air Force Base, Florida, was sprayed over an eight-year period with thousands of pounds of 2,4,5 -T with its trace contaminant TCDD.33 One test site in this area received 947 pounds per acre of 2,4,5 -T between 1962 and 1964 with a formulation that contained approximately 33 ppm TCDD. This test gives results obtained under unusually extreme conditions that would never be reached in actual practice. The highest use rate currently for Dow's 2,4,5-T product, ESTERO N* 245 Herbicide containing less than 0.1 ppm TCDD, is 16 pounds in 3 to 100 gallons of diluent applied to the basal stems and stumps of brush. This is a spot treatment and not an overall per acre treatment. Furthermore, it is not an annual application. The usual overall treatment is one-half to two pounds per acre and, except for rice, such treatments would not be applied annually. Range applications are made only once every three to five years. Forests are treated once or twice during their life span. This area at Eglin has been the subject of an intensive ecological study of plant and animal life, th e beach mouse, P e fo m y s c u s p o lio n o t u s , one of the major IfihAbitants of the area, was thoroughly studied. There was no g r M l^ M io lo g ic a l evidence of any carcinogenic or tratognie W K T in adults oo fetuses. The area originally defoliated after the Application of this tremendous quantity of 2,4,5-T is now covered with vegetation going through the normal succession stages for the area. Species diversity and food chain studies showed no significant differences from the untreated area. This ecological study33 on 2,4,5-T has clearly shown that there were no permanent harmful effects to wildlife forms and flora of the region even when tremendously excessive amounts of 2,4,5-T containing very large amounts of TCDD (33 ppm) were applied. 9  .The ( anal Academy of Sciences (NAS) offers another noteworthy study on the uses of 2,4,5-T in Vietnam.34 Also remember that the application rate of Herbicide Orange in Vietnam was approximately 26 pounds per acre of a mixture of 2,4-D and 2,4,5-T. This application was a much higher rate than would be encountered during normal agricultural uses. Their conclusions varied greatly from many sensational news articles that have appeared and still occasionally appear on this subject. NAS concluded that crops could be planted within one year or less from the last spraying (1971). They also point out there has been significant reforestation. It was specifically noted that much of the necessary reforestation was due to causes other than war. NAS concluded the sprayed forests would eventually be restored to productive levels if proper reforestation practices were followed. Thus, there is substantial evidence that no ecological problems have developed or will develop from the commercial use of 2,4,5-T with its trace contaminant TCDD. 2,4,5-T USE HISTORY How safe has 2,4,5-T really been when used for a long time? Manufacturers know a Variant of Murphy's Law should be: If a product can be made to cause a problem, the public will find the way to make it happen. Therefore, the record of public usage can be important in judging the safety of a product. Two states which have used 2,4,5-T extensively have studied the herbicide's safety record. The California Department of Food and Agriculture completed a detailed study April 6, 1978 on the aerial application of phenoxy herbicides in California.35 Public hearings were also held on this subject. 2,4,5-T and 2,4-D have been in use in this state for 25 years. In their summary it was stated: "At the public hearings, allegations were made concerning gross, readily apparent effects of the herbicides, and these alleged gross effects were the target of a subsequent investigation by the Phenoxy Herbicide Investigation Team. None of these effects, such as human illness, animal deaths or deformities, plant damage, or environmental damage, could be attributed to or associated with spraying of phenoxy herbicides. Similarly, no substantiation could be provided for any correlation between geographical locations of residents in relationship to the spray site and the etiology of disease. Examination of pesticide illness reports from California physicians by this Department have not revealed any significant health hazards that can be attributed to the phenoxy herbicides as used today in California." 10 6121 Texas is the state where the most 2,4,5-T has been ui Therefore, it is an excellent area to consider when studying the safety question of 2,4,5-T. Also, 82% of all the rangeland and pasture acreage treated with 2,4,5-T is in Texas and it is the largest producer of beef cattle in the United States. Comments of Texas Agricultural Authorities36 on the safety of 2,4,5-T to humans and animals are extremely pertinent. Their comments on this subject are quoted in their entirety: "The chemical has been used in Texas since 1949-1978 (29 years). In this span of years, approximately 50,000,000 acres have been treated, with many areas of land receiving 3 to 5 applications. To date there has not been a single lawsuit because of attributed health damage to man or animal. There have been lawsuits on damage to vegetation outside of target areas. Percentage of calf,'lam b and kid c ro p is up in Texas. There are less deformities in newborn animals than in the history of the livestock industry. The cause of practically all deformities has been traced to plants that historically cause deformities tp fetuses." t The Texas and California summations of their experiences is convincing evidence that in the real world 2,4,5-T with its trace contaminant TCDD is safe for humans and the environment. INDEPENDENT RISK ASSESSMENT OF 2,4,5-T Another independent group of scientists have recently reviewed the scientific data pertaining to the safety of 2,4,5-T. The Scientific Advisory Panel (SAP) consisting of seven members was authorized by Congress under FIFRA to advise EPA on scientific questions related to suspension or cancellation actions or any new proposed regulations of EPA. The SAP is particularly concerned with the effect of EPA's proposed actions on human health and the environment. The SAP on September 2 6 ,1 9 7 9 issued their review of EPA's proposed notice of intent to hold a hearing on the presently non-suspended uses of 2,4,5-T and silvex. The Panel s initial recommendation stated: "The Scientific Advisory ^ ^ ftic p m m e n d s that the Agency not hold such a meeting at tt^feJwfc'After extensive review of the data we find no evidehttr w ilt Immediate or'substantial hazard to human health or to the environment associated with the use of 2,4,5-T or silvex on rice, rangeland, orchards, sugarcane, and non-crop uses specified in the decision docum ents."37 This reference pertains to the present non-suspended uses of 2,4,5-T and silvex. But recognize that the Scientific Advisory Panel's safety evaluation of 2,4,5-T with its trace contaminant TCDD would also apply to the presently suspended uses of 2,4,5-T. 11 CONCLUSIONS In summary, there is a tremendous volume of scientific information available on 2,4,5-T. This herbicide has been the subject of many carefully controlled toxicological experiments, perhaps more than any other pesticide on the market today. The known scientific data about this chemical, combined with a 30-year history of safe use, fully support these following conclusions: 2,4,5-T is a safe, efficient, and selective herbicide to control weeds and brush and its use has not caused cancer, birth defects, or miscarriages. 2,4,5-T with its trace contaminant TCDD can be and has been used safely and effectively without harm to people, animals, or the environment. *** to to 12 BIBLIOGRAPHY 1. Report of the Consultative Council on Congenital Abnormalities in the Yarram District to the Minister of Health in Australia issued September 26, 1978. 2. World Health Organization Technical Report Series: Spontaneous and Induced Abortion No. 461, 1970. 3. Carr. D. H. Detection and Evaluation of Pregnancy Wastage. Wilson, J: G. and F. Clark Fraser. H a n d b o o k o f T e r a t o lo g y , Vol. 3, page 209, 1977. Plenum Press. 4. Yager, J. W. Congenital Malformations and Environmental Influence: The Occupational Environment oKLaboratory Workers. J o u r n a l o f O c c u p a tio n a l M e d ic in e 15:724-728, 1973. 5. Center for Disease Control: Congenital Malformations Surveillance Report April 1977 - March 1978. Issued November 1978. U.S. Department of Health, Education, and Welfare, Public Health Service, Center for Disease Control, Atlanta, Georgia 30333. 6. Wilson, J. G. Embryotoxicity of Drugs in Man, Wilson, J. G. and F. Clark Fraser. H a n d b o o k o f T e r a t o lo g y , pp. 3 0 9 -3 5 5 ,1 9 7 7 . Plenum Press. 7. Binns, W., L. Balls. Non-Teratogenic Effects of 2.4.5- Trichlorophenoxyacetic Acid and 2,4,5-T Propylene Glycol Butyl Ether Ester Herbicides in Sheep. T e r a t o lo g y 4 (2 ):2 4 5 ,1971. 8. Erne, K,, M. Nordkvist. Toxicity Studies with Phenoxy Herbicides on Reindeer. Svensk Veterinartidning 7:1-3, 1972. 9. Sparschu, G. L. et al. Study of the Effects of High Levels of 2.4.5- Trichlorophenoxyacetic Acid on Foetal Development in the Rat. F o o d a n d C o s m e tic T o x ic o lo g y 9:527-53 0,1971. 10. Emerson, J. L. et al. Teratogenic Studies on 2.4.5- Trichlorophenoxyacetic Acid in the Rat and Rabbit. F o o d . C o s m e tic a n d T o x ic o lo g y 9:395-404,1971. ~" 11. Dougherty, W. H. The the Teratogenic Effects of 2.4.5- Trichlorophenoxliifn^lnetd in the Rhsus Monkey. andE n v ir o n m e n t a l Q u a lit y Safety 5:89-96, 1976. 12. Collins, T. F. X. and Williams, C. H. Teratogenic Studies with 2.4.5- T and 2,4-D in the Hamster. Bulletin of E n v i r o n m e n t a l C o n ta m in a tio n a n d T o x ic o lo g y 6:559-567, 1971. 13. Khera, K. S. and McKinley, W. P. Pre- and Postnatal Studies on 2.4.5- Tricilorophenoxyacetic Acid, 2,4-Dichlorophenoxyacetic Acid and Their Derivatives in Rats. T o x ic o lo g y a n d A p p lie d P h a rm a c o lo g y 22:14-28,1972. 13 14. Scientific Dispute Resolution Conference on 2,4,5-T. 1979. American Farm Bureau Federation, 225 Touhy Avenue, Park Ridge. IL 60068. 15. Morgan, D. P. Personal Communication, Environmental Toxicology Division, Institute of Agricultural Medicine, University of Iowa, Oakdale Campus, Oakdale, Iowa 52319. 16. First Alsea Report to EPA. 1978. 17. Scientific Dispute Resolution Conference on 2,4,5-T Sponsored by The American Farm Bureau Federation, 225 Touhy Avenue, Park Ridge, IL 60068. 18. Lancet. November 24, 1979 page 1115. 19. Tung, T. T. Primary Carcinoma of the Liver in Viet Nam. Chirurgie 99(7):427-436, 1973. 20. Ford, R. E. et al. Mycotoxins -- Environmental Contaminants fn Nature. Illinois Research (Winter Issue), pp. 10-11,1978. 21. Leuschner, F. et al. Chronic Oral Toxicity of 2,4,5-T, Batch No. 503, Control No. 153574b -- Called for Short 2,4,5-T in Sprague-Dawley (51250) Rats. Repeated dosage Over 130 Weeks (With Special Attention to Carcinogenic Properties), April 9. 1979. Laboratorium Fur Pharmakologie und Toxikologie, Francoper Str. 66b D-2104 Hamburg 92 Germany. 22. Kociba, R. J. et al. Results of a Two-Year Chronic Toxicity and Oncogenic Study of Rats Ingesting Diets Containing 2,4,5-Trichlorophenoxyacetic Acid (2,4,5-T). F o o d a n d C o s m e t ic T o x ic o lo g y Vol. 17. pp. 205-221, 1979. 23. Federal Register, Vol. 44 (No. 241), 72324-72327, December 13, 1979. 24. Ott, M. G. et al. A Mortality Analysis of Employees Engaged in the Manufacture of 2,4,5-Trichlorophenoxyacetic Acid. J o u r n a l o f O c c u p a t io n a l M e d ic in e 22:47-50, 1980. 25. Council for Agricultural Science and Technology (CAST). The Phenoxy Herbicides (2nd edition) Report No. 77, August, 1978. 26. Zack, J. A. and R. R. Suskind. The Mortality Experience of Workers Exposed to Tetrachlorodibenzodioxin in a Trichlorophenol Process Accident. J o u r n a l o f O c c u p a tio n a l M e d ic in e 22:11-14, 1980. 27. Homberger, E. et al. The Seveso Accident: Its Nature, Extent and Consequences. A n n a ls O c c u p a tio n a l H y g ie n e . Vol. 22, i O p. 327-368, 1979. ^ 28. Scientific Dispute Resolution Conference on 2,4,5-T Sponsored by The American Farm Bureau Federation, 225 Touhy Avenue, Park Ridge, IL 60068. 14 29. Tuchmann-Dupleisis. H. Pollution of the Environment and Offspring Apropos of the Accident at Seveso. M e d e c in e et H y g ie n e 36:1758-1766. 1978. 30. Herbicide Handbook of the Weed Science Society of America, 4th edition -- 1979. page 421. Weed Science Society of America, 309 W. Clark St., Champaign, Illinois 61820. 31. Murray, F. J. et al. Three-Generation Reproduction Study of Rats Given 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) in the Diet. T o x ic o lo g y a n d A p p lie d P h a r m a c o lo g y 50:241-252, 1979. 32. Kilian, D. J. et al. Cytogenetic Studies of Personnel who Manufacture 2,4,5-T. Presented at New York Academy of Sciences Workshop on Occupational Monitoring and Genetic Hazards, March 28-29,1975. A 33. Young, A. L. et al. The Toxicology, Environmental Fate, and Human Risk of Herbicide Orange and Its Associated Dioxin. Report OEHL TR-78-92. 34. National Academy of Sciences, Washington, D.C. 1974. The Effects of Herbicides in South Vietnam Part A -- Summary and Conclusions. 35. California Department of Food and Agriculture-- News Release #78-48. CDFA Releases Report of Phenoxy Investigation. April 6, 1978. k 36. According to the USDA SCS Survey of 1978. U.S.D.A. Soil Conservation Service, State Office, Temple, Texas. 37. Federal Register. Vol. 44 (No. 241), 72324-72328. December 13, 1979. 38. Kociba, R. J. et al. Results of a two-year Chronic Toxicity and Oncogenicity Study of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin in Rats. T o x ic o lo g y a n d A p p lie d P h a r m a c o lo g y 46:279-303, 1978. .v;rt- 15 LZ i. LZ VO u i nt^ w * *'1 * !* f!S S 5 B S 8 W 8 * T The Development and Prognosis of Chronic Intoxication by Tetrachlordibenzo-p-dioxin inMen j ANA PAZDEROVA-VEJLUPKOVA, M.D. MARCELA NEMCOVA, Ph.D. JANE PICKOVA, Ph.D. LUBOR JIRASEK, Ph.D. Faculty o f General Medicine Charles University Prague, Czechoslovakia EDGAR LUKAs , Ph.D. Institute o f Hygiene and Epidemiology Prague, Czechoslovakia ABSTRACT. During 1965 to 1968, 8 0 workers who had en engaged in the production o f 2, 4 , 5-sodium trichlor- ^nenoxyacetate and butylester o f trichlorphenoxyacetate acid became ill. The cause o f the illness was 2 , 4 , 7 , 8-tetrachlordibenzo-p-dioxin. A 10-yr study has been conducted for 55 exposed individuals. The majority o f the patients developed chloracne, and 11 manifested porphyria cutanea tarda. Approximately one-half o f the patients suffered from metabolic disturbances, ix ., pathologically elevated lipids with abnormalities in the lipoprotein spectrum, and two-fifths o f the patients had pathological changes in the glucose tolerance test. One-third o f the patients had bio chemical deviations indicative o f a mild liver lesion. Histo logical examination revealed light steatosis, or periportal fibrosis, o r activation o f Kupffer cells. Fluorescence o f the liver tissues was present in ultraviolet light. In 17 persons symptoms o f nervous system focal damage existed, with predominance o f peripheral neuron lesion o f the lower extremities (verified by EMG examination). The majority of patients suffered from various psychological disorders. As of this date, two patients have died o f bronchogenic lung carcinoma; one o f liver cirrhosis; one o f a rapidly developed, extremely unusual type o f atherosclerosis precipue cerebri; and two patients have died in traffic acci dents. The conditions o f most other patients have improved. PERHAPS THE most potent map-made toxin presently own is 2 , 3,7,8-tetrachlordibenzo-p-dioxin (TCDD), a January/Febru iry 1981 (Vol. 36, No. 1) solid substance that is insoluble in water and slightly solu ble in fats and chlorinated solvent It is a heat-stable, amphoteric substance, and exerts its biological effects at extremely low concentrations. TCDD is not translocated in plants, and has a half-life in soil of about 1 yr. Microbial degradation o f TC DD is reported to rarely occur in nature. Irradiation o f TC D D in water produces few changes after 14 days.1 Due to its extreme toxicity, its chemistry has not been fully evaluated. There are considerable differences in species susceptibility, but in all laboratory animals the lethal effect is slow and ensues several days or weeks after a single dose.3 TC DD is formed as a by-product during the synthesis o f 2,4,5-trichlorphenol, which involves the hydrolysis o f 1,2,4,5-tetrachlorbenzene using methanol and caustic soda at atmospheric pressure. TC DD is formed in the distillate by the condensation o f two molecules o f sodium trichlorphenolate influenced by the highly exothermic decompo sition o f sodium-2-hydroxyethanol. Trichlorphenoxyacetic acid (2,4,5-T), a herbicide produced commercially prior to 1965, contained 30 mg/kg TCDD. Currently, 2,4,5-T, con taining < 0.05 mg/kg TCDD is produced in several countries and is available in commercial quantities.1 Several accidents have occurred during the industrial synthesis o f 2,4,5-trichlorphenol and 2,4,5-T, the conse quences o f which are well described in the literature.3' 7 The most recent large-scale TCDD intoxication that occurred in Seveso, Italy in 1976 renewed the interest o f specialists and the general public. Since we have acquired considerable information during the 10 years we have observed patients with chronic TCDD intoxication, we have chosen to present our findings in this study. , 6125 S Table 1.--Physiologic, Neurologic, Psychiatric, and Dermatologic Observations for Fifty-Five Males with TCDD Intoxication* Percent of patients (/V = SS) Medical lesions Porphyria cutanea tarda Only uroporphyrinuria Hypercholesterolemia Hyperlipemia Hyperphospholipemia Diabetes mellitus Low glucose tolerance test value Hepatic lesions Increased total blood proteins Increased plasma 7 globulins <Xj globulins Decreased plasma albumin Neurological lesions Pathological changes without any connection with exposure exposure to TCDD Polyneuropathy Encephalopathy Psychiatric changes Severe neurotic symptoms and signs with disorders of vegetative nervous system Neurasthenia syndromes with depressive component Depressive syndromes with endogenous component Pseudeoneurasthenla syndromes in patients with . arteriosclerosis of central nervous system * Skin lesions Chloracne of different severity r* All results were obtained at the beginning of intoxication. 20 21 56 67 42 8 19 20 13 36 44 33 8 23 7 64 11 8 14 9S MATERIALS AND METHODS The Department o f Occupational Diseases University Hospital in Prague admitted 55 males for the first time in 1968 and 1969 suffering from chronic TCDD intoxication, who had been engaged in the production o f sodium 2,4,5trichlorphenoxyacetate and butyl ester of 2,4,5trichlorphenoxyacetate acid. This incidence o f mass intoxi cation occurred during a time when alkaline hydrolysis of tetrachlorbenzene at atmospheric pressure was used to increase and shorten reaction time, and probably during the same time the mother liquor, which was originally dis posed of, was put back into production. The concentration o f TC D D in the work atmosphere was never measured; however, TC DD was found in the final product-Arboricide E -a n d several years later, was also found in the building and on wall paintings. Originally, 80 o f 400 persons who were engaged in this production became ill. Only 55 o f those persons have been 4 observed on a long-term basis; the remaining 25 persons either refused to be examined in our hospital or moved, leaving no address. Those who moved were usually for eigners who returned home. The mean age of the 55 intoxi cated individuals was 36.3 [standard error (SE) = 11.2] at the time the outbreak of illness occurred. We do not pro vide any further details about production conditions and the course o f the illness during the initial 3 to 4 y r in this article, since these were described in our 1 97 4 report;7 therefore, we shall only provide the most important data required for understanding the development o f the illness. RESULTS The first symptoms o f intoxication which occurred at the time o f exposure were: gradual, but rarely sudden, formation o f chloracne; a feeling o f sickness; fatigue; weakness in the lower extremities; and frequently, p a in - under the right coastal arch. In 10 patients, however, the first symptoms o f inioxication appeared several months after work with TCDD was completed. The intoxication affected several organs and systems (Table 1). It should be noted that only the most severely affected patients exhibited all o f the above-listed symptoms, and the extent o f organ damage was not uniform for these patients. The severity o f illness was not related to the duration o f expo sure, job status,i or age. p i p i' 6 Archives o f Environmental Health Table 2.--Came of Death for Six Patients with TCDD Intoxication Age (yr) Duration of Exposure Intoxication Severity of TCDD Intoxication Cause of Death and Post-Mortem Findings 1. 57 9 mo 2yr 2. 59 3. 47 4. 31 3 yr 2. Syr 15 shifts 2 yr 3 yr 4yr S. 63 6. 40 7 mo Syr 32 shifts 9 yr Severe type of TCDD Intoxication. Unusual type of very severe arteriosclerosis of cerebri, liver, pancreas, and kidneys. Dementia cerebri. Immediate cause of death: bronchopneumonia. Severe type of TCDD Intoxication. Bronchogenic carcinoma. Severe type of TCDD intoxication. Bronchogenic carcinoma. Slight signs of TCDD intoxication. Traffic accident--comminuited fractures of lower extremities. Immediate cause of death: fat embolisation to lungs. Severe chloracnc and slight signs of lipid metabolism disorder. Traffic accident--fractura coll femorls. Cause of death: bronchopneumonia hypostatlca. Severe type of TCDD Intoxication; about 3 yr before death; complicated with hepatitis epidemlca, type B. ^, Macronodular cirrhosis with signs of portal ' hypertension, ascites. Cause of death: hepatic coma. The progression o f illness was not linear. In some patients, symptoms and signs o f intoxication that were present from the very beginning o f the illness, became more severe during the 3-4 yr that followed intoxication. In others, however, organs and systems that were functionally normal during the beginning o f illness later became impaired. Deterioration occurred suddenly, the eliciting factors sometimes being intercurrent illness, stress, or unusual physical exertion. In other patients, however, deterioration could not be ascribed to specific factors, but was probably attributable to the spontaneous course o f the illness proper. Deterioration and subsequent improvement did not occur consistently in individual organs and sys tems. During 5 yr o f intoxication, the health status of most patients was stabilized; some patients' status even improved. During this time 6 patients died, the causes of which are listed in Table 2, and 5 refused our systematic medical care. The authors are therefore providing medical care to 44 o f the original 55 patients; all patients' condi tions have improved, but no patient is entirely healthy. Most o f these individuals gradually re-entered the work force, and established themselves in society. During their illness, 18 healthy children were born. The wives o f two patients had spontaneous abortions in their third month ' "egnancy, but the cause is not known because the ^ -ses were not autopsied. i The impact o f the intoxication varies. There are still lanuary/February 1981 (Vol. 36, No. 1 ) pathological deviations in lipid metabolism in most o f the patients. Figure 1 shows mean values o f total cholesterol measured when the illness was first noted and "to-date'' values, both compared with a control group. Figure 2 shows similar results for phospholipid measurements. A t the beginning o f intoxication, lipid values were pathologic in more than one-half o f the patients (mean = 13.85 g/L). Currently, the mean values o f lipids do not significantly differ from controls. Lipoproteins could be examined only in recent years; we found elevated mean values in the pre-beta fraction [V L D L (Fig. 3 )]. In the blood pro tein spectrum, pathologically increased alpha 1 and gamma globulin levels have normalized, but there are still elevated mean values of total blood proteins in comparison to con trols: 7.5404 (SE = 0.5499) against 7.0296 [SE = 0.4462 (/*= .0 1 )]. For all internal examinations we used the Stu dent's t test for statistical evaluation. Currently, one-fifth o f the patients has a pathological diabetic glucose tolerance test and another one-fifth has a pathological flat glucose tolerance test. Pathologically high excretion o f uroporphyrins, together with other signs o f porphyria cutanea tarda, were present at the outset o f intoxication in one-fifth o f the patients. The same fraction had a slightly increased uroporphyrin excretion in urine (to 100A/g/24 hr) without any skin manifestations. Excre tion o f coproporphyrin in urine was, only rarely, substan tially affected; mean values o f delta-aminolevulnic acid in 6127 7 Table 3.--Results of Neurological Examinations for Individuals Exposed to TCDD Onset (W -S5) At Present (N = 44) Normal neurological examination 62% Pathological changes without any connection with exposure to TCDD 1 6% Polyneuropathy 23% Encephalopathy 1% 51% 9% 31% 9% SIG N IFIC A N T DIFFERENCE Fig. 1. Values of cholesterol in serum of patients at the " beginning of intoxication" and "these days" in correlation with "control group." urine were, during the first years o f intoxication, signifi cantly higher than in controls. A t present, pathological excretions o f uroporphyrins and skin manifestations of porphyria cutanea tarda are very rare. Similarly, functional liver tests (i.e., bilirubin, thymol pyruvic transaminase in serum, bromsulphaiein test) are seldom pathological, whereas in the beginning of the illness, one-fifth o f the patients had mild hepatic lesions. Liver necropsy and biopsy showed that even for the most severe formsof intoxication, only slight morphological deviations in terms o f mild steatosis or periportal fibrosis occurred; even when most severely affected patient, who was the first victim o f intoxication, showed only slight activation of Kupffer cells. Only one patient, who died in hepatic coma attribut able to concommitant infectious hepatitis B (HBAG posi tive), displayed large-nodule active cirrhosis with manifes tations o f portal hypertension and ascites. In all decreased patients and for those in whom liver biopsy was performed, liver tissue fluorescence in ultra violet (U V ) light was present, even in cases where repeated examinations revealed normal values of urinary porphyrins. Throughout the entire observation period o f the whole patient group, goal-directed examinations did not indicate any signs o f toxic lesions in the myocardium or kidneys, and hemopoiesis was not affected. There were no patho logical values o f phosphatase alkaline serum and iron in serum, nor ophtalmological impairments that could be attributed to the effect o f TCDD. The results o f repeated neurological examinations are presented in Table 3. During the initial 3-4 yr o f illness, the lesion in the.peripheral neuron o f the lower extremi ties deteriorated, which in most patients, was present from the onset of intoxication. In some cases, polyneu ropathy appeared only during the course o f the illness; in these patients it could^be reliably documented that clinical and electromyographic examinations were normal at the 8 outset of intoxication. In addition, in four patients there was peripheral lesion N V II, which occurred either in con nection with polyneuropathy o f the lower extremities, or was isolated. After 4 yr o f illness, the neurological picture stabilized; three patients even showed improvement. Encephalopathy sometimes develops in persons aged 5065 yr, accompanied by organic psychosyndrome on the basis o f atherosclerosis o f cerebral arteries. Very rarely is ischemic heart disease concurrently present. The patient who presently has the most severe form o f the illness is also afflicted with paroxysms o f temporal epilepsis and # Fig. Z Phosphorus.of lipoids in serum at the "beginning of intoxi cation" and "these days" in correlation with "co n tro l group." 6128 Archives o f Environmental Health processes which still remain disturbed at a time when TC D D , in view o f its short biological half-life o f 21 days, should be eliminated from the organism. There is a con siderable species-specificity in the sensitivity o f laboratory animals to this toxic substance, and the impact on indi vidual organs differs in different species. In monkeys, as in humans, a permanent sign is skin lesions, while hepatic impairment is in the background. The long-term and relatively complex observation o f our patient sample with chronic TC DD intoxication per mits us to express a hypothesis on the nature and prog nosis o f this illness in man. There is no doubt that TC D D was present in the air o f the workshop, and because of the constantly changing technology, its concentration in air was inconstant TCDD caused intoxication which in turn, nonuniformly affected a number o f important organs and systems. The course of the illness was more severe in individuals when the illness started during exposure than when the first symptoms appeared several months after cessation o f this study. Even though most o f the patients did not experience all symptoms and signs o f intoxication, and some patients showed only symptoms and signs in different combina tions, we assume that in this type of intoxication all the systems and organs mentioned in this study were simul taneously affected, although some only slightly. This assumption is supported by several facts. Fluorescence o f liver tissues in U V light, which is a sign o f pathological porphyrin metabolism, was present in all cases o f necropsy and biopsy, i.e., in persons in whom long-term monitoring o f porphyrin excretion in urine and delta-aminolevulinic acid values were constantly within normal limits. Probably a slight subclinica! lesion was present Further evidence was furnished in repeated neurological examinations. Polyneuropathy of the lower extremities was manifest in some patients only in the third or fourth year o f illness; we have definite clinical and electromyographic evidence that the first examinations conducted when the illness commenced were entirely normal. The manifestation of these lesions was promoted by unspecific stress (e.g., greater physical exertion, intercurrent inflammation of upper respiratory pathways, stress situations, etc.), none o f which could, by itself, produce a similar illness. Simi larly, slight hepatic lesions and diabetes mellitus--manifest or latent--appeared in some patients 1 or 2 yr a fter intoxi cation, and were related with some unspecific stress, or sometimes they occurred independently. The alteration o f many metabolic processes and functional disturbances of several organs indicate a high probability that TCDD affects general enzymatic processes that are present and necessary for the activity of more systems. Other than the direct toxic effect of TCDD on nervous tissues, we also assume that indirect intervention may exist, i.e., impaired metabolic processes in lipid and hydro carbon metabolism. The incidence of polyneuropathy was more frequent in patients with manifest or latent diabetes. Changes were also marked in the central nervous system on the basis of atherosclerosis o f cerebral arteries, the development o f which might be enhanced by hypercholes terolemia, hyperlipemia, hyperphospholipemia, and higher pre-beta fraction (VLD L) in the lipoprotein spectrum. Unfortunately, we could not arrange the autopsy o f all deceased patients in a qualified, university surgery where detailed attention could have been given to atherosclerosis. The patient who was the first to die, and who had demon strated the most severe clinical and laboratory signs of intoxication, was thoroughly examined in this respect and autopsy revealed very severe, entirely untypical athero sclerosis. Detailed information is given in our study o f 1974.7 The mass occurrence o f psychic disturbances, pre- dominantly anxiety and depression, was in the first years o f illness mainly due to exogenous influences: fear o f death; disfigurement; invalidity; marital problems; and in young individuals, the difficulty o f entering intimate, close relationships because o f the disfigurement resulting from chloracne. Gradual adjustment to the illness, its improvement (especially on the visible skin area), and return to normal work and social life all contributed to decrease psychic disturbances, thus facilitating better adaptation to life. It does not appear that chronic intoxication in our patients unfavorably affected the quality o f offspring. All o f the 18 children bom to intoxicated individuals were free o f the developmental anomalies; their postnatal development has also been normal. Two spontaneous abortions in 10 (10%) pregnant wives o f our patients is less than the number o f worldwide spontaneous abortions relative to the number o f pregnancies (1 5-20%).2 In recent years the possible carcinogenicity o f TCDD has been widely discussed.1 Even though two o f our patients died o f bronchogenic lung carcinoma after 2 and 3 yr of the intoxication, no definite conclusions can be drawn in view o f the small number o f persons in the group. This illness is characterized by its non-uniformity, both in its developments and its effects on individual organs. Deterioration was always sudden, followed by less gradual improvement. This is a rather cheerless balance o f an ill ness, where the mechanism o f origin and cause o f unusual development we know virtually nothing. Being aware of this poor understanding, we were very careful in our therapy and concentrated on the prevention o f further possible stressful situations that could have aggravated the illness. We attempted to remove all neurotoxic, hepatotoxic, and dermatotoxic substances from the work and living areas. Each patient received a list o f drugs known for their hepato- or neurotoxicity, and those drugs suspected o f producing porphyria cutanea tarda, which he was instructed to avoid. Rarely did we apply medicines to alleviate symp toms which were particularly distressing. The treatment of chloracne is discussed elsewhere by the dermatologist, Jirasek.*' 9 -- In our paper we withed to indicate the importance o f having a thorough understanding and knowledge o f unde sired by-products resulting from synthesis or manufacture o f various products, being alert to changes in technology and to systematically protect the health o f workers. REFERENCES' 1. World Health Organization. 1477. Monographs on the Evalua tion o f the Carcinogenic Risk o f Chemical to M an, Vol. 15, 10 Archives of Environmental Health iiiMfir nxmiiim pp. 41-102. Lyon , France: International Agency for Research on Cancer. 2. Reggianl, G. 1978. Medical problems by the TCDD contamina tion In Scveso, Italy. A rch Toxicol 40: 161-88. 3. Bauer, H.; Schulz, K. H.; and Spiclgerg, V. 1961. Occupational intoxication during the production of chlor-phenol compounds. . Arch Gewerbepath Gewerbehyg (In German). 18: 538-5S. 4 Goldmann, P. J. 1972. The most severe acute chloracne: Mass intoxication by 2,3,7,8 TCOO. International Symposium of factory doctors In chemical Industry (In German). Medlchem. 5. Combos, 8.; Pechnovi, A.; Koziak, B.; Moscovlovi, E. 1969. Porphyria cutanea tarda and chloracne during the production of chlorinated carbohydrates. Brat Lek U s t (in Slov.). SI: 640-45. 6. May, G. 1973. Chloracne from the accidental production of tetrachlordlbenzodioxin. B r ] In d Med 30: 276-83. 7. Pazderova, ).; Lukas, E.; Nemcova, M.; Spacllova, M.; Jlrisek, L ; Kalensk, J.; John, J.; Jirasck, A.; and pfekova, J. 1974. Chronic Intoxication by chlorinated hydrocarbons, formed In the production of 2,4,5 sodium trichlorphcnoxyacetate. Pracov Lek (In Czech.). 26: 332-39. 8. Jirisek, L ; Kalensk, J.; Kubec, K.; Pazderovi, J.; Luki, E. 1976. Chloracne, porphyria cutanea tarda and other signs of Intoxication by herbicides. Houtarzt (In German). 27: 328-33. 9. Jirisek, L.; Kalensk, J.; Kubec, K. 1973. Acne chlorine and - porphyria cutanea tarda by the production of herbicides. ( 3 Dermat (In Czech.) 48: 306-17. f * * * * * * Submitted for publication February 29, 1980; revised;.accepted for publication April 24, 1980. Requests for reprints should be sent to: Jana PazderoviVeJIupkovi, M.O., Ph.D., Kllnlka nemocf z povolini, Prague 2, 12821, Vysehradski 49 Czechoslovakia. Tetrachloroazobenzene in 3,4-DichIoroaniline and Its Herbicidal Derivatives: Propanil, Diuron, Liiiuron, and Neburon ROBERT H. H IL L , JR., Ph.D. ZELDA J. ROLLEN, B.S. RENATE D. KIMBROUGH, M.D. DONALD F. GROCE, B.S. LA RR Y L. NEEDHAM , Ph.D. Center for Disease Control Public Health Service U.S. Department o f Health and Human Services Atlanta, Georgia ABSTRACT. The presence o f 3 ,3 ' ,4 ,4 ' -tetrachloroazoben zene (TCAB) was determined by high performance liquid chromatography in 3, 4-dichloroaniline and herbicides made therefrom. The concentrations o f TCAB in 3, 4-dichloroanilines and in different herbicides from a variety o f manufacturers ranged from 9 to 1400 pg/g (ppm). The chloracncgenic potential o f these products, as determined Jy rabbit ear test, suggests th a t.it is in the same range of 2, 3, 7, 8-tetrachlorodibenzodioxin, a known potent chloracnegenic agent. January/February 1981 (Vol. 36, No. 1) RECENTLY, some outbreaks o f chloracne in groups o f chemical workers have been attributed to 3,3',4,4tetrachloroazobenzene (TCAB) and 3,3',4,4-tctrachloroazoxybenzene (TCAOB) as contaminants in 3,4* dichloroaniline and its herbicidal drivatives.1'2 These contaminants are by-products of the commercial syn thetic process.3 In addition, several workers have reported that the herbicides degrade in soil to produce TCAB and TCAOB.4 Chlorinated azobenzenes are structurally simi lar (isostcric) to the chlorirtated dibenzodioxins and dibenzofurins, which also cause chloracne. Poland has reported that chlorinated dibenzofurans, dibenzodioxins, - 6 1 3 1 . 11 2<? 2? 6132 PROCEDURE FOR DETERMINATION OF MOHO-,DI-,TRI-, AND TETRACHLORO DIBENZO-P-DIOXINS IN 2,4-D ESTERS Reagents: 1. Silica gel 60 (E. Merke) 70-230 mesh activated overnight at 125C. 2. Alumina Basic (Woelm AI2O3 Activity I) 3. Anhydrous NaS04. Procedure: \ __ Oc.y, * 3 - 0 tny 1. Prepare a silica gel column using a glass column ^ cm x 1*5 cm I.D. fitted with a teflon stopcock. Add 50 nL. hexane to the column. With, a glass rod, pack the bottom of the column with a plug of glass wool. Top the plug with Ottawa sand to about 1 cm. Weigh 50.0 g. of activated silica gel, make a slurry of silica gel in hexane using about half of it, and pour into column with solvent flowing at a very slow rate. Slurry the remaining silica and pour it in. Allow the column to settle and the solvent to fall to just above the level. Wash down the gel from the sides of the glass column. Top off the silica gel with about 1.0 cm of anhydrous sodium sulphate. Allow the level of solvent to fall just below the sodium sulphate. 2. Weigh 2.0 g. of ester sample and" transfer onto silica gel column by using 5-10 mL. of 30% CH2Cl2/hexane. 3. Allow the level of the sample to fall below the top of the Na2S0/} layer. Elute using 150 mL. of 30% CH?Cl2/hexane. Discard first 30 mLs. Collect the remaining eluate into a 250 mL. R.B. flask. Concentrate the eluate to 1-2 mL. under reduced pressure on a rotavapor. 5. Prepare a basic alumina column (Woelm basic Alumina Activity I as is) using a glass column 25 cm x 1.5 cm I.D. fitted with a teflon stopcock. Pour about 10 mL. hexane into the column. Using a glass rod, pack a small glass wool plug at the bottom of the column making sure all air bubbles are removed. Pour Ottav/a Sand Standard sand to about 0.5 cm height on top of glass wool. Fill column to just below full. Pour 15 g. of alumina slowly into column while allowing solvent to slowly run out so that a well-packed, uniform bed of alumina is made. Wash down the column wall to remove adhering particles. With solvent a few cms above the top of the alumina, pour anhydrous sodium sulfate to a height of 0.5 cm on alumina.Wash wall,and allow solvent to just ' fall below the top of the sulfate layer, > 6 . Transfer residue from concentration step quantitatively onto the basic alumina,f column with 3 x 2 mL. hexane washings o f flaskl 1 6133 -2- 7. Elute the column with (1) 100 mL. hexane (2) 100 mL. 2 CH2CI2/ hexane (3) 100 mL. 5% CH2Cl?/hexane (4) 100 mL. 10% CH2Cl2/hexane (5) 50 mL. 30% CM2Cl2/hexane Discard 1 and 2 and collect fractions 3, 4 and 5 in a 500 mL. R.B. flask. 8 . Concentrate the fraction to 1-2 mL. under reduced pressure on a rotavapor. 9. Quantitatively transfer the residue to a 5 nL. graduated centrifuge tube with 3 x 1 mL. wash with benzene. Take the residue to dryness under a gentle stream of nitrogen with wanning in a water bath. 10. Make the residue to 0.100 mL. with hexane for GC/MS analysis. Mass Spectrometry Laboratory, Laboratory Services Division, Food Production and Inspection Branch, Agriculture Canada. May ,1981. > 218112 77.2-1 252 J 1-MONOCHLORDIOXtN 149 173 195 216 250 274 r p w .,r7l 1II"" I I i"""f ` I -T " I----- , 'i --r --I-- "T 1 DIOXIN STAN DARDS b^ /. COLUMN: 25M FUSED SILICA COATED WITH SP2100: 225 DEG; PRESSURE 20 PSt. 213.000 i 0.50C 294 311 345 t-- r-.r T 377 395 414 431 -- t-- 1--- .-- 1-- r i r 654. in co 2,7-DICHLORODIOXIN 252.000 0.500 111 *' 17.0 1 134 149 168 288- 201 227 251 277 305 324 340 366 390 403 435 r*----- 1-- ------- 1-- i 144. 1.2.4-TRICHLORODIOXIN 288.000 1 0.500 i 108 122 137 1 9.1-I 15? *. 178 196 222 235 mmI a"r''aI 1 V 261 322- 236 313 338 351 377 1.2.3.4.- TET'ACHLOilODI. 294 308 336 412 407 A 432 '7. 322.000 0.500 419 32.7-1 1124. R IC --I r 100 1:40 I I 150 2:30 I-'"1I I--- r I j ' i r 200 3:20 250 4:10 407 440 n -- r 450 S C A N 7:30 TIME ^9 N- & P.1 3 7 QO CO rH CO Fiq: Chromatograms showing separation of four tetrachlorodiox!~ isomers on (A) 1m x 2mm 3% SE-30 ultraphase packed column and U .25m SP2100 66.7 n 33.3 - Comparison of the low resolution mass-spectra of two trichlorodioxins with 3:0 (1,3,4-) and 3:1 (1,3,7-) rinq chlorine substitution. SPECT.RUM OF 1,2,4,--TR IC H L O R O D IO X IN 288. r 28373. do co V*H CO 160 144 108 ! ? 5 ltil^ .J i . I ^ p h p V L|UT . y .4 J4. Lb ;.'E <4 4-C 100 150 X97 1^9 233 T * 1"i" 1' |`r"T 1 'i > r T | 1 I ' I ' 1 ' . 200 250 300 1 . 1 :1 IT -1 i i tI 30. 0~! SPECTRUM OF 1,3,7-TRICHLORODJOXIN 3.0-1 12560. dioxin from a 2 4 -D 1so - o c t y 1 e s t e r sample to g e th e r w i t h accurate mass measurements on m/z 3?0, 332 and 324 i o n s . 103.0 n SAMPLE:* >240 ESTER - </S> DATA: 0K RB #36 `C A L I : U 0 H R B #36 BASE M/E: 322 RIC: 26336. 321.9 ELEMENTAL COMPOSITION 20/08/80 15:54:00 + 8:46 SAMPLE: 24D ESTER - </S) MIN INTEN: 40. DATA: 110HRB 36 CALI: 110HRB 1i 36 DEE: 0 M M U / 100 AMU 3ASE M/E: 322 RIC: 24704. 2516 o v=H CD MIN 310 MAX 327 MASS 0. 00 7. R A 40. 0 INTEN. 5. 0 02 1. 0 4 9. 0 C200. K400. C+, 02. CL4 MMU PPM BONDS FORMULA 319. 8966 81. 72 2056. 0. 0 n 7.. 0 C 12. H4. 02. C L 4 / 0 320. 9 0 0 8 7. 71 194. 0. 8 3 9. 0 Cl 1/l. H4. 02. C L 4 / 0 321. 8 9 3 2 100. 00 2516. -0. 4 1 3. 5 C 12. H4. 02. CL 3/1 322. 8964 12. 20 307. -0. 5 2 8. 5 Cll/1. H4. 02. CL3/1 323. 8 9 0 5 40. 66 1023. -0 1 0 3. 0 C 12. H 4 .02. C L 2 / 2 324. 8931 3 30 03. -0. 9 s J 3 0 C 1 1/l. H4. 02. C L 2 / 2 325.0082 6. 92 174. 0. 5 4 . 1 75 C 12 H4. 02. C L 1 / 3 c4 < i!11 !I Il r 1III LIl 256. 9310 350. 9 2 9 8 2*0. 9260 27. 25 15. 43 4 61 544. 308. 92 - 1.F -0 0 -0 0 if* CO '-1 Cl 1. H4. . CL 3/0 0 3 3. 0 t Z 1 1 H4. 0. CL2/1 0 1 1 H4. . CL. 1/2 r V 200 6141 Zi 6142 ili iif United States Environmental Protection Agency E1-^-540/9-80-005 January 1982 Recognition and Management of Pesticide Poisonings Third Edition 6143 RECOGNITION AND MANAGEMENT OF PESTICIDE POISONINGS Donald P. Morgan, M.D., Ph.D.* Support for this publication was provided by the National Pesticide Hazard Assessment Program, Health Effects Branch, Hazard Evaluation Division, Office of Pesticide Programs, U.S. Environmental Protection Agency, Wash ington, D.C. 20460. *low a Pesticide Hazard Assessment Project, located at University of Iowa Medical School, Iowa City, Iowa 52240. Third Edition For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, D.C. 20402 T h is printing not done at Governm ent expense 6144 Contents Page INTRODUCTION.......... .................................................. v CHAPTER 1--ORGANOPHOSPHATE CHOLINESTERASE-INHIBITING PESTICIDES........................................ 1 CHAPTER 2--CARBAMATE CHOLINESTERASEINHIBITING PESTICIDES.................. 9 CHAPTER 3--SOLID ORGANOCHLORINE PESTICIDES......................................... 14 CHAPTER 4-- PENTACHLOROPHENOL................ 19 CHAPTER 5-- NITROPHENOLIC AND NITROCRESOLIC HERBICIDES . . . . 23 CHAPTER 6--CHLOROPHENOXYCOMPOUNDS.. 27 CHAPTER 7-- PARAQUAT AND D IQ U A T................ 31 CHAPTER 8-- DITHIOCARBAMATES AND THIOCARBAMATES.......................... 36 CHAPTER 9-- PYRETHRUM, PYRETHRINS, PYRETHROIDS AND PIPERONYL B U T O X ID E .......................................... 42 CHAPTER 10--ARSENICAL PESTICIDES ................ 46 CHAPTER 11-- RODENTICIDES ................................ 54 CHAPTER 12-- FUM IG A NTS....................................... 68 CHAPTER 13-- MISCELLANEOUS PESTICIDES OF HIGH TOXICITY.................................. 77 CHAPTER 14-- MISCELLANEOUS PESTICIDES OF LOW OR MODERATE TOXICITY . . . . 82 INDEX TO PESTICIDE POISONINGS BY SYMPTOMS AND SIGNS.............................................. 88 PESTICIDE IN D E X ......................................................... 94 111 6145 INTRODUCTION This manual is designed to help professionals responsible for the health of persons exposed to pesticides to recognize and treat properly poisonings by these substances. This third edition discusses many more compounds than were dealt with in previous editions, and it updates particular management methods according to recently published clinical literature. No text or manual on so complex a topic can presume to take the place of good clinical judgment. But it is unrealistic to expect health professionals con fronted with a pesticide poisoning emergency to assemble quickly the many details of toxicology, diagnosis, and treatment that are essential to optimal management. This manual provides such information in a concise format. A deliberate effort has been made to suggest treatment that can be imple mented (or at least initiated) in small hospitals and clinics where victims of pesticide poisonings are likely to be received. At the expense of some repeti tion, details of treatment have been spelled out sequentially for the common classes of chemical poisonings. The author is deeply indebted to the following reviewers who have con tributed generously to this edition: S. H. Sandifer, M.D., Professor Director, Division of Preventive Medicine Department of Family Practice College of Medicine Medical University of South Carolina Charleston, South Carolina 29403 J. R. Reigart, M.D., Assoc. Professor Department of Pediatrics College o f Medicine Medical University of South Carolina Charleston, South Carolina 29403 Harold E. Trammel, Pharm.D., Assoc. Prof. Director of Poison Information Center College o f Pharmacy Medical University of South Carolina Charleston, South Carolina .) Arthur D. Nelson, M.D. Director Scottsdale Memorial Hospital Scottsdale, Arizona John E. Davies, M.D., M .P.H. Professor and Chairman Department o f Epidemiology and Public Health University of Miami School o f Medicine Jon E. Ford, Ph.D. Environmental Toxicologist Chevron Environmental Health Center Standard Oil Company of California Victor B. Beat, D.V.M., of the Iowa Pesticide Hazard Assessment Project compiled the many proprietary names of the products listed in the manual. Mrs. Pamela Mason and Ms. Diane Cornwall of the Iowa Project have pa tiently typed the manuscript drafts. Ms. Martha Finan of the Information Support Services Branch, Manage ment Support Division, Office of Pesticides and Toxic Substances of the United States Environmental Protection Agency has skillfully edited the manuscript. Staff of the Health Effects Branch, Hazard Evaluation Division of the Office of Pesticides and Toxic Substances, United States Environmental Protection Agency, have prepared the index and attended to the details of publication. en i--* en Chapter 1 ORGANOPHOSPHATE CHOLINESTERASE-INHIBITING PESTICIDES GENERAL CHEMICAL STRUCTURE C2H50 or CH3O \ C2H5O o rC H 30 P ^ ^ S (or O O) GLERAOVUIPNG COMMON COMMERCIAL PESTICIDE PRODUCTS* H ighly toxic: tetraethyl pyrophosphate (TEPP), phorate (Thimet), disulfotonf (Di-Syston), fensulfothion (Dasanit), demetonf (Systox), terbufos (Counter), mevinphos (Phosdrin), methidathion (Supracide), chlormephos (Dotan, MC2188), sulfotepp (Bladafum, Dithione), chlorthiophos (Celathion), monocrotophos (Azodrin), fonofos (Dyfonate), prothoate (Fac), fenamiphos (Nemacur), phosfolan (Cyolane), methyl parathion (Dalf, Penncap-M), schradan (OMPA), chlorfenvinphos (Birlane), ethyl parathion (Parathion, thiophos), azinphos-methyl (Guthion), phosphamidon (Dimecron), methamidophos (Monitor), dicrotophos (Bidrin), isofenphos (Amaze, Oftanol), bomyl (Swat), carbophenothion (Trithion), EPN, famphur, (Warbex, Bo-Ana, Famfos), fenophosphon (Agritox, trichloronate), dialifor (Torak), cyanofenphos (Surecide). M oderately toxic: bromophos-ethyl (Nexagan), leptophos (Phosvel), dichlorvos (DDVP, Vapona), coumaphos (Co-Ral), ethoprop (Mocap), quinalphos (Bayrusil), triazophos (Hostathion), demeton-methylf (Metasystox), propetamphos (Safrotin), chlorpyrifos (Lorsban, Dursban), sulprofos (Bolstar), dioxathion (Delnav), isoxathion (Karphos), phosalone (Zolone), thiometon (Ekatin), heptenophos (Hostaquick), crotoxyphos (Ciodrin), cythioate (Proban), phencapton (G28029), DEF (De-Green, E-Zoff D), ethion, dimethoate (Cygon, De-Fend), fenthion (Baytex, Entex, Tiguvon, Spotton, Lysoff), dichlofenthion (Mobilawn), EPBP (S-Seven), * These are listed approximately in order of descending toxicity. "Highly toxic" organophosphates have listed oral LD,0 values (rat) less than 50 mg/kg; "moderately toxic" agents have LD50 values in excess of 50 mg/kg. t These organophosphates are systemic; i.e., they are taken up by the plant and translocated into foliage and sometimes into the fruit. 1 diazinon (Spectracide), phosmet (Imidan, Prolate), formothion (Anthio), pro- fenofos (Cun 1), naled (Dibrom), phenthoate, trichlorfon (Dylox.Dipterex, Neguvon), pyrazophos (Afugan, Curamil), fenitrothion (Agrothion, Sumithion), cyanophos (Cyanox), pyridaphenthion (Ofunack), propylthiopyrophosphate (Aspon), acephate (Orthene), merphos (Folex), malathion (Cythion), etrimfos (Ekamet), phoxim (Baythion), pirimiphosmethyl (Actellic), iodofenphos (Nuvanol-N), bromophos (Nexion), tetrachlorvinphos (Gardona, Rabon), temephos (Abate, Abathion). TOXICOLOGY Organophosphates poison insects and mammals primarily by phosphoryla tion of the acetylcholinesterase enzyme at nerve endings. The enzyme is critical to normal transmission of nerve impulses from nerve fibers to innervated tissues. Some critical proportion of the tissue enzyme mass must be inactivated by phosphorylation before symptoms and signs of poisoning are manifest. At sufficient dosage, loss of enzyme function allows accumulation of acetylcholine (the impulse-transmitter substance) at cholinergic neuroeffector junctions (muscarinic effects), and at skeletal myoneural junctions and in autonomic ganglia (nicotinic effects). Organophosphates also impair nerve im pulse transmission in the brain, causing disturbances in sensorium, motor function, behavior, and respiratory drive. Depression of respiration is the usual cause of death in organophosphate poisoning. Recovery depends ulti mately on generation of new enzyme. Organophosphates are efficiently absorbed by inhalation, ingestion, and skin penetration. To a degree, toxicity depends on the rate at which specific organophosphates are metabolized in the body (principally by hydrolysis in the liver), thus limiting the amount of pesticide available to attack acetylcholinesterase enzyme in other tissues. Many organophosphates readily undergo conversion from -thions to -oxons (replacement of sulfur by oxygen). In general, -oxons are much more toxic than -thions. This conversion occurs in the environment under the influence of sunlight and in the body, mainly by the action of liver microsomes. Ultimate ly, both -oxons and -thions are inactivated by hydrolysis at the ester linkage, yielding alkyl phosphates and phenols which are readily excreted. The hydrolysis products present little toxic hazard. One to two days after organophosphate absorption, depending on the specific organophosphate, some phosphorylated acetylcholinesterase enzyme can be de-phosphorylated (reactivated) by certain oxime antidotes. After this interval, the nature of the enzyme-phosphoryl bond changes, rendering the enzyme inactivation irreversible. New enzyme must then be generated. Very rarely, organophosphate pesticides have produced a different type of neurotoxicity, consisting of damage to the myelin substance of peripheral CJ}nerves. This leads to a protracted peripheral neuropathy, characterized by numbness, pain, and weakness in the extremities, which persists for months or >^years. Organophosphates associated with these chronic illnesses have included some whose acute toxic potential is low; i.e., there appears be no relation ship between acute toxicity and the likelihood of a chronic n jpathic effect. Particularly suspect as neurotoxic agents of this type are the phenylphosphonothioate series, cyanofenphos, EPN, leptophos, and EPBP. Other unusual properties of specific organophosphates may render them more hazardous than basic toxicity data suggest. By-products can develop in long-stored malathion which strongly inhibit the hepatic enzymes operative in malathion catabolism, thus enhancing its toxicity. Certain organophosphates are exceptionally prone to storage in fat tissue, prolonging the need for an tidote when stored pesticide is released back into the circulation. It is possible that other unrecognized factors modify the toxicity of organophosphates. FREQUENT SYMPTOMS AND SIGNS OF POISONING Symptoms of acute poisoning develop during exposure or within 12 hours (usually within four hours) of contact. HEADACHE, DIZZINESS, WEAK NESS, INCOORDINATION, MUSCLE TWITCHING, TREMOR, NAUSEA, ABDOMINAL CRAMPS, DIARRHEA, and SWEATING are common early symptoms. Blurred or dark vision, confusion, tightness in the chest, wheezing, productive cough, and PULMONARY EDEMA may occur. Incontinence, un consciousness and convulsions indicate very severe poisoning. SLOW HEARTBEAT, salivation, and tearing are common. TOXIC PSYCHOSIS, with manic or bizarre behavior, has led to misdiagnosis of acute alcoholism. Slowing of the heartbeat may rarely progress to complete sinus arrest. RESPI RATORY DEPRESSION may be fatal. Continuing daily absorption of organophosphate at intermediate dosage may cause an INFLUENZA-LIKE ILLNESS characterized by weakness, anorexia, and malaise. The very few individuals who have suffered peripheral neuropathy follow ing organophosphate exposure exhibited diverse clinical courses. Onset of symptoms was generally slow, sometimes after an asymptomatic interval of several days following exposure. Principal symptoms have been numbness, tingling, pain and weakness of the arms and legs. Some recovered fully in a few weeks; a few others experienced muscle atrophy, leaving a degree of paresis and sensory loss. CONFIRMATION OF DIAGNOSIS CAUTION: If there are strong clinical indications of organophosphate poisoning, treat patient immediately. DO NOT WAIT for laboratory confirmation. Depressions of plasma pseudocholinesterase and/or RBC acetylcholinester ase enzyme activities are the most satisfactory and generally available bio chemical indices of excessive organophosphate absorption. A minimum amount of organophosphate must be absorbed to depress blood cholinesterase activities, but activities are lowered by dosage considerably less than are re quired to CcwSe symptomatic poisoning. The enzyme depression is usually ap parent immediately after, or within 12-24 hours of, significant absorption of organophosptr Depression of the plasma enzyme generally persists several days to a few eks; the RBC enzyme activity usually remains depressed longer, sometimes 1-3 months. Table 1 lists APPROXIMATE LOWER LIMITS OF NORMAL FOR PLASMA and RBC CHOLINESTERASE AC TIVITIES of human blood, measured by generally available methods. LOWER LEVELS usually indicate excessive absorption of a cholinesteraseinhibiting chemical. Whenever possible, comparison of the test sample with a pre-exposure value offers the best confirmation of organophosphate absorp tion: a depression of 25Vo or more is strong evidence of excessive absorption. In certain conditions, the activities of plasma and RBC cholinesterase are depressed in the absence of chemical inhibition. About 3% of individuals have a genetically determined low level of plasma cholinesterase. These persons are particularly vulnerable to the action of cholinesterase-inhibiting pesticides and to the drug succinylcholine, often administered to surgical patients. Patients with advanced liver disease, malnutrition, chronic alcoholism and dermatomyositis exhibit low plasma cholinesterase activities. A number of toxicants, notably carbon disulfide, benzalkonium salts, organic mercury compounds, ciguatoxins, and solanines may reduce plasma pseudocholinesterase activity. The RBC acetylcholinesterase is less likely than the plasma enzyme to be af fected by factors other than organophosphates. It is reduced, however, in cer tain conditions that damage the red cell membrane, such as hemolytic anemias. The alkyl phosphates and phenols to which organophosphates are hydro lyzed in the body can often be detected in the urine during pesticide absorption and up to 48 hours thereafter. These analyses are useful in identifying the ac tual pesticide to which workers have been exposed. Alkyl phosphate and phenol analyses can demonstrate organophosphate absorption at lower dosages than those required to depress cholinesterase activities. Detection of intact organophosphates in the blood is usually not possible ex cept after extreme exposures, such as ingestions of pesticide. Few organophos phates remain unhydrolyzed in the blood more than a few minutes or hours, unless the quantity absorbed is extraordinary or the hydrolyzing liver enzymes are inhibited. TREATMENT CAUTION: Persons attending the victim should avoid direct contact with heavily contaminated clothing and vomitus. Wear rubber gloves while washing pesticide from skin and hair. 1. Establish CLEAR AIRWAY by aspiration of secretions. Administer ^ OXYGEN by mechanically assisted pulmonary ventilation. Improve I . tissue oxygenation as much as possible before administering atropine to minimize the risk of ventricular fibrillation. (0 Administer ATROPINE SULFATE intravenously, or intramuscularly, if IV injection is not possible. Atropine protects the muscarinic end-organs from excessive concentrations of acetylcholine. It does not reactivate the 4 TABLE 1. Approximate Lower Limits o f Normal Plasm id Red Cell C h o lin e s te r a s e A c t i v i t i e s iin H u m a n s * METHOD A pH (Michel) pH Stat (Nabb- Whitfield) ChE-tel (Pfizer) A ChE-tel (Pfizer) BMC Reagent Set (Ellman-Boehringer) 1-Test Cholinesterase (EM Diagnostics) Acholest Test Paper Dupont ACA Garry-Routh (Micro) Merckotest GLC Method (Cranmer) Technicon WHOLE PLASMA RBC BLOOD 0.45 0.55 2.3 8 .0 40 210 1875 3.6 3000 >20 <8 Male 7.8 Female 5.8 3.0 2.1 8.2 2.0 8.0 UNITS A pH per hr per ml mM per min per ml ChE-tel units A ChE-tel units mU per min per ml Units per ml Minutes Units per ml mM-SH per 3 min per ml Units per ml mM per min per ml mM per min per ml * Because measurement technique varies among laboratories, more accurate estimates of minimum normal values are usually provided by individual laboratories. cholinesterase enzyme. Recrudescence of poisoning may occur if tissue concentrations of organophosphate remain high when the effect of atropine wears off. Atropine is the ideal antidote for muscarinic manifes tations; it is ineffective against nicotinic actions: muscle weakness and twitching, and respiratory depression. In MODERATELY SEVERE poisoning: Adult dosage, including children over 12 years: 0.4-2.0 mg repeated every 15 minutes until atropinization is achieved: tachycardia (pulse of 140 per minute), flushing, dry mouth, dilated pupils. Maintain atropinization by repeated doses for 2-12 hours or longer depending on severity of poison ing. Rles in the lung bases indicate inadequate atropinization. Miosis, nausea, bradycardia, and other cholinergic manifestations are also in dicative. Dosage for children under 12 years: 0.05 mg/kg body weight, repeated every 15 minutes until atropinization is achieved. Maintain atropinization with repeated dosage of 0.02-0.05 mg/kg. SEVERELY POISONED individuals may exhibit remarkable tolerance to atropine; two or more times the dosages suggested above may be 5 needed. Persons not poisoned or only slightly poisoned, however, may develop is o f atropine toxicity from such large dosages: F E V E R , muscle fu dilations, and delirium are the m ain signs o f atropine toxicity. I f these signs appear w hile the patient is fu lly atropinized, atropine adm inistration should be discontinued, at least tem porarily. 3. Draw a BLOOD SAMPLE for PLASMA and RBC CHOLINESTERASE analysis. 4. Administer PRALIDOXIME (Protopam-Ayerst, 2-PAM) in cases of severe poisoning by organophosphate pesticides in which respiratory depression, muscle weakness and twitchings are severe. When adminis tered early (usually less than 36 hours after poisoning) pralidoxime relieves the nicotinic effects of poisoning. Note: Pralidoxime is of questionable value in poisonings by the cholin esterase-inhibiting carbamate compounds. (See Chapter 2). A dult dosage (including children over 12 years): 1.0 gm intravenously at n o m o re than 0.5 gm per minute. C hild's dose (under 12 years): 20-50 mg/kg (depending on severity of poisoning) intravenously, injecting n o m o re than half the total dose per minute. Dosage of pralidoxime may be repeated in 1-2 hours, then at 10-12 hour intervals if needed. In very severe poisonings, dosage rates may be doubled. Note: s l o w a d m in is tr a tio n o f p r a lid o x im e is s tr o n g ly r e c o m m e n d e d , and may be achieved by administering the total dose in 250 ml 5% glucose solution over 30-60 minutes. If intravenous injection is not possible, pralidoxime may be given by deep intramuscular injection. CAUTION: Be prepared to assist pulmonary ventilation mechanically if respiration is depressed during and after pralidoxime in jection. 5. OBSERVE PATIENT CLOSELY for a t le a st 24 hours to insure that symptoms (sweating, visual disturbances, vomiting, diarrhea, chest and abdominal distress and sometimes PULMONARY EDEMA) do not recur as atropinization wears off. In very severe poisonings by ingested organophosphates, particularly the more lipophilic and slowly hydro lyzed compounds, metabolic disposition of toxicant may require as many as 5-10 days, during which atropinization must be maintained. Rising levels of blood cholinesterase activity are a useful signal that atropine dosage can be tapered off by lengthening the intervals between doses. As dosage is reduced, the lung bases should be checked frequently for rles. If rles are heard, or if there is a return of miosis, bradycardia, sweating or other cholinergic signs, atropinization must be re-established promptly. 6 . BATHE and SHAMPOO victim with soap and water if there is any chance that SKIN and HAIR are contaminated. 6 6149 7. IF PESTICIDE HAS BEEN INGESTED in quantity sufficient to cause poisoning, empty the stomach and intestine. A. IF victim is ALERT and respiration is not depressed, give SYRUP OF IPECAC, followed by 1-2 glasses of water to induce vomiting. Adults (12 years and over): 30 ml; children under 12 years: IS ml. CAUTION: OBSERVE victim closely AFTER administering IPECAC. If consciousness level declines, or if vomit ing has not occurred in 15 minutes, proceed immedi ately to INTUBATE the stomach. Following emesis, have victim drink a suspension of 30-50 gm ACTIVATED CHARCOAL in 3-4 ounces of water to limit absorp tion of toxicant remaining in the gut. B. IF victim is OBTUNDED or respiration is depressed, empty stomach by INTUBATION, ASPIRATION, and LAVAGE, using isotonic saline or 5% sodium bicarbonate. Because many pesticides are dissolved in petroleum distillates, emesis and intubation of the stomach involve a serious risk that solvent will be aspirated, leading to chemical pneumonitis. For this reason: (a) . If victim is unconscious or obtunded and facilities are at hand, insert ENDOTRACHEAL TUBE (cuffed, if available) prior to gastric intubation. (b) . Keep victim's HEAD BELOW LEVEL OF STOMACH dur ing in tu b a tio n a n d lavage (Trendelenburg, or left lateral decubitus, with head of table tipped downward). Keep victim's head turned to left. (c) . ASPIRATE PHARYNX as regularly as possible to remove gagged or vomited stomach contents. After aspiration of gastric contents and washing of stomach, instill 30-50 gm of ACTIVATED CHARCOAL in 3-4 ounces of water through stomach tube to limit absorption of remain ing toxicant. C. SAVE A SAMPLE of emesis, or the initial gastric washings, for chemical analysis. D. If bowel movement has not occurred in 4 hours, and if patient is fully conscious, give SODIUM SULFATE, 0.25 gm/kg, in 1-6 ounces water, as a cathartic. Magnesium sulfate and citrate are equally suitable at similar dosage if renal function is adequate. Re tained magnesium may depress CNS function. 8 . DO NOT give morphine, aminophylline, phenothiazines, reserpine, furosemide, or ethacrynic acid in poisonings by organophosphates. 9. Give adrenergic amines ONLY if there is a specific indication, such as marked hypotension. 7 10. Rarely, in severe organophosphate poisonings, CONVULSIONS occur which a nresponsive to atropine and pralidoxim e. Insure that causes unrelateu -<j pesticide toxicity are not responsible: head trauma, cerebral anoxia, or mixed poisoning. DIAZEPAM (Valium), 5-10 mg for adults, 0.1 mg/kg for children under 6 years or 23 kg is probably the safest and most reliable anticonvulsant to use under these circumstances. Give SLOWLY (no more than half the total dose per minute) intravenously. Severe protracted convulsions may require additional medication, as sug gested in the chapter on S o lid O rg a n o c h lo rin e P e stic id e s. CAUTION: Be prepared to assist pulmonary ventilation mechanically if respiration is depressed; to intubate the trachea, if laryngospasm occurs; and to counteract hypotensive reac tions. 11. Persons who have been clinically poisoned by organophosphate pesticides should not be re-exposed to cholinesterase-inhibiting chemicals until symptoms and signs have resolved completely and blood cholines terase activities have returned to at least 80 percent of pre-poisoning levels. If blood cholinesterase was not measured prior to poisoning, blood enzyme activities should reach at least minimum normal levels (Table 1) before the patient is returned to a pesticide-contaminated envi ronment. 12. DO NOT administer atropine or pralidoxime prophylactically to workers exposed to organophosphate pesticides. It is neither practical nor medically sound to do so. 6150 8 Chapter 2 CARBAMATE CHOLINESTERASE-INHIBITING PESTICIDES GENERAL CHEMICAL STRUCTURE H30 o LEAVING GROUP COMMON COMMERCIAL PESTICIDE PRODUCTS* Highly toxic**: aldicarbt (Temik), oxamyl (Vydate), carbofuran (Furadan), methomyl (Lannate, Nudrin), formetanate HC1 (Carzol, Dicarzol), aminocarb (Matacil), dimetilan (Snip Fly Bands). Moderately toxic***: promecarb (Carbamult), methiocarb (Mesurol, Draza), propoxur (Baygon), pirimicarb (Pirimor, Aphox, Rapid), bufencarb (Bux), carbaryl (Sevin). TOXICOLOGY Insecticides of this class cause reversible carbamylation of acetylcholinester ase enzyme, allowing accumulation of acetylcholine at cholinergic neuroeffec tor junctions (muscarinic effects), and at skeletal muscle myoneural junctions and in autonomic ganglia (nicotinic effects). Poison also impairs CNS func tion. The carbamyl-enzyme combination dissociates more readily than the phosphorylated enzyme produced by organophosphate insecticides. This lability tends to mitigate the toxicity of carbamates, but also limits the useful ness of blood enzyme measurements in diagnosis of poisoning. Carbamates are absorbed by inhalation, ingestion, and dermal penetration. They are ac tively metabolized by the liver, and the degradation products are excreted by the liver and kidneys. * Listed approximately in order of decreasing toxicity. ** Acute oral LDJ0 in the rat less than 50 mg/kg. *** Acute oral LD,0 in the rat above 50 mg/kg. t This carbamate is a systemic, i.e., it is taken up by the plant and trans located into foliage and sometimes into the fruit. 9 A few carbamate insecticides are formulated in methyl (wood) alcohol. In cases of inger ' of these formulations, the toxicology of the methanol must be taken fully ...iO consideration: severe gastroenteric irritation, acidosis, CNS injury, and neuropathy. FREQUENT SYMPTOMS AND SIGNS OF POISONING DIARRHEA, NAUSEA, VOMITING, ABDOMINAL PAIN, PROFUSE SWEATING, SALIVATION, and BLURRED VISION are frequently reported. Other common symptoms have been dyspnea, tremor, muscle twitching, ataxia, and headache. Temporary paralysis of the extremities has also occurred. Most reported illnesses have not exceeded a few hours, and the prognosis is generally better than in organophosphate intoxications. However, in severe poisonings, one should anticipate the possibility of RESPIRATORY DEPRESSION, pulmonary edema, and convulsions. Continuing absorption of intermediate quantities may cause protracted MALAISE, weakness, and anorexia, resembling influenza. CONFIRMATION OF DIAGNOSIS CAUTION: If there is strong clinical evidence of poisoning, treat pa tient immediately. DO NOT WAIT for laboratory confir mation. Depressions of plasma and/or RBC cholinesterase activities may be observed following absorption of extraordinary amounts of carbamate insecticide. However, enzyme activities commonly revert to normal within a few minutes or hours. They are not, therefore, reliable detectors of carbamate poisoning; i.e., intoxication may exist when blood cholinesterase activities are normal. The rapid methods for cholinesterase estimation (ACHOLTEST, ChE-tel, MERCKOTEST) are more likely to detect depressions than the longer test methods. Table 1 in the chapter on ORGANOPHOSPHATE PESTICIDES lists the approximate lower limits of normal plasma and red cell cholinesteraseinhibiting carbamates. A normal value does not preclude carbamate insecticide poisoning. Whenever possible, comparison of the test sample with pre exposure values offers the best confirmation of excessive carbamate absorp tion: a depression of 25% or more is strong evidence of excessive absorption. Consult the chapter on ORGANOPHOSPHATE PESTICIDES for detailed interpretation of the blood cholinesterase tests. Measurement of carbamate metabolites in urine within 48 hours of exposure represents a specific and sensitive method for confirming absorption of several pesticides of this class. A number of government and university laboratories in contact with poison control centers can perform these tests. Specimens for such analysis should be collected as promptly as possible after exposure. 05 10 TREATMENT CAUTION: Persons attending the victim should avoid direct contact with heavily contaminated clothing and vomitus. Wear rubber gloves while decontaminating skin and hair. 1. Establish CLEAR AIRWAY and TISSUE OXYGENATION by aspira tion of secretions, and if necessary, by assisted pulmonary ventilation with oxygen. Improve tissue oxygenation as much as possible before ad ministering atropine to minimize the risk of ventricular fibrillation. 2. Administer ATROPINE SULFATE intravenously, or intramuscularly if IV injection is not possible. Atropine protects the end-organs from ex cessive concentrations of acetylcholine. It does not reactivate the cholin esterase enzyme. Recrudescence of poisoning may occur if tissue concen trations of carbamate remain high when the effect of atropine wears off. Atropine is the ideal antidote for muscarinic symptoms; it is ineffective against nicotinic actions such as muscle weakness and twitching, and respiratory depression. In MODERATELY SEVERE poisoning: Adult dosage, including children over 12 years: 0.4-2.0 mg repeated every 15 minutes until atropinization is achieved (tachycardia, flushing, dry mouth, mydriasis). Maintain atropinization by repeated doses for 2-12 hours, or longer, depending on severity of poisoning. The appearance of rles in the lung bases, miosis, salivation, nausea, bradycardia, are all indications of in adequate atropinization. Dosage for children under 12 years: 0.05 mg/kg body weight repeated every 15 minutes until atropinization is achieved. Maintain atropiniza tion with repeated dosage of 0.02-0.05 mg/kg. SEVERELY POISONED individuals may exhibit remarkable tolerance to atropine; twice the doses suggested above may be needed. Persons not poisoned, or only slightly poisoned, may develop signs of atropine toxici ty if large doses are given: FEVER, muscle fibrillations, and delirium. If these appear while the patient is fully atropinized, atropine should be dis continued, at least temporarily. 3. Pralidoxime (Protopam-Ayerst, 2-PAM) is of doubtful value in poisonings by carbamate inhibitors of cholinesterase. Atropine alone is almost always an adequate antidote. Pralidoxime is probably contrain dicated in poisonings by carbaryl, specifically. If victim of carbamate poisoning exhibits severe muscle weakness and/or respiratory depres sion, or if poisoning involves a combination of carbamate and organophosphate, a dilute solution of pralidoxime (total dose in 250 ml 5% glucose solution) may be given cautiously IV. The infusion should be ter minated if patient's condition worsens. Pralidoxime dosage: adults, 1.0 gm; for children under 12 years, 20-50 mg/kg. 4. OBSERVE treated patients closely at least 24 HOURS to insure that symptoms (possibly pulmonary edema) do not recur as atropinization wears off. In very severe poisonings, metabolic disposition of toxicant 11 may require several hours or days during which atropinization must be maintair Markedly lower levels of urinary metabolites indicate that atropine dosage can be tapered off. As dosage is reduced, check the lung bases frequently for rles. If rles are heard, or if nausea, salivation, or bradycardia returns, RE-ESTABLISH ATROPINIZATION promptly. 5. BATHE and SHAMPOO victim with soap and water if there is any chance that SKIN and HAIR are contaminated. 6 . If pesticide has been INGESTED in quantity sufficient to cause poison ing, empty the stomach and intestine. A. If victim is alert and respiration is not depressed, give SYRUP OF IPECAC, followed by 1-2 glasses of water to induce vomiting; adults (including children over 12), 30 ml; children (under 12 years), 15 ml. CAUTION: OBSERVE victim closely AFTER administering IPECAC. If consciousness level declines, or if vomit ing has not occurred in 15 minutes, proceed immedi ately to INTUBATE the stomach. Following emesis, have victim drink a suspension of 30-50 gm ACTIVATED CHARCOAL in 3-4 ounces of water to bind toxicant remaining in the gastrointestinal tract. B. If victim is OBTUNDED or respiration is depressed, empty stomach by INTUBATION, ASPIRATION, and LAVAGE, using isotonic saline or 5Vo sodium bicarbonate. Because many pesticides are dissolved in petroleum distillates, emesis and intubation of the stomach involve a serious risk that solvent will be aspirated, leading to chemical pneumonitis. For this reason: (a) . If victim is unconscious or obtunded and facilities are at hand, insert ENDOTRACHEAL TUBE (cuffed, if available) prior to gastric intubation. (b) . Keep victim's HEAD BELOW LEVEL OF STOMACH dur ing intubation and lavage (Trendelenburg, or left lateral, 2 decubitus, with head of table tipped downward). Keep victim's head turned to left. (c) . ASPIRATE PHARYNX as regularly as possible to remove CJl gagged or vomited stomach contents. N> After aspiration of gastric contents and washing of stomach, instill 30-50 gm of ACTIVATED CHARCOAL in 3-4 ounces of water through the tube to limit absorption of remaining toxicant. C. SAVE A SAMPLE of emesis or initial gastric washings for chemical analysis. D. If bowel movement has not occurred in 4 hours and patient is fully conscious, give SODIUM SULFATE, 0.25 gm/kg in 1-6 ounces of water, as a cathartic. Magnesium sulfate or citrate is equally suitable if renal function is satisfactory. 12 7. DO NOT give morphine, aminophylline, phenothiames, reserpine, furosemide, or ethacrynic acid. 8 . Give adrenergic amines ONLY if there is a specific indication, such as severe hypotension. 9. CONVULSIONS are RARE manifestations of poisoning by carbamates. If they occur, causes other than direct carbamate action should be con sidered: cerebral anoxia, head trauma, mixed poisoning. Although not tested in these circumstances, DIAZEPAM (Valium) is probably the an ticonvulsant of choice. Dosage for adults and children over 6 years or 23 kg body weight is 5-10 mg given slowly intravenously (no more than half total dose per minute), or intramuscularly (deep). Dosage for children under 6 years or 23 kg body weight is 0.1 mg/kg. Repeat this dosage every 2-4 hours if needed to control convulsions. Be prepared to intubate and to assist pulmonary ventilaton mechanically if respiration is depressed. Hypotensive reactions may also occur. 10. Persons who have been clinically poisoned by carbamate pesticides should not be re-exposed to cholinesterase-inhibiting chemicals until symptoms and signs have resolved completely, and normal blood cholin esterase activities have been demonstrated. 11. DO NOT administer atropine prophylactically to workers exposed to car bamate insecticides. It is neither practical nor medically sound to do so. 13 Chapter 3 SOLID ORGANOCHLORINE PESTICIDES CHEMICAL STRUCTURES LINDANE Cl Cl Cl CHLORDANE Cl DIELDRIN Cl Cl HEXACHLOROBENZENE OCH3 METHOXYCHIOR COMMON COMMERCIAL PESTICIDE PRODUCTS* Highly toxic: endrin (Hexadrin), a stereoisomer of dieldrin. Moderately toxic: aldrin (Aldrite, Drinox), endosulfan (Thiodan), dieldrin (Dieldrite), toxaphene (Toxakil, Strobane-T), lindane (Gammexane), benzene hexachloride (BHC, HCH), DDT (chlorophenothane), heptachlor, kepone, terpene polychlorinates (Strobane), chlordane (Chlordan), dicofol (Kelthane), chlorobenzilate (Acaraben), mirex, methoxychlor (Marlate), dienochlor (Pentac), hexachlorobenzene (HCB), ethylan (Perthane). All except HCB are insec ticides or acaricides; HCB is a fungicide. The U.S. Environmental Protection Agency has sharply curtailed the availability of many organochlorines, particularly DDT, dieldrin, and chlor dane. Others, however, are still the active ingredients of various home and garden products and some agricultural and structural pest control agents. Hex achlorobenzene is used as a seed protectant. Lindane may no longer be used in continuous vaporizers, but it is the active ingredient of many products for pest control in the home and on the farm. It is the active ingredient of the scabicide Kwell. TOXICOLOGY Most organochlorines are efficiently absorbed from the gut and across the skin. In adequate dosage, they interfere with axonic transmission of nerve im pulses and, therefore, disrupt the function of the nervous system, principally that of the brain. This results in behavioral changes, sensory and equilibrium disturbances, involuntary muscle activity, and depression of vital centers, par ticularly those controlling respiration. Adequate doses of some organo chlorines increase myocardial irritability, and stimulate synthesis of hepatic drug-metabolizing enzymes. * Listed approximately in order of decreasing toxicity. 6153 14 Chlordane has apparently induced a few cases of self-limited megaloblastic anemia after protracted low-level exposures. The condi has resolved following termination of exposure. Kepone has caused nervousness, tremor, incoordination, weakness and in fertility in excessively exposed workers. Clinical improvement has occurred as the pesticide was excreted. Endrin is more toxic to the liver and kidneys than the other organochlorines at comparable dosages. Prolonged ingestion of HCB-treated grain produced porphyria cutanea tar da in several thousand Turkish citizens who mistakenly ate the seed grain. Disease was manifest as excretion of red urine, bullous dermatitis, hyper pigmentation, generalized hair growth, muscle wasting and liver enlargement. Slow improvement occurred when HCB ingestion was stopped. A series of anecdotal reports of bone marrow injury has tended to indict lin dane as a hematotoxic agent in certain predisposed individuals, but no rela tionship has been proved. Lindane, methoxychlor, terpene polychlorinates, chlorobenzilate, dicofol, and the constituents of chlordane, except heptachlor and oxychlordane, are excreted rapidly by humans, usually within 3-4 days of ingestion. Dieldrin, aldrin, endrin, hexachlorobenzene, heptachlor, and oxychlordane are excreted within weeks to several months of absorption by humans. DDT, kepone, mirex, and the beta isomer of benzene hexachloride are excreted very slowly, requiring months or years for elimination. The excretion kinetics of perthane, kelthane, and dienochlor are not known. Because of their lipophilicity, all organochlorines are likely to be excreted in the milk of lactating women. FREQUENT SYMPTOMS AND SIGNS OF POISONING APPREHENSION, EXCITABILITY, DIZZINESS, HEADACHE, DIS ORIENTATION, WEAKNESS, PARESTHESIAE, muscle twitching, tremor, tonic and clonic CONVULSIONS (often epileptiform), and uncon sciousness are the major manifestations. Soon after ingestion, nausea and vomiting commonly occur. When chemicals are absorbed dermally, apprehen sion, twitching, tremors, confusion, and convulsions may be the first symp toms. Respiratory depression is caused by the pesticide and by the petroleum solvents in which these pesticides are usually dissolved. Pallor occurs in moderate to severe poisoning. Cyanosis may result as convulsive activity in terferes with respiration. Even though convulsive activity may be severe, the prognosis in poisonings by these agents is far from hopeless. Although fatalities have occurred follow ing absorption of large amounts of some organochlorines, there is a substan tial likelihood of complete recovery if convulsions can be controlled, and vital functions sustained. 15 CONFIRMATION OF DIAGNOSIS Pesticide and/or metabolites can usually be identified in blood or urine by gas-liquid chromatographic examination of samples taken within 72 hours of poisoning. These tests can be performed by some private laboratories, and by state health department and university laboratories supported by the U.S. En vironmental Protection Agency. Such laboratories can be reached through poison control centers. Some chlorinated hydrocarbon pesticides (notably DDT) persist in the serum for weeks or months after absorption, but most are excreted in a few days. DO NOT DELAY TREATMENT of acute poisoning pending confirmatory blood analysis. Detection of chlorinated hydrocarbon residues in blood or tissues does not, of itself, indicate poisoning; actual con centrations are critical to a diagnosis of poisoning. TREATMENT 1. Establish CLEAR AIRWAY and TISSUE OXYGENATION by aspira tion of secretions, and, if necessary, by assisted pulmonary ventilation with oxygen. 2. CONTROL CONVULSIONS. DIAZEPAM (VALIUM) is a valuable anticonvulsant. Adult dosage, including children over 6 years of age or 23 kg in weight: 5-10 mg (1-2 ml) slowly, intravenously (no faster than one ml per minute), or give total dose intramuscularly (deep). Repeat in 2-4 hours if needed. Dosage for children under 6 years or 23 kg in weight: 0.1 mg/kg (0.02 ml/kg) intravenously, no faster than half the total dose per minute, or give total dose intramuscularly (deep). Repeat in 2-4 hours if needed. CAUTION: Administer intravenous diazepam slowly to avoid irrita tion of the vein, hypotension, and respiratory depression. A. Persons suffering SEVERE PROTRACTED CONVULSIONS may require additional anticonvulsant medication. Agents that have been used successfully in the past are pentobarbital (Numbutal), phenytoin (Dilantin), thiopental (Pentothal), and succinylcholine (Anectine). CAUTION: Be prepared to maintain pulmonary ventilation me chanically if respiration is depressed during adminis tration of anticonvulsants. Laryngospasm sometimes occurs during anticonvulsant therapy, and may neces sitate tracheostomy. (a). PENTOBARBITAL: 5 mg/kg body weight, or 0.20 ml/kg 0 5 body weight, using the usual 2.5 Vo solution. If possible, inject K* solution intravenously, at a rate not exceeding 25 mg (one ml) 07 16 per minute until convulsions are controlled if intravenous ad ministration is not possible, give total d rectally, not ex ceeding 5 mg/kg body weight (0.20 ml/kg of 2.5% solution). (b) . PHENYTOIN: loading dose 15-18 mg/kg. Maintenance dose 4-8 mg/kg q 4-24 hours as needed. Intramuscular administra tion is not recommended. Give IV slowly at no more than 20% total dose per minute. (c) . THIOPENTAL (PENTOTHAL): a solution of one gm in 500 ml of 5% glucose in water is given by intravenous drip at a rate just sufficient to suppress convulsions. (d) . SUCCINYLCHOLINE: occasionally, curarization may be re quired to stop seizures. Prior to curarization, the trachea must be intubated, and pulmonary ventilation maintained mechani cally. Blood gases and pH must be monitored. A person expe rienced in general anesthesia should conduct these procedures. 3. BATHE and SHAMPOO the victim vigorously with soap and water if skin and hair have been contaminated. 4. IF PESTICIDE HAS BEEN INGESTED in quantity sufficient to cause poisoning, the stomach and intestine must be emptied. A. IF victim is ALERT and gag reflex is not depressed, give SYRUP OF IPECAC to induce vomiting (adults and children 12 years and older: 30 ml; children under 12: 15 ml), followed by 1-2 glasses of water. CAUTION: OBSERVE the VICTIM closely after administering IPECAC. If consciousness level declines, or if vomiting has not occurred in 15 minutes, proceed im mediately to INTUBATE stomach. Following emesis, have victim drink a suspension of 30-50 gm AC TIVATED CHARCOAL in 3-4 ounces of water to limit absorption of toxicant remaining in the gut. B. If the victim is NOT FULLY ALERT, empty the stomach immedi ately by INTUBATION, ASPIRATION, and LAVAGE, using isotonic saline or 5% sodium bicarbonate. Because many pesticides are dissolved in petroleum distillates, emesis and intubation of the stomach involve a serious risk that solvent will be aspirated, leading to chemical pneumonitis. For this reason: (a) . If victim is unconscious or obtunded and if facilities are at hand, insert an ENDOTRACHEAL TUBE (cuffed, if avail able) prior to gastric intubation. (b) . Keep victim's HEAD BELOW LEVEL OF STOMACH and turned to left during intubation and lavage. (Trendelenburg, or left lateral decubitus, with head of table tipped downward). (c) . ASPIRATE PHARYNX as regularly as possible to remove gagged or vomited stomach contents. 17 C. After ' 'ration of gastric contents and washing of stomach, instill 30-50 of ACTIVATED CHARCOAL in 3-4 ounces of water through stomach tube to limit absorption of remaining toxicant. DO NOT instill milk, cream, or other substances containing vegetable or animal fats, which enhance absorption of chlorinated hydrocarbons. D. -SAVE A SAMPLE of emesis or gastric washings for chemical analysis. E. If bowel movement has not occurred in 4 hours and if patient is fully conscious, give SODIUM SULFATE, 0.25 gm/kg in 1-6 ounces of water, as a cathartic. Magnesium sulfate and citrate are as suitable as sodium sulfate if renal function is adequate. Retained magnesium may depress CNS function. 5. DO NOT give epinephrine or other adrenergic amines, because of the enhanced myocardial irritability induced by chlorinated hydrocarbons. 6 . CHOLESTYRAMINE resin may accelerate the biliary-gastrointestinal excretion of the more slowly eliminated organochlorine compounds. This is usually administered in 3-8 gm doses, 4 times a day, before meals and at bedtime. Dose should be mixed with a pulpy fruit or liquid. Prolonged treatment (several weeks or months) may be necessary. 7. During convalescence, enhance CARBOHYDRATE, PROTEIN, and VITAMIN intake by diet or parenteral therapy to minimize injury to the liver. 05 K* Of or 18 Chapter 4 PENTACH LOROPH ENOL CHEMICAL STRUCTURE Cl Cl Cl Cl COMMON COMMERCIAL PESTICIDE PRODUCTS Pentachlorophenol or Sodium Pentachlorophenate, PCP, Dow Pentachlorophenol, Dowicide EC-7, Penchlorol, Pentacon, Penwar, Veg-I-Kill, penta, Wood Preserver, Wood Tox 140, Purina Insect Oil Concentrate, Gardon Termi Tox, Usol Cabin Oil, Certified KiltroI-74 Weed Killer, Ciba-Geigy Ontrack OS3, 4 or 5, Ortho Triox Liquid Vegetation Killer, Black Leaf Grass Weed and Vegetation Killer Spray, DP-2 Antimicrobial, Priltox, Sinituho. Pentachlorophenol is used as an herbicide, defoliant, wood preservative, germicide, fungicide, and molluscicide. It is an ingredient of many formulated mixtures sold for one or more of these purposes. Pentachlorophenol volatilizes from treated wood and fabric. Excessively treated interior surfaces may represent a source of intensive PCP exposure. TOXICOLOGY Pentachlorophenol irritates the skin, eyes, and upper respiratory mucous membranes. It is efficiently absorbed across the skin, the lung, and the gastro intestinal lining. Like the nitrophenolic compounds, it stimulates cellular ox idative metabolism by uncoupling phosphorylation. In common with other phenols, it is toxic to the liver, kidney, and central nervous system. Impurities in the technical formulation may be responsible for chloracne in workers regularly exposed. Most severe poisonings have occurred in workers exposed to hot environ ments. However, a major epidemic of poisoning occurred in an American hospital among newborn infants who absorbed PCP from treated diapers. Dehydration and metabolic acidosis are important features of poisoning in children. Albuminuria, glycosuria, and elevated BUN reflect renal injury. Liver enlargement has been observed in some cases. Anemia and leukopenia have occurred in some chronically exposed workers, but leukocytosis is more com monly found in acute poisoning. in FREQUENT SYMPTOMS AND SIGNS OF POISONING IRRITAa.ON of nose, throat, eyes, and skin is the most common symptom of exposure to PCP. Severe or protracted exposure may result in CONTACT DERMATITIS. Intensive occupational exposure has resulted in chloracne. PROFUSE SWEATING, HEADACHE, WEAKNESS, and NAUSEA are the most consistent presenting symptoms of systemic poisoning by absorbed PCP. FEVER is usually present but may be minimal or absent. TACHYCAR DIA, TACHYPNEA, and PAIN in the CHEST and ABDOMEN are often prominent. THIRST is usually intense, but may be masked by nausea and vomiting. DECLINING MENTAL ALERTNESS may progress to stupor and/or convulsions. Protracted exposure may result in WEIGHT LOSS from increased basal metabolic rate. CONFIRMATION OF DIAGNOSIS PCP can be measured in blood, urine, and adipose tissue by gas-liquid chromatography. Up to about 100 parts per billion may be found in the blood and urine of persons having no recognized exposure. Based on studies of per sons occupationally exposed to PCP, manifestations of systemic toxicity prob ably do not appear in adults until blood and urine concentrations reach at least one part per million (0.1 mg%, or 1,000 parts per billion). If poisoning is strongly suspected on grounds of exposure, symptoms, and signs, DO NOT POSTPONE TREATMENT until diagnosis is confirmed. TREATMENT 1. BATHE and SHAMPOO contaminated SKIN and HAIR promptly with soap and water, or water alone if soap is not available. 2. FLUSH chemical from EYES with copious amounts of clean water. 3. IN EVENT OF SYSTEMIC POISONING: A. B. C. (--s. Of 03 REDUCE ELEVATED BODY TEMPERATURE BY PHYSICAL MEANS. Administer sponge baths and cover victim with lowtemperature blankets. In fully conscious patients, administer cold, sugar-containing liquids by mouth as tolerated. Administer OXYGEN continuously by mask to minimize tissue anoxia. Unless there are manifestations of cerebral edema, administer IN TRAVENOUS FLUIDS at maximum tolerated rates to enhance urinary excretion of toxicant and to support physiologic mechan isms for heat loss. Monitor fluid balance, blood electrolytes and sugar, adjusting IV infusions to stabilize electrolyte concentra tions, Follow urine contents of albumin and cells. In the presence of CEREBRAL EDEMA, intravenous FLUIDS must be administered very CAUTIOUSLY to avoid increasing the cerebral injury. 20 O. Administer SEDATIVES, if necessary, to control apprehension and excitement. DIAZEPAM9 (Valium) should be > ible, although its use has not been reported in this type of poisoning. Give slowly, intravenously, 5-10 mg in the adult, 0.1 mg/kg in children. Amobarbital or pentobarbital, 100-200 mg IM or slowly IV, every 4-6 hours may be needed. (Children's dose: up to 5 mg/kg.) CAUTION: Be prepared to assist pulmonary ventilation mechani cally in event of respiratory depression, and to counteract hypotensive reactions. 4. If toxicant has been INGESTED, evacuate the stomach and intestine. A. If victim is alert and respiration is not depressed, give SYRUP OF IPECAC, followed by 1-2 glasses of water, to induce vomiting. (Adults, 12 years and older: 30 ml; children under 12: 15 ml). CAUTION: OBSERVE the victim closely AFTER administering IPECAC. If consciousness level declines, or if vomit ing has not occurred in 15 minutes, proceed im mediately to INTUBATE the stomach. Following emesis, have the victim drink a suspension of 30-50 gm ACTIVATED CHARCOAL in 3-4 ounces of water to bind toxicant remaining in the gastrointestinal tract. B. If victim is not fully alert, empty the stomach immediately by IN TUBATION, ASPIRATION, and LAVAGE, using isotonic saline or 5Vo sodium bicarbonate. Because PCP is commonly dissolved in petroleum distillates, emesis and intubation of the stomach involve a serious risk that solvent will be aspirated, leading to chemical pneumonitis. For this reason: (a) . If victim is unconscious or obtunded and facilities are at hand, insert an ENDOTRACHEAL TUBE (cuffed, if available) prior to gastric intubation. (b) . Keep victim's HEAD BELOW LEVEL OF THE STOMACH, turned to left, during intubation and lavage. (Trendelenburg, or left lateral decubitus, with head of table tipped downward). (c) . ASPIRATE PHARYNX as regularly as possible to remove gagged or vomited stomach contents. (d) . After aspiration of gastric contents and washing of stomach, instill 30 gm of ACTIVATED CHARCOAL in 3-4 ounces of water through a stomach tube to limit absorption of remain ing toxicant. Do NOT instill milk, cream, or other materials containing vegetable or animal fats, which are likely to enhance absorption. C. If bowel movement has not occurred in 4 hours and patient is fully conscious, give SODIUM SULFATE as a cathartic: 0.25 gm/kg body weight in 1-6 ounces of water. Magnesium sulfate and citrate 21 are equally suitable unless renal function is impaired; retention of ma ium may depress CNS function and alter myocardial irrita bility . 5. DO NOT administer atropine, aspirin, or other antipyretics to control fever. These are likely to enhance the toxicity of phenolic compounds. 6 . During convalescence, administer high-calorie, high-vitamin diet to restore body fat and carbohydrate. 7. Discourage subsequent contact with the toxicant for at least 4 weeks to allow full restoration of normal metabolic processes. 8. HEMODIALYSIS and HEMOPERFUSION may be considered in PCP poisoning, although phenols are extensively bound to plasma protein. EXCHANGE TRANSFUSION was used to rescue the infants inadver tently poisoned by PCP in a hospital. Unless renal and liver functions are impaired, PCP is rapidly eliminated from the blood and tissues. 22 6157 Chapter 5 NITROPHENOLIC AND NITROCRESOLIC HERBICIDES GENERAL CHEMICAL STRUCTURE no2 0 2N ^ ^ O--H (or ESTER) (ALKYL) (ALKYL) COMMON COMMERCIAL PESTICIDE PRODUCTS Dinitrophenol (Chemox PE), dinitrocresol (DNOC, DNC, Sinox, Chemsect DNOC, Elgetol 30, Nitrador, Selinon, Trifocide), dinoseb (DNBP, Dinitro, Basanite, Caldon, Chemox General, Chemox PE, Chemsect DNBP, Dinitro-3, Dinitro General, Dow General Weed Killer, Dow Selective Weed Killer, Dynamyte, Elgetol 318, Gebutox, Kiloseb, Nitropone C, Premerge 3, Sinox General, Subitex, Unicrop DNBP, Vertac Dinitro Weed Killer), dinosam (DNAP), dinoprop, dinoterbon, dinoterb, dinosulfon, binapacryl (Morocide, Endosan, Ambox, Dapacryl), dinobuton (Acrex, Dessin, Dinofen, Drawinol, Talan), dinopenton, dinocap (Crotothane, Karathane). Several combinations are widely used: Dyanap and Klean Krop = dinoseb + riaptalam; Ancrack = sodium salts of dinoseb + naptalam; Naptro = dinitrophenol + naptalam. TOXICOLOGY These materials should be regarded as highly toxic to humans and animals. Most nitrophenols and nitrocresols are well absorbed from the gastrointestinal tract, across the skin, and by the lung when fine droplets are inhaled. Except in a few sensitive individuals, aromatic nitro-compounds are only moderately irritating to the skin. Like other phenols, they are toxic to the liver, kidney, and nervous system. The basic mechanism of toxicity is a stimulation of oxida tive metabolism in cell mitochondria, by interference with the normal coupling of carbohydrate oxidation to phosphorylation (ADP to ATP). Increased oxi dative metabolism leads to pyrexia, tachycardia, and dehydration, and ulti mately depletes carbohydrate and fat stores. Most severe poisonings from absorption of these compounds have occurred in workers who were concur rently exposed to hot environments. Pyrexia and direct action on the brain cause cerebral edema, manifest clinically as a toxic psychosis and sometimes 23 convulsions T iver parenchyma and renal tubules show degenerative changes. Album inur pyuria, hem aturia, and increased B U N are often prom inent signs o f renal in ju ry. Agranulocytosis has occurred in humans following large doses of dinitrophenol. Cataracts have occurred in some chronically poisoned laboratory species, but this effect has not been observed in humans. Nitrophenols and nitrocresols are efficiently excreted by the kidneys, and there is some hepatic excretion into the bile. Unless the absorbed dose was ex tremely high, or kidney function is impaired, nearly complete elimination from the body can be expected within 3-4 days. Death in nitrophenol poisoning is followed promptly by intense rigor mortis. FREQUENT SYMPTOMS AND SIGNS OF POISONING YELLOW STAINING of skin and hair often signify contact with a nitrophenolic chemical. Staining of the sclerae and urine indicate absorption of potentially toxic amounts. PROFUSE SWEATING, HEADACHE, THIRST, MALAISE, and LASSITUDE are the common early symptoms of poisoning. WARM, FLUSHED SKIN, TACHYCARDIA, and FEVER characterize a serious degree of poisoning. APPREHENSION, restlessness, anxiety, manic behavior, or unconsciousness reflect severe cerebral injury. CONVULSIONS occur in the most severe poisonings. Cyanosis, tachypnea and dyspnea result from stimulation of metabolism, pyrexia, and tissue anoxia. Weight loss oc curs in persons chronically poisoned at low dosages. CONFIRMATION OF DIAGNOSIS Unmetabolized nitrophenols and nitrocresols can be identified spectrophotometrically, or by gas-liquid chromatography, in the serum and urine at concentrations well below those necessary to cause poisoning. If poisoning is probable, DO NOT AWAIT CONFIRMATION before commencing treat ment. TREATMENT 1. WASH contaminated SKIN and HAIR promptly with soap and water, or with water alone if soap is not available. 2. FLUSH chemical from EYES with copious amounts of clean water. 3. IN EVENT OF SYSTEMIC POISONING: 0 5 B. or oo REDUCE ELEVATED BODY TEMPERATURE BY PHYSICAL MEANS. Administer sponge baths and cover victim with lowtemperature blankets. In fully conscious patients, administer cold, sugar-containing liquids by mouth as tolerated. Administer OXYGEN continuously by mask to minimize tissue anoxia. 24 C. Unless there are manifestations of cerebral edema, administer IN TRAVENOUS FLUIDS at maximum tolerated ratf enhance uri nary excretion of toxicant and to support physioloe--mechanisms for heat loss. IN the presence of CEREBRAL EDEMA, intravenous FLUIDS must be administered very CAUTIOUSLY to avoid increas ing the cerebral injury. Monitor fluid balance, blood electrolytes and sugar, adjusting IV infusions to stabilize electrolyte concentrations. Follow urine contents of albumin and cells. Follow serum alkaline phosphatase, GOT, and LDH to evaluate liver injury. D. Administer SEDATIVES, if necessary, to control apprehension, ex citement, and/or convulsions. Although not previously used in this type of poisoning, DIAZEPAM (Valium ) should help: adult dose, 5-10 mg slowly IV, or IM (deep); child's dose, 0.1 mg/kg. Repeat every 2-4 hours as needed. Amobarbital or pentobarbital may be needed. Dose in adults: 200 mg, IM or slowly IV, every 4-6 hours; child's dose: up to 5 mg/kg. CAUTION: Be prepared to counteract respiratory depression and hypotension which may follow administration of anticonvulsants and sedatives. 4. If toxicant has been INGESTED, evacuate the stomach and intestine. A. If victim is alert and respiration is not depressed, give SYRUP of IPECAC, followed by 1-2 glasses of water, to induce vomiting (adults 12 years and older: 30 ml; children under 12: 15 ml). CAUTION: OBSERVE victim closely AFTER administering IP ECAC. If consciousness level declines, or if vomiting has not occurred in 15 minutes, immediately IN TUBATE, ASPIRATE, and LAVAGE the stomach. Following emesis, have victim drink a suspension of 30-50 gm AC TIVATED CHARCOAL in 3-4 ounces of water to bind toxicant remaining in the gastrointestinal tract. B. IF VICTIM IS NOT FULLY ALERT, empty the stomach immedi ately by INTUBATION, ASPIRATION, and LAVAGE, using isotonic saline or 5Vo sodium bicarbonate. Because these pesticides are usually dissolved in petroleum distillates, emesis and intubation of the stomach involve serious risk that solvent will be aspirated, leading to chemical pneumonitis. For this reason: (a) . If victim is unconscious or obtunded and facilities are at hand, insert an ENDOTRACHEAL TUBE (cuffed, if available) prior to gastric intubation. (b) . Keep victim's HEAD BELOW LEVEL OF THE STOMACH and turned to the left, during intubation and lavage (Trendelenburg, or left lateral decubitus, with head of table tipped downward). 25 (c) . ASPIRATE PHARYNX as regularly as possible to remove jagged or vomited stomach contents. (d) . After aspiration of gastric contents and washing of stomach, instill 30-50 gm of ACTIVATED CHARCOAL in 3-4 ounces of water through the stomach tube to limit absorption of re maining toxicant. Do NOT instill cream, milk, or other materials containing vegetable or animal fats, as these are like ly to enhance absorption. C. If bowel movement has not occurred in 4 hours, and if patient is fully conscious, give SODIUM SULFATE as a cathartic: 0.25 gm/kg body weight in 1-6 ounces of water. Magnesium sulfate and citrate are equally suitable unless renal function is impaired; retention of magnesium may depress CNS function and alter myocardial irrita bility. 5. DO NOT administer atropine, aspirin, or other antipyretics to control fever. Animal tests indicate that aspirin enhances, rather than reduces, the toxicity of nitrophenolic and nitrocresolic compounds. 6. During convalescence, administer high-calorie, high-vitamin diet to facil itate repletion of body fat and carbohydrate. 7. Discourage subsequent contact with the toxicant for at least 4 weeks, to allow full restoration of normal metabolic processes. 8. HEMODIALYSIS and HEMOPERFUSION may be considered in severe poisonings by aromatic nitro-compounds, although most phenols are extensively bound to plasma proteins. EXCHANGE TRANSFU SION is another option in poisonings characterized by impaired renal function. So long as renal and liver functions are intact, these com pounds are efficiently excreted. <7i C/I CD 26 Chapter 6 CHLOROPHENOXY COMPOUNDS GENERAL CHEMICAL STRUCTURE (or C H 3) ESTER Cl O G RO UP h ' II Cl -- O -- c -- C -- O -- H or S O D IU M H (Cl) ALKYL AM INE COMMON COMMERCIAL PESTICIDE PRODUCTS Several hundred commercial products contain chlorophenoxy herbicides in various concentrations and combinations. Following are names of widely advertised formulations. In some cases, the same name is used for products with different ingredients. Exact composition must therefore be determined from product label. 2,4-D, or 2,4-dichlorophenoxyacetic acid (Weedonet, Agrotec, Amoxone, Aqua-Kleen, BH 2,4-D, Chipco Turf Herbicide "D" , Chloroxone, Crop Rider, D50, Dacamine 4D, Ded-Weed, Desormone, Dinoxol, DMA4, Dormone, Emulsamine BK, Emulsamine E-3, Envert DT or 171, Esteron 99 Con centrate, Esteron Four, Esteron Brush Killer, Estone, Fernoxone, Femimine, Ferxone, Femesta, Formula 40, Hedonal, Herbidal, Lawn-Keep, Macondray, Miracle, Netagrone 600, Pennamine D, Planotox, Plantgard, Rhodia, SalvoJ, Spritz-Hormin/2,4-D, Spritz-Hormit/2,4-D, Superormone Concentre, Super D Weedone, Transamine, U46, Verton 2D, Visko-Rhap, Weed-B-Gon, Weedar, Weed-Rhap, Weed Tox, Weedtrol, De broussaillant 600, Lithate, Dicotox, Field Clean Weed Killer). 2,4-DB is the butyric acid homologue of 2,4-D. Dichlorprop is the propionic acid homologue. 2,4,5-T or 2,4,5-trichlorophenoxyacetic acid (Brush-Rhap, Dacamine 4T, Dbroussaillant Concentre, Ded-Weed Brush Killer, Esteron 245, Fence Rider, Forron, Inverton 245, Line Rider, Spontox, Super D Weedone, Tormona, Transamine, Trinoxol, Trioxone, U46, Veon 245, Verton 2T, Weedar, Weedone Envert T). Common mixtures of 2,4-D and 2,4,5-T are: Dacamine 2D/2T, Esteron Brush Killer, Rhodia Low Volatile Brush Killer No. 2, U46 Special, Tributon, Visko-Rhap LV2D-2T, and Transamine. t A product of identical name containing pentachlorophenol (Chapter 4) as the active ingredient has been discontinued by Amchem Products Co. A product of identical name marketed by the Crystal Chemical Company contains cacodylic acid as the active ingredient (Chapter 10). 27 2,4,5-TP /o;lvex) is the propionic acid homologue of 2,4,5-T. Kuron is a low volatile est f 2,4,5-TP. 2,4,5-TB is the butyric acid homologue of 2,4,5-T. Fenac or chlorfenac is 2,3,6-trichlorophenylacetic acid. Dicamba (Banvel) is dichloroanisic acid. MCPA, MCPB, MCPB-Ethyl, MCPCA and MCPP (Mecoprop) are 2-methyl, 4-chlorophenoxy aliphatic acids and esters. TOXICOLOGY Some of the chlorophenoxy acids, salts, and esters are moderately irritating to skin, eyes, and respiratory and gastrointestinal linings. In a few individuals, local depigmentation has apparently resulted from prolonged and repeated dermal contact with chlorophenoxy materials. The chlorophenoxy compounds are absorbed across the gut wall, lung, and skin. They are not significantly fat storable. Excretion occurs within hours, or at most, days, primarily in the urine. Given in large doses to experimental animals, 2,4-D causes vomiting, diar rhea, anorexia, weight loss, ulcers of the mouth and pharynx, and toxic injury to the liver, kidneys, and central nervous system. Myotonia (stiffness and in coordination of hind extremities) develops in some species and is apparently due to CNS damage: demyelination has been observed in the dorsal columns of the cord, and EEG changes have indicated functional disturbances in the brains of heavily dosed experimental animals. Ingestion of large amounts of chlorophenoxy acids has resulted in severe metabolic acidosis in humans. Such cases have been associated with electro cardiographic changes, myotonia, muscle weakness, myoglobinuria, and ele vated serum creatine phosphokinase, all reflecting injury to striated muscle. Because chlorophenoxy acids are weak uncouplers of oxidative phosphoryla tion, extraordinary doses may produce hyperthermia from increased produc tion of body heat. PolyChlorinated DibenzoDioxin (CDD) compounds are generated in the synthesis of 2,4,5-T. The 2,3,7,8-Tetra CDD form is extraordinarily toxic to multiple mammalian tissues. Hexa- hepta-, and octa-compounds exhibit less systemic toxicity, but are the likely cause of chloracne (a chronic, disfiguring skin condition) seen in workers engaged in the manufacture of 2,4,5-T, and certain other chlorinated organic compounds. Although toxic effects, notably chloracne, have been observed in manufacturing plant workers, they have not been observed in formulators or applicators regularly exposed to 2,4,5-T. The medical literature contains several reports of peripheral neuropathy following what seemed to be minor dermal exposures to 2,4-D. It is not cer tain that exposures to other neurotoxicants were entirely excluded in these cases. Single doses of 5 mg/kg body weight of 2,4-D and 2,4,5-T have been ad ministered to human subjects without any adverse effects. One subject con sumed 500 mg of 2,4-D per day for 3 weeks without experiencing symptoms or signs of illness. 28 6160 F R E QUENT S Y M P T O M S A N D SIGNS OF POISONING Chlorophenoxy compounds are moderately IRRITATINE to skin and mucous membranes. Inhalation of sprays may cause burning sensations in the nasopharynx and chest, and coughing may result. Prolonged inhalation some times causes dizziness. When INGESTED, high concentrations of chlorophenoxy compounds may irritate the mouth, throat, and gastrointestinal tract. Prompt EMESIS, CHEST PAIN (from esophagitis), ABDOMINAL PAIN, and DIARRHEA commonly ensue. Injury to the GI tract does not usually progress to ulceration or perforation. Absorbed chlorophenoxy compounds have caused FIBRILLARY MUSCLE TWITCHING, skeletal muscle tenderness, and MYOTONIA (stiffness of muscles of the extremities). Ingestion of very large amounts has produced METABOLIC ACIDOSIS, fever, tachycardia, hyper ventilation, vasodilatation and sweating. Particular cases have been charac terized by coma and convulsions. CONFIRMATION OF DIAGNOSIS Gas-liquid chromatographic methods are available for detecting and mea suring the chlorophenoxy compounds in blood and urine. These analyses are useful in confirming and assessing the magnitude of chlorophenoxy absorp tion. Urine samples should be collected as soon as possible after exposure because the herbicides may be almost completely excreted in 24-72 hours, depending on the extent of toxicant absorption. Analyses can be performed at special laboratories operated by state health departments, chemical com panies, universities, and government facilities. If circumstances indicate strongly that excessive exposure to any of these compounds has occurred, ini tiate appropriate treatment measures immediately, not waiting for chemical confirmation of toxicant absorption. TREATMENT 1. BATHE and SHAMPOO with soap and water to remove chemicals from skin and hair. Individuals with chronic skin disease or known sensitivity to chemicals should either avoid using these herbicides or take extraordi nary measures to avoid contact. 2. FLUSH contaminating chemicals from eyes with copious amounts of clean water for 10-15 minutes. 3. If symptoms of illness occur during or following inhalation of spray, REMOVE victim FROM CONTACT with the material for at least two days. Allow subsequent contact with chlorophenoxy compounds only if effective respiratory protection is practiced. 4. IF substantial amounts of chlorophenoxy compounds have been IN GESTED, spontaneous emesis usually occurs. Ordinarily, this empties the stomach as effectively as intubation and lavage. If vigorous emesis 29 has not occurred and IF VICTIM IS FULLY ALERT, induce EMESIS with S' IP OF IPECAC (adults 12 years and older, 30 ml; children under 1 years, 15 ml), followed by 1-2 glasses of water. Following emesis, administer 30-50 gm of ACTIVATED CHARCOAL in a slurry of 6-8 ounces tap water, to limit absorption of herbicide remaining in the gut. 5. IF CONSCIOUSNESS LEVEL IS DEPRESSED or other signs of NEUROTOXICITY appear, SUSPECT additional or alternative in gested toxicants. Evacuate the stomach by INTUBATION, ASPIRA TION, and LAVAGE. Because petroleum distillates are commonly in cluded in chlorophenoxy formulations, gastric intubation incurs a risk of hydrocarbon pneumonitis from aspiration. For this reason: A. If victim is unconscious or obtunded and facilities are at hand, in sert an ENDOTRACHEAL TUBE (cuffed, if available) prior to gastric intubation. B. Keep victim's HEAD BELOW LEVEL OF THE STOMACH dur ing intubation and lavage (Trendelenburg, or left lateral decubitus, with head of table tipped downward). Keep victim's head turned to left. C. ASPIRATE PHARYNX as regularly as possible to remove gagged or vomited stomach contents. After aspiration of gastric contents and washing of stomach, instill 30-50 gm of ACTIVATED CHARCOAL in 3-4 ounces of water through the stomach tube to limit absorption of remaining toxicant. Do NOT instill milk, cream, or other materials containing vegetable or animal fats, as these are likely to enhance absorption. 6 . If bowel movement has not occurred in 4 hours and patient is fully con scious, give SODIUM SULFATE, 0.25 gm/kg, as a cathartic. Magne sium sulfate and citrate, in comparable dosages, are equally suitable if renal function is adequate. Retained magnesium may depress CNS func tion. 7. In SEVERE POISONINGS by very large amounts of ingested chloro phenoxy acids, forced ALKALINE DIURESIS may save the victim's life. Assess serum electrolyte concentrations, and serum and urine pH. If a metabolic acidosis is present, infuse solutions of sodium bicarbonate at rates sufficient to keep the urine distinctly alkaline, continuing until plasma concentrations of chlorophenoxy compounds are less than about 10Mg/ml. [Prescott, L F. et al., Br. J. Clin. Pharmacol. 7:11 (1979)] 30 6161 Chapter 7 PARAQUAT AND DIQUAT CHEMICAL STRUCTURES CH2--CH2 2 Br- PARAQUAT DIQUAT COMMON COMMERCIAL PESTICIDE PRODUCTS Paraquat products: paraquat dichloride (usually as a 21% concentrate). Other names: Ortho paraquat-CL, Crisquat, Dextrone X, Esgram. Mix tures: Priglone, Preeglone, Weedol--with diquat; Simpar, Terraklene--with simazine; Gramonol, Mofisal--with monolinuron; Pathclear--with diquat and simazine; TotaCol, Dexuron--with diuron. Diquat products: diquat (Reglone, Reglox, Aquacide, Dextrone, Weedtrine-D). Mixtures: Priglone, Preeglone, Weedol--with paraquat; Pathclear-- with paraquat and simazine. TOXICOLOGY These dipyridyls injure the epithelial tissues: skin, nails, cornea, liver, kid ney, and the linings of the GI and respiratory tracts. In addition to direct irri tant effects, injury may involve peroxidation of intracellular and extracellular phospholipids and inhibition of surfactant synthesis by lung tissue. These toxic properties may derive from the capacity of dipyridyls to generate free radicals in tissues. The injury is usually reversible; however, the pulmonary reaction which follows ingestion of paraquat is often fatal. Certain injuries have followed occupational contact with paraquat. Contact with the concentrate may cause irritation and Assuring of the skin of the hands, and cracking, discoloration, and sometimes loss of the fingernails. Splashed in the eye, paraquat concentrate causes conjunctivitis and, if not promptly removed, may result in protracted opacification of the cornea. Although nearly all systemic intoxications by paraquat have followed inges tion of the chemical, occasional poisonings have resulted from excessive dermal contact. Absorption of toxic amounts is much more likely to occur if the skin is abraded. Persons who have experienced extraordinary dermal contact with paraquat (especially the concentrate) should be examined, and tested for hazardous concentrations of the agent in the blood and urine (see section on Confirmation of Diagnosis). 31 None of these agents is a cholinesterase inhibitor. Thirair rritating to skin and mucous membranes. It has sensitized some individuals, generally after contact with rubber products containing residues of thiram used as a curing agent. The metallo dithiocarbamates and ethylene dithiocarbamates are moderately irritating to skin and the respiratory mucous membranes following contact with sprays or dusts. Thiram is the methyl analogue of disulfiram (Antabuse), an agent used to condition alcoholics against beverage alcohol. Much more is known of the tox ic effects-of disulfiram than of thiram, although the acute toxicity of thiram in laboratory animals is substantially greater. Given to animals in extreme doses, disulfiram has caused gastrointestinal irritation, demyelinization of CNS tissues, and necrosis of liver, splenic, and kidney tissues. Peripheral neuropa thy and psychotic reactions have occurred in humans taking large doses of disulfiram regularly. Functional and anatomic CNS damage has been demonstrated in rats on high chronic dosage regimens of iron and zinc dimethyldithiocarbamates. Because all of these agents are degraded partly to carbon disulfide in the body, a role of this metabolite in neurotoxic effects is suspected. Both thiram and disulfiram inhibit aldehyde dehydrogenase, and are there fore capable of inducing "Antabuse" reactions in persons who consume beverage alcohol following substantial absorption of dithiocarbamates. Reac tions may have occurred rarely in workers who imbibed after extraordinary oc cupational exposure to thiram. Theoretically, the metallo dithiocarbamates may also predispose to an "Antabuse" reaction. Peripheral vasodilation is the main pathophysiologic feature of the disulfiram-alcohol reaction, probably due to high tissue levels of acetaldehyde. This may occasionally lead to shock, and even more rarely, to myocardial ischemia, cardiac arrhythmias, circula tory failure, and death. Animal experimentation has suggested certain other biochemical mechanisms of toxicity involving reaction products of ethanol and disulfiram. The ethylene bis dithiocarbamates do not inhibit aldehyde dehydrogenase, and there is no evidence of neurotoxicity from them. They do, however, degrade in the environment, and in mammalian tissues, to ethylene thiourea, a compound known as a goitrogen and carcinogen in laboratory animals. This feature mandates extra care in the protection of harvesters, and in removal of residues from harvested crops. Except for some moderate irritant effects on skin, respiratory tract, and eyes, the (mono) thiocarbamate herbicides do not appear to be highly toxic. Extreme doses in laboratory animals do produce paralysis. There is a very remote possibility of "Antabuse" reactions from ethanol following extraor dinary exposure to these (mono) thiocarbamates. They do not form ethylene thiourea on degradation. 38 6165 S Y M P T O M S A N D SIGNS OF POISONING Thiram and mtallo bis dithiocarbamates Itching, redness, and eczematoid DERMATITIS have resulted when predis posed individuals have come into contact with these agents. Inhaled sprays and dusts have caused NASAL STUFFINESS, hoarseness, cough, and, rarely, pneumonitis. Repeated contact may produce sensitization. Ingestion of large amounts may produce nausea, VOMITING, and DIARRHEA. HYPO THERMIA and ataxia are characteristic of poisoning. Muscle WEAKNESS and/or ascending paralysis may progress to respiratory paralysis if absorbed dosages are equivalent to those tested in experimental animals. The reaction to beverage alcohol that may follow exceptional absorption of thiram and mtallo bis dithiocarbamates is characterized by FLUSHING, HEADACHE, SWEATING, warm sensations, weakness, nasal congestion, labored breathing, tightness in the chest, tachycardia, palpitation, and hypo tension. Extreme dosages may result in shock, convulsions, respiratory depres sion, and/or unconsciousness. Reactions are not likely to occur unless the absorbed dose is extraordinary. Ethylene bis dithiocarbamates and (mono) thiocarbamates Some of these agents are irritating to skin and respiratory mucous mem branes, causing ITCHING, SCRATCHY THROAT, SNEEZING, and COUGH, if excessive amounts of spray or dust are inhaled. Apart from this effect, toxic potential is low. Neurotoxic and post-ethanol "Antabuse" reac tions are not known to occur as a result of contact with these particular com pounds. CONFIRMATION OF DIAGNOSIS Skin testing may be useful in identifying sensitization to these agents. In general, these compounds are so rapidly metabolized in the body and ex creted, that detection in blood is rarely possible. There are methods for detec tion of ethylene thiourea (from the ethylene bis dithiocarbamates) in urine. TREATMENT 1. WASH contaminating chemical from SKIN and HAIR with soap and water. Persons sensitive to thiram (rubber-sensitive) should be per manently REMOVED FROM CONTACT with compounds of this nature. 2. FLUSH contaminant from EYES with fresh water for 10-15 minutes. 3. If THIRAM or METALLO DITHIOCARBAMATE compounds have been INGESTED: 39 A. V :gorous emesis has not already occurred and victim is fully alert, fe SYRUP OF IPECAC, followed by 1-2 glasses of water to in duce vomiting (adults, 12 years and older: 30 ml; children under 12: 15 ml). CAUTION: OBSERVE victim closely AFTER administering IPECAC. If CONSCIOUSNESS level declines or vomiting has not occurred in 15 minutes, empty the stomach by INTUBATION, ASPIRATION, and LAVAGE. B. IF consciousness level or respiration is DEPRESSED, empty the stomach by INTUBATION, ASPIRATION, and LAVAGE, using all available means to avoid aspiration of vomitus: left lateral Trendelenburg position, frequent aspiration of the pharynx and, in unconscious victims, tracheal intubation (using a cuffed tube) prior to gastric intubation. After aspiration of the stomach and washing with isotonic saline or sodium bicarbonate, instill 30-50 gm of ACTIVATED CHAR COAL in 3-4 ounces of water through the stomach tube to limit absorption of remaining toxicant. C. If the irritant properties of the toxicant fail to produce a bowel movement in 4 hours, administer SODIUM or MAGNESIUM SULFATE as a cathartic: 0.25 gm/kg body weight in 1-6 ounces of water. D. Administer glucose-containing fluids intravenously to accelerate ex cretion of toxicant. E. For adults and children over 12 years, inject 1.0 gm ASCORBIC ACID (Vitamin C) intravenously at a rate not exceeding 0.2 gm/minute. For children under 12, give 10-20 mg/kg body weight. As a hydrogen-donor, ascorbic acid may have significant antidotal action against absorbed, but unreacted, dithiocarbamate com pounds. F. The victim must AVOID consumption of any ALCOHOLIC bever age for 3 weeks. Gastrointestinal absorption of these substances is slow, and the enzyme inhibition which they cause is slowly reversed. 4. Management of a reaction to ETHANOL, following absorption of a DITHIOCARBAMATE: A. Administer 100% OXYGEN as long as the reaction continues. Ox ygen usually gives substantial relief from the distressing symptoms of vasodilation and hypotension. CAUTION: If respiration is depressed, administer oxygen by an intermittent positive pressure breathing device and observe the victim closely to maintain pulmonary ventilation mechanically in case of apnea. 6166 40 B. Gastric evacuation, charcoal administration, catharsis, intravenous fluids, and ascorbic acid administration (3 A,B,C,D, E) may be appropriate, depending on the amount of dithiocarbamate absorbed, the time interval between exposure and treatment, and the severity of symptoms. C. If the victim has suffered from arteriosclerosis, myocardial insuffi ciency, diabetes, neuropathy, cirrhosis, or other severe chronic disease, OBSERVE him CAREFULLY for 48 hours to insure that complications (especially myocardial infarction, toxic psychosis, and neuropathy) are treated promptly. 5. If an ETHYLENE BIS DITHIOCARBAMATE, or (mono) THIOCARBAMATE have been ingested: A. Give SYRUP OF IPECAC, followed by 1-2 glasses of water, to in duce vomiting (adults: 30 ml; children under 12 years: 15 ml). Fol lowing emesis, administer 30-50 gm ACTIVATED CHARCOAL to bind toxicant remaining in the gut. B. Follow charcoal with SODIUM or MAGNESIUM SULFATE, 0.25 gm/kg, to remove toxicant from the gut by catharsis. 41 Chapter 9 PYRETHRUM, PYRETHRINS, PYRETHROIDS, AND PIPERONYL BUTOXIDE Pyrethrum is the partly reflned extract of the chrysanthemum flower which has been used as an insecticide for more than 60 years. Pyrethrins are the insecticidally active ingredients of pyrethrum, now known to consist of ketoalcohol esters of pyrethric and chrysanthemic acids. The alcohols are pyrethrolone, cinerolone, and jasmololone, whose respective esters are known as pyrethrins, cinerins, and jasmolins. Pyrethroids are synthetic compounds based structurally on the pyrethrin molecule but modified to improve stability in the natural environment (light, heat, etc.) GENERAL CHEMICAL STRUCTURE RH H II I c -c - c II ch3 ch3-c ho I II c-c ch3 ch3 H \ / C* / C-R HC -- C = O H COMMON COMMERCIAL PESTICIDE PRODUCTS Pyrethrins: There are several hundred commercial products containing pyrethrins and pyrethroids. Commonly, these products combine pyrethrins or pyrethroids with a synergist, such as piperonyl butoxide, and an additional pesticide, for increased killing power. Many of these combinations are pack aged with a propellant in a spray can or bug-bomb. Pyrethroids: Allethrin (Pynamin), barthrin, bioresmethrin, cypermethrin (Ripcord), decamethrin, fenothrin, fenpropanate, fenvalerate (Belmark, Pydrin), permethrin (Ambush, Ectiban, Pounce), phthalthrin or tetramethrin (Neo-Pynamin), resmethrin (Synthrin, Chrysron). TOXICOLOGY ( These esters rapidly paralyze the insect nervous system, making them famous for their quick " knockdown" effect. Mammalian toxicity, however, is extraordinarily low for pyrethrins and pyrethroids. Oral LD50 values for these compounds in rats are several hundred or thousand mg/kg body weight. There is apparently less efficient absorption of pyrethrins across the GI lining and 42 6167 skin than across insect chitin, and much more rapid biodegradation (hydrolysis and oxidation) by the mammalian liver than by xt tissues. Some of the less purified pyrethrum extracts contain allergenic substances that induce attacks of allergic rhinitis and asthma in humans. Rarely, hyper sensitivity pneumonitis has followed pyrethrum inhalation. Administered orally to rodents in extraordinary dosage, pyrethrins and pyrethroids cause nervous irritability, tremors, and motor ataxia. Bloody tears and urinary incontinence have also been observed. Manifestations of toxicity occur at much lower dosage following intravenous administration than after oral dosing. Chronic feeding of these chemicals induces an increase in liver size and bile duct hyperplasia. To date, neither pyrethrins nor pyrethroids have been identified as mutagenic, carcinogenic, or teratogenic. Piperonyl butoxide inhibits the mixed function oxidase enzymes of the liver which catabolize pyrethrins and pyrethroids. The amount absorbed by humans during ordinary exposure is not likely to affect liver function measurably. FREQUENT SYMPTOMS AND SIGNS OF UNDUE EXPOSURE A STUFFY, RUNNY NOSE and scratchy throat from inhalation of partly purified pyrethrum extract is the most common adverse effect of these agents. Asthmatic WHEEZING may be precipitated by exposure of predisposed indi viduals. Sudden bronchospasm, swelling of oral and laryngeal mucous membranes, and shock (anaphylaxis) have been reported after pyrethrum inhalation. Delayed appearance of dyspnea, cough and fever, with patchy lung infiltrates on x-ray, suggest hypersensitivity pneumonitis. Nervous irritability, tremors, and ataxia have occurred rarely in persons who have had massive inhalation exposure to pyrethrins. Halocarbon propellents in bug-bomb products present a risk of CARDIAC ARRHYTHMIA and possibly fibrillation if inhaled to excess. Hydrocarbons used as solvents in spray products are likely to result in COUGH, FEVER, and CHEST PAIN (hydrocarbon pneumonitis) if these liquids are inadvertently aspirated. CONFIRMATION OF DIAGNOSIS Skin tests sometimes identify sensitivity to pyrethrum. Neither pyrethrins nor pyrethroids inhibit cholinesterase enzymes. There are gas-chromatographic methods for identifying some of these insecticides in environmental samples, but they are not likely to be useful in diagnosing poisoning because of the rapid metabolism of the esters following absorption. There are no methods for identifying urinary metabolites. 43 TREATMENT 1. WASH contaminating pesticide from the EYE with copious amounts of water. Wash contaminated SKIN with soap and water. 2. For life-threatening allergic reaction to pyrethrum (severe ASTHMA or ANAPHYLAXIS), give 0.1 to 0.5 ml of 1:1000 ADRENALIN intramus cularly, or slowly intravenously. Repeat if necessary to relieve respiratory distress and maintain blood pressure. Intravenous AMINOPHYLLINE (10 ml, slowly) may be indicated. Give HYDROCORTISONE (50-100 mg), or equivalent steroid, intravenously. Less severe allergic reactions (rhinitis) can be managed with ANTI HISTAMINES and DECONGESTANTS, given orally. HYPERSENSITIVITY PNEUMONITIS may require oxygen, ste roids, antibiotics and several days bedrest, depending on severity. 3. INGESTION of a SMALL AMOUNT of a pyrethrin or pyrethroid for mulation is not likely to cause poisoning. EXAMINE THE LABEL to identify additional insecticides, which may be more toxic. BASE TREATMENT ON THE MOST TOXIC ingredients. A. If a formulation contains ONLY pyrethrins, or pyrethroids, and synergists, ingestion of a small amount (up to about 5 mg/kg) is probably best treated by large doses of ACTIVATED CHAR COAL, 30-50 gm in 3-4 ounces of water, followed by cathartic doses of SODIUM or MAGNESIUM SULFATE, 0.25 gm/kg body weight in 1-6 ounces of water. 4. If LARGE AMOUNTS of pyrethrin or pyrethroid formulation have been INGESTED, the stomach and intestine must be evacuated: A. IF victim is ALERT and respiration is not depressed, give SYRUP OF IPECAC, followed by 1-2 glasses of water, to induce vomiting (adults and children 12 years and older: 30 ml; children under 12 years: 15 ml). CAUTION: OBSERVE VICTIM closely AFTER administering IPECAC. If consciousness level declines or vomiting has not occurred in 15 minutes, INTUBATE the stomach immediately. Following emesis, have victim drink a suspension of 30-50 gm AC TIVATED CHARCOAL in 3-4 ounces of water to limit absorption of toxicant remaining in the gut. B. IF victim is NOT FULLY ALERT, empty stomach immediately by INTUBATION, ASPIRATION, and LAVAGE, using isotonic saline or 57o sodium bicarbonate. Because many pesticides are dis solved in petroleum distillates, emesis and intubation of the stomach involve a risk that solvent will be aspirated, leading to chemical pneumonitis. For this reason: 6168 44 (a) . If victim is unconscious or obtunded and faci';>'es are at hand, insert an ENDOTRACHEAL TUBE(cuffed, vailable) prior to gastric intubation. (b) . Keep victim's HEAD BELOW LEVEL OF THE STOMACH during intubation and lavage (Trendelenburg, or left lateral decubitus, with head of table tipped downward). Keep victim's head turned to left. (c) . ASPIRATE PHARYNX as regularly as possible to remove gagged or vomited stomach contents. (d) . After aspiration of gastric contents and washing of stomach, instill 30-50 gm of ACTIVATED CHARCOAL in 3-4 ounces of water through stomach tube to limit absorption of remain ing toxicant. (e) . If bowel movement has not occurred in 4 hours and patient is fully conscious, give SODIUM or MAGNESIUM SULFATE as a cathartic: 0.25 gm/kg body weight in 1-6 ounces of water. 5. Do NOT administer or instill milk, cream, or other substances containing vegetable or animal fats, which enhance absorption of lipophilic sub stances, such as pyrethrins and pyrethroids. 6 . DIAZEPAM (Valium), 5-10 mg in adults, 0.1 mg/kg in children, given orally or slowly IV, should control nervousness and tremors in rare cases having these symptoms after extraordinary exposure to pyrethrins and pyrethroids. 45 Chapter 10 ARSENICAL PESTICIDES CHEMICAL STRUCTURES INORGANIC ARSENICALS Extremely Toxic / N As - 0 - As xoy ARSENIC TRIOXIDE Na - 0 - As = 0 SODIUM ARSENITE K 0 - As = 0 POTASSIUM ARSENITE Cu - (0 - C - CH3) 2 n o 3Cu * (As 2)2 COPPER ACETOARSENITE Highly Toxic Ca3(As 0 4) 2 CALCIUM ARSENATE Moderately Toxic Ca (As O2) 2 CALCIUM ARSENITE Cu - (As0 2) I 0 H COPPER ARSENITE (HO)3 As = 0 ARSENIC ACID 6169 Pb A s = 0 I 10 2H J LEAD ARSENATE 46 ORGANIC ARSENICALS Moderately Toxic "^3 v\ As \ 0 ch3 OH CACODYLIC ACID ch3 ONa O OH MONOSODIUM METHYL ARSONATE (MSMA) CH3 \ /O N H 4 As O OH MONOAMMONIUM METHANE ARSONATE CH, \ / OH ^ As ^\ 0 OH METHANE ARSONIC ACIt (MAA) c h 3v^ ^ ONa As \ 0 ONa DISODIUM METHYL ARSONATE (DSMA) 47 C O M M O N -''MMERCIAL ARSENIC PRODUCTS 1. Arsenic trioxide 2. Sodium arsenite: 3. Calcium arsenite: 4. Copper arsenite: 5. Copper acetoarsenite: 6 . Arsenic acid: 7. Sodium arsenate: 8 . Calcium arsenate: 9. Lead arsenate: 10. Methane arsonic acid: 11. Monosodium methyl arsonate: 12. Disodium methyl arsonate: 13. Monoammonium methyl arsonate: 14. Calcium acid methanearsonate: 15. Cacodylic acid: "White arsenic," arsenious oxide (registered only for ant pastes, veterinary medicinals, and marine antifouling preparations). Chem Pel^'C, Chem-Sen 56, KillAll, Penite, Prodalumnol Double. Mond^calcium arsenite. Chemonite. Paris green, Schweinfurt green, emerald green, French green, mitis green. Desiccant L-10, Hi-Yield Desic cant H-10. Jones Ant Killer, Terr Ant Killer. Pencal, Spra-cal, Security. Gypsine, Security, Soprabel, Talbot. MAA. MSMA, Ansar 170HC, methane arsonate, Ansar 529HC, Arsonate liquid, Bueno 6 , Daconate 6 , DalE-Rad, Herb-All, Merge 823, Mesamate, Target MSMA, TransVert, Weed-E-Rad, Weed-Hoe. DSMA, Ansar 8100, methane ar sonate, Ansar DSMA liquid, Arrhenal, Arsinyl, Chipco Crab Kleen, Crab-E-Rad, Dal-E-Rad 100, Di-Tac, DMA, DMA 100, Methar, Namate, Sodar, Weed-ERad, Weed-E-Rad 360, Weed-ERad DMA Powder, Weed-Hoe. MAMA, monoammonium meth anearsonate. CAMA, Super Crab-E-Rad-Calar, Super Dal-E-Rad " Calar" . Dilic, Phytar 560, Rad-E-Catc 25, Salvo, t [Crystal Chemical Com pany) 6170 t A product of identical name marketed by Crystal Chemical Company contains 2,4-D as the active ingredient (Chapter 6). 48 TOXICOLOGY Although there may be some degree of dermal and pulmonary absorption of arsenical liquids and sprays, ingestion is the route of intake involved in virtual ly all acute poisonings by the solid arsenicals. Inhalation of arsine gas (sometimes generated inadvertently in pesticide manufacturing plants) has caused serious illness and death by hemolytic action. Generally, the organic (methylated) pentavalent arsenicals are considerably less toxic than the trivalent inorganic arsenicals. In fact, methylation is the principal mechanism of detoxification of inorganic arsenicals in mammals. The less soluble inorganic forms (notably lead arsenate, and even arsenic triox ide) present less hazard than the highly soluble salts such as sodium arsenite and copper acetoarsenite. But because gastric pH, gastrointestinal motility, and gut bacterial action can enhance the absorption and toxicity of ingested compounds, it is safest to manage cases of arsenic ingestion as though all forms of arsenic are highly toxic. Trivalent arsenicals (or, more likely, an arsenious acid metabolite) bind effi ciently to the functional thiol groups of many tissue components, including en zymes. The affinity for thiol groups in keratin accounts for the accumulation of arsenic in skin, nails, and hair in cases of chronic poisoning. When absorbed across the gut wall, these arsenicals injure the splanchnic vasculature, causing abdominal pain, colic, and diarrhea. Once absorbed into the blood, they cause toxic damage to the liver, kidneys, brain, bone marrow, and peripheral nerves. Liver injury is manifest as hepatomegaly, jaundice, and increase in circulating hepatocellular enzymes LDH and GOT. Renal damage is reflected in albumin uria, hematuria, pyuria, cylindruria, then azotemia. Acute tubular necrosis may occur in severe poisoning. Injury to blood-forming tissues can take the form of agranulocytosis, aplastic anemia, thrombocytopenia, or pancytopenia. Toxic encephalopathy may be manifest as speech and behavioral disturbances. Peripheral neuropathy occurs in both acute and chronic forms. Sequelae of arsenic poisoning include cirrhosis, hypoplastic bone marrow, renal insufficiency, and peripheral neuropathy. Excessive exposures to arseni cals have caused hyperkeratosis and skin cancers. Excessive inhalation of dusts may cause bronchitis and pneumonia; protracted inhalation has been asso ciated epidemiologically with increased occurrence of lung cancer. FREQUENT SYMPTOMS AND SIGNS OF POISONING ACUTE arsenic poisoning COLIC, BURNING ABDOMINAL PAIN, VOMITING, and WATERY or BLOODY DIARRHEA are the primary manifestations of ingestion of solid arsenical poisons. Symptoms following ingestion of inorganic arsenicals are much more severe than those resulting from ingestion of pentavalent organic arsenicals. Symptoms are sometimes delayed for minutes or even hours after ingestion. HEADACHE, DIZZINESS, MUSCLE SPASMS, DELIRIUM, 49 and sometirr CONVULSIONS reflect direct injury to the central nervous system, as wt.. as extracellular electrolyte disturbances and shock. A GARLIC ODOR to the breath and feces helps to identify the responsible toxicant. SHOCK, TOXIC NEPHROSIS, HEPATITIS (hepatomegaly and jaundice), and NEUROLOGIC INJURY (delirium, paralysis, respiratory depression) may progress to a fatal outcome. SUBACUTE arsenic poisoning Repeated intakes less than those necessary to produce severe acute symp toms are known to cause CHRONIC HEADACHE, ABDOMINAL DIS TRESS, SALIVATION, LOW-GRADE FEVER, and PERSISTENT symp toms of UPPER RESPIRATORY IRRITATION. Stomatitis and garlicky breath are characteristic. CHRONIC arsenic poisoning Prolonged low intakes of arsenic cause peripheral neuropathy (PARESTHESIAE, PAIN, anesthesia, paresis, ataxia), encephalopathy (APATHY, disorientation), dermatologic disorders (KERATOSES, pigmentation, eczema, brittle nails, loss of hair), toxic hepatitis (HEPATOMEGALY, some times progressing to cirrhosis with ascites), and bone marrow injury (ANEMIA, leukopenia, WEAKNESS). Local EDEMA, frequently of the eye lids, characterizes some poisonings. ACUTE arsine gas poisoning The gas causes hemolysis of red blood cells, in addition to inhibition of cellular sulfhydryl respiratory enzymes. Hemolysis causes HEMOGLOBINEMIA and HEMOGLOBINURIA. This in turn, causes acute tubular necrosis. Early symptoms of poisoning (CHILLS, weakness, burning sensations) are followed by abdominal CRAMPS, vomiting, and prostration. Failing renal function deteriorates to ANURIA. CONFIRMATION OF DIAGNOSIS Measurement of 24-hour urinary excretion of arsenic is probably the best way to confirm excessive arsenic absorption, although methods for blood arsenic concentration are available. Persons on ordinary diets usually excrete less than 20 ig/day but diets rich in seafood may generate as much as 200 - - fxg/day. Excretions above 100 Mg/day should be viewed with suspicion and tests should be repeated. Excretions above 200/ug/day reflect a toxic intake, unless seafood was ingested. (The arsenic in seafood is apparently bound firm ly to an organic moiety that renders the arsenic essentially nontoxic and highly excretable.) The qualitative Gutzeit test for arsenic in the urine is available in most hospital laboratories, and is useful in identifying acute poisonings promptly. 50' 6171 Chronic storage of arsenic can be detected by analysis of h^ir or fingernails. The hemoglobinuria caused by arsine is identified by fin , free hemoglo bin in fresh urine. TREATMENT OF POISONING BY SOLID ARSENICALS 1. Flush contaminated EYES, HAIR and SKIN with copious amounts of fresh water. WASH SKIN and HAIR with soap and water. 2. In poisonings by INGESTED ARSENICALS A. INTUBATE the stomach, ASPIRATE, and LAVAGE with 3 liters of isotonic saline or 5% sodium bicarbonate. Use all possible pre cautions to avoid aspiration of vomitus: (1) If victim is unconscious or obtunded, insert an ENDO TRACHEAL TUBE (cuffed, if available) prior to gastric intu bation. (2) Keep victim's HEAD BELOW LEVEL OF THE STOMACH during intubation (Trendelenburg, or left lateral decubitus, with head of table tipped downward). Keep victim's head turned to the left. (3) ASPIRATE pharynx as regularly as possible to remove gagged or vomited stomach contents. B. After lavage, INSTILL 30-50 gm ACTIVATED CHARCOAL in the smallest amount of water necessary to deliver the charcoal through the tube. C. If diarrhea or colic has not ensued within an hour of gastric lavage and charcoal administration, give SODIUM SULFATE as a cathar tic 0.25 gm/kg body weight in 1-6 ounces of water. 3. An ABDOMINAL X-RAY film is useful in detecting concretions of the less soluble arsenicals (As20 3 and lead arsenate) in the gut. If not re moved these may become a repository of slowly absorbed toxicant. 4. Administer INTRAVENOUS ELECTROLYTE and GLUCOSE solu tions to maintain hydration and to accelerate toxicant excretion. COM BAT SHOCK with TRANSFUSIONS of WHOLE BLOOD, and by in halation of 100% OXYGEN. CAUTION: Monitor urine flow via catheter. Monitor fluid balance, body weight, and/or central venous pressure to guard against fluid overload that may result if tubular necrosis (anuria) supervenes. 5. Administer DIMERCAPROL (BAL) and PENICILLAMINE to acceler ate arsenic excretion. A. Give dimercaprol, 3-5 mg/kg q4h intramuscularly until abdominal pain and diarrhea subside and patient is regularly passing admin istered charcoal in the feces. IF victim is ALLERGIC to 51 PE^'CILLIN, continue dimercaprol therapy at 3-5 mg/kg q6h x 4 dot, then ql2h x 2 doses, then q24h X 10 doses, monitoring urine arsenic excretion periodically to judge effectiveness. CAUTION: DIMERCAPROL can cause troublesome side effects (hypertension, tachycardia, nausea, headache, paresthesiae and pain, lacrimation, sweating, anxiety, and restlessness). Although usually not so severe as to preclude treatment, they may require antihistaminic therapy. B. IF victim is NOT ALLERGIC to PENICILLIN, oral d-PENICILLAMINE is the therapy of choice and should REPLACE dimer caprol treatment as soon as the feces are laden with charcoal, limiting gut absorption of arsenic. Adult dosage is 0.5 gm four times daily (2 gm/day), given before meals, for 5 days. Dosage for children is 0.025 gm/kg four times daily, not to exceed 2 gm/day for 5 days. CAUTION: Although oral d-penicillamine therapy is usually better tolerated than intramuscular dimercaprol, serious reactions to it have occurred: the most common has been maculopapular rash, with fever, leukopenia, thrombocytopenia, eosinophilia, arthralgia and lymphadenopathy. It has also induced the nephrotic syn drome on occasion, and has caused thrombophlebitis, cheilosis, angioneurotic edema, and even fatal agran ulocytosis in particular patients given the drug over long periods for conditions unrelated to arsenic poi soning. Penicillin sensitive individuals are likely to be sensitive to d-penicillamine. (a). A single 5 day course of d-penicillamine therapy is usually suf ficient. However, if symptoms recur after treatment, addi tional d-penicillamine should be given at a dosage just suffi cient to abolish symptoms. 6 . Intense abdominal pain may require morphine (adults, 12 years and older: 4-15 mg; children under 12 years: 0.1-0.2 mg/kg). 7. Severe poisoning (especially when renal function is impaired) may re quire HEMODIALYSIS to remove arsenic combined with dimercaprol from the blood, and to control extracellular fluid composition. HEMOPERFUSION may be useful, but its effectiveness has not been reported. TREATMENT OF POISONING BY ARSINE GAS 1. REMOVE victim to FRESH AIR. 2. MAINTAIN RESPIRATION and CIRCULATION by resuscitation and cardiac massage, if necessary. 6172 52 3. Administer INTRAVENOUS FLUIDS promptly to dilute free hemoglo bin and minimize tubular injury. Include enough sodiu carbonate to keep the urine alkaline. CAUTION: Monitor urine flow via catheter. Monitor fluid balance, body weight, and/or central venous pressure to guard against fluid overload resulting from acute tubular necrosis. 4. Administer DIMERCAPROL as recommended in 5A even though it has only limited effect in arsine poisoning. 5. EXCHANGE BLOOD TRANSFUSIONS and PERITONEAL DIALY SIS have saved the lives of victims of arsine poisoning suffering acute tubular necrosis. 53 Chapter 11 RODENTICIDES STRUCTURES OF PRINCIPAL COMPOUNDS H --N \ C=S / HN H a - NAPHTHYL THIOUREA Zn /\ P - Zn P \/ Zn ZINC PHOSPHIDE CD fw m A -J CO ALKYL, PHENYL, DIPHENYLACETYL or CHLORODIPHENYLACETYL O 1,3 INDANDIONE HO I ii F - C - C - ONa I H SODIUM FLUOROACETATE P P P YELLOW PHOSPHORUS 54 O SCILLIROSIDE (Active principle of Red Squill) H i - S . N . C N - f \ -NO, H H II H O RH- 787 (Active ingredient of VACOR and DLP-787) / N* ch3- c c - ci H -C N I / N\ CH, CH, CRIMIDINE 55 C O M M O N COMMERCIAL RODENTICIDE PRODUCTS Coumarins: warfarin, coumafene, zoocoumarin (Kypfarin, Ratox, RAX, Rodex, Tox-Hid, Warfarin Plus); coumafuryl (Tomarin, Fumarin); bromadiolone (Bromone, Super-Caid, Ratimus), coumachlor (Tomorin). Indandiones: diphacinone (Diphacin, Promar, Ramik); chlorophacinone (Caid, Drat, Liphadione, Microzul, Ramucide, Ratomet, Raviac, Rozol, Topitox); pindone or pivaldione (Pival, Pivacin, Pivalyn, Tri-ban). Other anticoagulant rodenticides of different structure: difenacoum (Ratak); brodifacoum (Talon). Sodium fluoroacetate: 1080, Fratol, Yasoknock. Zinc phosphide: Phosvin, Zinc-Tox. Yellow phosphorus and strychnine have limited use and are generally identi fied by these long established common names. Crimidine: Castrix. RH-787: This product is no longer available for sale, but existing stocks present a continuing threat of poisoning. Commercial products are: Vacor Rat Killer (2% RH-787 in vehicle resembling corn meal); DLP-787 Bait (2% RH-787 in vehicle resembling corn meal); DLP-787 House Mouse Tracking Powder (10% RH-787 in a light green powder). Red squill: Dethdiet, Rodine. Antu: Krysid. Norbormide: Shoxin, Raticate. TOXICOLOGY Rodent poisons are generally added to baits, i.e., grain or paste designed to encourage consumption. Safety for pets, domestic animals, and humans depends on the toxicity of the agents, concentration of active ingredients in the baits, and the likelihood that a toxic dose will be consumed by nontarget species. The c o u m a rin s are reasonably effective against pest rodents and have a good safety record. This is due mainly to the low concentration of active in gredient in the bait: about 100 gm of the commercial bait must be ingested to yield 25 mg of anticoagulant. This is important in evaluating suspected poison ings by anticoagulants, which are the most widely available rodenticides for public use. Very small amounts of the extremely toxic rodenticides--sodium fluoro acetate, zinc phosphide, crimidine, strychnine, and yellow phosphorus--can cause fatal poisoning. Vacor should be considered highly toxic. Ingestion of less than 1 gm by an adult has caused severe poisoning. Antu, red squill, and norbormide present considerably less toxic hazard to humans and to domestic animals. t A rodenticide of identical trade name is still available in some areas which contains thallium sulfate as the active ingredient. Use of thallium in the ^ United States is now restricted. 56 Coamarins, indandiones, and other anticoagulants: Gastrointestinal absorp tion of these toxicants is efficient, beginning within minute ... ingestion and continuing for 2 to 3 days. Apparently warfarin can also be absorbed across the skin, although the circumstances under which this occurred were extraordi nary. These agents depress the hepatic synthesis of substances essential to blood clotting: prothrombin (factor II) and factors VII, IX, and X. The antipro thrombin effect is best known, and provides the basis for detection and assess ment of clinical poisoning. Direct damage to capillary permeability occurs concurrently. The ultimate effect of these actions is to induce widespread in ternal hemorrhage. This generally occurs in the rodent after several days of bait ingestion, although the modern products (diphacinone, chlorophacinone, pindone, difenacoum, and brodifacoum) may be lethal after fewer feedings. These modern agents should be considered more toxic than warfarin. In rare instances, coumarin-type anticoagulants have caused ecchymosis and extensive skin necrosis in humans for reasons not related to excessive dosage. Unlike the coumarin anticoagulants, the indandiones cause symptoms and signs of neurologic and cardiopulmonary injury in laboratory rats; these often lead to death before hemorrhage occurs. These actions may account for the somewhat greater toxicity of this class of anticoagulants. Neither cardiopul monary nor neurologic symptoms or signs have been reported in human poisonings. Lengthened prothrombin time from a toxic dose is usually evident within 24 hours of ingestion and reaches a maximum in 36 to 72 hours. Without inter vention, hypoprothrombinemia may persist 10 to 15 days, depending on the agent and dosage. Prothrombin depression occurs in response to doses much lower than those necessary to cause hemorrhage. Sodium fluoroacetate: the fluorocitrate metabolite of this poison blocks energy production in mammalian cells at the level of the tricarboxylic acid cy cle. The critical sites of toxic effect in humans are the myocardium (where ven tricular fibrillation is the usual cause of death) and the brain, where seizures are induced and respiration is depressed. Seizures, respiratory depression, and ventricular fibrillation are all causes of death. Zinc phosphide: this inorganic compound produces severe gastrointestinal irritation. It degrades in the gut to phosphine gas which, when absorbed, causes pulmonary edema and severe liver, kidney, CNS, and myocardial injury. Yellow phosphorus: this agent causes severe gastrointestinal irritation result ing in vomiting, diarrhea, and melena. Circulatory collapse.may occur and prove irreversible. Liver necrosis and acute renal tubular necrosis are equally ominous threats to life. Hemorrhage, from hypoprothrombinemia, and car diac arrest or fibrillation, account for some deaths. Strychnine: this natural poison acts directly on the cells of the brain and spinal cord to cause convulsions. Death is caused by convulsive interference with pulmonary gas exchange, by depression of respiratory center activity, or both. 57 Crimidine: this is a synthetic pesticide which, although unrelated chemically to strychnine erts toxic effects similar to those of strychnine, producing violent convulsions and secondary tissue anoxia by its action on the CNS. Vacor, DLP-787: the exact mechanism of RH-787 toxicity is not known although one established effect in rats is interference with nicotinamide metabolism. RH-787 has no anticoagulant action. Symptoms and signs in poisoned animals suggest toxic actions on the brain, peripheral nerves, myoneural junctions, pancreatic islet tissues, autonomic nervous system, and the conducting tissues of the heart. Abnormalities of renal and vascular func tion may be direct effects of poisoning, or they may reflect metabolic and autonomic nervous system disturbances, impaired vascular reactivity in par ticular. Red squill: this biological agent is unlikely to present a serious toxic hazard to humans or other vomiting species, because 1) it usually induces prompt emesis, 2) it is poorly absorbed from the gut, and 3) the active principles are in low concentration, and are rapidly excreted. Natural squill contains digitalis like glycosides, which might, theoretically, produce manifestations of digitali zation in humans. The glycoside known as scilliroside is the probable cause of convulsive death in the rat; convulsions have not been observed in human poisonings. Antu: this agent exhibits selective toxicity for the rat, causing pulmonary edema and pleural effusion. Only one human poisoning is recorded, and it was induced by a large suicidal dose. Vomiting was followed by dyspnea, cyanosis, and pulmonary rales, presumably reflecting pulmonary edema. The patient recovered. Norbormide: this is selectively toxic to Norway and roof rats, which it kills by inducing a generalized, sudden, and intense vasoconstriction. Other vari eties of rats are resistant, and the chemical is only moderately toxic to other mammals, including humans. Oral doses of 300 mg cause transient lowering of blood pressure and body temperature in humans. FREQUENT SYMPTOMS AND SIGNS OF POISONING Coumarins, indandiones, and other anticoagulants: In most cases of inges tion of anticoagulants, victims have remained asymptomatic, due to the small dosage taken. Even in cases involving ingestion of substantial amounts of anti coagulant compound (more often medication than rodenticide), hypoprothrombinemia has occurred without symptoms of poisoning. Hemorrhage ap pears only when extraordinary amounts have been absorbed. In reported cases, the anticoagulants were either taken deliberately, were absorbed over long periods out of neglect of elementary hygienic standards, or were ingested by starving indigents who used quantities of rodent bait as food. Victims of large doses exhibit HEMATURIA, NOSEBLEED, HEMATO* MATA, BLEEDING GUMS, and MELENA. ABDOMINAL PAIN and BACK PAIN probably reflect hemorrhage in the abdominal and retroperito^ n eal tissues. WEAKNESS occurs as a result of ANEMIA. RENAL COLIC *sl OI 58 often complicates severe hematuria. Nasal and gastrointestinal hemorrhages have occasionally caused death from exsanguination. Sodium fluoroacetate: A delay of several minutes or even hours may be ex pected before symptoms appear. Epigastric distress and vomiting often occur. Apprehension, PARESTHESIAE and hallucinations are the usual premonitory symptoms, leading to epileptiform CONVULSIONS. CARDIAC IRREGULARITIES (ectopic beats, pulsus alternans, ventricular tachycardia and fibrillation) appear after seizures commence. These are frequently fatal. Zinc phosphide: Intense NAUSEA, abdominal pain, excitement, and chills are early symptoms. Tightness in the chest, DYSPNEA and COUGH, produc tive of FROTHY SPUTUM, reflect pulmonary edema. SHOCK from toxic myocarditis is common. If these conditions are survived, JAUNDICE from liver necrosis, and ANURIA from renal tubular injury are later complications. Hypocalcemic TETANY and PURPURA have occurred in some poisonings. Yellow phosphorus: BURNING PAIN in the throat, chest, and abdomen reflect severe mucosal irritation. Vomiting and diarrhea ensue. Breath has garlicky odor. Feces may luminesce and "smoke" from phosphorus fumes. SHOCK often progresses to death in 1 to 2 days. The patient who survives may then be relatively symptom-free for several hours or even days, after which the delayed manifestations appear due to liver, CNS, myocardial and renal injury. Nausea and VOMITING persist. HEMORRHAGE at various sites reflects mainly depression of clotting-factor synthesis in the liver. SHOCK may be due to hemorrhage and/or toxic myocarditis. CONVUL SIONS, delirium, and coma are common. ANURIA usually ensues as a result of direct nephrotoxic effect of phosphorus, enhanced by biliary nephrosis (hepatorenal syndrome). Strychnine: Within 10 to 60 minutes of ingestion of an adequate dose (as lit tle as 16 mg), the victim suffers VIOLENT CONVULSIONS caused by clonic, then tonic contraction of all the skeletal muscles of the body. Cyanosis develops promptly. Brief periods of relaxation may occur, followed by even more severe seizures. Opisthotonus is common, and the muscles of the face are drawn into a grimace. Death is usually due to ASPHYXIA, a consequence of convulsive spasm of the respiratory muscles. Crimidine: Ingestion is followed promptly by VIOLENT CONVULSIONS, essentially like those caused by strychnine (see preceding paragraph). Vacor, DLP-787: Minimum toxic and lethal doses in humans are not known. Ingested amounts less than one gram have proved severely toxic. Symptoms may not appear for 4 to 48 hours after ingestion. Earliest symp toms are usually NAUSEA, vomiting, abdominal cramps, CHILLS, and CONFUSION. Later manifestations are aching and Fine tremors of the ex tremities, dilated pupils, plantar hyperesthesia, MUSCLE WEAKNESS, dysphagia, chest pain, postural hypotension, anorexia, diarrhea, urinary retention, and HYPOTHERMIA. Subsequently, DIABETES MELLITUS commonly develops, manifest as glycosuria, polyuria, ketoacidosis, and dehydration. Death may result from respiratory failure, cardiovascular col lapse, or ketoacidosis. Survivors of the acute phase of the poisoning are often 59 left with permanent sequelae: postural hypotension, diabetes mellitus, bladder dystonia (r iion or frequency), bowel dystonia (constipation or diarrhea), and peripheral neuropathy. Abnormal laboratory findings include hyperglycemia, glycosuria, ketosis (acidosis and electrolyte disturbances), and elevation of serum amylase and lipase activities. Red squill: Nausea and VOMITING are the predominant effects. In the unlikely event that significant amounts of glycosides are absorbed, cardiac ar rhythmias and slowing might be expected. Convulsions have not been observed in humans as they have in rats. Antu: Pulmonary rles, DYSPNEA and cyanosis may be expected follow ing ingestion of large amounts. Norbormide: No human poisonings have been reported. Ingestion of 300 mg by an individual caused a slight fall in body temperature and blood pressure. CONFIRMATION OF DIAGNOSIS Coumarins, indandiones, and other anticoagulants: Increase of the pro thrombin time (Quick) reflects a reduction in serum prothrombin concentra tion, and occurs in response to physiologically significant absorption of these toxicants. This widely available clinical test offers a sensitive and reliable diagnostic method for detecting a toxic effect of these compounds. Readily detectable change in prothrombin time appears within 24 to 48 hours of inges tion of anticoagulant. Zinc phosphide and phosphorus: Zinc phosphide smells like rotten fish and imparts a garlicky odor to the breath. Luminescence of vomitus or feces in dicates yellow phosphorus ingestion. Other rodenticides: There are analytical methods available for identifying some remaining rodenticides in food or liquids suspected of contamination, in gastric contents, and sometimes in blood and urine. (See Sunshine, I., Hand book of Analytical Toxicology (1969) published by the Chemical Rubber Company, 18901 Cranwood Parkway, Cleveland, Ohio 44128.) These methods are generally complex and must be performed by a toxicology labora tory experienced in these tests. Analysis is often time-consuming, limiting the usefulness of the results in clinical management. Analyses may be important, however, for legal reasons. TREATMENT Coumarins, indandiones, and other anticoagulants 1. If only a few grains of anticoagulant bait have been ingested by an adult or child having no antecedent liver or blood clotting disease, treatment is probably unnecessary. oe " -I A. If there is uncertainty about the amount of b^' ingested or the general health of the patient, PHYTONADL (vitamin K,, Mephyton) given orally protects against the anticoagulant effect of these rodenticides. For adults, give 15-25 mg; for children under 12, give 5-10 mg. Alternatively, a colloidal solution of phytonadione, Aquamephyton, may be given intramuscularly. For adults, give 5-10 mg; for children under 12, give 1-5 mg. CAUTION: PHYTONADIONE, specifically, is required. Neither vitamin Kj (menadione, Hykinone) nor vitamin K, (menadiol) is an antidote for these anticoagulants. B. Whatever the doage, insure that patients (especially children) will be CAREFULLY OBSERVED for 4-5 days after ingestion. The indandiones and the more recently introduced anticoagulants have toxic effects apart from anticoagulation that are not yet well defined. 2. If LARGE AMOUNTS of anticoagulant were ingested in the preceding 2-3 hours, INDUCE VOMITING with SYRUP OF IPECAC, followed by 1-2 glasses of water. For adults, give 30 ml; for children under 12, 15 ml. Following emesis, give 30-50 gm ACTIVATED CHARCOAL in 4-6 ounces of water to limit absorption of anticoagulant remaining in the gut. 3. If anticoagulant has been ingested any time in the preceding 15 days, determination of PROTHROMBIN TIME provides a basis for judging the severity of poisoning. A. If the prothrombin time is lengthened, give Aquamephyton, in tramuscularly: adult dose, 5-10 mg; child's dose: 1-5 mg. Decide dose according to the degree of prothrombin time lengthening and, in children, the age and weight of the child. B. Repeat prothrombin time in 24 hours. If it has not decreased from the original value, repeat Aquamephyton dosage. 4. If victim shows SYMPTOMS or SIGNS of ANTICOAGULANT POI SONING (bleeding) in addition to hypoprothrombinemia, administer Aquamephyton intramuscularly, up to 25 mg in the adult, and up to 0.6 mg/kg in children under 12 years. Phytonadione administration may be repeated in 24 hours if bleeding continues. A. In cases of SEVERE BLEEDING, it may be necessary to give Aquamephyton intravenously. This is especially true if the bleeding tendency is so severe that intramuscular injection is likely to cause hematoma formation. Dosage is up to 25 mg in the adult, up to 0.6 mg/kg in children under 12 years. Repeat this dose in 24 hours if bleeding continues. Inject at rates not exceeding 5% of the total dose per minute. INTRAVENOUS INFUSION of the Aquamephyton DILUTED IN SALINE OR GLUCOSE SOLU TION is recommended. Bleeding is usually controlled in 3-6 hours. 61 CAUTION: Adverse reactions, some fatal, have occurred from INTRAVENOUS phytonadione injections, even when recommended dosage limits and injection rates were observed. For this reason, the INTRAVENOUS route should be used ONLY IN cases of SEVERE POISONING. Flushing, dizziness, hypotension, dyspnea, and cyanosis have characterized adverse reactions. B. Antidotal therapy IN cases of SEVERE BLEEDING should be sup plemented with TRANSFUSIONS of FRESH BLOOD or FRESH FROZEN PLASMA. Use of fresh blood or plasma represents the most rapidly effective method of stopping hemorrhage due to these anticoagulants. C. Determine PROTHROMBIN TIMES (and hemoglobin concentra tions, if appropriate) every 6-12 hours to assess effectiveness of antihemorrhagic measures. D. When normal blood coagulation is restored, it may be advisab'i to drain large hematomata. E. Ferrous sulfate therapy may be appropriate in the recuperative period to rebuild lost erythrocyte mass. Sodium fluoroacetate 1. If this substance has been INGESTED, empty the stomach immediately by INTUBATION, ASPIRATION, and LAVAGE, using 5% sodium bicarbonate. Before withdrawing the lavage tube, instill a slurry of 30-50 gm ACTIVATED CHARCOAL. 2. MONITOR cardiac rhythm by continuous ELECTROCARDIOG RAPHY. 3. MONOACETIN (glyceryl monoacetate) has antidotal properties in ex perimental animals. The liberated acetate competes successfully with fluorocitrate in the tricarboxylic acid cycle. However, there is no sterile pharmaceutical preparation of this compound: high-quality, fresh laboratory grade material must be used. A. If victim is fully conscious and not convulsing, administer 100 ml of monoacetin in 500 ml of water, by mouth. Repeat in one hour. (Arena, J. M. P o iso n in g , 1970.) B. If victim is obtunded, unconscious, or convulsing, give 0.1-0.5 ml/kg of undiluted monoacetin by deep intramuscular injection every half hour for 4-6 hours, rotating the injection sites to minimize pain and swelling. Monoacetin can also be given intra venously on the same schedule, using a 1:5 dilution in sterile isotonic saline. OD 62 CAUTION: The use of parenteral monoacetin is hazardous. Tech nical grade material contains glyc' which, in ade quate dosage, may cause hemoly^', hypotension, convulsions, and paralysis. If a nonsterile solution is injected, the monoacetin should be cultured to guide the administration of antibiotics if sepsis develops. 4. CONTROL CONVULSIONS A. Administer 100Vo OXYGEN by positive pressure to provide as much pulmonary gas exchange as possible, despite seizures. B. ANTICONVULSANT DRUGS CAUTION: It may be difficult or impossible to stop the seizure activity without stopping respiration. Be prepared to maintain pulmonary ventilation mechanically. Tracheostomy may be necessary if seizures are pro longed. (a) . Diazepam (VALIUM) usually controls mild convulsions. For adults, give 5-10 mg, slowly, intravenously; for children under 6 years or 23 kg body weight, give 0.1 mg/kg body weight, slowly, IV. Repeat in 4-6 hours if necessary. (b) . Pentobarbital may be needed in addition to control severe convulsions. Dosage: 5 mg/kg body weight, or 0.20 ml/kg body weight, using the usual 2.5% solution. If possible, inject solution intravenously, at a rate not exceeding 25 mg (one ml) per minute until convulsions are controlled. If intravenous ad ministration is not possible, give total dose by deep intramus cular injection, not exceeding 5 mg/kg body weight (0.20 ml/kg of 2.5% solution). (c) . Phenytoin (DILANTIN) has prolonged anticonvulsant ac tion. Dosage: loading dose 15-18 mg/kg. Maintenance dose 4-8 mg/kg q 4-24 hours as needed. Intramuscular adminis tration is not recommended. Give IV slowly at no more than 2 0 % total dose per minute. (d) . Thiopental (PENTOTHAL), by continuous intravenous in fusion, may help to control severe seizures. Dissolve one gram in 500 ml of glucose solution, and infuse at a rate just suffi cient to stop seizures. CAUTION: Laryngospasm is a complication of anticonvul sant therapy and may require tracheostomy. (e) . In some instances, curarization with succinylcholine or a similar agent is required to stop convulsions. This requires tracheal intubation or tracheostomy and mechanical pulmo nary ventilation, with regular monitoring of blood gases and pH. 63 5. Many other agents tested in fluoroacetate poisoning are NOT EFFEC TIVE: ^ium acetate, calcium chloride, ethanol, propylene glycol, digitalis _ ycosides, di- and tri-acetates of glycerol. 6 . Administer IV electrolyte solutions cautiously to avoid fluid overload in presence of a weak and irritable myocardium. Zinc phosphide and yellow phosphorus 1. WASH SKIN BURNS due to yellow phosphorus with water and a 1% copper sulfate solution. Make sure all particles of phosphorus have been removed. Cover burned area with ointment. 2. Poisonings by INGESTED yellow phosphorus or zinc phosphide are ex tremely difficult to manage. The mortality rate of 50% is the result of either shock or pulmonary edema in the first few hours or days, or coma, seizures, and/or liver, kidney and myocardial damage in the ensuing days or weeks. CAUTION: Highly toxic phosphine gas may evolve from emesis. lavage fluid, and feces of victims of these poisons. The pa tient's room should be well ventilated. A. INTUBATE and ASPIRATE the stomach. LAVAGE with several quarts of 1:5000 potassium permanganate solution. CAUTION: Persons attending victim must avoid contact with yellow phosphorus, which causes skin burns. B. Combat shock and acidosis with TRANSFUSIONS of whole blood and INFUSIONS of glucose and electrolyte solutions. Monitor fluid balance and central venous pressure to avoid fluid overload. Monitor blood electrolytes and pH to guide choice of intravenous solutions. C. Administer 100% OXYGEN by mask or nasal tube. D. Combat pulmonary edema with intermittent or continuous POSI TIVE PRESSURE OXYGEN. E. MONITOR URINE albumin, glucose, and sediment to detect early renal injury. Monitor EKG to detect myocardial impairment. Moni tor serum alkaline phosphatase, LDH, prothrombin time, and bilirubin to evaluate liver damage. F. Include Aquamephyton (vitamin K.) in intravenous infusions if prothrombin level declines. Dosage of 10-50 mg per day may be re quired. Administer Aquamephyton slowly, intravenously; stop infusion if Hushing, cyanosis, paresthesiae, hypotension, or dyspnea occurs. G. MORPHINE SULFATE, 8-16 mg every few hours may be necessary to control pain. Child's dose: 0.1-0.2 mg/kg. 0 ^ H. CONTROL CONVULSIONS with diazepam, barbiturates, and/or phenytoin as suggested under tr e a tm e n t o f s o d iu m f lu o r o a c e ta te p o iso n in g . QQ I. CORTICOSTEROIDS at high dosages may be beneficial. 64 Strychnine and crimidine 1. Administer 100% OXYGEN by positive pressure. 2. CONTROL CONVULSIONS. This may be attempted with intravenous diazepam, barbiturates, and/or phenytoin, as described under m an age m ent o f sodium flu oroacetate poisoning. A. CURARIZATION is often required, using succinylcholine or similar agent. Tracheal intubation or tracheostomy and continuous mechanical pulmonary ventilation are necessary. Blood gases and pH must be monitored. 3. FORCED DIURESIS with mannitol accelerates the excretion of strychnine. Infusion of SODIUM BICARBONATE relieves metabolic acidosis. There may be some benefit from peritoneal dialysis, hemodialysis, and hemoperfusion. 4. Once seizures have been controlled, remove unabsorbed toxicant from the stomach by gastric INTUBATION, ASPIRATION, and LAVAGE. Leave a slurry of 30-50 gm ACTIVATED CHARCOAL in the stomach. Follow charcoal with SODIUM or MAGNESIUM SULFATE, 0.25 gm/kg, in 1-6 ounces of tap water, to induce catharsis. Repeat cathartic dosage as needed. Vacor, DLP-787 (Active ingredient RH-787) 1. If toxicant was ingested recently, EVACUATE the STOMACH by IN TUBATION, ASPIRATION, and LAVAGE with 2-3 liters isotonic saline. A. Before withdrawing stomach tube, instill 30-50 gm of ACTIVATED CHARCOAL as a slurry in 3-4 ounces of water, to limit absorption of remaining toxicant. B. As soon as patient can tolerate oral fluids after withdrawal of stomach tube, give SODIUM or MAGNESIUM SULFATE, 0.25 gm/kg body weight in 1-6 ounces of water to induce catharsis. Repeat dose in 4 hours if patient has had no bowel movement. 2. Administer NICOTINAMIDE (niacinamide) intravenously, slowly, or intramuscularly. For adults and children over 12 years, give 500 mg im mediately, then repeat injections of 200-400 mg every 4 hours for 10-12 doses. Within this range, select the dose on the basis of body weight and the estimated quantity of RH-787 ingested. If manifestations of RH-787 toxicity appear, give nicotinamide by continuous IV infusion at about 100 mg per hour. There is probably no advantage in giving more than 3000 mg per day of nicotinamide. A. Dosage of nicotinamide for children under 12 years, or 23 kg, is about half the dosage suggested for adults. B. After 2-3 days of parenteral therapy, give nicotinamide by mouth, 100 mg four times daily, for 2 weeks. 65 3. MONITOR blood and urine sugar concentrations, serum alkaline phosphata' amylase, LDH, and GOT activities, urine ketone concentra tions, bloc jlectrolytes and BUN. Examine the electrocardiogram for arrhythmias. 4. Unless the patient is able to void easily, put in place a RETENTION CATHETER to monitor urine flow and urinary glucose excretion. 5. Infuse ELECTROLYTE SOLUTIONS intravenously to accelerate toxi cant excretion and correct errors in specific ion concentrations. If ketoacidosis appears, use bicarbonate or Ringer's-lactate to control acidosis. 6. If DIABETIC KETOACIDOSIS appears (ketonuria, metabolic acidosis, hyperglycemia) administer enough regular insulin to control the acidosis and hyperglycemia, as in naturally occurring diabetic ketosis. The diabetes resulting from RH-787 tends to be brittle and correspondingly difficult to control. 7. In all cases of ingestion of Vacor or DLP-787 (whether or not acute poisoning occurs), follow the patient's clinical status carefully for at least 6 months. Look for indications of diabetes mellitus (glycosuria, hyper glycemia), and for consequences of autonomic nervous system damage: orthostatic hypotension, urinary retention, constipation, diarrhea, ab dominal cramping, pain and weakness in the limbs'. Red squill 1. Significant toxicity is not expected from this agent. If, for some reason, a significant amount is retained in the stomach, remove it by gastric IN TUBATION, ASPIRATION, and LAVAGE, followed by 0.25 gm/kg SODIUM or MAGNESIUM SULFATE in 1-6 ounces water. 2. Monitor ELECTROCARDIOGRAM for arrhythmias and conduction disturbances characteristic of digitalis. Antu 1. Significant toxicity is not expected from this agent. If an extraordinary amount has been ingested, empty the gut. Administer SYRUP OF IPECAC, then 1-2 glasses of water, to induce vomiting. Adult dose: 30 ml; dose for children under 12 years: 15 ml. Follow with 30-50 gm ac tivated charcoal in 3-4 ounces of water, then 0.25 gm/kg SODIUM or MAGNESIUM SULFATE in 1-6 ounces water. 2. If dyspnea appears, administer OXYGEN by continuous flow or by intermittent POSITIVE PRESSURE. Norbormide 1. Significant toxicity is not expected from this agent. If an extraordinary amount has been ingested, empty the gut. Administer SYRUP OF a :> 66 CD IPECAC, then 1-2 glasses of water, to induce vomiting. Adult dose: 30 ml; dose for children under 12 years: 15 ml. Follow wit' -50 gm AC TIVATED CHARCOAL in 3-4 ounces of water, the,. 0.25 gm/kg SODIUM or MAGNESIUM SULFATE in 1-6 ounces water. 2. Monitor BLOOD PRESSURE and BODY TEMPERATURE for several hours, if a large amount has been absorbed. 67 Chapter 12 FUMIGANTS CHEMICAL STRUCTURES HALOCARBONS Cl I Cl - C - Cl I Cl Carbon Tetrachloride Br Br Ii H C-- C - H II HH Ethylene Dibromide OXIDES AND ALDEHYDES / S c h 2 c h 2 Ethylene Oxide Cl II Cl - C H I Cl Chloroform Cl I Cl - c - n o 2 I Cl Chloropicrin H | H - C Br ! H Methyl Bromide Cl H Cl I II H -C -- C = C ii HH 1,3-Dichloropropene Br Br Cl II I H -C -C -C-H III HHH Dibromochloropropane Cl Cl II H -C -C H II HH Ethylene Dichloride CH2 - CH CH3 Propylene Oxide H C= 0 H Formaldhyde 0 r Hn Fc.] L iJ Hn Paraformaldhyde H HH I II C = C -c =0 I H Acrolein Oi ^**OE* 00 O 68 SULFUR AND PHOSPHORUS COMPOUNDS 0 =S=0 Sulfur Diox'de S=C=S Carbon Disulfide S=0 / F Sulfuryl Fluoride H .\ / . H P I| H Phosphine (from A l = P+ H20 ) CYANIDES H -C = N Hydrogen Cyanide HH II C = C C = I H Acrylonitrile C O M M O N C O M M ER C IA L FU M IG A N T PR O D U C TS Chloroform, carbon tetrachloride, methyl bromide (Brom-O-Gas, Fumi gant-1, Kayafume, Me Br, Meth-O-Gas, Pestmaster, Profume); chloropicrin (Acquinite, Chlor-O-Pic, Pic-Clor, Picfume, Tri-Clor); ethylene dichloride (EDC), ethylene dibromide (EDB, Bromofume, Celmide, Dowfume W-85, Kop-Fume, Nephis, Pestmaster EDB-85, Soilbrom); dichloroprop-ene and -ane (Telone, D-D), sulfuryl fluoride (Vikane), dibromochloropropane (DBCP). The Dowfume fumigants manufactured by the Dow Chemical Company are mixtures of halocarbons, mainly EDC, EDB, carbon tetrachloride, Me Br, and chloropicrin, formulated to meet specific needs. Ethylene oxide (ETO, oxirane); propylene oxide (epoxypropane); formalde hyde (Formalin is a 40% aqueous solution), propenal (Acrolein, Aqualin, Acrylaldehyde); carbon di- (or bi-) sulfide; hydrogen cyanide (prussic acid, Cyclon); acrylonitrile (ingredient of fumigant mixtures Acrylofume, Acritet, Carbacryl); aluminum phosphide (Phostoxin). TOXICOLOGY Fumigants have extraordinary power to penetrate the lining membranes of the respiratory and gastrointestinal tracts, and the skin. They also penetrate the rubber and plastics used in protective garb and they are not efficiently taken up by conventional adsorbents used in ordinary respirators. These prop erties make the protection of applicator personnel very difficult, essentially mandating methods of use that do not require on-site operator handling. Because these chemicals are either gases or volatile liquids at room tempera ture, inhalation is the most common route of absorption. Dermal injury does follow contact with some fumigants, ranging in severity from a mild chemical burn to vesiculation and ulceration. Fumigant gases irritate the eyes; liquid fumigant may cause blindness from corneal ulceration. Respiratory tract irritation is the most common and serious injury caused by fumigants. Some agents such as sulfur dioxide, chloropicrin, formaldehyde and acrolein cause so much irritation of the upper respiratory tract that the ex posed individual is unlikely to inhale a quantity of fumigant capable of damag ing the lung. Rarely, laryngeal edema or bronchospasm results from inhalation of high concentrations. Other gases, such as methyl bromide, phosphine, and ethylene oxide, are not so irritating to the nose, eyes, throat, and bronchi, but cause serious injury to the cells lining the fine air sacs of the lung. Thus, they are more likely than other fumigants to induce pulmonary edema, a major cause of death from fumigant exposure. In varying degrees, these fumigants depress the central nervous system. As in the case of the anesthetic chloroform, adequate dosage may lead to uncon sciousness. Depression or cessation of respiration is a major hazard of acute inhalation exposure to fumigants. Acute exposures to methyl bromide have in duced convulsions. Absorbed in lower concentrations over several consecutive 69 days, methyl bromide has impaired basal ganglion function in humans, caus ing ataxia for \ .s or months after exposure. Protracted exposure to carbon disulfide has caused peripheral neuropathy and changes in CNS function (chronic encephalopathy) of chronically exposed workers. The halocarbon fumigants increase the irritability of the heart muscle. In tensive exposures may lead to sudden death as a result of ventricular fibrilla tion. Liver and kidney damage occurs commonly following excessive exposure to fumigants. Liver injury may take the form of fatty infiltration, diffuse necrosis or massive necrosis. Elevated serum levels of GOT, LDH, alkaline phosphatase, and bilirubin reflect hepatocellular injury. The fumigants may inflict direct injury on glomerular and tubular elements of the kidney, leading to functional proteinuria and glycosuria, or to acute renal failure, depending on severity of toxicant exposure. In addition, hyperbilirubinemia resulting from liver damage may compound the tubular injury (hepatorenal syndrome). Inhaled phosphine gas (PH3) and ingested metal phosphides cause pulmonary edema, CNS depression, toxic myocarditis, and circulator, col lapse. Victims who survive these immediate actions suffer liver injury (fatty degeneration and necrosis) and acute renal tubular necrosis. Unlike its analogue arsine, phosphine is not hemolytic. Enzymatic mechanisms of toxici ty are not known. Ingested metal phosphide (from which phosphine is gener ated) causes intense gastrointestinal irritation, followed by degenerative and necrotizing lesions of the liver, kidney, and heart. Death is often due either to cardiogenic shock or pulmonary edema. Hydrogen cyanide (HCN) and its salts poison by inactivating the cytochrome oxidase of cells in critical tissues, primarily the heart and brain. Acrylonitrile degrades slowly to HCN in the body, and therefore acts primarily by the same mechanism, although the slow release of free cyanide renders it somewhat less toxic than HCN itself. Both HCN and acrylonitrile are suffi ciently absorbable across the skin to cause poisoning in the absence of inhala tion exposure. Manifestations of poisoning are due mainly to intracellular anoxia of brain tissue (leading to respiratory failure), and to the circulatory in sufficiency that results from myocardial weakness. The liver has substantial capacity for converting cyanide to the less toxic thiocyanate, a metabolic con version that is accelerated by therapeutically administered thiosulfate. Dibromochloropropane has reportedly caused sterility in manufacturing plant workers and reduced sperm counts in highly exposed applicators. FREQUENT SYMPTOMS AND SIGNS OF POISONING HEADACHE, DIZZINESS, NAUSEA, and vomiting are prominent early symptoms of excessive exposure to these gases. Sulfur dioxide, formaldehyde, chloropicrin, and acrolein are strong irritants, causing BURNING SENSA TIONS in the nose and throat, TEARING, COUGH, and sometimes hoarse ness and wheezing. Exposures to methyl bromide, phosphine and ethylene ox ide are^>re likely to produce prompt pulmonary edema: COUGHING of copious amounts of FROTHY FLUID, associated with Severe SHORTNESS OF BREATH and cyanosis. The remaining fumigants are less ly to cause respiratory tract injury. DROWSINESS, TREMORS, double vision, and weakness are the common early manifestations of central nervous system impairment. Tremors may progress to myoclonic movements, then to generalized SEIZURES, UNCON SCIOUSNESS, and death. Protracted low level exposure to methyl bromide causes ATAXIA and impairment of manual coordination. Injuries to the skin by liquid fumigants may be manifest as areas of redness or as BLISTERS which rupture, leaving raw skin or deep ulcers. If ingested, the LIQUID forms of HALOCARBONS often cause pulmonary edema and SHOCK within a few moments. If victim survives, injuries to the brain, liver and kidney are life-threatening. Longer-term low level inhalation of CHLOROCARBONS may cause liver damage, first manifest as ANOREXIA, then as JAUNDICE. Biochemical studies confirm hepatocellular injury. Poisoning by excessive inhalation of CARBON DISULFIDE is character ized by DIZZINESS, headache, nausea, and sometimes disorientation, paresthesiae, hallucinations, and, rarely, convulsions. Protracted low level exposures produce PAIN, tingling, WEAKNESS of the extremities, and deterioration of mental functions. Poisoning by PHOSPHINE gas is usually heralded by weakness, TREMORS, vomiting, a sense of pressure in the chest, COUGH, and dyspnea, sometimes progressing to PULMONARY EDEMA. Intense thirst results from hypotension and diarrhea. Severe poisonings lead to CONVULSIONS, coma, and death. Those who survive the acute phase suffer LIVER INJURY (eleva tion of serum GOT, LDH, and alkaline phosphatase, and sometimes, reduced prothrombin concentration, hemorrhage, and jaundice) and kidney damage (hematuria and sometimes anuria). Chronic exposures to lesser amounts have caused pain in the eyes and nose, nosebleeds, and abdominal pain. Ingestion of METAL PHOSPHIDES leads promptly to NAUSEA and VOMITING, followed by injury to the lung, liver, kidney, heart and central nervous system. Hypocalcmie tetany (from hyperphosphatemia) and metabolic acidosis develop several hours after ingestion of solid phosphides. Excessive inhalation of SULFURYL FLUORIDE may induce muscle twitch ing and convulsions. Persons repeatedly exposed risk injury to the lung (im paired pulmonary function) and kidney (proteinuria and azotemia). Poisoning by HYDROGEN CYANIDE or ACRYLONITRILE may pro duce sudden UNCONSCIOUSNESS and respiratory arrest without warning symptoms. Lesser exposures cause HEADACHE, nausea, and a sense of con striction in the throat, followed by hyperpnea, dizziness, and apprehension. Pulse and respiratory movements then become weak, slow, and irregular as consciousness is lost. CONVULSIONS, either tonic or epileptiform, may supervene. Opisthotonus and trismus commonly appear, and sphincter control is usually lost. The heart often continues to beat after respiration has stopped. The skin generally remains pink. 71 C O N FIR M A T IO N O F D IA G N O SIS Large industrial concerns monitor human absorption of halocarbons by analysis of expired air. Similar technology is available in many departments of anesthesiology. Such analyses are not often needed to identify the offending toxicant, because this is known from the exposure history. In managing dif ficult cases of poisoning, however, it may help to monitor breath concentra tions of toxic gas. Blood bromide concentrationst have some value in identifying poisonings by methyl bromide, and possibly ethylene dibromide, provided it can be estab lished that the person exposed to the fumigant has not recently taken inorganic bromide medication. A level of organic bromide higher than 5 m g/100 ml in dicates excessive absorption of fumigant. A blood concentration of more than 10 m g/100 ml of organic bromide represents a serious threat to health. A blood level of more than 15 mg/100 ml indicates an immediate threat to life. Methods for detecting the organic oxides, aldehydes, sulfur dioxide, and phosphine are not generally available, but they are rarely needed. A simple method is available for detecting carbon disulfide in urine (Djuric et al. Brit. J. Indust. Med. 22:321-323. 1965). Cyanide can be detected and measured in blood and tissues, as can the thiocyanate metabolite in urine and saliva. Odors of gases on the victim's breath are sometimes helpful diagnostic clues: cyanide smells like bitter almonds, carbon disulfide like rotten cabbage, and phosphine somewhat like garlic or acetylene. TREATMENT 1. FLUSH contaminating fumigant from the SKIN and EYES with copious amounts of water for at least 15 minutes. Contact with LIQUID fumigant can cause BLINDNESS or DEATH. Treat injuries IM MEDIATELY. 2. REMOVE victims of fumigant inhalation TO FRESH AIR. Even though initial symptoms and signs are mild, keep victim quiet, in a semireclining position. Reduction in physical activity reduces the likelihood of pulmo nary edema. 3. If victim is not breathing, RESUSCITATE with positive pressure oxygen breathing apparatus, if available. If apparatus is not available, use mouth-to-mouth or mouth-to-nose methods. If victim is pulseless,use cardiac resuscitation. 4. If PULMONARY EDEMA is evident, there are several measures avail able to sustain life. Medical judgment must be relied upon, however, in the management of each case. The following procedures are generally recommended: A. Put the victim in a SITTING position with a backrest. t Conway, E. J. Microdiffusion Analysis and Volumetric Error, 3rd edition. Crosby Lockwood, London 1950. 72 6182 B. Use intermittent and/or continuous positive pressure OXYGEN to relieve hypoxemia. (Do not give oxygen at greater c intrations or longer periods than necessary, because it may exaggerate the fumi gant injury to lung tissue. Monitor arterial p 0 2). C. Apply TOURNIQUETS in rotation to arms and legs to limit venous return. D. Administer AMINOPHYLLINE (0.25-0.50 gm) slowly, intraven ously. E. Administer MORPHINE in small doses (5-10 mg), slowly, intra venously, to allay anxiety and promote deeper respiratory excur sions. Children's dose, 0.1-0.2 mg/kg. F. Digitalization may be considered, but be alert to the serious risk of arrhythmias in an anoxic mycardium. G. Slowly administer FUROSEMIDE, 40 mg, or SODIUM ETHACRYNATE, 50 mg, to reduce venous load by inducing diuresis. H. TRACHEOSTOMY may be necessary in some cases to facilitate aspiration of large amounts of edema fluid. I. Epinephrine, atropine, and expectorants are generally NOT HELPFUL and may complicate treatment. J. STEROIDS at high dosage are usually recommended, although their effectiveness is unproved. K. If secondary pneumonitis occurs, administer ANTIBIOTICS. L. Watch for RECURRENT PULMONARY EDEMA, even up to 2 weeks after the initial episode. Limit victim's physical activity for at least 4 weeks. Severe physical weakness usually indicates persistent pulmonary injury. Serial pulmonary function testing may be useful in assessing recovery. 5. Combat SHOCK by placing victim in the Trendelenburg position and ad ministering blood plasma and/or electrolyte and glucose solutions intra venously, with great care, to avoid pulmonary edema. Central venous pressure should be monitored continuously. Vasopressor amines must be given with great caution, because of the irritability of the myocardium. 6. Control CONVULSIONS. Seizures are most likely to occur in poisonings by methyl bromide, carbon disulfide, phosphine, metal phosphide, cyanide, and acrylonitrile. A. Establish pulmonary gas exchange at the best possible level by ad ministering 100% OXYGEN by IPPB. B. In poisoning by CYANIDE and acrylonitrile, proceed directly with ANTIDOTAL therapy (see below, paragraph 10C). C. Control convulsions caused by other agents with careful IV injec tion of DIAZEPAM, 5-10 mg in the adult, 0.1 mg/kg in children under 12 years. Repeat dosage in 4-6 hours if necessary. CAUTION: Be prepared to maintain pulmonary ventilation mechanically, and to manage hypotension and car diac arrhythmias. 73 D. In methyl bromide poisoning, it may be necessary to give diazepam o rbiturates orally for some time after the acute poisoning to comrol involuntary motor activity. 7. If FUMIGANT LIQUIDS have been INGESTED, quantities remaining in the gut must be removed as effectively as possible by gastric INTUBA TION, ASPIRATION, and LAVAGE. A. IF victim is UNCONSCIOUS, put in place a cuffed endotracheal tube prior to gastric intubation. B. Place conscious victim in a left lateral Trendelenburg position for intubation, and aspirate the pharynx as effectively as possible to minimize likelihood of tracheal aspiration. C. After aspirating stomach contents, LAVAGE the stomach with 2-3 liters 0.9Vo saline or 5Vo sodium bicarbonate, containing 30-50 gm ACTIVATED CHARCOAL. After lavage, leave 30-50 gm activated charcoal in stomach before withdrawing tube. D. If diarrhea does not develop spontaneously, give SODIUM SULFATE orally, 0.25 mg/kg, to induce catharsis. 8. Intravenous INFUSIONS of GLUCOSE are valuable in limiting the hepatotoxicity of fumigants. Monitor central venous pressure to avoid precipitating, or aggravating, pulmonary edema by fluid overload. 9. MONITOR fumigant poisoning victims closely for recurrent pulmonary edema and bronchopneumonia. Chart fluid balance and check urine sediment regularly to detect incipient tubular necrosis. Measure serum alkaline phosphatase, LDH, and bilirubin to assess liver injury. 10. Certain SPECIFIC MEASURES are recommended in poisonings by par ticular fumigants: A. If given very soon after exposure to METHYL BROMIDE, there may be some value in administering DIMERCAPROL (BAL) in vegetable oil intramuscularly. For adults, give 3-5 mg/kg q6h for 4 doses. CAUTION: DIMERCAPROL may cause troublesome side ef fects (hypertension, tachycardia, nausea, headache, paresthesiae, pain, lacrimation, sweating, anxiety, and restlessness). Although usually not so severe as to preclude treatment, these manifestation may require antihistamine therapy for adequate control. B. Mild poisonings by CARBON DISULFIDE inhalation may be man aged best by no more than careful observation, even though sensory hallucinations, delirium, and behavioral aberrations can be alarm ing. Severe poisonings may require specific measures: 1. CAFFEINE and sodium benzoate (0.5 gm subcutaneously) may help to relieve CNS depression. 6183 74 2. If manic behavior threatens the safety o f the victim, DIAZEPAM, 5-10 mg, 0.1 mg/kg in chi. l, adminis tered cautiously, intravenously, may be helptul as a tran quilizer. Do not give catecholamine-releasing agents such as reserpine and amphetamines. C. Poisonings by HYDROGEN CYANIDE and ACRYLONITRILE gases are treated in essentially the same way as poisoning by cyanide salts. In addition to the general treatment described earlier, specific ANTIDOTES are required. (See line 6 for pediatric regimen). 1. Administer AMYL NITRITE (perles) by inhalation for 15-30 seconds of every minute, while a fresh solution of 3% sodium nitrite is being prepared. 2. As soon as solution is available, inject intravenously 10 ml of 3% SODIUM NITRITE solution over a 2-4 minute interval, keeping the NEEDLE IN PLACE. CAUTION: Monitor PULSE and BLOOD PRESSURE dur ing administration of amyl nitrite and sodium nitrite. If systolic blood pressure falls below 80 mm Hg, slow or stop nitrite administration un til blood pressure recovers. 3. Follow sodium nitrite injection with an infusion of 50 ml of 25% aqueous solution of SODIUM THIOSULFATE admin istered over 10-minute period. Initial adult dose should not ex ceed 12.5 gm. 4. If symptoms persist or recur, treatment by sodium nitrite and sodium thiosulfate should be REPEATED AT HALF THE DOSAGES listed in paragraphs 2 and 3. 5. Measure hemoglobin and methemoglobin in blood. If more than 50% of total hemoglobin has been converted to methe moglobin, BLOOD TRANSFUSION or exchange transfusion should be considered, because conversion back to normal hemoglobin proceeds slowly. 6. Dosage of ANTIDOTES in CHILDREN: C. M. Berlin (Pediatrics 46:793-796, 1970) has recom mended the following procedures in case of cyanide poi soning in children: (a) Children over 25 kg body weight should receive adult dosages of sodium nitrite and sodium thiosulfate. (b) Children less than 25 kg body weight should first have two 3-4 ml samples of blood drawn and then, through the same needle, receive 10 mg/kg (0.33 ml/kg of 3% solu tion) of SODIUM NITRITE injected over a 2-4 minute in terval. Following sodium nitrite, administer an infusion of 75 1.65 ml/kg of 25% SODIUM THIOSULFATE at rate of 3-5 ml per minute. (c) At this point, determine the hemoglobin content of the original blood sample. If symptoms and signs of poison ing persist or return, give su p p le m e n ta l infusions of sodium nitrite and sodium thiosulfate based on hemoglo bin level, as presented in TABLE 2. (These recommended quantities are calculated to avoid life-threatening methe moglobinemia in anemic children). TABLE 2. R e c o m m e n d e d d o s a g e s o f s u p p le m e n ta l s o d iu m n itr ite a n d so d iu m th iosu lfate b a sed on hem oglobin level. Initial Hemoglobin Concentration, gm/100 ml 14.0 13.0 12.0 11.0 10.0 9.0 8.0 7.0 Supplemental Volume o f 3% Sodium Nitrite, ml/kg 0.26 0.21 0.17 0.12 0.07 0.04 0 0 Supplemental Volume of 25% Sodium Thiosulfate, ml/kg 1.28 1.05 0.83 0.60 0.38 0.23 0 0 (d) When possible, monitor BLOOD LEVELS of METHEMOGLOBIN to achieve approximately 40% conversion of hemoglobin to methemoglobin. 6184 76 Chapter 13 MISCELLANEOUS PESTICIDES OF HIGH TOXICITY Pesticides included in this chapter are not similar in chemical structure or toxicologic actions to the major classes of pesticidal toxicants (organophosphates, arsenicals, etc.) In general, they are not widely used and opportunities for serious human exposure are rare. However, those included here are charac terized by either high toxicity or an important unique mechanism of toxic ac tion. Occasional poisonings by these chemicals have occurred in humans and domestic animals. 4-aminopyridine (Avitrol, 4-AP) This chemical, now used as a bird repellant, has caused severe poisoning in adult humans at dosages no greater than about 60 mg. This is only 2-3 times the dosage employed clinically in managing certain rare neuromuscular dis orders. The principal pharmacologic action of 4-aminopyridine is to facilitate release of transmitter substances at neuroeffector junctions and at synapses throughout the nervous system. Human poisonings have been characterized by thirst, nausea, dizziness, weakness, and intense diaphoresis, followed by toxic psychosis, ataxia, tremors, dyspnea, and tonic-clonic convulsions. Metabolic acidosis, leukocy tosis, and elevations of serum GOT, LDH, and alkaline phosphatase were notable laboratory findings. EKG may show nonspecific ST-T wave changes. Treatment Promptly evacuate gut by intubation, lavage, activated charcoal administra tion, and saline catharsis. Control convulsions with diazepam. Initiate diuresis with intravenous infusions, including mannitol. To date, poisoning victims have recovered in 24-48 hours without severe sequelae. Pancuronium is an antagonist of 4-aminopyridine, and can control seizures. It must be administered under the supervision of an anesthesiologist because of the likelihood of generalized paralysis. Propranolol may help to limit car diac toxicity. Atropine controls the gastrointestinal symptoms. Chlordimeform (Acaron, Fundal, Fundex, Galecron, Spanone) Although the acute toxicity of this ovicidal agent is low (oral LDJ0in the rat about 200 mg/kg), it is now known from an incident of excessive respiratory and dermal exposure to chlordimeform powder that it can cause acute illness and urinary bladder irritation. In all likelihood, the offending metabolite is 2-methyl-4-chloroaniline. Principal symptoms are dysuria, gross hematuria, urethral discharge, abdominal and back pain, and a hot sensation all over. Sleepiness, skin rash, anorexia, and a sweet taste in the mouth have also been 77 reported. Cystoscopic examination of victims of excessive exposure demonstrate ute hemorrhagic cystitis. Methods are available for detecting the 2-methyl-4-chloroaniline metabolite in the urine. Treatment Flush contaminant from eyes and wash from skin. Symptoms resulting from undue occupational exposure resolve in a few days if exposure is terminated. If chlordimeform has been recently ingested, it should be removed from the gut either by administering Syrup of Ipecac, or by gastric intubation, aspiration, and lavage with 0.9% sodium chloride, followed by activated charcoal and sodium sulfate catharsis. Serial urinanalyses should be performed to assess in jury to the urinary tract. Copper salts and organic complexes (oxide, hydroxide, arsenite, carbonate, chloride, oxalate, phosphate, silicate, sulfate, zinc chromate, acetate, naphthenate, oleate, quinolinolate, and resinate). These are commonly used as fungicides, either alone or in combination with other agents. There are several dozen proprietary products. LDJ0 values vary from 6 to 1000 mg/kg, depending mainly on the solubility and degree of ionization of the copper compound. Toxicity of copper-arsenite salts is due mainly to the arsenic content. All of these salts irritate the skin and eyes and damage mucous membranes. When ingested, they are powerfully emetic: the stomach usually empties promptly and automatically in fully conscious individuals. When retained and absorbed, toxic injury affects the gastrointestinal lining, capillaries, brain, liver, kidney, and formed elements of the blood. Copper salts are hemolytic. Manifestations of poisoning include burning pain in the chest and abdomen, intense nausea, vomiting, diarrhea, headache, sweating and shock. Later, the liver is enlarged. Jaundice may reflect hemolysis or liver damage or both. Anuria indicates kidney injury by copper and/or free hemoglobin. Death may occur from convulsions, coma, or hepatorenal failure. Elevated serum copper levels (maximum normal level is 125 Mg per 100 ml) indicate severity of poison ing. Treatment Wash contaminated skin and flush eyes with copious amounts of water. If copper salts have been ingested, lavage the stomach with 0 .1% potassium ferrocyanide, then instill a suspension of egg white. Intravenous fluids ac celerate excretion. If signs of systemic poisoning develop, give dimercaprol (see Arsenical Pesticides for dosage) or penicillamine, 0.5 gm orally four times daily, if patient can retain oral medication. Shock may require blood trans fusions and pain may require morphine. Exchange transfusions may be consid ered in severe poisonings. Renal failure may require protracted hemodialysis. Cycloheximide (naramycin, Acti-dione, Actispray, Hizarocin) This is an antibiotic fungicide of high toxicity: oral LDJ0 in rats is 2 mg/kg. 78 RI85 Dermal absorption is probably not efficient. When ingr -d, the agent causes excitement, tremors, salivation, diarrhea, and melena. .chanisms of toxicity are not well defined, but probably include irritation of the gut, stimulation of sympathetic and parasympathetic nervous systems, renal in jury, and damage to the adrenal cortex. There are no chemical tests to confirm cycloheximide poisoning. Treatment Remove toxicant from gut by lavage. Instill activated charcoal, then a cathartic dose of sodium sulfate. Intravenous fluids accelerate excretion. Hydrocortisone appears to be antidotal, particularly in combination with the adrenergic agent methoxyphenamine (Orthoxine). Atropine relieves the cholinergic symptoms. Endothall (Accelerate, Aquathol, Des-i-cate, Hydout, Hydrothol) Acute oral LDJ0 of this herbicide is 51 mg/kg. Dermal absorption of the commonly used salts is probably slight. It is irritating to eyes, mucous mem branes and skin, but it is not sensitizing. Mechanisms of systemic toxicity are not clear, but the central nervous system, heart, blood vessels, and gastrointes tinal lining appear to be primary targets. Poisoned animals exhibit ataxia, con vulsions, shock, and respiratory depression. Erosions and ulcers of the gastro intestinal tract follow ingestion. There are no standard analytical methods for confirming poisoning. Treatment Wash contaminated skin and flush eyes with copious amounts of water. In stead of gastric evacuation following ingestion, administer cold milk or aluminum hydroxide gel. This may be followed by saline catharsis. There is no specific antidote. Shock may require blood transfusions. Use of adrenergic amines is probably hazardous in view of myocardial irritability. Nicotine sulfate (Black Leaf 40) This time-honored natural insecticide is still used in horticulture. Lethal dose in humans is about 60 mg. Nicotine preparations, especially those using the free alkaloid, are well absorbed across the gut wall, lung, and skin. Poisoning symptoms from excessive doses appear promptly. They are due to transient stimulation, then prolonged depression, of the central nervous system, autonomic ganglia, and motor end-plates of skeletal muscle. Central nervous system injury is manifest as headache, dizziness, incoordination, tremors, then clonic convulsions leading to tonic-extensor convulsions which are often fatal. In some instances, convulsive activity is minimal and death by respiratory arrest occurs within a few minutes. Effects on autonomic ganglia give rise to sweating, salivation, nausea, abdominal pain, diarrhea, and hyper tension. The heart is usually slow, and often arrhythmic. Block of skeletal muscle motor end-plates causes profound weakness, then paralysis. Death may occur from respiratory depression or from shock. Nicotine can be measured in blood and urine to confirm poisoning. 79 Treatment Prompt yash contaminated skin and flush eyes with water. Ingestion of nicotine requires immediate gastric intubation, aspiration, and lavage, the lat ter preferably with 1.5% tannic acid solution, or 1:5000 potassium perman ganate solution. Before withdrawing the lavage tube, instill 3-4 ounces of ac tivated charcoal in a slurry of water. Diazepam and/or barbiturates may be re quired to control convulsions. Atropine and phenoxybenzamine (Dibenzaline) may help to control the autonomic manifestations. Positive pressure ventilation of the lungs with oxygen may be necessary to sustain life when respiration is arrested. Phenylmercuric salts. Most commonly used is phenylmercuric acetate (PMA, Agrosan, Cekusil, Gallotox, Hong Nien, Luquiphene, Mersolite, Phenmad, Phix, PMAS, Shimmer-ex) Phenylmercuric acetate is a widely used fungicide. Acute oral LDJ0 in the rat is 22 mg/kg. Other salts are also highly toxic. They probably undergo some dermal absorption. Because of lower volatility and less penetration of the brain, they are somewhat less toxic than alkyl mercury compounds. Early manifestations reflect injury to the central nervous system: ataxia, muscle weakness, visual impairment, and delirium. After a single moderate ex posure, these symptoms usually resolve promptly. Repeated intensive exposures cause symptoms and signs resembling amyotrophic lateral sclerosis: weakness and incoordination of the arms, difficulty in swallowing and talking, weakness and spasticity of the legs. Concurrent or later manifestations of excessive ab sorption reflect renal injury: albuminuria, hematuria, azotemia, and some times acute tubular necrosis. Induction of nephrotic syndrome has been reported. This is characterized by massive albuminuria, generalized edema, and hypercholesterolemia. Methods are available at specialized toxicology laboratories for measuring phenylmercuric compounds in urine. Treatment Wash contaminated skin and flush eyes with water. If ingested, remove the chemical from the gut by prompt gastric intubation, aspiration, and'lavage with 5% sodium bicarbonate solution and instillation of activated charcoal, followed by catharsis with sodium or magnesium sulfate. Intravenous infu sions of fluids accelerate excretion of mercurials and limit kidney damage. There is no specific antidote; dimercaprol is not very effective in limiting tox icity. Sodium chlorate (De-Fol-Ate, Drexel Defol, Drop-Leaf, Fall, Grain Sorghum Harvest-Aid, Klorex, Kusatol, Tumbleaf) Although the oral LD,0 in the rat is high (1200 mg/kg), there have been sev eral deaths from this herbicide-defoliant in the past decade. The principal mechanisms of toxicity are irritation of the gastrointestinal lining, central ner vous system depression, hemolysis, oxidation of free hemoglobin to methemoglobin, and renal tubular injury. Dermal absorption is minimal. If ingested, 80 6188 chlorate causes swelling of the oral and pharyngeal membranes and pain in the chest and abdomen. The victim is first restless, then apatheti n the third or fourth day after ingestion, lumbar pain, albuminuria, hematuria, then anuria with azotemia, reflect renal injury. Death may be due to hyperkalemia (hemolysis), tissue anoxia (methemoglobinemia), or renal failure. Although chlorate itself is not readily measured in the blood, free hemoglobin and methemoglobin in the plasma point to poisoning by an oxidiz ing agent. Treatment Remove from gut by prompt gastric intubation, aspiration, and lavage using 3 gm sodium thiosulfate in 300 ml 5% sodium bicarbonate. Instill 30-50 gm ac tivated charcoal in a slurry. Pain may require narcotics. Both hemodialysis and exchange transfusions have been used successfully in treating poisonings. Methylene blue is of no value in reducing the extracellular methemoglobin. In travenous infusions of 1% sodium thiosulfate (100-500 ml) limit the concen tration of circulating chlorate. Monitor serum electrolytes. Hemodialysis may be needed to sustain life in the event of extensive renal tubular necrosis. Sodium cyanide (Cymag) Occasionally, this is used as a rodenticide. Toxicity is extreme, similar to that of hydrogen cyanide gas used as a fumigant. CONSULT Chapter 12 on FUMIGANTS (hydrogen cyanide) for toxicology, poisoning manifestations, diagnosis, and management. Cyanide salts are not adsorbed on activated char coal. 81 Chapter 14 MISCELLANEOUS PESTICIDES OF LOW OR MODERATE TOXICITY These compounds are included in the manual because their wide use generates inquiries as to their potential for causing adverse effects. Description of the toxic potential of these chemicals as low or moderate does not preclude the need for cautious handling. Many agents have irritant prop erties, and individuals vary widely in their reactions to them. Certain predisposed persons may suffer dermal and respiratory illness from substances that have no effect on other persons or experimental animals. It is also true that the sum total of potential effects of a chemical, and by-products formed in synthesis and storage, plus the metabolites formed into vivo is never fully known. Reasonable precautions to avoid contact with pesticides are always recommended regardless of the reported toxicity of the principal active ingre dient. Lowest reported acute oral LD10 in the rat is cited in this listing as an indica tion of overall toxicity, manifest as killing power. The LD30 rating says nothing of dosages necessary to produce symptoms or signs, disease conditions characterized by long latency, subclinical biochemical effects, or other nonlethal effects on health. It is essential that high LD50 ratings not be interpreted as indications that the subject chemicals are innocuous. Knowledge of use is sometimes helpful in identifying chemicals. Agents on this list are used as herbicides (H), fungicides (F), or insecticides (I). There are many proprietary MIXTURES of these chemicals and it is common to tank mix many of them according to the grower's requirements. Intelligent management of exposures requires that the full list of active ingredients in mix tures be ascertained from the producer or applicator. In general, management is aimed at the most toxic ingredient. Chem ical Cl* Acetamld69 G e n e ric N am e altidochlor metotachlor Acetanilides alachlor propachlor propani! Uee -0, Proprietary N am e H 750 Randox, CDAA H 2,780 Dual, Bicep, Primagram, Prlmextra Known or Suapected Adverse Effect* Moderately Irritating to skin and eyes. H 1,800 Lasso, Lazo, Alanex Mild Irritant H 710 Ramrod, Bexton Dermal irritant and sensitizer H 1,384 DPA, Propanex, Riselecf, Rosanil, Stam F34, Strel, Super- _ Mild Irritant nox, Surcopur, Surpur, Vertac 8187 82 Chem ical C IM I Aliphatic Acids Alumlnofluorlde salt Benzenes G e n e ric N am e dlchloropropionic acid trichloro acetic acid sodium fluoroalumnate hexachlorobenzene (perchiorobenzene) paradlchlorobenzene U i* H H 1 F i Benzoic and Benzlllc Acid Derivatives pentachloronitrobenzene benzyl benzoate F 1 chlorobonzllate 1 Benzonltrlles Carbamates trlchlorobenzoic acid chlorothalonll dlchlobenll asulam benomyi chlorpropham H F H H F H Carbanllate Dlcarboxlmldes Dlnltrotoluidine Compounds terbucarb barban captafol captan tolpet (thlophal) benefln butralin dlnltroamlne fluchloralln Isopropalln oryzalln pendlmethalin profluralin H H F F F H H H H H H H H LO Proprietary Name wh or Suspected W en* EHeets 970 5,000 Dalapon, Dowpon, Crlsapon, Basfapon TCA r _ Skin and eye L1 Irritants >10,000 Cryolite, Kryoclde 10,000 HCB, No Bunt, Anticarie Slight Irritant [Chronic ingestion causes porphyria cutanea tarda 500 PDB, Paraclde 1,700 PCNB, Terrachlor Mild respiratory irritant and ihepatotoxln Skin Irritant 1,700 Benzyl benzoate Irritating to akin and 960 Acaraban, Akar, Benzllan, Kop- eyes. Mlte, Benz-O-Chlor 1,370 Benzac, TBA, TCBA, Trlbac - 10,000 Bravo, Daconll 2767 3,160 Casoron, Du-Sprex Moderately irritating to skin and respiratory tract 5,000 Aaulox 40, Asulox F Mild Irritants. 10,000 Benlata, Tersan 1961 3,800 Furfoe, Chloro fPC, CIPC, Sprout Nip, Taterpex, Unlcrop CIPC These carbamates do not Inhibit cholinesterase enzyme. 34,000 Azak, Azac, Azar - 600 Carbyne, Neoban, Caryne Irritant and dermal sensitizer 6,200 Dlfolatan 10,000 Captan, Merpan, Orthoclde Skin irritant Skin Irritant 10,000 Phallan, Folpan Skin Irritant 10,000 Benfluralln, Bethrodine, Balfin, Benefex, Ouilan 12,600 Amex 3,700 Olnltramlne, Cobex 1,550 Basalin 5,000 Paarlan 10,000 Surtan, Rycelan, Ryzetan Slightly to moderately Irritating to skin, eyes, and _ m ucous membrsnes. These agents do not uncouple oxidative phosphorylation. 1,250 Prowl, Herbadox, Stomp 1,808 Tolban, Pregard Chem ical C a Q a n arlc Name trlfluralln Oxadlazollnone oxadlazon Phthalate Plcollnlc acid Derivativa Pyrldazlnone chlorthaldimethyl picloram maleic hydrazide Phosphonomethyl glyphoaate glycine Thtadlazin (o) bentazon Trlazlnes cn> go UCJ (orrazole am airyn anilazlne atraton atrazlne cyanazine desmetryn Isomethlozin metrlbuzln prometone prometryn propazlne Slmazlne u L5o Proprietary N am e Known or Supctad Adverse Elteeta H >10,000 Treflan, Crlsallna, Dlgermln, Slightly to Elancofan, Ipersan to moderately Irritating to skin, eyes, and mucous membranes. These agents do not uncouple oxidative phosphorylation. H 3,500 Ronstar Irritating to skin and eyes H 3,000 Dacthal, DCPA Mild Irritant H 8,200 Tordon, Amdon i Irritating to skin, eyes, and ^respiratory tract Growth retardant 6,950 Burtolln, Chemform, De-Cut, De-Sprout, Regulox, KMH, Maintain, Stunt-Man Slightly Irritating H 4,300 Roundup Irritant to eyes and respiratory tract H 2.063 Basagran Moderately irritating to skin, eyes, respiratory tract. On Ingestion, has caused vomiting, diarrhea, dyspnea, tremors, weakness. F 1,077 Terrazole "Moderately Irritating to skin, eyes, and respiratory tract. H 1,750 Evlk, Ametrex, Gesapax -- H 5,000 Dyrene, Dlrez, Kemate, Trlasyn H 1,465 Atratone, Gesatamin H 3,080 AAtrex, Atranex, Gesaprim, Prlmatol A, Atred, Crl9azine, Vectal SC Some triazines are mildly irritating to H 334 Bladex, SD 15418 9kin, eyes, arid up per respiratory tract. H 1,390 Semeron -- Systemic toxicity Is unlikely unless very H 10,000 Tantlzon large amounts have been Ingested. H 1,100 Sencor, Lexone, Sencorex, Sencoral H 2,980 Pramltol, Gesafram-50, Prometon, Prlmatol 25E H 5,235 Caparol, Gesagard, Prlmatol Q, Prometrex H >5,000 Mllogard, Gesamll, Prlmatol P. Prozlnex H >10,000 Prlncep, Gasatop, Simadex, Slmanex 84 Chem ical C lass Trlazlnes Ganarte N am e terbuthytazine terbutryn Us* H H Uracils bromacil H lenacil terbacil Urea Derivatives chloroxuron chlortoluron difenoxuron diflubenzuron diuron H H H H H 1 H fluometuron isoproturon H H linuron H methabenzthiazuron metobromuron metoxuron H H H monolinuron H monuron neburon siduron tebuthiuron tetrafluoron H H H H H LD50 Proprietary Name , Known or Suspected Adverse Effects 2,610 Primatol-M, Gardoprim. GS 13529 2,500 Igran. Terbutrex Some triazines are mildly irritating to skin, eyes, and up per respiratory tract. Systemic toxicity is unlikely unless very large amounts have been ingested. 5,200 Hyvar X, Uragan, Urox B, Urox HX Irritant to skin, eyes, and respiratory tract. 11.000 Venzar 5,000 Sinbar Moderately Irritating 3,700 Tenoran, Chloroxifenidim 10,000 Dicuran, Tolurex, Clortokem 7,750 Lironion 4,640 Dimilin 3,400 Cekiuron, Crisuron, Dailon, Dlater, Di-on, Diurex, Dirurol Dynex, Karmex, Unidron, Urox D, Vonduron 6,416 Cotoran, Lanex, Cottonex 1,826 Arelon, Belgran, Graminon. Tolkan 1,500 Afalon, Hoe 2010, Linurex, Lorox, Premalin, Sarclex Many substituted ureas are moderate-- ly irritating to skin, eyes, and mucous membranes. 2,500 Tribunil 3,000 Patoran, Pattonex 3,200 Deftor, Dosanex, Dosaflo, Purivel 1,800 Aresin, Afesin. Arresin. Premalin 3,600 Monurex 11,000 Granurex, Kloben, Neburex 7,500 Tupersan 644 Spike 1,265 Tomilon 85 TOXICOJ ''GY Many of these compounds are primary irritants to skin, eyes, and respira tory tract. The ureas and uracils are perhaps the most common offenders, although captafol and chlorothalonil have apparently caused contact der matitis in some agricultural workers. Propachlor is a dermal sensitizer in predisposed individuals. Although hexachlorobenzene has low acute toxicity, long-term ingestion of HCB-treated seed grain caused an epidemic of porphyria cutanea tarda among Turkish farm families in the 1950's. No such effect has been found in HCB handlers in the United States. Given to cattle in extreme dosage, some triazines have caused neuromuscu lar abnormalities and damage to internal organs. It is unlikely that domestic animals would consume these amounts voluntarily, and still less likely that humans would be exposed to such extreme dosage. CONFIRMATION OF ABSORPTION The benzene derivatives and benzonitriles can be identified in plasma by gasliquid chromatography. Methods for benzoic acid and triazine metabolites in urine have been developed. Analytical methods used for agricultural residues of the remaining compounds might be adapted to analysis of gastric contents or skin wipings. Samples must be collected within hours of exposure, because most of these chemicals are promptly excreted. It is unlikely that such analyses will be required in cases of human exposure to these agents. In the event that workers experiencing protracted heavy ex posure develop suspicious manifestations of injury or toxicity, urine or blood analyses may help to confirm chemical absorption. Tests may be conducted in private or university laboratories, or laboratories supported by the state or federal government, i.e., the United States Environmental Protection Agency or Occupational Safety and Health Administration. TREATMENT 1. WASH contaminated SKIN with soap and water. 2. FLUSH contaminated EYES with copious amounts of fresh water for 15 minutes. 3. INGESTIONS of SMALL amounts (less than 10 mg/kg body weight) oc curring less than an hour before treatment, are probably best treated by: A. SYRUP OF IPECAC, followed by 1-2 glasses of water. Dose for adults and children over 12 years: 30 ml. Dose for children under 12 years: 15 ml. B. ACTIVATED CHARCOAL Administer 30-50 gm as a slurry in tap water, after vomiting stops. C. SODIUM OR MAGNESIUM SULFATE, 0.25 gm/kg in tap water, as a cathartic. 86 6189 4. INGESTIONS of LARGE amounts (more than 10 mg/kt?) occurring less than an hour before treatment, should probably be :ed by gastric lavage: A. INTUBATE stomach and ASPIRATE contents. B. LAVAGE stomach with slurry of ACTIVATED CHARCOAL in 0.9% saline. Leave 30-50 gm activated charcoal in the stomach be fore withdrawing tube. C. SODIUM SULFATE, 0.25 gm/kg in tap water, as a cathartic. CAUTION: Hydrocarbons (kerosene, petroleum distillates) are included in some formulations of these chemicals. In gestion of very LARGE AMOUNTS may cause CNS depression. In this case, IPECAC IS CONTRAIN DICATED. Also, gastric intubation incurs a risk of HYDROCARBON PNEUMONITIS. For this reason observe the following precautions: (1) If the victim is unconscious or obtunded and facilities are at hand, insert an ENDOTRA CHEAL TUBE (cuffed, if available) prior to gastric intubation. (2) Keep victim's HEAD BELOW LEVEL OF STOMACH during intubation and lavage (Trendelenburg, or left lateral decubitus, with head of table tipped downward). Keep victim's head turned to the left. (3) ASPIRATE PHARYNX as regularly as possible to remove gagged or vomited stomach contents. 5. INGESTIONS occurring MORE THAN an HOUR before treatment are probably best treated only by ACTIVATED CHARCOAL, 30-50 gm, and SODIUM or MAGNESIUM SULFATE, 0.25 gm/kg, as described above. 6. There are no specific antidotes for these chemicals. Because manifesta tions of toxicity do occasionally occur in peculiarly predisposed individ uals, MAINTAIN CONTACT with victim for at least 72 hours so that unexpected adverse effects can be treated promptly. 87 IN r" X TO PESTICIDE POISONINGS BY SYMPTOMS AND SIGNS A listing of pesticides capable of causing specific symptoms and signs may be of some help to professionals confronted with illnesses possibly caused by pesticides. However, the limitations of this kind of index should be clearly understood. Rarely are particular manifestations a lw a y s present in poisonings by a given chemical, and many poisonings are characterized by unexpected symptoms. Furthermore, there are usually many causes of particular symp toms and signs. The purpose of these lists is, therefore, only to direct the professional's at tention to a series of chemicals possibly responsible for various symptoms and signs, based on past experience. Starting from the major presenting feature of the illness, the interviewer can inquire closely into possible exposures to the principal causative toxicants, and then, if appropriate, assemble more substan tive evidence for or against a poisoning diagnosis, e.g., concurrence of multi ple manifestations of specific poisonings, and laboratory test findings. Not all manifestations of illness are included. Some symptoms, such as dizziness and weakness, are caused by so many chemicals by either direct or in direct mechanisms that they have little value diagnostically. This approach to clinical toxicology has been developed by Alan K. Done, M.D., of Wayne State School of Medicine. His general format of classifica tion (Solving the Poison Puzzle, E m e rg e n c y M e d ic in e , February 1979) is used in the following tables. Chemicals appearing in the lists headed "Characteristic of These Poisonings" have been substantially consistent in producing the symptoms or signs identified in the left column. Agents listed in the column headed "Occurs in These Poisonings" are found with sufficient frequency to deserve mention, but the association is not highly consistent. MANIFESTATIONS G eneral Breath odor of: Garlic Bitter almonds Rotten cabbage Fever Hypothermia Myalgia Chills CHARACTERISTIC OF THESE POISONINGS Arsenic Phosphorus Phosphides Phosphine Cyanide Carbon disulfide Nltro*. chloro- phenols Vacor Arsine Vacor OCCURS IN THESE POISONINGS Chlorophenoxy compounds Chlorophenoxy compounds o 88 CHARACTERISTIC OF MANIFESTATIONS_______________ THESE POISONINQS Thirst Nitro-, chloro-, phenols Amlnopyrldine Phosphine Anorexia Organophosphates Carbamate Insecticides Nicotine Hot sensations S kin a n d M u co u s M em branes Dry, cracked skin of hands Chlordlmelorm Arsine Paraquat Petroleum distillates Weed oil Loss of nails Paraquat Brittle nails inorganic arsenlcais Loss of hair Thallium Inorganic arsenlcais Sweating Organosphates Carbamate insecticides Nitro-, chloro- phenols Nicotine Amlnopyrldine Pallor Organchlorlnes Cyanosis Paraquat Strychnine Crlmldlne Nicotine Sodium fluoroacetate Scratchy throat and Irr ita te d eyes Sulfur d io x id e Acrolein Chloroplcrln Nitro-, chloro- phenols Formaldehyde Pyrethrlns Copper compounds Endothall Sodium chlorate Methyl bromide Blisters or burns Phosphorus Rash Sulfur Thlram Propachlor Barban Yellow stain Ecchymoses Keratoses Nltrophenols Anticoagulant rodenticides Phosphorus Phosphides Inorganic arsenlcais C '-'ru R S IN ______ THE- ISONINQS Fumigants Nitro-, chloro-, phenols Arsenlcais Anticoagulant rodenticides Organophosphates Carbamate Insecticides Organochlorlnes Paraquat Bisdithlocarbamates Ethylene bisdithlocarbamates Chloroaliphatic acids Liquid methyl bromide or ethylene oxide Plcloram Dlfolatan Captan Chlorothalonil Nitro-, chloro- phenols Many other herbicides and fungicides 89 MANIFESTATIONS Jaundice C t n t n l Nervous System Headache Ataxia Convulsions Muscle twitching Tremors Mental contusion Sudden unconsciousness C t n t r t l Nervous System Tingling end numbness In the extremities Tetany Myotonia CHARACTERISTIC OP OCCURS IN THESE POISONINGS ____________THESE P0I80NINQS Phosphorus Phosphides Phosphine Halocarbon fumigants Paraquat Inorganic arsenlcals Organophosphates Carbamate Insecticides Organochlorlnes Fumigants Nicotine Inorganic arsenlcals Organophosphates Carbamate Ineectlcldes Endothall Nicotine Phenyl mercuric acetate Organochlorlnes Strychnine Crlmldlne Phosphorus Cyanide Sodium fluoroacetate Nicotine Amlnopyrldlno Endothall Organophosphates Carbamate Insecticides Sulfuryl fluoride Organophosphates Carbamates Insecticides Phosphine Amlnopyrldlne Cyclohexlmlde Nicotine Organophosphates Carbamate Insecticides Nltrophenols Chlorophenols Cyanide Organochlorlnes Vacor Sodium fluoroacatata Carbon disulfide Amlnopyrldlne Cyclohexlmlde Cyanide Carbon disulfide Vacor Sodium fluoroacetate Phosphorus Phosphides Nltrophenols Chlorophenols Fumigants Inorganic arsenlcals Organochlorlnes Nitro-, chloro- phenols Organophosphates Carbamate Insecticides Sulfuryl fluoride Chlorophenoxy compounds Pyrethrins Nitro-, chloro- phenols Bentazon Sulfuryl fluoride Strychnine Crlmldlne Nicotine Inorganic arsenlcals Organophosphates Dlquat Carbamate Insecticides Halocarbon fumigants Inorganic arsenlcals Chlorophenoxy compounds CHARACTERISTIC OF OCCURS IN MANIFESTATIONS_______________ THESE POISONINGS_______________T M *M POISONINGS Miosis Organophosphates Carbamate insecticides G a s tro in te s tin a l Tract Nausea, vomitino, abdominal cramps, diarrhea Organophosphates Carbamate Insecticides Diquat Phosphorus Phosphides Phosphine Inorganic arsenlcals Arsine Fumigants Red squltl Cyciohexlmlde Endothall Nicotine Chlorates Copper Compounds Organochlorines Chloro-, nltro- phenols Blsdithiocarbamates Ethylene blsdithiocarbamates Chiorophenoxy compounds Organic arsenlcals Paraquat Bentazon Chloroaliphatlc acids Salivation Organophosphates Carbamate Insecticides Cycloheximide Nicotine R t s p lr a t o r y System Study nose, wheezing Pyrethrum Blsdithiocarbamates plus alcohol Nosebleed Coughing frothy sputum (pulmonary edema) Methyl bromide Phosphine Phosphorus Phosphides Ethylene oxide Paraquat Organophosphates Carbamate insecticides ANTU Rhinorrhea Organophosphates Carbamate insecticides Fumigants Tachypnea Nitro-, chloro- phenols Respiratory depression Organophosphates Carbamate Insecticides Fumigants Cyanide Acrylonitrile Nicotine Endothall Sodium chlorate Organochlorines Labored breathing Methyl bromide Organophosphates Carbamate insecticides Phosphine Phosphides Phosphorus Sulfuryl fluoride Chest pain Fumigants Sodium chlorate Organophosphates Carbamate Insecticides Chlorophenoxy herbicides Nitro-, chloro- phenols Chloroaliphatlc acids 91 MANIFr IONS C a rdiovascular System Bradycardia Tachycardia Hypotension, shock Irregular heart beat Hypertension R enal S ystem Renal failure Urinary frequency, dysuria Renal colic B lood Anemia Leukopenia CHARACTERISTIC OF THESE POISONINGS Organophosphatea Carbamate Insecticides Cyanide Nltrophenols Chlorophenols Phosphorus Phosphides Phosphine Vacor Endothall Cyanide Sodium fluoroacetate Halocarbon fumigants Endothall Nicotine Arsine Fumigants Cyclohexlmide Chlorates Chtordlmeform Vacor Anticoagulant rodenticldes Chlorates Naphthalene Anticoagulant rodenticldes Hypoprothrombinemia Depressed cholinesterase enzyme activities Methemoglobinemia Free hemoglobin in plasma Elevated alkaline phosphatase, GOT, LDH Elevated blood bromide Hyperbilirubinemia CO co CO Anticoagulant rodenticldes Organophosphates Chlorates Naphthalene Arsine Copper compounds Sodium chlorate Halocarbon fumigants Inorganic arsenicals Diquat Paraquat Amlnopyridine Methyl bromide Paraquat Diquat Phosphine Phosphorus Phosphides Copper compounds Inorganic arsenicals 92 OCCURS IN THESE POISONINGS Organochlorlnes Blsdithlocarbamates plus alcohol Inorganic arsenicals Anticoagulant rodenticldes Organochlorlnes Red squill Paraquat Diquat Inorganic arsenicata Copper compounds Inorganic arsenicals Nltrophenols Inorganic arsenicals Carbamate insecticides (large dosage) Endrln Halocarbon fumigants MANIFESTATIONS Elevated BUN, creatinine Hyperkalemia U rine Proteinuria Hematuria Ketonurla Hemoglobinuria Myoglobinuria Porphyrinuria Billrubinurla Glycosuria Feces Blood present (melena) Luminescence Semen Low sperm count CHARACTERISTIC OF THESE POISONINGS Paraquat Dlquat Fumigants Chlorates Inorganic arsenicals Naphthalene Chlorates Copper compounds Dlquat Paraquat Nitro-, chloro-, phenols Fumigants Cycloheximlde Copper compounds Phenyl mercuric acetate Sodium chlorate Anticoagulant rodenticldes Sodium chlorate Cycloheximlde Chtordimeform Vacor Aminopyrldlne Naphthalene Arsine Sodium chlorate Hexachlorobenzene Halocarbon fumigants Phosphorus Phosphides Phosphine Vacor Dlquat Sodium chlorate Anticoagulant rodentlcides Phosphorus Phosphides Endothall Cycloheximlde Phosphorus OCCURS IN : POISONINGS Sulfuryl nuorlde Nitro-, chloro-, phenols Endothall Sulfuryl fluoride Chlordlmeform Fumigants Paraquat Dlquat Phosphorus Phosphides Chlorophenoxy compounds Paraquat Dibromochloropropane Kepone 93 PESTICIDES INDEX -- A-- Paget 1080 .................................................................... 54 AAtack .............................................................. 36 AAtrex................................................................ 82 Abate.................................................................. 1 Abathion............................................................ 1 Acaraben............................................................. 14,82 Acaron................................................................ 77 Accelerate.......................................................... 77 acephate.............................................................. 1 Acquinite............................................................ 68 Acrex.................................................................. 23 Acritet................................................................ 68 Acrolein.............................................................. 68 Acrylaldhyde.................................................... 68 Acrylofume........................................................ 68 acrylonitrile........................................................ 68 Actellic................................................................ 1 Acti-dione.......................................................... 77 Actispray............................................................ 77 A falon................................................................ 82 Afesin.................................................................. 82 Afu^an................................................................ 1 Agritox................................................................ 1 Agrosan.............................................................. 77 Agrotec.............................................................. 27 Agrothion.......................................................... 1 Akar.................................................................... 82 alachlor.............................................................. 82 Alanex................................................................ 82 aldicarb.............................................................. 9 aldrin.................................................................. 14 Aldrite................................................................ 14 allethrin.............................................................. 42 allidochlor.......................................................... 82 alumino fluoride s a lt ......................................... 82 aluminum phosphide......................................... 68 A m aze................................................................ 1 fPage number refers to the beginning page of the chapter in which the pesticide is covered. Ambox................................................................ Ambush.............................................................. Amdon................................................................ Ametrex.............................................................. ametryn.............................................................. A m ex.................................................................. aminocarb.......................................................... 4-aminopyridine................................................ Amoxone............................................................ Ancrack.............................................................. anilazine.............................................................. Ansar 170 H C .................................................... Ansar 529 H C .................................................... Ansar 8100.......................................................... Ansar DSMA liquid........................................... A nthio................................................................ Anticarie............................................................ Anticoagulent rodenticides............................... a n tu .................................................................... 4 -A P .................................................................... A p h ox................................................................ A qu acid e.......... .. ................................................ Aqua-Kleen........................................................ A q u a lin .............................................................. Aquathol............................................................ Arasan................................................................ A relon................................................................ Aresin.................................................................. Arresin................................................................ Arrhenal............................................................ arsenic................................................................ arsenic a c id ........................................................ arsenic trioxide.................................................. arsenious oxide.................................................. arsine.................................................................. Arsinyl................................................................ Arsonate liquid.................................................. Aspon.................................................................. A sp o r .................................................................. a su la m ................................................................ Asulox 4 0 ............................................................ Asulox F ............................................................ A tr a n e x .............................................................. atraton................................................................ 23 >2 82 82 82 82 9 77 27 23 82 46 46 46 46 1 82 54 54 77 9 31 27 68 77 36 82 82 82 46 46 46 46 46 46 46 46 1 36 82 82 82 82 82 95 atrazine............ \t r e d ............... m l e s ............... Avadex.............. Avadex-BW___ A v itr o l.............. A zac................. A z a k ................. A zar.................. azinphos-methyl A z o d r in ............ --fi lialfin ....................... B a n v e l..................... barban ..................... barthrin................... Basagran................. Basalin..................... Basanite................... Basfapon................. Baygon ..................... Bayrusil................... B a y t e x ..................... Baythion................. Belgran..................... Belmark................... B e n e f e x ................... benefin..................... Benfluralin .............. Benlate..................... benomyl................... bentazon................. Benzac ..................... benzene hexachloride Benzilan................... Benz-O-Chlor.......... Benzyl benzoate___ bethrodine............... B e x to n ..................... BH 2,4-D ................. B H C ......................... Bicep ....................... 96 82 82 36 36 36 77 82 82 82 1 1 82 27 82 42 82 82 23 82 9 1 1 1 82 42 82 82 82 82 82 82 82 14 82 82 82 82 82 27 14 82 Bidrin............................................. binapacryl...................................................... bioresmethrin.................................................... Birlane................................................................ Black Leaf 4 0 .................................................... Black Leaf Grass, Weed and Vegetation Killer Spray.................................................... Bladafum............................................................ B la d e x ................................................................ Bo-Ana .............................................................. Bolstar................................................................ bomyl.................................................................. Bravo.................................................................. brodifacoum...................................................... bromacil.............................................................. bromadiolone.................................................... Bromofume........................................................ Brom-O-Gas...................................................... B r o m o n e............................................................ b ro m o p h o s........................................................ bromophos-ethyl ............................................... Brush-Rhap........................................................ Bueno 6 .............................................................. bufencarb .......................................................... Burtolin.............................................................. butralin .............................................................. butylate.............................................................. B u x ...................................................................... 1 23 42 1 77 19 1 82 1 1 1 82 54 82 54 68 68 54 1 1 27 46 9 82 82 36 9 --C-- cacodylic a c id .................................................... C aid .................................................................... calcium acid methanearsonate ......................... calcium arsenate................................................. calcium arsenite ................................................. Caldon................................................................ C A M A ................................................................ C a p a r o l.............................................................. c a p t a f o l.............................................................. captan ................................................................ Carbacryl............................................................ Carbamult.......................................................... Carbamates-cholinesterase-inhibiting.............. 46 54 46 46 46 23 46 82 82 82 68 9 9 0*7 c^'Haryl......................... 9 (. azinc .......................................................... 36 carbofuran.......................................................... 9 carbon bisulfide................................................. 68 carbon disulfide................................................ 68 carbon tetrachloride........................................... 68 carbophenothion ............................................... 1 Carbyne.............................................................. 82 Caryne................................................................ 82 Carzol ................................................................ 9 Casoron.............................................................. 82 Castrix................................................................ 54 C D A A ................................................................ 82 Cekiuron............................................................ 82 Cekusil................................................................ 77 Celathion............................................................ 1 Celmide.............................................................. 68 Certified Kiltrol-74 Weed Killer....................... 19 Chem Bam.......................................................... 36 Chemform.......................................................... 82 Chemonite.......................................................... 46 Chemox General................................................. 23 Chemox P E ........................................................ 23 Chem Pels C ...................................................... 46 Chemsect DNBP................................................ 23 Chemsect D N O C ............................................... 23 Chem-Sen 5 6 ...................................................... 46 Chipco Crab Kleen............................................. 46 Chipco Thiram 7 5 ............................................... 36 Chipco Turf Herbicide "D" ............................. 27 Chlordan............................................................ 14 chlordane............................................................ 14 chlordimeform................... 77 chlorfenac.......................................................... 27 chlorfenvinphos................................................. 1 chlormephos...................................................... 1 chlorobenzilate................................................... 14 chloroform........................................................ 68 chloro 1PC.......................................................... 82 chlorophacinone................................................. 54 chlorophenothane............................................ 14 Chlorophenoxy compounds............................. 27 Chlor-O-Pic........................................................ 68 chloropicrin........................................................ 68 O} to m 98 chlorothalonil.................................................. 82 chloroxifenidim.............................................. 82 Chloroxone........................................................ 27 chloroxuron........................................................ 82 chlorpropham.................................................... 82 chlorpyrifos........................................................ 1 chlorthaldimethyl.............................................. 82 chlorthiophos.................................................... 1 chlortoluron...................................................... 82 Chrysron............................................................ 42 Ciba-GeigyOntrack(OS3,4or5)................... 19 cinerins................................................................ 42 Ciodrin................................................................ 1 C IP C .................................................................. 82 Clortokem.......................................................... 82 Cobex.................................................................. 82 copper acetate.................................................... 77 copper acetoarsenite........................................... 46 copper arsenite...................................................46,77 copper carbonate.............................................. 77 copper chloride.................................................. 77 copper hydroxide.............................................. 77 copper naphthenate........................................... 77 copper oleate...................................................... 77 copper oxalate.................................................... 77 copper o xid e...................................................... 77 copper phosphate.............................................. 77 copper quinolinolate......................................... 77 copper resinate.................................................. 77 copper salts........................................................ 77 copper silicate.................................................... 77 copper sulfate.................................................... 77 copper zinc chromate......................................... 77 Co-Ral................................................................ 1 Corozate............................................................ 36 Cotoran.............................................................. 82 Cottonex............................................................ 82 coumachlor........................................................ 54 coumafene.......................................................... 54 coumafuryl........................................................ 54 coumaphos........................................................ 1 counter................................................................ 1 Crab-E-Rad........................................................ 46 crimidine............................................................ 54 99 C r isa lin a ___ rrisapon __ crisazine........ Crisquat........ Crisuron........ Crop Rider. . . Crotothane .. crotoxyphos.. cryolite.......... Cuman.......... Curacron___ Curamil........ cyanazine___ cyanofenphos cyanophos . . . Cyanox.......... cycloate........ cycloheximide C y c lo n .......... Cygon............ C y m a g .......... C y o la n e ........ cypermethrin. cythioate C y th io n ........ 2.4- D .............. D 5 0 ................... decamethrin........ Dacamine 2D/2T Dacamine 4D ___ Dacamine 4 T ___ Daconate 6 .......... Daconil 2787 Dacthal ............. D ailon ............... dalapon............. Dal-E-Rad......... D a lf ................... Dapacryl........... Dasanit............... 2.4- D B ............ --D-- 100 82 82 82 31 82 27 23 1 82 36 1 1 82 1 1 1 36 77 68 1 77 1 42 1 1 27 27 42 27 27 27 46 82 82 82 82 46 1 23 1 27 DBCP.............................................................. D C P A ................................................................ D-D .................................................................... D DT.................................................................... D D V P ................................................................ De broussaillant 600 ........................................... De broussaillant Concentre............................... De-Cut................................................................ Ded-Weed.......................................................... Ded-Weed Brush Killer..................................... DEF ................................................................... De-Fend.............................................................. D e -F o l-A te ........................................................ Deftor ................................................................ De-Green............................................................ D e ln a v ................................................................ demeton.............................................................. demeton-methyl................................................ Des-l-Cate.......................................................... Desiccant L -1 0 .................................................. desmetryn.......................................................... D e so r m o n e ........................................................ De-Sprout.......................................................... Dessin.................................................................. Dethdiet.............................................................. Dextrone............................................................ D e x tr o n e X ........................................................ Dexuron.............................................................. dialifor................................................................ diallate................................................................ Diater.................................................................. diazinon.............................................................. Dibrom .............................................................. dibromochloropropane ..................................... dicamba.............................................................. dicarzol.............................................................. dichlobenil.......................................................... dichloroanisic a cid ............................................. 2,4-dichlorophenoxyacetic acid ....................... dichloropropene (a n e)......................................... dichlofenthion.................................................... dichloropropionic acid....................................... dichlorprop........................................................ dichlorvos.......................................................... 68 82 68 14 1 27 27 82 27 27 1 1 77 82 1 1 1 1 77 46 82 27 82 23 54 31 31 31 1 36 82 1 1 68 27 9 82 27 27 68 1 82 27 1 mi dicofol................................................................ 14 ! t o x .......................................... 27 dicrotophos......................................................... 1 Dicuran.............................................................. 82 dieldrin............................. 14 Dieldrite.............................................................. 14 dienochlor.......................................................... 14 difenacoum......................................................... 54 difenoxuron......................................................... 82 diflubenzuron..................................................... 82 Difolatan............................................................. 82 Digermin............................................................. 82 D ilic.................................................................... 46 Dimecron............................................................. 1 dimethoate........................................................... 1 dimetilan............................................................. 9 Dimilin................................................................ 82 Dinitramine......................................................... 82 dinitro................................................................ 23 Dinitro-3........................... 23 dinitroamine....................................................... 82 dinitrocresol....................................................... 23 Dinitro General................................................... 23 dinitrophenol ..................................................... 23 dinobuton........................................................... 23 dinocap............................................................... 23 D inofen.............................................................. 23 dinopenton......................................................... 23 dinoprop............................................................. 23 dinosam............................................................... 23 dinoseb................................................................ 23 dinosulfon........................................................... 23 dinoterb............................................................... 23 dinoterbon........................................................... 23 D inoxol............................................................... 27 D i-o n .................................................................. 82 dioxathion........................................................... 1 Diphacin............................................................. 54 diphacinone......................................................... 54 Dipher................................................................ 36 Dipterex............................................................... 1 diquat.................................................................. 31 Direz.................................................................... 82 ^ 5 disodium methyl arsonate................................. 46 CD 102 d is u lf o t o n .......................................................... Di-Syston............................................................ D i-T a c ................................................................ Dithane (D14, M22, M45, or Z 7 8 )................... Dithiocarbamates.............................................. Dithione.............................................................. D iurex................................................................ Diurol.................................................................. diuron ................................................................ DLP-787 ............................................................ D M A .................................................................. DMA 4 ................................................................ DMA 100............................................................ D N A P ................................................................ DNBP ................................................................ D N C .................................................................... D NO C ................................................................ Dorinone............................................................ D osaflo.............................................................. Dosanex.............................................................. D o ta n .................................................................. Dow General Weed K iller................................. Dow Pentachlorophenol................................... Dow Selective Weed Killer................................. Dowfume fumigants........................................... DowicideEC-7.................................................. Dowpon.............................................................. DP-2 Antimicrobial........................................... D PA .................................................................... D rat.................................................................... Drawinol............................................................ Draza.................................................................. D r e x e lD e fo l...................................................... D r in o x ................................................................ Drop-Leaf.......................................................... Drupina 90.......................................................... D S E .................................................................... D SM A ................................................................ D ual.................................................................... Dursban.............................................................. Du-Sprex............................................................ Dyanap .............................................................. D y fo n a te ............................................................ D ylox.................................................................. 1 1 46 36 36 1 82 82 82 54 46 27 46 23 23 23 23 27 82 82 1 23 19 23 68 19 82 19 82 54 23 9 77 14 77 36 36 46 82 1 82 23 1 1 103 Dynamyte ~>ynex__ /yrene . .. 23 82 82 --E-- Ectiban................................................ 42 E D B .................................................................... 68 ED C .................................................................... 68 Ekamet................................................................ 1 Ekatin ................................................................ 1 Elancolan............................................................ 82 Elgetol 30............................................................ 23 Elgetol 318.......................................................... 23 emerald green.................................................... 46 Emulsamine B K ................................................. 27 Emulsamine E -3 ................................................ 27 Endosan.............................................................. 23 endosulfan.......................................................... 14 Endothall............................................................ 77 endrin.................................................................. 14 E ntex.................................................................. 1 Envert DT, T or 171........................................... 27 EPBP.................................................................. 1 E P N .................................................................... 1 epoxypropane.................................................... 68 Eptam ................................................................ 36 EPTC.................................. 36 Esgram................................................................ 31 Esteron Brush Killer........................................... 27 Esteron Four...................................................... 27 Esteron 99 Concentrate..................................... 27 Esteron 245 ........................................................ 27 E stone................................................................ 27 ethion.................................................................. 1 ethoprop............................................................ 1 Ethylan .............................................................. 14 ethyl parathion.................................................. 1 ethylene dibromide............................................. 68 ethylene dichloride............................................. 68 ethylene oxide.................................................... 68 ETO .......... ...................................................... 68 etrimfos.............................................................. 1 E v ik .................................................................... 82 CD E-Z-Off D .......................................................... 1 CO GO 104 -- F-- F a c ..................................................................... F a ll...................................................................... Famfos................................................................ famphur.............................................................. Far-Go................................................................ fenac.................................................................... fenamiphos........................................................ Fence Rider........................................................ fenitrothion........................................................ fenophosphon.................................................... fenothrin............................................................ fenpropanate...................................................... fensulfothion...................................................... fenthion.............................................................. fenvalerate.......................................................... fe r b a m ................................................................ Ferberk .............................................................. Fermide 850........................................................ Fernasan............................................................ Fernesta.............................................................. Fernimine .......................................................... Fernoxone.......................................................... Ferxone.............................................................. Field Clean Weed Killer..................................... fluchloralin........................................................ fluometuron ...................................................... Folex .................................................................. Folpan................................................................ folp et.................................................................. fonofos .............................................................. formaldehyde.................................................... F o r m a lin ............................................................ formetanate HCI .............................................. formothion........................................................ Formula 4 0 ........................................................ Forron................................................................ Framed................................................................ Fratol.................................................................. French green...................................................... Fuclasin U ltra.................................................... Fuklasin.............................................................. Fumarin.............................................................. Fumigant-1 ........................................................ Fumigants.......................................................... 1 77 1 1 36 27 1 27 1 1 42 42 1 1 42 36 36 36 36 27 27 27 27 27 82 82 1 82 82 1 68 68 9 1 27 27 82 54 46 36 36 54 68 68 Fundal . . . Fundex. .. Fungostop Furadan .. Furloe --G-- G 28029 ............................... G a lecro n ............................. Gallotox............................... Gammexane ....................... Gardon Termi T o x ............. Gardona............................... Gardoprim........................... Gebutox............................... G e sa fr a m 5 0 ....................... Gesagard............................. G e sa m il............................... Gesapax............................... Gesaprim............................. Gesatamin........................... Gesatop............................... glyphosate........................... Grain Sorghum Harvest-Aid Graminon........................... G r a m o n o l........................... Granurex............................. Griffin Manex..................... GS 13529 ............................. Guthion............................... G y p s in e ............................... --H-- H C B ..................... HCH ................... Hedonal................ heptachlor............ heptenophos........ Herbadox.............. Herb-All .............. Herbidal................ hexachlorobenzene 106 77 77 36 9 82 1 77 77 14 19 1 82 23 82 82 82 82 82 82 82 82 77 82 31 82 36 82 1 46 82 14 27 14 1 82 46 27 82 Hexadrin...................................................... Hexaferb............................................................ Hexathane.......................................................... Hexathir.............................................................. Hexazir .............................................................. Hi-Yield Desiccant H -1 0 ................................... Hizarocin............................................................ Hoe 2810............................................................ Hong Nien.......................................................... Hostaquick........................................................ Hostathion ........................................................ Hydout................................................................ hydrogen cyanide............................................... Hydrothoi.......................................................... Hyvar X ......................................... 14 36 36 36 36 46 77 82 77 1 1 77 68 77 82 --I-- Igran.................................................................... Imidan................................................................ Inorganic arsenicals........................................... Inverton 245 ...................................................... iodofenphos ...................................................... Ipersan................................................................ isofenphos.......................................................... isomethiozin...................................................... isopropalin ........................................................ isoproturon........................................................ isoxathion.......................................................... 82 1 46 27 1 82 1 82 82 82 1 --J-- jasmolins............................................................ 42 Jones Ant Killer................................................. 46 --K-- Karathane.......................................................... Karmex .............................................................. Karphos.............................................................. Kayafume.......................................................... Kelthane.............................................................. Kemate................................................................ kepone................................................................ .23 82 1 68 14 82 14 WVT Kill-All................................................................ Kiloseb................................................................ .lean K rop........................................................ Kloben........................... Klorex ................................................................ K M H .................................................................. Knockmate........................................................ Kop-Fume.......................................................... Kop-Mite............................................................ Kryocide............................................................ Krysid.................................................................. Kuron.................................................................. Kusatol................................................................ K w ell.................................................................. Kypfarin ............................................................ Kypman 80 ........................................................ Kypzin................................................................ 46 23 23 82 77 82 36 68 82 82 * 54 27 77 14 54 36 36 --L-- Lanex.................................................................. Lannate.............................................................. L asso.................................................................. Lawn-Keep........................................................ L a z o .................................................................... lead arsenate...................................................... lenacil.................................................................. leptophos............................................................ Lexone................................................................ lindane................................................................ Line Rider.......................................................... Linurex .............................................................. linuron................................................................ Liphadione........................................................ Liquiphene ........................................................ Lironion.............................................................. Lithate................................................................ L o n a c o l.............................................................. Lorox.................................................................. Lorsban.............................................................. L y so ff................................................................ 82 9 82 27 82 46 82 1 82 14 27 82 82 54 77 82 27 36 82 1 1 C73 0 Q O 108 --M-- M A A .................................................................. Macondray........................................................ M a intain ............................................................ malathion .......................................................... maleic hydrazide ................................................. M A M A .............................................................. M a n co ze b .......................................................... maneb ................................................................ Manebgan.......................................................... Manesan ............................................................ Manzate.............................................................. M anzeb.............................................................. Manzin................................................................ Marlate .............................................................. Matacil................................................................ MC2188.............................................................. M CPA................................................................ M CPB................................................................ MCPB-Ethyl...................................................... MCPCA.............................................................. M C PP................................................................ M eBr.................................................................. M ec o p r o p .......................................................... Mercuram.......................................................... Merge 823 .......................................................... Merpan .............................................................. merphos.............................................................. Mersolite............................................................ Mesamate .......................................................... Mesurol.............................................................. Metasystox ........................................................ methabenzthiazuron........................................... methamidophos................................................ methane arsonate.............................................. methane arsonic a c id ......................................... Methar................................................................ methidathion...................................................... methiocarb ........................................................ Meth-O-Gas ...................................................... methomyl............................................................ methoxychlor.................................................... methyl bromide.................................................. methyl parathion .............................................. metobromuron.................................................. 46 27 82 1 82 46 36 36 36 36 36 36 36 14 9 1 27 27 27 27 27 68 27 36 46 82 1 77 46 9 1 82 1 46 46 46 1 9 68 9 14 68 1 82 109 metolachlor........................................................ metoxuron.......................................................... metribuzin.......................................................... mevinphos.......................................................... Mezene................................................................ Microzul ............................................................ M ilogard ............................................................ Miracle................................................................ m irex.................................................................. mitis green.......................................................... Mobilawn .......................................................... M ocap................................................................ Mofisal................................................................ Monitor.............................................................. monoammonium methane arsonate................. monoammonium methyl arsonate................... mono-calcium arsenite....................................... monocrotophos.................................................. monolinuron...................................................... monosodium methyl arsonate........................... M o n u rex ............................................................ m o n u ro n ............................................................ Morocide............................................................ MSMA................................................................ 82 82 82 1 36 54 82 27 14 46 1 1 31 1 46 46 46 1 82 46 82 82 23 46 --N-- nabam ................................................................ Nabasan.............................................................. naled.................................................................... Namate .............................................................. naptalam............................................................ N a p tr o ................................................................ naramycin.......................................................... Neburex.............................................................. neburon.............................................................. Neguvon ............................................................ N em a cu r............................................................ Neoban .............................................................. Neo-Pynamin.................................................... N ephis................................................................ N e s p o r ................................................................ Netagrone 600 .................................................... Nexagan.............................................................. 36 36 1 46 23 23 77 82 82 1 1 82 42 68 36 27 1 6201 110 N e x io n ............................................................ nicotine sulfate.............................................. Nitrador.............................................................. Nitrophenolic and nitrocresolic herbicides . . . . Nitropone C ...................................................... No Bunt.............................................................. N o m e r sa n .......................................................... norbormide.......................................... Nudrin................................................................ Nuvanol-N.......................................................... 1 77 23 23 23 82 36 54 9 1 --O-- Oftanol .............................................................. Ofunack.............................................................. O M P A ................................................................ Organochlorines-solid....................................... Organophosphates-cholinesterase-inhibiting .. Orthene.............................................................. Orthocide............................................................ Ortho paraquat CL............................................ Ortho Triox Liquid Vegetation Killer............... oryzalin.............................................................. oxadiazon.......................................................... oxamyl................................................................ oxirane................................................................ 1 1 1 14 1 1 82 31 19 82 82 9 68 --P-- Paarlan.............................................................. Paracide.............................................................. paradichlorobenzene......................................... paraquat ............................................................ paraquat dichloride........................................... parathion............................................................ paris green.......................................................... Parzate................................................................ Pathclear............................................................ Patoran.............................................................. Pattonex ............................................................ PCNB.................................................................. P C P .................................................................... P D B .................................................................... pebulate.............................................................. 82 82 82 31 31 1 46 36 31 82 82 82 19 82 36 111 Pencal ........................... Penchlorol..................... pendimethalin................ Penite............................. Pennamine D .................. Penncap-M................... penta ............................. P entac........................... pentachloronitrobenzene pentachlorophenol........ Pentacon....................... Penwar........................... perchlorobenzene........... permethrin..................... Perthane....................... Pestmaster (EDB-85)__ Phaltan ......................... phencapton .................... Phenmad....................... phenthoate....................... phenylmercuric acetate . P h ix ................................. phorate............................. phosalone ..................... Phosdrin......................... phosfolan......................... phosmet........................... phosphamidon............... phosphine ....................... phosphonomethyl glycine phosphorus ..................... Phostoxin ....................... Phosvel ........................... P h o s v in ........................... phoxim............................. phthalthrin ..................... Phytar 560 ....................... Pic-Clor........................... P ic fu m e ........................... picloram........................... p in d o n e ........................... pirimicarb....................... Pirimor ........................... piperonyl butoxide.......... 11?. 46 19 82 46 27 1 19 14 82 19 19 19 82 42 14 68 82 1 77 1 77 77 1 1 1 1 1 1 68 82 54 68 1 54 1 42 46 68 68 82 54 9 9 42 pirimiphos-methyl............................................. Pivacin............................................................ Pival.................................................................... pivaldione.......................................................... Pivalyn................................................................ P la n o t o x ............................................................ Plantgard............................................................ PMA .................................................................. P M A S ................................................................ Polyram M ........................................................ Polyram Ultra.................................................... Polyram Z .......................................................... Pomarsol fo rte.................................................. Pomarsol Z Forte............................................... Pounce................................................................ Pramitol.............................................................. Preeglone............................................................ Pregard.............................................................. P r e m a lin ............................................................ Premerge 3 .......................................................... Priglone.............................................................. P r ilt o x ................................................................ Primagram ........................................................ Primatol (A, 25E, M, P, Q, or S ) ..................... Primextra............................................................ Princep................................................................ Proban................................................................ Prodalumnol Double......................................... Prodaram .......................................................... profenofos.......................................................... profluralin.......................................................... Profume.............................................................. Prolate................................................................ Promar................................................................ promecarb.......................................................... Prometon............................................................ Prometone.......................................................... Prometrex.......................................................... prometryn.......................................................... propachlor.......................................................... Propanex............................................................ propanil.............................................................. propazine............................................................ propenal.............................................................. propetamphos.................................................... 1 54 54 54 54 27 27 77 77 36 36 36 36 36 42 82 31 82 82 23 31 19 82 82 82 82 1 46 36 1 82 68 1 54 9 82 82 82 82 82 82 82 82 68 1 113 propoxur............................................................ propylene oxide.................................................. propylthiopyrophosphate................................. prothoate............................................................ P r o w l.................................................................. Prozinex.............................................................. prussic a cid ........................................................ Purina Insect Oil Concentrate........................... Purivel................................................................ P y d r in ................................................................ Pynamin ............................................................ pyrazophos........................................................ pyrethrins .......................................................... pyrethroids................... pyrethrum.......................................................... pyridaphenthion................................................ 9 68 1 1 82 82 68 19 82 42 42 1 42 42 42 1 --Q-- Q uilan................................................................ 82 quinalphos.......................................................... 1 --R-- Rabon ................................................................ Rad-E-Cate 25.................................................... Ramik ................................................................ Ramrod.............................................................. Ramucide............................................................ Randox .............................................................. Rapid.................................................................. Ratak.................................................................. Raticate.............................................................. Ratimus.............................................................. Ratomet.............................................................. R a to x .................................................................. R aviac................................................................ R a x ...................................................................... Red Squill.......................................................... R e g lo n e .............................................................. R eglox................................................................ resmethrin.......................................................... RH-787 .............................................................. Rhodia................................................................ Rhodia Low Volatile Brush Killer no. 2 ............ 1 46 54 82 54 82 9 54 54 54 54 54 54 54 54 31 31 42 54 27 27 6203 114 Ripcord............................................................ Riselect............................................................ Rodenticides...................................................... Rodex.................................................................. Rodine................................................................ R o -N e e t.............................................................. R o n s ta r .............................................................. Rosanil................................................................ Roundup............................................................ R ozol.................................................................. R y c e la n .............................................................. R y z e la n .............................................................. 42 82 54 54 54 36 82 82 82 54 82 82 --S-- Safrotin.............................................................. 1 Salvo .................................................................. 27,46 Sarclex................................................................ 82 schradan ............................................................ 1 Schweinfurt green.............................................. 46 SD 15418............................................................ 82 Security.............................................................. 46 Selinon................................................................ 23 Semeron.............................................................. 82 Sencor................................................................ 82 Sencoral.............................................................. 82 Sencorex ............................................................ 82 Sevin.................................................................... 9 Shimmer-ex........................................................ 77 Shoxin................................................................ 54 siduron................................................................ 82 Silvex.................................................................. 27 Simadex.............................................................. 82 Simanex.............................................................. 82 simazine.............................................................. 82 Simpar................................................................ 31 Sinbar.................................................................. 77 Sinituho.............................................................. 19 Sinox General.................................................... 23 Snip Fly B ands.................................................. 9 Sodar.................................................................. 46 sodium arsenate................................................ 46 sodium arsenite.................................................. 46 sodium chlorate ................................................ 77 sodium cyanide.................................................. 77 115 sodium fluoroacetate........ sodium fluoroaluminate .. sodium pentachlorophenate S o ilb ro m ........................... Soprabel............................. Spanone............................. Spectracide....................... S p ik e................................. Spontox............................. Spotrete............................. S p o t to n ............................. Spra-cal............................. Spring-Bak ....................... Spritz-Hormin/2,4-D........ Spritz-Hormit/2,4-D........ Sprout N ip......................... S-Seven ............................. Stam F 3 4 ........................... Stomp................................. S t r e l................................... Strobane........................... Strobane-T....................... strychnine......................... Stunt-Man......................... Subitex............................... sulfotepp........................... sulfuryl fluoride................ sulprofos ........................... Sumithion......................... Super-Caid ....................... Super Crab-E-Rad-Calar.. Super D Weedone.............. Super Dal-E-Rad-Calar -- Supernox ........................... Superormone Concentre .. Supracide........................... Surcopur ........................... Surecide............................. Surflan............................... Surpass............................... Surpur ............................... S u t a n ................................. Sw at................................... Synthrin............................. Systox................................. 1 IA 54 82 19 68 46 77 1 82 27 36 1 46 36 27 27 82 1 82 82 82 14 14 54 82 23 1 68 1 1 54 46 27 46 82 27 1 82 1 82 36 82 36 1 42 1 -- T-- 2.4.5- T ............................................................ T alan.................................................................. Talbot .......................................................... .. T alon .................................................................. Tantizon ............................................................ Target MSMA.................................................... Taterpex.............................................................. 2.4.5- TB.......................................................... T B A .................................................................... T C A .................................................................... TCBA.................................................................. tebuthiuron........................................................ T elone................................................................ tempephos.......................................................... Temik.................................................................. Tenoran.............................................................. T E P P .................................................................. terbacil................................................................ terbucarb............................................................ terbufos.............................................................. terbuthylazine.................................................... Terbutrex............................................................ terbutryn............................................................ terpene polychlorinates..................................... Terrachlor.......................................................... Terraklene.......................................................... Terrazole............................................................ T e r s a n ................................................................ Tersan 7 5 ............................................................ Tersan 1991........................................................ Tersan L SR ........................................................ tetrachlorvinphos............................................... tetraethyl pyrophosphate................................... tetrafluoron........................................................ tetramethrin ...................................................... Tetrapom............................................................ T h im e t................................................................ Thiodan.............................................................. Thioknock.......................................................... th io m e to n .......................................................... Thiophal ............................................................ Thiophos............................................................ Thiotex................................................................ thiram ................................................................ 27 23 46 54 82 46 82 27 82 82 82 82 68 1 9 82 1 82 82 1 82 82 82 14 82 31 82 36 36 82 36 1 1 82 42 36 1 14 36 1 82 1 36 36 Thiramad............................................................ 36 Thirasan.............................................................. 36 Thiuramin.......................................................... 36 Thylate................................................................ 36 Tiezene................................................................ 36 Tiguvon.............................................................. 1 Tillam.................................................................. 36 Tirampa.............................................................. 36 TMTDS.............................................................. 36 Tolban................................................................ 82 Tolkan................................................................ 82 Tolurex .............................................................. 82 Tomilon.............................................................. 82 Tomorin.............................................................. 54 T opitox.............................................................. 54 Torak.................................................................. 1 Tordon................................................................ 82 Tormona............................................................ 27 TotaCol.............................................................. 31 Toxakil................................................................ 14 toxaphene.......................................................... 14 Tox-Hid.............................................................. 54 2.4.5- TP.......................................................... 27 Trametan............................................................ 36 Transamine........................................................ 27 Trans-Vert.......................................................... 46 Treflan................................................................ 82 triallate................................................................ 36 Triasyn................................................................ 82 triazophos.......................................................... 1 Tribac.................................................................. 82 Tri-ban................................................................ 54 Tribunil.............................................................. 82 Tributon ............................................................ 27 Tricarbamix Z .................................................... 36 trichlorfon.......................................................... 1 trichloroacetic acid............................................. 82 trichloronate...................................................... 1 2.4.5- trichlorophenoxyacetic acid ................ 27 2,3,6 trichlorophenylacetic a c id ....................... 27 Tri-Clor.............................................................. 68 trifluralin............................................................ 82 Trifocide............................................................ 23 O'} Trifungol............................................................ 36 to O 118 Trimangol...................................................... Trinoxol........................................................ T r i o x o n e ............................................................ Tripomol............................................................ Triscabol............................................................ Trithion.............................................................. Tritoftorol.......................................................... Tuads.................................................................. Tubothane.......................................................... Tumbleaf............................................................ Tupersan............................................................ 36 27 27 36 36 1 36 36 36 77 82 --U-- U 4 6 .................................................................... U 46 Special........................................................ Unicrop CIPC.................................................... Unicrop D NBP.................................................. Unidron.............................................................. Uragan................................................................ Urox (B, D, or H x )............................................ Usol Cabin il .................................................. 27 27 82 23 82 82 82 4 --V-- Vacor Rat Killer................................................ Vancide FE-95.................................................... Vancide Maneb 8 0 ............................................ Vancide MZ-96.................................................. Vapona .............................................................. Vectal SC ............................................................ Veg-I-Kill............................................................ Venzar................................................................ Veon 245 ............................................................ V e r n a m .............................................................. vernolate............................................................ Vertac Dinitro Weed Killer............................... Verton 2 D .......................................................... Verton 2 T .......................................................... Vikane................................................................ Visko-Rhap........................................................ Visko-Rhap LV 2D-2T....................................... Vonduron.......................................................... Vydate................................................................ 54 36 36 36 1 82 19 82 27 36 36 23 27 27 68 27 27 82 9 119 -W- W a rb ex .............................................................. warfarin.............................................................. Warfarin P lus.................................................... Weed-B-Gon...................................................... Weed-E-Rad...................................................... Weed-E-Rad 360 ................................................ Weed-E-Rad DMA Powder............................... Weed-Hoe.......................................................... Weed-Rhap........................................................ Weed Tox .......................................................... Weedar................................................................ Weedol................................................................ W eed on e............................................................ Weedtrine-D...................................................... W eed trol............................................................ white arsenic...................................................... Wood Preserver................................................ Wood Tox 140.................................................... 1 54 54 27 46 46 46 46 27 27 27 31 27 31 27 46 J9 19 --Y-- Yasoknock................................................................ 54 yellow phosphorus............................................. 54 --Z-- Z-C Spray.......................................................... Z e b to x ................................................................ Zerlate................................................................ Zincmate............................................................ zinc phosphide.................................................. Zinc-Tox............................................................ zineb.................................................................... Z in o s a n .............................................................. ziram .................................................................. Ziramvis.............................................................. Zirasan90.......................................................... Zirberk................................................................ Zirex 9 0 .............................................................. Ziride.................................................................. Z o lo n e ................................................................ zoocoumarin...................................................... 36 36 36 36 54 54 36 36 36 36 36 36 36 36 1 54 6206 120 30 620 30 Special Article 127 Dioxin Effects on Human Health By W ILLIAM G. DUNAGIN, M .D . Colum bia HAY BE PROTECTED BY COPYRIGHT LAW (TITLE 17 U.S. CODE) D ioxin, and its possible effects on h ealth, h av e received an enorm ous am ount of exposure in the popular m edia. C oncerns w ere initially raised by the controversial use of the herbicide, A gent O range, in V ietnam . T h e alleged harm ful effects of this spray w ere attrib u ted to contam ination of the h erbicide w ith sm all quantities of dioxin. T h e issue was heig h ten ed by controversies over toxic w aste disposal and accidental spills, which have resulted in m any law suits. M ichael Brown, p ro b ably th e best know n popular w riter about toxic wastes and the rep o rte r w ho "exposed" the Love C anal story, has said th a t M issouri is th e " D ioxin capital of the w orld." 1 In conversations w ith local physicians and in second hand reports from patients of com m ents by th e ir doctors, th e v iew is often expressed th a t n o th in g m u ch is know n ab o u t dioxin. Actually, there is a great deal o f information about the effect o f dioxin on health in both anitm ls and humans. The problem is that these studies are scattered in a wide variety o f publications, usual ly toxicology or occupational medicine journals that have a small circulation. O nly a few attem pts have been m ade to consoli d a te a n d su m m a riz e th e in fo rm a tio n .2"4 T his a r ti cle is a b rie f rev iew o f som e o f th e highlights o f w hat is cu rren tly know n so th at physicians can respond to inquiries from their patients. Exposure D ioxin has b een called th e m ost toxic chem ical know n to m an.5 This statem ent refers to a specific chlorinated derivative, 2,3,7,8-tetrachlorodibenzodioxin, usually abbreviated as T C D D . In a strict chem ical sense, th e plain dioxin m olecule w ith o u t ch lo rin e is relativ ely harm less. T he a d d i tion o f chlorine m akes a m ore toxic m olecule, w ith four chlorines being th e w orst, T C D D (Fig. 1). In th e r e m a in d e r o f th e p a p e r, I w ill u se th e term s dioxin and T C D D interchangeably because this is th e stan d ard practice in th e new s m edia. O n a w eig h t-fo r-w eig h t basis, T C D D is o n e o f the m ost toxic synthetic chem icals in term s o f L D 50 fo r so m e sp e c ie s o f la b o ra to ry a n im a ls.6 T h is fact is th e basis for th e claim th a t dioxin is o n e o f th e m ost toxic chem icals know n. O n a practical level, how ever, it is v ery unlikely for anyone to co m e in co n tact w ith larg e am o u n ts o f dioxin. It is ordinarily found in quantities describ ed as parts p e r m illion o r p arts p e r billion. T h e re is no in dustrial use for dioxin. O utside o f a few research laboratories, no one in ten d s to directly synthesize th e harm ful chlorinated isom ers o f dioxin. T h e p ro b le m is th a t dioxin is o fte n an u n w a n te d by-product in sm all quantities o f th e m anufacture o f chlorinated phenols7 -- a group of chem icals that do have a w ide variety of im portant uses. Sm all q u an tities o f dioxin (and th e equally toxic dibenzofurans) are p re se n t in th e fly ash o f m u nicipal and industrial incinerators.8 Dioxin has even b een found in th e m ufflers o f trucks and cars from com bustion in diesel engines. M illions of p eo p le in industrial Regions o f th e w orld are ex posed to m in u te traces o f dioxin in ordinary house d u st.8 V ery small quantities of dioxin have been found in b e e f fat from cattle that grazed on rangeland sprayed w ith herbicides contam inated w ith low levels o f dioxin.8 M ost likely, such low expo sures are harm less. T h e b est inform ation about hum an exposure to dioxin has b een obtained by studying th e results o f several industrial accidents in w hich w orkers are exposed to chem icals. T he b est exam ple in the U nited S tates was a plant in N itro, W est Virginia that p roduced trichlorophenol. O n M arch 8, 1949, a violent reaction caused a relief valve to open, releasing fum es and residue from an auto clave into th e interior o f the building. Two hun dred and eighty-eight em ployees and clean up w orkers w ere exposed to the m aterial which in clu d ed 2 ,3 ,7 ,8 -tetrach Io ro d ib en zo d io x in Fig. I Chemical structure of 2,3,7,8-tetrachlorodi- benzodioxin (TCDD). The term dioxin is commonly used for this substance. > 6208 HAY BE PROTECTED BY COPYRIGHT LAW (TITLE 17 U.S. CODE) 128 DIXIS t t t L U l i ) U N H U M A N H t . A L . l H -- U U N A U I N M akch, 1MU M uch inform ation about dioxin has been published recently and several definite cases of dioxin toxicity have occurred in M issouri. However, m any other people who may be w orried about possible exposure actually h a v e very low a b s o rb e d doses a n d Bhow n o harm ful effects. Dioxin toxicity has a fairly consistent p a tte rn a n d is d o se-related . A p a tien t who has only subjective sym ptom s w ith o u t any objective signs should n o t be consid ered as having tru e adverse effects of dioxin. D r. D unagin is A ssistant P ro fe sso r o f M edicine, D ivision o f D erm atology, U ni versity of M issouri-Colum bia H ealth Scien ces C enter and H arry S T rum an V eterans A dm inistration H ospital. (T C D D ) .10 S im ilar a c c id e n ts in v o lv in g p la n ts th a t produce trichlorophenol have occurred at Ludw ig sh a fe n , W e s t G e rm a n y in 1 9 5 3 ;11 A m s te r dam , N etherlands in 1963; G renoble, F ran ce in 1966; C zech o slo v ak ia fro m 1965 to 1969;2, 12 a n d B o lso v er, U n ite d K in g d o m o n A p ril 23, 1 9 6 8 .13 H e a lth effects from all th e se accid en ts have b e e n re p o rte d in foreign m edical journals. O n July 10, 1976, an explosion in a trichlorophenol plant at Seveso, Italy, 20 m iles north of M ilan, resulted in th e spread of products including T C D D over an area of 700 acres and exposing about 28,000 peo ple. Seven hundred thirty-three people w ere in th e m ost heavily contam inated area. A large r epidem iologic screening program was established by th e Lom bardy regional governm ent, and the results of the acute effects of exposure have been p u b lis h e d .2, 3t 14, 15 In 1970 and 1971, a com pany in V erona, Mo. u sed trichlorophenol in th e m anufacture o f hexachlorophene. In 1972, the com pany w ent out of business after the FD A restricted th e use of hexachlorophene to prescription only. Through a M illions of people in industrial regions of the w orld are exposed to m inute traces of dioxin in ordinary house dust. round-about sequence of events, oily w astes con tam inated w ith high levels of T C D D , which had been stored at the site, ended up being sprayed on several horse arenas throughout M issouri for th e purpose of dust'control. T he effects on ani mals and hum ans at one horse aren a w ere p u b lis h e d in 1 9 7 5 .16 Soil from this site h as sh o w n th e I highest level of T C D D of all th e environm ental contam ination areas tested to date, about 30 parts p e r m illio n . 17 T h e full e x te n t o f th e u n au th o rized disposal o f dioxin in M issouri is unknow n. T he average soldier in V ietnam was probably exposed to e x tre m ely low co n cen tratio n s o f T C D D , if any, com pared to th e preceding cate gories. A total o f 11 m illion gallons o f A gent O ra n g e w as s p ra y e d o n 3 V*2m illio n acres in S o u th V ietnam betw een 1965 and 1971. Thd average concentration of T C D D in th e spray was 2 parts p e r m illion. T he estim ated seven-year total am ount ofT C D D for all of South V ietnam was 170 p o u n d s , 18 c o m p a re d to th e e s tim a te o f 20 p o u n d s for one h o rse a re n a in M oscow M ills, M o.3 Spraying m issions alm ost always occurred w hen allied troops w ere n o t p resen t; in fact, fighter aircraft usually strafed th e ground preceding the spraying aircraft. M ost v eteran s claim exposure by w alking th ro u g h v eg etatio n . T C D D is d e g ra d e d by u ltra violet light, and studies show th at it cannot b e d e te c te d o n v e g e ta tio n a fte r o n e d a y o f su n lig h t. 19 Dioxin, in low concentrations, can also b e d e g ra d e d b y soil b a c te r ia . 20 T h e a c tu a l d o se th a t w ould p en etrate through hum an skin by brushing against vegetation is conjectural. T he personnel actually involved in the spraying program , O peration R anch H and, w ould likely b e exposed to m uch h ig h e r levels than o th er sol diers. T he arm ed services are conducting an epidem iologic study o f personnel involved w ith O peration Ranch H and. T he prelim inary results should b e available in M ay, 1983. If no adverse effects are noted in this group w ho w orked w ith the chem ical daily, then it w ould be very unlikely for th e average soldier w ho h ad m uch less expo sure to have any effects. H ealth E ffects in H umans Thousands of people w ith know n definite expo sure to dioxin have b een observed; som e have been followed for 30 years after industrial acci dents at N itro, W est V irginia an d Ludw igshafen, W est G erm any. T h e only disease w hich une quivocally follows exp o su re is a ra re skin condi tion known as chloracne. M any other reported conditions m ust b e exam ined in detail from one report to another. U sing the accident at N itro as an exam ple, one can separate im m ediate, delayed and long-term effects. Imm ediate E ffects a Im m ediate sym ptom s at N itro w er$ irritation of th e skin, eyes and resp irato ry tract and 6209 Vo l u m e 8 0 Number 3 DIOXIN EFFECTS ON HUMAN HEALTH -- DUNAGIN 129 h e a d a c h e , d iz z in e ss a n d n a u s e a . 10 T h e s e s y m p tom s w ere probably due to o th er chem icals, such as chlorinated phenols, p re se n t in the reaction m ixture in m uch h ig h er concentrations. T he acci d en t at Bolsover, E ngland, resulted in different sym ptom s. In this case, w orkers w ere not ex posed to vapors from th e explosion. T he explosion occurred at night and the plant was closed for ten days. W hen work was resum ed, no im m ediate effects w ere noted. T he first abnorm ality d e tected was chloracne, m ostly in fitters, plum bers and electricians. Subsequently, it was shown that The Italian medical commission which thoroughly studied a large number of people at Seveso con cluded that chloracne was the most frequent and reliable indicator of TCDD exposure. T C D D was p resen t in greasy deposits on th e walls, roof and o th er surfaces of th e plant. T h e 79 w orkers who developed chloracne w ere the ones m ost likely to com e into direct contact w ith such s u rfa c e s .13, 21 S o m e o th e r cases in w h ich th e r e w ere no im m ediate effects of dioxin exposure in c lu d e tw o la b o ra to ry sc ie n tis ts in B rita in 22 a n d large num bers of people at Seveso, Italy. Ap parently, exposure to low or m oderate am ounts o f dioxin does not produce im m ediate sym ptom s. * D elayed E ffects C hloracne usually begins four to eight w eeks after exposure. This is th e m ost consistent finding and has b een rep o rted in all th e studies of know n dioxin exposure. T he Italian m edical com m ission, which thoroughly studied a large num ber of peo ple at Seveso, concluded that chloracne was the m ost frequent and reliable indicator of T C D D exposure, and its incidence was proportional to th e level of ex p o su re.3 C hloracne is a p ersisten t condition that m ay last for a year o r two after exposure. Som e cases last longer, and one has b e e n n o te d 15 y ears a fte r an in d u stria l a c c id e n t. 13 C hloracne consists prim arily o f open com edones w ith a low proportion of inflam m atory lesions v e r sus acne vulgaris. In addition, chloracne occurs in m any skin locations such as th e p inna w here acne v u lg aris is u n u s u a l.23 C hloracne appeared in 122 o f 288 w orkers at N itro after a delay of a few w eeks. O th er delayed sym ptom s w ere m uscle pains, fatigue, nervous ness, d ecrease in libido, dyspnea, vertigo and co ld in to le ra n c e . 10 S o m e o f th e s e sy m p to m s m ay have b een d u e to phenols and o th e r chem icals in the reaction m ixture. Som e sym ptom s are com m on everyday com plaints, are difficult to quantify and are not consistently p resen t in other studies. Very few objective findings w ere reported. At Bolsover, E ngland, even though m any of the chloracne cases w ere severe an d persisted up to four years, no o th er ailm ent th at could reasonably b e a ttrib u te d to dioxin w e re fo u n d .13 In p articu rlar, m onitoring o f results o f liver function tests and urinalyses w ere norm al. A fter th e accident at Ludw igshafen, 66 o f 74 w orkers developed chloracne. Tw enty-one of the m ost severely affected had o th e r com plaints re lated to polyneuritis, sensory im pairm ent or liver dam age. Again, th e re w ere m any o th e r chem icals beside T C D D in th e reaction m ixture. Signs o f porphyria cutanea tarda w ere n o ted in several w o rk e rs. 11 P C T w as also n o te d a fte r in d u strial exposure in Czeckoslovalda2 an d an unspecified p la n t in t h e U S A .24, 25 M o st o f t h e sig n s o f P C T are cutaneous: fragility o f th e skin, blisters, hir sutism and hyperpigm entation. H irsutism and hyperpigm entation w ere also n o te d in tw o labora tory scientists doing research on T C D D in G reat B rita in .22 A lth o u g h n o p o rp h y rin s w e re d e te c te d in th e urine, th e descriptions are com patible w ith PC T and, perhaps, the diagnostic tests w ere not as accurate as cu rren t ones. A fter th e accident in Seveso, Italy, no clinically ev id en t P C T was found, b u t su b tle changes in urinary porphyrin ratios w ere d e te c te d in som e p a tie n ts .26 T C D D is a p o te n t in d u c e r o f th e e n zym e d elta-am in o lev u lin ic acid synthetase, w hich is th e first ste p in th e fo rm atio n o f p o r p h y r in s .27 S o, t h e r e is a g o o d th e o re tic a l ex planation for th e occurrence o f P C T after dioxin exposure. Dioxin toxicity has a fairly consistent pattern and is dose-related. Sym ptom s o f n eu resth en ia (lack o f vigor, sleep disorder, etc.) have been rep o rted in several studies. A lthough these sym ptom s are subjective and difficult to quantify, they do seem to b e signif icant in persons likely to have large exposure to the chem ical as show n by chloracne. T here have been som e rep o rts of oljjective neurologic signs such s w eakness o f the low er extrem ities and nerve conduction deficits of the dem yelinization type. H ow ever, at Seveso, m ost people w ho had these changes w ere over 55 years old and had o th er possible predisposing conditions, such as i 6210 M is s o u r i M e d ic in e 130 DIOXIN EFFECTS ON HUMAN HEALTH -- DUNAGIN M a r c h , 1963 ^ 'V . .. M ore A b o u t th e A u th o r > A Topeka, Kan. native w ho graduated 1- sum m a cum laude fr o m the U niversity o f ' Kansas, D r. D unagin fin ish e d his m edical %:schooling a t the sam e in stitu tio n in 1975 and . %rhis derm atology residency a t th e U niversity |$ \o f M issouri-Colum bia School o f M edicine. .. D r. D unagin becam e d D iplom iite q jfth e if Am erican Board o fD erm atology {.2979 and . professional: society a f f ^ t t o k i include > fF iu o u i'A m e ric a n A cadem y x f Dermatology*" \r ~and m em bership in the S o cietyfo r Investiga- ' fe tfoe D erm atology, Am U rican .D erm atologic ; r-i-Society fo r A llergy arid Im m unology .and th e w R-M isso u ri State D erm atological Society fF j A m ong his other published articles a re if D rug Eruptions"(w ithco~authorL*E M il- . iik a n , M .D .) in th e Journal ofthfcM edical Climes of North America in 1980 and ica l Toxicity o f C hem otherapeutic Agents: _D erm a to lo g ic T o x ic ity ** i n Sem inars in ' I^Oncology in 1 9 8 2 ." ; diabetes or nutritional im pairm ent.3 Two peo p le w ho operated one o f th e horse arenas in M is souri developed sym ptom s of headache and nausea four days after the arena was sprayed w ith w aste oils containing dioxin. L ater, they d e veloped chloracne. Tw o children who played m th e area had headaches, diarrhea, epistaxis and chloracne. O ne developed an acute hem orrhagic cystitis, which required hospitalization b u t re so lv e d in th r e e d a y s.3, 16, 17, 28 An extensive epidem iologic study was con d u cted after the release o f dioxin at Seveso, Italy. O ne hundred eighty-seven cases of chloracne w ere discovered, m ostly in the zone w ith the highest levels of dioxin. T h ere was som e question about neurologic findings discussed above, but few o th e r significant problem s w ere found. T he Seveso M edical Com m ission looked extensively b u t found no evidence for hepatotoxicity, con genital m alform ations, spontaneous abortions, chrom osom e aberrations, im m unosuppression, su sc ep tib ility to infectio n o r overall d eath r a te .3, 14, 15 O th er delayed effects that have been reported occasionally after dioxin exposure include m uscu lar pain, hypercholesterolem ia, hepatic enzym e elevation, conjunctival irritatio n , prolonged p ro th ro m b in tim e and b lu rre d vision. T hese effects are not rep o rted 'freq u en tly and m ay be d u e to incidental disease, dioxin or oth er chem icals and irritan ts in th e industrial setting. T he subjective and objective findings that have b een re p o rte d co n sisten tly in p atien ts w ith know n dioxin e x p o su re a re liste d in T ab le 1. T here are very few cases of high level exposure. T he problem s listed for the high category should not b e taken as firm or exhaustive. Some are based on only one o r two cases in hum ans and analogies to anim al toxicity. ' ^ Long-Term E ffects A n o th er m ajor concern ab o u t dioxin is the possibility o f inducing cancer. T he evidence from anim al studies is conflicting. T h e Ames te st is positive in som e strains of bacteria but not in o th ers.4 C u ltu red m am m alian cells have not shown m utagenic responses.4 Som e strains o f laboratory anim als develop cancersafter continuous dioxin feeding, b u t th e dosage level req u ired is so high that m ultiple organ toxicides are p ro d u c e d .2 T h e thym us is particularly susceptible, and th e problem m ay be decreased im m une surveillance. N o particular ty p e of m alignancy has been found consistently. In long-term follow-up o f hum an exposure, no increase has been n o ted in overall m ortality. T hirty-year follow-up o f 122 w orkers at N itro, W . V. show ed no excess over th e expected rate o f m a lig n a n c y . 10 F o llo w -u p o f 74 w o rk e rs e x p o se d to dioxin at L udw igshafen, W est G erm any showed th ree deaths due to stom ach cancer, w ith less th a n one ex p ected statistically.11 No o th e r TABLE 1 DIOXIN TOXICITY Amount o f Exposure Subjective Symptoms Objective Signs Low M oderate High Headache Fatigue Chloracne The above plus The above plus Neuresthenia Porphyria cutanea tarda - --d e p re s s io n --blisters -- lack of vigor --fragility o f sldn --sleep disorder --hyperpigmentation -- loss of libido -- hirsutism --profound weakness Nausea Sensory peripheral nerve Muscle pains impairments Lack of Nerve conduction concentration abnormalities Anorexia The above plus Abdominal pain The above plus Hepatic necrosis T cell depression Bleeding tendency D iarrhea Prolonged prothrombin time | '* [ , j | { j , ' j J j ; j| / j 8211 Vo l u m e 60 Number 3 DIOXIN EFFECTS ON HUMAN HEALTH -- DUNACIN 131 disease or type of m alignancy was increased com p a re d to control populations. No increase in stom ach can cer has b e e n found in any o th e r study. T he other question about hum an cancer con cerns soft-tissue sarcom as. This question was in itially raised by a study o f Sw edish forestry w ork ers exposed to phenoxy herbicides. An increase in soft tissue sarcomas was noted in w orkers using herbicides contam inated w ith dioxin. H ow ever, a sim ilar increase was also noted in w orkers using herbicides that w ere no t contam inated w ith d io x in .29 F u r th e r m o re , s tu d ie s o f S w ed ish a g ri cultural and railroad w orkers and studies o f for estry w orkers in F inland and N ew Zealand w ho used the sam e herbicides did not show any in crease in m alignancy. O ne p a tie n t w ho developed chloracne after the accident at N itro died 29 years la te r o f m a lig n a n t fib ro u s h istio c y to m a .10 T w o people w ho w orked at o th er plants producing phenoxy herbicides have d ied offibrosarcom a and liposarcom a. Some people have suggested that these th ree soft-tissue sarcom as are m ore than e x p e c te d b y c h a n c e .29 H o w e v e r, n o so ft-tissu e sarcomas have been d etected after any of the industrial accidents in E urope. Su c c e ste d E valuation fo r D ioxin E xposure M any patients w ho claim exposure to dioxin have b een exposed to such low quantities, and ,, even low er absorbed doses, that they do not have any real toxicity. It is im p o rtan t to sep arate th o se people w ho have only psychosom atic com plaints from those w ho have tru e toxicity. E very p atien t should have a derm atological evaluation for chlor acne and porphyria cutanea tarda. Serum chem is try profiles and prothrom bin tim e should rule out hepatocellular dam age. A 24-hour urine collec tion for uroporphyrins should be done. A spot check o f u rin e for uroporphyrins is not reliable. M uscle w eakness or neuritis sym ptom s should be evaluated by electrom yography and m otor con duction velocity. Im m unologic evaluation m ay be considered in som eone w ith o th er organic disease and high exposure. Summary A large num ber of people w ith definite expo sure to dioxin have been rep o rted in the m edical literatu re. T h e co n sisten t effects w hich can reasonably b e attrib u ted to dioxin are listed in th e table. C h lo racn e is th e m ost significant o f th e objective signs, occurring in m ost cases o f tru e toxicity. C h lo racn e is a d istin ctiv e e n tity w hich m ay occur from topical or system ic absorption, and differs from acne vulgaris an d from acneiform e ru p tio n s s e c o n d a ry to to p ical ta r o r o il.23 It m ay occur in p re-pubertal children and the elderly. T h e am o u n t and tone of new s coverage o f dioxin m ay have a significant pow er o f suggestion, and m any p atien ts attrib u te psychosom atic com plaints to dioxin. H ow ever, a patient w ith no objective signs o f dioxin toxicity should not be co n sidered as having tru e ad v erse effects o f diox in. R eferences 1. Brown, M.: Speech at University of Missouri-Columbia, October, 1961. 2. Huff, J. E .. Moore, J. A., Saracci, R. et ah Long-Term Hazards of Polychlorinated Dibenzodioxins and Polychlorinated Dibenzofiirans. En- vironmentai Health Perspectives 36:221-240, 1960. 3. Reggiani, C .: Localized Contamination W ith TCDD-Seveso, Missouri, and O ther Areas, in Kimbrough RD. (ed). H alogenated Biphenyls. Ter- phenyls, N aphthalenes, D ibenzo Dioxins and R elated Products, Amsterdam: Elsevier/North Holland. 1980. 4. AMA Council on Scientific Affairs: Health Effects o f Agent Orange and Dioxin Contaminants. JAMA 246:1895-1897, 1962. 5. Conway, C.: Poisons in O ur Midst. C olum bia D aily Tribune, March 23, 1960, p.43. 6. McConnell. E. E ., Moore, J. A., Jaseman. J. et ah The Comparative Toxicity of Chlorinated Dibenzo-p-dioxins in M ice and Guinea Pigs. Toxicol. Appl. Pharmacol. 44:335-336. 1978. 7. H am s, M. W .. Moore, J. A. and Vos, J. C .: General Biological Effects of T C D D in Laboratory Animals. Envir. Health Persp. 5:101-109. 1973. 8. Bumb, R. R., Crum m ett, W. B., Cutie, S. S. e t ah Trace Chemistries of Fire: A Source of ChlorinatedDioxins. Science 210:385-390, 1980. 9. Westing. A. H.: The Safetv of 2,4,5-T (letter). Science 206:1135-1136. 1979. 10. Zack. J. A. and Suskind, R. R.: The Mortality Experience o f Workers Exposed to Tetrachlorodibedzodioxin in a Trichlorophetwl Process Accident J. Occup. Med. 22:11-14. 1980. 11. Tniess, A. M., Fentzel-Beyme. R. and Link. R.: Mortality Study of Persons Exposed to Dioxin in a Trichlorophenol-Process Accident That O ccurred in the BASF AC on November 17, 1953. Am. j . lod. Med. 3:179- 189, 1982. 12. Kimbrough. R D.; Occupational Exposure. In Halogen*tedB iphenyls. Terphenyis, N aphthalenes, D ibenzodioxins and R elated P roducts. Amster dam: Elsevier/North Holland. 1980. 13. May. G.: Chloracne From the Accidental Production of Tetrachlor- odibenzoaioxin. Br. J. Ind. Med. 30:276-283. 1973. 14. Pocchiari, Silano V. and Zampieri, A.: Human Health Effects From Accidental Release of Tetrachlorodibenzo-p-dioxin (TCDD) at Severn, Italy. Ann. N. Y. Acad. 320:311-320, 1979. 15. Reggiini, G.: Estimation of the TCD D Toxic Potential in the Light of the Seveso Accident. Arch. Toxicol. (Suppl.) 2:291-302, 1979. 16. Carter, C. D ., Kimbrough. R. D.. Liddle, J. A. e t aJ Tetrachlor- odibenzodioxin: An Accidental Poisoning Episode in Horse Arenas. Science. 188:738-740, 1975. 17. Kimbrough. R. D ., Carter, C. D.. Liddle. J. A. f t ah Epidemiology and Pathology of a Tetrachlorodihenzodioxin Poisoning Episode. Arch. Environ. Health 32:77-85, 1977. 18. Cleland, M.: Testimony Before the Subcommittee on Medical Facilities and Benefits of the Veterans Affairs Committee, House of Representatives, February 25, 1980. 19. Crosby, D. G. and Wong, A. S.: Environmental Degradatfcmof2,3,7,8- Tetrachlorodibenzo-p-dioxin (TCDD). Science. 195:1337-1338. 1977. 20. 2,4,5-T What next? (editorial). Lancet. 2:1114*1115. 1979. 21. Jensen, M .E ., Sneddon, 1. B. and Walker, A. E.: Tetrachlorodibenzo- dioxin and Chloracne. Trans. St. John's Hosp. Derm . Soc. 58:172-177, 1972. 22. Oliver. R. M.: Toxic Effects of2,3,7.8-Tetrachk>rodibeiim 1.4-Dioxin in Laboratory Workers. Br. J. Ind. Med. 32:49-53, 1975. 23. Crow, K. D .: Chloracne. Trans. St. John's Hosp. Derm . Soc. 56:79-99, 1970. 24. Bleiberg, J., Wallen, M., Brodkin, R. e t al: Industrially Acquired Porphyria. Arch. Dermatol. 89:793-797. 1964. 25. Poland, A. P., Smith, D .. M etier. G. e ta h A Health Survey o f Workers in a 2,4-D and 2,4,5-T Plant, With Special Attention to Chloracne, Porphyria Cutanea Tarda, and Psychologic Parameters. Arch. Environ. Health. 22:316- 327. 1971. ; 26. Strik. J. J.: Porphyrins in Urine as an Indication of Exposure o f Chlori nated Hydrocarbons. Ann. N. Y. Acad. Set. 320:306-310. 1979. 27. Poland. A. P. and Clover, E.: 2,3.7,&-TetrttMorodtbenzo-p-dioxin: A Potent Inducer of 6-amtnolevulintc Acid Synthetase. Science I <9:476-477, 1973. 28. Beale, M. C ., Shearer, W. T ., Karl. M. M. e ta l: Long-Term Effects of Dioxin Exposure (Letter). Lancet 1:748. 1977. 29. Coggan. D. and Acheson. E. D .; Do Phenoxy Herbicides Cause Cancer in Man? Lancet 1:1057-1059. 1982. ttn i r t t J J ; \ 1 J t * I ! ;! .i 1; ' -- 6212 3/ I --3 THE AGENT ORANGE CASE An Overview __________ Th - T h e ~ g 1 - - , ---g** Much has been written concerning how the Rudersham case was brought ito Victor Yannacone who, by 1978 had developed a reputation as\an environmental lawyer in the DDT cases, and how Yannacone subsequently formed a consortium of Long Island lawyers under the"\^name a\d style of Yamnacone & Associates to process the case. The reality haf/ this group of lawyers had to face was that, armed with only 'ph.eir own personal resources, they were being called upon to p/osetuto what was at best an arguable case against some of the .'largest:, wealthiest and best-connected corporations in the world. Their clients, at first just a few veterans and their families, weh^ in no position to assist in the financing of the effort. From the outset, strateg ies\ were attempted that would minimize or eliminate the advantage\that the defendants' unlimited finar.c/ial and professional resources would give them. i.ne first plan/to short-circuit the cas& was to move for a preliminary injunction under FIFRA and whatever other grounds were available to stop the manufacture and\jse of 2,4,5-T. A hearing on a/ preliminary injunction would force the defendants into a trial without any discovery and' before they could get prepared to conduct a war of attrition. Unfortunately, Judge Pratt could not be made to go along with this strategy. Instead, he deferred the claims to the EPA proceedings then pending without prejudice to renewal in the event the EPA proceeding should prove defectives , ' Phase II ' ' 6214 There were numerous motions directed to the Second and Third Amended Complaints which led to some serious litigation. Before considering those, however, it should be noted that Yannacone, in an effort to reduce some of the apparent disproportion between the parties, was travelling around the country publicizing the case and trying to drum up interest in the crusade. In this he was successful, but his activities drove the defendants to attempt to obtain a "gag" order against him. This was a high-powered effort for the defendants who spent a lot of time developing favorable law and facts. Judge Pratt denied the motion without opinion. Returning to the motions directed to the Complaints, the defendants questioned federal jurisdiction and also pushed statute of limitations as a defense. In his famous "Claiming to be the harbinger" opinion (506 F. Supp. 737), Judge Pratt denied the former grounds and found federal question jurisdiction. The latter he sidestepped by (1) not deciding the question while the jurisdiction matter was pending, and (2) conditionally certifying a class to toll the statute of limitations so as not to exacerbate any problems while the matter was sub judice. Indeed, he asked that no further complaints be filed to avoid burying the court clerk with paper. For a while merely the names and addresses of new plaintiffs were filed; then he dispensed with even that formality. 3^ '^ ' Federal question jurisdiction was important because -(1) there was no diversity between defendants and large numbers of plaintiffs, and (2) federal question jurisdiction would be a big help in ultimately overcoming Statute of Limitations problems. It was not too surprising, therefore, that Judge Pratt elected to; certify the question to the Court of Appeals ;for interlocutory ! consideration on November 21 , 1979. That certification put^-the ;>case somewhat in limbo for nearly d year. Aftefr certification, the focus of the ,1itigation shifted 6215 temporarily from the district court to the appeals courts. The matter was briefed and argued to the Court of Appeals on May 1, 1980. For some reason, the Court did not issue its opinion until November 24, 1980, at which time it reversed Judge Pratt and held that there was no federal question jurisdiction. Immediately thereafter, plaintiffs were obliged to seek a stay of the mandate (without bond) and also to seek a Writ of Certiorari under the caption "Chapman v. Do w .11 This was denied on December 14, 1981 (454 U.S. 1128) . While the appeal from the jurisdictional question was I pending, the parties sought to exchange first wave I interrogatories. At first the Court appeared to encourage discovery (there were some diversity actions that were clearly valid in any event). A few days later, however, the Judge ^'decided that the benefits of continuing discovery were outweighed by the possible difficulties inherent in the circumstancews and he effectively stayed all discovery until the appellate courts {should have spoken. Also, noting the various defenses asserted in the Answers, Judge Pratt ordered the defendants to bring motions for summary judgment on their defenses. The object was to simplify the pleadings, but it was clear that Judge Pratt was looking for one or possibly two key issues that would be dispositive of the case. In line with a general briefing of the issues, Judge Pratt directed a conference in July of 1980 to consider solely the Australian cases. He found that they were generally bound by all the same Feres-type rules applicable to the suits by atnerican servicemen. The period waiting for the Court of Appeals to decide jurisidiction.was also used to some extent to work out an outline for _in. extremis depositions and to -promote plaintiffs' plan for serial trials. Basically, plaintiffs sought in the latter to convince the^Court that it would be desirable ,to break the case 6216 ^up into a series of trials on critical issues, such as generic causation, or product use and abuse, rather than to attempt to resolve the entire case at one confused, incomprehensable trial. JWhile Judge Pratt ultimately rejected plaintiffs' precise formulation, the concept finally governed the case in another guise for a considerable period. The Government Contract Defense The efforts to simplify the pleadings led Judge Pratt to begin to concentrate on the so-called "Government Contract Defense" as a possible descrete, simplified issue that might turn the whole case. After the initial motions for summary judgment had been decided (505 F. Supp. 762), he called for further briefs refining this particular defense. These briefings led to his first opinion on the Government Contract Defense in 1982. 534 F. Supp. 1046. The opinion was a disappointment to the plaintiffs. In what Judge Pratt probably saw as an effort to streamline the defense, he eliminated numerous subtleties that plaintiffs believed were important considerations in the defense, such as indirect responsibility for the specifications, coercion and consciousness of choice on the part of the government. Instead, he reduced the effort into a showing of what the government knew, what the defendants knew, and what the defendants told the government. Having determined that those were the central issues to be considered, Judge Pratt directed discovery to begin on those issues. It might be noted that by far the greatest part of this discovery was at the "expense" of the government, in terms of time and effort, as well as money. Thus the plaintiffs were temporarily freed from crushing demands for discovery against themselves. The demands of keeping pace with the discovery against the government, however, was considerable. Some limited 6217 discovery was also had against the defendants on their knowledge and activities. The government's posture in the case at that point was somewhat ambiguous. In late 1981 and early 1982, Yannacone & Associates had attempted to file large numbers of Federal Form 95, the Administrative Claim Form under the Federal Tort Claims tAct, on behalf of their clients. The project was, in mnay ways, doomed from the outset. First of all, each form had to h.e prepared individually for each client and signed by him. Because of sheer numbers, that was a virtual impossibility. Secondly, administrative regulations made it mandatory to file the form at different places for different categories of claims or different kinds of individuals. A full staff would have taken months to accomplish the task, and Yannacone & Associates did not have the I staff to devote to the cause nor the months to spare. A couple of applications were made to the Court to try and bend the rules. Judge Pratt was asked to authorize the filing of a single administrative claim on behalf of all the class members, and he was also asked to at least get the government to accept service of all claims by class members at a centralized location. Judge Pratt, however, ruled that he had power to do neither. A further ploy was attempted in the guise of Ryan v. Clelland, a case that attempted to avoid the requirements of the Federal Tort Claims Act by seeking injunction, etc., without demanding a money judgment. Again, Judge Pratt ruled the Complaint could not prevail against the government. 531 F. Supp. 724. While Judge Pratt could not be convinced to evade the requirements of the Tort Claims Act or to simplify the administrative requirements under the Act, he declined to enter a final order dismissing either plaintiffs' di r.ect claims or the defendants' third-party claims against,it. As a practical matter, this meant that the government was available to cooperate in discovery requests like those pressed in pursuit o f ' the Government Cdntract Defense, whether it agreed ,to cooperate with 6218 such discovery or not. \1 With the completion of appellate review of the /jurisdictional Question on December 14, 1981, Judge Pratt decreed that the case would go to trial on the single issue of the government contract defense in jfune of 1983). He also appointed Sol Schreiber to act as Special Master to supervise discovery. It would not be appropriate in an "over view" to discuss the minutiae that were brought before the Special Master during this time. In addition to the details of discovery, the defendants kept before the Master and the plaintiffs their position that the case was essentially non-justiciable, at least before a jury, and that they did not accept the procedures being employed to advance the case. In March of 1983 the Court and the Special Master believed discovery was sufficiently advanced (and the trial sufficiently near) to authorize a further set of motions for summary judgment. These motions, now based on discovered facts, were governed by the November, 1982 decision. The marshalling of the facts and the law for and against these motions constituted one of the principal landmarks in the case up to that point in time. The motions were submitted in April, 1983. Shortly after the papers were in, the Court announced it would issue its decision on May 20, 1933, but that all discovery was to halt until then. Judge Pratt's decision was, again, a disappointment for the plaintiffs because he disregarded, at least for purposes of the motion, a series of factors that plaintiffs regarded as critical for the government contractor defense. Specifically, he disregarded the concept of "level of responsibility" and held that the'knowledge of the lowest private was equivalent, tor purposes of the government contractor defense, with the knowledge of the President of the United States. He disregarded any 6219 concept of vicarious liability based on conspiracy to withhold from the government information about the toxicity of dioxin. Such a conspiracy had emerged from discovery, but Judge Pratt was prepared to dismiss from the case any defendant against whom nothing more could be shown. On the other hand, Judge Pratt appeared to accept the idea that a defendant could prevail on the ^.efense no matter what his other conduct if he could show that he produced a "clean" product for the government, which Judge Pratt accepted to be a product containing no more than 1 part per \ A million of dioxin. Given these criteria, Judge Pratt dism'issed Riverdale Chemical and (as to whom no real argument had been raised) but he also dismissed Hercules Chemical Company, a primary actor in the conspiracy to conceal from the government, but a producer of what Judge Pratt considered to be a "clean" product. 565 F.Supp. 1263. The Summer of 1983 and the Breakdown of Control under Yannacone & Associates The exercise with the motions for summary judgment on the government contractor defense convinced Judge Pratt that it would not be possible to segregate that issue as a discrete one for separate trial. On the contrary, it convinced him that the trial would have to be broadened to include issues of liability and causality. Accordingly, he cancelled the June, 1983 deadline and opened discovery up as to matters of causality and fault between plain tiffs and defendants. The summer of 1983 was largely consumed with the discovery thus directed. Roughly depositions were held in days. Even before the institution of that discovery schedule, however, yannacone & Associates had begun to czximble tinder the pressures of the case. In the spring of 1983, just before 'the motions for summary judgment, they had agreed to accept what they had heretofore resisted, the formation of a plaintiffs' 6220 management committee including other counsel. Indeed, such jjew attorneys made a valuable contribution to the resistance to the moj:ions . With the accelerated discovery schedule, however, even greater deficiencies appeared-- -ij) the Yannacone organization. Certainly ability and dedication remained, but the discipline necessary to get the job done in an orderly fashion seemed lacking. Depositions were missed or nearly missed and commitments were not kept. Plaintiffs' attorneys were obliged to expend their efforts reacting to the demands of the defendants and did little by way of seizing the initiative. Most importantly, though, the financial demands of the case were beginning to get ahead of plaintiffs' counsel. Bills from court reporters, for example, mounted to upwards of $50,000. Such failings did not bode well for a group that proposed to put on a major case against some of the most seasoned and best equipped defense organizations in the not-too-distant future. Various solutions were proposed. One organization offered to work with the existing counsel group provided they agreed to subordinate their management prerogatives to that organization. While it was not questioned that the offer was well-intentioned, it was rejected. Instead, Yannacone & Associates moved to be relieved as counsel altogether, giving assurances to any successor that they would cooperate in the further management of the case, but that they could not cope with the financial burdens of the case as it was developing. It was in this context that the present Management Committee, as augmented from time to time thereafter, accepted the challenge and took over management of the case with the approval of Judge Pratt. Composed of seasoned trial lawyers with experience in mass tort personal injury cases, its members also brought with them the financial capabilities;of seeing the case to its conclusion. A' Shortly after the new management committee took over the case, Judge Pratt made it known he could no lopger supervise the 6221 > case (he had, in the meantime, been appointed to the United States Court of Appeals for the Second Circuit) and the matter was turned over to Chief Judge Jack B. Weinstein. A New Judge and a New Management Committee Judge Weinstein made it plain from the outset that he had a different view of the case than Judge Pratt. In the first place, whereas Judge Pratt had largely accepted in conce-pt plaintiffs' idea of limited subtrials, Judge Weinstein saw the case as involving just one major trial encompassing all issues. Where Judge Pratt had accepted the idea of 'generic causation' as a trial issue, Judge Weinstein, while acknowledging that something like generic causation would have to be tried, also wanted the case pinned down the case of specified individuals. Lastly, while Judge Pratt had dismissed those whom he felt did not belong in the case, Judge Weinstein made public his feeling that no one should be dismissed from the case before trial. Within weeks of his comments, plaintiffs had moved to bring Hercules and Thompson back into the case and had succeeded. Even more dramatically, the defendants moved to reinstitute their third-party complaints against the government, and were rewarded with success. For their part, the new Management Committee moved in the direction of taking control of the case. Armed with a depth of personnel and resources not available to Yannacone & Associates, the new Management Committee organized itself into groups with specific responsabiiities and began to take the initiative. A comprehensive approach to the management of the causality trial was planned and carried into execution, and much groundwork was done to bring the legal considerations of the trial into a line advantageous to the plaintiffs. New looks were suggested-at the interplay between*the doctrines of negligence, strict liability and failure to warn; and wholly new formulations of the government contractor defense were suggested. 6222 32- 6223 (\rsDWxC>CXJr ( Firms knew dioxin effect. memos Th>MinriilifIPr-- ouri, including the town of . TINIONDALE, N.Y. - Chemi Times Beach.' cal; companies making dioxin- One of the documents, a Feb. contaminated Agent Orange 22,1965, Dow memo, summarized secretly discussed the extreme a meeting at which 13executives toxicity of the Vietnam War de- discussed -dioxin contamination foilaat.many times before its of 2,4,5-T, one of the two ingred bap. in' 1970, according to court ients of Agent Orange. It also - : documents released Tuesday. contained the herbicide 2,4-D. The documents show that The Dow officials decided to ! company officials discussed contact other makers of 2,4,5-T, i "known health problems" and short for 2,4,5-trichlorophenoL described dioxin as "exception- Another Dow report indicates; - .* ally toxic" and that they wanted that the company was aware in '. tosolve the contamination prob- 1957 of an incident two years I lem before outsiders "cause us earlier in West Germany where m i na end of grief." there were "severe cases, (of ; nm^-r^Iliealls.of.the internal indus- chloracne), including some sus- . pected fatalities." That document includes'; ......................................................... among the entries for effects in humans: "Usually not disabling, ----------------- tion-federal court suit' filed by but may be fatal," "liver injury" '.Vietnam veterans against major and "long-term - two to five ` j f t f i j B t o - V: : -.chemical ' manufacturers.'. 'The years to recover." -v, . -Sia* - -*?;. r.JS^Vdocments previously had beep In March 1965, Dow official ^ ^ S H a l e d , .V . ' VJC Bowe called a meeting of - .^^vv^^Jttorneya. for the veterans executives of Monsanto; Hooker-' j v contend "that "silence and confi- Chemical, which operated the : *g*w- ' * : ; C"?. dentiality were the code words Love Canal dump; Diamond AK; ' r'::'.^trU Jited to conceal the knowl- kali, a predecessor of Diamond-;-; T MgftiVhlch - these defendants Shamrock; and the -Hercules 1 ----------. . amassed concerning the po- Powder Co., now Hercules Inc. : ffeaBlfhalth hazards"-.assort- The meeting's purpose, ac-"; i i et S<? A nt Orange eontami- cording to the documents, w as'; :'and shot > ^ * cS rt o ? ^ "to discuss the toxicological. problems caused by the pres ence of certain highly toxic im- . ^\j-V --iXblrtdeiTof a wide range of ail- purities" in samples of2,4-T.: : ' said 'Nasta was ments, including a severe' skin Dow officials distributed a ; ..Sunday after disorder,called chloracne, liver memo dated Nov. 30,1964, which; k^^iotleed :inconsistencies'- disease ``and birth defects in' called dioxin a "causative factor av e rsioann of events. -'' i>- - offspring. in the known health problems." : r-Coonty Homicide tn(Carey said five ^ i s w w w i- at- the home - -The five defendants - Dow Chemical, Monsanto, DiamondShamrock, Uniroyal and Thompson-Hayward Chemical - . say Later, E.L. Chandler of Dia-'; mond-Shamrock wrote a memo that said the meeting "was obvi-. ously designed to help 'd*'solve that if dioxin caused illnesses, this , problem -before -putsldera; they didnt know it, claiming that confuse the issue <hnd<cause us' - .y, (government knew more no end ofgrief." .'`i v *;?./.' . ''l a r e s ''home,- be*?-1about it at that time than they C.L. Dunn of Hercules,, di*'/*; > life-insurance.' did.~ ;; ' missed as a defendant'in the : Swmldjiave given Nasta,, i' lThe plaintiffs contend that Agent Orange case, said in a:; i supervisor for forer .the: companies knew of the memo for his company that Dow; ~ tiseTown-of Hemp- .'health hazards and did not tell said "their examination bfth e ir : ,, twaf.Department,-and ((between $150,000 and t)w government .'.' Dioxin is short for tetracho- own and competitors';-':2,445-T-lproducts shows that some may : trjCoant.yh_o_m_P rodlbenzo-p-dioxln, also known. contain what-they term `surpria-: Shaun 8pP:V- as TCDD, composed of chlorine tConferenee'' ahd hydrocarbons, it has been' theffastga had linked- to skin 'disorders, birth" "In addition tbtfie 'klneffect,; fohma^dyetahres,whAardmnylo'-'-dIneifenicltsl^a-n^d-'-c.aV.n.c-er in laboratory married couple^ -, ; While' ' *' liver damage is severe' .1 even ; vig.or.ou.s 'washing ofJ 'Bta') not prevent damage and may-'' she doesrrt ` federal Environmental Protec possibly enhance absorption 6f ` tion. Agency report said expo- the material," Dunn wrote on Jo.-the-most toxe tbrm,-0f;^March28,196?-^ ijtould] ntR'jUbidnhdd been associated wWhsi^-Thre zntBC! tvliyw'dame,-remotional.:xlladr&3i_n_g,KKwwttoollddBBoess 1 _^ _^ _U_M__*_ : L s i t trItHUvvI ihtryt 'to- :ligh' tD,'T tist 'kl tnrr-' ' aammaannoas ga werww4itthhTDY ow Chemical of li^'-hrtery degeneration, chloracne,. Canada, in a memo that dioxin.; ' ' involuntary rapid movement of "is exceptionally.toxic; it has a ;. thd'eye, hormone imbalances,', tremendous potential for p ro -e dethrionfian 'of immune ducing chloracne and fyatemic';- . . -terns and pains in the Joints. "r ] injury." ____ ....___E" -:-wAccording to the federal Cen-`J Rowe also warned that dioxin: r(a;)'piw;p trole rist" te n for. Disease Control at At- could form In product*(sold to;!- firxt'step to ( bail" lxnta/a maximum safe exposure the public. and could lead ' to^'. SaCJadge Eli MellaAre-' .`W; human* is Just one part per chloracne cases among1.(coiK;: `Ahaphztrtyhot" ' billion.;-:.' '. sumera. '-- `'v -tST; ' tdna- aald the axrest was -vj ^-High'-level* of dioxin have The le tte r c a rrie d - dKpaUic-sntU Tuesday ' been found at former chemical postscript: "Under no circtim- i e'-pOuee a t first were not plant sites in New Jersey, and stances may this letter be repro-' ; wither ebmeone else was dioxin-contaminated oil was d u r p H fthftwr. n r p n t trt T v v n n ' UUUb34 6224 33 / 6225 33 business Westinghouse retrenches on synfuels Westinghouse is moving to unload its synfuels divi sion, which includes a coal-gasification pilot plant at Waltz Mill, Pa. The plant, with a capacity of 35 tons/ day, has logged over 10,000 hours of operation since 1975 on a wide variety of coals. Westinghouse claims that it has had "serious discussions" about the syn fuels division with several potential buyers but has not disclosed their identity or the asking price. Westinghouse adds that it has not decided whether the division will be liquidated if a sale cannot be ar ranged. The apparent indecision is related to diverse trends in the synfuels business. Although the decline in world oil prices favors the division's divestment, Westinghouse still hopes that the U. S. Synthetic Fu els Corp. will support Westinghouse's Keystone Pro ject in Pennsylvania, a venture that would burn 2,000 tons/day of coal to produce 120 million cu ft/day of medium-Btu gas for local utilities. Foremost-McKesson is now McKesson At the annual meeting last week, Foremost-McKes son shareholders approved a corporate name change to McKesson. The move stems from the $62 million sale last fall of its Foremost Dairies. The switch also signals a broader change of direction. "Over the past decade, we have divested ourselves of some $225 irytflion of assets and reinvested $650 million in new growth businesses," emphasizes Thomas E. Drohan, president and chief executive officer. For the next several years, the $4 billion distributor of health care products, chemicals, and spirits will invest $100 million/year in new businesses and acquisitions. Esmark prevails in its takeover battle Another pair of corporate giants were united last week as Esmark won its takeover battle for Norton Simon. The Chicago-based maker of food, personalcare products and fertilizers succeeded in gaining 89% of Norton Simon's 24.8 million shares outstand ing before the $35.50/share tender offer expired last Monday night. In addition, Norton Simon directors elected Donald P. Kelly, Esmark chairman, as chief executive officer of the New York-based company. Norton Simon's businesses include Avis car rental, Max Factor cosmetics, and Hunt-Wesson foods. ^Vertac beefs up in herbicides Vertac Chemical (Memphis, Tenn.) has taken another step toward strengthening its position as. a herbicides producer (C W \ A p r . 6, p . 9). Lhst week, the privatelyheld firm acquired the U. . rights to Dow'Chemical's 2,4-D trademarks. Included are lights to Formula 40 weed killer, Esteron weed and brush killer, DMA her bicide, and 99 herbicide. Vertac, a $100 million compa ny, also gets the registration rights, inventories, for mulation recipes and marketing data for the phenoxy herbicides. In addition, Dow will assign Vertac the exclusive U. S. rights to market and use the Dowpon grass killer trademark. A. Charles Fischer, herbicide business manager for Dow's U. S. Ag Dept., says that the sale will allow Dow "to utilize more of our resources on newer, growth-oriented products," in cluding Lorsban insecticide, N-Serve nitrogen stabi lizer, and four h e r b i c i d e s . _____________ A split for Mobil Chemical's plastics segment Mobil Chemical has split the operations of its Plastics Div. into two new units. The restructuring "reflects projected growth for both our established and newlyintroduced plastic products," says Arthur E. Biggs, president. Mobil Chemical's new Consumer Products Div. will govern the company's Hefty, Kordite and Baggies brandname product lines, which primarily include trash bags, sandwich bags, and disposable plates and cups. The Plastic Packaging Div. will con sist of stretch films, plastic grocery sacks, industrial waste bags, and plastic foam products such as egg cartons, meat trays and fast-food containers. Croft C. Hangartner, formerly head of the Plastics Div., is the general manager of the Plastics Packaging Div., and William C. Seanor, formerly manager of planning coordinations for petrochemicals and plastics, is the general manager of the Consumer Products Div. Grace acquires a lubricants m aker. . . W.R. Grace has acquired privately-held S. H. Mack, of St. Charles, 111., a producer of synthetic lubricants used in making two-piece cans. "S. H. Mack will com plement our existing can-related specialty chemicals," says Jack Rimmer, Grace executive vice-president and head of the company's Industrial Chemicals Group. Grace will operate Mack as a unit of its Dew ey and Almy Chemical Div. .* . . and forms two research ventures W.R. Grace has formed 50/50 joint ventures with two German companies. One partnership, with Feldmuehle, of Dsseldorf, will study the world market for ceramic materials in internal combustion engines. The other venture, with Qynamit Nobel, of Troisdorf, will study the North American market for high-puri ty silicon. Both partnerships will be ba^ed in New York. Feldmuehle is a leading European paper pro ducer and a maker of technical ceramics. Dynamit supplies specialty chemicals and high-purity silicons. -------- :-- F 2 2 6 ------------------ August 3, 1983/Chemical Week 9 iI iI i I t: > 6227 3H i i ii. i* 'i !l \ i tofo) (a Warner, which shares ownership of Cos-Mar 50/50 with Cosden, Thomas Caltrider, business manager for petro chemicals, says, "We have a substantial commitment to the merchant market, and we intend to keep it that way." And Caltrider adds, "We have contractual positions with our customers, and we see no reason at all why we can't honor our commitments." Why the sudden squeeze. The tight ness was brought about by a second- quarter surge in demand for styrenic plastics and a spate of temporary shut downs for maintenance and debottlen ecking in July. In addition, El Paso had to put its customers on allocation when its small plant in Odessa, Tex., was closed down because of fouling in the purification system. Moreover, says Cal trider, inventories were low when the upturn started. There's plenty of active capacity for styrene--over 8 billion lb/year, count ing the expansion of Amoco's Texas City unit to 790 million lb/year from 615 million lb/year. And American Hoechst has an idle 600-million-lb/year unit in Baton Rouge, La., that could be reacti vated, though it's not considered likely to start up soon. Producers turned the material out at the rate of 5.7 billion lb/year in the first quarter and actually cut back produc tion slightly in April. But, says the U. S. International Trade Commission, sty er, and Hoechst has delayed its sched rene production in May was 585 million uled three-week maintenance shutdown lb, equal to 7.1 billion lb/year and more from October to November, when the than 85%of capacity. Marketing manag market is expected to be easier. ers for styrene producers say that How tight the market will be through much of their planned output in the the rest of this year will also depend on third and fourth quarters is already demand for downstream resins such as committed, either to supply customers polystyrene and ABS. All the styrene or to repay material borrowed during producers but El Paso make either poly recent shutdowns. styrene or other styrenic resins, and Restarting. The result, according to one they will keep substantial quantities of Gulf Coast observer, is "a powerful in styrene to supply their downstream op centive to restart plants." Domestic de erations if necessary. And demand for mand seems sure to continue strong be those materials has heated up. cause of the accelerating pace of the The key factor is strength in the mar economic recovery. And a Gulf Coast kets for polystyrene, the biggest use trader points to "vibrant Far East inter for the intermediate. Sales and captive est in soaking up any excess styrene use of polystyrene rose to 1.39 billion lb supplies," even at higher prices. in the first five months of this year, Prices of both styrene and polysty compared with 1.28 billion lb in the rene have been a sore point with pro same period of 1982. But that rise fol ducers for a long time. Styrene market lows three straight years of decline, and ers have been trying to get prices up it leaves movement for the five-month above 30e/lb and recently posted prices period about 18% below that of the of 33t/lb. But the spot market is now same period of 1979, when polystyrene 30-31c/lb, and the European price is markets hit their peak. 1810 deutschemark/metric ton, a little Styrene makers thus need continuing over 301 /lb at recent foreign-exchange improvement in polystyrene demand. It rates. looks, say marketers, as though they Some of the idled plants started up *'will get that improvement, despite re- recently, and most of the rest will soon ports of a sluggish PS market in June. be back onstream. But a New York- Still, it may take more time for styrene based trader says that even with the buyers to fully accept that prognosis. shutdown capacity starting up again, "it Meanwhile, says one observer, styrene will be weeks before the market sees output will be limited by available ca any slack." Others say that the snug pacity, but prices are more likely to re ness in the market will last much long- spond to the strength of demand. t | ; j I Dow sells its 2,4-D trademarks One company's commodity may be an other firm's premium product In Dow Chemical's eyes, 2,4-dichlorophenoxy herbicides are too common to warrant the expense of marketing Dow's own 2,4-D trademarks. So Dow has sold most of its 2,4-D trademarks to Vertac, a privately held Memphis firm with both a position as a 2,4-D maker and an appetite for product acquisition. Dow has made 2,4-D since the late 1940s. The company has been both a purveyor of 2,4-D "technical" materi al--the basic ingredient used to formu late 2,4-D herbicides--and its own trade mark products. The problem, Dow says, is that marketing the trademark prod ucts was too demanding for what the company deems a commodity. So Dow is selling off its trademarks but will still supply technical 2,4-D to herbicide formulators, including Vertac. "We are not reducing out capacity to produce 2,4-D," insists A. Charles Fi- j scher, herbicide business manager for j Dow Chemical's domestic Agriculture ' Dept "We have decided not to take it i all the way to the distributor." j Dow's deal with Vertac includes the [ sale of several 2,4-D trademarks: For- f mula 40 weed killer, Esteron weed and brush killer, DMA herbicide, and 99 her- ! bicide. Vertac is also buying Dow's : DMA-6 trademark for Dow's technical 2.4- D, but Dow will keep the right to ` use it. Dow is throwing in several non- i 2.4- D product lines, including Dowpon, a dalapon product that Vertac will sell un- ' der a trademark license, since Dow wpn't sell a trademark bearing its 1 name. Vertac is also buying Veon, a f 2,4,5-T product. ( I Dow's sales of technical 2,4-D to for- ; mulators--especially to Vertac--could ; actually increase because of the sale, says Fischer. "Vertac will put more ef- ; 8 Chemical Week/August 10, 1983 ' C.*"^pr^py Mnn-^** fort into it than we were able to," he explains. The only other remaining U. S. maker of 2,4-D is SDS-BioTech, a 50-50 joint venture of Diamond Shamrock and Japan's Showa Denko that has taken over Diamond's 2,4-D production and marketing. A spokesman says the firm is "surprised at Dow's move." But the sale is readily understood by others. Lacking strong patent protec tion, 2,4-D has had commodity status for three decades. Two others, Mon santo and Du Pont, have already ceased production, choosing to stress propri etary herbicides instead. Dow, too, wants to focus on proprietary products. Overall trends in the 2,4-D market are not encouraging, since growth has been rather flat in recent years. "It's probably held fairly steady" over the last decade, says the purchasing manag er for a Midwestern agricultural prod ucts distribution firm, since 2,4-D has "found its niche" in com and small grains. But he thinks the advent of Du Pont's Glean herbicide may spell dimin ished sales for 2,4-D, since Glean covers many of the same crops as 2,4-D. Jack P. Taylor, Union Carbide's prod uct manager for phenoxy herbicides, concedes that Glean "could impact the consumption of 2,4-D considerably." Taylor estimates that the U. S. market for 2,4-D is now 40-45 million lb/year. Vertac president C. P. Bomar, Jr., says he is undaunted by such trends. He hopes to convince farmers that 2,4-D is as effective as newer herbicide prod ucts, even though applying 2,4-D prod ucts may take more work. Bomar says Vertac will continue to sell its own 2,4D label goods along with the Dow trademarks, which he says it will sell "more or less as a premium line." Beefing up. And Bomar thinks Dow's trademarks will strengthen Vertac in the Midwest and the Pacific Northwest, where its position is weak. To maximize the value of the trademark and some other acquisitions, he says, Vertac will expand its marketing force by 25%. Vertac's purchases of Dow's 2,4-D is the latest in a string of recent herbicide acquisitions by the company. In 1981, Vertac bought Dow's Dinoseb weed kill er. As with the 2,4-D sale, Vertac al ready manufactured that type of herbi cide. Last year, the company bought a line of monosodium methanarcyanate herbicides from now-defunct Crystal Chemical. And this February the firm bought Rhone-Poulenc's 2,4-DB herbi cides for soybeans and peanuts.^ Herbicides represent about 60% of Vertac's business. The company, which projects $70 million in total sales for 1983, is the only U. S. producer of potas sium nitrate, and it makes related in dustrial products. It is also a custom synthesizer' of herbicides for others. Now, Bomar says, Vertac wants to expand into fungicides and insecticides, but his strategy is to minimize research costs by acquiring rather than develop ing new products. "They are never go ing to invent a new molecule," observes Dow's Fischer. "They aren't even trying to invent a new molecule. They are gearing up to be profitable marketers of commodity products." Textile-import accord-- maybe The U. S. and China have been haggling since last summer over replacing the three-year-old textile trade agreement that expired Dec. 31, 1982. Now, after much maneuvering, stalling, and bar gaining, the two countries have reached a new bilateral accord that specifies al lowable growth rates for textile imports from China for the next five years. But even though the pact's details haven't yet been made public, textile producers are voicing their disapproval. Industry officials walked out of nego tiation talks held two weeks ago in Ge neva, Switzerland, because th agree ment was more generous to China-than the manufacturers had wanted. Indus try had been pushing to hold yearly growth of certain textile imports from China--the fastest-developing exporter of such goods--to 1%/year, considera bly below the 4.3% rate permitted under the earlier three-year contract China had been bargaining for 6%/yr. Accord ing to some government reports, the new agreement, which is retroactive to Jan. 1, places a 2-3%/year growth ceil ing on the imports. Skeptics. U. S. trade officials,. muzzled until the formal exchange is signed in Beijing at the end of this month, hesi tate to confirm the 2-3%figilre, and this has led to industry skepticism. "I wouldn't be surprised if it were more [than 3%]," says Larry K. Martin, vice- president of the Man-Made Fiber Pro ducers Assn. (MMFPA). Industry con tends that any import limit surpassing the current annual growth rate--1.01.5%--of the domestic market for tex tiles and apparel is punishing to U. S. producers. Since 1979, China has positioned itself as a major textile exporter to the U. S., tagging behind only the Big Three-- South Korea, Hong Kong and Taiwan. Commerce Dept, figures show that U. S. textile imports from China ad vanced about 15% in 1979, 41% in 1980, 73%in 1981, and 19%in 1982, when they reached 671 million sq yd (chart). On a dollar basis, that volume--an 11%share of all U. S. textile imports--was worth $800 million. The Big Three accounted for about 60% of U. S. textile imports. But the impact the proposed agree ment will have on import volumes will be difficult to calculate, says Ann R. Berry, a textile negotiator for the U. S. Trade Representative's Office. That's because the ceiling does not affect all textile and apparel imports even-handedly. The original agreement restricted only 17 of the more than 100 categories of textiles and apparel established by Commerce, and the new proposal ex pands that coverage to only 33 catego ries, Berry explains. And though the U. S. has restricted those textiles with the highest import The CW weekly. index of chemical prices 375 350 325 _ 300 275 300 291 283 275 ________ July. . \ Latest Latest week 286.3 Previous week 286.4 1 1 Month ago 287.8 -- 1 -- - -- L - _____ Year ago . 290.0 Aug. -- 7 ~ ------------;------------ * . 1982 250 ! 11 i 1 11 1 1 i i i i i i i l M JF MA M' J J A S ON O : 6229 August 10, 1983/Chemical Week 9 35 > C 6230 International Study Is Urged j Of Agent Orange in Vietnam ----------1------------ .hil'l' - By PHILIP M.BOFFEY 11A Special to The New York Tim es WASHINGTON, Jan. 20--The senior veterans than he had expected, based member o( the House Veterans Affairs on complaints by American veterans. , Committee today called for an interna tional study of whether Agent Orange, a herbicide used to defoliate trees and kill crops in the Vietnam War, had caused harm to the Vietnamese who were exposed to it. Some Vietnamese officials said male veterans were suffering from itchy skin, inability to sleep and other health problems, he reported, and one doctor said he was convinced that male veterans had chromosome damage. But Mr. 1 J Representative Don Edwards, Edwards said that Vietnam was such a j Democrat of California, who recently primitive country that it had made no returned from a week in Vietnam, said real effort to keep track of its veterans 1 an objective study conducted there and determine their health problems. 1 could help resolve the dispute over whether the herbicide caused long Mr. Edwards said he would issue a term harm to American troops. It was used to destroy vegetation that pro report next week calling for an interna- tional study. He said it should be con- . vided cover for the Vietcong. ducted by a respected international or- i ganization, perhaps the World Health I "We can't resolve the problem here, Organization or the Food and Agricul- j apparently," Mr. Edwards said in a telephone interview. " I concluded that tural Organization, both of which are specialized United Nations agencies, a study of what happened over there because studies begun by either the ; would assist greatly in the American United States or Vietnam alone would ' studies of our veteran population. It lack credibility. just doesn't make sense not to go where the living laboratory is." He said he did not know if Agent Vietnamese See a Link Orange was connected with the genuine health problems experienced by Viet . Mr. Edwards said Vietnamese hospi nam veterans, but added, " We have an tal administrators, scientists and doc obligation to get an answer to this tors had told of health damage to conundrum." women who had apparently been ex posed to the herbicide as girls in jungle i villages. He said he had been told there 1 was a high rate of cancer of the uterus and of abnormal births among these - women. J "Maybe Agent Orange had nothing to do with it," Mr. Edwards said, " but , r d that should be established. An investi gation should be done." < Vietnamese scientists have con l ducted studies concluding that birth de I d fects and cancer appear related to Agent Orange. One group of scientists 1 c KS ''S Isth ie- from Western and Communist bloc countries that visited Vietnam a year ago said it found the studies " sugges tive" but not conclusive. t f tf n- The group, of which Arthur H. West Jyd, re ing, an ecologist at Hampshire College in Amherst, Mass., was the co-leader, called for cooperation between Viet I t I m namese and question. other scientists on the i J >y Itching Skin and Sleeplessness ( S- I m The Federal Government is sponsor 1 ing more than 50 studies of Agent I 10 i-h a . iis Orange in this country. The key studies require accurate records of where p>eo- c ple were at the time the herbicide was sprayed and of subsequent health prob FC lems. Some American scientists doubt that adequate records for such a study exist in Vietnam. e ,"S Mr. Edwards said that in visiting' I A hospitals in both Ho Chi MirSi City and r Hanoi he heard far fewer complaints of buffering among male Vietnamese c 6231 U S Committee for Scientific Cooperation with Viet Nam M c ' / p f llrlOn T\ C O N T E N T S ________________________________________________________________ _____ ___ COMMITTEE NEWS ___________________________ ' ______ _______________________. 2 REPORT Edward L Cooperman 4 TELEGRAM ON TYPHOON NANCY Do Thl Tai IN MEHORIAM: PROFESSOR TON THAT TUNG 5 IN MEHORIAM: PROFESSOR TON THAT TUNG ( 1 9 1 2 - 1 9 8 2 ) Edward L Coopernan 6 VIET NAM, SEEN FROM AMERICA Ton That Tung HEALTH SCIENCES__________________________________________________ 8 THE OUESTION OF DIOXIN LEVELS IN VIET NAM, THEN AND NOW Arthur Westing 9 THE PRESENT STATE OF NUTRITION IN VIET NAM Tu Giay MATHEMATICS/COMPUTER SCIENCE________________________________________ 1 2 REPORT ON THE VI SI T BY DR HA HUY KHOAI Neal Kobll tz 14 E x c e r p t s from: S e c o n d N o t i c e of t h e I F 1 P WORKING CONFERENCE ON SYSTEM MODELING &. OPTIMIZATION SOCIAL S C I E N C E S _______________________________________________________________ \ 14 19 AMERICAN UNI VERSI TI ES AND VIET NAM Pham Huy Th ong REPORT ON THE CONFERENCE "A CRITICAL EXAMINATION OF THE VIET Jayne Werner NAM EXPERIENCE SINCE 1975" NEWSBRIEFS___________________________________________________ __ ___________ 21 A NEW AGRICULTURAL SCIENCES I NSTI TUTE 2 2 VIET NAM AT THE 1 9 8 2 INTERNATIONAL MATH OLYMPIAD 2 2 DR NGUYEN VAN H1EU ELECTED TO THE SOVIET ACADEMY OF SCIENCES I i VOLUME 1 NUMBER 2 . 6232 EALL 1982 2 COMMITTEE NEWS REPORT Edward L Cooperman Organizational Structure Due to the rapidly expanding a c t i v i t i e s o f our Com m ittee, we a r e now In t h e p r o c e s s o f c o n s t i t u t i n g a "National Board". L isted below are t h o s e Committee members who h a v e agreed to join. Other members are invited to participate. National Board members are e x p e c te d to p a r t i c i p a t e a c t i v e l y In f o r m u l a t i n g t h e exchange program, organize lntinerar ie s of v i s i t o r s , e t c . and a s s i s t in formulating future a ctiv ities of the Commmittee. e s p e c ia lly in th e ir p r o fession al areas of in te r e st. This may e n t a : t o n e or more v i s i t s t o Vietnam. The National Board members a r e grouped by their a r e a s of i n t e r e s t : Social Sciences P r o f e s s o r JAYNE WERNER ( 1 ) Southern Asia In stitu te r o i urn hi a U n i v e r s i t y P r o f e s s o r STEVE O'HARROW. C h a i r Dept of Indo-Pacific Languages U n iv e r s ity of Hawaii M athematics and Computer S c i e n c e s P r o f e s s o r NEAL K0BLI T2 Cl ) Dept of Mathematics University of Washington A g ricu ltu re and B iological S c i e n c e s P r o f e s s o r ARTHUR Dept of Biology Yale University I GALSTON C2 ) P r o f e s s o r ALAN HOOPER <1> Dept of Cell Biblogy & G e n e t ic s University of Minnesota Health Sciences P r o f e s s o r JUDITH LADINSKY (1) Dept of P reven tive Medicine University of Wisconson Dr GLENN GORDON, MD. F a CS . E u g e n e , OR P r o f e s s o r JOHN LEVAN Chicago Medical School P r o f e s s o r JAMES DWYER Dept of Psychology S t a t e U n i v e r s i t y o f New Stony Brook York Dr WILLIAM EISMAN, DDS S a n F r a n c i s c o , CA Physical Sciences P r o f e s s o r E L COOPERMAN <1, 2> Dept of Physics California S ta te University Fuilerton (1) Subcommittee coord in ator (2) E x e c u tiv e Board member Actl v ltles At t h e b e g in n in g o f n e x t y e a r . P r o f e s s o r HOANG THUY NGUYEN. D i r e c tor, In stitu te of Epeidemlology snd Hygiene (Pasteur In stitu te) and Pre s id e n t , Medical R esearch Council of Vietnam will be our g u e s t . One of h is g o a ls is to s e t up an ongoing e x c h a n g e program in th e medical s c i e n c e s . A lso, we e x p e c t two d e l e gations of agrlcultural/microblolog i c a l e x p e r t s , t h e D e a n o f t h e Ho Chi Mln-h C i t y D e n t a l S c h o o l , t h e P r e sid e n t of th e Chemical S o c ie ty of Vietnam, two jo u r n a lists, and one mathematician. Our Committee i s c o o p e r a t i n g with two International C onferences t o b e h e l d in V i e t Nam in J a n u a r y 1963.^ ii__________ wo 1 1. " I n t e r n a t i o n a l Sym posium on the Long-Term Ecological and Human C o n a e q u e n c e s o f C h e m i c a l War f a r e In V i e t n a m " , Ho Chi Mlnh C i t y , 12-19 January. A copy of the preli minary program Is available upon r e q u e s t. P a r tic ip a tio n la by Invi t a t i o n only. C u rrently t h e r e a r e 40 internation al p a r tic ip a n te and o b s e r v e r s from e le v e n c o u n t r ie s with an equal number of Vietnam ese p a r t ic i pants. 2. "IFIP Working C o n f e r e n c e on R e c e n t A d v a n c e s In S y stem Modeling and Optimization", Hanoi. 10-14 January. D etails in th e f ir s t is s u e of the "Bulletin". The Committee now h a s e s t a b l i s hed working rela tio n s with five Vietnamese organ ization s! Vietnam Science Center, Vietnamese S tate Committee for S c ien ce and T echnology, Social S c ie n c e s Commission, Ministry of Health, and th e Ministry of Higher Education (university p ro fesso rs exchange program). fully furnished ambulance was d eli v e r e d t o S t Paul H o s p i t a l In Hanoi (jointly with the U S-Vletnam Friend ship Association of Northern Califor n i a ). St Paul i s t h e main h o s p i t a l for Hanoi, and had only one ambu lance available. In a d d i t i o n t o o n - g o l n g r e s e a r c h programs on the e f f e c t s of Agent O ran ge, our Committee i s in v o lv e d in a program to improve the h eath -care d e l i v e r y s y s t e m , and in s e t t i n g up prototype village-level solar energyoperated grain and v eg etab le dryers. We a r e a s s l t i n g i n t h e d e s i g n and co n stru ctio n of solar energy h o t - w a t e r h e a t e r s i n s e v e r a l Ho Chi Minh C i t y h o s p i t a l s , a s w e l l a s p a r tic ip a tin g in improving a g r ic u l t u r a l p r o d u c t i o n In t h e Mekong D e lta (Can Tho U n i v e r s i t y ) . Where p o s s i b l e . C o m m i t t e e m e m b e r s a r e a s s i s t i n g In United N ations-sponsor ed projecte. Inquiries about th is Committee may be made t o ! The exch an ge program with th e Social S c ie n c e s Commission has d e v e loped rapidly th is year with the v i s i t t o t h e U S o f P r o f e s s o r PHAM HUY THONG, V i c e - C h a i r o f t h i s Com mittee. Other a c tiv itie s include the continual sending of s c ie n t if i c and technical books, and medical jour nals and s u p p lie s to v a r io u s V ie tn a mese lib raries and h o s p ita ls . A E L Cooperman Department of Physics California S tate University F u l l e r t o n , CA 9 2 6 3 4 . A rticles for submission to this "Bulletin" as well as comments should be sen t to "Bulletin" editor! D B Phuoc Box 4617 B e r k e l e y , CA 94704. 4 COMHITTEE NEWS T E L E G R A M ON TYPHOON N A N CY We r e g r e t t o i n f o r m t h a t t y p h o o n 0 7 ( N a n c y ) o n 18 O c t o b e r 1 9 8 2 , with w in d sp eed s up t o 140 km/hr, h e a v ily d e s t r o y e d Nghe Tlnh p r o v in c e , ca u sin g to rren tial rains and big flood th e re and provin ces: Thanh H o a , Ha Nam N l n h , T h a i B i n h . (1) Great l o s s e s c a u s e d by th e typhoon ar e f o c u s e d on Nghe Tinh w h e r e s e v e n d i s t r i c t s - - N g h l L o c , N g h i X u a n , D i e n C h a u , Nam D a n , Thanh Chuong, Hung Nguyen and Vinh (in Dien Chau) - - a r e h e a v ily d e s t r o y e d ; s a l t w a t e r I n t r u d e d i n t o a n a r e a 1 5 km l o n g a n d 3 km w i d e ; another eight d is tr ic ts are variously a ffe c te d ; all the above d is t r i c t s mainly produce food. 1,335,000 people in 255,000 h ou seh old s were a f f e c t e d ; with 70 d ead , 290 injured and 194,200 h om eless. 68,894 were broken down with roofs torn off another 125,930. Thirteen d is tr lc t/p r o v in c la l h o s p ita ls were d e s tr o y e d ; 194 com mune h ealth c e n t r e s co m p letely broken down. 4,233 classroom s were broken down, 1,353 heavily damaged, 100,000 books soaked; 185,000 pupils out of sch o o l, 585 k in d ergarten s down, r o o f s torn o ff an oth er 104. 47 b a r g e s and 449 fish in g b o a t s sunk. A number o f main and s u p p o r t i v e d i k e s and i r r i g a t i o n c o n s t r u c tio n s were crushed: 661,000 cubic m eters of ea rth and 13,160 cubic meters of stones. (2) Crop l o s s e s were: in Nghe Tlnh, 4 3 ,0 0 0 h e c t a r e s o f r i c e were Inundated, 28,100 com pletely lo st and 15,000 partially d estro y ed . In o th e r p rovin ces, th e r e s p e c t iv e fig u r e s were: for Thanh Hoa, 6 6 ,800, 4 , 0 0 0 , 5 7 , 0 0 0 ; Ha Nam N l n h , 5 7 , 1 0 0 , 9 , 0 0 0 , 4 7 , 3 0 0 ; T h a i B i n h , 4 0 , 0 0 0 , 7,uuG, 33,000. Output l o s s e s were about 300,000 ton s of food. F a c i n g t h e a b o v e n a t u r a l c a l a m i t y , AIDRECEP u r g e n t l y a p p e a l s t o you for active emergency aids of materials to the a ffected areas out of your traditional c h a rity , friendship and so lid a r ity with th e V iet namese people. T h e n e e d s a r e f o r : FOOD, FERTILIZERS. PESTICIDES, ANTIBIO T I C S , CLOTH, PAPER a n d ROOFING MATERIALS. P l e a s e s e n d a n y r e l i e f g o o d s t o t h e a d d r e s s : AIDRECEP/VTKC 8 2 , s o t h a t we c a n e a s i l y d i s t r i b u te them to the a f f e c t e d a r e a s and re p o r t to you. Anxious to receiv e your a c tiv e r e sp o n se.' Beat regards, TH1 TAr P r e s i d e n t o f AIDRECEP 6235 NOTE: TAX-DEDUCTIBLE c o n t r i b u t i o n s f o r t h e - b e n e f i t o f t h e v i c t i m s o f t h i s t y p h o o n may b e m a d e t o t h e "FOUNDATION FOR SCIENTIFIC COOPERATION WITH VIET NAM" a n d s e n t t o t h e C o m m i t t e e , c / o . 3 e o r t s e n t o f P h y s i c s , C a l i f o r n i a S t a t e U n i v e r s i t y F u l l e r t o n CA 9 2 6 3 r . L i N f* B h O R l A h ' f ' R O F i o ; . J K' 1 U N T H A " r u i t . , IN 'M E M O R I A M : PROFESSOR TO N THAT Edward L Cooperman TUNQ 0912-1 9 6 2 ) i P r o f e s s o r Ton T h a t T u n g d i e d o n 7 May 1 9 8 2 , t h r e e d a y s b e f o r e h i s s e v e n t i e t h b irth d a y , from h e a r t fa ilu r e at his home in Hanoi. 4 To many o f u s who knew him h l a d y n a m i c p e r s o n a l i t y , h i s e x u b e r a n c e , h is d e s ir e t o help h is p e o p le , s t r o n g l y a f f e c t e d and to u c h e d us. His sh o c k o f pure w hite hair, his s p o n t a n e o u s sm ile, and to t h o s e who knew him w e l l , h i s c a u s t i c w i t a n d c r i t i c l e m , will make him h a r d t o f o r g e t . P ro fesso r Tung was among th e f ir s t "native" medical d o c to r s to g r a d u a t e from t h e Hanoi M e d ic a l C o l l e g e in 1 9 3 9 . He b e c a m e well known in tern a tio n a lly as an acclaimed liver c a n c e r surgeon., but th is s h o r t memorlam i s n o t t o e m p h a siz e h i s p r o f e s s i o n a l q u a l i t i e s , but r a t h e r h i s human q u a l i t i e s . Tung's f i r s t c h o ic e was made e a r ly during t h e V ietnam ese r e s i s t a n c e . The Emperor a s k e d him t o b e h i s p e r s o n a l p h y s i c i a n a t t h e C o u r t in Hue. Tung t o l d t h i s w r i t e r t h a t a t t h i s t i m e h e met Ho Chi Minh. Ho Chi Mlnh n e v e r a s k e d him t o g o w i t h him t o t h e j u n g l e s , b u t Tung said he knew in h is h e a r t what he had t o do. Tung was V iceM inister of Public H ealth in 1947, but r e s ig n e d t o r e tu r n to h is V ietDuc H o s p i t a l w h e r e h e s e r v e d a s C h ie f o f S u r g e r y . He f o s t e r e d many h ea lth -rela ted programs during his life , and most r e c e n tly was the chairman of the coordin ating committee which was planning the "Inter n a t i o n a l Sym posium o n t h e t h e L o n g -T e r m E c o l o g i c a l a n d Human C o n s e q u e n c e s o f C h e m i c a l W a r f a r e i n V i e t n a m " ( 1 2 - 1 9 J a n u a r y 1 9 8 3 , Ho Chi Mlnh City). Tung worked long and hard t o tr y t o d eterm in e th e la s t in g e f f e c t s of dioxin im p u rities in t h e h e r b ic id e s u se d in Vietnam. Tung was one o f t h e major s u p p o r t e r s of t h e U S Committee. letter to this writer shortly before he died, he again reltereated need to develop s c ie n t if ic and medical e x c h a n g e s between our two p e o p l e s , but s a id t h a t t h i s would b e "a lo n g term p r o j e c t " . In a the By p e r s e v e r i n g we will s u c c e e d in T u n g ' s M in ister Pham Van Dong s a i d t o u s , " s c i e n t i f i c mutual r e s p e c t , then to t r u s t , and e v e n tu a lly establishing peace between nations". goa l, which, as Prime exchange leads to is Important toward I___ 6 IN MEMORIAM: P R O F E S S O R TON THAT TUNG VIET N A M ^ SEEN FROM AMERICA Ton That Tung T h i s A p r i l (1 9 7 9 J , wh en I w a s about to leave for ay visit to the United S ta te s , I was quite anxious. T h i s w a s my f i r s t t r i p t o A m e r i c a , I didn't sp eak English well, and f o r t h e m o s t p a r t I h a d n e v e r my s c ie n tis t friends th ere, but only knew them through our c o r r e sp o n d e n ce. B esides, the United S ta te s is regarded as the most sc ien tifica lly a d v a n c e d c o u n t r y In t h e world. What would t h e y th in k o f t h e work I was doing in our s e v e r e ly limited c o n d i t i o n s ? What would t h e y t h in k of Vietnam ese medicine? But I also r e a li2ed th a t th is was an u n p rece d e n t e d o p p o r t u n i t y f o r me t o make o b je ctiv e o b se r v a tio n s and comparl- ina, and at th e same time to s e e now Americans regard our c o u n try , our work, our people and our s c ie n ce. Many A m e r ic a n s c e n e s l e f t d e e p impressions: the tall skyscrappers, the broad highways sometimes on two le v e ls , packed with c o u n t less vehicles yet so very orderly, th e bright g reen c o u n tr y sid e with wheat s ilo s s c a t t e r e d h e r e and there like white tow ers, a broad carpet of flow ers and g r a ss surroun ding c lu s t e r s of charming wooden h o u s e s . When I w e n t t o v i s i t u n i v e r s i t i e s in t h e c i t i e s o f New York, New H av en , B o s t o n , A m herst, Chicago, Philadelphia, Madison, Washington and San Francisco, I usually s t a y e d in th e homes of p r o f e s s o r s or d o c to r s , living with t h e i r f a m i l i e s . T h i s g a v e me t h e chance to talk frankly with them, t o g e t to know Americana, and to < n a c le a r s e n s e ofj th e ir a t t i t u d e s toward our people and our work. I One c u r i o u s th in g was t h a t w h en ever I met American i n t e l l e c t u a l s , th e ir f i r s t s e n t e n c e would b e , " I w a s a g a i n s t t h e V i e t Nani war". There was only one e x c e p tio n -- P ro fesso r Alien at the University o f W i s c o n s i n , M a d i s o n . He a d m i t t e d t o m e , 1 "I w a s o n e o f t h o s e w h o supp orted the American government i n t h e V i e t Nam w a r , b u t s i n c e I met you I've changed ranks". This shows' the ch ara cteristic spontaneity and flex ib ility of the Americans; th e y will rea d ily ch a n g e th e ir opinions if their perceptions change. In t h e p a s t t h e u n i v e r s i t i e s were strongly opposed to the aggres s i v e war i n V i e t Nam. T h e y s e t up s c ie n t if i c groups which s t ill want t o h e l p V i e t Nam. T h e s e g r o u p s a t Columbia U n i v e r s i t y in New York, a t th e u n iv e r s it ie s in Chicago, P o r t land and Irvine, and r e s e a r c h e r s at biological and environm ental la b o r a to r ie s all a c r o s s America offered t o c o o p e r a t e w i t h me i n wor k in environmental s c ie n c e s and g e n e tic s. The image e tc h e d moat deeply i n my m e m o r y i s t h a t o f a n A m e r i c a n youth in th e b eau tifu l c it y of P o r t l a n d . He s t o o d w a i t i n g f o r me at the. door of th e lectu re hall a f t e r I h a d g i v e n my l e c t u r e a n d d i s c u s s e d t h e d i o x i n p r o b l e m . With a d i s t r e s s e d e x p r e s s i o n , he came up t o me a n d s a i d , "I u s e d t o b e in t h e Air F o r c e . I'm v e r y s o r r y t o have spread such s u ffe r in g in your country. I want to apologize to you". I took his hand and said , "From now on we must l o o k to w a r d the future". A m e r i c a n v e t e r a n s o f V i e t Nam have realized they are victims of t h e U* S g o v e r n m e n t b e c a u s e o f / t h e e f f e c t s -- th ey compare them to the e x p l o s i o n o f a d e l a y e d - a c t i o n bomb -- ca u sed by variou s d e f o lia n t s , e sp ecia lly by Agent Orange which c a r r ie s an extrem ely dangerous c o n taminant called dioxin. 023^ -1 T 3 I r i! o Ten y e a r s a g o , I had been th e first to deapribe those e ffe c ts, snd had p r e s e n t e d sy fin d in gs to two in te r n a tio n a l c o n f e r e n c e s , in Paris and Copenhagen, and had w rit t e n many a r t i c l e s f o r t h e P a r i s p r e s s . At t h a t time o n e s e g m e n t o f public opinion had criticized sy ideas as a n ti-s c le n tlflc and as anti-American propaganda. But a f terwards e x p e r is e n ts and o b s e r v a tions supported th ese findings. Two y e a r s a g o , some p e o p l e in O r e gon mounted a str u g g le calling on American s c i e n t i s t s to recogn ize the terrible e f f e c t s of Agent Oran ge. Thousands of American v e te r a n s o f V i e t Nam s t o o d s h o u l d e r t o s h o u l der with th e people of Oregon in that struggle calling for a special c a t e g o r y o f " V i e t Nam v e t e r a n s " w h o could be o b se r v e d for e f f e c t s of the chemicals and calling for large p a y m e n ts a s c o m p e n s a t i o n u n d er Ame rican law. T h ese v e t e r a n s follow ed me s n d g u a r d e d me c a r e f u l l y . Th a n k a t o t h a t I w a s n e v e r h a r a s s e d o r a t t a c k e d , e v e n t h o u g h s o m e o f my a c t iv it ie s were in a r e a s like Cali fo rn ia where a g r e a t many S aigon soldiers have taken refuge. In America t h e r e i s a w i d e spread lo s s of c o n fid e n c e in sur-- geons and ev e ry o n e ta lk s about "malpractice". So Americans are very in t e r e s t e d in the organ ization of medicine in oth er c o u n t r ie s , e s p e c i a l l y in V i e t Nam, a c o u n t r y which has had to endure 30 y e a r s of war with a backward econ om ic i n f r a structure. In t a l k i n g w ith A m erican f r i e n d we b r o u g h t o u t two c h a r a c te r is tic s of Vietnamese medicine. First, our medicine is combat medi cin e which took sh a p e beginning in the years of the resistan ce against t h e F rench. At t h a t time V ie tn a m e s e d o c to rs were f ig h t e r s in a ction 1th t h e g u e r i l l a s o r t^he r e g u l a r army on t h e b a t t l e f ^ l d , and t h o s e were the b est sch ools for our medi c a l c a d r e s . Very e a r l y on we uaed Vietnamese as our language of in s tr u c tio n , in c o n s t r s e t to other co u n tries of S ou th east Asia where English is still used, and thanks t o t h a t we wiped out t h e r o o t s of the c la s s monopoly on medicine which 'still e x i s t s in o th e r former colon ies. Thanks to our use of the Vietnamese language and to our expandion of secondary education, we w e r e q u i c k l y a b l e t o build a large corps of a ssista n t doctors a n d d o c t o r s f o r t h e n o r t h . We h a d one a ssista n t doctor or doctor for every 800 people, a ratio not yet a c h i e v e d in a n y o t h e r Third World country. The secon d point is t h s t V iet namese medicine s e t its e lf the goal of serving p a tie n ts no m atter what t h e c ir c u m s t a n c e s . If we were short of medicines or other resou r c e s , we would i n v e n t r e p l a c e m e n t s , we would r e ly on t r a d i t i o n a l medi c in e , and th a n k s t o t h a t we were able to solve such problems ss carrying on su rgery in wartime, p r e v e n t i n g common ep id em ic d i s e a s e s , and taking health care d irectly to the countryside. I have to say th a t one weak point in American s c ie n c e is th a t i t r e l i e s t o o much on m a ch in ery and animal exp erim en ts and c o n d u c ts too little ob servation of people. Take the problem of cancer. D espite years of research costin g millions of d o lla rs, and although American science has discovered viruses which c a u s e c a n c e r in anim als, it has not been s u c c e s s f u l in d i s c o v e ring v i r u s e s in human c a n c e r . Thus American r e s e a r c h e r s h a v e now made a 9 0 -d e g r e e turn and have proposed epidemiological stu d ies of various c a n c e r s In a n e f f o r t t o t r a c e t h e causes. Vietnam ese d o c to r s took an overall apporach to the problem of harmful, e f f e c t s of d e f o li a n t s begin- 6238 a HEALTH SCIENCES ning in 1970. But in o t h e r c o u n t r i e s no one was willing to follow th e e f f e c t s in p eople e v en though Agent Orange was in u se in America, F ran ce. England and Sweden. So far only France has banned the use of 2 ,4 ,5-T. Carrying a bell to ring it abroad, I was happy to find that th a n k s to our p eople's just and v icto rio u s stru ggle, thanks to our p e o p l e ' s g r e a t a cco m p lish m en ts in many a r e a s d e s p it e our v ery d i f f i c u lt s itu a tio n , and thanks to our g o v e r n m e n t's c o r r e c t c o u r s e in fo reign p o lic y , when t h e V ietnam ese bell s o u n d s in America it s t iil e c h o e s c l e a r i y and in t u n e . And t h a t f a c t m a k e s me f e e l e x t r e m e l y proud, of our people and of the g r e a t t a s k we h a v e t a k e n on. ^ o t e The a b o v e e x c e r p t s from a len gth y a r tic le by P r o fe s s o r Ton T h a t T u n g w e r e t r a n s l a t e d b y JOHN SPRAGENS, a s t a f f a s s o c i a t e a t t h e Center for International Policy, W a s h i n g t o n , DC. THE Q U E S T IO N D IO X IN LEVELS IN V IE T N A M . THEN AND NOW OF A r th u r W estin g Large numbers of individuals in Indochina, both military and civilian, were inadvertently e x p o s e d t o d i o x i n CTCDD: 2 , 3 , 7 , 8 tetrachlorodibenzo-para-dioxin) as a resu lt of U S actions during the se co n d Indochina war. This c o n t i nues to be a matter of grave con cern owing to the to x ic , t e r a t o g e nic, carcin o g en ic, and mutagenic properties of this substance. I provide the following information o n d i o x i n l e v e l s i n V i e t Nam o w i n g to the widely divergent views that k e e p ap p earin g e s p e c i a l l y In t h e popular and semi-popular lite ra tu r e , o f t e n i n c o r r e c t l y a t t r i b u t e d t o me. Dioxin was dissem inated as impurity of th e 2 ,4 ,5-T (2,4,5trichiorophenoxyacetic acid) compo n e n t o f t h e now "notorious a n t i plant chemical weapon code-named g e n t O ran ge; and a l s o o f i t s much ,ore modestly used cflose r e la tiv e s ( A g e n t s Orange II, Pink, P u rp le, and Green), all subsumed here under Ag e n t O r a n g e 121. Th e A g e n t O r a n g e was d isp e n se d by th e U S betw een 1962 and 1970 (although primarily betw een 1966 and 1970) in a t t a c k in g inland and c o a s ta l f o r e s t s and some crop lands. Although Kampuchea ( 1 1 , L a o s [ 41 a n d n o r t h V i e t Nam were all thus a tta c k e d , it was s o u t h V i e t Nam ( a n d e s p e c i a l l y i t s former Military Region III, a la r g e a r e a c e n t e r e d a r o u n d Ho Chi Minh City) th a t was the major r e c ip ie n t C33. Approximately 44.3 thousand cubic m eters (57.0 million kg) of Agent Orange was expended by th e U S during th e war, con tain in g about 24.1 million kg of '2 ,4 ,5-T per s e 12, p 261. It i s d i f f i c u l t t o make a reliable estim ate of the actual amounts of dioxin c o n ta in e d in th e Agent Oranage used in Indochina owing to the untimely d e s tr u c tio n by t h e U S Air F o r c e a n d t h e Dow Chemical Company of t h e r e f e r e n c e samples of most of the lo ts th a t h a d b e e n e x p e n d e d . An e s t i m a t e b a s e d on Dow d e t e r m i n a t i o n s r e l e a s e d b y t h e lb S Air F o r c e in 1 9 7 4 i s th at the Agent range had an a v e rage dioxin conten t of 2.5 grams p e r c u b i c m e t e r s , l e , 1 . 9 m g / k g C2, p 44-453. This c o n c e n tr a tio n su g g e s t s th a t a to ta l of a t le a s t 110 kg of dioxin was dissem inated. Some new inform ation r e le a s e d by ;n a . i '' _i ti > h: j t h e U S Air F o r c e In 1 9 8 0 I n d i c a t e s th a t the t o t a l waa somewhat higher than thia, perhaps 170 kg [5, p 3 6 8 ) . Aa d u b i t e b l e a a t h e s e Do w/ Air F o r c e d g t a a r e . I am a w a r e o f no o t h e r s from which t o make b e t t e r e stim a te s (and would welcome being referred to any reliab le new in fo r mation). It should alao be noted here that the total amount of dio x i n i n V i e t Nam. w h a t e v e r i t w a s , was probably augmented to a alight e x t e n t aa a r e su lt of th e burning o f wood th a t had been s p r a y e d with 2,4,5-T. It appears th a t on th e order of half the amount of aerially applied dioxin decom poses within a few days, with the remainder b eco ming more p erm a n en tly i n c o r p o r a t e d in to the aoil and biota. Here it can work lta way food c h a i n s , in cluding th o se culminating in humans, becoming c o n c e n t r a t e d in th e p ro c e s s . The dioxin th u s in c o r p o r a te d into the ecosystem appears to disap pear following first-o rd er k in etics, having an environm ental h a lf - lif e o f p erh a p s 3.5 y e a r s 3, p 290; 5, p 3 6 8 ) . In t h e c a s e o f V i e t Nam, if one makes the simplifying assump tio n s that the amount of dioxin In tro d u c ed waa. Indeed, 170 kg and t h a t i t h a d b e e n a ll i n t r o d u c e d In 1968, th en p e r h a p s 8 kg remained at la r g e in 19 8 0 , 3 kg will be p r e s e n t in 1985, and 1 kg in 1990. I ts legacy, on the other hand, could p ersist far longer. Ref eran cea ( 1 ) W e s t i n g , A H. 1 9 7 2 . H e r b i c i d a l dam age t o Cambodia. In: N e i l a n d s . J B e t a l . H a r v e s t o f D e a t h . NY: MacMillan F r e e P r e s s , 304 pp: pp 177-205 121 - . 1 9 7 6 . E c o l o g i c a l C o n s e q u e n c e s o f t h e S e c o n d I n d o c h i n a War. Stockholm: Almqvist & Wiksell, 119 pp 31 1 9 7 8 . E c o l o g i c a l r e g a r d i n g maaslve environmental contamination with 2,3,7,8-tetrach lorod lb en zopara-dloxin. Ecological Bulletin 27:285-294 41 1 9 8 1 . L a o t i a n p o s t c r i p t . Nature 294:606 5) -. 1 9 62. E n viron m en tal a f t e r m a t h o f w a r f a r e i n V i e t Nam. SIPRI Yearbook 1982:363-389 The author is P rofessor at H a m p s h i r e C o l l e g e , A m h e r e t . MA. THE PRESENT STATE OF NUTRITION IN V I E T N A M To Giay Forty con secu tive years of war, profound c o n s e q u e n c e s of c h e mical war, r e p e a te d flo o d s accom pa nied by s e v e r e d r o u g h t s o f r e c e n t yeara have left their tra ce of d evastation with r e s p e c t to the nourishment of the Vietnamese people. The National I n s t i t u t e of N u tri tion of the S ocialist Republic of V i e t Nam, f o u n d e d i n 1 9 8 0 , h a s b e g u n work- i n i t i a l l y in e s t a b l i s h i n g t h e con crete s ta te of nutrition of the country. The f ir s t s u r v e y s have given us sign ifican t preliminary r e su lts. The a v erage d iet of a Vietnamese peasant suffers a calorie deficit of 10-15* and amounts to only 1,800-2,000 kcal a day. Calories from p rotein s o u r c e s c o n s t i t u t e only 9-10X of the energy value of the diet. There is very little p r o te in of animal o rigin (only 1015* of t o ta l p rotein in the d iet). Energy from lipids is only 6-8*. Data already gathered are summarized in th e ta b le below: 6240  HEALTH SCIENCES A V E R AGE D A I L Y D I E T FOR A P E A S A N T A b E P I B - `iv* n e a r b ( T n e f a (ii l I y 1 s Mei 1 f. L r e d O k * 1 r <r ic* i* ) R E G IO N 0 ) THE COUNT R Y : V 1LLAGE NAME: N E A R E S T C I T Y OR P R O V I N C E : SURVEY DATE: FOOD ITEMS Rice Wheat Meat Fish, fr e s h -*a te r crab, Fat Eggs Beans, peas, peanuts V egetables, fr u it 5 u ga r Soybean cake Soy, fis h sauce Di'^wr.5 h o r t her 'r( Cent r a 1 Co Bi Ha no l Van Thier, Thanh Hoa S e p t e m b e r 1 9fai? M arch 1961 u$4 g w9 33 g 34 g 41 g 9 1 g 175 g 5 g 30 g S o u t h e r r. E i r.h T r Jf.C Ho C h i M 1f - l i N : er, i t e - 1 9fc 1 43 c 9 19 5E 1 '3 9 9 g 41 9 bg b4 q 19 12 9 C C. 9 total k il o c a l o r ie s PROTEINS LIP ID S MEAT P R O 'E lN S 021 53 g <10. 8 a ) 1 1? g ( 4 . 7 % ) ( 1 1 %) 14 10 a . m q { 6 %) 5 . 3 g ( 2. 5X> aS I? l 2 6 0 9 n c . 2>. i 11 9 < 5 . 1 *Ai l a %) The above ta b le show s th a t the p e a s a n t s i n s o u t h e r n V i e t Nasi h a v e a much o r e v aried d i e t . The r e g io n o f Thanh Hoa was h i t by a t y p h o o n i n O c t o b e r 1 9 8 0 Cand more r e c e n t l y by typhoon Nancy in O ctober 1982). F ifte e n -y e a r old children in th is fre q u en tly flooded region weigh on the average six to eight kilograms l e s s than th o se in o th er p a r ts of the country. Investigations on the nutri tional sta tu s of younger children Cone t o t h r e e y e a r s o f a g e ) y i e l d ore alarming r e su lts . The average diet is about 700 to 800 kcal, less t h a n t h e n o r m f i x e d i n V i e t Nam ( 1 .1 0 0 k c a l ) . much l e s s t h a t t h e norm in d e v e lo p e d c o u n t r i e s C l.300 kcal). The p rotein p rop ortion is v ery low and a t t a i n s l e s s th an 20 barely half the ration of youngera of th e same agp 'in d e v e lo p ed c o u n t r i e s (normally h ig h e r th a n 40 g). Animal p r o t e i n s c o n s t i t u t e only 20x of all p rotein s (required n o r m i s m o r e t h a n SOX) . 'L i p i d proportion is even lower: only 5 g and b a rely 10x o f th e norm; th e e s t a b l i s h e d norm in d e v e lo p e d c o u n t r i e s i s SO g . The c o n se q u e n c e s of sh o r ta g e of e n e r g y , p r o te in s and lip id s, and the lack of atten tion to vitamins and minerals are the development of m alnutrition. kwashiorkor, anemia, children l e s s than th ree y e a rs old r a n g e s from 12 t o 18X. This p ercen tage is even higher if in tern ation al norms are taken into a cco u n t. The a v erage weight and height of tw o-year-old children i n V i e t Nam a r e o n l y 8 0 X a n d 9 0 x o f the Harvard norms, r e sp ec tiv e ly . . T h e percen tage of malnourished children in flooded r e g io n s r e a c h e s 2 4 X ; a n d t h i s n u m b e r c l i m b s t o 4 0 `; in t h o s e r e g i o n s , lik e Binh Tri Thien p r o v lc e , which has been d e v a s t a t e d b.y c h e m i c a l w a r . It i s e q r e t t a b l e t h a t we have 6241 H E . A _ . T z : 'i. l t N . t: not been able to get ore detailed tu d le e on th e in flu e n c e of malnut r i t i o n on th e child grow th, on health, development of infectious d i s e a s e s and d eficien cy-in d u ced s i c k n e s s e s . But it is ciear that the present sta te of the country's nutrition p oses urgent problems which must be solved on a s c i e n t i fic b a sis with m ulti-disciplinary means. It is in th is sp irit th at our Government has posed the problem of nutrition for the people as a State . p r o b l e m o f u t m o s t u r g e n c y . We k n o w that our dally meals are th e r e su lts of a long p r o c e s s of work and c o l l a b o r a t i o n b e tw e e n many d i f f e r e n t b ra n ch es of the economy and s c ie n c e Meanwhile, th e fir s t duty of the physician is to study the nutri tional needs of the organism, e s t a blish different diet requirements for each age group and p r o fe s s io n , .n d ic a te how to econom ically fu l fill one's needs with alimentary producta, demonstrate the efficacy of a rational nutrition on physical developm ent and work a b ility , con trol the nutritional value of a meal and h y g ien ic c o n d itio n s of food e n te r p r is e s , carry out mass work for r a tio n a l n u tr itio n . In t h i s d i r e c t i o n , t h e G o v er n ment h a s c h o se n a p h y sicia n t o head the S ta te program to aearch for rational nutrition for the popula t i o n . He h a s t h r e e v i c e - m i n i s t e r s as a ssistan te: vice-m inister of a g r ic u ltu r e , of food Industry and o f internal commerce. The a c tiv e members of the program are e x p e r ts of agriculture, husbandry, food technology, organization of collec tive nutrition; economists, special is t s of culinary 'art, of mechaniza tion of food preparation; doctors ohyaiologists, biochemists, hygie- , s t s , . . . ) . T h ese s p e c i a l i s t s in different branches of the economy, s c ie n c e and ag r ic u ltu r e show the scop e and variety of the program. The national food program for 1981-1985 encompasses these six major problems: , 1. The s t u d y o f n u t r i t i o n a l needs and establishm ent of special d ie ts for each ecological region of the co u n try, based on local food stuffs; 2. The n u t r itio n a l value of local foodstuffs; 3. The e x p l o i t a t i o n of a clo sed ecological system (gardening - husbandry - p iscicu ltu re) for fam ilies and small c o lle c t iv e s to contribute a supplementary source of p r o tein s, lipids and vitamins; 4. Applied n u tr itio n in o r g a n i z a t i o n and food t e c h n o lo g y in solvin g en erg y problems in the countVyside; 5. Child n u t r it io n ; and 6. N u tritional d i e t s in h o s pitals. Cadre training and nutritional e d u c a t i o n p lay a s p e c i a l r o le in t h e p r o g r a m . The c r e a t i o n o f 12 p ilot v illa g e s in d iffe r e n t e c o r e glon s (d elta , normal, mountainous, p la te a u , c o a s t a l , new economic z o n e ) f r o m n o r t h t o s o u t h V i e t Nam, a s well a s th e crea tio n of models o f n u tr itio n c o l l e c t i v e s in the c it ie s and fa c to r ie s are places w h er e t h e program p r o m o te r s will concentrate their attention. The ex p er ie n c e of th e se pilot programs will be d issem in ated throughout the country for develop ment and for th e final goal of intensifying agricultural produc tion, reducing the rate of popula tion growth, increasing the consump tion of fo o d stu ffs for each person and* a m e l i o r a t e tfhe n u t r i t i o n a l s i t u a t io n o f t h e V ietn am ese p eo p le in its entirety. The- au th or is D irector of th e Inst l t u t e 'o f N u t r i t i o n a n d t h e S t a t e Program for Popular Nutrition. * MATHEMATICS/COMPUTER SCIENCE J R E P O R T ON T H E VISIT BY DR HA HUY KHOAI CA p r l l - M a y 1 Q S 2 > N e a l K o b l Jtz In S e a t t l e , Dr Ha Huy K h o a l gave two seminar talk s during his two weeks at the University of W ashington: (1) p -ad ic meromorphic f u n c t i o n s ; (2) a new c o n s t r u c t i o n r e l a t e d t o t h e Kuzin problem in s e v e r a l complex v ariab les. The work d e s c r ib e d in th e flr a t of t h e s e ta lk s is th e f ir s t major s t t e m p t to work s y s t e m a tic a lly with I n t e r p o la t io n by p -a d ic meromorphic f u n c t i o n s . The work a r o s e p a rtly In r e s p o n s e to a problem posed by P r o f e s s o r B Mazur o f H a r v a r d , and partly because of the natural d esire to carry over some very basic f a c t s from complex an alysis to the p-adic o m a i n . T h i s w o r k i n t e r e s t s me a n d o th e r algeb raic number t h e o r i s t s (especially R Greenberg) because much o f our own work h a s b e e n r e l a t e d to problems in p-adjc I n t e r p o la tio n and Gauss su m s.' The Uni v e r s ity of Washington happens to have active groups of researchers in b oth of Khoal'a major i n t e r e s t s (number th eory and s e v e r a l complex v a r ia b le s ). The secon d seminar t a l k , on th e Kuzin problem, was very well received by the group working in se v er a l complex v a r ia b l e s (L S t o u t , J Morrow, J King). Even though th is work had been done Jt*y K h o a l a b o u t n i n e y e a r s f f f o , i t w as only published in V ietnam ese, was unknown in th e West, and had not been superceded since that tim e. S to u t and King s u g g e s t e d t h a t he publish it in a European language. At H a rv a rd , a s p e c i a l s e m in a r s scheduled, so th^t'Khoal could p r e s e n t his work on p -a d ic N evanlinna theory to the Harvard mathemati cia n s. I have sin ce spoken with P r o f M a z u r , w h o t o l d me t h a t t h e t a l k w e n t v e r y w e l l . He and P r o f Tate (th e two lead in g number t h e o r is t s at Harvard) had numerous d i s c u s s i o n s with Khoal during his v i s i t . , In p a r t i c u l a r , Mazur g a v e him s o m e a d v i c e o n f u r t h e r d i r e c tio n s of r e s e a r c h th a t he might want to p u r s u e . Here, Khoal wrote th e f'irat d r a ft of a s h o r t a r t i c le on his c o n s tr u c t io n of th e in v e rse Mellin-Mazur transform , and also s t a r t e d work on a major a r t i c l e on p-adic Nevanlinna th eo ry . The l a t ter article has sin ce been comple ted , and will be subm itted to the "Duke M athem atical Journal". Prof Mazur c o m m e n t e d t o me t h a t i t w o u l d be good for Khoal t o p u b lish in American or European journals so th a t W estern c o ll e a g u e s are in touch with what he is doing. Khoal did e x t e n s iv e library r e s e a r c h , taking advantage of his five-week s t a y in a math d ep artm en t o f f i c e at Harvard right near library fa c ili t i e s which In many r e s p e c t s a r e even better that what's available in Moscow. In a d d i t i o n , he a t t e n ded se v er a l sem inars, and r e a cte d very favorably to the mathematical atmosphere at Harvard. B esides Moscow, t h e main c e n t e r s o f r e se a rc h in his field are Harvard, P rinceton and Paris. Khoal was struck by th e international en v iro n ment a t H a r v a r d , In p a r t i c u l a r , in the Mathematics Department. The graduate s tu d e n ts and other mathe m a tic ia n s com e from many c o u n t r i e s , including Thailand, China and India. Khoal g a v e a talk a t P r in c e ton 's weekly algebra seminar on his p-adic Nevanlinna theory. The talk was very well a tte n d e d , and I have heard several favorable reactions f r o m , my a c q u a i n t a n c e s w h o w e r e t h e r e . Khoai met many m ath em ati cians both at the In stitu te for Advanced Study and at Princeton U n i v e r s i t y , i n c l u d i n g k e y p e o p l e ..i his fie ld , su c h a s B Dwork. P Robba and N Katz. Most of Khoai's weeklong visit to Princeton was hosted 6243 n A '. ri h n A 7 I C i / C O n P ' J T > iLhCE by the Bulgarian m athem atician Andrei Todorov (probably the leading mathe matician of hia g e n e r a t i o n in B u lg a r ia ) , who was a t t h a t time v i s i t i n g the Institute for Advanced Study. Todorov waa helpfu l in in tr o d u c in g hi around. Over the y e a r s, Todo rov has served as a bridge between East and West in c e r t a in f ie ld s of m athem atics, and he h a s now become In te r e s te d in m athem atics in Viet Nam. Fo r a f e w d a y s , K h o a i s t a y e d with th e Slaby fam ily, and much enjoyed their hospitality. It i s c l e a r from t h e a b o v e d i s c u s s i o n t h a t Dr K h o a l ' s v i s i t t o t h e U S waa high ly s u c c e s s f u l b oth in r e la tio n to h is own r e s e a r c h program and from th e s ta n d p o in t of developing relations between the Vietnamese and American m athemati cal communities. I waa a b le t o h a v e e x t e n s i v e informal d is c u s s io n s with Khoai about the s itu a tio n in Vietnam ese mathematics. I also have a b etter idea of what books and su p p lies are needed. I understand that the e a r lie r problem in a d m in istra tio n of th e Hanoi M athem atics I n s t i t u t e lib r s r y is now c le a r e d up, s o t h a t I can feel more c o n fid e n t th a t books donated will be well used. In a d d i t i o n , i t i s c l e a r t h a t b o o k s s h o u l d o n l y b e s h i p p e d in t h e Com m ittee's shipments, if possible personally accompanied to Hanoi. There are s till g r e a t problems in s h i p p i n g t h i n g s t o V i e t Nam b y t h e ordinary postal routes. Ouite c o r r e c t l y , V iet Nam's primary em phasis is in applied areas of sc ie n c e . But it shows Impressive fo re sig h t on th eir part th at they give support and en co u ra g e m e n t t o somecTne who w o r k s in a highly abstract area of research . Even though Khoal's work, and the s p e c if ic f ie ld s he a/tudled while in th e U S, have no bearing on Viet Nam's p r a c t i c a l p r o b le m s, h is s c i e n - tiflc su c c ess brings prestige to V i e t Nam, and h i s v i s i t h a s l e d t o I n c r e a s i n g i n t e r e s t i n V i e t Nam o n th e part of an in flu en tial group of American in te lle c tu a ls. Moreover, applied mathematics can only flou rish in an environment in which b a s i c r e s e a r c h a n d ''p u r e " m a t h e m a t i c s are a lso emphasized. The in te r r e la tio n and In tera ctio n b e t ween various branches of mathema t i c s , and between pure and applied mathematics, is so extensive that no particular branch of mathematics is lik ely to d evelop in iso la tio n from th e mainstream of pure mathe m a t i c s . In a d d i t i o n , it sh o u ld be noted that pure mathematics, unlike most applied sc ie n c e s , does not require s large capital investment. T h u s . V i e t Nam c a n r e l a t i v e l y "cheaply" a tta in a high level of develppment and a good in te r n a tio nal r e p u t a t i o n In m a t h e m a t i c s , e s p e c ia lly in view of th e already high c a lib r e of th e s p e c i a l i s t s in the field and the mathematical traditions that have been esta b li s h e d in V i e t Nam. I t would b e much h a r d e r f o r V i e t Nam t o d e v e l o p in ternation al prominence in, for e x a m p l e , DNA r e s e a r c h o r p a r t i c l e p h y s i c s . Thus, it is in Viet Nam's long-range in terest to continue to support and encourage re se a r c h e rs in both pu re and applied mathema t i c s . Perhaps th is is ob vious and u n n ecessa ry to s ta te ; however, it is I n te r e s tin g to note th at among the developing cou ntries only India. C h i n a a n d V i e t Nam s u p p o r t m a t h e m a tica l development at a high level ( a s f a r a s I am a w a r e ) . M a t h e m a t i cian s I have talked with about Viet Nam a r e a l w a y s s u r p r i s e d a n d i m p r e s sed to learn of the high level of m a t h e m a t i c a l a c t i v i t y t h a t V i e t Nam has been able to sustain despite all^ t h e y e a r s o f war and h a r d s h ip . 'The a u t h o r i s with t h e D e p a r t m e n t of M athem atics, U n iversity of Wash in gton , S e a t tle ; and c o o r d in a te s C o m m i tft e e a c t i v i t i e s i n m a t h e m a t i c s and c o m p u te r s c i e n c e . 1 4 SOCIAL SCIENCES E x c e r p t s t j r i_>m : S e c o n d N o t: 1c e o f t h e IF IP W O R K IN G C O N FER EN C E ON A D V A N C E S IN S Y S T E M M O D E L I N G ,6. O P T I M I Z A T I O N H a n o i , io - 1 4 JJ a n 1 2 The following have been confirmed to present invited lectures: J P Aubln (France), A V Balakhrlahnan ( U S A ) , K H E l s t e r (GDR), Yu G E v t u s h e n k o (USSR), D H i n r i c h a e n (FRG), Huynh H T (Canada), Hoang Tuy (Viet Nam), S E J a c o b s e n (USA), R Kluge (GDR), N Levan (USA), J L L io n s (F r a n c e ), N N Moiseev (USSR), P Nepomlastchy (France), M Peachel (GDR), Phan Dlnh Dieu (V iet Nam), 0 F V a s i l l e v (USSR). A limited number of c o n t r ib u t e d p a p e r s will be p r e s e n t e d in a f t e r - <on s e s s i o n s , f o l l o w i n g t h e ln .t e d le c tu r e s . The time limit for e a c h c o n tr ib u te d paper is 30 minu t e s (including discussion). All p a r tic ip a n ts and companions are kindly invited to a welcome party o n Monday e v e n i n g (Opening d a y , 10 J a n u a r y ). A C o n fe r e n c e d in n er will b e held on Thursday even in g (13 January). S ig h t s e e i n g to u r s will be arran ged b y t h e V i e t Nam T r a v e l A g e n c y . A t r i p t o t h e f a m o u s B a y o f Ha L o n g will be o r g a n iz e d on S a t u r d a y , 15 a n d S un day, 16 J a n u a r y . Immediately following the Confe r e n c e . a sh o rt Winter School on `S y s t e m s A n a l y s i s a n d O p t i m i z a t i o n " will be held in Hue, t h e old c a p i t a l o f V i e t Nam, f ro m 17 t o 24 J a n u a r y . T h i s Win-ter S c h o o l , s p o n s o r e d b y t h e V i e t Nam C e n t e r f o r F -ie n tific Research in conjunction ^ _h t h e A c a d e m y o f S j c f e n c e a o f t h e GDR, i s i n t e n d e d t o i n t r o d u c e y o u n g resea rch worker* to he current s t a t e of t h e a r t In S y s t e m * A n aly s i s and Optimization. AMERICAN UNIVERSITIES AND VIET NAM Pham Huy Thong 1 had ju st a rriv ed in Honolu lu, just s e t foot on American soil, when I had th e op p ortu n ity to g la n c e through a c a ta lo g of more than 200 books of r e se a r c h on Asia, d is tr ib u te d by the U n iversity of C a l i f o r n i a P r e s s . In among t h e listings for art, history, politi cal sc ie n c e , b u sin ess and e c o n o mics, litera tu re and language, phi losophy and religion , s o c io lo g y and humanities was a listing headed "V i e t Nam" . In c o n t r a s t t o t h e books on Japan, China, India, Thai land and Indonesia, which were scattered through the various c a te g o r i e s , t h e b o o k s o n V i e t Nam w e r e s e t apart in a s e c t io n of th eir own. It was a real p le a su r e t o s e e t h a t t h e t o p i c o f V i e t Nam r e c e i v e d such sp ecial a tte n tio n , with each project introduced quite a ttr a c ti vely. Here was one on th e r o o ts of the Vietnamese nation through the 10th Century; another d ea lt with th e u p h eavals in tra d itio n a l V ie t namese so c ie ty during the years of the resistan ce against French colo nialism, then the momentous period of the August 1945 Revolution; yet another contained^the animated re c o lle c tio n s of American sp e c ia l rep resen ta tiv e Archimedes Patti a b o u t t h e V ie t Mlnh, a b o u t P r e s i d e n t Ho Chi Mlnh, a n d a b o u t t h e d ays which gave birth t o th e Demo c r a t i c R e p u b l i c ' o f V i e t Nam. P r o f e s s o r a Solheim and O'Har row, who met our d e l e g a t i o n o ( Vietnamese social s c ie n tis ts at the Honolulu a irp o rt, on th e Hawaiian islands, said that the study of V i e t Nam i s m a k i n g r e m a r k a b l e p r o - 6245g r e a a , n o t j u s t i n C a l i f o r n i a , b u t throughout the United S ta te s . LTM 2>OCi A u S C I t N C K w 1 Honolulu, for example. Is alao a c e n t e r o f r e s e a r c h o n V i e t Nam. Here, American a r c h e o lo g is ts are prepared to coordinate their work with Vietnamese a c le n tla ta to a h ed lig h t on t h e a n c i e n t Hoa Binh cu ltu re which, some 10,000 years a g o , l e f t i t a t r a c e s In w h a t la now V i e t Nam - - a d e f i n i t e a d v a n c e In t h e human r a c e . That c u l t u r e , known to French r e s e a r c h e r s for 50 y e a r a , n eed s to be r e c o n sid e r ed and r e e v a lu a t e d in ligh t of r e c e n t d i s c o v e r i e s we h a v e made in Viet Nam a n d d i s c o v e r i e s m a d e b y A m e r i cana and o th era in Thailand. There a re a lso American docum ents on th e Kalanay c u ltu r e in th e P h ilip p in es, w hich may b e c o m p a r a b le t o d o c u m e n ts we h a v e on t h e Sa Huynh c u l t u r e in o u r own c o u n t r y . And t h e remains of ancient people which Americana have c o lle c te d in the P a c i f i c a n d S o u t h e a s t A s i a may b e com parable to remains d is c o v e r e d in sur country. One a rea in which t h e r e is c lo s e agreem ent between American s c h o la r s in Honolulu and Vietnamese r e s e a r c h e r s in h is to r y and l i t e r a tu r e is in recogn izin g and a n a ly zing th e attachm ent of the V iet namese people to their national t e r r i t o r y t h r o u g h t h e a g e s . In r e s e a r c h i n g exemplary p a t r i o t s in each p a tr io ts , d iscu ssin g Shih Hsieh or Nguyen Tral, discu ssin g "nom" c h a r a c t e r s o r t h e " q u o c n g u " alphabet, both aidea consider that the awakening of various su c c e s s iv e g e n e r a t i o n s i n V i e t Nam a s t h e y c r e a te d a culture was a lso a pro c e ss of fortifying the foundations of a national identity. Another point worth noting about Vietnamese s t u d ie s in Honolulu is i t s wideranging nature. ^Alongside h istory they stu dy litera tu re and language. There -have been initial e ffo r ts to ranalate and Introduce Vietnamese poetry. There is research into the stru ctu re of the Vietnameae lan guage and other languages of Viet Nam s u c h a a Mu o n g a n d Hmo n g , through th e prism of modern t h e o r ie s of s e m a n tic s and grammar. Hawaii and California -- uni v e r s i t i e s in America's West, l o o king out towards Asia -- are d e v e l o p i n g V i e t n a m e a e s t u d i e s . At t h e same time the development of V iet n a m es e s t u d i e s i n A m e r i c a i s n o t determ ined by geography; it has its r o o ts in h is to r y . At o n e tim e, now long p a s t , a number of American u n i v e r s i t ie s carried out psychological warfare research for the benefit of the American e x p e d i t i o n a r y f o r c e s in V i e t Nam. T h a t e f f o r t l e d t o r e s u lts which are clear to everyone: American so c ia l s c i e n t i s t s did not wait until 1973 or 1975 to change their orientation, to begin re sea rch in to th e h is to r y and c u l tu re, th e people and s o c ie t y of V i e t Nam i n t h e " p o s t - V i e t Nam" spirit of today. The military d e f e a t , the to ta l d e f e a t o f American imperialism in V i e t Nam j o l t e d t h e A m e r i c a n p u b l i c and American i n t e l l e c t u a l s in t o an aw areness of the re a lity of Viet Nam. A s m a l l n a t i o n , r e s t r a i n e d f o r mdny y e a r s by p o v e r t y , b a c k wardness and o p p ressio n , and yet it dared s ta n d up t o th e United S ta te s, one of the great powers, and had t h e s t r e n g t h t o k e e p up t h e b a t t l e u n til it fou gh t i t s way fr e e -- such a nation deserved con sid e ration and c a r efu l r e s e a r c h . That conclusion, that attitu d e, is sh a r e d by many American s o c ia l s c i e n t i s t s , even some who once c o n f r o n t e d us bn th e b a t t l e f i e l d . Research .and teaching on th e h is to ry, psych ology, cu ltu re and a r ts of 4, V i e t Nam, s e e k i n g o u t V i e t n a m e s e s t u d i e s of h is to r y and c u ltu r e and other achievem ents of Vietnamese social s c ie n t is t s -- th e s e are not l i m i t e d .0 u n i v e r s i t i e s i n t h e 1 6 SOCIAL SCIENCES Weat, nor are they only the concern a of small r e se a r c h c e n t e r s or individual sc h o la r s . A movement tor Vietnamese stu d ie s la spreading t h r o u g h many American u n i v e r s i t i e s . Is it p o ssib le to consider a n o t h e r s t e p fo rw a r d ? At t h e s c h o larly c o n fe r e n c e which th e American A ssociation for Aslan Studies r e c e n tly organized in Chicago, s c h o la r s from th e S o v ie t Union, China and a number of o th e r Aslan co u n t r i e s p a r t i c i p a t e d . V i e t Nam w a s in v ite d to p r e s e n t a paper and defend its archeological principles and a rgu m en ts. Only a r c h e o lo g y t h is time. But a f t e r t h a t , in m e e t i n g s w i t h t h e C o o r d i n a t i n g Com m itte e for V ietn am ese S t u d i e s in A m e r ic a , and in v i s i t i n g many Ame rican u n iv e r sitie s and social sc ie n c e research c e n te r s, our Viet namese delegation had the opportu nity to explain to large numbers of our American c o l l e a g u e s how we organize, tea ch and carry out r e s e a r c h in t h e s o c i a l s c i e n c e s In V i e t Nam. We w e r e a l s o a b l e t o gain an understanding of the basic c h a r a c te r istic s of the development of social sciences -- especially V i e t n a m e s e s t u d i e s -- when we met A m e r i c a n s c h o l a r s in C h i c a g o , New Yuift, B o s t o n , Cambridge, P h ila d e l phia, Los A ngeles, Honolulu and many o t h e r p l a c e s . H istory is given fir s t impor tan ce. Ancient h isto r y , and modern h is to r y . John Wlthmore, Keith Tay lor, Holmgren, O'Harrow, W olters -- from t h e A s ia tic mode of p r o d u c tio n in the Red River d e lta and th e Dong Son cu ltu re to Chinese c h a r a c te r s, "non" c h a r a c te r s , Tran lite ra tu r e , and th e writing of Nguyen Tral, the fie ld o f V ietn a m ese s t u d i e s in America, with the sch o la rs mentlonned above, la dem onstrating the iatln ctlve cultural pnd a r tistic accomplishments of the various ge n e r a t i o n s o f a n c i e n tI V i e t n a m e s e who, s t e p by s t e p , c r e a t e d our unique national ch aracterist les , our c a p a c ity aa a nation to stand r e s o l u t e . L i k e w i s e , Davi d Marr and Gary P o r t e r , J a y n e Werner an d Karl T h a y e r , William Duiker and G e o r g e Kahln, Tice and J e ffr e y Race are p r e s e n t i n g t h e h i s t o r y o f V i e t Nam in r e c e n t d e c a d e s -- th e h is t o r y of the V ietnam ese revolu tion , from the fight against the French to that a g a in s t th e United S t a t e s , in all its sweep, its excitement, its wonder. History is the g r e a te st s t r e n g t h , e s p e c i a l l y a t su c h major u n iv e r s it ie s as Cornell, Yale and Berkeley. The famous university Harvard has emphasized literatu re. A f t e r e f f o r t s s p a n n in g many y e a r s , th is June they Organized a c o n fe ren ce o f s c h o la r s on Vietnamese literatu re prior to the August (1945) Revolution. The organizers realized th a t, even though it was week-long co n fer e n c e , with very serious debates, these sessions could only give an overview , a "kindergarten" view. But they hoped that once the issu es were a u n ea rth ed and sp rea d around -- from th e affirm ation of th e "quoc ngu" a l p h a b e t In t h e j o u r n a l "Nam P h o n g " and th e S elf-R elia n ce L itera tu re Group t o th e Communist P a r ty 's t h e s i s on lit e r a t u r e -- and with a number o f Vietnam ese s c h o la r s par ticipating, the conference could perform a certa in useful function: opening th e way to seek in g a deeper u n d e r s t a n d i n g o f V i e t Nam t h r o u g h Vietnamese perceptions of them selves. E n th u sia stic resea rch on Viet Nam, w h i c h f i r s t b e g a n t o bloom In th e antiwar movement, did not d e cline a fte r th end of the war. Instead It has spread and grown more e n t h u s i a s t i c in r e c e n t tim es, 4 with th e d is c o v e r y of a number of unique c h a r a c te r is tic s of the c iv i lization and the national tra d i t i o n s o f V i e t Nam. In V i e t n a m e s e s o c ia l ^sciences th e "human s c l e n cea", l it e r a t u r e and h is to r y , are jL _ S O C , AL. 1 E N l h .=, 1/ now th e o a t a t t r a c t i v e to Ameri c a n a . In t h e r e c e n t p a s t , b e c a u s e of the pressure of public opinion, more than a hundred c e n t e r s of t e a c h i n g o r r e s e a r c h o n V i e t Nam r e c e i v e d g o v e r n m e n t s u p p o r t . Now, t h e Reagan a d m i n i s t r a t i o n . In o r d e r to fuel th e arms r a c e , has a policy of decreasing the budget for cu l tu r e , a c ie n c e and e d u c a tio n , which has hit budgets for Vietnamese stu d ie s hard. They have agreed to fund fewer than 40 c e n t e r s . R e se a r c h e r s and t e a c h e r s In t h e V i e t n a mese stu d ies field have reacted sharply. What h a s s p a r k e d t h i s s p i r i t o f stru g g le? After nearly a month in the United S t a te s , talking with hundreds of American s c h o la r s . I can affirm: it is a h e a r tfe lt r e sp e c t for our people, a deep enthusiasm for trying to understand our people, our s o c ie t y and our civ iliza tio n . It is not tru e th a t Americans, who do n ot have a longlived c u ltu re of th eir own, do not know how t o a p p r e c ia t e old c u l t u r e s . For A m e r i c a n s , t h e Hoa Blnh and Dong Son c u ltu r e s and th e l i t e ratu re of the Ly-Tran period are marvels. But t h is Is not all t h e r e la to It. There are some p rogressive Americans who are g r a te f u l to Viet Nam f o r , b y t h e i r s t r u g g l e , a w a k e ning Americana to th e Issue of m o ra lity In f o r e i g n p o l i c y . To them, honor for the United S ta te s d o e s not mean u sing i t s s t r e n g t h t o put o b s t a c le s in th e way of oth er peoples, but respecting every na tion, whether large or small, gua ra n teein g a life of p ea ce and e q u a lit y among th e p e o p le s of all c o u n t r i e s . The le s s o n t o be drawn from "he a g g r e s s i v e w a r i n V i e t Nam i s hat America a c te d q o n tra ry to morality, and for that reason was d e f e a t e d and lo s t c r e d i b i l i t y in t h e w o r l d . Now t h o a e v e r y c i r c l e s in America who are eager to I n te r v e n e i n o t h e r c o u n t r i e s , l i k e El S a l v a d o r , a r e i n s i s t i n g , "El S a l v a d o r l a n o t V i e t Nam", a t t h e v e r y time when, more than e v e r . It is impossible to disregard the lessons o f V i e t Nam. R e c o g n i z i n g t h a t , i t is very commendable th at two h is t o r y p r o f e s s o r s in New York, who have *taught about Asian history but n o t a b o u t V i e t Nam b e c a u s e i t i s outside their specialization, have had d iscu ssio n s about revising their program beginning next year t o t e a c h a b o u t V i e t Nam. Other well-informed Americans think t h a t , whether or not Ameri c a n s l ik e Viet Nam's c o u r s e of d e v e l o p m e n t , s t i l l V i e t Nam -- w i t h its p a st civilization , with its role in r e c e n t h is to r y , with i t s c u r r e n t p o p u l a t i o n - - h o l d s an im p o r ta n t p o s itio n in an Asia on th e threshold of the 21st Century. Immediately, is it possible to continue forever the current situ a tion with S ou theast Asia divided into two opposing blocs without e n d a n g e r in g t h e common s e c u r i t y ? Or t o p u t i t t h e o t h e r w a y r o u n d , if people want S o u th ea st Asia to become a peaceful region and -alon g.w lth S o u th e a st Asia -- want all of E ast Asia, South Asia and th e P a c ific to enjOy q u iet under the s t a r s and a c r o ss th e waves, t h e n h o w c a n t h e y b e l i t t l e V i e t Nam and not make an e f f o r t to gain a deep understanding of the reality o f V i e t Nam? Then th ere are some Americans -- t e a c h e r s and r e s e a r c h e s , and even a c o n sid e r able number of young p eo p le -- who are h e a te d ly deman ding a continuation of .university t e a c h i n g a n d r e s e a r c h o n Viet, Nam, b e c a u s e V i e t Nam h a s b e c o m e ^ l i n k e d with th eir personal i n t e r e s t s . Every r e se a r c h c e n te r which is shut d o w n or, w h i c h h a d t o r e d u c e i t s a c t i v i t i e s means a number of people 6248 1 6 SOCIAL SCIENCES ut of work, a number of books which cannot be w ritten or printed. Vet th ere are Americans, and their number la not small -- sc h o la r s . In te lle c tu a ls, en trep ren eu rs or s o c i a l a c t i v i s t s - - who have linked th eir I n te r e s ts and their future w i t h V i e t Nam, an i n s e p a r a b l e p a r t o f the Asian c o n tin e n t and of t o morrow's world. Faced with the danger of being pushed back a step , the area of Vietnamese stu d ies is defending I ts e lf with determ ination -- b e cause of the personal in te r e sts of the scholars, because of the long term In terest of the United S ta te s, or for reasons of morality, of scholarship or of personal a ttr a c t i o n . If It c a n n o t y e t d e v e lo p , cannot yet expand, then so be it, but don't narrow It, don't decrease It. So in d i s c u s s i o n s with u s, their Vietnamese colleagues, both aides were looking forward, not b a c k . We m u s t s t r e n g t h e n o u r r e l a tio n s, that is a point of- clear determination: exchange publica tions, exchange documents; exchange resea rch es to p resen t papers, lead sem inars, p a r tic ip a te in sym posia, train and give r e fr e sh e r s for young cad re, organize ex h ib its and p e r formances. There is no lack of d lffic u ltie s , and the numbers are not small: language, tra v el and m a t e r ia l r e s o u r c e s . All t h e s a m e , in our d iscu ssio n s th e determ ina tio n and enthusiasm were c e n tr a l. But th e enthusiasm was th e re a l r e a d y . We s a w t h a t c l e a r l y w h e n we a r r iv e d . I will r is k sa y in g t h a t when we l e f t , t h e e n th u sia sm was turning into determination. Our American f r i e n d s w e r e th in k in g : ) we h a v e t h e c o o p e r a t i o n o f V iet i. m., V i e t n a m e s e s t u d i e ) s ' i n A m e r i c a will not s t o p with p r o j e c t s of simple, superficial d escrip tio n , but can be precise, looking beneath th e s u r f a c e in a tru ly s c i e n t i f i c f ashlon. The d e s i r e o f many American I n t e l l e c t u a l s who a re a c t i v e ly building the field of Vietnamese stu d ies is thus linked closely to sch o la rly c o o p e r a tio n with their c o lle a g u e s in th e so cia l s c ie n c e s in V i e t Nam. T h e U S C o m m it te e f o r S cien tific Cooperation with Viet Nam w i l l b e a b l e t o m a k e p r a c t i c a l contributions to putting this prin ciple into practice. The c u r r e n t s tr u g g le to d e v e lop the field of Vietnamese stu d ies in America is to our c o u n tr y 's advantage, to the advantage of the American p eop le, and to the advan ta g e of th e p r o g r e ssiv e world. S ch o la rs of th e two c o u n tr ie s want to join hands and work t o g e t h e r . The national leadership of the A ssociation for Asian Studies r e s p e c tfu lly r e c e iv e d our g i f t s from V i e t Nam -- t w o a r t i f a c t s r e p r e s e n t a t i v e o f t h e p r o d u c t s o f th e Dong Son culture -- and announced that they were "a very graciou s g e s ture", "evidence of the friendly sp irit of the S ocialist Republic of V i e t Nam". P e o p l e a t t h e Museum o f th e U niversity of Pennsylvania were deep ly moved when I came to v is it t h e p la c e where C h este r Gorman, th e famous American a r c h e o lo g is t , stru g g led to work during the la st years of his life, a fte r he was taken dangerously -ill, s o I could write a few lines to ex p r e ss the friendship and the high regard for his sc h o la r s h ip f e l t by his V ietn a mese colleagu es. E xperiences like t h e s e f r o m t h e f h o r t p e r i o d o f my r e c e n t v isit to America are surely a fine opening toward a promising cooperation. ^ The author is V ice-D irector of the V i e t Nam S o c i a l S c i e n c e s *C o m m i s s i o n . He v i s i t e d t h e II ^ In A p r i l 1 9 8 2 w i t h h i s . c o l l e a g u e D1NH GIA KHANH, D irector tof th e Folklore I n s titu te . T r a n s l a t i o n i s b y JOHN SPRAGENS. REPORT ON THE C O N F E R E N C E "A CRITICAL EXAMINATION OF THE VIET NAM EXPERIENCE SINCE 19-7 5 ' A m s t e r d a m , <1-- fc> J u n & 2 Jayne Werner The purpose of the Conference was to bring to g eth er aid organlzat i o n a w o r k i n g in V i e t Nam, " a o l l d a rlty organizations", academic spec i a l i a t a c o n c e r n e d w i t h V i e t Nam, and o f f i c i a l s from V iet Kan, t o d i a c u a a W e a t e r n a i d t o V i e t Nam a n d contem porary economic laauea. The c o n fer e n c e was organized by the Transnational In stitu te, the Euro pean affiliate of the Institute for P o l i c y S t u d i e s i n W a s h i n g t o n , DC. T h e r e p r e s e n t a t i v e s f r o m V i e t Nam were Hoang Nguyen, e d ito r of th e " V i e t Nam C o u r i e r " , a n d D a o Va n T a p , D irector of the Economica In stitu te o f th e Social S c ie n c e s Commission. o th are from Hanoi. T h ere were 40 t o 50 Western p a r tic ip a n ts , from aid orga n iza tio n s, u n iv e r s itie s , and the p r e s s . They came from s e v e r a l Euro pean co u n tries and the United States. Vietnam ese o f f i c ia l s , which led to a discu ssion on the relationship b e t ween a c c u r a te reportage and a s s i s t a n c e t o V i e t Nam. T h i s t h e m e came up again in th e c o n fe r e n c e and, given the d iv ersity of the p a r tic i pants, was not ultimately resolved. The c o n fe r e n c e 's theme was c r it i cized by some of the p a rticip a n ts. O thers s u g g e s t e d that one can n ot be a " f r i e n d " o f V i e t Nam ( s i n c e V i e t Nam i s a s t a t e , w i t h w h i c h i t i s anomalous for individuals and groups to be "friends"), although th ere can b e s y m p a t h y t o w a r d V i e t Nam. Da o Van Tap s a i d t h a t "we a c c e p t c r i t i cism which h e l p s u n d e r s ta n d in g " . It was agreed, however, that all the participants shared the objective of working toward breaking the U S economic b lockade and diplomatic i s o l a t i o n o f V i e t Nam. a The workinq s e s s i o n s led to a detailed discussion of the current d ifflc u ltie s , th e food situ a tio n and th e n a tu r e o f th e new econom ic reforms that have been in stitu ted . The r e so lu tio n s of the Fifth Party Congress were analyzed. The role of th e market in t h e economy and th e p r o c e ss and problems of in d u stria li zation were brought up. The c o n feren ce opened with a public se ssio n d iscu ssin g Western s i d t o V i e t Nam. T h e s p e a k e r s w e r e Hoang Nguyen, who made g e n e r a l r e marks on Viet Nam's aid n e e d s . Eric Wulff, a long-tim e a c t i v i s t from Germany, Lennart K lackenberg, a fo r mer member o f t h e S w ed ish P a r lia ment, and Charles Fournlau, Chair person of the French-Vietnamese Friendship A ssociation, talked about aid programs from th e ir r e s p e c t i v e c o u n t r i e s t o V i e t Nam. N a y a n C h a n d a , th e diplomatic correspond en t for the "Far Eastern Economic Review", d is cu ssed the economic problems faced b y V i e t Nam. T h e r e w a s a b r i e f x c h a n g e between Hoang Nguyen and lands on jo u r n a lists obtain ing fra n k and a c c u r a t e inform ation from The s e r i o u s n e s s of th e cu rren t economic d iffic u ltie s came out most f o r c e f u l l y . V i e t Nam w i l l h a v e d iffic u lty moving forward, or even sta y in g in th e same p la c e, without foreign a s s is ta n c e . Foreign aid is critical to a solution of the food problem. Internal dom estic co n d i tions were particularly highlighted, giving us a g r e a te r understanding of t h e o b s t a c l e s V i e t Nam f a c e s . T h e conference also brought out that V i e t Nam i s c u r r e n t l y f a c i n g a " wa r of sa b o ta g e" by the U S and i t s northern neighbor, and is su fferin g greatly for it. ^International evertta pose the g r e a te st problems for economic development. The point y a s brought ou t that > 6250 cz 2 0 SOCIAL SCIENCES th e r e la a atrong re la tio n sh ip b e t ween development and national d e f e n s e . The r e s o lu t io n s of the Fifth Party Congress decided Viet Nam s h o u l d d e v o t e l t a r e s o u r c e s e q u ally to national d e f e n s e and s o c i a l i s t c o n s t r u c t io n . It a lso made d e c isio n s relatin g t o the r e la tio n s h ip between a g r ic u ltu r e and industry, the inclusion of the south in the so c ia list revolution, poli c i e s on consumer good s, and tech n lc a l/sc le n tific a sp ects of economic development. These resolutions con tinue to str e s s industry as the c e n t r a l t a s k , but in th e 1980'a, th e P a r t y will c o n c e n t r a t e on a g r i c u l t u r e . This will be accom pan ied by th e production of consumer goods and th e s e le c tiv e building of some s e c t o r s o f h e a v y i n d u s t r y . V i e t Nam will continue the th r ee-fo ld revolu tio n in ideology, c u ltu re and s c ie n c e / t e c h n o l o g y . " S o c i a l i s m " i n V i e t Nam s t ill means w ide-scale in d u stria li zation. In r e s p o n s e t o a p a p e r on t h e F ifth Party Congress, Hoang Nguyen said that the Congress looked into t h e m is t a k e s made by l t a l e a d e r s h i p . The "subjective" reason s for the failure of economic policies were publicly recognized. These mistakes were a ttrib u ted to Inadequate know ledge of conditions and inexperience in econom ic management. In 1979, at t h e s ix t h plenum of t h e Fourth Party C on gress, new methods of economic management were Introd uced and were developed further at the recent C o n g r e s s . Hoang N g u y en s a i d , "we reco g n ize th e fa ilu r e s we've made, b u t we c o u n t on making l e s s and l e a s " . He a l s o s a i d t h a t V i e t Nam h a s much l e s s o u t s i d e aid t h a n b e fore. Other p resen ta tio n s pointed out h at t h e main ec o n o m ic problem la iihe c r i s i s in food p r o d u c t io n . As a r e s u lt , a new c o n tr a c tin g system has been Introd u ced in th e a g r ic u ltu r a l co o p era tlv es. Quotas and piece-work h a v e b e e n i n s t i t u t e d . In some p l a c e s , t h e s e new m ethods have been in o p e r a tio n for two y e a r s . The idea la to link the s e l f - i n t e r e s t of individual p easan ts to production, or rath er to the volume of food produced. Hoang Nguyen mentioned that the objective of th ese changes is to increase agricultural produc t i o n fco t h a t t h e i m p o r t o f g r a i n s can be term inated. Viet Nam's l e a d e r s have adm it ted that th ere is s seriou s economic crisis. There has been a recovery since 1978. but the level of produc-, tion in th a t year was s till lower t h a t in 1966. Imports will be needed at le a st until 1985. This means continued o v e r se a s aid, given th e problem of balance of payments. 1981 was a good year for rice p ro d u c tion, but overall yield was still low, which was 180 kilograms of paddy per person. As to th e p o t e n tia l o f th e new c o n t r a c t i n g s y s t e m t o g e t V i e t Nam out of its agricultural production d ifficu lties, a Vietnamese residing in th e West e x p r e s s e d pessimism th a t t h is would be a long-term s o lu tio n . ,An i n t e r e s t i n g p r e s e n t a t i o n w a s given by F eth i Benammer during a discussion of the industrialization p r o c e s s . Benammer la an e n g in e e r wh o s p e n t t h r e e y e a r s i n V i e t Nam o n a German-funded project. A spinning plant was built in Hanoi, which o f f i c i a l s adm itted t o Benammer was meant to be a show case both for fo reig n ers and for the local popula tion. But the plant c o n str u c tio n fa ce d numerous d i f f i c u lt ie s . It took s e v e r a l au th o riza tio n s to move small q u a n titie s of su p p lies, s in c e the* o f f i c i a l s with whom t h e c r e w . worked seemed to try to avoid resp on s ib ilit y fo r making d e c is i o n s . There were also great di ff c - with th e work fo r c e which ia cn eo the n e cessa ry resp ect for the machinery in t h e p la n t. It was n o t a m atter 6251 y 6252 United States Environmental Protection * Agency Water Ambient Office of Water Regulations and Standards W ashington, OC 20460 EPA 440/5-84-007 February 1984 Water Quality Criteria for 2, 3, 7, 8 - Tetra ehioro- dibenzo - p - dioxin > w' 6253 AMBIENT WATER QUALITY CRITERIA FOR 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN > Prepared By U.S. ENVIRONMENTAL PROTECTION AGENCY Office of Water Rgulations and Standards Criteria and Standards Division Washington, D.C. Office of Research and Development Environmental Criteria and Assessment Office Cincinnati, Ohio Carcinogen Assessment Group Washington, D.C. Reproductive Effects Assessment Group Washington, D.C. Environmental Research Laboratories Corvallis, Oregon Duluth, Minnesota Gulf Breeze, Florida Narragansett, Rhode Islandl I l 6254 INTRODUCTION The major source of 2,3,7,8-tetrachlorod1benzo--d1ox1n (2,3,7,8-TCDD) (CAS Number 1746-01-8) appears to be as a contaminant formed during the pro duction of 2,4,5-trlchlorophenol (2,4,5-TCP) from 1 ,2,4,5-tetrachlorobenzene (Mines, 1971; K1mm1g and Schulz, 1957; Firestone et al., 1972). 2,4,5-TCP Is the major chemical feedstock In the production of several herbicides Including 2,4,5-trlchlorophenoxyacetlc acid (2,4,5-T), 2,4,5-T esters and Sllvex. Each of these chemicals may contain 2,3,7,8-TCDD as a contaminant (Buser and Bosshardt, 1974; Courtney et al., 1970; Edmunds et al., 1973; Zltko and Choi, 1971). It has also been reported that 2,3,7,8-TCDO may be formed during the pyrolysis of chlorinated phenols (Buu-Hol et al., 1971a,b), chlorinated benzenes (Buser, 1979) and polychlorinated diphenyl ethers (Lindahl et al., 1980), and thus can also be emitted by municipal t Incinerators (Rappe et al., 1983a; Lustenhouwer et al., 1980; 011e et al., 1982, 1983). There 1s no clear-evidence that 2,3,7,8-TCDD 1s a typical con taminant 1n the herbicide 2,4-d1chlorophenoxyacet1c acid (2,4-0) (Woolson et al., 1972; Henshaw et al., 1975; Cochrane et al., 1981). Physical Properties 2,3,7,8-TCDD 1s a symmetrical, nearly planar molecule with the empirical formula C^H^Cl^Oj. The four chlorine atoms are Indistinguishable from one another (Poland and Glover, 1973). 2,3,7,8-TCDD 1s a white crys talline solid with a melting point range of 302-305C (Sparschu et al., 1971; Elvldge, 1971) and has a molecular weight of 321.9. The vapor pres- sure of this compound Is estimated to be 10"* mm of Hg (0.1 mPa) at 1 atmosphere and 25C (Habey et al., 1981). The Henry's constant has been estimated to be 2.1x10"3 atmosphere m 3 .mol~1 (Mabey et al., 1981). 2,3,7,8-TCDD Is lipophilic, exhibiting some solubility In fats, oils and I A-l 6255 other relatively nonpolar solvents, and Is only slightly soluble 1n water (0.2 yg/l) (Crummet and Stehl, 1973; Norris, 1981). The solubility of 2,3,7,8-TCDQ 1n various organic solvents 1s given below (Crummet and Stehl, 1973): Solvent Solubility (ppm) lard oil benzene o-d1chlorobenzene chloroform acetone n-octanol methanol 44 570 1400 370 110 50 10 The partition coefficient of 2,3,7,8-TCDD 1n a water:hexane system has been reported to be 1000 (Matsumura and Benezet, 1973). The octanol/water partition coefficient (KQW) has been calculated by the methods of Hansch and Leo (1979) and has been experimentally measured. Calculated values for log Kq w range from 6.84-7.28, and a measured value of 6.15 has been reported (see Section B, B1oapcumulat1on). Cocontaminants of 2.3.7.8-TC00 1n Chlorinated Products 2,3,7,8-TCDD 1s only one of many trace contaminants found 1n some chlorinated Industrial products Including a few chlorinated phenols, a few chlorinated phenoxy acids (especially the herbicides 2,4,5-T and Sllvex) and hexachlorophene. Among the other trace contaminants found 1n these products are members of the polychlorinated d1benzo-j)-d1ox1ns (PCDDs), polychlori nated dlbenzofurans (PCDFs), polychlorinated dlphenylethers (PCDPEs), poly chlorinated phenoxyphenols (PCPPs), polychlorinated biphenyls (PCBs) and polychlorinated benzenes (PCBz^. Of these, some possess properties that make them difficult to separate analytically from the 2,3,7,8-TCDD Isomer (KlmbTough, 1974; U.S. EPA, 1980; Bumb et al., 1980? Rappe t al.V~1983b). A-2 Synthesis 2.3.7.8- TCDD has been synthesized by several methods 1n moderate yield (e.g., reaction of dlchlorocatechol salts with o-chlorobenzene by refluxing in alkaline dlmethylsulfoxlde; chlorination of dlbenzo-j)-d1oxln 1n the pres ence of ferric chloride and Iodine; UV Irradiation of PCDDs of high chlorine content; Ullman reaction of chlorinated phenolates at 180-400C; pyrolysis of chlorinated phenolates and chlorinated phenols; heating 1 ,2,4-tr1chloro- 5-n1trobenzene and 4,5-d1chlorocatechol 1n the presence of base). These processes have been reviewed 1n U.S. EPA (1980). Chemistry 2.3.7.8- TCDO 1s considered to be relatively stable toward heat, acids and alkalies. It begins to decdmpose at 500C, and at a temperature of 800C, virtually complete degradation occurs within 21 seconds (Stehl et al., 1973). From a theoretical equation for thermal dissociation constant K 1015'5 exp(-80,000/RT) sec"1 ' K = dissociation constant, R = universal gas constant, T = temperature for tetrachlorod1benzo--d1ox1ns formulated by Staub and Tsang (1983), the 99.99% gas phase dioxin dissociation at 727C will require about 15.4 minutes. The same equation predicts a 99.99% decomposition of tetrachloro- d1benzo--d1ox1ns 1n 0.3 seconds at 977C. Gamma radiation degrades the molecule (Fanelll et al., 1978). 2,3,7,8-TCDO can be perchlorInated (Hutzlnger et al., 1972). 2.3.7.8- TCDO 1s transformed very slowly 1n aquatic systems. Of the four transformation processes (photoreaction, biotransformation, hydrolysis and radical oxidation) that control the fate of a chemical In aquatic media only the first two processes are throught to effect the transformation of 2,3,7,8-TCDO (Matsumura et al., 1983). In organic solvents, 2,3,7,8-TCDO undergoes reductive photodechlorlnatlon at wavelengths <320 nm (Crosby et* 6257 a1.t 1971; L1bert1 et al., 1978). In aqueous solution hydroxylatlve dechlo rination probably occurs, although this has not been seen. Llbertl et al. (1978) showed that 2,3,7,8-TCDO spread oversilica gel, aluminum, glass, ceramic tile and marble 1n the absence of an organic solvent showed various decomposition rates on UV Irradiation. Little decomposition occurred on glass or marble, but substantial degradation occurred on silica gel and aluminum. Also, 1:1 ethyl oleate/xylene was found to be a satisfactory H donor. Pllmmer et al. (1973)reported that a 2,3,7,8-TCDO suspension 1n distilled water remained unchanged when Irradiated with a sunlamp. Simi larly, a thin dry film of 2,3,7,8-TCDO on a glass plate or 2,3,7,8-TCDD on dry and wet soils showed negligible photodegradation after Irradiation with sunlamps (Crosby et al., 1971). In contrast, 2,3,7,8-TCDD 1n methanol solu tion, or a benzene solution of 2,3,7,8TCDD 1n water In the presence of a surfactant underwent substantial photodegradation under sunlamp or sunlight Irradiation {Pllmmer et al., 1973; Crosby et al., 1971). Nestrlck et al. (1980) experimentally determined the photolytlc half-Hfe of 2,3,7,8-TCDD In n-hexa-dccane under sunlamp Irradiation to be -57 minutes. The surfactant, l-hexyldecylpyr1o1n1um chloride, sensitized the photodecomposition 1n aque ous solution (Botre et al., 1978). The evolution of 2,3,7,8-TCDD from more highly chlorinated PCDDs on UV Irradiation from sunlight 1s unlikely since dechlorination 1n organic solvents and 1n the presence of artificial UV sources occurs preferentially at the 2,3,7,8-positions (Buser and Rappe, 1978; Nestrlck et al., 1980). Analytical Methods for TCDD * Host of the current analytical methods used for' the Identification and quant1tat4on of 2,3,7,8-TCDD are based upon gas chromafrbgraphy/mass spectro- metry (GC/MS). This method provides both high sensitivity (detection at l' , ; A-4 6258 31 l "V I cc February 27, 1984 Steve or E d , E n c l o s e d p l e a s e f i n d y o u r c o p y of 1) additional expanded summaries as r eq ue s t e d by Shindlin, and Ed, since our copies were (originals) were missing pages I have sent the court a copy, you must have enough copies to send to Service List (all Defendants and Plaintiffs Mgmt Committee 2) P l a i n t i f f s ' G o v e r n m e n t C a u s a t i o n Witnesses and Compliance with US G u i d e l i n e page 34, as order ed by Judge Weinstein, including copies of the EPA Documents 1983 - these must be copied and hand delivered to all Defendants and our committee no later than 2pm F e b r u a r y 27, 1984 3) A c o p y of A l i s t a i r H a y e x p a n d e d Summary for Benton along with a portion.of the transcript from Nov. 21, 1984 regarding Thompson Request for Summary Judgement, and its denial for Benton. Please have these xeroxed Monday and passed out. We have sent a copy to Ms. G r e t c he n Witt, US Dept of Justice, W a s h i n g t o n DC and to the C o u r t so we c o u l d b e g i n t h e d e p o s i t i o n on T h u r s d a y , M a r c h 1, 1 984 and have complied with his Honor's ruling. Thanks , Alison > 6261 DEBORAH A. BARSOTTI, Ph.D. I. QUALIFICATIONS Dr. Barsotti is an Assistant Professor of Tocicology in the Department of Pharmacology and Toxicology of the Philadelphia College of Pharmacy and Science in Philadelphia, Pennsylvania. Her curriculum vitae is attached. II. SUBJECT MATTER Dr. Barsotti is a toxicologist who has done substantial personal investigative work with halogenated aromatic hydrocarbons. This category of chemicals includes various biphenyls and dioxins, and specifically includes tetrachlorodibenzo-p-dioxin (TCDD). She will testify as to the relative chemical stability and lipophilicity of these chemicals as well as their resistance to degradation, and will testify that these qualities are what account for the perceived and documented bioaccumulation of the chemicals in the human system. Dr. Barsotti will emphasize the difference in results between chronic and acute exposures to these chemicals, testifying as to the varying types of responses to acute and chronic exposures. Dr. Barsotti will discuss her own work as well as review the literature in these areas, noting differences in routes of 6262 administration, and in the species and genetic strain of the animals involved. She will explain these variations and where they permit extrapolation of results from animals to humans. In particular, Dr. Barsotti will also testify as to the similarities in response to these chemicals by rhesus monkeys and by humans, and will explain how the similarities permit extrapolation in this instance. Dr. Barsotti will also discuss reproductive toxicity, teratology and post-natal toxicity, including instances where no gross or clinical signs of maternal toxicity could be detected. III. SCIENTIFIC PRINCIPLES See General Statement of Scientific Principles and Assumed Facts attached. IV. SUBSTANCE OF OPINIONS A. That dioxins are toxic, and in particular TCDD is exceptionally toxic. B. That dioxins bioaccumulate because of their chemical stability, lepophilicity, and resistance to degradation. ^4 C. That chronic low level exposure to dioxins is significantly ^toxic. 6263 D. That TCDD accumulates and persists in the lipid stores. E. That TCDD, in chronic doses, is toxic, is parti cularly toxic to reproductive system, is teratogenic, and is fetotoxic. F. There are ample scientific bases, for extrapolat ing animal experimental data to man, in the case of TCDD, for example, as demonstrated by Dr. Barsotti's work on rhesus monkeys. V. GROUNDS FOR EACH OPINION A. . General Review of applicable medical and scientific litera ture; education and training; personal research. The work on the chronic toxicity of HAHs in rhesus monkeys has culminated in numerous publications as presented in Dr. Barsotti's curriculum vitae. In addition, she has been invited to speak or present her work in various atmospheres including community meetings and scientific symposia. B. Specific 1. With respect to opinion IV A, see generally references attached. %f 2. With respect to Opinion IV B, note the following: I 8264 In the course of Dr. Barsotti's graduate and post graduate studies, she has had the opportunity to conduct research and evaluate others' work on members of the class of chemicals called halogenated aromatic hydrocarbons (HAHs). She will discuss the fact that this class of chemicals includes the chlorinated -dibenzo-p-dioxins and the halogenated biphenyls (polychlorinated and polybrominated biphenyls) and that HAHs are similar in chemical structure, in the pattern of toxic responses that they produce and in the mechanism by which they are believed to act (Allen et al . , 1979; Poland and Knutson, 19 82) . Although individual HAHs vary in potency, their chemical stability and lipophilicity, as well as their resistance to degradation results in bioaccumulation (Isensee and Jones, 1975; Meselson et al., 1978; Marinucci and Bartha, 1982; Mes et al., 1982). 3. With respect to opinion IV C, note the follow ing; Thesis work performed by Dr. Barsotti at the Univer sity of Wisconsin with polychlorinated biphenyls indicated that evaluation of the toxic effects of HAHs in the Rhesus monkeys was valuable to the understanding of the potential hazards of HAHs in the environment (i.e. chronic exposure). In addition, this work indicated, unlike rodent models, that there were similarities in the response of humans and rhesus monkeys to these chemical toxi cants (Barsotti, 1980). Like man, the rhesus monkey is genetically diverse and responded to PCB exposure on an individual basis. I 6265 Dr. Barsotti will contrast the acute toxicity that one observes in accidental or intentional ingestion of toxic or lethal doses of chemicals with the effects of chronic or lower levels of exposure to chemicals such as HAHs. 4. With respect to Opinion IV D, note the following: Dr. Barsotti will comment on the state of the literature on the fate of TCDD once in the body, i.e. TCDD metabolism (Vinopal and Cassida, 1973; Ramsey et a l ., 1979; Schlatter, 1979). Efforts to identify metabolites in tissues and excreta from various studies have been unsuccessful. Recent advances in detection methodology indicate elevated levels of TCDD in Vietnam veterans and other exposed persons. Generally, however, the data indicate that if metabolism does occur the rate is slow (Guenthner et a l ., 1979) The ramification of this finding is that the body would be incapable of or slow in ridding itself of TCDD and TCDD would accumulate and persist in the lipid stores. In Dr. Barsotti's work, as well as others', this appears to be the case with rhesus monkeys and man (Montagna et a l ., 1979; Van Miller, 1981; McNulty et a l ., 1983) . 5. With respect to opinion IV E, note the following: Not only did the rhesus monkey appear a good model for HAH toxicity but established, as had been in other animal species, that the reproductive system was extremely sensitive to PCBs at intake levels below that required for the manifestation of toxic signs~in the adult (Barsotti et .al., 1976). "In addition to PCB induced reproductive toxicity, PCBs were found to be fetotoxic I 6266 three months in animals receiving TCDD in the diets at levels of 500 parts per trillion (ppt) and in animals consuming diets contain ing 50 ppt TCDD these same symptoms occurred after consuming the diets for 30 months (Allen et al., 1977; Schantz et al,, 1979). This indicates cumulative toxicity associated with ingestion of TCDD. Thus, there is evidence for bioaccumulation and associated chronic toxicity at lower doses than that required for acute toxi city in rhesus monkeys and presumably man (Pazderova e t a^, 1981; Ideo et _al., 1982.) 6. With respect to Opinion IV F, see genera references attached and V A above. 6267 D. A. Barsotti, L.J. Abrahamson and J.R. Allen, Bull. Environ. Contam. Toxicol., 21, 463, 1979 - R.E. Bowman, M.P. Heironimus and D.A. Barsotti, Neurotoxicol,m 2, 251, 1981. K.D. Courtney and J.A. Moore, Toxicol. Appl. Pharmacol., 20, 396, 1971. T.M. Guenthner, J.M. Fysh and D.W. Nebert, Pharmacol., 19 12, 1979- G. Ideo, G. Bellati, Al Bellobuono, P. Mocarelli, A. Marochhi and P. Brambilla,- Clinica Chimica Acta, 120, 273, 1982. A.R. Isensee and G.E. Jones, Environ. Sei. Technol., 9, 668, 1975 E. E. McConnell, J.A. Moore, J.K. Haseman and M.W. Harris, Toxicol. Appl. Pharmacol., 44, 335, 1978 a. E.E. McConnell, J.A. Moore, and D.W. Dalgard, Toxicol. Appl. Pharmacol., 175, 1978 b. W.P. McNulty,K.A. Nielsen-Smith, J.O. Lay, D.L. Lippstreu, N.L. Kangas,^P.A. Lyon and M.L. Gross, 4F d . Chem. Toxic., 20, 371, 19 8 2 . I' 6268 I. Manara, P. Coccia and T. Croci, Drug Met. Rev., 13, 423, 1982. A.C. Marinucci and R. Bartha, Bull. Environm. Contain. Toxicol., 29, 326, 1982. J. Mes, D.J. Davies and D. Turton, Bull. Environm. Contain. Toxicol., 28 97, 1982. M. Meselson, P. O'Keefe and R. Baughman, In: Symposium on the use of herbicides in forestry, 91, February 21-22, 1978. M. Montagna, A. Fornari and S. Facchetti, In: Forensic Toxicology, 78, 1979 - J.R. Olson, M.A. Holscher, and R.A. Neal, Toxicol., Appl. Pharmacol., 55, 67, 1980. J. Pazderova, M. Nemcova, J. Pickova, L. Jirasek and E. Lucas, Arch. Environ. Health, 36, 5, 1981. A. Poland and E. Glover, Molec. Pharmacol., 17, 86, 1980. A. Poland and J.C. Knutson, Ann. Rev. Pharmacol. Toxicol.,22, 517, 19 8 2 . H. Poger, H. Buser, H. Weber, U. Zweifel and C. Schlatter, ^4 Experimentia, 4 484, 1982. I p ') a Oj R. C. Ramsey, J.G. Hefner, R.J. Karbowski, W.H. Braun and P.J. Gehring, Toxicol. App l . Pharmacol., 47, A162, 1979* S. L. Schantz, D.A. Barsotti and J.R. Allen, Toxicol. Appl. Pharmacol., 46, 180. 1979* S.L. Schantz and R.E. Bowman, The Toxicologist, Vol. 4, Abstract number 333, March, 1984- J.P. Van Miller, Doctoral Thesis, University of Wisconsin, 1981. J.H. Vinopal and J.E. Cassida, Arch. Environ. Contam. Toxicol. 1, 122, 1973. f 6270 A L A S T A IR W. M. H AY, P h . D . I. QUALIFICATIONS Dr. Hay is a lecturer on Chemical Pathology, Department of Chemical Pathology, Old Medical School, University of Leeds, Leeds, England. His Curriculum Vitae is attached. A list of seminars, meetings and awards is also attached. II. SUBJECT MATTER Dr. Hay will provide background testimony on a broad range of matters relating to Agent Orange, phenoxy herbicides, and their contaminants, including 2, 3, 7, 8-TCDD. Dr. Hay will discuss in detail his knowledge of the various phenoxy herbicides and their contaminants, including but not limited to the various aspects of: chemistry; biochemistry; manufacture and/or production; fate in the environment, animals, and humans; modes of exposure, i.e. absorption, ingestion and in halation, specifically by the veterans who served in Vietnam; toxicity; and the state of the medical and scientific literature at various times since at least 1957 forward. Dr. Hay's testimony regarding the medical and scientific literature will include an exposition of the definitions and 4 ' explanations, and their applicability to the troops exposed in Vietnam, of th< phenoxy herbicides and their contaminants, in 6272 the following areas: plant physiology; toxicology; neuro-toxi cology, both neurological and psychological; epidemiology; immunology; mutagenicity; teratology; embryotoxicity; reproductive toxicology; and carcinogenicity. III. SCIENTIFIC PRINCIPLES See General Statement of Scientific Principles and Assumed Facts attached. IV. SUBSTANCE OF OPINION Dr. Hay will testify to the following opinions : A. That phenoxy herbicides, including Agent Orange, and 2, 4, 5-T, and their contaminants, especially TCDD, 1. Highly toxic 2. Neurotoxic 3. Immunosuppressive 4. Teratogenic and Embryotoxic 5. Potentially Mutagenic 6 . Carcinogenic. B. That there is no "minimum effect" level for 2, 3, 7, 8-TCDD and all other dioxins or, in other words, there is no known "safe level" for any human intake of 2, 3, 7, 8-TCDD and all other dioxins. V. GROUNDS FOR EACH OPINION A. General The medical and scientific literature, attendance and participation in various symposia, review of various documents of certain defendants, personal research, and experience form the bases of whatever facts and opinions to which Dr. Hay will testify. B. More specifically, the phenoxy herbicides, including Agent Orange, 2,4,-D and 2,4,5-T and their contaminants, including dioxin, especially TCDD, are: 1. Highly toxic McConnell, E.E., et a l . Toxicology & Applied Pharmacology 44, 355-356 (1978); Schwetz, B.A., et al. Advances in Chemistry Series, ed. E. H. Blair, 120 55-69 (1973); Greig, J.B., et al. Food & Cosmetics Toxicology, 11,585-595 (1973); 2. Neurotoxic 3. Immunosuppressive / Kimmig, J. & Schultz, K. H. Dermatologica 115, 540-546 (1957); Bauer, et al. Archiv. Fuer Gewerbepathology un Gewerbehygin, 18,538-555 (1961) 4 Vos, J.G., & Moore, J.A. Internal Archives of Allergy and Applied Immunology 47,777-794 (1974); Faith, R.;E. , and Luster, M.I. Annals of The N.'Y. Acad, of Sciences, 320, 564-571 (1979) 4. Teratogenic and Embryotoxic 5. Potentially Mutagenic 6. Carcinogenic Neubert, D., and Dillmann, I. Naunym Schmiedebergs Archives and Pharmacology (Berlin) 272 (3), 243-264 (1972) Neubert, D . Environmental Health Perspectives 5, 67-79 (1973); Courtney, K.D., and Moore, J.A. Toxicology and Applied Pharmacology, 20, 396-403 (1971); Courtney, K.D. Bulletin of Environmental Contamination and Toxicology, 16, 674-681 (1976); Smith, F.A., et a l . Toxicology and Applied Pharmacology 38, 517-523 (1976) ; Moore, J.A., et a l . Environ mental Health Perspectives 5, 81-85 (1973); Sparschu, G.L., et al. Food and Cosmetic Toxicology, 9, 405-412 (1971); Roll, R. Food and Cosmetic Toxicology, 9,671-676 (1971) Rogers, A.M., et al., Mutation Research 105, 445-449 (1982); Bronzetti, G., et a l . in Chlorinated Dioxins and Related Compounds: Impact on the Environment (pergamon Press, Oxford, NY (1982) pp 429-436; Hay, A. in The Chemical Scythe (Plenum Press, 1982) pp. 43 Allen, et a l ., Chemosphere, 9,537-544 (1977) ; Kociba, R.J., et al. Toxi cology and Applied Pharmacology. 46, 279-:303 (1978); Anonymous. Bioassay of 2,3,7,8-tetrachlorodi- benzo-p-dioxin for possible carcino genicity (gavage study), National Cancer Institute DHHS Publication No. (NIH) 80-1757 (1980); Toth, K.S., et al. Nature (London) 278,548-549 (1979); Anonymous. National Cancer Institute Technical Report Series No. 123 (1979); Anonymous. Bioassay of a mixture of 1,2,3,6,7,8- and 1,2,3,7,8,9-hexachlorodibenzo-p- dioxin for possible carcinogenicity (gavage study), National Cancer Institute, Technical ReDort Series No. 198 (1980); Anonymous. Bioassav of a mixture of 1/2/3/6/7/8- and 1/2/3/7/8/9- ^ hexachlorodibenzo-p-dioxin for bd i possible ^carcinogenicity (dermal study), National Cancer Institute, Technical Report Series No. 202 (1980) Dr. Hay will testify to examples of the grounds which support the above, including: knowledge of spraying Agent Orange, especially its effect on the Vietnamese countryside; the purpose and historical tracing of the animal studies; historical tracing of the human data, including the various industrial incidenta.since 1949 (Hay, A. The Chemical Scythe, Plenum, N.Y. (1982) pp 95-146); references to specific documents such as the EPA Dioxin document (presently in draft form); various cancer epidemiology; (Hardell, L & Sandstrom, A. British Journal of Canc e r , 39_, 711-717 (1979) ; Hardell, et a l . British Journal of Cancer, 43, 169-176 (1981); Honchor, P.A. and Halperin, W.E. Lancet, I. 268-269 (1981); and Cook, R.R., Lancet, I. 618-619 (1981); pertinent teratology epidemiology (Hanity, J.A., et al., Science, 2 1 2 , 349-351 (1981); Field, B., and Kerr, C. Lancet I. 1341-1342 (1979)); various studie of the Vietnamese (Tung, T.T., LaRevue de Medicine, L4, 653-657 (1977)); especially reproduction toxicology (Constable, J. Report of the Workshop on Reproductive epidemiology. International Sym posium on Herbicides and Defoliants in War: The long term effects on Man and Nature. Ho Chi Minh City 13-20 January 1983; to be published in Herbicides in War. Ed. A.H. Westing, SIPRI); and those reports of the symptoms and diagnoses of the U. S. Vietnam veterans. C. The above will be relied upon to show that ther is no "minimum effect" level for 2,3J,7,8-TCDD or'other dioxins. 'S ai O ,Q Name : Alastair Watt M a c m t y r e HAY 21 April 1947 Marital Status: M a m ed Chi 1cren: 1 sen (Tom) Place of Birth: Glasgow, Scotland. Naticnali ty: British Degrees: B.Sc. (Hons), Chemistry IIA - London 1969 Ph.D., Eiochemistry, Lonccn 1973 Home Address: School House, Arthington Lane, Arthington, Leeds LS21 1PE England. Work Address: Department of Chemical Old Medical School, University of Leeds, Leeds LS2 9NL England. Pathology, Place of Secondary Education: Gifford Technical High School, Bulowavo, Zimbabwe (formerly Rhodesia) Present Appointment: University lecturer in Chemical Pathology since April 1979 (University of Leeds) Leeds, England. Former Appointments: Research Fellow - Zoological Soc. of London September 1972 - November 1977 Research Fellow - University of Leeds, Department of Animal Physiology and Nutrition December 1977 - March 1979 Societies: Biochemical Society Nutrition Society Expert Committees: PUBLICATIONS: 1983 EPA Review Panel on Dioxins for Environmental Criteria and Assessment Office. Books 1. Alastair Hay, The Chemical Scythe: Lessons of 2,4,5-T and Dioxin. Plenum Press. 265 pp. August 1982. 2. Sean Murphy, Alastair Hay and S t e v e n Rose. No Fire: No Thunder. The threat of chemical and biological warfare. Pluto Press. (To be published in January 1984). 135pp. i 6277 1. S i n c l a i r , A . J . , F i e n n e s , R.N.T.W.. Hay, A.W.M.. Watson. G ., C r a w f o r c , M.A.., & H a r t , M.G. L i n o l e n i c a c i d d e p r i v a t i o n i n C a p u c h i n m o n k e y s . P r o c . N u t r . S o c . , _3_3, 49A ( 1 9 7 4 ) . 2 . H a y , A . W . M . , S i n c l a i r , A . . J . , & Ray, W.G. Some u s e f u l t e c h n i q u e s in t h i n l a y e r c h r o m a to g r a p h y . J. Lab. P r a c t . 23, 433-484 (1974). 3. Hay, A.W.M. & Ray, W.G. A s i m p l e m a c r o t o m e . J . L a b . P r a c t . 24. 35 ( 1 9 7 5 ) . 4. Hay, A.W.M. C o m p a r a t i v e a s p e c t s o f v i t a m i n D t r a n s p o r t . In: Calcium R e g u l a t i n g Hormones (E xcerpta Medica, Amsterdam). The Proc. o f the 5th P a r a t h y r o id C o n fe r en ce , O x f o r d . - pp 405407 (1975). 5 . Hay, A. W. M. & W a t s o n , G. B i n d i n g o f 2 5 - h v d r o x y v i t a m i n t o p l a s m a p r o t e i n i n New Wor l d m o n k e y s . N a t u r e , 2 5 6 , 150 (1 9 7 5 ). 6 . Hay, A.W.M. The t r a n s p o r t o f 2 5 - h v d r o x y c h o l e c a l c i f e r o l i n a New Wo r l d mo n k e y . B i o c h e m . J . 1 5 1 , 1 9 3 - 1 9 6 ( 1 9 7 5 ) . 7 . Hay, A. W. M. & Watson-, G. The p l a s m a t r a n s p o r t p r o t e i n s o f 2 5 - h y d r o x y c h o l e c a l c i f e r o l i n mammals. Comp. B i o c h e m . B h y s i o l . 53E, 163-166 (1976). 8 . Hay, A. W. M. & W a t s o n , G. The p l a s m a t r a n s p o r t p r o t e i n o f 2 5 - h y c r c x y c h c le c a lc i f e r o l in f i s h , amphibia, r e p t i l e s and b i r d s . Comp. B i o c h e m . P h y s i o l . 53B, 1 6 7 - 1 7 2 ( 1 9 7 6 ) . 9. Hay, A.W.M. The t r a n s p o r t o f v i t a m i n D i n t h e G i a n t P a n d a . Trans. Zool. Soc. Lone., 33, 139-140. (1976). 10. Hay,A.W.M. Vitamin D t r a n s p o r t i n v e r t e b r a t e s . P roc. Anat. Soc. J. A nat. 1 2 2 , 195 (1 9 7 6 ) . 1 1 . Hay, A.W.M. A p o s s i b l e r o l e f o r v i t a m i n D-, i n v e r t e b r a t e e v o l u t i o n . P r o c . o f t h e 2nd I n t e r n a t i o n Workshop on C a l c i f i e d T i s s u e s . ( A b s t r a c t ) . I s r . J . Med. S c i . JJ2, 3 1 - 3 2 ( 1 9 7 6 ) . 1 2 . Hay, A. W. M. & W a t s o n , G. The b i n d i n g o f 2 5 - h y d r o x y c h o l e c a l c i f e r e and 2 5 -h y d r o x y e r g o c a lc if e r o l to t i s s u e b in d in g p r o t e in s in a New Wo r l d and an O l d Wo r l d p r i m a t e . Comp. B i o c h e m . P h y s i o l . 56B, 131-134 (1 9 7 7 ). 1 3 . Hay, A . W. M. , & W a t s o n , G. V i t a m i n D-, i n v e r t e b r a t e e v o l u t i o n . Comp. B i o c h e m . P h y s i o l . 56B, 3 7 5 - 3 8 0 ( 1 9 7 7 ) . 1 4 . Hay, A. W. M. & W a t s o n , G. B i n d i n g p r o p e r t i e s o f s e r u m v i t a m i n D t r a n s p o r t p r o t e i n s i n v e r t e b r a t e s f o r 24R, 2 5 - h y d r o x y c - h o l e c a l c i f e a nd 2 4 S , 2 5 - h y d r o x y c h o l e c a l c i f e r o l i n v i t r o . Comp. B i o c h e m . P h y s i o l . 58 B, 4 2 - 4 8 ( 1 9 7 7 ) . . 6278 1 5 . Hay, A . K . H . & W a t s o n , G. E v o l u t i o n o f v i t a m i n D serum, t r a n s p o r t p r o t e i n s i n v i t a m i n Dr B i o c h e m i c a l , C h e m i c a l and C l i n i c a l Aspects r e l a t e d to Calcium M etabolism (Ed. by Norman, A.W. e t a l ) W a l t e r de G r u v t e r , B e r l i n & New York (1977) pp 4S3 - 4 S 9 . 1 6 . Hay, A..W.M. V i t a m i n D a t A s i l o m a r , R e p o r t o f 3r d W o r k s h o p on V i t a m i n D. N a t u r e 2 6 6 , 1 7 - 1 8 ( 1 9 7 7 ) . 17. Hay, A.W.M. C o m b a t t i n g r i c k e t s . N a t u r e 2 7 0 , 259 ( 1 9 7 7 ) . 18. Hay, A.W.M. V i t a m i n D0 m e t a b o l i s m i n New Worl d p r i m a t e s . Proc. o f the 3rd I n t e r n a t i o n a l Workshop on C a l c i f i e d T is s u e s , I s r r a e l 6 - 9 t h March 1978 ( i n p r e s s ) . 1 9 . Hay, A. W. M. , D a r l i n g , M. , W a t s o n , G. R i c k e t s a nd v i t a m i n D m e t a b o l i s m i n p r i m a t e s . P r o c . N u t r . S o c . _3_7, 42A. ( 1 9 7 8 ) . 2 0 . Hay, A.W.M. T e t r a c h l o r o a i b e n z o - p - d i o x i n r e l e a s e a t S e v e s o . D isasters 1(4) 289-308 (1977). 2 1 . Hay, A.W.M. I d e n t i f y i n g c a r c i n o g e n s . N a t u r e , (1977) . 269, 468-470 2 2 . Hay, A.W.M. S e v e s o : No a n s w e r s y e t . D i s a s t e r s 2_. 1 6 3 - 1 6 8 (1978) . 2 3 . Hay, A.W.M. V i t a m i n D t r a n s p o r t ( R e v i e w ) . C . R . C . Handbook s e r i e s in N u t r it io n and Food (in p r e ss) . 2 4 . Hay, A.W.M. R e s u r g e n c e o f V i t a m i n D. N a t u r e , 426-427 (1978). 273, 2 5 . Kay, A.W.M. H a l o c e n a t e a H y d r o c a r b o n E f f e c t s . N a t u r e , 2 7 4 , 533-534. (1978).' 2 6 . Hay, A.W.M. & J o n e s , G. The e l u t i o n p r o f i l e o f v i t a m i n m e t a b o l i t e s on S e p h a a e x LH20. C l i n . Chem. 2_5_, 4 7 3 - 4 7 5 (1979) . 2 7 . Hay, A.W.M. A c c i d e n t s i n t r i c h l o r o p h e n o l p l a n t s : a n e e d f o r r e a l i s t i c surveys to a s c e r t a in r i s k to h e a lth . Proc. of N.Y. Acad, o f S c i . 320, 321-324 (1979). 2 8 . R i v e r s , J . P . W . , F r a n k e l , T . L . , J u t t l a , S . , & Hay, A.W.M. V i t a m i n D i n th e N u t r i t i o n o f t h e C a t . P r o c . N u t r . Soc-. 38., 36A ( 1 9 7 9 ) . 2 9 . Hay, A.W.M., Hassam, A . G . , C ra wfo rd , M.A., S t e v e n s , P . A . , Mawer, E . B . & C a s e , L. The a b i l i t y o f l a , 2 5 - d i h y d r o x y c h o l e c a lc ife r o l to a lter the fa tty acid composition of phospnoglyceric in r a t i n t e s t i n a l mucosa and smooth m uscle in V itam in D Basic? R e s e a r c h and i t s C l i n i c a l A p p l i c a t i d n (Ed. by Norman, A.W., e t a l ) . Walter de Gruyter, B e r lin , & N.Y. (1979). / G279 30. Care. A.D., P i c k a r d , D.W., Ross, R ., Hay, A.W.M., G a r ei, J.M. & Recel, J. A comparison of the e f f e c t s of 25,26-dihydrcxyc h o i e c a l e i f e r o l (25,26-DHCC) and 24,25-DHCC on c a l c i t o n i n secretion rate in vitamin D depleted p ic s. J. Endocrinoloay 85, (2), 5 4p-55p (1 9 6 0 ). 31. F l e m i n g , J . C o op e r, E . H . , Hay, A.W.M., Morgan, D . E . , and T a r a p i a , L. Tubul o p r o t e i n u n a i n C a n c e r C h e m o t h e r a p y . La R i c e r c a C l i n La b. _1_0, 1 3 5 - 1 4 1 ( 1 9 8 0 ) . 32. Hay, A. C o m p l e c a t i o n o f v i t a m i n D m e t a b o l i s m s t i l l i n c r e a s m e Nature, 218, 509-510 (1979). 3 3 . Hay, A.W.M. E s s e n t i a l f a t t y a c i d r e s t r i c t i o n i n h i b i t s vitamin D dependent Calcium absorption. LiDids. 15, 251-4 (1980). 34. I n t e s t in a l, la, 2 5 -d ih v d r o x y c h o le c a lc ife r o l-d e p e n d e n t ca lciu m a b s o r p t i o n i n h i b i t e d by e s s e n t i a l f a t t y a c id r e s t r i c t i o n . P r o c e e d i n g s o f N u t r . S o c . G9, 89A ( 1 9 8 0 ) . 35. H a l o g e n a t e d h y d r o c a r b o n . Hay, A.W.M. i n 1981 EST Y e a r b o o k of Science & Technology. McGraw-Hill ppl98-200. 3 6 . Hay. A.W.M. E x p o s u r e t o TCDD: t h e h e a l t h r i s k s . C h lo r in a t e d d i o x i n s and r e l a t e d compounds. Impact on the E n v i r o n m e n t . O. H u t z i n g e r , e t a l . P e r g a mo n P r e s s , O x f o r d , N.Y. (1982). 37. Fl em i n g , J . J . , C h i l d , J . A . , Cooper, E .H ., Hay, A.M., Morgan, D.B. & P a r a p i a , L. R e na l t u b u l a r damage w i t h o u t glomeular damage a f t e r c y t o t o x i c drugs and a m in o g ly c o sid e B i o m e d i c i n e _3_3, 2 5 1 - 2 5 4 ( 1 9 8 0 ) . 3 8 . Hay, A l a s t a i r . New p a t h w a y s f o r c h l o r i n a t e d d i o x i n s . Nature. 294. 514-515 (1981). 3 9 . Hay, A.W.M. , Mawer, E . B . , H a s s a n , A . G . , C r a w f o r d , M.A. & S t e v e n s , P.A . The R o l e o f e s s e n t i a l f a t t y a c i d s i n v i t a m i n D dependent calcium absorption in the in t e s t in e . Proc. of 5th v i t a m i n D w o r k s h o p . W i l l i a m s b u r g , U . S . A . New i n V i t a m i n D, c h e m i c a l b i o c h e m i c a l a n d c l i n i c a l e n d o c r i n o l o g y o f ca lciu m m etabolism . W alter de G uyter. B e r lin , N . Y . (1982) pp309-311. 4 0 . Hay, A l a s t a i r . V i t a m i n D: s u n l i g h t and p r e c u r s o r s . N ature. 2 9 7 . 364 ( 1 9 8 2 ) . 4 1 . S h e l t a w v , M., Hay, A.W.M., H u l l i n , R . P . , and Morgan, D. B. V i t a m i n D2 a nd D 3 i n t h e n u t r i t i o n o f e l d e r l y . C l i n . S c i . 62, 15-16 (1982) (a b stra ct). 42. Hay," A. H e r b i c i d e s , t r i c h l o r b ' p h e n o l s and s o f t t i s s u e ' sarcomas. Lancet I, 1240 (1982). I 6280 5 4 2 . h a y , A. I t k i l l s w e e d s , b u t w h a t a b o u t p e o c l e ? New S c i e n t i s t . _9, N o . 1314 p p l S S - 1 6 1 ( 1 9 6 2 ) 4 4 . Hay, A.., Murphy, S . . R o b i n s o n , J . P . & R o s e , S . The p o i s o n c l o u d h a n g i n g o v e r E u r o p e . New S c i e n t i s t 9 3 . No. 1296 ppc 3 0 - 6 35 " (1 982) 4 5 . Hay, A. E x p e r i m e n t a l T o x i c o l o g y and c y t o g e n e t i c s : an o v e r v i e w . i n " H e r b i c i d e s a nd War" t o be p u b l i s h e d by Stockholm I n t e r n a t i o n a l Peace R esearch I n s t i t u t e 1984 A. Vies t i n g . E d i t . 4 6 . Hay, A. The M u t a g e n i c P r o p e r t i e s o f 2 , 3 . 7 , 8 - T e t r a c h l o r o a i b e n z o p -a io x in in "Chlorinated D ioxins and Dibenzofurar.s in the T o ta l Environment. Vol I I . E d i t , by K eith . L.H. e t a l to be p u b lish e d in 1984. 4 7 . J o n e s , C ., Hay, A.W.M., Morgan, D . 3 . , and H u l l i n , R .P . Response of the serum 25-hyaroxy vitam in D to minimal exposure to sunshin in p atien ts in a long stay mental h o s p i t a l . ( a b s t r a c t ) Tc be p u b l i s h e d in November 1983 P r o c e e d i n g s o f t h e UK Bone a n d T o o t h S o c i e t y . 4 8 . S h e l t a w y , M., Newton, H., Hay, A . , and Morgan, D.B. and H u ll, R.P. The c o n t r i b u t i o n o f d i e t and s u n l i g h t t o th e p l a s m a 2 5 - h y d r o x y v i t a m i n D. ( a b s t r a c t ) t o b e p u b l i s h e d i n No v e mb e r 1 9 3 3 . P r o c e e d i n g s o f UK Bo ne and T o o t h S o c i e t y . 4 9 . F e e l y , M., Hay, A . , C l a r k e , N . , P r i c e , D . , an d C o c k e , J . "mini-Dose" Pher.obarbitone: A u s e f u l marker o f compliance s u b m i t t e d t o IUPHAJR 9 t h I n t e r n a t i o n a l C o n g r e s s o f P h a r m a c o l o g y . 5 0 . S h e l t a w y , M . , N e w t o n , H. , Hay, A . , Mo r g a n, D . B . , a nd H u l l i n , R.I The c o n t r i b u t i o n o f d i e t a r y v i t a m i n D and s u n l i g h t t o th e plasma 25-hydroxv vitam in D in the e ld e r l y . Submitted to C lin ica l Nutrition/Human N utrition. Other S c i e n t i f i c Art c l e s and Book Reviews 1 . Hay, A l a s t a i r . T o x i c c l o u d o v e r S e v e s o . N a t u r e 2 5 2 , 6 3 6 - 6 3 8 (1976). 2 . Hay, A l a s t a i r . R e c i p e f o r l e s s d i s a s t e r . N a t u r e 2 6 3 , 270 (1976) 3. Hay, A l a s t a i r . S e v e s o : t h e a f t e r m a t h . N a t u r e 2 6 3 , 5 3 8 - 5 4 0 . (1976) 4 4 . Hay, A l a s t a i r . Towards a n t i c i p a t i n g d i s a s t e r . N a t u r e 264 310 (1976) . i 5. Hay, A l a s t a i r . S e v e s o : p u t t i n g t i t r i g h t . N a tu r e 2 6 4 , 504 (1976) r 6 . Hay, A l a s t a i r . S e v e n months o n . 265, N a t u r e , 490 ( 1 9 7 7 ) . R281 . A l a s t a i r -lav, S e v e s c : D i o x i r . d a m a o e . Na t u r e 2 6 6 , 7 - S ( 1 9 7 7 ) . 8 . Hay, A l a s t a i r . Zoo s t o r y . N a t u r e 2 6 7 , 9 4 - 9 5 ( 1 9 7 7 ) . 9. Hay, A l a s t a i r . I t a l y : D i s t a n t drums. N a tu r e 2 6 7 , 301 ( 1 9 7 7 ) . 10. Hay, A l a s t a i r . S e v e s o s o l i c i t u d e . N a t u r e . 2 6 7 . 3 8 4 - 3 8 5 (1577) 11. Hay, A l a s t a i r . An a i d t o d e v e l o p m e n t ? N a t u r e , 2 6 7 , 571-572 (1977) 12. Hay, A l a s t a i r . R o c h e ' s r e p l y . N a t u r e , 2 6 7 , 749 (1977) 13. Hay, A l a s t a i r . T w el v e months a f t e r S e v e s o . N a t u r e , 268 90 (1 9 7 7 ) . 14. Hay, A l a s t a i r . S e v e s o Row. N a t u r e , 2 6 8 , 395 (1 977) 15. Hay, A l a s t a i r . T im e ly d e l a y . N a t u r e , 2 6 9 , 279 ( 1 9 7 7 ) . 16. Hay, A l a s t a i r . I n f o r m i n g on 2 , 4 , 5 - T . N a tu r e , 2 6 9 , 749^-750 (1977) . 17. Hay, A l a s t a i r . H e a l t h and s a f e t y 3 y e a r s on. N a t u r e , 2 7 0 , 91-93 (1977) . 18. Hay, A l a s t a i r . C o m b a t t i n g r i c k e t s . N a t u r e , 2 7 0 , 289 ( 1 9 7 7 ) . 19. Hay, A l a s t a i r . S c i e n c e Key t o V ie t n a m s R e co v e ry , N a t u r e 2 7 1 , 101-2 (1978). 20. Hay, A l a s t a i r . S c i e n c e h e l p s t o r e b u i l d Vietnam. N ature, 271, 101-102 (1978) . 21. Hay, A l a s t a i r . D io x in m e e t in g recommends c a n c e r s t u d v . Nature. 221. 202 (1978). 2 2 . Hay A l a s t a i r . V i e t n a m s D i o x i n P r o b l e m . N a t u r e , 2 7 1 , 5 9 7 - 5 9 8 (1978) . 23. Hay, A l a s t a i r . V ie tn a m c a l l s i t s s c i e n t i s t s t o arms. 2 7 3 , 94-95 (1978). 24. Hay, A l a s t a i r . I s r a e l ' s S c i e n t i s t - P r e s i d e n t R e s i c n s . Nature, 2 7 3 , 93 ( 1 9 7 8 ) . 25. Hay, A l a s t a i r . V ietnam e x t e n d s s c i e n t i f i c l i n k s . N a tu r e . 273, 419 (1978) . 26. Hay, A l a s t a i r . Commonwealth S c i e n c e C o u n c il C o o r d in a t e s a p p r o a c h t o UNCSTD. N a t u r e , ^ 2 7 3 , 6 9 7 - 6 ' 9 8 ( 1 9 7 8 ) . 27. Hay. A l a s t a i r . Company's c l a i m s p a r k s f r e s h c o n t r o v e r s y over S e p e s o . Nature, 274, 108 (1 9 7 8 ) . 6282 Hay, A l a s t a i r . N e u r o t o x i n s rr.av g o u n r e c o c r a s e d . N a t u r e . 274, 206 (1978). 29. Hay, A l a s t a i r . D i o x i n s o u r c e i s ' s a f e ' . N a t u r e , 2 7 4 , 52 6 (1578). 30. Hay, A l a s t a i r . V i e t n a m s t i l l l o c k i n g f o r f o r e i g n a i d . Nature, 275, 6-7 (1978) 31. Hay. A l a s t a i r . V i e t n a m ' s s c i e n t i s t s w a i t f o r b o c k s and equipment. Nature, 276, 203 (1978). 3 2. Hay, A l a s t a i r . D i o x i n w o r k s h o p . N a t u r e , 2 7 6 , 304 . ( 1 9 7 8 3 3 . Hay A l a s t a i r . H e a l t h a nd s a f e t y r e s e a r c h g e t s u n d e r w a y . Nature, 276, 435-437 (1973). 34. Hay, A l a s t a i r . S w i t z e r l a n d t o c o n s i d e r r e v i s e d a u i d e l i n e s . Nature, 277, 341-342 (1979). 35. Hav, A l a s t a i r . I t a l i a n Commission c o v e r e d u d S e v e s o d e l a y s . Nature, 277, 588-589 (1979). 36. Hay, A l a s t a i r . D i o x i n : t h e 10 y e a r b a t t l e t h a t b eg a n with Agent Orange. Nature. 278, 108-110 (1979). 3 7 . Hay, A l a s t a i r . UK m i n i s t r y g i v e s g r e e n l i g h t t o 2 , 4 , 5 - T . Nature, 2 7 8 , 388 (1 9 7 9 ). 38. Hay, A l a s t a i r . C o m p l e x i t i e s o f v i t a m i n D m e t a b o l i s m s t i l l increasing. Nature, 278, 509-510 (1979). 39. Hay, A l a s t a i r . C r i t i c s c h a l l e n g e d a t a t h a t l e d t o 2 , 4 , 5 - T bar,. N ature, 2 7 9 , 3 ( 1 9 7 9 ) . 40. Hay, A l a s t a i r . S k i n t o x i c o l o g y . N a t u r e . 2 7 9 , 375 ( 1 9 7 9 ) . 4 1 . Kay, A l a s t a i r . US D e f e n s e D e p a r t m e n t d e s t r o y s e v i d e n c e o f Vietnam d e v a s ta tio n . Nature, 279, 662 (1979). 4 2 . Hay, A l a s t a i r . What c a u s e d t h e S e v e s o e x p l o s i o n ? N a t u r e , 273, 582-583 (1979). 4 3 . Hay, A l a s t a i r . US s c i e n t i s t s t o j o i n I t a l i a n s i n d i o x i n s t u d y . N a tu r e . 277. 338 ( 1 9 7 9 ) . 44 . Hay, A l a s t a i r . R i c k e t s u n d e r c o n t r o l a g a i n i n UK. N a t u r e , 279, 749 (1979). 45. Hay, A l a s t a i r . Vietnam v e t e r a n s s t u d i e d fo r h e r b i c i d e . exposure. Nature, 279, 667. (1979). 46. Hay, A l a s t a i r . Handle us w i t h c a r e . N a t u r e , 2 8 0 , 8 - 9 (1979) . f 6283 wo 47 . Hay, A l a s t a i r . Me l f o r m a t i o n s a t b i r t h i n c r e a s e d i n S e v e s o l a s t y e a r . . Nature , 280 , 184 (1979) . 48 . Hay, A l a s t a i r . Pr e s s ba n ne d from c o n f ( p r e n c e . N a t u r e , 280. 623 (1979), 49. Hay, A l a s t a i r . As b e s t o s : k i l l e r d u s t . s a y s b o o k . N a t u r e , 281, 172 (1979) 50 . Hay, A l a s t a i r . Se v e s o : t h e c r u c i a l q u e s t i o n o f r e a c t o r s a f e t y N a t u r e . 2 8 1 , 52!1 ( 1 9 7 9 ) . 5 1 . Hay, A l a s t a i r . D i s p u t e o v e r Dow C h e m i c a l s t h e o r y o f d i o x i n traces. Nature, 2S1, 619-620 (1979). 5 2 . Hay, A l a s t a i r . UK t o t i g h t e n a s b e s t o s c o n t r o l s . N a t u r e , 282, 5 (1979). 5 3 . Hay, A l a s t a i r . EPA p a n e l r e c o mme n d s p o s t p o n e m e n t o f 2 , 4 , 5 - T h e a r i n g s . N ature. 282, 124 (1 9 7 9 ). 54. Hay, A l a s t a i r . S h o r t te r m t e s t s ca n p r e d i c t p o t e n t i a l c a r c in o g e n s , sa y s s t u d y . Nature, 2 8 2 , 664 (1 9 7 9 ). 55. Hay, A l a s t a i r . D i o x i n a s a h e a l t h h a z a r d . Book R evie w . Nature, 283, 229-230 (1980). 56. Hay, A l a s t a i r . H e a l t h m o n i t o r i n g e n d a n g e r e d a t S e v e s o . Nature, 283, 237 (1930). 57. Hay, A l a s t a i r . D io x in d e t e c t i o n . N ature, 2 8 3 . 426 (1 9 8 0 ). 58. Hay, A l a s t a i r . Study f i n d s m a l n u t r i t i o n i n 7% o f e l d e r l y . N a t u r e , 283., 612 (1980) . 59 Hav, A l a s t a i r . C h e m ic al company s t u d y shows no d i o x i n h a z a r d . N a t u r e , 2S 3 , 613 ( 1 9 8 0 ) . 6 0 . Hay, A l a s t a i r . Chem ic al company s u p p r e s s e s d i o x i n r e p o r t . Nature, 284, 2 (1980). 61. Hav, A l a s t a i r . D io x in and 2 , 4 , 5 - T : what a r e t h e r i s k s ? Nature, 284, 111 (1980). 62. Hav, A l a s t a i r . The C IA 's t o x i c a g e n t s . N a t u r e , 2 8 4 . 296 (1980) . 63 . Hay, A l a s t a i r . C o a l i t e h e a l t h s u r v e y t a l k s . Nature, 2 8 4 . (1980) . 64 . Hay,* A l a s t a i r . Red f a c e s (and h o t t e m p e r s ) on 2 , 4 , 5 - T . Nature, 2 8 6 , 97 (1980). 65. Hay, A l i s t a i r . A p l e a f o r 2 , 4 , 5 - T . N a tu r e , 2 8 7 , 6 5 9 - 5 7 0 (1980) . c 6 . Hay, A l a s t a i r . H e r b i c i d e s a f e t y : a i l l o f H e a l t h . N a t u r e , 2 8 9 , -i - 5 (19 3 1 ) . 67 . Hay, A l a s t a i r . R i c k e t s a t b a v . N a t u r e , 2 9 , 113 (1931) . 6 8 . Hay, A l a s t a i r . C h l o r i n a t e d d i o x i n s and t h e e n v i r o n m e n t . Nature, 289, 351-352, (1981). 69 . Hay, A l a s t a i r . S e v e s o : t h e i n t r i g u e and t h e i n f i g h t i n g . Book R e v ie w . N a t u r e , 2 9 0 , 7 1 - 7 2 (1961) . 7 0 . Hay, A l a s t a i r . D i s p o s i n g o f d i o x i n s by o x i d a t i o n . Nature, 290, 294, (1981). 71. Hay, A l a s t a i r . S e c r e c y a t C o a l i t e . Nature, 2 9 0 , 729, (1981) . 7 2 . Hay, A . , Murphy, S . , R o b i n s o n , J . P . On C h e m i c a l War. Nature, 294, 204 (1981). 7 3 . Hay, A l a s t a i r . S p o t t h e p o t e n t i a l c a r c i n o g e n . N a t u r e , 296, 100, (1982) . 74. Hay, A l a s t a i r . R e l a t i n g t o h a l e n a t e d h y d r o c a r b o n s . Nature, 296, 688 (1982). 75 . Hay, A l a s t a i r . C h e m i s t r y a t War. N a t u r e , 2 9 3 , 2 0 5 - 2 0 6 (1982). 7 6 . Hay, A l a s t a i r . The o f f i c i a l ' s book o f r i s k y b u s i n e s s . Book Review. Nature, 301, 640 ( 1 9 8 3 ) . 7 7 . Hay, A l a s t a i r . D e f o l i a n t s i n V ietnam: t h e l o n g term e f f e c t s . Nature, .302, 208 -2 0 9 (1983) . 78. Hay, A l a s t a i r . Empowered t o s e t s t a n d a r d s . Book r e v i e w . Nature, 305. 77 (1983) . 7 9 . Hay, A l a s t a i r . . .a nd i t s c o n t r o l . J o u r n a l R e v ie w . N a t u r e . 305, 486 ( 1983) . 8 0 . Hay, A l a s t a i r . F r e sh s u p p o r t f o r a p ia n o r i g i n . N a tu r e . 306. 8 (1983). f 6285 HAY, A l a s t a i r W .M . Additional Papers 1. Paper: " R e la tio n s h ip between Sex Hormones and F r u c to s e Metabolisms in Rat L iv e r" ; P resented a t N u t r it io n S o c ie ty , London, December 7, 1972. 2. P a r t i c i p a n t : I n t e r n a t i o n a l Agency f o r R e s e a r c h on C a n c e r , NIEHS/IARC Working Group on th e C o o rd in a tio n o f E p id e m io lo g ic a l S t u d ie s on the Long-Term Hazards of C hlorinated Dibenzo D io x in s-C h lo rin ated Dibenzo Phurons; Lyon, Lyon, France, January 10-11, 1978. 3. Member: P a n e l on Human O b s e r v a t i o n o f t h e C o n s e q u e n c e s o f Dioxon Exposure; Meeting: I n t e r n a t i o n a l Symposium on C h lo rin a te d Dioxins and Related Compounds, A rlin g to n , V ir g in ia , O ctober, 1981. 4. P ap er: "The Role o f Membrane L i p i d s i n t h e E x p r e s s i o n of V itam in D Function in the In te stin a l Nucosal Cell"; Presented at the Biochemical Society, London, December, 1981. 5. Paper: "The M anufacture of 2 ,4 ,5 - T r i c h lo r o p h e n o l and i t s S o c ial Consequences"; Presented a t the Royal Society of Chemistry, Education D ivision Meeting, Leeds, England, September, 1981. 6. P r e s e n t a t i o n : "Renal T o x ic ity to th e Y o rk sh ire R egional H ealth A u th o rity Meeting on A spects of P a th o lo g y :; H a r ig a t , Ja n u ary , 1980. 7. P a p e r : "TCDD M u t a g e n i c P r o p e r t y " ; P r e s e n t e d a t t h e I n t e r n a t i o n a l Symposium on H e r b ic i d e s and D e f o l i a n t s i n War; Long-Term E f f e c t s on Man and N a t u r e ; h e l d i n Ho Chi Minh C i t y , V i e t n a m ; A l s o , r e p e r t o i r e of working group on e x p e rim e n tal to x ic o lo g y and c y to g e n t ic s a t t h i s Conference. I 6287 HERBERT KAYE, P h .D . I . QUALIFICATIONS Dr. Herbert Kaye, Ph.D., is a psychologist in the Department of Ps yc h o lo g y a t t h e S t a t e U n i v e r s i t y of New York a t S t o n e y b r o o k , Long I s l a n d and a v i s i t i n g A s s o c i a t e P r o f e s s o r i n t h e D e p a r tm e n t o f P s y c h i a t r y a t New York U niversity Medical C enter. See attach ed curriculum v ita e . I I . SUBJECT MATTER OF TESTIMONY Dr. Kaye w i l l t e s t i f y co ncerning the s i g n i f i c a n c e of a b a t t e r y of q u a n ti ta t iv e neurophysiological t e s t s c a lle d neurom etries which w ill be performed on v a r i o u s p l a i n t i f f s . The p r o c e d u r e s were d e ve lope d i n p a r t by Dr. Kaye i n c o n j u n c t i o n w ith m e d ic al and p s y c h o l o g i c a l r e s e a r c h e r s from t h i s and o t h e r c o u n t r i e s . He w i l l t e s t i f y t h a t n e u r o m e t r i e s , on which he h as w r i t t e n extensively, is a sophisticated battery of e le c tric a l te sts in use for about f i f t y y e a r s , w h ic h a r e h i g h l y e f f i c i e n t i n t h e d e t e r m i n i n g c o r t i c a l EEG and evoked responses. Dr. Kaye w i l l e x p la in th e model usdd in the c o m p u te riz a tio n a g a in s t which t h e t e s t r e s u l t s a r e compared and w i l l e x p l a i n how d e v i a t i o n s from normal produce c e rta in e ffe c ts. Dr. Kaye w i l l a ls o d is c u s s th e mechanism by which t o x in s produce these a l t e r e d re s p o n s e s , and what e f f e c t those a l t e r e d responses have upon the in d iv id u al v eteran s at p rese n t, and the prognosis for any a d d itio n a l changes or d e te r io r a ti o n in the fu tu re based upon an assumed bicaccumulation io f th e t o x ih m a t e r i a l s i n th e system . In doing s o , he w i l l r e l y on h i s e x p e r i e n c e i n d i a g n o s i n g many V ie tn am v e t e r a n s e x p o s ed t o Agent Oran ge . 1 I' I l l GENERAL S C I E N T I F I C P R I N C I P L E S RELEVANT TO AREA: The s c i e n t i f i c p r i n c i p l e s a r i s e from t h r e e g e n e ra l d i s c i p l i n e s : neurophysiology, mathematics, and neuropsychology. The a re a of neurophysiology in c lu d e s th e work on neuro-anatom y, neurochemistry, neuropharmacology, and applied or c l i n i c a l electro p h y sio lo g y . The work i n m ath e m a tic s r e p r e s e n t s m u l t i v a r i a t e s t a t i s t i c s . The work in neuropsychology includes d i r e c t and i n d ir e c t brain-behavior research and clinical diagnostics. The n e u r o p h y s i o lo g i c a l b a s i s of th e development of n e u ro m e trie s i s p r e s e n te d i n Volumes I and I I of F u n c t io n a l N e u r o s c i e n c e s , p u b lis h e d i n 1977 by Lawrence Erlbaum A s s o c i a t e s , p u b l i s h e r s , H i l l s i d e , New J e r s e y . However, th is work rep re sen ts an in te g ra tio n of research and a p p lic atio n s in the n e u r o s c i e n c e s o v e r a p e r i o d f o u r d e c a d e s , i n i t i a t e d w i t h t h e s e m i n a l EEG work of Gibbs (s e e , f o r example, A tla s of E le c tro e n c e p h a lo g ra p h y , Cambridge, M a s s a c h u s e t t s , A dd i s o n -W e s le y ) W. Gray W a l t e r ( s e e , f o r e x am pl e, E lectronic E ngineering, 1943, 16, pp. 9-13) ahd going through the s p e c if ic and e x te n s iv e q u a n t i t a t i v e work of Matousek and P e te r s o n (Automation of C l i n i c a l E l e c t r o e n c e p h a l o g r a p h y , New Yo rk , Raven P r e s s , 1973, pp . 75-1 02) and c u r r e n t work by q u a n t i t a t i v e e l e c t r o p h y s i o l o g i s t s su ch a s A. S. G e v i n s , C. S h a g a s s , Th e od o re G a s s e r , Enoch C a l l o w a y , T. M. I t i l , L. G o l d s t e i n , and others. (See, for example, Neuro-psychopharmacologv, Proceedings of the Tenth Congress of the Collegium In te rn atio n ale Neuro-psycho-psychopharmacologicum, I Quebec, J u l y 4 - 9 , 19 76 , e d i t e d by P. D e n i k e r , C. Radouco-Thomas and A. V i l l e n e u v g , Volume I I ; and P. Kelloway and Ingemar P e t e r s o n , e d i t o r s , Q u a n t i t a t i v e A n a l y t i c S t u d i e s i n E p i l e p s y , Raven P r e s s , New Y o r k , 1 9 7 5 ) . The c l i n i c a l d e s c r i p t i o n and o r i g i n a l v a l i d a t i n g s t u d i e s were p u b l i s h e d by E. R. J o h n , e t a l . , i n S c i e n c e , Volume 196, 1977. S e v e r a l ad d itio n al stu d ies u t i l i z i n g the neurom etries technology have been published and r e f e r r e d in i n v it e d a r t i c l e , p r e s e n t a t i o n , c h a p te r s , review s, e tc . I n e s s e n c e , t h e work i n q u a n t i t a t i v e e l e c t r o p h y s i o l o g y p r o v i d e s a much more r e l i a b l e n u m erica l in d ex in g of v a r i a b l e s p r e v i o u s l y and c u r r e n t l y c o n s id e re d to be of c l i n i c a l sig n ific a n ce to the n eu ro lo g ist and n e u ro p s y c h ia tris t, t h a n may b e o b t a i n e d from c o n v e n t i o n a l EEG t r a c i n g s t h a t a r e v i s u a l l y i n s p e c t e d and i n t e r p r e t e d . This l a t t e r tech n iq u e i s c u r r e n t l y the only o th e r means fo r a s se s s in g the dynamic fu n ctio n in g b r a in from an e le c tr o p h y s io lo g ic a l prospective. The m athem atical p r i n c i p l e s employed a re th o se p e r t a in i n g to i n f e r e n t i a l s t a t i s t i c s , p r o b a b i l i t y theory and m u l t i v a r i a t e v e c to r c o n s tr u c ti o n . The mathematics developed fo r neurom etries were done in conjunction with work and a s s is ta n c e from P ro fe sso r John Pukey, P h .D ., one of the c o u n tr y 's o u t standing s t a t i s t i c i a n s , and with the a s s is ta n c e of Dr. Paul Easton, a mathe m a tic ia n . The m athem atical s t r a t e g i e s employed to reduce the huge amount of d ata to the v a ria b le s employed in the neurom etries b a tte ry a re stan d ard . However, these d a ta , fo r any i n d iv id u a l, a re f u r t h e r transform ed in a manner i d e n t ic a l to the transform ations used in making the o r ig in a l se t conformed to a Gaussihn d i s t r i b u t i o n , and t h i s , then* provides the domparison to the -3 - e ig h t h r e le v a n t norm . (S e e J o h n , e t a l . , S c i e n c e , V olum e 2 1 0 , 1 9 8 0 ) . Neuropsychological lite ra tu re represents the third strand. This r e p r e s e n t s the melding of b r a i n e le c tr o p h y s io l o g y and o t h e r n e u r o p h y s io lo g ic a l techniques with those of psychology, or the study of m ental and behavioral p r o c e s s e s . There i s a huge l i t e r a t u r e in the a r e a , and r e c e n t work by such re se a rch ers as Gevins, G alin, Tucker, Thatcher, Needieman, and others, as w ell as those s t u d i e s of Dr. Kaye and h i s s tu d e n ts and c o lle a g u e s indicate that quantitative electrophysiology is valuable in diagnosing underlying cortical processes serving certain behaviors. IV. SUBSTANCE OF OPINION1 1. Agent Orange rep re sen ts a neurotoxic agent th a t works in d ire c tly by a f f e c t i n g l i v e r f u n c t i o n and the l i v e r ' s p ro d u c tio n of heme; and in doing so makes an i n d i v i d u a l , so a f f e c t e d , v u ln e r a b le to neurohypoxia. 2. Agent Orange may a l s o work a t a l o c a l l e v e l on enzymes r e l e v a n t to the pro d u ctio n and m o b iliz a tio n s of n 'e u r o tr a n s m itte r s . 3. Agent Orange, which is l i p i d , so lu ab le, is l ik e ly to be stored in myelin and o th er f a t t y m a t e r i a l and i s c o l l e c t i v e l y "time re le a s e d " under "stress". 4. Storage is l i k e l y to be g r e a te r in the long f i b e r t r a c t s , such as the major pathways from spinal cord to peripheral cutaneous receptors, pathways from f ro n ta l c o r t i c a l regions to the thalimus and in sp in al c o rtic a l motor pathways. 5. Changes in c o r t i c a l f u n c tio n in g , r e p r e s e n t e d by each EEG's slow ing, rep resen t breakdown of neural m etabolic function occurring as a r e s u lt of progressive neurotoxic assault. 6. Changes jin* c o r t i c a l f u n c t i o n i n g r e p r e s e n t e d by i n t e r - h e m i s p h e r i c asymmetries and wave-shape incoherence re p re s e n t |the d i s r u p t io n of neural -4- 6291 timing e ith e r through the breakdown of c o r t i c a l p acers, or through the fa ilu re of tra n s c o rtic a l communication via the corpus collosum. 7. The o c c u r r e n c e of sharp-wave a c t i v i t y i s caused by d i s r u p t i o n of i n h ib i to r y n e u ro tr a n s m itte r s and r e p r e s e n ts a mechanism th a t can p a r t i a l l y a c c o u n t f o r mood l a b i l i t y , which a l o n g w i t h s e l e c t i v e s u p p r e s s i o n of f r o n t a l lobe fu n ctio n would provide the b a s is fo r behavioral d i s c e n t r o l . V. GROUNDS FOR Mb' OPINION ' A r e c e n t study by Needleman (Acta P s y c h i a t r i c a - S c a n d i r . a v i c a , 19S3, Supplement No. 303, pp. 26-37) i n d i c a t e s t h e a b i l i t y to u t i l i z e s im p le q u a n t i t a t i v e EEG s p e c t r a l m e a s u r e s a l o n g w i t h t h e p a c . h o l c g i c a l m ea s u r es to c l a s s i f y c h ild re n from the "normal" p o p u latio n t ' have high and low lead le v e ls (using dentyne lead l e v e l s ) . The d is r e im in a tin g v a r i a b le s fo r the EEG wer e t h e v a r i a b l e s a s s o c i a t e d i n o u r and i n c o n v e n t i o n a l EEG work w i t h a b n o r m a li ti e s ; t h a t i s , e x c e s s iv e slow wave energy. Recent work in our ev a lu a tio n u n it has examined the abnormality p r o f i l e s of t h i r t y - t w o Vietnam v e t e r a n s . In summary, approxim ately f i f t y p e r c e n t showed s p e c t r a l a b n o r m a l i t i e s , f i f t y p e r c e n t showed power asymm etries, f i f t y p e r c e n t showed wave-shape in c o h e r e n c e , and f i f t y p e rc e n t showed sharp wave a c t i v i t y . I n a l l , e i g h t y - f o u r p e r c e n t showed some s i g n i f i c a n t d e g r e e of abnormality. C orrelation of these p a tie n ts ' neurometries p ro file s with o th er b eh av io ral and p h y s io lo g ic a l data is pro g ressin g . S p e c ific c o rr e la tio n of n e u r o m e t r i e s p r o f i l e s and b e h a v i o r a l r e p o r t s o f i n d i v i d u a l p a t i e n t s who were exposed to h e rb ic id e s while engaged in n o n -m ilitary a c t i v i t i e s is a lso proceeding. F i n a ll y , th ere i s a growing body of data r e l a ti n g research with people ^ t4 who w er e ex po sed t o low l e v e l s o f t o x i c m a t e r i a l and who shew t h e ran ge o f e f f e c ts present j n 't n e Vietnam v e te ran s exposed to Agent Grange. In p a r t i c u l a r , -5- 6292 r e s e a r c h on the mechanisms u n d e r l y i n g heavy m etal t o x i c i t y (such as w ith lead and with methyl mercury) suggests possible mechanisms fo r both n e u r o t o n i c and g e n e t i c e f f e c t s . ( S e e , f o r exa mpl e, Chang, L.W. " P a t h o g e n e t i c Mechanisms of th e N e u r o to x ic ity of Methyl Mercury" in Mechanism of Actions of N e u r o t o x i c S u b s t a n c e s , e d i t e d by K.N. P r a s a d and A. V e r r . a g a k i s , Raven P r e s s , New Y o r k , 1982; a n d , Egan, e t a l . , " E x p e r i m e n t a l D e s i g n f o r Animal T o x i c i t y S t u d i e s " in E x p e r i m e n t a l and C l i n i c a l N e u r o t o x i c o l o g y , e d i t e d by P .S . Spenser and H.H. Schaumberg, W illiams and W ilk in s , B a ltim o r e , 1980. i -6- 6293 a r~ *-:f1 ch exi \ co -V r (V # f * ALAN SCOTT LEVIN, M.D. I . QUALIFICATIONS Dr. Levin i s engaged in th e p r a c t i c e of medicine in San Franciso. His Curriculum V ita e and Addendum, l i s t i n g P r o f e s s i o n a l S o c i e t i e s and Awards, are attached. I I . SUBJECT MATTER Dr. Le v in w i l l d i s c u s s t h e f o l l o w i n g i n h i s t e s t i m o n y : t h e immune system, with i t s organic, c e l l u l a r , and humoral components - most e sp ec ially w i t h r e g a r d t o t h e l a t t e r , T - h e l p e r c e l l s , B - c e l l s , p las m a c e l l s and immuno g l o b u l i n p r o d u c t i o n ; immune r e s p o n s e , b o t h b e n e f i c i a l and h a r m f u l ; t h e v a r i o u s experimental stu d ie s , p a r tic u la r ly those demonstrating atrophy of the thymus, weight lo ss, depletion of lymphoid organs, lymphopenia, cutaneous type delayed h y p e rs e n s itiv ity (skin th ic k n e ss) and a lte r e d b a c t e r i a l immunity. In a d d i t i o n , Dr. Levin w i l l d is c u s s t h e follow ing and t h e i r s i g n i f i c a n c e : immunology a s m o l e c u l a r b i o l o g y ; c h e m i c a l - i n d u c e d immune d i s r e g u l a t i o n ; T - c e l l s ( l y m p h o c y t e s from thymus) a c t i n g as immune m o d u l a t o r s ( f o r which t h e r e i s "no e f f e c t " l e v e l ) ; immune s u r v e i l l a n c e ; t h e s i m i l a r i t y of t h e immune, n e u r o l o g i c , and e n d o c rin e systems and t h e i r s i g n i f i c a n c e in t h e a r e a o f i m m u n o - t o x i c i t y ; t h e r e l a t i o n s h i p o f immune d i s r e g u l a t i o n c a u se d by chemicals a n d " c a rc in o g e n ic ity , including cancer and the oncogene theory. Also, Dr. Levin w i l l d is c u s s c l i n i c a l u ses of the epidemologic I approach, i . e . , c lin ic a l epidemiology. 6295 i And, Dr. Levin w i l l d is c u s s t h e problems of diagnosing " p s y c h i a t r i c disease" and th e m isdiagnosis which frequently occurs. III. attached. SCIENTIFIC PRINCIPLES See G e n e r a l S ta te m e n t of S c i e n t i f i c P r i n c i p l e s and Assumed F a c t s IV. SUBSTANCE OF OPINIONS A. T h a t phenoxy h e r b i c i d e s and t h e i r c o n t a m i n a n t s , s p e c i f i c a l l y d i o x i n , most e s p e c i a l l y 2 , 3 , 7 ,8-TCDD, c a u s e an a s s o r t m e n t of immunological r e s p o n s e s , i . e . i m m u n o - t o x i c i t y , which p r e d i s p o s e p e r s o n s exposed, by a b s o r p t i o n and/or in g estio n and/or in h a la tio n , to such chemicals to a whole host of adverse h e a lth e f f e c t s , such as: chloracne or o th e r skin r a s h e s ; l i v e r and o th er organ damage; v a r i o u s n e u r o - t o x ic e f f e c t s ; r e p r o d u c t i v e e f f e c t s ; and neoplasm. B. T h a t , i n c o n n e c t i o n w i t h t h e c a r c i n o g e n i c e f f e c t , t h e r e i s no s a f e l e v e l f o r TCDD o r any o t h e r c a r c i n o g e n , and t h a t a s i n g l e e x p o s u r e s e v e r a l y e a r s e a r l i e r can r e s u l t i n human c a n c e r many y e a r s l a t e r . C. Dr. L e v i n w i l l t h e n t e s t i f y t o t h e c a u s a l r e l a t i o n s h i p o f t h e various Agent Orange/dioxin re la te d adverse h ealth e'ffects of the r e p r e s e n ta tiv e r 4 p l a i n t i f f s , in clu d in g : chloracne; l i v e r damage; n e u ro -to x ic e f f e c t s , both n e u ro lo g i c a l and psychological"; rep ro d u c tiv e to x ic e f f e c t s , both m isc a rria g e s and b i r t h t d efects; and such neoplastic processes as s o ft tis s u e sarcoma, as here a 6298 > ? rhabdomyosarcoma, l y m p h o c y ti c lymphoma and b a s a l c e l l c a rc in o m a . V. GROUNDS FOR EACH OPINION A. G e n e r a l The bases f o r such f a c t s and o p in io n s ex pressed h e re in by Dr. Levin include: review of th e medical and s c i e n t i f i c l i t e r a t u r e , including both animal and human d a t a ; h i s p e r s o n a l r e s e a r c h e s ; h i s c l i n i c a l e x p e r i e n c e s ; and h i s p e r sonal knowledge of th e d e f o l i a t io n of Vietnam by such phenoxy h e rb ic id e s and d io x in s , w ith such chemicals in th e presence of th e v e te ra n s and t h e i r presumed exposure thereby; and review of a l l p e rtin e n t medical data of the re p re se n ta tiv e p l a i n t i f f s , p a r t i c u l a r l y w i t h r e s p e c t t o O p i n i o n IV C. B. With r e s p e c t t o O p i n i o n IV A, n o t e t h e f o l l o w i n g : The b a s i c d i s c u s s i o n on t h e immune r e s p o n s e w i l l be drawn from a s e r i e s of a r t i c l e s i n a v a r i e t y of immunology t e x t s and jo u r n a l a r t i c l e s . In addition to th e a r t i c l e s in Dr. L evin's bibliography, the references are outlined i n t h e e n c l o s e d copy of "A P l e a For T h o u g h t f u l C o n s i d e r a t i o n " which was p r e s e n t e d to the Medical Board of the State of C alifo rn ia. Dr. Levin w i l l a ls o r e f e r t o a r t i c l e s on t h e e f f e c t of d io x in on the immune s y s t e m and r e f e r t o t h e a r t i c l e s i n t h e l i s t e n t i t l e d " D i o x in and t h e Immune S ys tem ". Dr. Levin w ill also reply upon the findings of William Rea, M.D., whose b ib lio g ra p h y is a tta c h e d . A d d i t io n a ll y , he w i l l r e l y upon an a r t i c l e Dr. Rea has w r i t t e n w i t h Dr. L a s s i t e r i n t h e A r c h iv e s of C l i n i c a l Ecology in 1983 on p e sta c id e and h e rb ic id e d e t o x i c if ic a t io n . 6297 ALAN SCOTT L E V IN , M . D . ADDENDUM Professional Societies1 1. Alpha Omega Alpha Honor M e d i c a l S o c i e t y 2. C e r t i f i e d Diplomate-American Board of A lle rg y and Immunology 3. C e r tif ie d Diplomate-American Board of Pathology-C linical Pathology 4. Member-Medical Q u ality Review Committee #4, Board of Medical Quality Assurance, State of C alifornia 5. Fellow-American College of Emergency P hysicians 6. Fellow -C ollegeof American P a t h o lo g i s ts 7. Fellow-American S o c iety of C l i n i c a l P a t h o l o g i s t s 8. Member-American Academy of A l l e r g y 9. Member-American A s s o c ia tio n of C l i n i c a l Chemists 10. Member-Americal Medical A ssociation 11. Member-California Medical A ssociation 12. Member-San Francisco Medical Society 13. Member-Society fo r C lin ic a l Ecology Awards 1. American Cancer S o c i e t y F a c u l t y R e s e a rc h Award \> i ' . e Dr. Levin w i l l a lso re ly on th e following a r t i c l e s : G a llo , R.C. The V iru s-C an cer Story: H o s p ita l P r a c t i c e pp. 79-89, June 1983. Leder, P. Genetic C o ntrol of Immunoglobulin P ro d u ctio n : H o sp ital P r a c t i c e pp 73-82, F e b ru ary 1983. Bishop, J.M. Oncogenes and Proto-Oncogenes: H ospital P ra ctice pp. 67-74, August 1983. B i o l o g i c a l R e l e v a n c e o f Immune S u p p r e s s i o n a s In du ce d by G e n e t i c , T h e r a p e u t i c and E n v i r o n m e n t a l F a c t o r s : J . H. Dean and M. L. P a d a r a t h s i n g h E d i t o r s , L i t t o n B i o n e t i c s , Van N o s t r a n d R e i n h o l d Co. New York, C i n c i n a n t i , London, 1981. I n a d v e r t e n t M o d i f i c a t i o n o f t h e Immune Re sp o ns e : The E f f e c t s of Foods, Drugs and Environmental Contaminantsl Proceedings of the 4 t h FDA S c i e n c e Symposium A u gu s t 2 8 - 3 0 , 1978. Immunologic C o n s id e ra tio n s i n Toxicology Vol 1 & 2, Raghubir P. Sharma, CRC P r e s s , I n c . Boca R a t o n , F l a . 1981. Pathology of Drug-Induced and Toxic D is e a s e s : R.H. R id d e ll e d i t o r . C h u r c h i l l L i v i n g s t o n e , New York and London, 1983. Goldberg, R.J. C lin ic a l Uses of the Epidemiologic Approach: Hospital P ra ctice pp. 177-188, August 1983. C. With r e s p e c t t o O p i n i o n IV B, n o t e t h e f o l l o w i n g IARC. Monographs on t h e E v a l u a t i o n o f t h e C a r c i n o g e n i c Risk of Chemicals t o Humans. EPA C r i t e r i a Documents, P u b l i c a t i o n s and A s s o r t e d R e f e r e n c e s Re: TCDD I 3~7c MARVIN A . SCHNEIDERMAN, P h . D . I. QUALIFICATIONS M a rv i n A. S c hn e id e r m a n o f B e t h e s d a , M ary la n d i s a s t a t i s t i c i a n and e p i d e m i o l o g i s t who i s t h e fo rm e r C h i e f o f S t a t i s t i c s and E p id e m io lo g y and the former D ir e c to r fo r Science P o lic y of th e N a tio n a l Cancer I n s t i t u t e . He i s c u r r e n t l y a c o n s u l t a n t . His c u r r i c u l u m v i t a e i s a t t a c h e d . I I . SUBJECT MATTER Dr. Schneiderman w ill t e s t if y in areas concerning mathematical models, s t a t i s t i c s , and epidemiology p a r t i c u l a r l y in the area of the d e t e r m i n a t i o n o f c a n c e r c a u s a t i o n . He w i l l a l s o d i s c u s s t h e e p i d e m i o l o g y of dioxins and t h e i r contaminants s p e c i f ic a ll y as t h a t r e l a te s to cancer in humans s p e c i f i c a l l y s o f t t i s s u e s a rc o m a , stoma ch c a n c e r s and lymphomas. He w ill fu rth er t e s tif y to the relationship of exposure to the time of m anifestation of disease, i .e . the "latency period" for the development of neoplasms. Included w ithin h is testimony w ill be a d isc u ssio n of the m u ltip lication of base rates in the production of cancers; the presentation of a m u lti-s ta g e model for cancer induction; the age r e l a ti o n s h ip s and the r o le age plays in the v a rio u s stages of cancer development as they are e ffe c te d by d i o x i n s a n d / o r t h e i r c o n t a m i n a t e s . He w i l l a l s o d i s c u s s and p r e s e n t t h e p e r t i n e n t animal d a ta and the f a c t t h a t the animal d a ta in the r e p u ta b le and respected medical and s c i e n t i f i c l i t e r a t u r e 4 is c o n s is te n t with the epidem iological s tu d i e s p e r t a i n i n g to d ioxin e f f e c t s in humans and t h a t the animal d a ta is an accu rate and appropriate method fo r the e x tra p o la tio n and p r e d ic tio n of d isease in humans. His presentation w ill include a discussion of a mathematical model for the a s s o c ia tio n of the m u lti- f a c e te d p r e s e n ta tio n of signs and symptoms i n t h e v e t e r a n who was e x p o s ed t o Agent Orange and t h e c o r r e l a t i o n between t h o s e s i g n s and symptoms and s a i d ex p o su re and t h e c a u s a l r e l a t i o n s betw een t h o s e two e l e m e n t s . Dr. S c h ne id e r m a n w i l l , o f n e c e s s i t y , d i s c u s s the incidence of these rare cancers in the general population for a comparison of the onset ages in the general population as compared to the ages of onset for these cancers observed in the Vietnam veterans. His testimony sh all also include a discussion of the relatio n sh ip of c a n c e r i n d u c t i o n t o immune d e f i c i e n c i e s o r d e f i c i t s a s b r o u g h t a b o u t by the immuno-suppressive e f f e c ts of exposure to dioxin and w ill re ly upon the ex p e rien c e w ith organ t r a n s p l a n t p a t i e n t s and th e development of lymphomas and s o f t t i s s u e sarcomas which he w i l l t e s t i f y v a lid a te s h is opinions as to the cancer induction in the representative veterans. F inally, his testimony shall include a discussion of the question o f a t h r e s h o l d e x p o s u re t o a known c a r c i n o g e n f o r t h e i n d u c t i o n o f c a n c e r . This w i l l in clu d e testim ony to the e f f e c t t h a t th e r e i s no " s a f e " l e v e l f o r e x p o s u r e t o a c a r c i n o g e n , t h a t a s i n g l e e x p o s u r e may c a u s e c a n c e r , and t h a t t h e r e i s no "no e f f e c t " l e v e l t o a known c a r c i n o g e n . I n h i s t e s t i m o n y he w i l l p r e s e n t h i s o p i n i o n t h a t TCDD i s t h e most t o x i c and p o t e n t c a r c i n o g e n e v er s y n t h e s i z e d by man. And, f i n a l l y , h i s te s tim o n y s h a ll . co v er th e w id e ly held b e l i e f in the re s p e c te d medical and s c i e n t i f i c community t h a t an f 6302 e n t i t y known t o be c a r c i n o g e n i c o f one o r g a n w i l l , i n a l l p r o b a b i l i t y , be c a r c i n o g e n a t m u l t i p l e s i g h t s w i t h i n t h e human body d e p e n d a n t upon d o s e , d u rra tio n of dose, and latency periods. I I I . SCIENTIFIC PRINCIPLES See General Statement of S c i e n t i f i c P r in c ip le s and assumed facts attached. IV. SUBSTANCE OF OPINIONS 1. Epidaniology and B io s t a t i s t i c s are th e sc ie n c e s and methods through which "cause and e ffe c t" r e la tio n s h ip s are developed. 2. The research work and r e s u lta n t epidem iology on anim als e s ta b lis h e s th a t TCDD i s ca rcin o g en ic. 3. The epidem iology developed in human cohorts i s c o n s is te n t w ith th at developed in the animal stu d ie s. 4. Epidemiology has e sta b lis h e d a cause and e f f e c t r e la tio n s h ip between exposure to TCDD and s o f t - t i s s u e sarconas. 5. Epidaniology has e sta b lis h e d a cause and e f f e c t r e la tio n s h ip between exposure to TCDD and lymphonas. 6 . TCDD i s th e most to x ic substance sy n th esized by man. 7. TCDD i s a ccm plete carcinogen. 8 . There i s no sa fe le v e l fo r exposure to a carcinogen. 9. There i s no "no e ffe c t" le v e l fo r exposure to TCDD. 4 ' 10. TCDD i s carcin ogen ic a t extrem ely low le v e l s o f exposure. 11. TC|)D' e f f e c t s th e immune system so as to make the body more su scep tib le to ca rcin o g en esis, i n c l u d i n g but not l i m i t e d t o , s o f t - t i s s u e sarcomas, lymphomas and s k i n c a n c e r s . 12. A carcinogen capable of causing cancer in one organ or system i s more p ro b ab ly th an n o t c a p a b le of c a u s in g c a n ce r in a v a r i e t y of o rg an s or systems. 13. The c a n ce rs p r e s e n t in r e p r e s e n t a t i v e p l a i n t i f f s Lambiotte and Ford a r e c o n s i s t e n t w i t h TCDD e x p o s u r e . 14. I t i s more probable than not th a t the cancers p resen t in P l a i n t i f f s Ford and Lambiotte were caused by t h e i r exposure to Agent Orange. V. BASES FOR OPINIONS A. G e n e r a l Dr. Schneiderman's opinion w ill be based upon h is education, tr a i n in g , experiences, p a r t i c i p a t i o n in on-going s c i e n t i f i c rese a rc h and in v e s t ig a t io n s , a review of the medical and s c i e n t i f i c rese a rc h , and a review of the medical records of the p la in tiffs . B. S p e c i f i c 1. Epidemiology of Cancer 1. H a rd e ll, L . , 1981, Epidem iological Studies of S o f t - t i s s u e Sarcoma and M a l i g n a n t Lymphoma and T h e i r R e l a t i o n t o Phenoxy Acid o r C h l o r o p h e n o l E x p o s u r e , Ume U n i v e r s i t y M e d i c a l D i s s e r t a t i o n s , U S e r i e s , No. 65-ISSN 0346-6612, Umel, Sweden, 1981. 2. A x e l s o n , 0 . and L. S u n d e l l , K. A n d e r s o n , C. E d l i n g , C. H o e s t e d t and H. K l i n g , 1 9 80 , H e r b i c i d e Ex p o s u r e and Tumor M o r t a l i t y : An U p d a t e d Epidem iologic I n v e s t i g a t i o n on Swedish R a ilro a d Workers, S c a ndinavian J o u r n a l o f Work, E nvironm ent and H e a l t h , Volume 6 : 7 3 - 7 9 . 3. Young, A . L . , M.R. F l i c k e r , H.K. Kang, B.M. S h e p a r d , 1983, H e a l t h r S u rv eillan ce of Vietnam Veterans Claiming Ageht Orange Exposure presented at American Chemical Society National Meeting, Washington, D.C., August 30, 1983 f o r p u b l ic a ti o n in Proceedings of the Symposium "C hlorinated Dioxins and Dibenzofurans in the Total E r.vironm ent-II", Ann A r b o r S c i e n c e , 1984. 6304 4. Zack, J.A . and R.R. Suskind, 1980, The M o r ta lity Experience of Workers Exposed to T etracnlorodibenzo Dioxin in a Trichlorophenol Process A c c i d e n t , J o u r n a l o f O c c u p a t i o n a l M e d i c i n e , 22, Mo. 1, 1 1 - 1 4 . 5. Cook, R . R . , J . C . Townsend, M.G. O t t , L.G. S i i v e r s t e i n , 1980, M o r t a l i t y Experience ot Employees Exposed to 2 , 3 , 7 ,8 -te tra c h lo ro c ib e n z o -o -d io x in , J o u r n a l of O c c u p a t i o n a l M e d ic in e 22 (8),: 530-32. 6. O t t , M.G., D.B. Holder and R.D. Olson, 1980, M o rta lity A nalysis of Employees Engaged in the Manufacture of 2 , 4 ,5 -tric h lo ro p 'n e n o x v a c e ric a c i d , J o u r n a l of O c c u p a t i o n a l M e d ic i n e 22 ( 1 ) : 4 7 - 5 0 . 7. O l s s o n , H. and L. B r a n d t , 1981, Non -Hodckins Lymphoma o f t h e Skin and O c c u p a t i o n a l Exposure t o H e r b i c i d e s , L a n c e t , 12 September 19S1, p. 579. 8. Ho nc ha r, P.A. and W.E. H a l p e r i n , 19 81, 2 , 4 , 5 - t r i c h i o r o p h e n o i and S o f t t i s s u e Sarcoma, L a n c e t , No. 8214: 269-269. 9. Cook, R .R ., 1981, D ioxin, Chloracne and S o f t - t i s s u e Sarcoma, Lancet: 618-619. 10. Cook, R.R., 1981, M o r t a li ty Experience of Employees Exposed to 2 , 3 , 7 , 8 - t e t r a c 'n l o r o d i b e n z o - p - d i o x i n (TCDD) , J o u r n a l o f O c c u p a t i o n a l M e d i c i n e , 23 ( 1 ) : 8. 11. H a rd e ll, L ., and E rik sso n , M., 1981, S o f t - t i s s u e Sarcomas, Phenoxy H erbicides and C hlorinated Phenols, L a n c e t: 8240, 1 August 1981. 12. B a r t h e l , E . , 1981, I n c r e a s e d Risk of Lung Cancer in P e s t i c i d e Exposed Male A g r ic u ltu ra l Workers, Jo u rn a l of Tox. and Environmental H ealth, 8:1027-1040. 13. B i s h o p , C.M. and A.H. J o n e s , 19 8 1, Non-Hodgkins Lymphoma of t h e S c a lp in Workers Exposed to Dioxin, Lancet (2), 369. 14. Coulston, F. and F. P o c c h ia ri, 1983, E d ito rs , A ccidental Exposure to D i o x i n s , Human H e a l t h A s p e c t s , Academic P r e s s , New Yor k, New Yor k. 15. H a r d e l l , L . , B. J o h a n s s o n , and 0 . A x e l s s o n , 1982, E p i d e m i o l o g i c Stu dy of Nasal and Nasal Pharyngeal Cancer and Their R elation to Phenoxy Ac id o r C h l o r o p h e n o l E x p o s u r e , Am. J o u r n a l of I n d . M e d i c i n e , 3: 2 4 7 - 2 5 7 . ' 16. M a cl e n n an , R . , J . F o r d and M. C o a t e s , 1982, C an ce r i n t h e 31ue M o u n ta i n s of New Sout h W ale s, M e d i c a l J o u r n a l o f A u s t r a l i a , 2 : 3 1 9 - 3 2 3 . 17. Moses, M., and I . J . S e lik o f f , 1981, S o f t- tis s u e Sarcoma, Phenoxy H erbicides and C hlorinated Phenols, Lancet (!): 1370. 18. R iih im ak i, 2 . , S. Asp, and S. Hernberg, 1982, M o r ta lity of 2,4-D and 2 ,4,5-T H erbicide A p p lic a to rs in Finland: F i r s t Report of an Ongoing P r o s p e c t i v e C oIh o r t S t u d y' , Sc a n. J . of Work, Env. and H e a l t h , 3 : 3 7 - 4 2 . 19. R iih im a k i, Z ., S. Asp, E. P u k k a la, and S. Hernberg, 1983, N e r t a l i r v and C a n c e r M o r b i d i t y Among C h l o r i n a t e d Phenoxy Acid A p p l i c a t o r s in F i n l a n d , Chemosphere 12: 779.-;784. 6305 2 0 . Sarma, P.R. and J . Jaco p s, 1982, Thoracic S o f t- t is s u e Sarcoma in Vete`r a n s Expos ed t o A g en t O r a n g e , N e w E n g l a n d J o u r n a l o f M e d i c i n e 306:1109. 21. Sm it h , A . H . , D.O. F i s h e r , H . J . G i l e s and P e a r c e , 19 8 3, The New Z e a l a n d S o f t- t is s u e Sarcoma Case Control Scudy; Interview Findings Concerning Phenoxy A c e tic Acid Exposure, Chemosphere 12: 565-571. 22. T h i e s s , A.M. and R. F r e n t z e i - B e y m e , and R. L i n k , 19 8 2, M o r t a l i t y of Persons Exposed to Dioxin in a T richlorophencl Process Accident That O c c u r r e d a t t h e BASF AG on November 1 7 , 1953, American J o u r n a l o f In d u strial Medicine, 3:179-189. 23. N e a l , M.W., and D.K. 3 a s u ( f o r t h e S y a c r u s e R e s e a r c h C o r p o r a t i o n ) , I1' 0 C 1 Working Document p rep a re d f o r Environm ental C r i t e r i a and Assessment O f f i c e , EPA, C i n c i n n a t i , Ohio " H a z a r d o u s A i r P o l l u t a n t Document on 2 , 3 , 7 , 8-TCDD", 23 L'n i t e d S t a t e s D e p a r t m e n t o f H e a l t h , E d u c a t i o n and W elfare, 1964, Smoking and Health.; Report of the Advisory Committee to t h e Su rg eo n G e n e r a l of t h e P u b l i c H e a l t h S e r v i c e , PKS P u b l i c a t i o n 1103. 24. United S ta te s Department of H ealth , Education and W elfare, 1979, Smoking and H e a lth : The R eport of th e Surgeon G eneral O f f ic e on Smoking and H e a l t h , DHEW P u b l i c a t i o n No. (PHS) 7 9 -5 00 66 . 25. U.S. D e p a r t m e n t o f H e a l t h and Human S e r v i c e s , 19 82, The H e a l t h C o n s e q u e n c es of Smoking: Cancer, a Report of the Surgeon General O f f ic e on Smoking and H ealth. 2. M ulti-Stage Theory o f Carcinogenesis Sane concepts o f la te n c y , concepts o f th re sh o ld s, e x tr a p o la tio n , and r is k assessm ent. 1. Armitage, ?. and R. Doll, 1954, The Age D i stribution of C a n c e r and a M u l t i - s t a g e T h e o r y of C a r c i n o g e n e s i s , British Journal of Cancer, 8: 1-12 2. A rm ita g e , ? . and R. D o l l , 1961, S t o c h a s t i c Models of C a r c i n o g e n e s i s in Neyman, J . , E d i t o r , P r o c e e d i n g s of the F o u r th B e r k le y Symposium on M a th e m a t ic a l S t a t i s t i c s and P r o b a b i l i t y , Volume 4, U n i v e r s i t y of C a l i f o r n i a P r e s s , B e r k l e y , CA, p p . 1 9 - 3 8 . 3. 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P e t o , 1976, Fu n d a m e n t a l C a r c i n o g e n i c P r o c e s s e s and T h e i r I m p l i c a t i o n s f o r Low Dose R i s k Assessment, Cancer Research 36:2973-2979. 8. Falk, H.L., 1978, B io lo g ic a l Evidence for the Existence of Threshold Chemical C a rc in o g e n e sis, Environmental Health P r o s p e c tiv e , 22: 167-170. 9. Gaylor, D.W., and R.L. K o d e ll, 1980, L in ear I n t e r c a l a t i o n Algorithm f o r Low Dose R i s k A s s e s s m e n t o f To x ic S u b s t a n c e s , J o u r n a l of Environmental Pathology and Toxicology, 4: 305-312. 10. C o rn field , J . , 1977, C arcinogenic Risk Assessment, Science 198: 693-699. 11. Gehring, P . J . , P.G. Watanabe, and J.D . Young, 1977, The Relevance of Dose Dependent P h a rm a c o k in e tic s in the Assessment of C a rcin o g en ic Hazard of C h e m ic a ls i n O r i g i n s o f Human C a n c e r , E d i t o r s , H.H. H i a t t , J.D. Watson, and J.A . 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S c h n e i d e m a n , M.A. , ? . D e c o u s l e , and C.C. Brown, 1979, Th.resho Environmental Cancers: B io lo g ical and S t a t i s t i c a l Considerado' A n n a l s New 'f o r k Academy o f S c i e n c e 329: 9 2 - 1 2 0 . i T r u h a u t , R. , 1979 , An O ve rv ie w of t h e Pr o b le m o f T h r e s h o l d f o r Chemical C arcinogens in C arcin o g e n ic Risk, S t r a t e g i e s f o r I n t e r en E d i t o r s , W. D a v i s , C. R o s e r . f e l d , IAF.C P u b l i c a t i o n No. 25, p. 1 I n t e r n a t i o n a l Agency f o r R e se a rc h on Cancer, Lyon, France. on. Weil, C .S ., 1972, S t a t i s t i c s Versus S afety F a c to rs and S c i e n t i f i c Ju dg me nt i n t h e E v a l u a t i o n o f S a f e t y f o r Man, T o x i c o l o g y and A p p l i e d Pharmacology 21: 454. W hittemcre, A.S. and J .3 . K e lle r , 1973, Q u a n tita tiv e Theories o C a r c i n o g e n e s i s , SIAM Review 20: 1 - 3 0 . 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Sellir.gh.am, 41969 , A M achem acical Motel f o r t h e Age D i s t r i b u t i o n of C a n c e r i n Man, I n t e r n a t i o n a l Jo u rn a l . o f Cancer 4: Ha er.se e l , Cancer ar. --J 6308 33. N a c io n al Academy of S c i e n c e / N a c i o n a l R e s e a rc h C o u n c i l, 1950, P r i n c i p l e s of T oxicological In te rac c i n Associated with M ultiple Chemical Exposure, N a t i o n a l Academy P r e s s , W ashington, D.C. 39. U.S. D e p a r tm e n t of H e a l t h and Human S e r v i c e s , 1931, S u r v e i l l a n c e : E p i d e m i o l o g 2/ and End R e s u l t s : I n c i d e n c e and M o r t a l i t y Da ta 1 9 7 3 - 1 9 7 7 , NIH P u b l i c a t i o n S l - 2 3 3 0 , U.S. DHKS N a t i o n a l C a n c e r I n s t i t u t e , 3 e t h e s d n , Maryland. 40. N icholson, W illiam J . , 1979, A sbestos-The TLV Approach. Ne^ York Academy o f Sciences, 271:152-169. 41. Shabad, L.M. 1966. Hygiene & S a n ita tio n . 31:174-180 42. IR.AC. tomographs on th e E valuation o f th e C arcinogenic Risk o f Chemicals to Humans 3. Laboratory Data 1. C r i p k e , M .L ., and B o r s o s , C . , 1974, Immune S u r v e i l l a n c e R e v i s t e d , Journal of N ational Cancer I n s t i t u t e , 52: 1393-1395. 2. Prehn, R .T ., 1971, I m m u n o -s u r v e illa n c e , R e g e n e ra tio n and O ncog e n e sis, P r o g r e s s i n E x p t. Tumor R e s e a r c h , 14: 1-24. 3. Hoover, R. and J . F . F ra u m e n i, J r . , 1973, R isk of Cancer i n Renal T r a n s p l a n t E x h i b i t , Lancet 2: 55-57. 4. M o l l e r , G. and E, H o l i e r , 19 75, C o n s i d e r a t i o n of Some C u r r e n t C o n c e p t s in Cancer Research, Journal of the National Cancer I n s t i t u t e , 55: 755-759. 5. Penn, I . , 1977, Developments of Cancer as a Complication of C l i n ic a l T r a n s p l a n t a t i o n , P ro c ee d in g s 9: 1121-1127. 6. S efer, A., 1971, Immunotherapy of Cancer, Journal of N ational Cancer I n s t i tu t e , 47: VII-XII. 7. C l a r k , D . A . , J . G a u l d i , M.R. Szewczuk, and G. Sweeney, 1981, Enhanced Suppressor C e ll A c t i v i t y and a Mechanism of Immunosuppression by 2 , 3 , 7 , 8 t e t r a c 'n l o r o d i b e n z o - p - d i o x i n , P r o c e e d i n g of t h e S o c i e t y f o r E x p e r i m e n t a l Biology in Medicine, 1968: 290-299. 8. L u s t e r , M . I . , J . H . Dean and G.A. Boorman, 19 8 2, A l t e r e d Immune F u n c t i o n s i n R o d e n ts T r e a t e d w i t h 2 , 3 , 7 , 8-TCDD, P h o r b o l - 1 2 - M y r i s t a t e - 1 3 - a c e t a t e and b e n z p ( a ) p y r e n e , Banbury R e p o r t No. 11, E n v i r o n m e n t a l F a c t o r s i n Human Growth and D e v e l o p m e n t, pp. 199 -2 15 . 9. N e a l , M.W. and D.K. B a s u , 198 4 , R e v i s i o n and U pd at e o f H a z a r d o u s A i r P o l l u t a n t Document on 2 , 3 , 7 , 8-TCDD (Working Document p r e p a r e d f o r t h e E n v i r o n m e n t a l C r i t e r i a and A s s e s s m e n t O f f i c e , US EPA, C i n c i n n a t i , O h i o , By t h e S y a c r u s e R e s e a r c h C o r p o r a t i o n ) , S e c t i o n 8 . 1 . 4 . Immunologic Effect. 10. Van M i l l e r , J . T . , J . J . L a l i c h , J . R . A l l e n , 1977, I n c r e a s e d I n c i d e n c e of Neoplasm i n R a t s Exposed to Low L e v e l s of 2 , 3 , 7 , 8 - t e t r a c h l o r o d i b e n z o - p d io x in , Chemosphpre 6 (9 ,1 0 ), 537-544 and 625-632. ----- ----------f-- __________ _______ 830$ 1 1 . Kocifca, R . J . , D.G. Keyes, ana J . E . s e v e r , 1976, R e s e l l s of a Two Year Chronic T oxicity and Oncogenicity Study of 2 ,3 ,7 ,8 -te tra c h io ro d ib e n z o -p d i o x i n i n R a t s , T o x i c o l o g y and A p p l i e d Fha r m a c o io g y , 46 ( 2 ) : 2 7 9 - 3 0 3 . 12. K o c i b a , R . J . , D.G. Ke ye s, and J . E . B e y e r , and R.M. C a r r e o n , P.G. Ge'nring, 1979, Long-Term T o x icity S tudies of 2,3 ,7 , S -te tra c h lo ro d ib en z o -p a ra -d io x in (TCDD) i n L a b o r a t o r y A n i m a l s , A n n a l s o f th e New York Academy of S c i e n c e s , 320: 379-404. 13. N i s b e t , I . C . , and M.B. P a x t o n , 19S2, S t a t i s t i c a l A s p e c t s of T h r e e G e n e r a t i o n S t u d i e s o f t h e R e p r o d u c t i v e T o x i c i t y o f TCDD and 2 , 4 , 5 - T , Am erican S ta tis tic ia n , 36(3) 290-298. 14. N ational Toxicology Program (NTP), 1980, Bioassav 2 , 3 , 7 , 8 -te tra c h lo r o d ib e n z o p - d i o x i n f o r P o s s i b l e C a r c i n o g e n i c i t y , Gavage Study DHKS P u b l i c a t i o n No. NIH 82- 1754 and 8 2 - 1 7 6 5 . De rmal Study DKKS P u b l i c a t i o n No. (NIH) 82-1757 82 - 1 7 5 8 , C a r c i o n g e n e s i s T e s t i n g Program NCI NIH B e t h e s a a , M ary la n d and N a t i o n a l T o x i c o l o g y Pro gra m (NTP) R e s e a r c h T r i a n g l e P a r k , N o r t h C a r o l i n a , P . 0 . Box 12233. 15. Toth, K., S. Sugar, S. Som fai-R elle and J . Bence, 1978, Carcinogenic 3 io assay of t h e H e r b i c i d e 2 , 4 , 5 - t r i c h l o r o p h e n o x y e t h e n o l (TCPE) With D i f f e r e n t 2 , 3 , 7 , 5 T etrachlorodibenzo-p-dioxin (Dioxin), Content in Swiss Mice, Prog, in B i o c 'nem. and P h a r a m a c . , 14: 8 2 - 9 3 . 16. P i e t o t , A . C . , T. G o l d s w o r t h y , and H. P o l a n d , 1980, P r o m o t i o n by 2 , 3 , 7 , 8 te tr a c 'n io ro a ib e n z o -p -d io x in of H epatocarcinogenesis From D ie th y ln ig ro s a m in e , Cancer Research 40: 3616-3620. 17. Cohen, G.M, W.M. B r a c k e n , R . P . I y e r , D.L. B e r r y , J . K . S e l k i r k , and T . J . Slaga, 1979, A nticarcinogenic E ffect of 2 ,3 ,7 ,8 -te tra c h lo ro a ib e n z o -p -d io x in on Benzo(a) Pyrene and 7 , 1 2 - d in e t h y lb e n z (a ) a n th r a c e n e and i t s R e l a ti o n s h i p t o DNA B i n d i n g , C a n c e r R e s e a r c h 39 ( 1 0 ) : 4027 -4 03 3. 18. C o u r i , R . E . , T.H. Ruaa, R. J o g l e k a r , e t a l . , 1978, 2 , 3 , 7 , 8 - t e t r a c h l o r o d i b e n z o p-dioxin as a Co-carcinogen causing Free Methylcholanthrene In itia te d S u b c u t a n e o u s Tumors i n Mice G e n e t i c a l l y " N o n - r e s p o n s i v e " a t Ah L o c u s , C a nc e r R e s e a r c h 38 (9) 2 7 77-2783. 19. B e r r y , D . L . , T . J . S l a g a and J . D i G i o v a n n i , and M.R. J u c h a u , 19 79, S t u d i e s with Chlorinated D ibenzo-p-dioxins Polvbrominated Biphenyls, and Poly c h l o r i n a t e d b i p h e n y l s i n a T w o - s t a g e System of Mouse S k i n T u m o r o g e n e s i s : P o t e n t A n t i - c a r c i n o g e n i c E f f e c t , A n n a l s o f t h e New York Academy o f S c i e n c e s , 320: 405-414. I 6310 35* ^ z^ u e^ 3 /. S/eaj<c^y A ttorney A t Law 514 26th A venue T uscaloosa. A labama 35401 T elephone 205-345-3441 March 16, 1984 Mr. Tom Henderson 1612 Frick Building Pittsburgh, PA 15219 Dear Tom: Attached are some ideas that I have had or collected for posters regarding scientific causation for the agent orange case. For each veteran/test case, I think we should have a poster showing that veteran's different weights over the years, as well as, another poster for each vetern showing the medical problems that veteran has had that we attribute to agent orange. Yours truly, MTS/mlv Enclosures cc: Mr. Phillip Brown Mr. Stanley Chesley Mr. David Dean Ms. Jan Levin Mr. Gene Locks Mr. Benton Musslewhite Mr. Neil Peterson Ms. Alison Pettiette Mr. Newton Schwartz Margie T. Searcy I 6312 NERVOUS SYSTEM / 6313 NERVE CELL ! 6314 I HOW DIOXIN IS FORMED: 6315 2ti Zf re Do DIOXIN (TCDD) + HUMAN LIVER \ ENZYMES'THAT / ARE HARMFUL TO THE BODY t 6316 % THE MAJOR STEPS IN -.MANUFACTURING AGENT ORANGE: 1 WAYS VETERANS WERE EXPOSED TO DIOXIN (TCDD): 1. Breathing 2. Eating 3. Drinking 4. Touching ; I 8318 HOW DIOXIN TRAVELED IN THE ENVIRONMENT: 1. D irect Spray 2. Drift 3. Volitization 4. Evaporation 5. Leaching 6. Movement by Animal, Machines, and Plants, etc. > I V. 8319 3^ UNITED STATES DISTRICT COURT EASTERN DISTRICT OF NEW YORK In re: "AGENT ORANGE" Product Liability Litigation x ---- x MDL #381 PLAINTIFFS' MEMORANDUM ON CAUSATION PLAINTIFFS' MANAGEMENT COMMITTEE Thomas W. Henderson, Esquire I 6321 I . Introduction II. Pertinent Litigation History III. Medical Causation A. Background B. Causation in Fact C. Expert Opinion D. Disease Litigation E. Application to Agent Orange Case 1. Agent Orange/dioxin is highly toxic and carcinogenic. 2. Agent Orange/dioxin has no safe level of exposure. 3. Plaintiffs were exposed to Agent Orange/dioxin. A. Agent Orange/dioxin did cause an array of adverse health effects in the 9 representative Plaintiffs. a. Dermatological b. Systemic i . liver ii. immuno-suppressive c. Neuro-toxic i. neurological ii . neuro-behavi oral d . Cancer e. Birth defects IV. Conclusion > I 8322 I . INTRODUCTION This memorandum is submitted on behalf of all members of the class by the Plaintiffs' Management Committee. The request for leave to submit it was occasioned by virtue of comments made on various occasions by the Court concerning the strengths, or, we respectfully submit, as the Court has erroneously indicated, the great weaknesses in the Plaintiffs' cases on medical causation issues. The Management Committee has been concerned for some time now that the Court misperceives the requirements of proof on causation issues, especially the proper use and weight to be afforded statistics, and more recently, from comments made by the Court at the first hearing regarding fee and expense applications, concerning the relationship between proofs on causation issues and whether this case should have been brought at all. In its Preliminary Memorandum and Order on Settlement dated September 25, 1984, this Court touched on problems it perceives in Plaintiffs' cases on causation issues, i.e. ''III. Factual Problems with Claims", pp. 96-150. These problems were known and would have been handled in the presentation of Plaintiffs' proofs. The Committee none theless acknowledges that there were several factors, most of which were included in said Memorandum of the Court, which led to its evaluation and conclusion that the proposed settlement of this litigation is in the best interests of the class members as a whole (See, generally, Plaintiffs' Fairness Brief dated August 7, 1984). However,'the Committee believes nhe / Court's suggestions that Plaintiffs' counsel (both Committee members,and other counsel ^representing certain Plaintiffs) were unabtle to prove causation . 832 CO by a preponderance of the evidence of adverse health effects other than chloracne, are misplaced. The Court misperceives the strengths of the proofs adduced with respect to the individual representative Plaintiffs. Indeed, the Court places an inappropriate burden upon Plaintiffs in disease litigation generally in suggesting a "statistical requirement" as a form of "litmus paper test" in order to proceed. The Committee strongly believes the Court's view is erroneous, because, if adopted, it would discourage the prosecution of many types of valid occupational and environmental disease claims. To support our belief, we shall set forth the pertinent history of this litigation, an exposition of the legal sufficiency of the proof on causation in disease litigation, and specific relevant Court documents, especially those pertaining to experts' opinions. The Committee therefore submits that it can adduce legally sufficient and clear evidence of CAUSE. II. PERTINENT LITIGATION HISTORY In its Preliminary Memorandum and Order on Settlement dated September 25, 1984, this Court gives an accurate chronology of the institution and early procedural history of this litigation, and the transfer and consolidation of actions pursuant to 28 U.S.C. 1407 (See, Opinion at pp. 20-31). What is lacking there, but pertinent here, is a brief working history of the litigation. Early in the litigation Judge Pratt, in fundamental agreement with the procedural aspects of the motion of the Plaintiffs to conduct serial trials of various issues common to class members' claims, ordered that the government contractor defense be tried first and separately, and permitted discovery to proceed on issues pertaining to that defense (See, 506 F.Supp. at 762). This was done under the supervision primarily of Special Master Sol Schreiber. The then lead counsel group accomplished the discovery necessary to prepare for Judge Pratt's "Phase One" trial through the taking of numerous depositions and the review of voluminous documents produced. In addition, they briefed the early legal positions on various issues and responded successfully to the Defendants' motions for summary judgment based upon the government contractor defense. Judge Pratt dismissed the veterans' complaints against two of the Defendants, Hercules and Thompson Chemical, which were subsequently brought back into the litigation. Another significant;aspect of his opinion was that issues regarding liability, general medical causation, and * government contractor defense were interrelated. Therefore, he determined that the "Phasfe One" trial was no longer appropriate in Jhis "Case Management" -3- 6325 of the litigation. Judge Pratt instructed Special Master Schreiber to continue in his role, and to recommend an appropriate timetable for remaining discovery (on the vastly enlarged issues) "with the objective being a trial at the earliest reasonable date." (See, 565 F.Supp. at 1277, June 22, 1983). Following this order, Special Master Schreiber began to supervise and schedule remaining discovery pertaining to government witnesses requested by the Defendants and, soon thereafter; discovery of liability issue witnesses, including employees and former employees of Defendants. The transfer of the litigation to Chief Judge Weinstein and his Order in October of 1983 to further expand the issues through the device of choosing representative individual cases that were to be tried to verdict, placed Immense burdens on Plaintiffs' counsel. That occurred within just 3 weeks of the motion of Yannacone & Associates to be relieved of their duties as lead counsel, primarily for financial reasons, and the appointment of Messrs. Henderson, Schlegel and Musslewhite to the position of the Management Committee or lead counsel, which appointment was filed with the Court on October 5, 1983. At that time Special Master Schreiber was supervising a discovery schedule of depositions of liability witnesses which was proceeding on a multiple track basis, with as many as 15 depositions scheduled each week all over the country. Judge Weinstein's direction to choose individual representative cases from the thousands that were on file required a phenomenal amount of work on the part of Henderson's causation "team" and the expanded Management Committee. - * A determination as to the location and content of medical records I pertaining to individual Plaintiffs from all .over the country had to be ' -4- 8326 made. (This is but one example of the tremendous burdens placed upon the Committee to comply with an almost unbelievable timetable. Further examples are contained in Appendix 1 attached hereto). Where records were not complete, they had to be obtained. Plaintiffs with diagnosed diseases which could be related to Agent Orange had to be found. Their local counsel had to be consulted. Interviews with prospective represen tatives and their families were held. Experts from a variety of scientific disciplines had to be consulted and retained. The importance of making the right choices, and the consequences to the individual Plaintiffs involved were monumental. All of this work was accomplished in the space of just a few months. The Committee believes that the consequence of the choices of the representative Plaintiffs and of the testimony adduced from the highly qualified experts, Defendants' protestations notwithstanding, resulted in the Defendants' presumed conclusion that causation issues would be submitted to the jury. In our view, that was the primary reason why the Defendants agreed to settle this litigation. The type and quantity of discovery taken is important to note. No significant prior discovery had been taken on causation issues prior to October 5, 1983, the date when the Management Committee was appointed by Judge Pratt. Counsel's first meeting with Judge Weinstein took place on October 21, 1983, and it was only thereafter that causation issues became the subject of any substantial legal effort. Records on file with the Court indicate that' 157 depositions were taken between the outset of the litigatipn in 1979 and June 22, 1983, virtually all of which had to do with government contractor defense I issues, and many of which were quite short in duration. -5- 6327 After expansion of the issues, however, the pace quickened dramatically. Between June 22, 1983 and May 7, 1984, over 216 depositions were completed. During the first four months of 1984, over 100 depositions were taken and of these, more than 60 pertained to causation issues, both general and specific. The depositions during this period of expert witnesses and representative Plaintiffs were not only technical and complex in nature, but were two days (or longer) in most instances. During the post October 21, 1983 period it was obviously necessary to interview and prepare experts and Plaintiffs for their testimony. The appointment of Magistrate Scheindlin to supervise discovery, both as to scheduling, progress and claimed abuses was another factor which, although very helpful to all (and we congratulate her on a job magnificently performed) added still more demands on the causation "team11. Rule 26(b)(4) summaries, in extraordinary detail, were ordered to be submitted, requiring extensive review of source materials by lawyers and experts as well. We believe the talents and efforts of defense counsel deserve some mention. In terms of causation issues there simply has never been a litigation in which Plaintiffs' efforts were so strongly defended, not just in spirit, but with resources and efforts that were unparalleled. For example, nearly every opinion given by Plaintiffs' witnesses was attacked from a wide variety of perspectives. Mo cost or effort was spared. Despite the defense effort, and as is chronicled hereafter, the Plaintiffs' causation case was ready for trial on May 7, 1984. There was substantial probability of success on those issues as they relate to the representative Plaintiffs. We could prove that each wa$t exposed to Agent Orange/dioxin and suffered from one or more adverse health effects as a result of sucli exposure. . -6- 6328 III. MEDICAL CAUSATION A. Background The relationship between Agent Orange and disease, i.e. cause, while not as easily perceived as, for example, physical trauma and a broken bone, is by no means as perplexing and complicated as has been suggested. The legal standard of establishing cause is identical, whether the adverse health effect results from a single event producing trauma, a single acute exposure to a toxic substance, or a chronic low level exposure to one or more toxic substances; that standard of legal sufficiency is whether the particular toxic substance more likely than not caused, or contributed to, r aggravated the disease (adverse health effect). While the "actual" exposure to any toxic substance, specifically here Agent Orange, perforce must be decided on an individual basis, and otherwise be convincing to the fact-finder on the "more probably than not" standard, for purposes of the expert's opinion on cause, the exposure is always hypothetically assumed by the expert. There are several reasons for this: 1 ) the expert is almost never present when the alleged exposures take place; 2 ) testing to determine the levels of contamination of a particular toxin, e.g. air sampling, rarely can be performed, even after the fact; and 3) even if such testing were possible, the difficulties in establishing admissible testimony, i.e. by reproducing identical, even substantially similar conditions as were prevalent at the time of exposure, often several ^r 4 years later, are manifest. The ^rg'uments advanced by the defendants - that the Plaintiffs' inability to scientifically establish a "toxic dose" in any particular -7- 6329 Plaintiff, that any exposure to Agent Orange/dioxin in Vietnam cannot be distinguished from an etiologic standpoint from other sources of dioxin contamination in the environment, and even that no exposure to Agent Orange/dioxin can be established, are inappropriate and/or simply have no merit. In the last analysis, all of these defense positions are to be decided by the fact-finder, based upon the various forms of admissible evidence. Exposure is determined by the fact-finder, taking into account such admissible evidence as oral testimony of the Plaintiff or the individual allegedly exposed, co-workers or, in this case, other military personnel having relevant knowledge of that individual's alleged exposure to Agent Orange, and such documentary evidence, i.e. relevant military records, which would be helpful to the fact-finder, and even certain opinion testimony of probable or greater exposure, as, for example, from Richard Christian. Specifically, in those areas of toxic tort litigation wherein trial and/or appellate courts have addressed this matter in both general and specific terms, e.g. asbestos, silica, benzene and radiation, the requirement of a plaintiff having to prove his particular "toxic dose" has been thoroughly rejected. Indeed, an overwhelming majority of such cases rely exclusively on the oral testimony of a plaintiff and/or co workers for legally sufficient exposure evidence. Where exposure to a toxin is "established", i.e. to the satisfaction of the fact-finder, the Inquiry turns to that which exists in the scientific literature in the areas of toxicology, epidemiology, and clinicial medicine, and even the impressions and expressions of qualified clinicians who^have performed the appropriate battery of tests and have interpreted the medical data resulting therefrom. ^ -8- There is no requirement that statistical evidence be adduced to a probability of 50+% to submit to a jury or to persuade any other fact finder that the exposure is a cause, or contributed to, or aggravated, the disease or adverse health effect. This error is a judicial construct under which the epidemiologic term "statistical significance" has been expropriated inappropriately into a judicial setting, the effect of which is to predetermine a matter adversely to a plaintiff when courts do not routinely consider such burdens to be properly on a plaintiff. For example, where a given plaintiff has 4 separate lung conditions - silicosis, bronchitis, emphysema, and asbestosis - all of which contribute to a total disability, it cannot logically be said that any one of the 4 disease processes is the cause of the disability, even from the perspective of a 50+% probability. However, in such cases, courts routinely permit an expert to testify that asbestos exposure w a s , to a level of reasonable medical probability or certainty, a substantial contributing factor in the disability. That is not to say that where statistical evidence is available, it is not useful. To the contrary, the existence of such statistics is very helpful. Those statistical analyses are present in all 3 relevant areas of medical science, i.e. toxicology, epidemiology and clinical medicine. Indeed, those disciplines require the use of statistics in their respective evaluations of the pertinent data. Specifically, Defendants advanced arguments in support of their position on causation during the course of the pretrial discovery in two of those disciplines, i.e. toxicology and epidemiology. ^> 4 With respect to toxicology, the Defendants postulated that, since all substance^ can cause harm or even death if taken in high enough doses, I >* -9- 6331 and since Plaintiffs were unable to prove a specific dosage of dioxin which may have been absorbed, the Plaintiffs' proof therefore fails. The circularity of this argument is manifest. Since there is no known safe level to dioxin, and the fact that exposure at some level may be assumed by the experts, as set forth above, an appropriate opinion as to the relationship between the "fact" of exposure and the particular adverse health effect may be admitted. In animal toxicology, the scientific discipline of statistics is an essential component in the utilization of control groups of the species under observation, and in the analyses of whether the toxin or carcinogen under study is indeed toxic or carcinogenic. The suggestion by the Defendants, therefore, that the evaluation of animal data cannot be extrapo lated to the human experience in an evaluation of cause in humans in this context is outrageous. No one suggests that human experimentation is proper; indeed it is immoral and illegal. The Defendants' position in this regard is thus reduced to the absurd claim that a requirement which is proscribed must be satisfied, i.e. that only epidemiological data from a human can establish cause and effect in humans. From a policy standpoint, that is, in a word, unacceptable; from a scientific standpoint it is ridiculous. Nevertheless, the Defendants argue (1) that there are insufficient human data to establish "cause and effect" relationships; (2 ) that there are no data to support the claims of Plaintiffs with respect to exposure to Agent Orange/dioxin while in Vietnam; and (3) that, in any event, epidemiology is designed to assess risks in the regulatory sense, but cannot be used to prove individual causation. The first and second aspects of these contentions are, to put it bluntly, not so. To the contrary, there is an abundance of human studies -10- 6332 regarding dioxin, including specifically 2,3,7,8-TCDD. Moreover, the Vietnamese studies on male-mediated birth defects as reviewed by Hatch and Constable, Ranch Hand II, and the Center for Disease Control (CDC) study of birth defects in relation to a father's service in Vietnam all demonstrate the presumed causal association between Agent Orange/dioxin exposure in Vietnam and various adverse health effects including male-mediated birth defects. Moreover, epidemiology can certainly be used on an individual basis. Where exposure is established, that individual becomes part of the exposed group, and the relative risk otherwise ascertained by relevant epidemiology studies is applicable to that individual, i.e. in this case any one or more of the representative Plaintiffs who were exposed in Vietnam. Otherwise, it (the discipline of epidemiology) would be useless except on a theoretical level. By definition, epidemiology deals with human experience, and perforce therefore includes individuals in its statistical analyses. Certainly, epidemiology relies very heavily on statistics and statistical techniques. The important relevant distinction is between the respective levels of scientific and legal proof in the demonstration of cause, i.e. why epidemiology is not essential in this consideration and determination of cause. Scientific proof in the context of epidemiology and its application of statistics often is expressed in terms of 95% or 99% probability, (i.e. where P < 0.05 and P ^ 0.01, respectively), that the event considered is not due solely to chance; this translates into a conclusion that the event (adverse health effect) results from chance alone less than 5% or le5s than 1%, as the case may be. ^ Such "statistical significance" concepts are far different from the legal standard of "more probably than -11- 6333 Lastly, the question of whether a given Plaintiff was exposed to one or more variables (chlordane, DDT, malathion, lindane, aflatoxin, etc.) is simply a "red herring". The concern of an expert in sorting out possible competing causes is manifest in toxic tort litigation; the expert testimony would have been presented with consideration of all such possible competing causes. The issue is no different conceptually in Agent Orange than in any other toxic substance litigation, e.g. lung disease and smoking. The presence of such confounders in a given case does not prevent expert testimony but only mandates a restructuring thereof if it is to have any weight. Likewise, the analyses by a clinician of various objective tests and their resultant data necessarily imply the use of statistics, in that statistical techniques already have been employed and statistical analyses already have been made to establish the "normal" range of responses for each of those tests. The evaluations and diagnoses by clinicians, together with clear expressions of cause of such diagnoses, are performed every day. In the context of a toxic substance, clinicians frequently make diagnoses and at the same time ascribe cause and prescribe treatment based upon the patient's history of exposure. For example, a patient may exhibit an asthma condition of recent origin after having been exposed to a particular toxin known to cause asthma during the same time period. In this case, a clinician's recommendation that the patient should not be further exposed to such substance Impliedly concludes that the substance caused or contributed to the asthma. Furthermore, that situation has nothing to do with asctibing cause in the medico-legal sense. Yet, the clinician cpuld certainly,and should be permitted to, testify to cause, in this context. I -12- 6334 In the Agent Orange case, the Plaintiffs can amply demonstrate exposure to Agent Orange/dioxin. The scientific literature is replete with both toxicological and epidemiological data regarding dioxin, especially 2,3,7,8-TCDD. Moreover, one or more clinicians and other scientists were and are prepared to tie in the various objective medical criteria to formulate diagnoses and "cause" resulting from such exposure. The case of each representative Plaintiff would be analyzed accordingly, specifically with respect to the pertinent testimony of the various "worldclass scientists". The Plaintiffs were and are prepared, in the legal sense, to prove CAUSE. -13- 6335 B. Causation in Fact Causation is a key issue in all personal injury litigation. As a threshold matter in any tort action, the plaintiff must establish a reasonable connection between the conduct of the defendant(s) and the damage suffered. Conceptually, the causation issue is framed in terms of "causation in fact". (See, Prosser and Keeton on The Law of Torts, 5th ed., 1984, |41). The inquiry surrounds whether the identifiable incident (such as an accident, exposure to a toxic substance, or medical treatment) is a proximate cause of the injury, either totally, as a substantial factor, or as an aggravating and underlying disorder, resulting in death or impairment sooner than would have occurred otherwise. A detailed analysis of Prosser and Keeton, 41, Causation in Fact is appropriate. As described therein: the term "cause in fact" embraces all things which have so far contributed to the result that without them it would not have occurred. 41 at 265. Certain "rules" with modifications come into play in this analysis. The so-called "but for" rule is defined as: The defendant's conduct is a cause of the event if the event would not have occurred but for that conduct; conversely, the defendant's conduct is not a cause of the event, if the event would have occurred without it. 41 at 266. The authors, however, recognize that the "but for" rule cannot be 1 applied universally, specifically where more.than one variable may "cause" -14- 6336 the event. In recognition of such inadequacy of the "but for" rule, various courts have fashioned the so-called "substantial factor" rule as follows: The defendant's conduct is a cause of the event if it was a material element and a substantial factor in bringing it about. It has been considered that "substantial factor" is a phrase sufficiently intelligible to furnish an adequate guide in instruction to the jury, and that is neither possible nor desirable to reduce it to any lower terms. 41 at 267 (Footnotes and citations omitted). In particular, the "substantial factor" test has been adopted by the New York Court of Appeals. Dunham v. Village of Canisteo, 303 N.Y. 498, 104 N.E.2d 872 (1952); see also Restatement (Second) of Torts, 430-433 (1965). At least one commentator seems to couch "substantial factor" in the form of "causal linkage". See Calabresi, "Concerning Cause and the Law of Torts", 43 U. Chi. L.Rev. 69 (1975). Specifically, "causal linkage" is defined in part as when ". . . the occurrence of activity A will increase the chances of injury B." (at 71, footnote 4). The "substantial factor" test also has been described by another commentator as the "material and contributing factor" test in cases of mixed causation; this requires only that plaintiff show defendant's conduct contributed to the injury. See, Delgado, "Beyond Sindell: Relaxation of Cause-In-Fact Rules for Indeterminite Plaintiffs", 70 Cal. L.Rev. 881, 887 (1983). (The lack of pertinence of the so-called "indeterminate plaintiff problem" will be discussed hereinafter) Insofar as proof on the issue of causation, Prosser and Keeton indicate clearly that expert testimony may provide a sufficient basis for it (see, 41 at 269); see also Pritchard v. Liggett & Myers Tobacco Co., 3d Cir. -15- b 1961, 295 F.2d 292 (1961); Grinnell v. Charles Pfizer Co., 274 Cal. App. 2d 424, 79 Cal. Rptr. 369 (1969). In addition, it is noted there that ". . . fact of causation is incapable of mathematical proof." Plaintiffs' proof in the Agent Orange case was sufficient under either "rule" to establish "causation in fact." However, we submit that the "but for" rule is singularly inappropriate in the general context of "disease litigation." The "substantial factor" rule is conceptually more akin to the medical and scientific realities in the qualitative and quantitative assessment of cause in a possible multi-factorial context, e.g. Agent Orange disease. This will be discussed and developed more fully hereinafter. Medical causation is vitally important to a physician in treating his patient. Indeed, "diagnosis" has been defined as "a medical term, meaning the source of a patient's illness or the determination of the nature of his disease from a study of its symptoms." Black's Law Dictionary, 408 (rev. 5th ed. 1979) (Emphasis supplied). Medical causation, although related to "causation in fact", is nonetheless analytically distinct. See, Olson v. St. Croix Valley Memorial Hospital, Inc., 55 Wis. 2d 628, 201 N.W.2d 63, 65-66 (1972). Thus, a patient may be advised of the source or nature of his disease, and yet have insufficient medical evidence as a plaintiff to prove tha't any particular defendant was the proximate cause of his injuries. The difference between causation in fact and medical causation has been well-described in the following terms: ~* The physician who testifies in proceedings aimed at answering the basic question of legal causation is placed *in a professionally uncomfortable position, because the legal approach to causation differs markedly from the medical approach to which the -16- 6338 physician is accustomed through his specialized training and experience. For example, in viewing a patient's current medical problems, physicians more or less instinctively search for the basic cause or causes of the disorder that underlies those problems. Judges and attorneys, in contrast, seek to determine whether one particular event precipitated, hastened, or aggravated the patient's current condition. Furthermore, physicians, oriented toward treating the entire patient, strive to identify and to understand all aspects of the patient's condition, whereas judges and attorneys tend to limit their concern to only that aspect of the patient's condition that allegedly was precipitated, hastened, or aggravated by the event in question. Danner, Douglas, "Medicolegal Causation: A Source of Professional Mis understanding", 3 Am. J. Law & Med., 303, 304 (1977). The plaintiff in a tort case is required only to introduce evidence which establishes that the acts of the defendants "more probably than not" caused, contributed to or aggravated the injury (disease), taking into consideration all admissible evidence, including experts' opinions. I -17- ...S :) C. Expert Opinion An "expert" is a witness who is permitted to testify as to matters about which the trier of fact has insufficient knowledge to make the necessary inferences to arrive at a decision on the ultimate issues in dispute. Similarly, "expert testimony" is that class of matters as to which a person acquires knowledge only by means of some experience, knowledge or training not shared by the general population. Expert testimony is even required in certain types of cases. For example, in a medical malpractice case, a plaintiff must normally establish through a medical expert the appropriate standard of care in the locality. The expert must also prove that defendant was negligent in light of that standard and that his lack of skill or care proximately caused plaintiff's injury. See, Kalski v. Tiesenga, 72 111, 2d 249 (1978) and Borowski v. Von Solbrig, 60 111. 2d 418 (1975). Traditionally, the expert has derived his facts and data to support his opinions from two sources. First, the expert could render an opinion based on his firsthand knowledge of the facts, as, for example, a treating physician. Second, the expert could render an opinion based upon facts given to him in a hypothetical question. A treating physician, for example, could testify as to his observations, treatment, and diagnosis of a patient based on his firsthand knowledge~of those facts. If the treating physician was1not qualified to read x-rays, then the radiologist could testify to the radiological findings and those findings could be incorporated in a hypothetical question as -18- 6340 additional facts to be considered by the physician in forming his opinion. If further corroborating testimony of the treating physician's opinions was deemed necessary, a non-treating physician could be called as an expert witness. He could then be asked a hypothetical question, incorporating the treating physician's findings and opinions, the radiologist's findings and opinions, and the plaintiff's account of the incident, as bases for his opinion. The use of expert testimony was streamlined and simplified in 1975 by the adoption of the Federal Rules of Evidence, and thereafter by the many states which have incorporated them in whole or in part. Rule 702 states: If scientific, technical, or other specialized knowledge will assist the trier of fact to understand the evidence or to determine a fact in issue, a witness qualified as an expert by knowledge, skill, experience, training, or education, may testify thereto in the form of an opinion or otherwise. Rule 702 speaks for itself. Rule 703 states: The facts or data in the particular case upon which an expert bases an opinion or inference may be those perceived by or made known to him at or before the hearing. If of a type reasonably relied upon by experts in the particular field in forming opinions or inferences upon the subject, the facts or data need not be admissible in evidence. The purpose of Federal Rule 703 is to eliminate the expenditure of substantial time and effort in producing and examining various authenticating witnesses. As long as the requirement is met that the A facts or data "be of a type reasonably relied upon by experts in the particular fi^ld", the rule is satisfied. The assumption is that the f -19- 6341 expert himself is fully competent to assess the reliability of infor mation received from others. Rule 704 states: Testimony in the form of an opinion or inference otherwise admissible is not objectionable because it embraces an ultimate issue to be decided by the trier of fact. As in Rule 702, Rule 704 is clear on its face. Rule 705 states: The expert may testify in terms of opinion or inference and give his reasons therefor without prior disclosure of the underlying facts or data, unless the court requires otherwise. The expert may in any event be required to disclose the underlying facts or data on cross-examination. The purpose of Rule 705 is to eliminate the necessity of the hypothetical question during trial. As the Advisory Committee has noted, "[t]he hypothetical question has been the target of a great deal of criticism as encouraging partisan bias, affording an opportunity for summing up in the middle of the case, and as complex and time consuming . . . While the rule allows counsel to make disclosure of the underlying facts or data as a preliminary to the giving of an expert opinion, if he chooses, the instances in which he is required to do so are reduced." Fed. R. Evid. 705, Advisory Committee Note. A key element in applying Rules 703 and 705 is whether the information upon which the expert bases his opinion is of a type which is "reliable". Federal courts have allowed expert opinion testimony based upon a wide 4 variety of informational sources since 1975. A trial court's discretionary supervision inj determining what information is "reasonably relied upon" by an expert can.lead to admission of expert opinion testimony based on an -20- 6342 expanding variety of inadmissible facts and data. While the facts or data that the Federal courts have determined to be "reasonably reliable" can be challenged, the burden is placed on the cross-examiner to do so. The general rule on opinion testimony as it relates to causation-in-fact is whether the injury is "more probably than not" related to the event, in this case, the exposure to Agent Orange. Various courts have couched the standard of legal sufficiency in this regard to "reasonable degree of medical certainty", "reasonable medical probability", even "might have caused" or "could have caused". In the last analysis, however, the differences are essentially semantic. See, e.g., Miller v. National Cabinet Co., 8 N.Y.2d 277, 168 N.E.2d 811, 204 N.Y.S.2d 129 (1969). What the courts actually require, as noted above, is that evidence transcends "conjecture or speculation" to that which a jury may reasonably conclude that the event (exposure) resulted in the condition (adverse health effect). This Court had already concluded that the standard of "more probably than not" was to be employed, presumably in accordance with the prevailing view and New York law. See, e.g. Matott v. Ward,423 N.Y.S.2d 645, 47 N.Y.2d 455, 399 N.E.2d 532 (1979); Sentilles v. Inter-Carribean Shipping Corp., 361 U.S. 107, 80 S.Ct. 173, 4 L.Ed.2d 142 (1959). In Sentilles, supra, the Supreme Court reinstated plaintiff's District Court jury verdict. The Court held that the failure of medical experts to testify that plaintiff's tubercular condition had in fact been caused by a work-related accident did not preclude the jury from drawing a legal conclusion of causation, which was specifically noted to be its (the jury'"s) duty: -* The jury's power to draw the inference that the aggravation of petitioner's tubercular condition, evident so shortly after the accident, was in fact -21- 6343 caused by that accident, was not impaired by the failure of any medical witness to testify that it was in fact the cause. Neither can it be impaired by the lack of medical unanimity as to the respective likelihood of the potential causes of the aggravation, or by the fact that other potential causes existed and were not conclusively negated by the proofs. . . . The members of the .jury, not the medical witnesses, were sworn to make a legal determination of the question of causation. They were entitled to take all the circumstances, including the medical testimony, into consideration. 361 U.S. at 109-110 (Emphasis supplied). In short, the Federal Rules of Evidence specifically provide for opinion testimony by qualified experts (Plaintiffs' experts were eminently qualified). See, Fed. R. Evid. 702. Opinion evidence may include expressions of causation in fact, negligence, "outrageous conduct", or any other "ultimate issue". See, Fed. R. Evid. 704. Most importantly, the decisional law, i.e. Sentilles, etc. mandates that the fact-finder, here the jury, ". . . make a legal determination of the question of causation." / I -22- D. D isea se L it ig a t io n With this background on causation, and the modern use of experts under the Federal Rules of Evidence, it is appropriate to examine specific cases involving personal injuries, with specific causation problems, especially in the area of disease and related litigation. While the cases fall into different categories, the vast majority of Courts have held that there is sufficient evidence to go to the fact-finder, even where there are conflicts between expert testimony. The Courts hold that the conflict is for the fact-finder to resolve. The general standard of opinion testimony as to whether the disease resulted from the exposure is on a "more probably than not" basis. Host Courts have agreed that this standard is sufficient to raise a jury question, recognizing that some uncertainty exists in every issue of fact. As well summarized by one commentator: There is universal recognition that some uncertainty must attach to all human affairs. So the general quantum of civil proof required is recognizably not perfection ("absolute") but "reasonable certainty" or "reasonable probability" which may be established by the preponderance of the evidence. "Preponderance of the evidence" is generally recognized as the "greater weight" of evidence which tips the scales of justice in favor of the prevailing party. It need not "satisfy the minds" of the jury to the establishment of the facts, but need only allow reason able men conclude that the greater probability J.ies with the plaintiff. Belli, Modern jTrials, 5.2 (2d ed. 1982) (Citations omitted). -23- In American L ife In s. Co. v . Moore, 216 Ark. 44, 223 S.W.2d 1019 (1949), the doctor for the plaintiff stated that in his opinion the fracture of the decedent's leg, which he had received while cutting timber, was the probable cause of the pulmonary embolism and subsequent death of the decedent. Plaintiff's expert did not preclude all other causes. The defendant's doctor denied any causal relation and stated that the time lapse between the accident and the pulmonary embolism was too great to justify such a relation. The court said: This conflicting expert testimony presented a question for the jury . . . when medical men differ about the matter the verdict is not contrary to natural or scientific principles, nor is it based on what is not and could not be true. 216 Ark. at 45. In Smith v. Humboldt Dye Works, Inc., 34 A.D. 2d 1041, 312 N.Y.S.2d 612 (1970), a worker allegedly contracted cancer of the bladder after exposure to aniline dyes. He had been an assistant dyer, dyer and foreman in charge of dyeing wool y a m for a period of about twenty-five years. Claimant's two medical expert witnesses concluded that the cancer was caused by exposure to finished dyes containing anilines, beta naphthy- lamines and alpha naphthylamines. The employer sought review of a disability award. The court affirmed, explaining: Appellants' two medical experts testified that, in their opinion, there was no causal relation between claimant's work and the disease. The issue of causal relation thus presents the usual conflict of medical testimony which is a question of fact for the board to determine * * * The record contains substantial evidence to support the board's finding of causal relationship. 312 N.Y.S.2d >at 614 (Citations omitted). i -24- In Fink, Appel., v. Sheldon Axle & Spring Co., 270 Pa. 476, 113 Atl. 6 6 6 , 667 (1921), the plaintiff sought workers' compensation for a paralysis which he claimed was caused by being struck in his employer's establishment. The court said: It must be understood, however, that when, in cases of this class, expert testimony is relied on to show the connection between an alleged cause and a certain result, it is not enough for the doctors to say simply that the ailment in question might have resulted from the assigned cause, or that the one could have brought about the other; they must go further and testify at leas t that, taking into consideration all the attending data, it is their professional opinion the result in question most probably came from the cause alleged. 270 Pa. at 479 (Emphasis supplied). In Kling v. Central Lumber & Millwork Co., 3 N.J. Super. 151 (1949), the plaintiff fell from a platform while on duty. It was held that the trauma probably aggravated a brain tumor was sufficient. Similarly, in Sundquist v. Madison Rys. Co., 197 Wis. 83, 221 N.W. 392 (1928), a plaintiff claimed hysterical paralysis as the result of a collision with a streetcar two months earlier. The court allowed recovery on testimony of two doctors that such a result may probably follow, or is likely, liable or apt to follow an accident. At least one Federal Court has criticized the use of the terms "probable" and "possible" as frequently converting the trial into a "semantic ritual or hassle." Norland v. Washington General Hospital, 461 F.2d 694, (8 th Cir. 1972). The court then stated that regardless of the term used in a doctor's testimony: ^A . . . if his testimony is such in nature and basis of hypothesis as to judicially impress that the opinion expressed represents his professional judgment as to the most likely one among the possible causes of the ,' -25- 6347 conditions involved, the court is entitled to admit the opinion and leave its weight to the jury. 461 F.2d at 697. In Dzurik v. Tamura, 44 Haw. 327, 359 P.2d 164 (1960), the court explained: When causation of the injury is a medical issue, as it is here, "the matter does not turn on the use of a particular form of words by the physicians in giving their testimony," since it is for the trier of facts, not the medical witnesses, to make a legal determination of the question of causation. Hence, the failure of a medical witness to testify positively as to what was the cause of the injury, or his statement that the accident "might" be or "probably" was the cause of the injury, is merely a circumstance to be taken into consideration by the trier of facts. 359 P.2d at 165-66. In Eli Witt Cigar and Tobacco Company v. Matatics, 55 So.2d 549 (Fla. 1951), the Supreme Court of Florida held that the time sequence of the accident and the symptoms of the condition, plus expert testimony that the condition "could have" been caused by the accident were sufficient to create a jury question on the issue of causation. The court explained: The plaintiff testified that he had never suffered dizzy spells prior to the first accident, that he began to suffer such spells immediately thereafter, and that he had such a spell only three or four days prior to the second accident. It was also shown by the expert testimony of a physician that a loss of equilibrium could result from a brain concussion. We think that such evidence fairly warranted an inference of proximate cause and effect between the brain concussion and the dizzy spells, under the authority of Southern States Power Company v. Clark, 181 Fla. 521, 159 So. 881. 55 So.2d at 551 (Emphasis supplied). 4 > In Itfeal Food Products Co. v. Rupe, 76 Ariz. 175, 261 P.2d 992 ) (1953), plaintiff claimed that she contracted traumatic arthritis from a -26- 6348 f a l l caused by th e d e fe n d a n t's n e g lig e n c e . The court s ta te d : . . . [W]e held that where there was expert testimony that the injury possibly was or could have been the cause, together with other evidentiary circumstances indicating the verity of the causal relationship, same could legitimately be found. 76 Ariz. at 178 (Emphasis in original). Two recent cases which are most analogous to the specific causation issues addressed herein are Ferebee v. Chevron Chemical Co., 552 F.Supp. 1293 (D.C. 1982); aff'd 736 F.2d 1529 (D.C. Cir. 1984), cert, denied (See Appendix 3) and Allen v. United States, 588 F.Supp. 247 (D. Utah 1984). In Ferebee, supra,an agricultural worker was exposed to the herbicide paraquat. He ordinarily sprayed it six or seven times a month for between one and three hours during the outdoor growing seasons of 1977-1979 in Maryland. He allegedly developed pulmonary fibrosis, which caused his death. Decedent's estate offered both of plaintiff's treating physicians as expert witnesses. They testified that, in their opinion, paraquat had caused plaintiff's illness. This was based not only on their own observations of plaintiff and medical tests that they performed on him, but also on medical studies which they asserted suggested that dermal absorption of paraquat could lead to chronic lung abnormalities. The defendant urged that there was insufficient medical evidence to support this theory of causation. The jury resolved the issue in favor of the plaintiff. In seeking judgment n.o.v., the defendant again attacked the scientific methodology of the plaintiff: ' ^ Defendants [sic] also argue, based upon the evidence of Dy.'Carrington, that plaintiff's experts did not base their conclusions upon proper scientific methodology, as -27- is required of a medical expert. * * * Dr. Carrington stated that the only proper way to establish a medical hypothesis scientifically would be either to do a number of animal studies on the subject or to conduct a population study, surveying a large number of cases. Since cases of dermal paraquat poisoning of any kind are so rare, a population study is impossible, and, according to Dr. Carrington, animal studies have not yet been done in sufficient numbers to support the hypothesis that dermal exposure can cause this kind of disease. 552 F.Supp. at 1301 (Citations omitted). The District Court rejected the argument of the defendant in no uncertain terms: It is true that medical expert testimony must be grounded in proper scientific methodology, but the extremely stringent standard that defendant suggests is beyond reason. Product liability law, especially as it relates to relatively new products or those with a relatively rare yet significant danger, would be rendered next to meaningless if a plaintiff could prove he was injured by a product only after a "statistically significant" number of other people were also injured. A civilized legal system does not require that much human sacrifice before it can intervene. The fact that this is the first case of this exact type-- or at least the first of its exact type in which the involvement of paraquat was discovered by alert doctors-- -cannot be enough by itself to shield defendant from liability. Defendant's experts were not able to fault Dr. Crystal for his basic diagnostic methodology; in fact, they used the same kinds of test results, consultations, and other tools that he did. What they disagreed with chiefly were his conclusions. 552 F.Supp. at 1301 (Emphasis supplied). On appeal, Chevron again attacked the jury's verdict. It urged that there had never been any scientific evidence nor suggestion that paraquat could cause chronic lung injury, and, in any event, decedent ^ -4 ' > J' could not have been exposed to enough paraquat to injure him as claimedv/ ; The C<^urt of Appeals for the District of Columbia Circuit affirmed, i explaining: ^ ft,t'" p L>45 i ' -28- i I I The short answer to Chevron's argument is that two expert witnesses refuted it and that the jury was entitled to believe those experts. Both Drs. Crystal and Yusuf, who are eminent specialists in [ pulmonary medicine and who were Ferebee's treating physicians, testified that paraquat poisoning was the cause of Ferebee's illness and death. Both i admitted that cases like Ferebee's were rare, but Dr. Crystal identified three other cases he felt were similar to that of Mr. Ferebee. Chevron argues that these cases can be distinguished from i Mr. Ferebee's, but it is not our role to decide the merits of Chevron's attempted distinctions; Dr. Crystal thought the cases were similar, and the 1 jury was entitled to believe him. Chevron of course introduced its own experts who were of the view that Ferebee's illness was not caused by paraquat, but the testimony of those witnesses, who did not treat Mr. i Ferebee or examine him, can hardly be deemed so substantial that the jury had no choice but to accept it. The experts on both sides relied on essentially I the same diagnostic methodology; they differed sole ly on the conclusions they drew from the test results and other information. The case was thus a classic i battle of the experts, a battle which the jury must decide the victor. * * * 736 F.2d 1529 at 1535 (D.C. Cir. 1984) (Citation omitted)(Emphasis supplied). i s - The Court of Appeals rejected the argument of Chevron that the 1. approach of plaintiff's expert witnesses was not sufficiently reliable: Chevron seeks to avoid this conclusion by asserting 1 that expert opinion testimony must be generally accepted in the scientific community before it can be introduced I as evidence and that the views of Drs. Crystal and Yusuf, while not rejected by the medical community, are sufficient ly novel at this point as to be inadmissible. As support for this proposition, Chevron cites the Maryland Court I of Appeal's statement in the criminal case of Reed v. State, 283 Md. 374, 381, 391 A.2d 364, 368 (1978): "before a scientific opinion will be received in evidence I at trial, the basis of that opinion must be shown to be generally accepted as reliable within the expert's particular scientific field." The court in Reed, however, tfas referring to the introduction of evidence based on i: novel scientific techniques or methodologies, see, id. 391 A.2d at 367-68, and carefully distinguished the test Applied to such evidence from that involved in the admission of scientific opinion testimony that, while i . -29- controversial in its conclusions, is based on wellfounded methodologies. ("The question of the re liability of a scientific technique or process is unlike the question, for example, of the helpfulness of particular expert testimony to the trier of facts in a specific case.") Id. 736 F.2d at 1535 (Emphasis in original). The Court of Appeals also rejected Chevron's assertion that a cause-and-effeet relationship had to be clearly established by animal or epidemiological studies before plaintiffs' expert testimony could be given any weight: . . . a cause-effect relationship need not be clearly established by animal or epidemiological studies before a doctor can testify that, in his opinion, such a relationship exists. As long as the basic methodology employed to reach such a conclusion is sound, such as use of tissue samples, standard tests, and patient examination, products liability law does not preclude recovery until a "statistically significant" number of people have been injured or until science has had the time and resources to complete sophisticated laboratory studies of the chemical. In a courtroom, the test for allowing a plaintiff to recover in a tort suit of this type is not scientific certainty but legal sufficiency if reasonable jurors could conclude from the expert testimony that paraquat more likely than not caused Ferebee's injury, the fact that another jury might reach the opposite conclusion or that science would require more evidence before conclusively considering the causation question resolved is Irrelevant. That Ferebee's case may have been the first of its exact type, or that his doctors may have been the first alert enough to recognize such a case, does not mean that the testimony of those doctors, who are concededly well qualified in their fields, should not have been admitted. 736 F.2d at 1535-1536 (Emphasis' in original). The policy enunciated by both Ferebee Courts is clearly appropriate, and we urge its adoption by this Court. ^ On the substantive level, the facts in the Agent Orange case are even more compelling. Here, both toxicolqgical and epidemiological . -30- 6352 s tu d ie s have been conducted as w e ll as th e "standard t e s t s and p a tie n t examination" included in Ferebee. Clearly, those studies are relevant in demonstrating a probable relationship between exposure to Agent Orange and the various adverse health effects. See, e.g., Hall and Silbergeld, "Reappraising Epidemiology: A Response to Mr. Dore." 7 Harv. Envtl. L.Rev. 441, 445 (1983). Finally, in Ferebee, the Court of Appeals refused to hold, as a matter of law, that a low level of exposure to a toxic chemical, such as paraquat, could have no adverse health effects on plaintiff: Finally, Chevron argues that its expert, Dr. Fisher, proved that it was physically impossible for Ferebee to have been exposed to enough paraquat to cause him any injury. Dr. Fisher's testimony, however, went only to the amount of paraquat necessary to cause the short-term illnesses that have long been recognized to follow from paraquat exposure. Accepting Dr. Fisher's testimony as true, as plaintiff's did not at trial, it still would not necessarily follow that the same amount is needed to trigger a chronic case like that which Ferebee allegedly contracted. The jury could therefore have concluded that Ferebee had been exposed to sufficient amounts of paraquat to cause the chronic disease from which he, suffered-- even if that exposure was not substantial enough to produce acute symptoms. The dose-response relationship at low levels of exposure for admittedly toxic chemicals like paraquat is one of the most sharply contested questions currently being debated in the medical community, see generally Leape, Quantitative Risk Assessment in Regulation of Environmental Carcinogens, 4 HARVARD ENVT'L L. REV. 8 6 , 100-103 (1980); surely it would be rash for a court to declare as a matter of law that, below a certain threshold level of exposure, dermal absorption of paraquat has no detrimental effect. We therefore conclude that there was sufficient evidence of causation to justify submission of that issue t.o the jury. 736 F.2d at 1536. I -31- n or; O Ju-- The language in Ferebee i s p a r tic u la r ly p e r tin e n t, in th at the factual setting in Agent Orange is remarkably similar to that which confronted the District of Columbia Court of Appeals! The effort to fashion a fair and just "rule of law" often involves an analysis of appropriate policy considerations. As one commentator, see, Malone, "Ruminations on Cause-in-Fact", 9 Stanford L.Rev. 60 (1956), puts it: . . . Whenever it can be said with fair certainty that the rule of conduct relied upon by the plaintiff was designed to protect against the very type of risk to which the plaintiff was exposed, courts have shown very little patience with the efforts of defendant to question the sufficiency of the proof on cause. Such cases nearly always reach the jury if the plaintiff's contention on the issue has the slightest factual possibility . . . . 9 Stanford L.Rev. at 73 (Emphasis supplied). A similar functional approach to "causation in fact" is described by another commentator, see, Calabresi, "Concerning Cause and the Law of Torts", 43 U. Chi. L.Rev. 69 (1975), where it is stated: Causal requirements, like all other legal requirements, must ultimately justify themselves in functional terms. Law is a human construct designed to accomplish certain goals . . . object of law is to serve human needs, and thus legal terms . . . must sooner or later be linked to the service of human needs. 43 U. Chi. L.Rev. at 105. As demonstrated, even to the highly emotional level, at the Fairness Hearings conducted in 5 cities by this Court, the magnitude of the suffering of these veterans and their families should be, to the extent possible, "linked to the service of human needs." The "causal requirements" therefore should,' as t a policy matteq, 'serve those needs. -32- 6354 Clearly, in the Agent Orange cases, we were prepared to prove . . that the rule of conduct relied upon by the plaintiff was designed to protect against the very type of risk to which the plaintiff was exposed . . . Recently, the District of Utah spoke to that concept. In Allen v. United States, 588 F.Supp. 247 (D. Utah 1984), plaintiffs sought to recover for cancer or leukemia allegedly caused by United States testing of atomic devices prior to 1953. The court first explained that the issue of causation was very difficult: In this case, the factual connection singling out the defendant as the source of the plaintiffs' injuries and deaths is very much in genuine dispute. Determination of the cause-in-fact, or factual connection, issue is complicated by the nature of the injuries suffered (various forms of cancer and leukemia), the nature of the causation mechanism alleged (ionizing radiation from nuclear fallout, as opposed to ionizing radiation from other sources, or other carcinogenic mechanisms), the extraordinary time factors and other variables involved in tracing any causal'relationship between the two. 588 F.Supp. at 405. The court also noted that the issue of causation was further complicated by the long delay between the exposure to radiation and the observed cancer or leukemia. 588 F.Supp. at 405. Nonetheless, the court said that a remedial framework could still be fashioned to fairly compensate a plaintiff's injuries. 588 F.Supp. at 414-415. The Allen court is to be commended for, grappling so well with such a complex problem. The real value is that the Allen "causation solution" is ^t the same time scientifically sound, judicially workable i because of its relative simplicity, and most;importantly, fair and just from a policy standpoint. The court had extensively discussed a series of cases dealing with the problem of indeterminate causation in which a plaintiff was able to rely on a series of factual connections which established a rational, reasonably exclusive relationship between a defendant's conduct in releasing lethally hazardous chemicals into the environment and each claimant's injuries. 588 F.Supp. at 407-414. In these cases, the burden then shifted to the defendant to show that his conduct had not played a substantial factor in causing the harm. In Allen, the court then held: Where a defendant who negligently creates a radio logical hazard which puts an identifiable population group at increased risk, and a member of that group at risk develops a biological condition which is consistent with having been caused by the hazard to which he has been negligently subjected, such consistency having been demonstrated by substantial, appropriate, persuasive and connecting factors, a fact finder may reasonably conclude that the hazard caused the condition absent persuasive proof to the contrary offered by the defendant. In this case, such factors shall include, among others: (1 ) the probability that plaintiff was exposed to ionizing radiation due to nuclear fallout from atmospheric testing at the Nevada Test Site at rates in excess of natural background radiation; (2 ) that plaintiff's injury is of a type consistent with those known to be caused by exposure to radiation;' and (3) that plaintiff resided in geographical proximity to the Nevada Test Site for some time between 1951 and 1962. Other factual connections may include but are not limited to such things as time and extent of exposure to fallout, radiation sensitivity factors such as age or special sensitivities of the afflicted organ or tissue, retroactive internal or external dose estimation by current researchers, a latency period consistent with a radiation etiology, or an observed statistical incidence of the alleged injury greater than the expected incidence in .the same population. . 588 F.Supp. at 415. i -34- The striking similarity to the types of disease associated with Agent Orange, especially various forms of cancer, is manifest, and we submit, compelling. Also it is consistent with the approach taken by 2 commentators, i.e. Hall and Silbergeld, "Reappraising Epidemiology: A Response to Mr. Dore", 7 Harv. Envtl. L.Rev. 441, 445 (1983). Finally, the court noted that the government's own negligence at the time of the incidence in this case was an additional persuasive factor warranting a shift in the burden of causation, given the other connecting factors: . . . the Government's negligent failure to adequately monitor and record the actual external and internal radiation exposures of off-site residents on a personspecific basis has yielded many glaring deficiencies in the evidentiary record as it relates directly to the question of causation. The current multi-million dollar effort to reconstruct the radiation dosages received by plaintiffs or their decedents is constantly hampered by the failure of the off-site radiation safety personnel to gather whole categories of exposure data at the time that the exposures actually took place. Furthermore, had Government personnel provided adequate warnings of risk and information as to precautions minimizing the amount of exposure, a materially different picture as to appropriate inferences about factual connection and cause-in fact might now be presented. Accurate monitoring of persons largely was not undertaken; adequate warnings and information were almost entirely omitted from the operational radiation safety activities. A strong additional reason for shifting the burden of proof on the cause-in-fact question is thus readily apparent from the record. 588 F.Supp. at 412-413. - -35- 6357 As to the burden-shifting aspect, in particular its applicability to the case against the chemical companies, please see Plaintiffs' Memorandum of Points and Authorities in Opposition to the United States' Motion to Dismiss filed October 10, 1984, specifically "9. Burden Shifting" , pp. 131-191, inclusive. 'This Court, in its Preliminary Memorandum and Order on Settlement dated September 25, 1984, strongly indicates approval of the burden- shifting concept in these circumstances when it states: The solution that would most readily suggest itself is a burden shifting approach, analogous to that used in the indeterminate defendant situation already discussed. Allen v. United States provides a good example of how burden-shifting would be applied in an indeterminate plaintiff case. A plaintiff must show that the co defendant, in that case the United States, negligently put "an identifiable population group" of which he was a member at "increased risk" and that his injury is "consistent with having been caused by the hazard to which he has been negligently subjected, such consistency having been demonstrated by substantial, appropriate, persuasive and connecting factors, a fact finder may reasonably conclude that the hazard caused the condition". Allen, slip op at 343. At that point, the burden shifts to the defendant who will be held liable unless it can offer "persuasive proof" of noncausation. Id. at 344. The argument applies with equal force to the chemical companies. The introduction of similar pertinent evidence would have laid the factual predicate for this "burden shifting approach" as t the defendants (chemical companies). Plaintiffs however take strong issue with the Court when it says that "it would be impossible in most cases to identify the individual class members who were injured by Agent Orange". (Prel.^Memo., pp. 296- 297). While the class device was appropriate for reasons expressed at length and often, each individual's case in terms of causation in fact, J ' 6358 -36- . proxim ate cau se and damages must be handled "on a c a s e -b y -c a s e b a s is using the preponderance-of-the evidence rule". This is the essential reason why the "indeterminate plaintiff" problem is not relevant to this case, Delgado's hypothesis notwithstanding. See, 70 Cal. L.Rev. supra at 887 (footnote 27). (Prelim. Memo, at 273 citing Santosky v. Kramer, 455 U.S. 745, 755, 102 S.Ct. 1388, 1395 (1982); W. Prosser, Handbook of the Law of Torts, 38 at 208-09 (1971); [Keeton and Prosser, The Law of Torts, 38 at 239 (1984)]; Kaplan, Decision Theory and the Fact Finding Process, 20 Stan. L. Rev. 1065, 1072 (1968)). With respect to the statistical evidence in Allen v. United States, supra (see, Prel. Memo, at 273), we submit that there are stronger positive associations in certain Agent Orange/dioxin-related cancers, e.g. soft-tissue sarcoma and lymphoma, than exist with low-level ionizing radiation and leukemia. As noted a few pages later (see, Prel. Memo, at 278), the fact finder (the Court in Allen) noted significant variation in experts' interpretations of statistical evidence, but notwithstanding such variation, found in favor of those plaintiffs based upon the analyses set forth earlier. In the last analysis, what the Courts did in Allen and Ferebee were to let the fact-finder resolve issues of credibility, giving appropriate weight to conflicting testimony - whether analyses and/or conclusions of expert witnesses. Nothing is as fundamental and so deep-seated in our system of American jurisprudence. We ask for no more! E. Application to Agent Orange Case 1. Agent Orange/Dioxin is highly toxic and carcinogenic. The most toxic of the several dioxin isomers is 2,3,7,8 -Tetra- chlorodibenzo-para-dioxin (TCDD) - commonly referred to as "the most toxic substance ever synthesized by man." TCDD has also been shown to be the most potent of all known carcinogens. These facts have been forcefully confirmed in agency reports, medical and scientific literature, and in testimony from Plaintiff, defense and government expert witnesses. The United States Environmental Protection Agency effectively characterized the extreme toxicity of TCDD in their "Ambient Water Criteria Document for 2,3,7,8 -Tetrachlorodibenzo-p-dioxin" of February, 1984 stating: 2,3,7,8-TCDD is one of the most toxic substances known. It exhibits a delayed biological response in many species and is highly lethal at low doses to aquatic organisms, birds and mammals. It has been shown to be acnegenic, fetotoxic, teratogenic, mutagenic (in a limited number of mutagenicity tests) and carcinogenic, and affects the immune responses in mammals. These findings, in conjunction with the wide distribution of contaminated products and its extreme stability in the environment, lead to the conclusion that 2,3,7,8TCDD represents a potential hazard to both aquatic and terrestrial life, and makes 2,3,7,8-TCDD one of the major concerns for public health. (Ambient Water Criteria Document for 2,3,7,8-TCDD, p. A-8 ) When Plaintiffs' government causation witness, K. Diane Courtney, Ph.D., was questioned "Is there any man-made substance that is any more toxic, to your knowledge, than TCDD?", she replied, "Based on my knowledge, I do not know of any man-made compound that is more toxic." ;(Courtney depo., 347:18-22) -Government witness Philip Landrigan of the National Institute for Occupational Safety and Health (NIOSH) described the extreme toxicity of TCDD differently, claiming that he did not know "of any other man-made toxin that J> -38- 6360 produces lethal results In any animal species at doses less than TCDD." (Landrigan depo., 251:6-8) Additionally, Plaintiffs' expert witness, Deborah Barsotti, Ph.D., testified "that dioxins are toxic, and in particular TCDD is exceptionally toxic", and, "that chronic low level exposure to dioxins is significantly toxic." (Barsotti 26(b)(4) Statement). Several Plaintiff, defense and government witnesses were prepared to further express both the extreme toxicity as well as the exceptional carcinogenicity of 2,3,7,8-TCDD. Dr. Donald Barnes, the Senior Science Advisor to the Assistant for Pesticides and Toxic Substances for the EPA claimed that: Certainly in terms of traditional measures of toxicity, it (2,3,7,8-TCDD) is in my opinion clearly demonstrated to be a particularly toxic chemical . . . (Barnes depo., 12:7-11) Dr. Barnes later added, "I would certainly characterize 2,3,7,8-TCDD as exquisitely or a uniquely toxic chemical . . .". (Barnes depo., 262:3-5) In addition, Dr. Barnes claimed: . . . that in animal studies 2,3,7,8-TCDD . . . can elicit a carcinogenic response. There are some data to suggest . . . that 2,3,7,8-TCDD may be -- exposure to 2,3,7,8-TCDD may be associated with the Incidence of cancer in humans. (Barnes depo., 77:12-17) Elaborating on the carcinogenicity of TCDD, six scientists involved in the peer review of the previously cited EPA Criteria study stated that: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is probably carcinogenic for humans on the basis of animal ' carcinogenicity studies which were positive in multiple species and organs. Epidemiological studies of workers exposejd ' to chemicals contaminated with TCDD such as 2,4,5-T (trichlorophenoxyacetic acid) and 2,4,5-trichlorophenol are consistent with the position that TCDD is -39- carcinogenic for humans; the available evidence indicates an excess incidence of soft tissue sarcomas. (Consensus Statement of July 29, 1983). Similarly, Plaintiffs' expert witness, Theodor D. Sterling, Fh.D., was prepared to testify: That there exists a considerable body of medical and scientific evidence which demonstrates that the preparations of 2,4,5-T and 2,4-D are toxic, teratogenic and carcinogenic . . based on the reviews of the literature and critical evaluation of data pertaining to the health effects of 2,4,5-T and 2,4-D on animals and humans and is contained in documents of which Dr. Sterling is the sole author. (Sterling 26(b)(4) Statement). Defendants' expert witness, Dr. Vernon Houk, agreed with these findings, claiming that: TCDD is carcinogenic in several species of animals, produces cancer in those animals in at least three different routes of exposure . . . (and) [i]t is very likely that it is a carcinogen in man. (Houk depo. , 113:7-12) Defendants' government causation witness, Dr. Han Kang, also affirmed the toxicity and carcinogenicity of TCDD. (See, Kang depo., 97-98, 141). Plaintiffs' expert witnesses, Drs. Codario, Legator, Orris, Hay and Silbergeld each intended to testify that Agent Orange and its contaminant TCDD is (1) highly toxic and (2) carcinogenic. (See generally, the 26(b) (4) Statements and supplements of Plaintiffs' expert witnesses). Specifically, Dr. Peter Orris is and was prepared to testify that: A r Dioxins are extremely toxic particularly 2,3,7,8-TCDD . . . Th$t TCDD is extremely toxic at extremely low levelsK . . That TCDD is carcinogenic, specifically causing soft tissue sarcomas and lymphomas . . . That TCDD as a carcinegen [sic] does not affect one organ, -40- but many . . . (and) . . . That additional sites of cancer may be caused by exposure to TCDD. (Orris 26(b)(A) Statement). Certain witnesses elaborated specifically on the strength of TCDD as a carcinogen. Drs. Ellen Silbergeld, Marvin Legator and Marvin Schneiderman testified that dioxin is a complete carcinogen. (See, Legator depo., 118, 147-148; Schneiderman depo., 357:4-19; Silbergeld depo., 221: 12-22, as well as subsection (d) infra). Stated differently: Dioxin is capable of contributing to all of the stages necessary to produce cancer and can enormously increase the incidence of cancer when prior carcinogenic exposure has occurred. (Schneiderman depo., 283:16-25, 284:1-8) Furthermore, Dr. Lennart Hardell is prepared to testify to the causal relationship between exposure to phenoxy herbicides and human cancer, particularly soft-tissue sarcoma and malignant lymphoma. (Hardell 26(b)(4) Statement). Finally, several expert witnesses testified to the overwhelming potency of TCDD relative to other carcinogens. Dr. Steven Bayard, a member of the Carcinogen Assessment Group (CAG), stated that 2,3,7,'8-TCDD was "the most potent of the 54 chemicals which the CAG evaluated as potential carcinogens . . .". (Bayard depo., 80:1-11) and that, With respect to relative potency, we (CAG) found that it (2,3,7,8-TCDD) was 100 times more potent than the next most potent chemical, which is benzidene, and 1 0 0 million times more potent than vinyl chloride. ; (Bayard depo., 80:19-22), 4 . y. t Moreover, Plaintiffs' government causation witness, Dr. Janet Springer, and Dr. Marvin Schneiderman and the, Environmental Protection Agency -41- 6363 each reiterated these relative potencies. (See, Springer depo., 41-42; Schneiderman 26(b)(4) Statement; Ambient Water Criteria Document). It is obviously clear that Agent Orange, with its contaminant 2,3,7,8-TCDD is the most toxic substance known to man. Testimony from both Plaintiffs and defendants agree on this point. These witnesses also acknowledge that TCDD is not only a proven carcinogen, but the most potent of all known carcinogens. Due to the extremely toxic and carcinogenic nature of TCDD, no "no effect" or "safe level" of exposure can be determined. (See the following section 2 ). > I . -42- 2. Agent Orange/dioxin has no safe level of exposure. Due to Its extreme toxicity, as detailed in subsection (1) supra, experts cannot determine what, if any, safe level or "no effect" level of dioxin exposure exists. In fact, Plaintiff and defense expert witnesses have testified (1) that there is no "safe level" of dioxin exposure, and (2) specifically, that as a carcinogen, there is no known "no effect" or "minimum effect" level. Addressing the exposure level of TCDD in general, Dr. Ronald Codario stated: . . . I think it's very important for us to understand that since scientists throughout the world can never agree on a safe limit for dioxin, we certainly must assume until proven otherwise that any exposure to TCDD, regardless of the amount, cannot be considered safe as of this time. (Codario depo., 427:2-7) Dr. Donald Barnes* deposition emphasized the uncertainty surrounding the levels of dioxin exposure. The testimony followed: Q. As it relates to 2,3,7,8-TCDD in toxicological terms, at what level do you believe there is a no effect, a minimum level? A. I don't think that's been established . . . Q. . . . What do you mean when you say it has not been established? A. I don't know what that level might be. (Barnes depo., 103:10-25, 104:1) The questioning continued: Q. In the case specifically of 2,3,7,8-TCDD, is^there any known level which is acceptable? Is there any known level today that is acceptable for risk for human beings being pxposed to this chemical? -43- A. There's nothing established on the books of any agency or Government or so on that I'm aware of. (Barnes depo., 104:13-16, 20-21) Stated differently, Dr. Schneiderman explained: . . . that dioxin has the steepest dose-response curve of any material that EPA has reported on, and that there's no material . . . that has a dose-response curve within that range . . . (Schneiderman depo., 185:10-16) Dr. Schneiderman concluded "I believe, and I think most people who are working in this field believe that there is no threshold, i.e. any level of exposure has some finite probability of causing the disease . . .". (Schneiderman depo., 236:20-24) Dr. Legator supplemented Dr. Schneiderman's statement in his deposition claiming: . . . TCDD is unique in every way . . . I am saying that TCDD is a unique chemical, and then by that I mean because it is so much more active than these other chemicals, that, indeed, you may get a greater blurring of a dose response curve than you would with a chemical that is less active in terms of inducibility. (Legator depo., 108:25, 109:1-7) As a known carcinogen, experts further contend that there is no known "no effect" level below which there is no increased risk of cancer Dr. Ellen Silbergeld effectively capsulized in her deposition testimony: . . . that once you have a known carcinogen . . . that is a substance which is known to produce carcinogenic effects within a range of doses below a lethal dose, there is no level below which that substance will not produce an increased risk . . . -44- In th e Annals o f th e New York Academy o f S cie n c es (NYAS), Volume on "Occupational Carcinogenesis", Dr. William J. Nicholson wrote, "In spite of considerable research on the effects of carcinogenic substances, no data exist that would define a threshold for any carcinogen, (Annals of the NYAS, Vol. 271, "Occupational Carcinogenesis", 155: 1976). In a subsequent volume of the NYAS on "Public Control of Environmental Health Hazards", Plaintiffs' expert, Dr. Marvin Schneiderman, summarized: We see little or no evidence for the existence of thresholds in human cancer. There is much conjecture, some of it high quality and there are some scattered data, but convincing evidence for threshold is not at hand either from animals or from man. Dose-response studies in the laboratory are consistent with there being no threshold for a carcinogen. (Annals of the NYAS, Vol. 329, 126: 1979). Defendants' expert witness, James G. Wilson, revealed that he did not know the dose relationship of cancer or the level of TCDD which does not cause cancer. (Wilson depo., 194:1-8). Dr. Marvin Legator further stated that: . . . with carcinogens, it's . . .difficult to establish a threshold if one does even theoretically exist, and TCDD is in particular, by the very nature of response we're seeing with it, I would venture to say that any amount of exposure could be detrimental. (Legator depo., 105:5-10) In addition, Plaintiffs' expert witnesses, Drs. Schneiderman, Levin, Legator and Orris are and were prepared to testify that no safe level exists for the highly potent carcinogen TCDD. Dr. Theodor Sterling planned to testify that: . . I There is no credible scientific evidence of a no effect level, said another way, as a carcinogen, there is no safe level and therefore, a single exposure years -45- ago may be responsible for human cancer which develops today. (Sterling 26(b)(4) Statement) Similarly, Dr. Alan Levin was prepared to state: That, in connection with the carcinogenic effect, there is no safe level for TCDD or any other carcinogen, and that a single exposure several years earlier can result in human cnacer many years later. (Levin 26(b)(4) Statement) Lastly, Drs. Schneiderman and Orris affirmed that there is no known safe level for TCDD - a known carcinogen. (See, Schneiderman depo., 239-240; Orris 26(b)(4) Statement). In summary, dioxin is highly toxic and carcinogenic at extremely low levels. For this reason, neither defense nor Plaintiffs' expert witnesses can state that a "safe level" of dioxin exposure exists. These witnesses instead hold that, in fact, no "minimum effect" or "no effect", or "threshold" level of dioxin exists. Furthermore, due to its extraordinary carcinogenicity, no safe level exists below which no increased risk of cancer occurs. It is clearly evident from the testimony and literature described herein that dioxin is uniquely toxic, rendering it virtually impossible to determine a "no effect" or "safe level" of exposure. 1 -46- 3. P la in t if f s were exposed to Agent O range/dioxin. Proving direct or proximate exposure of an individual Plaintiff to Agent Orange can be approached in different ways. Exposure to Agent Orange can be verified through testimony of the Plaintiff or his military co-personnel. This testimony can certify direct spraying, undocumented missions in sprayed areas, and the ingestion and inhalation of Agent Orange through eating, drinking, and living in defoliated areas. See, generally, depositions of representative Plaintiffs, e.g., depositions of George Ewalt taken 2/20/84 and 2/21/84, pp. 37-38; 72-96; 146-169; 264; 275-378; depositions of Dan Ford Taken 2/20/84 and 2/21/84, pp. 108-190; 222-292; 322-323; 376-422; 425-426; 430-439; 443-450; 464-482; depositions of Dan Jordan taken 2/22/84, 2/23/84 and 4/30/84, pp. 114-116; 120-121; 248-252; 281-490; 504-664; deposition of David Lambiotte taken 2/24/84, pp. 142-326; depositions of Mike Ryan taken 2/13/84 and 3/6/84, pp. 38-41; 121-127; 164; 223-408. Furthermore, Plaintiffs' expert witnesses were and are prepared to testify to the various methods of exposure as well as to the specific individual exposure of the representative Plaintiffs. (See the depositions and 26(b)(4) Statements and supplements of Plaintiffs' expert witnesses in general, and specifically: Codario depo., 109, 222-225, 562-563 and 26(b)(4) statement and supplements; Schneiderman depo., 190; Levin depo, 17-20). A second method of verifying individual exposure is through specific military documents. These documents can potentially prove exposure in and of themselves, or strengthen the Plaintiff or co-personnel testimony described above. In fact, the Army Agent Orange Task Force used these records along ^ith the spray mission tapes and general military knowledge - _47_ S369 to determine levels of exposure in the individual representative Plaintiffs. See, results of the Army Agent Orange Task Force Study attached as Appendix 2. Presumably, through determining the movement of a Plaintiff's military unit and correlating these movements with the spray mission tapes, individual exposure can be assessed. However, the documents used by the Task Force in their study and subsequently, a large portion of the military documents produced in discovery, were written on the Division or Batallion levels. Written on such high levels, these documents often excluded mention of any individual soldier's or their respective company's and unit's movements. Therefore, to construe the Army Agent Orange Task Force Study as complete in including all relevant exposure information would be inaccurate. For example, the Task Force determined that Plaintiff David Lambiotte was "not exposed". (See, Appendix 2 at p. A2-4) However, deposition testimony of the Plaintiff and/or his co-personnel would reveal that he frequently went on convoys in or near defoliated areas. The methods of proving individual Plaintiff exposure to Agent Orange described above can be further supplemented through testimony of specific military personnel, for example, Richard Christian. Such testimony could add to the validity or highlight the limitations of the military documents in addition to verifying and possibly supplementing individual Plaintiff or co-personnel testimony. -48- 4. Agent Orange/dioxin did cause an array of adverse health affects in the 9 representative Plaintiffs. The proof of Plaintiffs' causation case was premised upon a two- tier approach as the case was to be presented to the jury as a class action utilizing representative plaintiffs. One level of proof was to be an exhaustive explanation of the incredible toxicity of 2,3,7,8-TCDD (dioxin) and the many bodily systems which dioxin can affect. This testimony was to describe the animal studies, retrospective human studies, and the current epidemiological studies which all confirm that dioxin is capable of causing a multitude of pathologies, i.e. dermatological problems, liver and other systemic disorders, immunological disorders, neuro-toxic effects, cancers, and reproductive problems, including birth defects. Specifically, this proof would have established that dioxin is a "complete" carcinogen, i.e. both as an "initiator" and potent "promoter"; that therefore there is no safe level of exposure, and conversely, that any level of exposure is capable of causing disease. Plaintiffs' witnesses on causation would have testified within the scope of this level of proof, as well as the other aspect of causation proof, i.e. "cause-in-fact" which would have dealt with the specific problems presented on behalf of the class through the representative Plaintiffs. More particularly, some of the expert witnesses would have testified as to the cause in fact, i.e. exposure of Agent Orange in relationship to the adverse health conditions in the representative Plaintiffs. This dual level of proof was necessary to form the proper foundation for damageson behalf of the entire class as well' as for the jury to fully a 1 r comprehend the individual causation in the representative Plaintiffs. Without the overview of^toxicity, methods of testing for toxicity and carcinogenicity, -49- Q,1 i L and methodology of epidemiology as It relates to presumptive conclusions of causation, the testimony of exposure and "cause and effect" would have been received in a vacuum and would have been difficult for the jury to understand. When reviewing the current presentation of Plaintiffs' causation witnesses in this capsule summary, it must be remembered that the majority of the testimony was developed by counsel for the defendants through the discovery process. Had this matter proceeded to trial the same subject matter would have been structured and articulated in a positive and direct fashion rather than in an adversarial setting. Regardless of these limitations, the testimony and evidence presented herein will show that the Plaintiffs' causation case was complete and comprehensive and fully capable of establishing causation on behalf of the class, and for the representative Plaintiffs, within a reasonable degree of medical and scientific probability. A summary of each of the major areas of injury will be discussed below and will be followed by specific references to testimony as to the diseases present in each representative Plaintiff, together with factual support from the Record of the relationship of such diseases to the particular veteran-Plaintiffs' exposure to Agent Orange. I -50- 6372 a. Derm atological On this issue there can be no real dispute; TCDD can cause chloracne. As clearly stated by the United States Environmental Protection Agenty ("EPA"): The most commonly reported symptom related to 2,3,7,8TCDD exposure in man has been chloracne (Bauer et al., 1961; Kimmig and Schulz, 1957; Schulz, 1957; Firestone, 1977; Dugois and Colomb, 1956, 1957; Dugois et al., 1958; Bleiberg et al., 1964; Oliver, 1975; Poland et al., 1971; Kimbrough, 1980). (Ambient Water Quality Criteria for 2,3,7,8-Tetrachlorodibenzo-p-dioxin, U.S. EPA Office of Water Regulations and Standards, February, 1984, p. C-62) The fact that TCDD can cause chloracne was also repeated by Defense, Plaintiff and Government causation witnesses. Dr. Donald Barnes, a Ph.D. in chemistry and physics, called as a "government causation" witness, stated that TCDD has "clearly been demonstrated to be a particularly toxic chemical". (Barnes depo., 12:8-9) Dr. Barnes was the Science Advisor to the Assistant Administrator for Pesticide and Toxic Substances for the EPA and had participated in preparing the peer review documents of the EPA pertaining to TCDD. He was clearly of the scientific opinion that TCDD affects the skin and is acnegenic, i.e. it causes chloracne. (Barnes depo., 126:13-18) Dr. Barnes further acknowledged that all possible routes of exposure, i.e. inhalation, dermal absorption and ingestion, can result in adverse health effects. (Barnes depo., 157:4-13) Dr. Debdas Mukerjee, a Ph.D. in genetics and cytogenetics, while testifying primarily as to carcinogenicity .and reproductive problems, stated / s' that "TCDD at acute or subchronic exposures had demonstrated adverse health f' effects on the skin . . ." (Mukerjee depo., 98:6) and specifically, that 6373 *-51- "TCDD is acnegenic." (Mukerjee depo., \00:25) Furthermore, among Plaintiffs' witnesses, Dr. Deborah Barsotti, a toxicologist having done a substantial amount of research in halogenated aromatic hydrocarbons, including TCDD, stated: I have an opinion that on an individual basis, the halogenated aromatic hyrdocarbons, members of that class of compounds will induce chloracne in those species which are susceptible to chloracne. (Barsotti depo., 91:19-22) She supported her statement further, noting: "There are at this time indications that chloracne is a TCDD symptom in exposed animals and this is also certainly in the literature for humans." (Barsotti depo., 193:17-19) Plaintiffs' two primary expert witnesses, Dr. Ronald Codario and Dr. Peter Orris, stated clearly that the existence of chloracne is a significant sign of TCDD exposure and that, . . there is no question . . . chloracne has been found in humans so exposed to trichlorophenol and TCDD." (Codario depo., 576:15-18) The strength of dioxin to cause 6kin eruptions was expressed as: Chloracne may develop anywhere, especially with systemic exposure to these chemicals, but it has predominance in the exposed areas of the skin that may have been exposed to higher quantities of these chemicals than other areas. With respect to dioxin from herbicides or others, -you may find it in . . . areas other than exposed because clothes get soaked and various parts of the body were exposed, close relationship to the skin and that area of clothing. (Orris depo., 147:19-25, 148:1-3) More specifically, Dr. Codario indicated the significance of the location and cause of chloracne in representative Plaintiff Mike Ryan's case. /' In his examination and subsequent report on Mike Ryan (February 15, 1984), Dr. Codario noted: . . . and most significantly of all he developed a scarring acne-like eruption around the temples, cheeks and groin which still persist today . . . This gentle man has marked peripheral neuropathy along with an acne-like eruption in his groin. This combination of physical findings is highly consistent with TCDD poisoning and should be considered so unless proven otherwise. Young points out that when the acne eruption occurs in the groin, the diagnosis of chloracne is highly likely! (Codario report dated February 15, 1984) Dr. Ronald Codario affirmed Mike Ryan's diagnosis of chloracne in his deposition and attributed this condition to Ryan's dioxin exposure in Vietnam. Furthermore, Dr. Peter Orris recognized Plaintiff Dan Ford's "acneform lesions" as a condition confirming his exposure and thereby strengthening the association between his exposure and subsequent develop ment of soft-tissue sarcoma. Dr. Orris stated these factors after his examination of Dan Ford's medical records in his report of April 9, 1984, stating: In light of Mr. Ford's exposure to TCDD containing herbicides in Vietnam; the development of acneform lesions at that time, and the absence of any confounding exposures, it is likely in my opinion that his soft tissue sarcoma, that was diagnosed in 1980, was caused by his TCDD exposure in Vietnam. (Orris report to Thomas W. Henderson, Esq. dated April 9, 1984) The defendants recognized the causal relationship between TCDD exposure and chloracne. The defendants argued that absent chloracne, a specific individual could not associate other adverse health effects with their dioxin exposure. In other words, without having a diagnosis of chloracne, an i/ndividual plaintiff could not consider dioxin exposure a "cause" of any>of his subsequent medical conditions. - -53- 8375 Nevertheless, Plaintiffs were and are prepared to prove causation on a variety of adverse health effects (as outlined previously in subsection A) without chloracne as a necessary precursor. Plaintiffs' are of the opinion that chloracne is by no means a necessary presequisite for other Agent Orange/dioxin-related adverse health effects. Dr. Peter Orris elaborated on this, stating: The soft tissue sarcomas were not associated [with chloracne] to my knowledge, The patients that developed porphyria cutanea tarda did not necessarily have chloracne. The patients with acute and chronic neuropsychiatric problems did not necessarily have chloracne. I believe the patients with peripheral neuropathy as well did not have chloracne and case reports of hepatitis I don't think were associated 100 percent to chloracne. It is my reading of the literature that chloracne cannot be used as an index of exposure. (Orris depo., 152:25, 153:1-11) Nevertheless, it is clear that chloracne is a significant indicator of dioxin exposure. Plaintiffs hold, however, that chloracne is only one sign of exposure; more specifically, of acute, as opposed to chronic, exposure. Plaintiffs will set out in subparts b through e to prove specific individual causation on a variety of health problems which are not predicated on the presence of chloracne. b. Systemic Exposure to dioxin can cause systemic effects, that is, conditions or diseases involving the entire body as opposed to a localized condition. The primary systemic effects involve (1)the liver and (2) the immuno suppressive responses. i. liver The liver is the primary site of several metabolic activities. The liver's metabolism of TCDD, however, is not normal. TCDD is chemically stable, lipophilic and resists degradation, thus attributing to its bio accumulation (Barsotti 26(b)(4) Statement). Because TCDD is not water but fat soluble, it cannot be eliminated by the kidneys, "unless it is converted to a water soluble substance which does not appear to occur in humans." (Codario 26(b)(4) Statement, Section 111) Plaintiffs' expert witness. Dr. Deborah Barsotti, described this further, stating: Generally, however, the data indicate that if metabolism does occur the rate is slow (Guenther et al., 1979). The ramification of this finding is that the body would be in capable of or slow in ridding itself of TCDD and TCDD would accumulate and persist in the lipid stores. In Dr. Barsotti's work, as well as others', this appears to be the case with rhesus monkeys and man (Montagna et al., 1979; Van Miller, 1981; McNulty et al., 1983). (Barsotti 26(b)(4) Statement, Section V, subsection 2) TCDD, therefore, can be stored in the fat, furnishing a constant or chronic source of exposure. Plaintiffs' experts were and' are prepared to .testify / that, "The literature and . . . research documents that chronic exposure ' to TCDD exhibits^ many more deleterious effects than single or acute exposures," (Codario 26(b)(4) statement, Section IV, subpart 5) and that, 55- 8377 "stored in the lipid compartment . . . it can cause problems that continue on beyond the point that detectable dioxin can be found in the adipose tissue." (Levin depo., 136:10-13) By storing in fat, TCDD affects lipid profiles, causing increases in blood cholesterol and triglyceride levels; the increased blood cholesterol levels being a significant risk factor for cardiovascular disease. When asked whether TCDD affects lipid profiles, Dr. Hay responded: Yes, it does. The men in industry who have been exposed to TCDD have high blood cholesterol and high triglyceride levels. (Hay depo., 279:6-10) In addition, Dr. Hay testified that dioxin will cause blood cholesterol levels to rise. (Hay depo., 337:3-5) The EPA cited in its Ambient Water Quality Criteria Study several studies on TCDD-exposed workers noting significant liver disorders including raised levels of blood cholesterol and total lipids. (US EPA Ambient Water Quality Criteria for 2,3,7,8-Tetrachlorodibenzo- p-dioxin, C-62 to C-70, February, 1984) Exposure to TCDD also initiates enzyme induction, specifically upsetting the porphyrin metabolism which occurs in the liver. Drs. Hay, Silbergeld and Codario were prepared to testify on the effects of TCDD on porphyrins as well as to the porphyrin disturbances of specific representative cases. In his report on George Ewalt, Dr. Codario stated: In addition, Mr. Ewalt has a porphyrin disturbance, confirmed by special testing at Abbott-Northwestern Hospital- world renowned for porphyrin research. The TCDD contaminant of the herbicides is known to cause this type of disturbance. -> 4 3/ Strik, J. (1979) "Porphyrins in Urine as an Indication of Exposure to Chlorinated Hydrocarbons." Ann. N.Y. Acad. Sci. 320:398-310. (Codario report to Gene Locks, Esq., 1984) -56- Additionally, Dr. Herbert Kaye was prepared to testify that: Agent Orange represents a neurotoxic agent that works indirectly be affecting liver function and the liver's production of heme (an iron compound of protoporphyrin); and in doing so makes an individual, so affected, vulnerable to neurohypoxia. (Kaye 26(b)(4) Statement, Section IV. subpart A) Because the liver performs several metabolic functions, TCDD affects these functions in several different ways, examples of which have been discussed herein. Plaintiffs' expert witnesses were and are prepared to testify to the various toxic effects of TCDD on the liver's functions, based on their research, experience, the medical and scientific literature, as well as on their clinical data and observations on the individual representative Plaintiffs. ii. immune system A second major area of systemic concern is the effect of TCDD on immuno-suppressive responses. Both animal and human data indicate that dioxin is an immune suppressant. (Schneiderman depo., 316:1-6) Dr. Ronald Kerman, a Ph.D. in immunology, was to testify on immuno-toxicology, "which has been defined as 'the undesirable effects of an inappropriate response of the immune system.'" The substance of his opinions, and the significant areas of concern, are A. That TCDD is immunosuppressive. B. That a person exposed to TCDD might have increased predisposition to increased infection, neoplasm (cancer), and other diseases (Kerman 26(b)(4) Statement, Section II). In addressing the first concern, Dr. Alastair Hay testified that TCDD is immunosuppressive in humans based on "the substantial body of animal evidence that TCDD affects the immune system . . " (Hay;depo., 73:9-11) Plaintiffs'~expert witness, Alan Scott Levin, M.D., testified that "After -57- h avin g read a la r g e number~ f m u tile s , including, th e Ranch Hand Stu dy "(He) had formulated an opinion that Agent Orange can be the cause of chemically-induced immune disregulation." (C.I.I.D. (Levin depo., 244:22- 25, 245:1) Dr. Levin also planned on using the clinical data he had gathered after testing the representative Plaintiffs to support his opinion on the causal relationship between dioxin exposure and immune dysfunction. Plaintiffs underwent immunological testing from Plaintiffs' expert witnesses Drs. Alan Levin and Ronald Kerman. Both found significantly abnormal results. In discussing the findings from his testing, Dr. Levin revealed that: Generally it [the testing] indicated that the individuals that we studied had immune disregulation. The questioning continued: In those individuals in which you found immune dis regulation, what did that tell you about the ability of their immune systems to actually function properly . . . It was an indicator that there was some alteration in their capacity to respond appropriately to the demands placed on the normal immune system. (Levin depo., 63-64: 22-23, 1-15) Dr. Levin summarized his findings in his affidavit to Thomas W. Henderson dated 11/18/84. Of significant part, Dr. Levin stated: 1 1 . 1 have obtained and reviewed the medical records and detailed medical histories of the plaintiffs. ' The histories and physical findings in these plaintiffs are totally consistant [sic] with immune dysrgulation caused by exposure to 2,3,7,8-TCDD. 12. We have performed immunologic tests on the plaintiffs. These tests are totally consistant [sic] with immune dys rgulation caused by exposure to 2,3,7,8 -TCDD. /T -58- J l  13. The cause of the damage to cells In the Immune system Is biochemically similar to damage to germ line cells. (A. Levin Affidavit dated 11/18/84) Dr. Kerman substantiated these results, finding abnormal values for the representative Plaintiffs including Plaintiff Michael Jordan. As previously stated, the second area of major concern is that TCDD may cause an increased predisposition to infection, cancer and other diseases in exposed individuals. The substance of Dr. Alan Levin's testimony is and was: That phenoxy herbicides and their contaminants, specifically dioxin, most especially 2,3,7,8-TCDD, cause an assortment of immunological responses, i.e. immuno-toxicity, which predispose persons exposed, by absorption and/or ingestion and/or inhalation, to such chemicals to a whole host of adverse health effects, such as: chloracne or other skin rashes; liver and other organ damage; various neuro-toxic effects; reproductive effects; and neoplasm. (Levin 26(b)(4) Statement, Section IV, subpart A) Specifically, Dr. Levin testified that "each of the plaintiffs in this case have evidence of chemically-induced immune disregulation (C.I.l.D.)" (Levin depo., 177:14-16) C.I.l.D. is "a state when an individual has an increased propensity to developing diseases associated with exposures to other chemicals, virus, bacterium, and also natural malignant degeneration of cells within the individual's own body." (Levin depo., 180:2-6) Dr. Kerman expressed significant concern of this immuno-toxic effect, emphasizing: What is most distressing and of greatest concern is the data reflecting decreased immunocomptence following TCDD exposure leading to increased susceptibility to infection and/or possible tumor challenge in experimental animals. It indicates a fundamental inbalance [sic] in immunoregulation. (Kerman 26(b)(4) statement, Section V) -59- 6381 Plaintiffs' witness, John Garofalo, M.D., an immunologist, explained that Agent Orange "can affect the immune system by producing changes in the number of distribution of T cells, T helper cells, and T suppressor cells . . . " and that, "the effect on helper T cells may result in a heightened immune response, leading to the formation of auto-immune diseases. These in turn may lead to excess cancer formation . . . and nerve damage . . .". (Garofalo 26(b)(4) Statement, Section IV). In summary, it is clear that TCDD is immuno-suppressive. Medical and scientific research and literature as well as clinical data indicate that the representative Plaintiffs suffer from TCDD-induced immune dysregulation. More significantly, the TCDD exposure is capable of causing these Plaintiffs' susceptibility to a wide variety of diseases, including cancer. In conclusion, as stated by Dr. Levin, "Dioxin has a long-term detrimental effect on the immune response." (Levin depo., 337:25, 338-1) I --60-- 638 n C c. N eurological The neurological effects of TCDD exposure can be both physiological and psychological - range from peripheral and central nervous system disorders to neurasthenia and neurohypoxia. Medical and scientific research and literature, as veil as clinical tests, observations and data all indicate these neurological effects. Plaintiffs' expert witnesses, specifically Drs. Raymond Singer, Ernest Baran, Ellen Silbergeld and Herbert Kaye were and are prepared to testify to the several neuro-toxic effects of TCDD as specified in their respective 25(B)(4) Statements and supplements. Additionally, Plaintiffs' witnesses were and are prepared to testify to the specific neuro-toxic effects suffered by the representative Plaintiffs as a result of their exposure to Agent Orange and its dioxin contaminant. As stated by Dr. Alastair Hay, a Ph.D. in biochemistry at the Chemical Pathology Department of the University of Leeds, England, the representative Plaintiff cases further substantiated his opinion that Agent Orange is neurotoxic to humans: I mean the specific [representative] cases that will form part of this case, the specific veterans who were in Vietnam and who have symptoms which are covered by neurotoxic. They have some peripheral neuropathy. A number of others have documented that, and the doctors examining them have documented that they have neurological problems. The basis for saying that I believe that Agent Orange is neurotoxic in humans is because if you look through the scientific literature on the effects of exposure to TCDD in industry, you will find,that going back to 1957, even earlier than that, the accident at Monsanto in 1949, that people who were exposed in this accident and the people exposed in industrial accidents since then, neurotoxic problems are a common feature of the exposure to this chemical agent, TCDD. 1 (Hay depo., 60:16-25, 61:1-6) 1 -61- 6 3 8 :o The representative Plaintiffs exhibited both peripheral and central nervous system disorders. Dr. Raymond Singer explained in his 26(B)(4) statement that: Agent Orange and its contaminant TCDD produce peripheral nervous system effect [sic] which include: a. Numbness b. Loss of feeling c. Weakness d. Pain (Singer 26(B)(4) Statement, Section IV) Prevalent among each of the representative Veteran Plaintiffs was and remains a condition diagnosed as "peripheral neuropathy". Neuropathy is defined as "any functional disturbances and/or pathological changes in the peripheral nervous system . . .". (Dorland's Pocket Medical Dictionary, 23rd Ed., 1982). Specifically, in 1980, Plaintiff George Ewalt had a nerve biopsy at the University of Pennsylvania, "which confirmed the presence of a demyelinating neuropathy." (Codario report to Gene Locks, Esq., 1984) Dr. Codario distinguished George Ewalt*s condition stating: The peripheral neuropathy that this man has is definitely not an inherited one and has all the characteristics of a toxin induced neuropathy. The only toxic substance that Mr. Ewalt was exposed [to] was herbicides (with their TCDD contaminant). TCDD and the herbicides can cause this type of neuropathy. There is no question to me that this man has this neuropathy due to herbicides and TCDD exposure. (Codario report to Gene Locks, Esq., 1984) (References omitted) Dr. Hay also confirmed that Agent Orange was the cause of George Ewalt's peripheral neuropathy. (Hay depo., 164:19-22) Dr. Codario further > found that Mike Ryan's "marked peripheral neuropathy along with an acne^like eruption in thp groin" was a combination of effects, "highly consistent with TCDD poisoning." (Codario report to Gene Locks, Esq., 1984). As stated differently, "Michael Ryan has a- severe peripheral neuropathy, that in my medical opinion is re -62- 6 3 8 4 [ r lated to herbicide exposure." (Codario depo. 166: 20-22). i After examining and testing representative Plaintiff Dan Jordan, Dr. Codario indicated that, "Mr. Jordan's constellation of symptoms and f clinical signs of peripheral neuropathy . . . are most consistent with TCDD exposure." (Codario report to Gene Locks, Esq., 2/18/84) Drs. Codario I and Orris also associated Dan Ford's and David Lambiotte's peripheral neuropathies to their Agent Orange exposure. (See, Codario 26(b)(4) Statement i. and Orris report to Thomas W. Henderson, Esq., 4/9/84). [ In addition to the peripheral neurological effects, TCDD has been associated with central nervous system disorders. (See, Hay depo., 160) i Central nervous system disorders include "a. Irritability, b. Nervousness, c. Sleep Disorders, d. Memory Problems" and "e. Other Mental Dysfunctions." i (Dr. Raymond Singer, 26(b)(4) Statement, Section IV). The "Ranch Hand II" i Study revealed that "a variety of subjective defects (fatigue, anger, fear, etc.) were significantly more common in the high school educated Ranch i Handers." (Ranch Hand II, 2/24/84, p. ii) These "defects" can also include: lack of drive, insomnia and loss of libido . (Codario depo., I 63:1-12) Dr. Peter Orris diagnosed representative Plaintiff George Ewalt i as having a "central nervous system neuropsychiatrie disorder." (Orris report i to Thomas W. Henderson, Esq., 4/9/84) Dr. Codario, having treated Mr. Ewalt since 1981, stated that George Ewalt " . . . came to the office complaining i of personality problems, fatigue . . . episodes of violent rages, difficulty concentrating, memory lapses . . . headaches . . .". (Codario report to Gene i Locks, Esq., 1984). After also examining George walt's medical records and ( history, Dr. Orris claimed that the association between TCDD and George Ewalt's * neurological disprders are well documented in the literature, and in his opinion, i likely caused by his exposure to TCDD. (Orris report to Thomas W. Henderson, Esq. 4/9/84) i -63- 6385 In r e p r e se n ta tiv e P l a i n t i f f David L am biotte's c a s e , Dr. Peter Orris stated: Neuropsychiatrie disorders associated with exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin are a recurrent theme in the literature from as early as initial case reports in 1958 to a most recent publication from Pazderova-Vejupkova, et al. in 1981 5/. Peripheral neuropathic abnormalities as well are frequently noted in conjunction with this exposure. 6 / In light of this patient's [David Lambiotte] history of exposure; development of neuropsychiatrie and peripheral neuropathic disorders; malignant lymphoma as well as neoplastic skin changes; it is my opinion that it is probable that these conditions were caused by this patient's contact with herbicides in Vietnam containing the contaminant 2,3,7,8 -Tetrachlorodibenzop-dioxin. A/ Oliver, R.M. - Toxic Effects of 2,3,7,8-Tetrachlorodibenzo-1, A, Dioxin in Laboratory Workers, British Journal of Industrial Medicine, 32 (1) A9-53, 1975. 5/ Pazderova-Vejupkova, J.M., et al. - The Development and Prognosis of Chronic Intoxication by Tetrachlorodibenzop-dioxin in Men. Archives of Environmental Health. 6 / Ambient Water Quality Criteria for 2,3,7,8-Tetrachlorodibenzo-p-dioxin, prepared by the U. S. Environmental Protection Agency, 198A. (Report of Peter Orris to Thomas W. Henderson, April 9, 198A) Dr. Orris also claimed that neuropsychiatrie disturbances can result from exposure to TCDD without evidence of chloracne. (Orris depo., 163:19-25, 16A.-1-A) Furthermore, representative Plaintiff Mike Ryan "complains of anxiety, nervousness . . . headaches . . . " and "easy fatigability." (Codario report to Gene Locks, A/15/8A) Dan Jordan "complains of temper problems, nervousness, memory lapses" and "depression." (Codario report to Gene Locks, 2/18/8A) It should be notpd*also that a great proportion of the Veterans interviewed nationally in the selection of the representative Plaintiffs indicated suffering 6388 -64- i i from one and often several of these "subjective defects." In summary, TCDD can affect the nervous system in several ways. Clearly, the representative Veteran Plaintiffs suffer a cross-section of neuro-toxic effects associated with their TCDD exposure. As documented herein, Plaintiffs' expert witnesses were and are prepared to testify as to the causal relationship between these neurological conditions and their respective TCDD exposure. Plaintiffs' witnesses were also prepared to testify to: the additional neuro-toxic effects of TCDD, including the effects of TCDD on specific nervous system functions; the methods for assessing these functions; and the "interrelationships between effects on other organ systems and the nervous system." (Silbergeld 26(b)(4) Statement, Section II). (See also, 26(b)(4) Statements of Drs. Baran, Kaye, and Singer). The above stated testimony was to be supported by a vast body of literature, experience, research, clinical data and observations as cited in Plaintiffs' expert witness 26(b)(4)(A)(i) Statements. I -65- ! 6387 d. Cancer TCDD is a known animal and human carcinogen. This fact is supported by a substantial body of literature and research (See the affidavit of Dr. Bertram Warren Carnow dated October 16, 198A and the 26(b)(A) statements and supplements of plaintiff's expert witnesses for references). Several of plaintiff's expert witnesses were and are prepared to testify to the extreme carcinogenicity of TCDD. Plaintiff's expert witnesses were further prepared to discuss the tremendous strength of TCDD as a carcinogen, not only in terms of its extreme potency relative to other carcinogens, but also to its "complete" carcinogenicity. In other words, dioxin acts as an early stage, promoter and late stage carcinogen. Among plaintiff's witnesses, Drs. Legator, Schneiderman and Silbergeld were prepared to testify as to the complete carcinogenicity of TCDD. As stated by Dr. Legator: With TCDD, not only are we talking about promotion, but we're also talking about induction . . . With TCDD, we are talking about a complete carcinogen versus just one that has promotional activity. (Legator depo. 110-111:23-25, 6-9) Dr. Ellen Silbergeld elaborated on this, explaining: The animal bioassays clearly indicate that dioxin is a complete carcinogen. That is without pre exposure of an initiator or concomitant exposure with a promoter, it can produce cancer in experi mental animals. In addition, I accept as a matter of reasonable scientific certainty the work of PITOT and other* that dioxin is also the most powerful promoter which has ever been studied in mammalian systems. (Silbergeld depo. 221:13-22) 6388 -66- Several of Plaintiffs' expert witnesses also were prepared to testify on individual causation in the representative Plaintiff cases. Plaintiffs George Ewalt, Dan Ford and David Lambiotte each suffered from different types of dioxin-related cancer. Plaintiff George Ewalt developed basal cell carcinoma, a condition, "likely . . . caused by his exposure to 2,3,7,8-Tetrachloro- dibenzo-p-dioxin (TCDD)." (Orris report to Thomas W. Henderson dated 4/9/84) Plaintiffs' expert witness as well as George Ewalt's treating physician, Dr. Ronald Codario, claimed "George Ewalt has basal cell carcinoma . . . related to his exposure to phenoxy acids in Vietnam . . (Codario depo., 260:22-25) Plaintiffs' experts pointed out that the location of George Ewalt's basal cell carcinoma was atypical as well as not usually related to sun exposure, as argued by defendants. (Codario depo., 205:19-20; Hardell depo., 56:8-18, 277:20, 278:13) In addition, Dr. Marvin Schneiderman, a statistician, epidemiologist and former Chief of Policy for the National Cancer Institute, noted that George Ewalt's basal cell carcinoma is consistent with existing data relating basal cell carcionma with Agent Orange. (Schneiderman depo., 159:8-10, 160:6-10) Plaintiffs' witness, Dr. Alastair Hay also associated George Ewalt's carcinoma with his prior TCDD exposure. (Hay depo, 164:19-22) Representative Plaintiff, David Lambiotte, also has had basal cell carcinoma. In discussing David Lambiotte's carcinoma, Dr. Marvin Schneiderman claimed: . . . basal cell carcinoma is consistent with the preliminary findings of the Ranch Hand Study in which the exposed persons apparently had a sub- ^ stantial increase in the relative risk of basal cell carcinoma. / (Schneiderman dipo., 158:9-13) --67- More devastating from a medical standpoint, Plaintiff David Lambiotte was also diagnosed as suffering from lymphocytic lymphoma. Dr. Lennart Hardell planned to testify with a reasonable degree of medical certainty that David Lambiotte's lymphoma was caused by Agent Orange. Hardell explained: . . . I base that upon his [Lambiotte's] service in Vietnam, during the period when the area was heavily exposed, sprayed on with Agent Orange and I base it upon my experience in this field. (Hardell depo., 78:1-4) Dr. Hay shared this opinion noting that "lymphoma is documented as one tumor that is increased in people who have been exposed to similar agents or chemicals." (Hay depo., 481:22-25) Dr. Ellen Silbergeld associated David Lambiotte's lymphocytic lymphoma with his Agent Orange exposure based on human and animal data regarding "the carcinogenicity of TCDD in Agent Orange." (Silbergeld depo., 321:8-9) Dr. Schneiderman further stated the relationship of Agent Orange exposure and lymphocytic lymphoma indicating that: . . . The proportion of these cases (lymphocytic lymphomas) occurring in persons of his (Lambiotte's) age group is relatively low, it's two percent of all cases, and under these circumstances, in the absence of information or evidence to the contrary, this would have to be my primary suspect. (Schneiderman depo., 144:17-25) wrote: In conclusion, Dr. Peter Orris in his report of April 9, 1984 4 ^ In light of this patient's [David Lambiotte's] history of exposure; development of neuropsychiatrie and -68- peripheral neuropathic disorders; malignant lymphoma as well as neoplastic skin changes; it is my opinion that it is probable that these conditions were caused by this patient's contact with herbicides in Vietnam containing the contaminant 2,3,7,8-Tetrachlorodibenzop-dioxin. (Orris report to Thomas W. Henderson, Esq., 4/9/84) Representative Plaintiff Dan Ford suffers from a different dioxin- related cancer known as rhabdomyosarcoma, one of the forms of soft-tissue sarcoma. Dr. Lennart Hardell, an M.D. and Ph.D. at the Department of e Oncology, University Hospital, Umea, Sweden, has performed extensive personal research on the exposure to phenoxy herbicides and chlorophenol and the risk of developing different types of cancer. After reviewing Dan Ford's case, Dr. Hardell stated: Regarding the [Dan Ford's] rhabdomyosarcoma, it is a soft tissue sarcoma and in reference to our studies about soft tissue sarcomas and exposure to phenoxy herbicides it's highly probable that exposure to Agent Orange has caused so much [sic] tissue sarcoma in Dan Ford. (Hardell depo., 61:6-12) After examining Dan Ford, Dr. Ronald Codario stated: . . . it is my medical opinion that this gentleman [Dan Ford] has developed this soft tissue sarcoma as a result of his exposure to phenoxy acids and/or tetrachlorodibenzo-para-dioxin. (Codario depo., 301:16-24) Dr. Codario based this statement on the related body of literature as well as on the following: The fact that he has peripheral neuropathy, the fact that this individual was in an area where herbicides were used, the clinical symptomatology that is con sistent with the clinical symptomatology that I've seen described in the literature and ,the clinical .-69- symptomatology that I have observed in evaluating 500 individuals that have been exposed to herbicides. (Codario depo., 302:7-14) Drs. Peter Orris, Alastair Hay, Alan Levin, Marvin Schneiderman, and Ellen Silbergeld also attributed Dan Ford's rhabdomyosarcoma to his TCDD exposure. (See generally, Plaintiffs' expert witnesses' depositions and 26(b)(4) State ments. Dr. Alan Levin testified that Dan Ford's soft tissue sarcoma developed as a result of his C.l.l.D., or, chemically-induced immune dis- regulation. (Levin depo., 493:22-25) He further stated: I'm testifying that the pattern that Mr. Ford presents, that being rhabdomyosarcoma, and a benign growth of the right kidney, is consistent with disease caused by exposures to high concentration of 2,3,7,8 -TCDD. (Levin depo., 491:17-21) Dr. Marvin Schneiderman noted that embryonal rhabdomyosarcoma like Dan Ford's generally appears in the 8-15 age group. (Schneiderman depo., 72:6-15) Dr. Schneiderman also dispelled defendants' claim that Dan Ford's prior trauma in the cancerous site led to his subsequent development of rhabdomyosarcoma. On the contrary, Dr. Schneiderman claimed: Dan Ford's rhabdomyosarcoma has been related to human and animal defoliant exposure. The fact of his broken leg and metal exposure [the insertion of a metal plate] would seem to add to the probability that the additional exposure to dioxin led to this rhabdomyosarcoma. (Schneiderman depo., 203:4-23) Dr. Schneiderman concluded: I would say that the appearance of rhabdomyosarcoma in a person who has been exposed, and in the absence of any other knowledge of the cause of rhabdomyosarcoma in th4t individual is more likely, in my opinion, to have been related to that exposure than to some other not known ill-defined set of causes.: (Schneiderman depo., 49:12-25, 50:1-6) - -70- 6392 I I J It is a proven fact that TCDD is an extremely powerful carcinogen, as previously detailed in Section E, subpart 1. TCDD has further been [ shown to be a "complete" carcinogen. Specifically, Plaintiffs' expert j.' witnesses have testified that the basal cell carcinoma, lymphocytic lymphoma * and rhabdomyosarcoma suffered by the three (3) representative Plaintiffs | were caused by their exposure to Agent Orange/dioxin. The testimony of these several witnesses, coupled with their supporting literature and experience | is strong. Plaintiffs were and are prepared to show individual causation. ( I -71- S393 e. Birth D efects Reproductive studies on both animals and humans indicate that dioxin can be teratogenic, mutagenic, fetotoxic, embryotoxic and gonadotoxic. As stated by Dr. Deborah Barsotti: Reproductive dysfunction has been associated with exposure to TCDD in experimental animals and man as well. (Barsotti depo., 194:24-25, 195:1) Plaintiffs' government causation witness, Dr. K. Diane Courtney, a research scientist for the Environmental Protection Agency, claimed that no recent studies have changed her conclusions that: It is evident that all species of pregnant animals treated or exposed to TCDD responded with abortions, fetal death, fetal toxicities or malformations. The routes of exposure were oral, diet or dermal. Since all species have responded adversely to TCDD in micrograms per kilogram or nanograms dose range, it could be expected that the human being would also respond adversely to these doses of TCDD. At this time, there is insufficient data to establish a no effect dose level. (Courtney depo., 353:6-16) Among Plaintiffs' expert witnesses, Dr. Maureen Hatch, Assistant Professor of the Division of Epidemiology at Columbia University, testified that there is positive evidence between Agent Orange exposure and birth defects. (Hatch depo., 55:19-22) In addition, Dr. Alastair Hay felt that the evidence "would suggest that it is probable that TCDD is involved in causing untoward pregnancy outcomes and birth defects." XHay depo., 513: 9-12) Dr. Alastair Hay testified with a reasonable degree of scientific i IJ certainty that TCDD is teratogenic in humans. ` Dr. Hay based this opinion on: 8394 -72- . . . the substantial body of animal evidence which shows that TCDD is teratogenic, and in evidence on the human side, . . . the recent Ranch Hand Study that's been published, the morbidity study, . . . evidence from the conference . . .[he] attended in Vietnam, in particular an article by Hatch and Constable which reviews evidence from Vietnam on the effects of Vietnam veterans, Vietnamese Vietnam Veterans exposed to Agent Orange who reported an increased incidence of birth related problems. (Hay depo., 83:14-25) This article Dr. Hay refers to, co-authored by Plaintiffs' expert Maureen Hatch, finds that the reproductive studies in North Vietnam report an association between paternal exposure to herbicides, prior to or at conception, and congenital defects in subsequent offspring, particularly certain anomalies, e.g., anencephaly and orofacial defects. (Constable, J.D. and Hatch, M . , Reproductive Effects of Herbicide Exposure in Vietnam: Recent Studies by the Vietnamese and Others, 1984). Plaintiffs' expert witnesses also explained that the AH Locus of the chromosome in man is the target site for TCDD (Legator depo., 82:4-6) and that gonadotoxicity and hormonal dysfunction involve the TCDD receptor (or AH Locus) as a mechanism of action. (See, Silbergeld depo., 209:14-20) Dr. Legator associated reproductive problems, "such as cleft palate . . . and other toxic effects . . . to the interaction between TCDD, the genetically controlled AH Locus." (Legator depo., 81:22-25, 82:1-2) Dr. Levin explained additional mechanisms of action in his Affidavit of November 18, 1984. Therein he described three mechanisms by which a toxic chemical can damage particular proteins thus leading to birth defects in the progeny of the host. (Levin Affidavit, .Section~9) Included in the body of research, literature and testimony on the reproductive'toxicity of TCDD are studies indicating male-mediated -73- ij <J> [ I j reproductive effects. Although significantly more difficult to prove, Plaintiffs were and are prepared to testify to the various mechanisms of | male-mediated toxicity, as well as to the resulting male-mediated genetic effects, including birth defects, miscarriages and untoward pregnancy [ outcomes. . In discussing the reproductive toxicity of TCDD, specifically \ male-mediated reproductive toxicity, Dr. Maureen Hatch stated: It is my opinion based on the weight of evidence to date that exposure to the male human from Agent Orange is associated with an increased risk of birth defects, I a modest to moderate increased risk of birth defects among his offspring. r (Hatch depo., 139:4-8) Dr. Hatch went on to state: It's my professional judgment at this point that the data are sufficient to, with reasonable certainty, say that Agent Orange exposure appears to have a causal association with congenital malformation in offspring of exposed fathers. (Hatch depo., 418:21-25, 419:1) Dr. Alan Levin supported the above claim in his Affidavit dated November 18, 1984, writing: I have reviewed, in detail, the "Ranch Hand Study" performed by the United States Air Force on Agent Orange Exposed personnel. This study proved that Agent Orange Exposure of the father is associated with birth defects in the children. Although the population studied is quite different from the plaintiff group (they are significantly older-and the nature of their exposure was entirely different) the increased incidence of birth defects in the^ plaintiff population can also be4positively associated with Agent Orange exposure. (Levin Affidavit of November 18, 1984) , -74- 639e Dr. Levin a ls o revealed th a t: It's known that dioxin will promote the development of birth defects in humans and in animals, and the mechanism by which they do is some transmissible defect that is male mediated. (Levin depo., 614:1-3) Dr. Ellen Silbergeld claimed that TCDD and 2,4,5-T can cause "male-mediated transmittable damage." (Silbergeld depo., 222:9-12) The substance of Dr. Silbergeld's testimony is and was that: TCDD and 2,4,5-T can cause male mediated transmittable damage manifested by birth defects, miscarriages, and other untoward pregnancy outomes when certain circum stances occur. These circumstances are when the amount of exposure to TCDD and to 2,4,5-T, either alone or together (this amount being measured by intensity and duration) is appropriately paired with the timing of that exposure in relationship to spermatogenesis and the participation of the male in reproduction. (Silbergeld 26(b)(4) Supplement) Specifically, Dr. Marvin Legator explained that male-mediated toxicological effects: . . . i.e. birth defects and miscarriages, of Agent Orange and/or TCDD . . . can occur through one or more of the following biological mechanisms: (1 ) decreased quality of sperm resulting from gonadal lesion during spermatogenesis, altered hormonal regulation, or transmittable defects in heritable characteristics of sperm; (2 ) potentiation of xenobiotic metabolism in gonadal tissue; (3) secretion of chemicals in Agent Orange or their metabolites into seminal fluid and subsequent transfer to the womb. These mechanisms can result from either the long-term effects of past exposure to Agent Orange or from the continuing presence of bfologically active concentration, of Agent Orange and metabolites of its constituent chemicals within the bodies of exposed persons. / (Legator 26(b)(4) Statement) Moreover, Defendants' expert witness, Dr. James G. Wilson, testified that he agreed "that TCDD in the male's body can move into his body fluids, in general, including seminal fluids . . (Wilson depo., 69:12-14) Plaintiffs' expert witnesses were also prepared to testify specifically that the birth defects and untoward pregnancy outcomes suffered by the Jordan and Ryan families were a result of Plaintiffs Dan Jordan and Michael Ryan's respective TCDD exposure. In the Jordan family, both Mrs. Donna Jordan and her children, Michael and Chad, suffered the male-mediated toxic effects associated with Plaintiff Dan Jordan's TCDD exposure. Donna Jordan endured a miscarriage while several months pregnant. In discussing Mrs. Jordan's untoward pregnancy outome, Dr. Levin stated: I will tell you what I know about the (Jordan) miscarriage. It was caused by her husband's exposure to TCDD. (Levin depo., 614:1-3) Dr. Silbergeld further confirmed that Donna Jordan's miscarriage before term was consistent with and caused by her husband's exposure to Agent Orange in Vietnam. (See, Silbergeld depo., 282:7-12; 284:21-24). Dr. Silbergeld justified her opinion stating: First off is the fact that her husband was indeed in Vietnam prior to impregnating Donna Jordan, and that relying on the records I have, he was exposed to Agent Orange while in Vietnam. Second is the other reproductive history of this family, which includes two other untoward reproductive events. So that this miscarriage cannot be seen in isolation. Third, that all of these events, all o'f these reproductive events are consistent with the animal toxicology . . . (Silbergeld d^po., 285:1-13) -76- P l a i n t i f f s ' w itn e s s e s a ls o a s s o c ia te d Chad and M ichael Jordan's birth defects with their father Dan Jordan's Agent Orange/dioxin exposure. Dr. Alastair Hay was prepared to testify that Dan Jordan's "exposure to Agent Orange was the cause of his children having birth defects." (Hay depo., 164:7-10) When questioned as to what "was caused to Mr. Jordan and any of his family by his claimed exposure to Agent Orange?", Dr. Hay responded: That the birth defects, the limb deformities that his children had, particularly the thumb and the missing digits, and the absence of one bone in one of his children was caused by (Dan Jordan's) exposure to Agent Orange. (Hay depo., 166:4-11) In addition, Plaintiffs' experts Drs. Legator and Silbergeld testified that Chad and Michael Jordan's birth defects were consistent with and caused by Mr. Jordan's TCDD exposure. Defendants argued that the Jordan's had a history of minor birth defects thus attributing to Chad and Michael Jordan's deformities. Dr. Levin challenged this defense claiming that this history strengthens the concept that TCDD initiated these children's defects. Dr. Levin explained: I believe that the individual possibility or probably [sic] carried a genetic propensity, which was then expressed by the 2,3,7,8-TCDD. This is commonly'what happens, for instance in the development of cancer. The chemicals per se bring out the expression of the oncogene, the oncogene then is associated with the development of cancer. (Levin depo., 623:22-25, 624:1-3) / Dr. Marvin Legator strengthened Plaintiffs' position regarding'the Jordan's history of congenital malformations stating: 6399 -77- . . . it is my view that whenever we have a genetic effect . . . that any further insult (e.g. TCDD exposure) can either accelerate, enlarge upon the affliction, or show us more diverse effects, and seeing that there was a history . . . then 1 would anticipate that exposure to dioxin, given what we know about dioxin, could, indeed, worsen the situation in terms of more effects. (Legator depo., 288:20-25, 289:1-5) Dr. Legator argued that given Dan Jordan's family history and his TCDD exposure, that "here . . . we have identified a chemical . . . which would substantially contribute to the adverse health outcome." (Legator depo., 289:18-21) Dr. Legator further contended that Kerry Ryan's deformities were attributable to the father's (Plaintiff Michael Ryan) TCDD exposure. Dr. Legator asserted that: . . . the congenital malformations and birth defects of Kerry Ryan, daughter of Mr. and Mrs. Michael F. Ryan, are consistent with the presumed exposure of . . . Ryan to phenoxy herbicides and dioxins specifically 2,3,7,8-TCDD - - while being in Vietnam. (Legator 26(b)(4) Statement) Plaintiffs' witness, Dr. Hay, stated that Michael Ryan's "exposure to Agent Orange was the cause of the birth defects in his child." (Hay depo., 164: 15-18) He further testified, "that the deformities in Kerry Ryan were attributable to Mr. Ryan's exposure to Agent Orange." (Hay depo., 166:16-20) In summary, TCDD has been clearly implicated in causing reproductive toxic effects in animals and humans. Additionally, research and literature as well as 'expert testimony have described* several mechanisms of male-mediated / reproductive toxicity. Plaintiffs also specifically contend that the TCDD / exposure of representative Plaintiffs Dan Jordan and Mikd Ryan attributed to -78- 6400 the reproductive toxic effects suffered by their children and Mrs. Jordan. As stated by Dr. Marvin Legator: Based on the fact that we are dealing With an agent that has the properties w e 've already described to TCDD and that there was demonstrated exposure of the two veterans in point, Ryan and Jordan, that certainly the congenital malformations would be consistent with an adverse effect of this chemical. (Legator depo., 287:15-25) ! -79- IV. CONCLUSION The proof of "cause" between exposure to Agent Orange and the multitude of adverse health effects from which the 9 representative plaintiffs claimed damages very simply has been overwhelmingly demonstrated. ! -80- DIFFICULTIES/COMPLEXITIES IN AO DISCOVERY RELATING TO CAUSATION 1. INTERVIEWING VETERANS - Gathering names of potential representative plaintiffs from several sources. - Briefing paralegals on interviewing veterans for pertinent exposure and medical information. - Extensive telephone conversations with veterans and veterans' wives (evenings, weekends, every day), lasting approximately 2 hours in length for each initial "screening" telephone call. - Asking veteran detailed questions on his medical condition(s) (including past and present symptoms and problems); his wife's history (including her medical condition and child bearing history); the veteran's military history (including information on his M.O.S. and exposure); potential variables such as the veteran's exposure to drugs and chemicals, as well as his family employment history, etc; and his children's history (including complete medical conditions). - Summarizing all information to narrow down and screen the number of potential representative plaintiffs. - Re-interviewing veterans for more detailed medical information, including all physicians and hospitalizations (of veterans, wives, and children), as well as additional descriptions and dates of occurrence of all symptoms and medical conditions. 2. MEDICAL RECORDS (VA, Physician and Hospital) - Searching for proper names and current addresses of past and often deceased physicians. - Mailing hundreds of court orders for medical records of veterans, wives arid children. APPENDIX 1 - Following-up mailings with extensive telephone calls to explain the urgency of our request; to justify expediting what is normally a several week-long request to days; to remedy simultaneous (dual) requests from defendants and plaintiffs. - Payments required before receipt of recbrds; inevitable delays. - Organizing, separating and indexing all medical records consisting of thousands of pages of records for veterans, wives and children. - Keeping track of medical records received and those never received; more telephone calls. - Sending medical records to computer service for disbursement to defendants as they came in. - Re-verification with veterans of all physicians and hospitals. - Reorganizing and assessing final representative plaintiffs' medical records. (Travel to Pittsburgh, Philadelphia); shipping to Philadelphia for final indexing; copying for defendants. - Trying to track down remaining medical records. 3. SELECTION OF REPRESENTATIVE PLAINTIFFS - Medical record review. - Summaries of veteran interviews. - Consultations with treating physicians. - Consultations with causation experts. 4. CONTINUOUS CONTACT WITH REPRESENTATIVE PLAINTIFFS AND DEFENDANTS - Answering continuous defendant inquiries on representative plaintiffs. - Addressing all representative plaintiffs' inquiries, problems, schedule conflicts; listening. - Calling plaintiffs to explain aspects of litigatiofi requiring their immediate assistance, e.g. - depositions; interrogatory answers; medical testing. r* A-2 Q 5. INTERROGATORIES ON INDIVIDUAL REPRESENTATIVE PLAINTIFFS - Travel to New York. - Numerous telephone calls to veterans, veterans' local attorneys (if applicable). - Review of medical and military records. - Coordinating, changing and adapting local counsels' interrogatory answers to individual plaintiffs' interrogatories. - Time constraints; creating a uniform format to put information on the computer. - Extensive telephone calls to plaintiffs to complete detailed interrogatories (nights, days, weekends, etc.). - Adapting answers to rulings by Judge Weinstein and Magistrate Scheindlin. - Completing interrogatories for Elmo Zumwalt. - Supplementing answers in accordance with Magistrate Scheindlin's rulings. 6 . EXPERT SUMMARIES - Compiling and copying expert summaries; traveling to Philadelphia to merge with Neil Peterson's for filing the same day in New York. - Supplementing - expanding. - Adapting/expanding to confirm with modified rulings. 7. REPRESENTATIVE PLAINTIFFS' DEPOSITIONS - Scheduling conflicts, illness; numerous telephone conversations. - Time constraints. - Preparation l' A -3 t 8. PLAINTIFFS' EXPERTS' DEPOSITIONS - Preparation. - Scheduling, rescheduling. - Time constraints. - Handling (responding to) and making objections. 9. DEFENDANTS' EXPERTS' DEPOSITIONS - Onerous schedule. - Back-to-back time schedule/weekends/not enough attorneys. - Researching defendants' experts' literature. - Medline/Toxline searches. - Hiring and supervising several students in Pittsburgh to gather and copy articles. - Summarizing hundreds of articles for deposition preparation. - Gathering more articles in New York. 10. MILITARY (EXPOSURE) DOCUMENTS - Travel for document productions and briefings. - Photocopying thousands of military documents. - Researching method to utilize various types of records produced to determine exposure of representative plaintiffs. - Analyzing the Agent Orange Army Task Force Study results, assessing alternative approaches to the Task Force Study protocol. - Organizing and shipping thousands of records. -A-4 o 11. PRETRIAL ORDER - Telephone calls to plaintiffs to determine Pact and Exposure witnesses and their (respective) testimony. - Telephone calls to potential witnesses re: testimony, additional information; possible additional witnesses. - Time constraints. - Summarizing all witness testimony - directly plugging into computer. - Listing all plaintiffs' treating physicians, addresses and summarizing testimony. - Travel back and forth from Long Island. - Citing medical and scientific literature. - Summarizing Plaintiffs' expert witnesses' testimony. - Listing and describing causation exhibits. - Summarizing Plaintiffs' government causation witnesses' testimony. I A-5  iJAME: tW/VLT. George v.'I O : RANK: ESN: MSN: - V l t R A M SEF S 1 C E : February 25, 1967 - February 26, 1968 UNIT OF ASSIGNMENT: 1st Satcalion, 26th Infantry, 1st Brigade, 1st Infantry Division POSITION: Infantry man __ E X P O S U R E EXTREMELY -LIKELY v MOST LIKELY E X P O S E D __ __?POEAELY EXPOSED' ' ' ^. ____ PROBABLY NOT E ^ S E D ' __~ NOT E X P O S E D - REASON: During Mr. Ewalt's tour in Vietnam, his unit moved around in the Fhuoc Vinh, Quan Loi, Phu Loi, 6 Lai Khe area. When going through the Ranch Hand, on the first grid coordinate extracted, I had 9 8 km. hits, due to his job description as an infantryman, he would have many reasons for going outside of the perimeter. For this reason, and also for the amount of hits on the 1st grid coordinate, we have determined him as Fostly Likely Exposed Ranch Hand Orange Services Orange Services Unknown - 2km/3day O- _______ Bkm/90day: I " /Z2- - 22- Appendix2 6408- m a m e : Danny L. Ford ID : RANK: E-4 SS AN: 365-52-1794 f'SN: US 54-976-275 VIETNAM SERVICE: 27 September 196S- 16 iSeptember 1969 UNIT OF AS S SNM Battery C, ls' Battalion, 92nd Artillery, USArmy, Pacific POS IT ICN/MO Z : 1 2Al 0- Cannoneer _____ EXPOSURE EXTREMELY LIKELY ____ MOST LIKELY EXPOSED XX PR0BA3LY EXPOSED __ _ _ FP.03ASLY NOT EXPOSED ___ EXPOSURE EXTREMELY. UNLIKELY REASON: Mr. Ford's unit was located in the II Corps area of Vietnam. It was a highly ircbile unit which roved about in the Kontum and Pieilru Provinces. His unit was within Bkm and 90 days of 11 sprays at two locations- Fire Support Base 12 (5 sprays) and Landing Done Swinger (6 sprays). For the above reasons this individual is being classified as probably e>pcsed. Ranch Hand Orange Services Orange Services Unknown 2W3aay Q Q - 8km/90ay _______i p 5 _____________ ( p /________ ______*7^ I IvvME: MD: RANX: JORDAN, DANNY G.* _5 SSN: 443-70-2511 US 16 6 5 9 5 9 * v ie t ::am sek ^ic z : C o m p a n y D, 1 E a t t a l i o n , 5th C a v a l r y , 1 C a v a l r y D i v i s i o n : M a r c h 1 - Sept. Company E, 1 Eattalion,' 5th Cavalry, 1 Cavalry Division: Sept. 2 - February 16, 1969 UNIT OF ASSICDEhT: P u x' POSITION: Mortar Gunner, Gunner, Crewman Sguac Leader X EXPOSURE SCIrSDE-Y -LIKELY >CST LIKELY EXPOSED % ____ PROBABLY EXPOSED ____ PROBABLY tOT EXPOSED NOT IDJ O S ED REASON: During Mr. Jordan's Vietnam service, he was with the above units. These units were in several areas in I -Corps and III Corps. I Corps places were such as Landing Zone Jane, Vender Beach, LZ Barbara &Einh An. In III Corps, his units base carps were such as Katur., landing Zone Eleanor, Deng Xoai, and Landing Zone Dolly. V.Tnile with these units, and only searching through the Ranch Hand Herbs Tape, we found 28 hits, 9 of which were 2 kilcreter hits, or less. For this reason, w e have determined him as exposure extremely likely. 4 ' f Fanch liana Orange S e r v ic e s Orange S e r v ic e s Unknown 2km/3day: Ekm/90dav: //5 A2-3 # NAME: WID: RANK: ESN: MSN: LAMBICTCTE, E-4 223-68-3395 US52913119 VTETtCAM SERVICE: May 26, 1967 - 15 Kay, 1968 UTilT OF ASSICTME'.T: <22rc Qirhiit Support Repair Parts Cornpany POSITION: Supply Clerk & Greer Supply Clerk Specialist ____ EXPOSURE ?C7S?iELY LIKELY ____ MOST LZ-ZLY E>PCSED ____ PEOEASLY EXPOSED '* ' ____ PROBABLY NOT EXPOSED X NOT EKPCSEO REASON: While with the <23 Repair Parts Company during Mr. Lambiotte's Vietnam service, his n i t ' s base carp vas'Cam Ranh Eay. We were unable to locate any perimeter hits curing this time period, therefore we have determined him not exposed. Ranch Hand Orange Services Orange Services Unknown r 2km/3aay: Q q CD Bkm/90dey c 0 I A2-A I \ I tiAME: M i c h a e l F. R y a n I WID: I RANTC: SP 4, E-4 SSN: i MSN: us 51 5 7 9 87?. . I VIETI^lM SERVICE: A u g u s t 11 , 1 9 6 6 - A u g u s t 20, 1 9 6 7 S I UNIT OF ASSIGNMENT: H e a d q u a r t e r s T r o o p , 3rd S q u a d r o n , 1 1 t h A r m o r e d C a v a l r y I Regiment POSITION: C o u r t M a r t i a l Clerfc ( I ___ EXPOSURE EXTREMELY -LIKELY ___ MOST LIKELY EXPOSED I X PROBABLY EXPOSED ' ___ PROBABLY IOT EXPOSED I . NOT EXPOSED I REASON: Mr. R y a n ' s u n i t w a s h i g h l y m o b i l e w i t h i n t h e III C o r p s r e g i o n in I Vietnam. Unit records have placed his unit at Xuan Loc, Long Giao, Phu Hoi, and Ben Cat, and also his unit was providing security for the Long Einh - -Bien Kca a rea in t he s o u t h e r n p o r t i o n o f t h e Iron T r i a n g l e . Some I of these areas were hea v i l y sprayed in 1967, but Mr. Ryan's position as a clerk would not put him in direct contact with the herbicides. Therefore, due to his mobility and the probability that he may have beeen put on guard duty, we have determined that Mr. Ryan is p r obably exposed. ! Ranch Hand Orange Services Orange Services Unknown 2km/3day; q i - > -O Ekm/^Ccay; 1 * 4 ' I J? o A2-5 )) SUPREME COURT THE UNITED STATES O FFIC E OF THE CLERK W A SH IN G TO N. D. C. 2 0 5 4 3 Mr. Loren Kleve Steptoe t Johnson 1250 Connecticut Avenue/ N.U. Washington/ DC 20C36 November 26/ 1984 Re: Chevron Chemical Company/ v. Richaro Leander Ferebce/ Jr./ et al. ho. 84-491 Dear Mr. Kieve: The Court today entered the following order in the above entitled case: The petition for a writ of certiorari is denied. Justice O'Connor took no part in the consideration or decision of this petition. Very truly yours/ Alexander L. Stevas/ Clerk I Appendix 3 KJ' Vo 14 LENNART HARDELL, M . D . , P h . D . I . QUALIFICATIONS Dr. H a r d e l l is employed by the U n i v e r s i t y H o s pital in its Department of Oncology in Umea, Sweden, w h e r e he specializes in internal medicine and oncology. His work includes diagnosis, treatment, and evaluation of p ossible causes of cancer, and education of medical students. His C u r r i c u l u m Vitae is attached. A list of seminars is also attached. . II . Subject Matter Dr. Hardell will testify to several epidemiological studies which he and his colleagues have conducted in Sweden. This research includes investigations concerning the relationship between the risk for different types of cancer and exposure to phenoxy herbicides and c h l o r o p h e n o l s . The research has been published in the medical and scientific literature. These studies utilized the case-control study as the vehicle for investi g a t i o n . Certain m e t h o d o l o g i c a l aspects, such as selection of cases, selection of controls, a ssessment of exposure, and statistical m e thods, were considered; and then utilization was based / t upon t h o r o u g h l y considered aspects of bias, all of which were well controlled] Dr. Hardell has also seen in his clinical practice basal cell carcinoma of persons previously exposed to phenoxy herbicides, with no other known confounding variables. III. Scientific Principles See General Statement of Scientific Principles and Assumed Facts attached. * Dr. Hardell will use as a factual base for his testimony his hands-on diagnoses and treatment of various cancer victims as well as his review of the m e d i c a l records and e x a m i n a t i o n s of cases involved in his epidemiological studies. His additional clinical experiences also form a factual basis for his testimony, especially those patients with basal cell carcinoma. Dr. H a r d e l l will also review the m e d i c a l records of George E w a l t , Danny Ford, and David Lambiotte for the opinions which he will express regarding the causation (in the legal sense) and their exposure to Agent Orange and basal cell carcinoma, rhab domyo sarcoma (form of soft tissue Sarcoma) and malignant lymphocytic lymphoma. I IV. Substance of Opinions A. Specifically, Dr. Hardell's studies, four in number, involved soft tissue sarcomas, malignant lymphomas, and colon cancer. Highly statistically significant risks of soft tissue sarcomas and malignant lymphoma were found, whereas no assiciation was found for colon cancer. In point of fact, the negative finding for colon cancer strongly supports the statistical significance of the increased risk demonstrated for soft tissue sarcomas and malignant lymphomas, and that there exists a presumed causal t> relationship between exposure to phenoxy herbicides and human cancer, particularly of soft tissue sarcoma and malignant lymphoma. B. With respect td 'those cases with soft tissue sa malignant lymphoma, and basal cell carcinomas, Dr. Hardell will testify that the presumed exposure to Agent Orange caused, in significant part, such neoplastic processes. V. Grounds for Each Opinion A. General The bases for Dr. Hardell's testimony as to various facts and opinions include: educational background, professional training, and experience; diagnosis and treatment of patients, review of the applicable medical and scientific;literature; personal research; and a review of the pertinent medical djita of the relevant representative plaintiffs. I B. Specific 1. Soft tissue s a r c o m a s and m a l i g n a n t lymphoma Ref erences: Cook RR (1981): Dioxin, chloracne, and soft-tissue sarcoma. Lancet i. 618-619. E r i ksson M, Hardell L, Berg NO, M o l l e r T, Axel s o n 0 (1981): Soft-tissue sarcomas and exposure to chemical substances; a c a s e - r e f e r e n c e study. Br J Ind Med 38: 27-33. Hardell L (1979): Malignant lymphoma of histiocytic type and exposure to phenoxyacetic acids or chloro p h e n o l s . Lancet i: 55-56. ,, Hardell L (1981): Relation of soft-tissue sarcoma, malignant lymphoma and colon cancer to phenoxy acids, chlorophenols and other agents. Scand J W o r k E n v i r o n H e a l t h 7: 119-130. T* Hardell, L, S a n d s t r o m A (1979): C a s e - c o n t r o l study; softtissue sarcomas and exposure to phenoxyacetic acids or chloro phenols. Br J Cancer 39: 711-717. H a r d e l l L, E r i k s s o n J, Lenner P, L u n d g r e n E (1981): Ma l i g n a n t lymphoma and exposure to chemicals, especially organic solvents, chlorophenols and phenoxy acids; a case-control study. Br J Cancer 43: 169-176 Honchar PA, Halperin WE (1981): 2,4,5-T t r i c h l o r o p h e n o l , and soft tissue sarcoma. Lancet i: 268-269. J o h n s o n FE, Kugler M A , Brown SM (1981): so f t - t i s s u e sarcomas and chlori n a t e d phenols. Lancet I: 1370. M oses M, Selikoff IJ (1981): s o f t - t i s s u e sarcomas, phenoxy h e r b i c i d e s and c h l o r inated phenols. La n c e t i: 1370 Pitot H C , Golds worthy T , Poland H (1980): Pro m o t i o n by 2,3, 7,8-tetrachlorodibenzo-p-dioxin of hepatojarcinc^genesis from d i e t h y l n i t r o s a m i n e . Cancer Res 40: 3616-3620. y t Poland A, Palen D, Glover E (1982): Tum o u r pro m o t i o n by TCDD in skin* of HRS/J h a i rless mice. N a t u r e 3D0: 271-273. Sarma PR, Jacobs J (1982) Thoracic soft-tissue sarcoma in V i e t n a m v e t e r a n s exposed to agent orange. N. Engl J. Med 306: 1109 2. Basal Cell Ca r c i n o m a Case history: W oman born in 1946. In 1964 o p e rated for a cyst on one of her ovaries. No other diseases. In the end of the 1960's she developed a blister on her left shoulder and in the 1970's several ones on her back. In June 1977, two basal cell carcinomas were surgically removed from her back. In Sep t e m b e r 1977 nine more and in December 1977, two more basal cell carcinomas were excised from ' her back. In January 1983 one basal cell carcinoma on her shoulder and another on her back were cured by radiotherapy. In October 1983 five t u m o r s were removed from tier back; two basal cell carcinomas and three basal cell carcinomas in situ. D u r i n g s u m m e r t i m e in 1959, 1960, and 1961 the patient affor e s t e d for one month each summer. The seedlings were treated with DDT. Moreover, she carried water for the dilution of phenoxy acids used by back pack sprayers. She walker in newly sprayed areas. In 1960 she used to basal bark spray for six weeks and in 1961 for two weeks. The chemical used was a combination of 2,4,5-T and 2,4,-D. She was thereby stripped to her waist but for a;brassiere. She used no gloves. * ^ . .. The patient reported no heredity for basal cell carcinoma. I used any special drugs or been exposed to arsenic!. She had not 6419 Curriculum Vitae Lennart Hardell M.D.,Ph.D. Department of Oncology, University Hospital, S-901 85 UMEA, Sweden Born in October 18, 1944. Medical degree from University of Upsala, Sweden October 27, 1971. "^ , ifession, National Board of Health Specialized in internal medicine October 18, 1976. Specialized in oncology, June 20, 1979. Medical dissertation University of Ume, May 15, 1981. Direct testimony before the United'States Environmental Protection Agency in the matter of the hearing of 2r4,5-T and Silvex, Washington DC, September 29-30 1980 and February 9, 1981. Receiver of the Fernstrom Award, University of Ume, October 9, 1982. Delivered by the King Carl XVI Gustaf of Sweden. Member of "Expert Panel on Dioxin Documents", United States Environmental Protection Agency, Cincinnati, Ohio, July 27-29, 1983. Qualified for Associate Professor of oncology, University of Ume, December 9, 1983. Member of the Swedish Medical Association. Member ofTlordic Radiotherapy Club 1 Member of Swedish Association of Radiotherapy Member of Swedish Association of Oncology Member of Swedish Epidemiological Association ^ s' 6420 JOHN A. GAROFALO, M.D. I. QUALIFICATIONS See attached curriculum vitae. II. SUBJECT MATTER The subject matter of Dr. Garofalo's testimony will per tain to the field of immunology. He will elaborate on the effect that Agent Orange (dioxin) can have on the immune system. III. GENERAL SCIENTIFIC PRINCIPLES The field of immunology involves the study of how the body responds to antigenic (foreign) stimulation. Peripheral blood lymphocytes are made up of B-cells; T-cells; and T cell subsets (also referred to as the immunoregulatory cells of the immune system). During the past two decades, the field of immunology has recorded a number of dramatic advances. The most significant of which have been the recognition of the various classes of T and B lymphocytes, hybridoma technology (provides a reliable and consis tent method for providing large quantities of monoclonal antibodies directed against specific cell surface antigens) and the technological advances in flow cytometry. T lymphocytes (65-85% of lymphocytes) are responsible for a spectrum of immune responses referred to as cell-mediated immunity which in clude delayed hypersensitivity; allograph rejection; tumor cyto toxicity, whereby they destroy host Gells bearing'1foreign anti- S gens; and cell-mediated resistance to infectious agents (fungi, i viruses, and intracellular faculative bacteria). ` Two functionally 8421 distinct subsets of T cells have been defined with monoclonal antibodies. T4+ cells represent the helper/inducer population 38-53%) whereas T8+ cells represent the suppressor/cytotoxic pop ulation (18-30%) (cytotoxic refers to the major effector functions of T cells, the capacity to kill specific cells to which they are sensitized). T4+ (helper/inducer) cells regulate the immune re sponse by means of cell-cell interactions as well as by producing biologically potent regulatory molecules. T4+ cells provide indu cer function in T-T cell (required for optimal development of cy totoxicity by the T8+ cells); T-B cell (induces B cells to pro liferate and differentiateinto immunoglobulin containing plasma); and T-macrophage interactions. T4+ cells produce humoral factors such as lymphocyte mitogenic factor, which induces proliferation of all major lymphocyte subclasses. Antigen stimulated T4+ cells produce helper factors that modulate erythroid stem-cell production and are important in hematopietic differentiation. T8+ cells con tain cells with suppressor/cytotoxic functions. This subset suppresses B cell immunoglobulin synthesis and has the capacity to kill cells to which they are sensitized. B lymphocytes are cells coded to product immunoglobulins, which are proteins found in blood and various secretions. B cells product Ig which belong to four major gorups: IgG - responsible for defense against bacterial infections i.e. pneumonia and strep throat; IgU - responsible for the defense against anerobic bacterial infections i.e. bowel pathogens; IgA - defends us against viral infections and is found in large quantities in our secretions; IgE - responsible for our defense against allergens. 6422 -2- HYBRIDOMA TECHNOLOGY -- The advent of hybridome technology has pro vided a new approach to immunology research. With its application monoclonal antibodies capable of recognizing with precision the functional components of the immune system provide the medical community with highly specific reagents for the study of T lympho cyte maturation and for the identification of T lymphocyte syb- populations. ORTHO SPECTRUM III utilizes the observation that human lymphocytes, monocytes and granulocytes posses different light scattering characteristics. Cells undergoing analysis travel in single file through a quartz cuvette where they intersect a nar rowly focused 488nm wavelength beam of light from an argon-ion laser. The illuminated cells scatter the light in all directions. A solid-state sensor collects low angle forward scatter to discrim i n a t e si ze of cells, a n d a p h o t o m u l t i p l i e r t u b e (PMT) set at 90. These signals produce a histogram of cells counted based on in tensity of green fluorescence. Analysis of peripheral blood samples is p e r f o r m e d u s i n g w h o l e blood. The cells are labeled by direct immunofluorescence, in which the monoclonal, antibody directed against the desired cell surface antigen is conjugated with a flourescent dye, or by indirect immunofluorescence, in which the m o n o c l o n a l a ntibody, h a v i n g b e e n f o u n d to the cll surface, is v i s u a l i z e d w i t h a s e c o n d f l u o r e s c e i n a , t e d a n t i b o d y ^ d i r e c t e d a g ayif n s t the monoclonal immunoglobulin. ' 6423 In *the evaluation of lymphocyte populations both per centages and absolute values are taken into consideration. The mechanism of how abnormal lymphocyte populations affects the im- mue response will be set out. The basic theorem is that changes in lymphocyte populations are suggestive of disease processer and often but not universally relate to dysfunction. For the purposes of this litigation, it is important to distinguish between immune deficiencies and immuno-suppression. Suppression referring to an acquired immune deficiency that can be the result of exposure to chemical toxins. Dr. Garofalo has had particular clinical experience rele vant to this litigation. He has, since December, 1983, examined about thirty-five (35) Vietnam veterans for Agent Orange-related immune abberations. To the best of his knowledge, the published literature does not contain any reports of data comparable to that which he has acquired. A general review of his date indicates that the Vietnam veterans exposed to Agent Orange have slightly elevated levels of lymphocytes, with particular reference to T helper cells. There is even some elevation of suppressor T cells. IV. SUBSTANCE OF OPINIONS 1. Agent Orange can affect the immune system by produ cing changes in the numbers and distribution of T cells, T helper cells, and T suppressors cells, though it is much more likely that it has its effect through changes in the latter two types of cells. 2. The effect on helper T cells may'result in a heigh tened immune response, leading to the formation <af auto-immurie diseases. These in turn may lead to excess cancer formation, arthritis, and* nerve damage, the latter including both central -4 - nerve damage and peripheral neuropathy, of which the "dying back" variant is typical. 3. Agent Orange can cause an excess of T8+ cells (suppressor/cytotoxic). This may represent an increase in either the suppressor population which in turn can interfere with helper T cell and B cell function or the cytotoxic cell population which have the capacity to kill specific cells to which they are sensi tized . 4. Agent Orange may act as an antigen bound to body tissues resulting in the formation of autoantibodies and cytotoxic cells directed against the sensitized tissue. Auto Antibody: "Auto" refers to self; "Antibody" refers to a protein formed by the immune system in a response to antigen exposure. An autoantibody is thus an antibody that is formed within a person against their own tissues, i.e., red blood cells, platelers, nerve tissue, skin). 5. Individual opinions concerning the representative plaintiffs are contained in their individual reports. V. GROUNDS FOR OPINIONS Dr. Garofalo will rely upon his own experience in the evaluation of other veterans he has evaluated in the past or whom he will evaluate in the future, and upoh the attached list of articles. s 4 / S' Ii 8425 -5 - * / I o \ 41 Appointments by Dr Lennart Harden After authorization worked as: General practitioner, Primary Health Centre, Haparanda, November 1 1971 - August 31 1972. Junior registrar, Department of Psychiatry, County Hospital, Kristinehamn, September 1-30, 1972. Junior registrar, Department of Psychiatry, County Hospital, Boden, October 1 - December 31 1972. From January 1 1973 to August 31 1976 various appointments as Junior registrar, Senior registrar and consultant at the Department of Internal Medicine, County Hospital, Boden. From September 1 1976 various appointments as a Junior registrar, Senior registrar and consultant at the Department of Oncology, University Hospital, UmeS. September 1 - December 31 1983 Head and consultant, Centre of Oncology, University Hospital, UmeS. M For the moment appointed as consultant at the Department of Oncology, University Hospital, Umea, Sweden. 25. Seminar on Drugs and Pesticides; The Swedish Branch of Friends of Earth International ((nvited speaker) Conference on Biological Mechanisms of Dioxin Action Symposium on Toxicology; Swedish and Finnish Association of Toxicology (Invited speaker - unable to attend) Symposium on Leukemia and Related Diseases; International Association for Comparative Research (Invited speaker - unable to attend) Internation Symposium on Herbicides and Defoliants in War; The Long-Term Effects on Man and Nature (Invited speaker - unable to attend) Symposium on Public Health and Risks of Chlorinated Dioxins (Invited speaker - unable to attend) Congress on the Scientific and Social Response from Exposure to Dioxins and Related Material; Association of Occupational and Environmental Health (Invited speaker - unable to attend) I Biskopnarno, Sweden Banbury Center, NY November 26-27, 1983' April 1-4, 1984 t *v Stockholm, Sweden May 16, 1981 QO CM CO Los Angeles, CA i Ho Chi Minh City, Vietnam August 31-September 4, 1981 January 13-20, 1983 Rockefeiler University October 19-20, 1983 New York A rlington, V irginia December 6 -7 , 1983 9. Seminar on the Work with Pesticides and Associated Risk; The National Swedish Environmental Protection Board (Invited to participate) 10. Seminar on the Use of Phenoxy Acids - in the Agriculture; Swedish National Board of Occupational Safety and Health (Invited to participate) 11. Conference on the Use of Pesticides in Forestries - Swedish Association of Churches (Invited speaker) 12. Conference by the Swedish Association of Pesticide Manufacturers; Phenoxy Acids and Cancer (Invited speaker) 13. Committee on the Use of Pesticides in Forestry and Agriculture The Swedish Parliment (Invited speaker) * 14. Conference on Use and Regulation of Pesticides - Nordic Counsel of Workers in Agriculture and Horticulture; Health Effects of Phenoxy Acids (Invited speaker) 15. Tenth Annual Meeting of European Environmental Mutagen; Society on Environmental Mutagenisis (Invited speaker) 16. Seminar on Demands Made by the Society for Registration and Use of PesticidesAssociation of Nordic Agricultural Research (Invited speaker) Stockholm, Sweden 1 ; 's . September 20, 1979 <73 "CH CO Stockholm, Sweden October 3, 1979 1 -v Sodrahoka, Sweden November 6, 1979 Stockholm, Sweden November 27, 1979 Stockholm, Sweden February 20, 1980 Istab, Sweden Athens, Greece September 1-5, 1980 t September 14-19, 1980 Helleiud, Norway November 12-13, 1980 IIARDELL, Lennart 1. Conference organized by the Swedish Society of Medical Radiology (Invited speaker) 2. Conference by the Finnish Medical Association; Duodecim and Medical Faculty 3. Malignant Tumors and Chemical Risk Sectors in the Environment (Invited speaker) 4. Meeting on Phenoxy Acids; The Committee on Agriculture of Swedish Parliment (Invited speaker) 5. Soft-tissue Sarcoma and Exposure to Phenoxy Acids or Chlorophenols; Meeting by the Swedish Pharmaceptical Association in Ume (Invited speaker) 6. Conference on Pesticides and Human Health - Society for Occupational and Environmental Health (Invited speaker) 7. Symposium by Nordic Counsel on Arctic Medical Research (Invited speaker) 8. Seminar by Ume University Before The Swedish Work Environmental Fund; Chemical Substances in-the Environment (Invited speaker) Ume, Sweden Oulu, Finland Oulu, Finland September 23-24, 1977February 22-23, 1978 Stockholm, Sweden October 17, 1978 Ume, Sweden November 9, 1978 Washington, D.C. December 10-13, 1978 Leykgavik, Iceland June 29-30, 1979 , Sweden September 11-12, 1979 30. Hardell L, Eriksson M, Lenner P, Lundgren E. Malignant lymphoma and ex posure to chemicals, especially organic solvents, chlorophenols, and phenoxy acids: A case-control study. Poster at the 13th International Cancer Congress, September 8-15, 1982. Seattle, Washington USA. 31. Hardell L. Epidemiological studies on soft-tissue sarcoma, malignant lymphoma, nasal, and nasopharyngeal cancer and their relation to phenoxy acid or chlorophenol exposure. In: Chlorinated Dioxins and Dibenzofurans in the Total Environment. Eds. Choudhary, Keith, Rappe. Butterworth Publishers, Boston, pp. 367-374, 1983. 32. Bengtsson NO, Hardell L, Eriksson M. Asbestos exposure and malignant lymphoma. Lancet ii (1982) 1463. 33. Hardell L, Bengtsson NO. Epidemiological study of socioeconomic factors and clinical findings in Hodgkin's disease, and reanalysis of previous data regarding chemical exposure. Br. J. Cancer 48 (1983) 217-225. # 34. Sandahl, Ronnlund U, Hardell L. Koststudie vid onkologisk klinik. Nutritionsstatus hos radioterapibehandlade head- och neckpatienter. UrneS Universitet 1983. (In Swedish). 35. Hardell L. Epidemiological studies on soft-tissue sarcoma, malignant lym phoma, nasal, and nasopharyngeal cancer and their relation to phenoxy acid or chlorophenol exposure. Abstract before Dividsion of Environmental Chemistry, American Chemical Society, Kansas City, Missouri, September 15-16, 1982. 36. Direct testimony of Dr. Lennart Hardell, "The Herbicide Court Case", Nova Scotia, Canada, May 1983 (presented by Dr. M. Eriksson). 37. Hardell L. Axelson 0, Rappe C. Nasal cancer and chlorophenols. Lancet i (1983) 1167. 38. Sandahl C, Ronnlund U, Hardell L. Battre naringsstatus hos cancerpatieater med hjalp a\Tnutritionsgrupp och kostombud? Lakartidningefi 80 (1983) 2234-2235. (In Swedish). ' ^431 / 39. Domellof L. Hansson M. Hardell L. Nygren M f Rappe C. Levels of polychlorinated dihenzodioxins (PCDDs) and dibenzofurans (PCDFs) in fat tissue from cancerpatients and controls. Abstract before the AACR annual meeting May 9-12, 1984, Toronto, Ontario, Canada. ARTICLES UPON WHICH DR. GAROFALO MAY RELY IN WHOLE, OR IN PART, ARE: J. Hopkins Dioxin: Carcinogenicity FD. COSMET. TOXICOL. 1980 Voi. 18, pp. 739-741 J. Hopkins, P. Cooper Dioxin Dangers to Man FD. COSMET. TOXICOL. 1980 Voi. 18, pp. 541-546 J. E. Huff, J. A. Moore, R. Caracci and L. Tomatis Long-Term Hazards of Polychlorinated Dibenzodioxins and Polychlor inated Dibenzofurans ENVIRONMENTAL HEALTH PERSPECTIVES 1980 V o l . 36, pp. 221-240 David Paen & Edward Glover Our Promotion by 0 in Skin of HRS/J Hairless Mice MACMILLAN JOURNAL November 18, 1982 Vol. 300, pp. 271-273 G. Reggiani, F. Hoffmann Acute Human Exposure to TCDD in Seveso Italy JOURNALOF TOXICOLOGY AND ENVIRONMENTAL HEALTH 1980 Vol. 6, pp. 27-43 Michael I. Luster, Gary A. Boorman, Jack H. Dean, Martha W. Harris, Robert W. Luebke, Martin L. Padarathsingh and John A. Moore Examination of Bone Marrow, Immunologic Parameters and Host Susceptibility Following Pre- and Postnatal Exposure to 2,3,7,8Tetrachlorodibenzo-p-Dioxin (TCDD) INT. J. IMMUNOPHARMACY 1980 Vol. 2, ppj 301-310 William G. Dun&g'in, M.D. Dioxin Effects on Human Health MISSOURI MEDICINE March, 1983 Vol. 80, No. 3, pp': 127-131 > 6432 R. P. Sharma, P. J. Gehring Effects of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) On Splenic Lymphocyte Transformation in Mice After Single and Repeated Exposures ANNALS NEW YORK ACADEMY OF SCIENCES 1979 pp. 487-497 S. J. Stohs, M.Q. Hassan and W. J. Murray Lipid Peroxidation as a Possible Cause of TCDD Toxicity BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS March 29, 1983 Volume 111, No. 3, 1984, pp. 854-859 David A. Clark, Jack Gauldie, Myron R. Szewczuk and George Sweeney Enhanced Supressor Cell Activity as a Mechanism of Immunosuppres sion by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (41275) PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE 19 81 pp. 290-299 Graziella Filippini, M.D., Bianca Bordo, M.D., Paolo Crenna, M.D., Nicoletta Massetto, M . D . , Massimo Musicco, M.D., Renato Boeri, M.D. Relationship Between Clinical and Electrophysiological Findings and Indicators of Heavy Exposure to 2,3,7,8-Tetrachlorodibenxodioxin SCAND J WORK ENVIRON HEALTH 1981 Voi. 7, pp. 257-262 C. M. Bishop, A. H. Jones Non-Hodgkin's Lymphoma of the Scalp in Workers Exposed to Dioxins THE LANCET August 15, 1981 p. 369 Jana Pazderova-Vejlupkova, M.D., Marcela Nemcova, Ph.D., Jane Pickova, Ph.D., Lubor Jirasek, Ph.D., Edgar Lukas, Ph.D. The Development and Prognosis of Chronic Intoxication by Tetrachlordibenzo-p-dioxin in Men ARCHIVES OF ENVIRONMENTAL HEALTH January/February, 1981 Vol. 36, No. 1, pp. 5-11 -7- Henry C. Pitot, Thomas Goldsworthy, H. A. Campbell, and Alan Poland Quantitative Evaluation of the Promotion by 2,3,7,8,-Tetrachlorodibenzo-p-dioxin of Hepatocarcinogenesis from Diethylnitrosamine CANCER RESEARCH October, 19 80 Vol. 40, pp.3316-3620 J. G. Vos, J. G. Kreeftenberg, H. W. B. Engle, A. Minderhoud and L. M. Van Noorle Jansen Studies on 2,3,7,8-Tetrachlorodibenzo-p-Dioxin-Induced Immune Suppression and Decreased Resistance to Infection: Endotoxin Hypersensitivity, Serum Zinc Concentrations and Effect of Thymosin Treatment TOXICOLOGY 1978 Vol. 9, pp. 75-86 Michael I. Luster, Robert E. Faith and George Clark Laboratory Studies on the Immune Effects of Halogenated Aromatics ANNALS NEW YORK ACADEMY OF SCIENCES 1979 pp. 473-483 Ralph R. Cook Dioxin, Chloracne, and Soft Tissue Sarcoma THE LANCET March 14, 1981 A. Mantovani, A. Vecchi, W. Luini, M. sironi, G. P. Candiani, F. Spreafico and S. Farattini Effect of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin on Macrophage and Natural Killer Cell-Mediated Cytotoxicity in Mice BIOMEDICINE 1980 Vol. 32, pp. 200-204 Michael I. Luster and Robert E. Faith Assessment of Immunologic Alterations Caused by Halogenated Aromatic Hydrocarbons ANNALS NEW YORK ACADEMY OF SCIENCES 19 79 ~ pp. 572-577 l -8 - John A. Garofalo, M.D. 847 Old Lancaster Road Bryn M a w r , PA 19010 Date of Birth: August 15, 1946 SPECIALTY: Hematology - Oncology - Immunology AFFILIATIONS: Assistant Professor of Medicine Thomas Jefferson University Hospital Philadelphia, Pennsylvania Assistant Attending Department of Medicine Bryn Mawr Hospital Bryn Mawr, Pennsylvania EDUCATION: 1977-1980 1977-1980 1976-1977 1975-1976 1974-1975 1969-1974 1964-1969 Clinical Fellow - Immunology - Oncology Memorial Sloan Kettering Cancer Center New York, New York. Research Fellow - Immunobiology Memorial Sloan Kettering Cancer Center New York, New York. Medical Resident - Pennsylvania Hospital, Philadelphia, Pennsylvania. Medical Intern, Philadelphia General Hospital, Philadelphia, Pennsylvania. Research Fellow - Immunobiology, Memorial Sloan Kettering Cancer Center New York, New York. University of Rome, Faculty of Medicine. Oklahoma State University, Stillwater, Oklahoma - Bachelor of Science in Physiology. 1983 1983 Medical Director - Home Cancer Care, INC. Home Health Care Agency Medical Director - Immunodiagnostics Clinical Laboratories, INC., Reference Immunology Laboratory. I 5 BIBLIOGRAPHY John A. Garofalo, M.D. I. Letters to the Editor 1. AIUTI, F., GAROFALO, J.A.: Rectal immunoglobulin synthesis in ulcerative colitis. To the Editor: New Enqland Journal of Medicine, voi 287, No. 22, 1151, 1972. 2. GAROFALO, J.A., STRONG, E., GOOD, R.A.: Zinc and intestinal bypass procedures. To the Editor: Annals of Internal Medicine, June 1979. II. Abstracts 1. GAROFALO, J.A., CUNNINGHAM-RUNDLES, S.: In vitro effects of zinc chloride on lymphocyte transformation. Fed. Proc. 37(6), 3154, 1978. 2. GAROFALO, J.A., STRONG, E., CUNNINGHAM-RUNDLES, S., ERLANDSON, E., MENENDEZ-BOTET, C., SCHWARTZ, M., GOOD, R.A.: Serum zinc in patients with epidermoid cancer of the head and neck. Fed. Proc. 38(3), 2651, 1979. 3. CUNNINGHAM-RUNDLES, C., CUNNINGHAM-RUNDLES, S., GAROFALO, J., IWATA, T., INCEFY, G., TWOMEY, J., GOOD, R.A.: Increased T lymphocyte function and thymopoietin following zinc replacement in man. Fed. Proc. 38(3), 5259, 1979. 4. CUNNINGHAM-RUNDLES, S., CUNNINGHAM-RUNDLES, C., GAROFALO, J., DUPONT, B., GOOD, R.A.: Effect of zinc on human B cell activation. Fed. Proc. 38(3), 3735, 1979. 5. GAROFALO, J.A., LEE, B., LACHER, M., OCHOA, M., LEWIS, J., STRONG, E., ERLANDSON, E., COIRO, D., SCHWARTZ, M., GOOD, R.A.: Serum zinc and copper and the Cu/Zn ratio in patients with cancer. AACR/ASCO, 733, 1980. 6. GAROFALO, J.A., ERLANDSON, E., LESSER, M., GEROLD, F., SCHWARTZ, M.K., GOOD, R.A., STRONG, E.W.: Serum zinc, serum copper and the Cu/Zn ratio in patients with epidermoid cancer of the head and neck. International Head and Neck Oncology Research Conference, September 10, 1980. Ill. Pub!ications 1. AIUII, F., LACAVA, V., GAROFALO, J;A., D'AMELIO, R., D'ASERO, C.: Surface markers on human lymphocytes: Studies of normal subjectsand of patients with primary immunodeficiencies. Clin. Exp. Immunol. 15:43-52,, 1973. VZ- AvjW \q?3 ) COMMISSION MEMBERS ICNATONIi C l o u a i *'h a v n u o io n MIMIOALI WILLIAM r . MAi MOMCWOOO -- ir*n or iLUNOii AGENT ORANGE STUOY COMMISSION 1107 STRATTON BUILDING SPRINGFIELD. ILLINOIS 0 X7 0 AREACOOC Xf 7/ 7 0 1 -4 4 X0 CHICAGO AM M. VAOALAI CMI COWANOIVILLC ITATIVCII LAWOCMC o iro n CMICAOO WUT CHICAGO JOHN T. 0 *COMMCLL w iiT in n iorihci M IIIIIT J. riCL lOUTH MOLLAHO PUBLIC M< (TONIHGTOH CMICA 0 Dear Friend: The Illinois Agent Orange Study Commission Is proud to have hosted the first national Agent Orange Medical Symposium. It is of major significance that 13 of the 20 staces with Agent Orange Commissions or programs at tended the Symposium. The Symposium was the culmination of a great effort on the part of Che Illinois Agent Orange Study Commission's staff and Che leadership of other state commissions in pro moting and organizing such a successful and productive event. The panelists also deserve much appreciation for their gratis appearance. Without such waivers of honoraria the Illinois Agent Orange Study Commission would have been unable to tjold such a program because of budgetary constraints. It was the intention of the Illinois Agent Orange Study Commission to allow physicians and researchers familiar with herbicide exposure and its physiological ramifications to have a forum from which they could speak. They did so in an eloquent and comprehensive manner. IMIMCflCtO CHICAGO It is my hope chat this publication of the Symposium's transcript will benefit those who have concerns regarding the Agent Orange issue. While questions still remain, we believe our efforts represent a positive step coward Che ultimate resolution of this most complex and profound matter. M R . O 'C O N N E L L : G o o d m o rn in g . M y n a m e is J o h n O 'C o n n e ll. I am a sta te rep re se n ta tiv e fro m Illin o is. A n d o n b e h a lf o f Illinois. I 'd like to w elco m e y o u to o u r s ta le a n d the city o f C h ic a g o and o u r beautiful fall w eather. I am a lso th e ch airm an o f the Illinois A gent O ran g e S tu d y C o m m issio n , w hich has been in existence in this state for a little over a year and a half. A n d in that year an d a half, in addition to our public hearings that we have had throughout the state, we have had the opportunity to meet several o th er state com m ission representatives. It o c c u rre d to us so m e tim e a g o th a t it w o u ld b e a v ery e x p e n d itio u s e x p en d itu re o f m o n ey a n d tim e to h av e a sy m p o siu m , w herein w e could reach o u t a n d find a n a rra y o f experts in the field o f d io x in a n d th e A g e n t O ra n g e a n d p resent it fo r the re c o rd s o th a t all o f u s co u ld b en efit. ,, In that reg ard , I think you will, upon review o f o u r p ro g ram today, agree that we have p e rh a p s as co m p re h en siv e an d p restigious a group o f sp eak ers o n th is issue as you will ever find in this c o u n try . W e have tw elve states th a t have indicated th a t they will be in atten d an ce. A nd we have som e d is tin g u is h e d g u e sts in th e a u d ie n c e . A s a n overview o f to d a y 's m e e tin g , I a llu d e d e a rlie r to th e fact th at all o f us are looking for the sam e answ ers. In o u r ow n states, we have pursued an endeavor to find som e answ ers fo r o u r citizens, the V ietnam veterans, and their fam ilies. T his, we recognize as a s ta te , is se c o n d a ry to th e overall federal p ro b e o f th e A g en t O ra n g e issue. B ut, we at least in Illinois, a n d I suspect o th e r states, felt th at w hat w as needed w as involvem ent o n b eh alf o f the various states to p u ru se a th ird -p arty evaluation o f this issue. W e, in Illinois, felt th a t in d eterm in in g th e an sw ers to w h e th e r th ere is a causal fa c to r o f erious d efects a n d diseases in exp o su re to A gent O ra n g e , th e fed eral gov ern m en t w as in an a d v er sarial p o stu re . A n d in th a t adversarial p o stu re, it w as b o th th e p la in tiff a n d th e d efe n d a n t, if you will. A n d therefore, to m ake certain th at the evidence was com plete and w hole, w e as a state had a respon s ib ility to 's u b m it te s tim o n y fro m o u r re sid e n ts a s to th e s y m p to m s t h a t th e y h a v e in c u rre d . In that regard, we have had eight public hearings th ro u g h o u t o u r state and developed a record o f testim ony. . A y e a r a g o , w e h ad a hearing w hich featured m edical p ra c titio n e rs in this area , as well as one o r tw o o u t-o f-to w n guests, including D r. C o d ario w ho will sp eak ag ain this m orning. W e felt th a t the I te stim o n y elicited a t th a t hearing w as so valuable in term s o f an overall reco rd th at dup licatio n o f th a t, Only on a b ro a d e r sp e c tru m , w ould be o f extrem e v alu e to us in p re se n tin g this overall reco rd o f evidence o n the issue. A nd in light o f the controversy over th e issue a n d the m yriad o f reports th a t are c o m in g o u t, w etfelt in d e e d it w as to p ic a l a t this tim e th a t w e s h o u ld p re se n t to th e v a rio u s states a n d to th e federal governm ent a record o f testim ony from people w ho have m ad e a career o f studying this issue a n d , o f course, evaluating the victim s. L T o d a y , i f n o th in g m o re is gained th a n a tra n s c rip t o f a g r o u p o f p restig io u s in d iv id u a ls-- p ro fessio n als offerin g th eir ow n experiences, it is in d eed a success. I w ould like to c o m m e n c e th is p ro g ra m by in tro d u cin g o u r first speaker, w ho is D r. B ertra m C a rn o w . L D r. C a rn o w is president a n d sen io r scientist fo r C a rn o w , C o n ib e a r & A ssociates, an e n v iro n m e n ta l a n d o c c u p a tio n a l h ealth consulting firm h ere in C h ic a g o . T h is is th e second tim e th a t the Illinois A gent O ran g e C om m ission has had the pleasure o f in tro d u cin g D r. C arnow . H e was a partici Lp a n t a t o u r m e d ic a l h e a rin g s last O c to b e r . D r. C a r n o w is a g r a d u a t e o f th e U n iv e rsity o f C h ic a g o S chool o f M edicine. H e is a veteran o f the United S tates A ir F prce, an d has been director o f o ccu p a tio n a l a n d e n v iro n m e n ta l m e d ic in e at th e U n iv ersity o f Illin o is S c h o o l o f P u b lic H e a lth . A n d h e is cu r- L I renily professor and director of G reat Lakes C enter for O ccupational Safety and H ealth o f the U niversity o f Illinois School o f M edicine. D r. C a rn o w is a lso a m u ch pu b lish ed and m u c h -so u g h t-a fte r sp eak er. A nd he had the d u b io u s d is tin c tio n o f a p p e a rin g w ith m e o n a television s h o w th a t a ire d at 6 :0 0 o 'clock in the m o rn in g . S o w ith o u t fu rth e r a d o , 1 w o u ld like to in tro d u c e D r. B ertram C arn o w . (A pplause.) D R . C A R N O W : Thank you, M r. C hairm an. I t 's a p le a su re to b e h ere to ta lk w ith y o u to d a y . 1 e x p e c t o r h o p e th a t by th e e n d o f th e d a y , all o f you will be ab le to answ er the question o r q uestions th at seem to be plaguing m any o f us. P o ssib ly th e m o st ask ed q u estio n is " is dioxin really to x ic ? " E very tim e I hear that I cringe because a huge am o u n t o f scientific d a ta has been gathered a n d rep o rted including reviews by the V eterans A d m in istratio n and th e E P A , o u r studies, and the 2,000 o r m o re scientific reports which have appeared in th e s c ie n tific lite r a tu r e . T h e re a p p e a rs to b e n o q u e s tio n th a t d io x in is the m o st p o te n t tox ic a g e n t ever pro d u ced by m an T he only substances m ore toxic are pure extracts o f biological toxins including te n ta n u s to x in , d ip th e ria to x in , an d bo tu lin u m to x in . It h as a lso been show n th a t it will kill a y o u n g guinea pig at a co n cen tratio n o f approxim ately five p arts per trillio n .,' S o th e q u e s tio n o f to x ic ity I d o n 't th in k is a t issu e h e re . AtiC4(cr q u e stio n is-- " w h a t d a m a g e d o e s it d o a n d h o w d o e s it d o it? " I w o n 't d iscu ss th e s e in d e p th b e c a u se th e re will b e a lot o f d is c u s s io n a b o u t th o s e q u e s tio n s th is a fte rn o o n . Let m e tell y o u o n ly b rie fly w h a t it d o c s b ecau se it relates to o u r stu d y . It m oves in to th e body cells particularly in the liver a n d affects stru ctu res in these cells in cluding o n e called endoplasm ic reticulum and a n o th e r called m ito ch o n d ria. It causes the endoplasm ic reticulum , a m a jo r reg u lato r o f production o f enzym es, fats, an d proteins, to go w ild. As a result the body overproduces enzym es an d accelerates the destruction a n d rem oval from the body o f essential chem icals. T h e body in tu rn then keeps trying to m an u factu re m o re and m ore o f these chem icals at an incredible rate. In doing so, it disrupts many essential activities o f the body. T he group o f enzym es w hich atx-particularly affected, called m ixed function oxidases a re essential to body function. It a lso destro y s m ito ch o n d ria. They a rc critical in energy tra n sfe r in m uscle an d o th e r o rg an s. M usclcs,-tn o rd er to w ork, use a great deal o f energy. A nd th e body has an energy transfer system w hich tra n sfo rm s fo o d in to energy w hich then pro v id es fuel fo r m uscle use. D ioxin, by destroying the m ito ch o n d ria interfere w ith this energy transfer. v S o w e k n o w a g re a t d e a l ev en a b o u t d io x i n 's m e c h a n is m s o f d e s tr u c tio n , ev e n a t a m o le c u la r -- -- "lev el. T h e jiext q u e stio n is, given th a t this is tru e , " d o e s it d o very m u ch clin k S IIy r'frern ra'ciisease / sta n d p o in t? " Let m e tell you that every single species o f an im al th at has been exam ined follow ing p o iso n in g w ith dioxin has sh o wn testicular dam agC ydam age to^tije im m u n e system , a n d dam age to the liver. E v ery single'spccies. m iT is ex trao rd in ary fo r a toxic a g e n t! A n d th ere arc in n u m erab le exam ples o f w h a t it h a s d o n e to h u m a n s in in d u stria l ao cid en ts. M a n y o f ^ o u k n o w a b o u t th o se so 1 w o n 't dw ell o n th e m . I believe th a t o th ers will discuss them in g re a te r d etail th is a fte rn o o n . A n d finally, there has been another question which has been interjected, nam ely "w h at about chloracnc, a particularly nasty form o f acne found after som e accidental plant explosions and other ex p o su res?" " I f you d o n 't have chloracne, can you have dioxin in to x icatio n ?" Because chloracne in volved th e sk in o f th e face, ears and trunk and w as disfiguring, it received a great deal o f atten tio n . T h o se a ffe c te d by d jp x in w ith this co n d itio n w ere sent to skin sp ecialists w h o tre a te d it as a p rim ary skin p ro b le m . A n d fro m this th e fiction developed th a t ch lo ra c n e w as th e sine qu a n o n o f diokin in- 2 40 c a tio n . It w a s n 't tru e o f th o se e x p o se d in S evcso a n d it w a s n 't tru e in th e a lm o st 400 people e x am in ed by u s. In b o th g ro u p s a p p ro x im a te ly 10 to 15970 o f th o s e a ffe c te d h a d c h lo ra c n e a n d these w ere younger people with a history o f com m on adolescent acne. Y ou do not have to have chloracne to have dioxin intoxication. T hose are m y answ ers to those fo u r q u estio n s. H o p efu lly o th ers will address these an d o th er questions in m ore detail. N ow , let m e then get on to o u r studies. W e w ere asked to exam ine a g ro u p o f w orkers w ho had .been exposed w hile cleaning up a spill o f dioxin, co n tam in a ted an d chlorinated phenol and other p h e n o ls. A n d w hile the o th e r chem icals present m ay lead to a n a c u te clinical picture w hich is slightly d ifferen t from th at presented by veterans w ho were exposed, we belive the m ajo r effects, the long term effects were from the dioxin to which o u r study group w as exposed. Since that tim e, we have studied m any others w ho had o th er types o f exposure to dioxin. W c have also studied a small group o f v eterans, but they represent a very sm all percentage o f o u r to tal. 1 am able only to discuss with you the 47 railroad w orkers. E v e n tu a lly w c will d isc u ss a n d p u b lish all o f o u r fin d in g s. H o w e v e r, let m e a ssu re you th a t in the exam in atio n o f m any o f the o th e rs, th e pattern th a t I will describe to you em erges over and over a n d o v e r ag ain . A n d 1 will sh o w y o u w h at I believe to be a p a tte rn o r fin g erp rin t o f a disease w hich we call ch ro n ic chem ical intoxication from dioxin. T hese exam inations w ere carried out by our team o f occupational m edicine specialists at C aro w , C onibear & A ssociates, incuding D r. Shirley C onibcar, D r. G eorge Benjam in and m e. H ow do you go about studying such an exposed group? H ow do you m ake a determ ination * first, w hether these people are ill? S econdly, if they a rc ill, w hat kind o f illness d o they have, w hat o rg a n s a r e involved a n d h o w se rio u s is it? T h ird , is h o w d o y o u th e n m a k e a d e te rm in a tio n o f w h eth er o r n o t th e disease th a t they have is related to an external cau se? G en erally , m ost o f us w ere trained to d ia g n o se a n d treat disease; but except fo r bacterial diseases th e re is little em phasis o n exam ining q u es tio n s o f cau satio n . F or those o f you w h o m ay be in terested , th e re will be published shortly, a p aper th a t D r. C o n ib e ar an d I w rote o n the probability o f cau satio n o f chem ical disease, which suggests w ays o f looking at diseases to m ake determ inations o f how they m ight relate to som e type o f external cause. In o rd er to d o this, we first determ ined all o f the things th at o th ers knew ab o u t w hat dioxin d id . W h at organ system s, w hat m echanism s, w hat functions o f the body were affected by this ch em ical. A fter j^now ning this, wc then set up a p ro to co l, a test p ro to c o l, w hich looked at all o f these fu n ctio n s. If w eT ound th at people show ed evidence o f o rg an disease th at fit w hat others have found an d these were people w ho had been exposed to diosin, an d the tem p o ral relationship between ex po su re an d disease was a reasonable one, we could say that (hey are causally related. W ith som e toxic agents, cause and effect are m ore easily determ ined. If som eone inhales a la rg e a m o u n t o f c y a n id e gas a n d d ies im m e d ia te ly a f te r w a r d , th e c a u se a n d effe c t re la tio n sh ip is fairly o b v io u s . I f so m e b o d y , h o w ev er, is e x p o sed to a ch em ical a n d five m o n th s later o r tw o years la te r or th r e e y e a rs la te r h e b eco m es ill, it b e c o m e s a little m o re c o m p le x . O n e o f th e d iffic u ltie s w e h av e w ith d io x in is th a t it d o e s n 't kill d irec tly lik e c y a n id e . It a ffe c ts e n z y m e sy ste m s w h ich in tu rn affe c t m a n y b o d y activ ities so th a t th e effects a rc very m uch d elay ed . T h is is tru e w ith a n im a ls as well as h u m a n s. W h a t 1 w ill b e d isc u ssin g w ith y o u n o w a r e th e re s u lts th a t w'c f o u n d o n a d m in is te rin g th e se tests to this g ro u p o f individual w orkers. T he histogram s sh o w the percentage o f exposed individuals with sy m p to m s reflecting ab n o rm alities o f various o rgan system s. A s can be seen, virtually every m a- l .t jo r organ system was affected in som eway, with a large m a jo rity com plaining o f headaches, depres sion a n ttp io fo u n d fatigue. W e believe the depression to be o f the type called neurovegetative depression by som e E u ro p e a n sc ie n tists. I t 's d escrib e d p ro m in e n tly in v irtu a lly e v e ry d io x in e x p o se d g ro u p th at has b een studied; B A SF in G erm any, the group in C zech o slo v ak ia, the g ro u p at N itro , and m any o f the o th e r g ro u p s a n d is th e result o f toxic d e p ressio n o f b ra in fu n c tio n . S o m e o f o u r p a tie n ts w ere p o te n tially suicidal. T h e genitourinary system also w as affected as no ted . S om e o f you m ay have heard o f the young children in M issouri exposed in 1972 w hen a n u m b e r o f h o rse aren as w ere sprayed with a w aste oil c o n ta in in g d io x in . T h e ch ild ren b e c a m e ill a n d s o m e 85 h o rs e s w a s te d a n d d ie d . G e n ito u rin a ry sym ptom s an d kidney destruction were pro m in en tly present in the horses an d in som e o f the children. U rgency and burning on urination, getting up at night to u rin ate, frequency of urination, decreased libido (decreased desire for sexual activity) also w ere n o te d . A n d in som e cases decreased ability to have sexual activity. In regard to the lungs, half o f the people co m plained o f shortness o f breath. Som e o f those w ere a c u te s y m p to m s p resen t im m ed iately a fte r th e e x p o s u re . S in ce th e re w as p h en o l p resen t, it m a y have been that this w as the problem because we did not find that chronic lung disease was a very prom inent factor in o u r exam inations. In regard to other system s, 10% or m ore com plained o f benign fatty tum ors developing under the skin. O ne m an deveoped 50 o r 60 o f them . W eight loss w as prom inent in som e an d seem ed to be an early p h en om enon which went aw ay after ab o u t three or fo u r m onths. In anim als th e w eight loss w as even m o re severe. M an y o f them died o f a w asting disease. T hese included m onkeys and the horses from the M issouri aren a s. S om e o f the horses weighted only 90 o r lQ flpounds w hen they died. W eakness w as also prom inent but not as m uch as general fatigue. W eakness and fatigue arc som etiTnes d ifficu lt to sep arate. F atig u e is a g en eral feelin g o f n o t b ein g rested . Y ou get u p in th e m o rn in g , y o u a re tire d . Y ou a re tired all d a y . It d o e s n 't m a tte r w h a t y o u d o . T h e tiredness re m a in s. W e a k n e s s is s o m e w h a t d iffe re n t in th a t y o u m a y feel w ell a f t e r a g o o d n i g h t 's sleep b u t w h e n y o u begin a task you run out o f steam . For exam ple, we fo u n d w ith som e that if they lifted their arm s to d o a task, th^ir arm s w ould tire very rapidly. Y ou have to u n d erstan d that these people w ere m a in te n a n c e a n d w a y p e o p le . I t 's p h y sic a lly o n e o f th e m o s t d e m a n d in g j o b s o n th e r a ilro a d . M a n y o f the m en had w orked fo r the railroad for 20 o r 30 years. M ost o f them w ere hunters and sportsm en and m a n y h a d sm all f a r m s th a t th e y w o u ld o p e r a te a f te r th e y fin is h e d th e ir d a y 's ,,work o n th e r a ilr o a d . S o m e h a d n 't m isse d a d a y o f w o rk in 10 y e a rs b e c a u se o f illn e sse s. T h e average age w as only 33 in this g ro u p , th u s m a n y w ere q u ite y o u n g an d previously very h e a lth y . H eadache and fatigue were the m ost co m m o n o f th e sy m p to m s. T h e headaches were general ly characteristic. They w ere frontal o r bitem poral; that is, they w ould start in the front o f the head o r acro ss the tem ples. M an y com plained o f th ro b b in g in th e h ead m a d e w orse if they bent over, alth o u g h n o t all o f them h ad th ro b b in g headaches. A nd they w ere o fte n very severe. In^othcr groups we have stu d ie d sin ce th e n , a sim ilar h e a d a c h e p a tte rn is p re s e n t. ' ./ T h e sym ptom s arc critical and probably the most im p o rtan t com ponent o f the medical ' 4 I evaluation, but o th er exam inations co n trib u te to u n d erstan d in g an d defining the disease process. l T hese include the physical exam and la b o rato ry an d o th e r tests. First let's look at liver disease. W e fo u n d th at in th is g ro u p , liver enzym es w ere a b n o rm a l in so m e . T h e o n e w hich seem ed to be m ost c o m m o n ly a b n o rm a l w as the S G P T in eight people. O n e o f th e things we fo u n d in other groups that we h a v e s tu d ie d , is th a t th is in fla m m a tio n o f th e liver is s o m e th in g th a t d e v e lo p s relatively early a n d in a lo t o f p e o p le s o rt o f b u rn s o u t. T h is d o e s n 't m e a n th a t th e liver d ise a se is g o n e -- o n ly th a t i t 's becom e low grade and chronic. L iver biopsies d o n e in som e suggest th at it d o e s n 't g o aw ay . G ro u p s th a t we studied m an y years a fte r ex p o su re did n o t show a lot o f enzym e a b n o rm a litie s, n o r did they show a lot o f a b n o r m a litie s o f b iliru b in , w hich is a chem ical p ro d u c e d in th e liver. S o m e sh o w e d a n a b n o rm a lity o f an e n z y m e called a lk a lin e p h o sp h a ta se w hich is so m eth in g w e see w hen th e re is increased b o n e activity in th e b o d y , b u t a ls o s o m e th in g we can sec w h ere th e re is c h ro n ic liver d ise a se a n d it m a y , in fact, re p re sent chronic liver disease. W e a ls o f o u n d a b n o r m a l levels o f fa tty s u b s ta n c e s (lip id s) w h o se p r o d u c tio n is g enerally c o n tro lled by the liver. A n d w e know that dioxin causes d istu rb a n c e s in fat m etab o lism . A n d , in fact, h a lf o f the people that w e exam ined had abnorm ally high triglycerides. M an y o f them had abnorm ally high cholesterol. A nd even m ore had depressed high density lipoproteins (H D L ), a type o f fatty substances t h e b o d y w a n ts . P e o p le w ith h ig h H D L h a v e less c o r o n a r y d is e a s e g e n e ra lly . T h e m o re y o u have o f it th e better o ff you arc. In this group, 28 had a depression o f H D L . T hey also had abnorm alities o f lip o p ro te in e le c tro p o re sis, w hich is a n o th e r w ay o f lo o k in g a t th e se fa tty s u b sta n c e s. T h is d istu rb a n c e o f fat m etabolism in the b o d y is very im p o rta n t because the brain and the p erip h eral nerves o f the body use lipids in their fu n ctio n . A lso high tryglycerides an d cholesterol and lo w H D L are associated w ith heart diseasci stroke and high b lo o d pressure. A n o th e r critical b o d y activity is p o rp h y rin m e ta b o lis m . T h e re is a ra re genetic disease w ith d is tu rb e d p ro d u c tio n a n d ex cretio n o f p o rp h y rin s called p o rp h y ria . M o re re c e n tly it h as been show n th a t to x ic c h e m ic a ls in c lu d in g s o m e o f th e b en z e n e s, d io x in , a n d P C B 's, c a n c a u s e a b n o rm a litie s o f p o rp h y rin m etab o lism . P o rp h y rin s are essential in the pro d u ctio n , o f red b lo o d cells in the body. T hey also are very im p o rtan t in the form ation o f special p ro tein s, called h em ep ro tein s, w hich arc critical to th e form ation o f those enzym es that I talked about b efore. A nd w hen the body starts overproducing en z y m e s a s h a p p e n s a f te r a b so rb in g d io x in , it req u ires la rg e a m o u n ts o f th e se p ro te in s. T h is an d o th e r 'acto rs cause a very severe disruption o f norm al porp h y rin m etabolism w ith som e porphyrins ab n o r m ally increased aiid others abnorm ally decreased. W e also fo u n d in these people abnorm ality o f a critical m uscle enzym e called C P K . Tw entyw o o f o u r forty-seven patients had abnorm ally low C P K . W e a lso fo u n d a b n o rm a lities in p ro th ro m b in w hich is in v o lv ed in b le ed in g a n d clo ttin g . T h e ib n o rm alitics w ere not enough to cause hem orrhaging in people, but they w ere present. A nd we have n e x p la n a tio n f o r it w h ich w e th in k is a re a so n a b le o n e w h ich will b e p u b lis h e d s h o rtly . A n d th e re [ -ere ab n o rm alities o f an o th er bleeding and clotting co m p o n en t called P T T . T h e s e a b n o rm a litie s g en erally re la te to liver fu n c tio n . T h e liv er is a v ery c o m p lex o rg a n . It is m u ltip le fu n ctio n s w hich begin or take place in the liver. W e also fo u n d ab n o rm a lities o f proteins, | irtic u la rly o f g lo b u lin s . A n d this to o is so m e th in g w h ich is a ffe c te d by th a t e n d o p la sm ic reticu lu m ~nd p ro c e sse d in th e liver. W h at w e are seeing now is a p a tte r n , a c o m p le x o f fin d in g s w hich you ju st >n't fin d in o th e r d is e a s e s . 6443 i In reg ard to the kidneys, we fo u n d a significant n u m b e r o f ab n o rm a lities in kidney functions with ab n o rm a l levels o f BU N, creatinine, and uric acid. W e kn o w also that in anim al ex p erim en tatio n , dioxin certa in ly can affect the kidneys. A nd in o th e r g ro u p s o f h u m a n s th a t have been stu d ie d , it a lso h a s a ffe c te d th e k id n e y s. In regard to the central nervous system , w hat we did w as to develop a very extensive n cu ro b eh a v io ral b attery o f tests. O u r psychologists w h o a d m in iste r this lest feel and we feel that you can differentiate psychological from organic brain dam age by these tests. W e fo u n d extensive abnorm alities in c o n c e n tra tio n , re te n tio n a n d m em ory, which we feel rep resen ts d iffu se cerebral d y sfu n ctio n ; that is, d am ag e to the cere b ra l hem ispheres o f the brain. A n d on th e neu ro lo g ic physical exam in atio n s, we fo u n d in significant n u m b e rs, changes w hich we felt in dicated som e dam age to the central nervous system. In regard to the peripheral nervous system , we found th at seven o f these people had ab n o r m a l E M G 's. Six o f th e m h a d a b n o rm a l nerv e c o n d u c tio n , a slo w in g o f n e rv e c o n d u c tio n . T h e second tim e we exam ined them , there seem ed to be a decrease in peripheral neurologic co n d u ctio n abnorm alities. But the E M G abnorm alities, w hich generally reflect irreversible dam age re m ained abnorm al at seven. A nd on the neurological physical ex am in atio n , which incudes sensory a b norm alities, touch an d pinprick, there were large num bers th at w ere ab n o rm al. N ow , let m e again say that all o f these things w ere lo o k ed at in rela tio n to the sym ptom s. But the physicians w ho took the history o n these patients w ere not th e sam e people w ho did physical ex am in atio n s. T he people w ho did the physical exam inations w ere o th e r physicians w ho perform ed them on th e sam e d ay an d had no know ledge about w hat w as fou n d in th e h istory. So these were indepentent activities w hich w ere then looked at in an integrated fash io n . A n d th en a t the en d , we w ould look at the sym ptom s, the physical findings, the laboratory findings fo r each org an system and in teg rate, them . Since each com ponent was done by another physician o r g ro u p , th ere was a great deal of o b jectivity in looking at these findings. T he physicians w ho did th e physical exam inations did not take a h is to r y a n d w e re n o t in flu e n c e d by th e p a tie n t's h is to ry . In regard to exam ination o f the lungs, as I po in ted out b e fo re , w e did not find a great deal. N ow , in regard to the skin, som e o f them had-- w hat looked like a b u rn . A nd that m ay have been fro m th e phenol, w hich went in and w ent out o f the b o d y fairly rap id ly . It doesn't stay around like dioxin does. O t t e r s h a d c h a n g e s w e call s c le ro d e rm a titis -- lik e c h a n g e s . I t 's a th in n in g o u t o f th e s k in w h ich b eco m es th in a n d frag ile. It bleeds easily, it b re a k s e a sily . A n d it d o e s n 't heal w ell. W e fo u n d this in a fair num ber. In re g a rd to c h lo ra c n e , 14 o f o u r p a tie n ts , 2 5 % , h a d c h l o r a c n e . In o th e r g r o u p s , w e f o u n d less. A n d in o n e g ro u p o f people w ho w orked directly w ith the p ro d u c tio n o f A gent O range and even cleaned ou t reactors, we found extraordinary num bers w ith ch lo racn e. S om e o f them were people w ho w ere in a n explosion in 1949, an d developed chloracne a fte r th ree o r fo u r d ay s, w hich they called w eed bum ps. A nd they have been squeezing-- that chloracne m aterial o u t o f those bum ps for 30 years, 40 years som e o f them . M an y o f them still have severe chloracne. But th o se w ere p eo p le w h o had m assive exposure. A n d th o s e w ere th e p eo p le w h o w ere seen by th e sk in d o c to rs w h o th e n s a id " w ell, if you d o n 't h av e chloracne, you d o n 't have dioxin intoxication.'' ! 6 v I I | B ut, you know , when we first began to see tuberculosis, people w ould sec us because o f h e m o rrh a g in g fro m (he lungs. N o b o d y to d a y w o u ld say th at if you d o n 't have h em orrhaging you d o n 't h a v e tu b e rc u lo s is . W h a t h e m o rrh a g in g is to tu b e rc u lo sis, th a t is a la te m a n ife sta tio n o f th e | d isease, c h lo ra c n e is to d io x in . A n d if y ou ju s t look for c h lo ra c n e , you a rc going to m iss 80 o r 90/o o f y o u r cases. C ertainly th is is tr u e in S ev cso . I t 's tru e in o u r g r o u p . Y ou te n d to fin d it in y o u n g e r p e o p le . A n d y o u te n d to II fin d it in p eo p le w h o h a v e a h isto ry o f a c n e vulgaris. T h o se a re p e o p le w h o seem to be m o re p ro n e to 1 the developm ent o f chloracne. In reg ard to p re c a n c e ro u s lesions, w hat w e call k erato se s, w h ich lo o k like basal cell cancers | | a n d w hich m ay o r m ay n o t be early cancers, we fo u n d nine. A n d we fo u n d fo u r people with skin 1 cancers w hich developed a fte r ex p o su re. O n e m an h ad six can cers. O n e o f them h ad recurred three tim es. A n d then he h ad three others rem oved. So that skin cancer was a serious problem . I T h e rep ro d u ctiv e system was also seriously affected in so m e cases. I pointed o u t to you that . every anim al that has been studied has show n an abnorm ality o f testicular function. A nd we found th a t 18 o f o u r p a tie n ts h a d a b n o rm a l, d ep ressed te sto ste ro n e level. A n d 17 o f th em h a d a b n o rm a l I s p e r m c o u n ts . O n e re p e a t e x a m in a tio n , a f te r 1 lA y e a rs o f th e n u m b e r d e c re a s e d . T h e re w as o n e m a n * w ith a very low sperm count. T h e next tim e we saw him about a year later, his count im proved con sid erab ly . A n d , in fact, his w ife h ad becom e p reg n an t. So in som e cases individuals seem to have got- . ten b etter. W e also looked at sperm m otility and sperm activity. A n d we found very large num bers * w h o h a d a d e c re a s e d level o f a c tiv ity . N o rm a lly a t th e e n d o f fo u r h o u r s , 6 0 % o f s p e rm sh o u ld b e ac- e. A nd w e found people w ith 4 0 % , 20% , 10% , an d som e w here the sp erm w ere all dead w hen we J . e x a m in e d th e m . T h e o th e r th in g th a t w e fo u n d w hich is very in terestin g , is a d e fo rm ity o f th e penis. ' * 1 m entioned the C PK was also abnorm al. W e also found that 11 people had abnorm al blood [ su g ars.T h ere was an increase in diabetes. | . D ioxin can affect the pancreas. I I W e did extensive testing o f the im m une system along w ith everything else. I understand (hat D r. P rin ce will discuss in m o re d etail, later to d ay these tests on o u r p atien ts. M an y were found to be I ab n o rm a l which causes reduced resistance to infection and to developm ent o f cancer. I l W e did not find a lot o f abnorm alities in p u lm o n ary fu n ctio n . In regard to cardiac function, -Ij a f a ir n u m b e r o f m u r m u r s w ere f o u n d , b u t n o t la rg e n u m b e rs o f a b n o r m a l E K G 's. W e also found som e abnorm alities o f the blood, including som e people w ith anem ias. W e 1 L fo u n d a lo w er thitn n o rm a l n u m b e r o f leukocytes. N o rm ally , 5 0 % o r m o re o f th e w hite b lo o d cells are leukocytes. W e also fo u n d in th e sam e people an increase in ly m p h o cy tes-- a n o th e r kind o f w hite b lo o d cell. T h e se w ere e le v a te d . T h is p a tte rn is seen w h en th e im m u n e sy ste m is d e p re sse d . [ V ario u s u rin a ry trac t ab n o rm a lities w ere fo u n d . S ignificant n u m b e rs h ad b acteria o r pus cells i in the urine, fo u r h ad blood on m icroscopic exam an d tw o had elevated glucose (sugar) suggesting | diabetes. 1 T o reiterate-- this was a group o f people-- healthy, rural, hard-w orking people w ho were su d d en ly ex p o sed to a chem ical a n d w ho then proceed to d evelop a series o f p ro b lem s w hich fit a com - n o n p a tte r n . N o t o n ly d id they d e v elo p sim ilar th in g s a m o n g th e m se lv e s; s o it w a s n 't a n in d iv id u al | h in g , b u t it w as v ery m u c h like w h at w e expected to find b ased o n w h a t w e k n ew a b o u t an im al find- :ngs a n d fin d in g s in o th e r g ro u p s o f h u m a n s w ho h ad been ex p o sed . W hen you have that kind o f p attern , and that kind o f a p ictu re, you can w ith scientific cer- L 1 ' 1 644o l. ' i la in ty , w h ic h a g a in is a high level o f p ro b a b ility , sa y th a t th is is a d isease e n tity . T o ftnd an individual in this society w ho has not been exposed to this chem ical with im m une d y sfu n ctio n , w ith a b n o rm a l testosterone, with a b n o rm a l p o rp h y rin s, w ith all o f the things that we found w ould be extraordinary and way beyond probability. B ut a g a in , if it w alk s like a d u c k a n d it ta lk s like a d u c k , y o u k n o w , it c a n be a c h ick en , b u t it isn 't a ch ick en . A n d 1 th in k th a t there is n o m ystery. T h e re is still a ten d en cy to m a k e a m ystery o f all o f th is. D oes d ioxin really d o this, or w h at d o c s it d o ? W e d o n 't k n o w en o u g h . 1 h av e tw enty v o lu m es o f re p rin ts o n scien tific articles, h u n d re d s an d h u ndreds and h u n d red s o f scientific articles w hich represent an enorm ous body o f know ledge. A n d it's v irtu a lly u n ifo rm in w h at it says a n d w h a t it fin d s. A n d 1 th in k th a t w h at this m e a n s to you for those o f you w ho are interested and concerned ab o u t m aking a determ ination about w h eth er the veterans w h o are alleging dam ages o r are, in fact, dam ag ed . A nd if they arc dam aged, arc they dam aged from dioxin? W h at is n ece ssary is to develop such a p ro to c o l, c a rry it o u t d isp assio n ately a n d sec w hat y o u c o m e u p w ith . A n d I th in k if you d o th a t, then you will lay to rest a lot o f th e concerns, fru stratio n s, fears, a n d angers th a t have been exhibited in som e places by so m any people. A n d 1 th in k i t 's so m e th in g th a t will h av e to b e d o n e . A n d I th in k th a t w e c e rta in ly h a v e th e scientific expertise to d o it. T hank you very m uch. (A pplause.) M R . O 'C O N N E L L : T h a n k y o u . D r. C a r n o w . T h is m o r n in g w e w ill g o th r o u g h o u r m o r n in g sp e a k e rs, a n d p rio r to th e lu n ch , we will have a q u estio n a n d an sw er session. T h ere is a m icro p h o n e at th e b a c k o f th e r o o m . I f y o u w ish to a d d re s s a q u e s tio n , id e n tif y y o u r s e lf f o r th e re c o rd sin ce it's b e in g tran scrib ed . A s to th e transcription o f to d ay 's sem inar, o rd e r fo rm s are available in the hall to re q u e s t. t h e tr a n s c r i p t o f th is m o r n in g 's s y m p o siu m . S o i f y o u w ish to o rd e r, please fill o u t th a t fo rm . T h e re is a five d o lla r co p y charge fo r the tra n s c rip t. O u r next sp eak er has com e to us from the S tate U niversity o f N ew Y ork in S tonybrook. D r. H o f C arlso n is a distinguished leaching p ro fesso r in the d ep artm en t o f biochem istry at th e S ta te U n iv ersity o f N ew Y ork at S to n y b ro o k . H e is a g eneticist w hose in terests a re ex p erim en tal m u ta g e n e sis jn fru it fiies, a n d in sp o n tan eo u s m u ta tio n in h u m a n s. H e is th e a u th o r o f The Gene, A C ritica l H ist'ory, w ritte n in 1966. A n d Genes, R adiation, a n d S ociety, th e L ife an d W ork o f H.J. M uller, w ritte n in 1981. H e has w orked on m utagenesis testing an d ionizing rad iatio n alkylating agents, L SD , an d h erb ic id e c o m p o n e n ts. D r. C arlson will speak to us o n th e g enetic d ev elo p m en t and biological effects o f h erb icid es, a n d will also give his appraisal o f V ietnam ese d a ta presen ted a t a sym posium in H o C hi M in h C ity, form erly S aigon, last Jan u ary . D r. C arlson. D R . C A R L S O N : 1 will discuss the genetic a n d b iological effects o f A gent O ran g e an d their c o m p o n e n ts . F irst, as a b ack g ro u n d , in V ietnam , th ree m a jo r herbicides w ere used in the spray in g p r o g r a m . 61 p e rc e n t o f th e herbicides w e sp ray ed w ere A g en t O ra n g e , w h ich is a o n e to o n e m ix tu re o f herbicides 24D and 245T. A second agent used was A gent W hite,.w hich consists o f 24D and a co m p o u n d sim ila r to 2 4 5 T in its effects, called p id o ra m ; 28 p erce n t o f th e sp ra y in g in v o lv ed A geni W h ite . B oth A gent O range an d A gent W hite were m ainly used for forests and jungle grow th. A gent B lue, ft 0 w hich co n stitu te d 11 p erce n t o! w hat we sp ra y e d , w as in te n d e d m a in ly for c ro p la n d . A gent Blue c o n sists o f cacodylic a c id , a n a rse n ic c o m p o u n d . It is n o t a h e rb ic id e o f th e sa m e c a teg o ry as 24D , 245 T o r P ic lo ra m . T C D D o r d io x in is p resen t in th e sy n th esis o f 2 4 5 T .' Early spraying involved com m ercial production w ith high dioxin content. A fter 1968, a decreased tem perature was used in the synthesis o f 245T . dim inishing the am ount o f dioxin present. Visually, 24D does not produce dioxin as a consequence o f synthesis. T h ere is so m e d e b a te a b o u t h o w m uch h erb icid e w as sp ray ed . A m erican estim ates claim a b o u t 75 m illion liters s p ra y e d o n a b o u t 14 p e rc e n t o f th e la n d m a ss o f S o u th V ie tn a m . T h e V iet nam ese claim a m uch higher am ount sprayed on their land an d claim 44 percent o f their land m ass was s p ra y e d . T h a t's th e b a c k g ro u n d . T h ere is o n e o th e r item o f b a c k g ro u n d in terest 1 w an t y o u to bear in m in d . I will talk a b o u t m utagenesis and o th e r biological studies in w hich doses are expressed in p arts per m illion o r parts per trillion. O ther than astronom ers and a few other scientists w ho play with the very sm all or the very large num bers, m ost o f us d o n 't appreciate w hat a part per billion or a part per trillion m eans. But if you were to run a string from this room to the m oon, an d you w ere to m ove one sixteenth o f an inch, y o u will h av e m o v e d o n e p a rt p e r trillio n . I t 's a v ery sm a ll d o s e . I f it is a very sm all d o se , a n d if w e a rc ta lk in g a b o u t d io x in in p a rts p e r trillion fo r its toxic e f fect, a n d we are talk in g a b o u t ex p erim en tal studies w ith 24D a n d 245T in p a rts per m illion, then recall that for each gallon sprayed, there was approxim ately 24 pounds o f 24D and four pounds o f 245T. T his is n o t p arts p er m illio n , b u t p arts p e r ten. A t its release o n th e ju n g le c a n o p y , the sp ray h a d a very severe effect o n the life, both plant a n d anim al, that was present in the sprayed areas. T h ere w ould, o f course, have been a dilution from th e aerosol m ist, from d rift, from the percolating dow n m o tio n , m ost o f which w ould have been a b sorbed through the leaves. T roops o r V ietnam ese civilians w ho w ere underneath the jungle grow th w o u ld have received lesser a m o u n ts. B ut it is very d iffic u lt to estim ate w hat the g ro u n d level exposure w as, either for those veterans w ho were exposed directly o r for those w ho were follow ing proper p ro cedures and entered into sprayed areas 30 days or so a fte r exposure. E stim ates will v ary fro m p arts per trillion o f a c tu a l v eteran exposure to p a n s per ten for m an y w ho were hit by p ro p w ash and o th er accidents th at m ay have occurred as a consequence o f the w ay in which the spraying took place. Early J u d ie s o n m utagenesis (attem p ts to in d u ce m u tatio n s in a num ber o f experim ental system s) were inconclusive. B acteria are studied by sp o t tests. A d ro p o f a know n concentration o f m u ta g e n is p u t o n a p e tri d ish w hich h as a n a g a r g ro w th . T h is w as sp read o v er w ith b a c te ria , b e fo re th e d ro p o f the agent is placed o n it. A clear zone arises w h ere th e bacteria are killed o ff. Y ou can look fo r certain survivors th a t w ould have been induced as a result o f m u tatio n s in these tests an d you can co u n t the num ber o f colonies. Those spot tests w ere m ostly negative for herbicides in bacteria tested. But som e bacterial stra in s w ere positive, p articu larly bacterial strains in w hich the h erbicide had a reduced P H . T he in ter p reta tio n o f the conflicting evidence betw een positive a n d negative results seem s to be w hether or not th e cell takes in 24D o r 245T . A b a c terial cell h a s a th ic k w all a ro u n d it, u n d e rn e a th w h ich is a m e m b ra n e . It m a y be th a t e i t h e r th e w all itse lf o r tlTe m e m b r a n e serv es as a n im p e n e tr a b le b a r r ie r fo r th e m o v e m e n t o f 2 4D o r 2 ^ 5 T into the cell. A test o f plant an d anim al cells grow n in tissue cultures has also been inconclusive. v bui the m ain findings seem 10 be (his: in plan! cells, the herbicide 24D or 245T acts as a plant horm one stim ulating cell division. T he rate o f cell division increases. In an im al cells, the herbicide acts as an in h ib ito r o f cell division. T h e in terferen ce in cell d iv i sion involves tw o th in g s, o n e o f w hich is specific fo r th e an im als, w hich is a n in te rfe re n c e in D N A sy n th e sis. O n e o f th e f o u r c o m p o n e n ts th a t g o in to D N A is n o t p ro d u c e d in its n o rm a l q u a n tity , a n d it slow s dow n cell division. T h e o th e r conseq u en ce to an im al cells is an interference not at th e level o f the gene o r th e ch ro m o so m e, but o f fibers th at m ove ch rom osom es during cell division; they are called spindle fibers. T he fibers a rc m ade u p o f chem ical units called tubulin. T hey are im properly put together as a conse q u e n c e o f exposure to 24D o r 245T. A s a result, in bo th plants an d an im als, w hen spindle fibers are not norm ally form ed, chrom osom es lag. C hrom osom e breaks form . C hrom osom es get duplicated or d o u b le d in n um ber. T h e technical nam es fo r this defect, polyploidy o r e n d o red u p licatio n , will ap p ear in the literatu re. T hese have been observed in both plant an d anim al tissue culture. M ost o f these w ould be self-elim inating. F o r exam ple, veterans exposed an d w ho m ay have in their tests polyploid sperm reproductive cells, w ould not be able to produce norm al children from such sperm . In fact, the chance o f an im p lan tatio n o f th e fertilized egg at an early stage o f pregnancy w ould be very slim for such p o ly p lo id o r e n d o re d u p lic a ie d cells. T h e re is n o ev id en ce o f such sp e rm fo rm in g e ith e r sp o n ta n e o u sly o r induced by herbicides. In anim als, there are a num ber o f other tissue culture abnorm alities. Studies done on ham ster cells, o n m o u se a n d ra t cells, an d h u m a n tissue cu ltu re are fairly co n sisten t. T hey show the slow m itosis. A lso, w hen stan d ard procedures arc used to stain the chrom osom es; cut these out after p h o to g ra p h in g a n d m a k e w hat is called a karyotype, a size p late arran g em en t o f th e chrom osom es. T he chrom osom es show chrom osom e breakage. U sually the breakage involves one, not both, o f the stra n d s th a t a re u su ally present in th e ch ro m o so m e at th e tim e w hen th e c h ro m o so m e is prepared fo r th e k ary o ty p e. T hese a re called single-break o r ch ro m a tid events an d they are characteristically seen in s ta n d a rd cy to lo g ical te c h n iq u e s. A seco n d a b n o rm a lity is called a m u ltib re a k ev en t. T h ese m u ltib re ak events p ro d u ce unusual chrom osom e figures that look like a m altese cross u n d er the m icroscope. They are also recognized in m ouse, ra t, h am ster, and h u m an tissue cu ltu re studies depending on th e dose a n d d e p e n d in g o n th e in v e s tig a to r 's te c h n iq u e s . It is a m ix e d re s u lt. N o t all s tu d ie s h a v e c o n s is te n tly show n these abnorm al figures. M y o w n field fo r experim ental m utagenesis uses fruit flies. F ru it flies w ere first used in 1926 to d em o n strate that X -rays induce m u tatio n . T hey w ere first used in the 1940s to show that alkylating ag en ts such as, m u sta rd gas a n d n itrogen m u stard in duce m u ta tio n . F ru it flies w ere the first organism s u se d to sh o w th a t c h ro m o s o m e b re a k a g e is in d u c e d b y io n izin g ra d ia tio n a n d b y c h em ica ls. T h e n u m b e r o f te c h n iq u e s a v a ila b le to test th e p a rtic u la r c a te g o ry o f g en etic d a m a g e is well w o rk e d o u t in th e 50-year h isto ry in w hich fruit flics have been used fo r such studies. In a d d itio n to studying rad iatio n induced m utagenesis a n d its characteristic effects, I have also studied a n u m b er o f chem icals, including ethyl m ethane sulfonate, a very potent alkylating agent, a co m p o u n d that not only alters genes but also breaks chrom osom es, alth o u g h not as effectively as X -rays d o fo r ch ro m o so m e breakage. In general, chem ica] m utagens are far m ore efficient than X -ray s in alterin g in d iv id u al genes. In the 1960s, I studied LSD because a particular com pound I w as w orking w ith at the tim e. / q u in acrin e m u s ta rd , w as very sim ilar in structure to L S D . 1 rem em ber discussing with several students in m y la b o ra to ry w h eth er o r not LSD , because o f th e sim ilarity o f its stru ctu re , m ight be m utagenic o r n o t. A t th a t tim e, a n u m b er o f papers cam e out claim ing that LSD w as a very potent m utagen. M ost o f these w ere based on karyotypes, on ch ro m o so m e analysis, looking for single breaks, o r for m ultiple b reak s w ith these curious cross-like c o n fig u ra tio n s . W hen we ra n o u r experim ents o n LSD, we injected it in to fru it flies, th ro u g h the ab d o m en -- y o u have to have ste a d y h an d s for this because the fly is a n eig h th o f a n inch in length. W e injected them until they bloated up like a balloon. 1 calculated (hat the dose 1 adm inistered to the m ale fruit flies w as 75,000 tim es a h u m an trip dose. This was a m assive c o n c e n tra tio n . A pproxim ately 500 parts per m illion was the actual concentration of LSD being used. It produced no m utation, no c h ro m o so m e b reak a g e, n o loss o f chrom osom es, a n d n o evid en ce o f a n y genetic abnorm alities w h a t soever. O n e o f the th in g s o n e learns in the field o f m u tag en esis is th a t th e sam e o rg an ism , fo r the sam e testing procedure, can be used very satisfactorily for ionizing rad ia tio n or very potent alkylating a g e n ts, giving u n a m b ig u o u s results; yet it becom es e x tre m ely d iffic u lt to use th a t sam e system , w hen y o u are looking fo r agents w hose genetic effects, if an y , a re ra th e r m o d est. N ow , I am g o in g to show slides in which 1 will very q u ic k ly sh o w th e d a ta on m y ow n w ork. A n d th e n I 'm g o in g to discuss th e V ietnam ese w o rk . T h is first slid e sh o w s a s ta n d a rd te ch n iq u e, the o n e th a t H e rm a n M u lle r first developed in 1927 to sh o w h o w X -ra y s a re induced. T h e technical d escrip tio n is co m p lica ted , but essentially w hat it lo o k s fo r is th e a b se n c e o f an expected category o f ,es, w hich ju s t d o n 't a p p e a r. All the o th e r progeny th a t sh o u ld b e th e re a re there, but th e one c a te g o ry th a t sh o u ld b e p resent is m issing. A n d in th e case o f d iffe re n t tre a tm e n ts o f 24D up to a c o n c e n tra tio n o f 500 p a rts p e r m illion there is n o d ifferen ce fro m th e c o n tro l. A t a c o n c e n tra tio n o f 125 p arts 245T per m illion w e fo u n d n o lethals in d u ced . A n A gent O ra n g e m ix tu re w hich I m a d e artificially by using a o n e to o n e m ix tu re o f 24D a n d 245T, 75 p arts o f eac h , giving A O 150 show ed one percent lethals. B ut the c o n tro l rates v ary up to one percent. T his sh o w s th ere was n o sig n ifican t difference in that ex p erim en t. A re p e a t o f th e 2 4 D 500 sh o w e d n o d iffe re n c e f r o m th e c o n t r o l . S o th e X lin k e d le th a l d a t a is n o t o f , b u t d o e s n 't n ece ssarily ru le o u t, a w e a k m u t a g e n ic e ffe c t a t th o s e d o s e s . T h e s e d o ses o f 500 parts p er m illion are com parable to the doses o f ethyl m e th an e sulfonate that w ould p ro d u c e ab o u t 30 prcent X linked lethals. If 24D or 245T induced m u ta tio n s they could not be inducing m o re than tw p o r th ree tim es the control rate for the sam ple size we o b serv ed , but even here we did not fin d evidence o f that. A second scries involved a particular gene m utation called d u m p y , a reasonably m utable gene th a t I studied w ith X -ray s, quinacrine m ustard, and ethyl m e th an e su lfo n ate. It m utates at a sp o n ta n e o u s freq u en cy a t a b o u t o n e in seven thousand flics sh o w in g a n ew d u m p y m u ta tio n . W ith X -rays I at a b o u t ten tim es a h u m a n m ean lethal dose, m ainly at a b o u t 4500 ro e n tg e n s, you w ould get ab o u t a o n e percent o r a little less than a one percent m utation rate. W ith ethyl m ethane sulfonate at about 500 parts p er m illion o r quinacrine m ustard at 500 l >arts p er m illio n , 1 w o u ld get a one to tw o percent d u m p y m u ta tio n ra te . A s yo u see in the slide fo r th e 2 4 D w ork there w ere tw o put o f three thousand. The co n tro l had o n e out o f threc^thousand. This was to t sig n ific a n t. S o th e re w as n o evidence at the individual g en e level th a t e ith e r 24D in this p a rtic u la r case was m utagenic. A th ird experim ent involved a phenom enon called n o n d isju n ctio n . If spindle fibers are not p ro p erly a tta c h e d a n d th e ch ro m o so m es d o n 't se p a ra te n o rm a lly , y o u pick u p ab n o rm a l o ffsp rin g . T he expected a b n o rm a l offspring, w hich are represented in the low er, b o tto m , horizontal line d id not ap p ear, indicating the absence out o f som e 1100 progeny o f any n ondisjunctional events. This again suggests th a t if th e re is an effect o n a b n o rm a l cell d iv isio n in w hich c h ro m o so m e s sh o u ld lag as a resu lt o f sp in d le fib ers being im p ro p erly p u t to g eth er, th ese s h o u ld sh o w u p ; b u t th ey d id n 't. T h e final test o f this m utagenesis was fo r a n o rm al type o f ch ro m o so m e breakage found in o u r sex cells. W henever we m anufacture our ow n sperm o r eggs the chrom osom es we obtained from o u r m o th e r a n d th e ch ro m o so m es fro m o u r fa th e r co m e to g e th er a n d exchange pieces. T his is called crossing o v er. I looked for a category o f crossing over in w hich the m iddle o f the three genes sw itched places betw een the original chrom osom e that cam e from the sperm and the chrom osom e that cam e from the egg o f th at individual fem ale fly. T he results show ed no d ifferen ce in 24D at a concentration o f 500 p arts per m illion for double crossover flies. In co n trast to those negative results for chrom osom e breakage, chrom osom e m utation, an d loss o r gain o f ch ro m o so m es in their total n u m b e r, m y stu d en ts a n d 1 fo u n d developm ental effects w hich w ere strikingly significant. Y ou can see in this slide th a t c o n tro l flies begin hatching out a p p ro x im ately ten days after the eggs are laid. They reach a very d ram atic peak tw o days later and then this peak crash es a n d p lateau s very rapidly. W ithin a b o u t 16 d ay s o r so , m ost o f the flies have em erged. A lso , fem ales ten d to em erge earlier th a n m ales. T h e ra tio o f m ales a n d fem ales will eventually show about a one to one ratio. O n th e o th e r h a n d , w hen 24D o r 245T is placed in th e fo o d a n d th e flies lay eggs in th a t fo o d , a p h e n o m e n o n arises th a t I call developm ental d elay . T h e life cycle is drag g ed o u t. O n the 12th d ay w hen m ost c o n tro l flies a re hatching o u t, th e 24D o r 245T flies a re still in a m aggot stage, an d m ost have n o t u n d erg o n e m etam orphosis. T h e herbicides slow d o w n th e m etabolism an d life cycle o f these flies. A lso, m ales tend to hatch out m uch earlier th an fem ales a n d in g reater num bers. I t 's v e ry d iffic u lt to e x tra p o la te w h a t th is d e v e lo p m e n ta l d e la y m e a n s in h u m a n te rm s because the w ay th e fruit flies produce offspring a re clearly d iffere n t fro m the w ay hum ans p ro d u ce o ffsp rin g . A lso , a m o n g th e th o u san d s o f flies th a t w ere p ro d u c e d as a co n seq u en ce o f developm ental delay, I looked fo r an y evidence o f teratogenic effects th at p ro d u ce ab n o rm alities o f the w ings, legs, eyes, m alfor^nities o f th e genitalia, o r o th er co m p o n en ts o f th e fly; a n d I fou n d none th at I could iden tify as teratogenic consequences. T h a t d o e s n 't m ean in a m am m al o r a h u m a n these d elay in g effects, m ight h ap p en , p a rtic u la r ly th o se in th o se tissues that are lipid rich, an d cause ab n o rm alities. If w e gave th e flies an o p tio n o f w hat food to choose, using fo u r dishes -- one o f control, one o f 24D 500, o n e o f 245T, an d one w ith the A gent O range m ix tu re -- they usually laid eggs on th e co n trol d ish . W e allow ed them to lay eggs in a p o p u latio n cage in w hich th ere w ere four dishes. W e set this up th ree tim es w ith th e dishes to elim inate tem p eratu re g rad es a n d o th e r possible factors in the b a c k g ro u n d . C o n siste n tly , th e flics laid m ore eggs o n th e c o n tro l fo o d . T h e fruit flies recognize th e fo o d as being to x ic a n d it inhibits egg laying. T his w e tested re p e a te d ly , a n d co n sisten tly fo u n d th a t an aversion to laying eggs on either 24D , 245T, o r A gent O range fo o d . > I'm g o in g to shift now to the conference in V ietham , a n d discuss som e o f the w o rk -d o n e there. I 12 6450 fingers. P eo p le w h o developed this developed a n e u ro p a th y ; w ould have aching in their legs an d in their arm s, w hich they w ould decribe as a deep ache. T hey c o u ld n 't put their finger on it. A nd it's the kind o f th in e th a t k eep s you aw ak e at night o r w ak es you u p at n ig h t. T h a t is classic n eu ro p ath y . A n d it m a y o r m a y not be asso ciated w ith w e a k n e ss. W h en y o u hav e extensive n e u ro p a th y , you get fool d ro p an d wrist drop. But w ith a lot o f these people, there seem ed to be a sequence. T he first th in g se e m e d to b e n u m b n e ss a n d tin g lin g . I f th e y re s te d th e ir a rm o n th e c a r w in d o w le d g e, it w ould fall asleep. If th ey crossed their legs, the legs w ould fall asleep fairly rapidly. All o f us have had that experience a fte r a long period o f tim e, but it h a p p e n s to them very rapidly. A nd a lot o f those p eo p le d o n 't h a v e p e rip h e ra l nerve c o n d u c tio n a b n o rm a litie s . S o th a t, in som e peo p le, we w o u ld fin d the sym ptom s, they w ould have the sym ptom s, but we w ould find the abnorm ality. In som e people, we found peripheral n eu ro p ath y o r a slow ing o f conduction. A nd som e o f th em d id n 't h av e n u m b n e ss a n d tin g lin g . But th e re is g en era lly a p a tte rn , a p attern w ith the cen tral nervous system fu n ctio n , in w hich w e found large nu m b ers o f people related to attentional deficits, som e m em ory deficits. So, if you w ant to d o a quick and dirty you w ould do a digit span. You read forw ard num bers an d b ack w ard num bers. T h ey can read fo rw ard n u m b ers, but they can only read a few n u m b ers b ack w ard s. T h e re arc o th e r deficits in c o n c e n tra tio n -- in m em o ry that we fo und. T h at seem ed to be a co m m o n p a tte rn , the kind o f pattern th at you see in the d iffuse cerebral dysfunction from toxic agents. N ot all o f th em had general u rinary sy m p to m s. N ot all o f them had liver enzym e a b n o r m alities, but a large n u m b er o f them d id . O ne o f the things th at 1 did not discuss was gastrointestinal dysfunction. A lot o f them had sym ptom s that sounded like ulcers. A nd a lot o f them had x-rays taken. In m any, n o ulcers w ere fo u n d . W hat w as fo u n d , w ere diffuse inflam m atory changes. W e are not sure w hat th e m echanism o f that is. O f course, each o n e o f these sym ptom s an d every one o f these findings can be caused by a n o th er disease because th e b o d y can o nly react in a certain num ber o f w a y s. T h e d iffe re n c e -is th a t y o u get a g r o u p o f th e s e th in g s . I t 's a lm o s t lik e p ic tu re g am es w e p la y e d as children w here you w ould expose one eye, then the nose an d tty to identify a person. Eventually, you say, O h !, th at is F ra n k S in a tra o r J o h n W ayne, w h en you h ad en o u g h in fo rm a tio n . D R . A N D E R S O N : T h a t 's w h a t I w as try in g t o g et a t . Is th e re s o m e -- t h a t 's-- o b v io u s ly , people have u a n d p eo p le react in d iffere n t w ays. B ut in y o u r 47 people, w hich you characterized very carefully, w erg there som e groups th a t were m uch m ore co m m o n and occurred together than the o th e rs ? W a s th e n e rv e c o n d u c t io n -- w a s it s e n s o ry o r m o t o r ---o r b o th ? D R . C A R N O W : It w a s m o r e m o t o r th a n s e n s o r y , b u t w e s a w a fa ir a m o u n t o f s e n s o ry . It was m edian nerve n eropathy, diagnosed by orthopedic physicians as, carpal tunnel syndrom e, because it a ffe c ts th e n e rv e a s it g o es th ro u g h a tissu e tu n n e l. B ut y o u see, th e c a rp a l tu n n e l is w here th e m e d ia n nerve is co m p re ssed a n d th e re fo re susceptible to d a m a g e . It is o u r experience th at w hen you have toxic d a m a g e to a n e rv e , it is g o in g to o c c u r at th e p o in t w h ere th e n erv e is u n d e r th e greatest tra u m a , b ecause d a m a g e w h e re a n erve is m o v in g th e m o st is w h ere it te n d s to be tra u m a tiz e d w hen it is d e fi cient. T h a t is w h y p a in te rs w ho w ere exposed to lead , w o u ld get w rist d ro p o f their w orking arm , because that w as the nerve that w orked the hardest, and the one that needed the m ost nutrition. And so we fo und th e earliec.signs tended to be o f th e m edian nerve in th e carp a l tunnel. M R . D IE S N E R : S enator D iesncr from M innesota. D r. C arn o w , you listed a w hole group o f laboratory tests here as being ab norm al. A nd I was w ondering ab o u t the degree o f abnorm ality. Are l D 22 these things borderline abnorm alities or mild abnorm alities? D R . C A R N O W : W ell, w hen we say ab n o rm a l, w hat we are talking about are two standard deviations from the m ean. S o, w hen we are talking about som ething being abnorm al, we are not talking about one stan d a r d d e v ia tio n . W e a r e ta lk in g a b o u t so m e th in g th a t is m o re th a n tw o . T h a t m a k e s it a b n o rm a l. S o w hen y o u say m ildly a b n o rm a l, you a re talking a b o u t so m eth in g th a t is a lre a d y b eyond tw o stan d a rd deviations. W e did not find that a lot o f these people had gross abnorm alities-- som e did. For exam ple, triglycerides a re a b n o rm a l ab o v e 170. W e found so m e people w ith 900, 1,200, 1,400-- 1 had never seen a n y th in g lik e th a t b e f o r e . S o w e saw s o m e p e o p le w ith p r o p h y r ia . A n y u r o p o r p h y r in th a t is o v er 60 is v ery , v ery h ig h . N o w , w e sa y th a t n o rm a l is fro m 15 to 60. B u t, th e n u m b e r o f p eo p le that 1 saw w ith 60 o r 58 is ex trem ely lo w . S o , it is very h a rd to give y o u an an sw er to h o w sever is severe. M R . D IE S N E R : M ay I use your term inology? D R . C A R N O W : Sure, go ahead. M R . D IE S N E R : H ow m any o f those w ere beyond three o r four stan d ard deviations? D R . C A R N O W : I d o n 't k n o w . I c a n 't tell y o u th a t. M R . D IE S N E R : A few o r a lot o f them ? D R . C A R N O W : It depends on w hat tests you are talking ab o u t. M R . D IE S N E R : W ell, pick any. D R . C A R N O W : I d o n 't k n o w . W e d id n o t lo o k a t it th a t w ay. M R . D IESN ER : T hank you. M R . M cC A R T H Y : F rank M cC arthy, P resident o f th e V ietnam V eteran A gent O range Vic tim s, and representing the C onnecticut S tate C om m ission. D o c to r, w h a t w e a re try in g to fin d o u t a t th is p o in t th a t is m o st c ru c ia l to us is treatm en t fo r the various sym ptom s a n d effects. N ow , the V ietnam veterans w ere all m edically scrutinized prior to g oing to V ietn am . T h e y w ere considered m edically fit, physically fit a n d c o m b a t ready. W e have literally p u t so m e o f o u r veterans in a blender. A n d w e realize th at there a re q u ite extensive variables w hich are involved w hich arc exposed to A gent O range, P inkj P u rp le, W hite, D D T altheine, and v ario u s o th e r chem icals asid e fro m the illnesses fro m V ietnam . B ut th o s e o f u s w ith c h lo ra c n e -- n o w , th e V e te ra n s' A d m in is tra tio n is telling us th a t it's o f a te e n a g e -ty p e . A n d w e realize th a t th a t is not tru e . B ut w ith y o u r tra c k w o rk e rs w h o w ere defin itely d ia g n o se d as h iv in g c h lo ra c n e , is th ere an y tre a tm e n t being a d m in iste re d to th ese people o r d o you know o f any treatm ent? D R . C A R N O W : W ell, a lot o f people w ho have very severe ch lo racn e w ould have them e v a c u a te d . T h a t 's all th e y c o u ld d o . I f they d id n 't e v a c u a te th e m a te ria l, th e y w o u ld d ev elo p this m aterial w hich has a terrible, terrible o d o r. In severe ch loracne they w ould evacuate them . A nd d er m atologists tried all sorts o f treatm ents; none o f them really w o rk ed . In som e people, they go aw ay a fte r a y ear o r tw o . A n d 1 said th ere w ere others w h o have h a d it n o w fo r 4 0 y ears. A nd their wives still squeeze o u t these bum ps w hen they get bad enough. B u t I d o n 't k n o w th a t a n y tr e a tm e n t h a s h e lp e d . S o m e o f th e s e p e cip le h a d ra d ia tio n fo r th e s k in e a rly o n in th e 5 0 's. T h a t w o u ld b e e x tre m e ly h a z a r d o u s in m y v ie w . M R . M c C A R T H Y : D o c to r , la st q u e s tio n . W e h a v e b e e n to l d th a t th e T a t b io p s y is a w ay o f d e te c tin g d io x in w ith in th e fa tty tissue. In your o p in io n , is it n o t tru e th a t d io x in c o u ld have en tered the system .'done (he d am ag e, and (hen lefi (he system w ithout leaving an y residue? D R . C A R N O W : W ell. 1 think that we all agree that that m ay be the case. 1 think that there m a y still b e s o m e re s id u e , but i t 's d iffu s e d . Y ou a r e ta lk in g a b o u t a v e ry sm a ll q u a n tity to begin w ith . Y ou th en d iffu s e it b e c a u se i t 's fo u n d in the p a n c re a s , th e liv e r, th e a d r e n a ls , th e b ra in , th e k id n e y , and other organs, and the fat. In so m e cases, biopsies were d o n e and th e highest c o n c e n tra tio n s w ere found in the p ancreas, so m e in th e liv e r, a n d so m e in th e f a t. S o i t 's v ery , v ery d iffic u lt t o m e a s u r e . Y o u w o u ld p ro b a b ly n eed a huge am ount o f fat because you are talking ab o u t a very sm all co n cen tratio n , a very small concen tration o f m aterial. Such surgery w ould be som ew hat m utilating an d -- probably not a useful procedure. W hat we a re d o in g is w e a re g e ttin g access to th is au to p sy m a te ria l a n d ail th e w o rk e rs w ho w ere exposed y ears ag o an d w ho a re d y in g . A nd w e will be doing m easu rem en ts in th e ir tissues to sec w hat levels we fin d . S o m e o f th e se p e o p le h a v e n o t been e x p o se d fo r 10 o r 15 y e a rs . A n d th a t m a y b e v ery usefu l in f o r m a tio n . But until w e h av e better in fo rm a tio n , I think th at if so m eb o d y is ex p o sed , if they have this kind o f a s y m p to m c o m p le x o r a t least so m e o f the th in g s th a t w e fin d h e re , it seem s to m e th a t it w o u ld be re a s o n a b le a n d p r u d e n t to m a k e a ju d g m e n t th a t th e y w e re e x p o s e d a n d a ffe c te d . B ut a g a in , it depends on w hat you are looking at. Y ou are looking at m edical prudence. M R . O 'C O N N E L L : I 'd lik e to re tu rn a t 11:15 s o w e c a n g e t o n w ith o u r la tte r p a rt o f th e m o r n in g . A t th is tim e I 'd like to th a n k D r. C a rn o w a n d D r. C a r ls o n o n a v ery in te re s tin g p r e s e n ta tion. (A pplause.) (W hereupon, a short recess w as h ad .) M R . O 'C O N N E L L : C o u ld w e s ta r t th e p r o g r a m ? Since w e began this m orning w e have h ad the arrival o f several o th e r states. C onnecticut has arrived w ith F ran k M cC arthy. R uth Levered from N ew Y ork arrived. H an k H ah n from C alifornia has arrived. D r. A n d erso n , o f course, cam e in fro m W isconsin. So w e hav e a pretty good representa tio n . W e w elcom e o u r next sp eak er back to his h o m eto w n o f C h ic a g o . D r. M ark T h o m a n is a g ra d u a te o f th e U n iv ersity o f M issouri School o f M edicine. H e is c u rre n tly th e p resident o f the A m erican A cadem y o f C linical T oxicology. H e is a Fellow o f the A m eric an A cadcem y o f P ediatrics, a n d a clinical fa c u lty m e m b e r a t D ra k e U niversity in to x ico lo g y a n d p h a rm a c o lo g y . T h is is to n am e b u t a few o f his m an y qualifications. D r.'T h o m a n will discuss dioxin past, presen t, a n d fu tu re w ith a n em phasis o n fetal a b n o r m alities and on the effects o f dioxin on future generations. D r. T h o m an . D R . T H O M A N : T h a n k y o u . W e ll, it's g o o d to b e b a c k in th e h o m e to w n . I w ould like to bring us up to date and touch on som e o f the things that have already been discussed very ad eq u ately by D r. C arlson and D r. C arnow , an d not go over old g ro u n d . I think f o r brevity an d to give us som e tim e for questions at the end o f the session this m o rning, I w ould like to talk a b o u t a very b asic th in g . 1 w ould sim ply an d initially talk a b o u t th e co m p lex ities o f th o se o f us in clinical practice in clinical toxicology. T he A cadem y o f C linical T o x icology has been aro u n d since 1968. S o i t 's a re la tiv e ly n ew sp e c ia lty . 1 g ra d u a te d fro m m e d ic a l s c h o o l in 1962. A n d to x ic o lo g y a n d e c o lo g y w e re w o r d s th a t w e h e a r d , b u t w e ju st d i d n 't th in k w e re e v e r g o in g to b e m u c h in th e w a y o f s p e c ia ltie s . B u t th e n i r r t h e 1930's a n d 4 0 's ...f o r th o s e o f us th a t w e re a r o u n d irt th e e a rly 3 0 's a n d 4 0 's, wc grew up w ith th e p hrase " Better Living Through C h em istry ." I think that we arc seeing one thing, : u 6453 a n d lh a i is w e e v e n tu a lly " pay th e p ip e r." I have g iv e n q u ite a n u m b e r o f p re s e n ta tio n s in referen ce to specifically, th e c h lo rin a te d h y d ro carb o n s. I'm g o in g back to th e P C B in fo rm a tio n that cam e o u t som e years a g o as it re la te d to th e so called c o la -c o lo re d b ab ies th a t o c c u rre d in Y u sh o , Jap an a n d this is a chem ical cousin to th e dioxin we are talking a b o u t. But they h av e their o w n characteristic chem ical effects. N o w , le t's ta lk a b o u t h o w o n e g ets p o is o n e d . L e t's ta lk a b o u t b a sic to x ic o lo g y . Ed P ress in E vanston, Illinois, started the first poison center as a pilot study associated w ith the N orthw estern U niversity. T h is w as p rim arily fo r o th e r d o c to rs w h o w o u ld call in say in g , " I 've g o t a child th a t's ta k e n g r a n d p a 's m e d ic in e .'' A n d th e p h y sician w o u ld sa y w h a t to d o a b o u t it, a n d th e signs a n d s y m p tom s that you look for. P ediatricians to o k care o f the children th at w ould accidentally ingest toxins. They are big e n o u g h to gel in to th in g s, b u t n o t big en o u g h to k n o w a n y b e tte r. T h e to d d le r is th e o n e w ho is a m ain candidate for poisoning. This has now expanded. O ver the years, we d o n 't just have the accidental ingestion o f poisoning by the toddler, but we also have the intentional ingestion by som e people that w ant to gel a high w ith certain chem icals. S o the first w ay y o u get p o iso n ed , o r m o st co m m o n w ay m o st o f us th in k o f is th e ingestion. S eco n d is in h a la tio n . A n d w hen we talk a b o u t d io x in , w e ta lk a b o u t n o t necessarily ingestion, b u t in h a latio n . In h a la tio n is breathing in the m aterial. W h e n i t 's b r e a th e d in , it is sw allo w ed w ith th e m u c o u s . It is o f te n c o u g h e d u p , th e n sw allow - id, hence, an indirect ingestion. T his is a cycle th a t o fte n incorporates o th e r m e th o d s o f toxicity. W e ta lk a b o u t sim ple c o n tact o r sim ple inhalation. W e are often talking ab o u t a m ore com plex situation th an that. But inhala tio n can be accid en tal as it is in m ost cases in situ a tio n s w here th e re is an incident o f a w orkm an w o rk ing aro u n d dioxin, the railro ad w orker we talked a b o u t in th e previous study. W e talked about lead poisoning and so on . A nd this can cause the industrial toxic exposure. C o n ta c t is a real p ro b lem in the agricultural states, su ch as Illinois, M isso u ri, Iow a. A nd the contact w ith th e org an o p h o sp h ates-- contact w ith this particu lar g ro u p o f toxins certainly has to be co n sid ere d . T h ere a rc situ a tio n s w here som eone c a n a b so rb c h o u g h by c o n ta c t th a t it w ould cause o v e n s ig n s a n d s y m p to m s w h e re it w o u ld h a m p e r f u n c t i o n ...t h e r e f o r e h a v e a to x ic e ffe c t. I 'm ta lk in g a b o u t m a la th io n -p a ra th io n insecticides a n d h erb icid es. C o n ta c t is a ls o a p ro b le m w ith d io x in . In jec ti6 n d o es n o t necessarily apply here, b u t in jectio n is th e next w ay o n e gets poisoned. N o w , this could be accidental o r intentional. A ccidental w ould be so m eo n e inadvertently-- giving an in je c tio n -- th e w ro n g m a te ria l is given to a p atien t. T h e d e lib e ra te in je c tio n is w h e re s o m e o n e is giving them selves so m eth in g to give them som e kind o f an effect; su ch is th e case in h ero in ad d icts o r cocaine users. I w as d ire c to r o f th e heroin d in ic for eight years in m y city. Finally, rad iatio n . A nd Dr. C arlson had m entioned this earlier regarding the effects o f radia tio n . In fact, w hen we talk ab o u t the teratology o r the effect o n th e developing fetus, we really thought th a t the fetus w as fairly safe, en capsulated in a ro o m all its o w n . th a t isn 't a ffe c te d by o utside w orld influences. But in th e I9 4 0 's we found out that rubella (o r 3-day m easles virus) could cause certain p re d ic ta b le e ffe c ts in t h e f e t u s . W e th o u g h t it w as a fa irly u n iq u e c a p s u le u n til th e n . H ow ever, now w ith radiation and with three-day m easles we know now that cataracts, con- n ita l h e a rt d is e a s e , a n d c e rta in a b n o rm a litie s a r c p re d ic ta b le . A n d t h a t 's w h y th e p a tte rn th a t D r. I 25 O d T h e c o n fe re n c e w as held in J a n u a ry o f 1983. 1( w as a n in te rn a tio n a l sy m p o siu m w ith representatives from 20 nations; about a third o f them from E uropean and W estern H em isphere n a tio n s . T h e re w ere s o m e 13 A m e ric a n d eleg ate s. T h e d e le g a te s w ere selected th ro u g h a m eeting th a t in itially began w hen th e V ietnam ese A m bassador in the U nited N ations contacted C yrus Vance w ho used to be o n e o f the neg o tiato rs for the treaty settlem ent in the V ietnam w ar. Vance was asked by the V ietnam ese delegate to see if he could get an A m erican delegation to go over. A rth u r W esting in the U nited States was then contacted by Vance, and he asked him to identify a num ber o f people w ho w ere w orking w ith A gent O range. T hey included physicians studying clinical effects, epidem iologists, toxicologists, geneticists, and ecologists. T he purpose o f the conference was to study the ecolpgical and health effects o f Agent O r a n g e . T h e c o n fe re n c e la ste d 12 d a y s a n d co n siste d o f s o m e p le n a ry sessio n s at th e b eg in n in g a n d at the en d . T h ere w ere seven w orkshops, four dealing w ith ecological effects and three dealing with h e a lth effects. D elegates could only w ork in o ne w o rk sh o p . S o I can only rep o rt o n d irect-hand ex perience o n th e w o rk sh o p effects dealing with toxicology a n d genetic effects. W e to o k tw o field trips. O ne w as to an area ab o u t 75 m iles northeast o f Saigon (now called H o C h i M inh C ity) su rro u n d ed by tw o rivers, the M a D a R iver, a n d the D ong N ai R iver. Between the M a D a a n d th e D o n g N ai R iver is th e M a D a F o rest. T h e M a D a F o rest w as sp ray ed in the early 1960s to cu t a ro ad across the tw o rivers because it was very difficult to tran sp o rt m en and m aterial along the rivers. T o cut tim e, the road w ent right through the forest. T h e forest was not a hum an inhabited fo re st; it w as p rim arily a w ildlife preserve. T h e sp ray in g c o n tin u e d fro m ro u g h ly 1963 through 1968 cveral tim es a y ear th e ro ad w ould be sprayed. T h e ro ad p ro d u c e d by spraying still th ere today. W hat y o u see in th e fo re g ro u n d o f this p ictu re o f th e ro a d is g rass. T h e grass is called im p erata grass. T h e im p e ra ta g ra ss is a replacem ent fo r th e trees th a t y o u see in th e b a c k g ro u n d . F o r a d ista n c e o f ap p ro x im ately a q u a rte r o f a m ile in each d irec tio n , left a n d right o f the ro a d , there a re no trees except fo r a few straggler trees th a t have survived th e spraying. A lso w hat you see in the b a c k g ro u n d , is th e ju n g le as it looks to d a y . If yo u co u ld see th e ju n g le as it existed b efo re the spraying, th e trees w ould n o t only be taller, but there w ould be a can o p y o n to p o f them . T he canopy was wiped . o u t fo r a considerable distance from the effects o f 24D and 245T in the spraying. ' T h e im p erata grass tends to get very d ry d u rin g th e d ry seaso n , an d m ay b u rn either from lig h tn in g o r n a tu ra l events; it m ay also be artificially b u rn ed b y th o se w ho w ant to establish slash and b u rn a g ric u ltu ra l techniques. W hen the fires o ccur, they m ove all th e w ay to the tree line, som etim es l ta k in g aw a y m re trees, instead o f the jungle com ing back, the ju n g le has been m oving back on either sid e o f ih e ro a d . T h is is ap p ro x im ately ten years a fte r th e sp ray in g h as sto p p e d . N o te in this next slide th e s tr a g g le r tree s. H e re is a b u rn e d o n e th a t show s th e e ffe c ts o f th e b u rn a n d th e im p e ra ta grass has I g ro w n b ack in the foreground. T h e second field trip w as to a w ar m useum . T his w as a p ro p ag an d a m useum th at had an ti p erso n n el equipm ent o f various sorts, such as captured A m erican tan k s. T here w ere cannisters w ith a 1 d ro g u (parachute th a t w ere d ropped w ith explosive jelly , blasting o u t an instant landing pad for helicojytors. N ote in this slide the stripe on the drum s that indicate the different herbicides; A geni O r a n g e A g en t W h ite, A gent Blue. This drum w as A gent W h ite because th e stripe w as painted w hite. L f `hi* H ad been A gent O ran g e, there w ould have been a n o ra n g e strip e o n those d ru m s. In sid e th e w ar nTUseum w ere so m e p h o to g rap h s o f a b n o rm a litie s a n d preserved specim ens-f [ ario u v b irth defects. These cannot be taken as good science d a ta , how ever, because there arc no charts, show ing frequencies o f abnorm alities and control rates. But three things are represented called hydatidiform m olar pregnancies. These are quite co m m o n . T he specim en in the m iddle show s conjoined tw ins, w hat are called S iam ese tw ins, w hich o ccur very rarely in all p arts o f the w orld. T h e V ietnam ese have reported such tw ins occurring w ith unusual frequency in sprayed areas. T h e th ird specim en is a m o n stro sity from w hich you see a ru m p a n d leg sticking u p in the lo w e r rig h t o f th e b a tte r y j a r , but y o u d o n 't see a to rs o . T h is is a n a c a r d ia c m o n s te r w h ich is u s u a lly associated w ith tw ins and m ay or m ay not be significant. A n d n ow , 1 will go in to the V ietnam ese d a ta . T he evidence fo r A g en t O ran g e health effects th at the V ietnam ese presented cam e in several p arts. First, they claim th at th ere w ere teratogenic ef fects in the sprayed area s as well as am o n g S outh V ietnam ese veteran s w h o w ent back to th e N o rth V ietnam ese and m arried N orth V ietnam ese w ho were not exposed. A m o n g the abnorm alities that w ere associated w ith th is, b o th in th e m ales th at went back to N o rth V ietn am a n d those w ho m arried in S o u th V ietnam an d a rc still there, w ere the co njoined o r Siam ese tw ins an d w hat arc called d e ftin g anom alies. T hese arc very gross m utilations o f the fetus which som etim es causes am putations o f fingers or lim bs, an d som etim es causes horrendous disfigurem ent o f the face. It caused by an adhesion o f th e fetal tissue to th e m em branes th a t su rro u n d it. A s th e e m b ry o o r fetus g ro w s, th ere is a tearin g ap art w ith strands o f tissue cutting into the developing tissue. A third defect that they also showed at the w ar m useum as p h o to g rap h s were abnorm alities sim ilar to th e th a lid o m id e ab n o rm alities fo u n d in E u ro p e d u rin g th e 1960s, w hich w ere called p h r o c o m e lic o r e c tro m e lic d e fo rm itie s w h e re th e a rm s o r legs a r e a b s e n t, lo o k lik e a s e a lio n 's flip p e rs, o r lo o k disfigured w ith slim bones w ith m issing digits. T hese defects are relatively rare throughout the w orld. In fact, w hen the thalidom ide case first broke in G erm an y and people w ere looking for p hotographs o f in fan ts that were b o m w ith phocom elia, the best th at G erm an m edical schools w ould com e up w ith w ere steel-cut engravings from the 1850s, because they w ere so rare they d id n 't have any.recent cases. T he frequency o f m iscarriage rates in the heavily sprayed areas a re very high. T hey report up to 50 percent m iscarriage rate in the pregnancies in the m ost heavily sp ray ed areas. N one o f these claim s by.thcm selves w ere convincing because th eir co n tro l rates w ere so low. U nlike the very beautiful w ork we heard about this m orning from D r. C arn o w , there were no double blin d n o r trip le-b lin d experim ents. T h e re is, instead, an ascertain m en t b ias. T h e perso n s w h o rep o rt d am ag e consciously o r unconsciously m ay be looking fo r so m eth in g to b lam e, artd m ay identify them selves as having been in a sprayed area w hen they m ay not have. T h ere is n o w ay to check fo r in dep en d en t veracity, to see if the reported claim s are w hat they are. P erh ap s th e reason that the control rates a te so low in V ietnam is th a t m a n y o f th e people w ho sh o u ld h av e been in th e co n tro l g ro u p are in th e p o sitiv e g ro u p . T h e y m a y h av e claim ed th a t th eir in fa n t is a b n o rm a l b e c a u se th ey w ere in a sprayed area. This shift o f self-reported birth defects w ould produce an ab n o rm al am o u n t o f low con tro l rates. W hen 1 raised this q uestion in the w ork sh o p their resp o n se w as th a t they w ere a T h ird W orld N atio n . T hey w ere not heavily industrialized, they w ere not exposed to chem icals and other p o llu ta n ts th a t th e W est h a s. In fact, th e n claim ed th a t th e c o n tro l ra te in th e W est is a b n o rm a lly h igh. T h e re is a w ay to check this. 1 hope so m ed ay so m eo n e w ill d o so b ecau se o n e co u ld check in the rural areas o f M alaysia and other areas o f A sia that are nearby an d co m p arab le to the develop m en t present in V ietnam . I 14 6 | mr r" I fell ihe m o st convincing piece o f evidence lhai (hey presented was on (he hydatidiform m o les. Let m e d e s c rib e th e se p re g n a n c ie s . A m o la r p re g n a n c y in th e W est is rela tiv e ly ra re ; a b o u t o n e in fifteen h u n d red o r so pregnancies have this. T hey arc fairly com m on in tropical areas, with a fre quency a b o u t o n e p ercen t in S outh A m erican an d o th e r parts o f A sia. In V ie tn a m , th e pregnancies in th e sprayed are a have a m o la r p reg n an cy ra te o f 10 percent. T h is is a very high p e rc e n ta g e , it is a lso a high risk p reg n an cy b ecau se m o la r pregnancies have a tendency to becom e cancerous. T he thing that I d id n o t know at the tim e o f the m eeting but which I fo u n d o u t in artic le s th a t a p p e a re d in N ature a f te r 1 g o t back w as th e o rig in o f m o la r p reg n an cies. M olar pregnancies a re produced by the fertilization o f an egg by a perfectly norm al sperm . T he egg h a s n o n u c le u s in it. N o r m a lly , w h en a n e g g is p r o d u c e d in a w o m a n 's o v a r y , s h e th ro w s ou* o n e o f the tw o nuclei th a t a re fo rm ed in cell division into a little bud called a p o lar body. T h e other nucleus, w hich is th e egg n u c le u s, is h eld in reserve for th e fertilizatio n . In a m o la r p reg n an c y , both o f th e nuclei a rc to ssed o u t s o th a t y o u have a n em p ty egg. T h e em p ty egg is fertilized by a norm al sp erm . T h e n o rm al sp erm rep resses th e cell division an d it leads to a ch ro m o so m e n u m b er o f 46. So the 23 c h ro m o s o m e s f r o m th e m a le 's s p e rm n o w b e c o m e 4 6 m a le c h ro m o s o m e s . T h e h y d a tid ifo rm m ole results in an a b n o rm a l m ass o f cells that acts as an im planting unit w ith the o u te r rin d o f a blastocyst but lacking the in n er cell m ass th a t sh ould becom e the em bryo. It can n o t fo rm a n em b ry o b u t it can im plant and fo rm the placental m em branes th a t are characteristic o f a pregnancy. I believe we can respect the d a ta because unlike the claim s they m ade fo r ectro m d ic lim bs and he ab n o rm al d e ftin g d efects o r o th e r b irth defects occuring in the sprayed areas o r am ong the spouses in N o rth V ietnam o f v eteran s retu rn in g to N orth V ietnam w hose wives w ere n o t sprayed, they claim th e m o lar p re g n a n d e s d id n o t increase in th e N o rth . T h is is consistent w ith th e id ea th a t pregnanries w ould have n o thing to d o w ith w hether a veteran w as exposed to A gent O range com ponents or not. I th in k t h a t 's s o m e th in g t h a t 's a ls o w o rth lo o k in g in to b e c a u s e D r. C a m o w m e n tio n e d th e im p o rta n c e o f lipid m etabolism a n d th e im portance o f that agent getting into lipid-rich tissues. T h is is tru e in m y ow n d a ta o n th e developm ental delay w here th e fem ales are differentially I killed at a hig h er ra te th a n the m ales an d fem ales are m ore seriously affected th a n m ales. O n th e o th e r h a n d , the w ork d o n e on ch ro m o so m e b reak ag e am o n g th e V ietnam ese in either th e sp ray ed are a s o r in th e retu rn in g V ietnam ese v eteran s w ho m oved back to th e n o rth in b o th cases I felt were seriously flaw ed. T hey lacked double-blind experim entation. T hey lacked m ore reliable i techniques available in th e W est. V ietnam , o f course, is an im poverished n atio n an d (hey lack both fu n d s and eq u ip m en t. T h e ir preparations o f karyotypes w ere not better than the state o f the art in the . U .S . in th e 1960s. I f y o u lo o k at th e kary o ty p e techniques a n d p rep aratio n s d o n e in the W est and the l U nited S tates to d ay , y o u w ould sec how m uch m ore detail you can get from the m odern studies. T he flaw s associated w ith th e L SD studies o n chrom osom es in th e 1960s w ere present in these V ietnam ese stu d ie s. S m all sa m p le sizes o f six people sprayed versus eight people w ho a rc co n tro ls w ere used in one [ stu d y . T h o se a re n o t g o o d n u m b ers to use. Y ou need to use h u n d red s o f individuals in o rd e r to get statistically significant differences. i Y o u h a v e to u se d o u b le b lin d p re c a u tio n s to m a k e su re th a t th e p e rso n w ho is d o in g th e ( analysis d o e sn 't k n o w w h eth er the tissue culture cam e fro m a person in an unsprqyed o r sprayed area. T he V ietnam ese d a ta I felt was suggestive enough o f m any things that need to be done. First, we have to rem em b er th a t unlike all except a few people exposed to acute exposures from accidents. (he V ietn am ese rec e iv e d m assiv e q u a n titie s o f 2 4 D a n d 2 4 5 T in c o n c e n tr a tio n s th a t a rc g re a te r th a n is norm ally used in fo restry o r agricultural practices in the rest o f the w orld. T he evidence, ep id im io lo g ica lly a n d d c v e lo p m e n ta lly , is very su g gestive th a t s o m e th in g is g o in g o n . T h e re sh o u ld be m ore anim al tests. 1 w as ap palled in looking th ro u g h the literatu re at how few careful experim ents have been do n e for tests o f chrom osom e breakage, chrom osom e m u ta tio n , loss o f chrom osom es and th e like. W h y this is s o in th e lite ra tu re 1 d o n 't k n o w . It ju s t m a y b e th a t p eo p le a r e n 't in terested in w o rk in g o n w eak m u ta g e n s a n d feel i t 's ju s t to o m u c h w o rk a n d e f f o r t fo r to o little resu lts. But certainly, i w ould try to encourage m ore o f those studies because I think the evidence has suggested en ough th a t there are biological effects o f A gent O ran g e a n d its co m p o n en ts even if the d ire c t ev id en ce fo r m u ta g e n e s is is v e ry w eak . (A pplause.) M R . O 'C O N N E L L : N o w I w o u ld like to get in to a q u e s tio n a n d a n s w e r p e rio d fo r D r. C a r- now an d for D r. C a rlso n . F ollow ing th e question an d an sw er p e rio d , w e will then break for coffee, w hich will be a v ailab le right o u tsid e . S o w hen y o u o ffe r th e q u e stio n , p lease sta te y o u r nam e fo r the record. M R . W O J O W O T A : M y n a m e is J a c k W o jo w o ta . I 'm w ith V ie tN o w . I h a v e a q u e s tio n fo r D r. C a ra o w . W ill th e s e p ro b le m s th a t y o u s tu d ie d -- is it p assed d o w n t o th e c h ild re n ? D R . C A R N O W : W e ll, I th in k th a t's b e tte r a d d re s s e d b y th e p e r s o n w h o s p o k e a f te r m e . W e found, and others have also found, som e teratogenic effects from dioxin including finding a retarded developm ent. W e fo u n d a num ber o f children w ho w ere exposed not in u tero , but w ere children w hen exposed. Their bone grow th w as about a year o r year and a h alf behind their chronological age. A nd w e are not sure w hat th is m eans. W e will know m ore as they go th ro u g h p u b erty . M R . W O JO W O T A : 1 have o n e for D r. C arlso n . W h at is th e life sp an o f th e dio x in ? Is it still taking effect on the forests? D R . C A R L S O N : Y es, th e d io x in s in th e soil h av e a life o f ten y e a rs . In h u m a n tissu e it's p ro b a b ly less th a n a y e a r . M o s t e v id e n c e f o r 2 4D risk is a f te r o n e y e a r. I t 's n o t d e te c ta b le . I w ould like to ask D r. C arn o w about the synergistic effects o n cancers. If lipids pick u p her bicides, an d herbicides a re very p o o rly soluble in w ater an d -p referen cially get in to tissue an d o th er lipid rich areas, w ould this suggest th a t one reason for the ch io racn e show ing u p as a first sym ptom w o u ld b e th e a m o u n t o f fa t t h a t 's d e p o s ite d in th e s k in ? B e c a u s e t h e V ie tn a m e s e h a v e v ery little ch io racn e an d ^ h ey d o n 't h ave as m uch m eat an d fat in th eir d iet. D R . C A R N O W : T h a t 's p o ssib le . T h e q u e s tio n o f w h e th e r th e c h io ra c n e is r e la te d -- to lip id m e tab o lism h as n o t b e e n d e te rm in e d . W h a t is k n o w n is th a t th o se w ith a h isto ry o f te en ag e a c n e tend to be m ore prone to develop chioracne. C h io ra c n e is th e m o st o b v io u s finding b eca u se it is c o s m e tic a lly d is fig u rin g -- b u t it is n o t the m o st co m m o n fin d in g . Y ou c a n 't d ep en d on th e presence o f c h io ra c n e to m ak e a ju d g em en t ab o u t w hether o r not som eb o d y m ay have been significantly exposed. D R . C A R L S O N : W hen d o m elanom as norm ally show up? A nd have there been any rep o rte d incidents o f increases in m elanom as to veterans w ho live in th e S un Belt co m p ared to veteran s w ho live in th e S o u th ? -- D R . C A R N O ^ : W ell, w e h a v e a co n ce rn a b o u t th a t. O n e o f th e th in g s w e d o is ad v ise all o f o u r p atien ts, all p eo p le w e have exam ined w ho w e fell h ave been sig n ifican tly ex posed, to stay o u t o f he su n . O r if th ey g o in to the su n , to use a sun b lo ck . T h a t's h a rd to tell to a M issouri I 16 b a c k w o o d s m a n . Bu( w e tell i( 10 ih c m a n y h o w f o r tw o re a s o n s ; o n e , b e c a u se th ey h av e p o rp h y rin a b n o rm a litie s. A n d p e o p le w ho h av e p o rp h y ria , w h ic h is to o m u c h p o r p h y r in s in th e b lo o d , m ay be v ery sun sensitive and get blistering and a very bad su n b u rn w ith little exposure. T h e o th e r th in g a b o u t it is th a t th e su n c a n c a u s e sk in c a n c e rs p a rtic u la rly in people w ho a re very light skinned-- sailors, farm ers, develop skin blem ishes called actinic keratoses, which can becom e cancerous. Dioxin seems to accelerate (hose rem ark ab ly . A n d som e people that we have seen have had 20 o r 30 cancers rem oved from their skin. So w e strongly recom m end that. W e also strongly recom m end th at they sto p sm oking because w hile w e have not established a synergism betw een cigarette sm o k in g a n d dio x in , d io x in is an e x tra o rd in a ry can cer p ro m o ter. C ig a rettes a re a n in itia to r. D ioxin is also a n in itia to r, b u t n o t as stro n g as a p ro m o te r, w hich m eans (hat th e re is a n o th e r carc in o g en a ro u n d , d io x in m ay a c c e le ra te its a c tiv ity u p to a m illion tim es. A m a jo r p ro b le m we h a v e is th a t w e c a n 't get th e d io x in o u t o f th e b o d y . W e k n o w o f n o w ay to alter changes w hich have taken place in the tissues, th e changes in endoplasm ic reticulum 1 m en tio n ed at th e beginning. So w hat we h av e developed is k in d o f a s e c o n d a ry p rev en tio n program for o u r patients w hich tries to protect them by having them av o id o th e r exposures w hich m ight add to the risk im posed by the dioxin. D R . W O L FSO N : Paul W olfson o f Q uad C ities V ets, a V ietnam V eterans' group. D r. C arnow , 1 have a couple questions fo r y o u . N u m b er o n e, are these endoplasm ic reticulum -- are you-- are they the g ran u lar, sm ooth o r b o th ? D R . C A R N O W : W ell, I w as, ta lk in g a b o u t b o th . R o u g h e n d o p la sm ic reticu lu m is p ro b a b ly affected m ore because when w e talk ab o u t rough en d o p lasm ic reticu lu m , w e arc talking about rib o s o m e s . 1 d o n 't w a n t to g e t in to a w h o le th in g a b o u t th is . B u t it w o u ld a p p e a r th a t b o th a re a f fected. N o w , th ere is so m e evidence th a t suggests th a t w h a t, in fa c t, m a y o c c u r is a transition from sm o o th to rough endoplasm ic reticulum . A nd there is also so m e ev id en ce th a t suggests som e changes in the endoplasm ic reticulum , at least in anim als, w hich a p p e a r to be irreversible. T hey becom e rough an d striated. Y ou can only see this under an ultram icroscope. But they seem to be changed. T he pro b le m w e h a v e is first in k n o w in g w h e th e r o r n o t d io x in is re m o v e d f r o m th e b o d y . A n d th e seco n d is if it is rem oved from the bo d y , w hat changes in the e n d o p lasim c reticu lu m a re perm anent and w hat arc reversible. W e d o n 't k n o w all o f the answ ers to th a t. T h e p ro b le m , o f co u rse, rela tes to (he h a lf life in th e b o d y o f th e d io x in . O n c e it gets in to the fa t o r o n c e it cts in to th e p a n c re a s, b ra in , liver o r w h a te v e r, it c a u s e s c h a n g e s a n d is a lso very slow ly re m o v e d if a t a ll. T h e p ro b lem w e h av e w ith 2 , 3 , 7, 8 , T C D D is th a t o n e o f th e w ays o f rem oving chem icals fro m th e b o d y is by a process called h y d ro x y la tio n . T h a t m a k es ch em icals m o re w ater solu ble enabling them to be rem oved from the body. T his happens no rm ally at the 2, 3, 7, or 8 position. A n d the 2 ,3 ,7 ,8 positions o f dioxin are blocked by the ch lo rin e. A nd so it's one o f the reasons we think dioxin m a y stay in th e b o d y fo r a long tim e. T he two big sets o f changes, p ro b ab ly irreversible, are th e ch an g es in th e en d o p la sm ic reticulum and in the m itochondria. W e now have som e biopsy m aterial w hich show a crystalization o f the m itochondria. T h e y arc destroyed an d crystalized. A n d the m ito ch o n d ria a re the sta rtin g p oint for the cycle which gives m uscles th e ir en erg y . T h a t cycle is b lo c k ed . T h a t is o n e o f th e re a s o n s p e o p le feel w eak. W e are trying to develop a kind o f secondary p rev en tio n a p p ro a c h because we really d o n 't h a v e a n y w ay o f r e m o v in g th e d io x in . S o w h a t w e a r e try in g to d o is p r o te c t th o s e o rg a n sy stem s w hich h a v e already been affected to keep them from being affected even m ore. D R . W O L F S O N : Is the G olgi com plex affected also? D R . C A R N O W : Yes, that is p a rt o f th e m ito c h o n d ria l system . D R . W O L F S O N : A nd just o ne m ore quick question on the astrocyte central nervous system an d the oligodendroglia-- are they affected? H ave you do n e anything in th a t area? D R . C A R N O W : N o , we h a v e n 't. W e have not seen a lot o f au to p sy m aterial. P art o f the p ro b le m -- is th a t th e b ra in is a heavy o x y g en d e m a n d system , a n d th e a b ility o f th e b o d y to use oxygen is im paired. S o I c a n 't tell w h e th e r th o se cells are d a m a g e d . W e d o k n o w th a t cells o f th e p eripheral n e r vous sytem dem yelinate an d are d am ag ed . Early m yelin tends to reju v en ate itself, but with recurrent d am age, irreversible dam age to the nerves occurs. D R . C A R L S O N : W hen w ould you look for o r expect to find cancers o f the central nervous system ? M ost solid cancers take 20 to 40 years to show up. D R . C A R N O W : T h at is c o rre c t. N ow , th e sarco m as a p p a re n tly have been show ing up a little s o o n e r an d th e re is u n q u e stio n a b ly a rela tio n sh ip . S om e stu d ies th a t w ere do n e show ed a m ark e d in crease in b lad d er can cers. T h e p ro b lem w ith th at is th at so m e o f th e p eo p le w ho show ed up w ith b la d d er cancers, w ere also exposed to P ara-am in o biphenyl (P A B ). 1 believe th at the com bination o f PA B a n d th e dioxin caused the bladder cancers. C ertainly, soft tissue sarco m as are in excess and skin can cers are in excess. A nd again, it m ay be that th ere has not been a long enough tim e for the cancers to appear. O n e g ro u p o f p e o p le th a t w e h av e stu d ie d w ere e x p o se d a lo n g tim e a g o . A n d th e p ro b lem w ith th a t is t h a t th e ir e x p o s u re w a s s o m a ssiv e , a lo t o f th e m d ie d b e f o r e th e y c o u ld d e v e lo p c a n c e r. I t 's v ery h a r d , given the latency period o f cancer, to give you any m ore answ ers. T h e r e a r e s o m e r e p o r ts , 1 th in k fro m T im e s B e a c h , b u t I h a v e n 't seen th e m p u b lish e d . T h e y are heresay. T here w as a statem ent m ade, at a congressional hearing th at I appeared at som e weeks a g o , in w hich th e re a p p e a re d to be so m e n eu ro b lasto m as th a t d ev elo p ed in children, tw o children in one fam ily. A V O IC E : D r. C am o w , in y o u r w ork, have you rioted any increased incidents o f lipom as in the veterans and civilians that you have exam ined, an d if so, d o you have any hypothesis as to the m echanism and the cause o f these lipom as and how you are treating these? D R . C A R N O W : T h e w ay y o u treat a lip o m a is y o u rem o v e it i f it is big en ough and b o th e r som e en o u g n . In one g ro u p , we saw a lot o f them . In an o th er g ro u p , w e did not see very m any o f th e m . A n d I 'm n o t s u r e w h y th e d if f e r e n c e . P a r t o f t h e p r o b le m t h a t w e h a v e is w e th in k th a t p e o p le w h o h a v e less e x p o s u re m a y n o t n e c e ssa rily h a v e less d is e a s e . I t 's j u s t t h a t clin ica l d ise a se m a y c o m e o n la te r. W e fin d th a t th e laten cy p e rio d is greater in th o se less e x p o sed . W e fo u n d th a t som e o f them d id n 't d e v e lo p a n y th in g u n til th re e y e a rs a fte r e x p o s u re . S o th e re w a s a la te n c y . A n d th ey te n d e d to be th e o n es w ho w ere exposed less. But so m e o f them h a d diseases w hich w ere quite severe. O ne o f the big p ro b le m s w e have w ith d io x in , o f co u rse, is th a t so m e p eo p le a re m o re sensitive to its effects th a n o th e rs . (j D ioxin affects a system called the aryl-hydroxylase (A H ) system . N ow , people have a genetic p re d is p o s itio n to h a v in g a n A H system w hich is m o re o r less a c tiv e . T h e m o re^ ctiv e o u r A H system is. th e m o re p ro n e we a r i to develop co m p o u n d s in o u r bodies w hich m ay cause cancers. P eople w ho have a m ore active AH system tend to get m ore cancers. T hose people w ould I 18 8460 tend to be m u c h m o re sensitive to d io x in . O ne o f o u r p ro b le m s is we d o n 't have a g o o d test to m ak e a determ ination o f w ho has m ore A H inducibility than o th er people. D R . O 'G R A D Y : M y n a m e is D r. M ich ael O 'G r a d y . I 'm a n e n v iro n m e n ta l p h y sician . 1 h a v e a couple q u estio n s fo r D r. C a rn o w , if y o u d o n 't m in d a g a in . A re y o u a w a re o f a n y d e a th s th a t have o c c u rre d as a result o f d ioxin ex p o su re in th e literatu re anywhere? A re there d eath s th at are directly attributable to dioxin? D R . C A R N O W : N o w , y o u sa y directly a ttrib u ta b le to d io x in . I'm n o t su re w hat you m ean by that. I h ad o n e m an w ho h ad m ultiple fat em bolism s in his blo o d vessels. H e h ad a triglyceride o f 1400. B efore his exposure, his triglyceride was n orm al. I consider th at directly attributable. D R . O 'G R A D Y : B u t, s ir, w h a t l m e an is, h a s th e c a u s e o f d e a th b een given as th e d io x in e x posure? D R . C A R N O W : W ell, 1 d o n 't know th at th ere a re a lot o f physicians w ho have diagnosed people as having dioxin disease. A nd so , l think th e cause o f d eath m ay not have been given as dioxin exposure. T h e tendency w ould be to diagnose the disease as liver, kidney, brain, etc., depending on which organ failed. D R . O 'G R A D Y : A n d th e s u b je c ts y o u a r e e x a m in in g f o r th e r a ilr o a d , th e 47 p eo p le, w o u ld agree that these people h ad a know ledge o f why they w ere being exam ined. D R . C A R N O W : Y es. But they were exam ined long b efo re we exam ined them and long before anybody knew an y th in g ab o u t dioxin. A nd they h ad the sam e sym ptom s and the sam e findings w hen ex am in ed by th e ir local p h y sician s in M issouri w hich is w hy th e y saw th o se physicians. If y o u a re suggesting th a t this g ro u p o f people, m an y o f w hose fathers w o rk ed for the railroads fo r 40 years, an d w h o com e fro m ru ra l M isso u ri, p eo p le w ho h av e never ta k e n a nickle fro m an y b o d y in the w hole w orld, suddenly have becom e m alingerers-- 1suggest you are w rong. T o suggest th at a m an w ho has w orked for the railroad fo r 35 years, w ho w orked a 400-acre f a r m f o r 4 0 y e a rs , is a f a k e w h o is try in g t o get a c o u p le o f b u c k s o u t o f s o m e b o d y , y o u k n o w , i t 's ju s t unreal. So I reject th a t. I think th at possibly there m ay have been people w ho w ere exam ined and w ho atte m p te d to ex ag g erate th e ir sto ry . O u r biggest p ro b le m w ith th ese people is th a t they ten d ed to m inim ize their sym ptom s because they w ere afraid to ad m it to them selves that they w ere sick. A nd th e y w ere a s h a m e d o f th e f a c t th a t th e y c o u ld n 't w o r k b e c a u s e th e s e w e re m e n w h o w o rk e d h a r d a ll o f th e ir lives a n d / d t , so m eh o w , th a t th ey w ere n o t a d e q u a te ly d isch arg in g their responsibilities to their fam ilies because they c o u ld n 't w o rk . So they w ould m inim ize th d r problem s w ith th e people th a t w e w ould say to them , " Y ou are healthy-- you can w o rk .'* A n d , in fact, a lot o f them co n tin u ed to w ork. M any-that we exam ined are still w orking, b u t they a re having g reat difficulty in w ork in g . T h e fact th at these people knew w hat th ey were being exam ined, unless they w ere students o f m e d id n e -- an d a lot o f students o f m edicine d i d n 't k n o w a b o u t th e s y m p to m s o f d io x in -- it w o u ld b e r e m a r k a b le t o g et th is k in d o f s y m p to m s com plex. A lso, unless they talked to the people in C zech o slo v ak ia, w ho also had the sam e sym ptom s o r th e people in th e S oviet U n io n , o r th e people in V ietn am , o r th e p eo p le in B A SF in G e rm a n y , o r the p e o p le in N e w a rk , u n less th e y d isc u sse d it w ith all o f th e se p e o p le , y o u w o u lck h av e to say this is an en o rm o u s in tern atio n al co n sp iracy to develop sym ptom s o f dioxin poisoning. 1 find that even m ore d iffic u lt. IV These people had not been told that there was anything there. They did not know there was dioxin, only p h en o l. T h ere w as a lot o f objective dam age, objective disease. P erip h eral n e u ro p a th y in 20 o r 30 p eo p le, c e n tra l n ervous system d am ag e, you c a n 't m alin g er im m u n e su p p re ssio n , p o rp h y ria , o r any o f the o th er things that these people had. T h e re is a p a tte r n th e re . N o w , I'm su g g estin g to y o u th a t th e se a r e n o t p e o p le w h o w a n t a h a n d o u t so m ew h ere a lo n g th e ro ad . B u t, I'm n o t su re th a t p eople have been a d e q u a te ly ex am in ed to m a k e such a d e te rm in a tio n . I think a d eterm in atio n w as m a d e in a d v a n c e . A n d 1 th in k th a t w h at is n eed ed , in ste ad o f th e k ind o f discussion w hich 1 am h av in g no w , w h ich I th in k is a b a d o n e -- I 'm so rry , 1 lost m y c o o l. B ut th e thing th a t I am suggesting n o w is th a t a p ro to c o l b e g e n e ra te d a n d developed; that people d o gel an adequate w orkup, and then a judgm ent can be m ade about w hat the score is. A n d 1 th in k th a t there w ould be so m uch less conflict an d so m u ch less d iffic u lty if th a t w ere d o n e . I am n o t su g g e stin g th a t ev ery b o d y w ho com es fo rw a rd is sick-- o n th e o th e r h a n d , d io x in is ex traordinarily toxic. A n d we found a disease which we say fits a pattern o f dioxin intoxication because it lo o k s lik e w h a t h a p p e n s in a n im a ls , a n d it's lik e w h a t h a p p e n e d to a lot o f p e o p le a r o u n d th e w o rld w ho w ere exposed to dioxin in industrial explosions o r o th er activities. A n d th o s e p e o p le d o n 't k n o w w hat d io x in is-- th e y ju s t k n o w th a t th e y w e re sick a n d th e y co u ld n 't w o rk . D R . O 'G R A D Y : I 'm a fra id y o u m isu n d e rsto o d th e q u e s tio n . I 'm n o t in a n y w a y su g g e s tin g that the 47-- and certainly not the veterans-- D R . C A R N O W : W ell, I apologize. But the question o f w hether o r not they knew w hether th e y w e re b e in g e x a m in e d f o r d io x in , I d o n 't th in k is re le v a n t. D R . O 'G R A D Y : T h e p u rp o s e o f th e q u e s tio n w a s t o p o in t o u t th e fa c t th a t th e re w e re p e o p le w h o w ere aw are o f w h a t w as going o n , rather th a n a co n tro l g ro u p . A lso , th e re is n o in tro d u c tio n o f the w ord m alingerer in to the question. I w ould like-to ask a question o f Dr. C arlson--just one question. Is there an y m echanism that you know w here a m ale exposing can transm it a genetic deficiency in th e case o f dioxin o r fo r that m atter, any oth er type o f exposure? D R . C A R L S O N : O h, yes, radiation. H igh doses o f radiation can lead to dam age; either a reduced fertility o r sp o n tan eo u s abortion. H iroshim a-N agasaki d a ta show ed a lot o f th e abnorm alities in p regnancy^n th e first few m onths after exposure. But you are quite right in the im plication that m ost m utagens even in m assive doses d o not show a lot o f genetic effect. T h a t d o e s n 't m e a n th e genetic effect w a s n 't in d u c ed . L ess th a n o n e p e rc e n t o f all g en e m u ta tions a re d o m in an t m u tatio n s. 99 percent o f induced m u tatio n s in all o rg an ism s stu d ied , m ice, fruit flies, c o m , m an y o th e r system s, show that they are recessive. S o even in H iro sh im a an d N agasaki, geneticists predicted long before the A tom ic B om b C asualty C om m ission began its study th at they w ould n o t find o ffsp rin g show ing gross abnorm alities. T here a re tw o reaso n s fo r this. N ot o n ly will an in d u ced recessive b e p ro tec ted by the norm al gene c o rresp o n d in g to it fro m th e o th e r p a re n t, b u t also even am ong th e d o m in an t m utations, very few o f w hat are called d o m in an t m u tatio n s produce m onstrosities. M ost m onstrosities are not a consequence o f gene m utation, but a consequence of chrom osom e abnorm alities. M ost chrom osom e abnorm alities that are induced are gross enough to a b o r t. V ery fe w c o m e to te rm . S o i t 's o n ly th e tip o f th e ic e b e rg to lo o k f o r d e f o r m e d in f a n ts as a 6462 20 1 m easure o f radiation dam age to a population. W hen the A to m ic B om b C asualty C om m ission begins to look at children w ho are the pro duct o f first cousins, som e 70 o r 80 years dow n the line from the initial exposure o f an individual at H iroshim a or N agasaki, they m ay be able to uncover som e o f the recessive abnorm alities. Part of the d iffic u lty o f e p id em io lo g ica l stu d ies, is th at th ey stress m o n stro sitie s. It is easier to pick up m o n stro sities o f a n o n g e n c lic so rt th a n it is to in d u c e m o n stro sitie s by g en etic m e a n s. { M R . C H A IR S K O : D r. C arlso n ? M y n a m e is M ike C h a irsk o o f M id A m erican R adio News. Y o u h a d m e n tio n e d w h e n d iscu ssin g th e a p p lic a tio n o f T C D D o r -- I 'm s o r r y . A g e n t O ra n g e ov er - V ietn am th a t T C D D a p p lic a tio n s for c o n ce n tratio n v ary fro m a few p a rts p e r trillio n to a few parts in | ten. C ould you elaborate on that? D R . C A R L S O N : Yes, the actual m ixture in the spraying on an y o n e run involved a thousand g allo n tank w ith an aero so l spraying for a fo u r-m in u te ru n in O p eratio n R anch H a n d , w hich was the [ n a m e o f th e p ro je c t f o r s p ra y in g th e fo re sts o r field s. T h e m ix tu re is a p p r o x im a te ly fo u r p o u n d s each o f 24D an d 245T . T h a t's p arts per ten. A d ifficu lty arises in estim ating how m uch herbicide did a veteran get. Som etim es a ground crew that was loading a plane m ay have gotten prop wash and spray | w h ere they w ere g ettin g p a rts per ten each . If they w ashed o f f im m ediately a fte rw a rd s (an d not all m ay h a v e h ad th e lu x u ry u n d e r b attle co n d itio n s to d o th a t ty p e o f w ashing) th a t w o u ld still give quite a bit co m p ared to the p arts th a t we usually talk about. i W hen we are talking about experim ental studies o f m utagenic o r toxic doses, these are m e asu re d in p art p er m illion. M R . C H A IR S K O : But were these veterans exposed to p an s o f ten o f T C D D ? . D R . C A R L S O N : N o. N ot o f T C D D itself; only o f A gent O range in som e cases. 1 D R . C A R N O W : L et m e ju st a d d in so m e o f th e federal d a ta -- A ir F o rce d a ta . It was sug g e ste d th a t eleven a n d a h a lf m illion g allo n s o f A g en t O ra n g e w as sp ra y e d . A n d an aly sis show s levels . o f u p to 40 parts p er m illion. N ow , it was highly variable. B ut there w as also A gent P u rp le and Agent 1 G re e n . T h o se w ere so m e o f th e o th e r co m binations. E arlier batches h ad m uch higher levels o f dioxin. T h o se batches w ere d irtie r in term s o f dioxin th an w ere th e o th ers. . D R . A N D E R S O N : D r. A n d e rs o n , w ith th e W isc o n sin D iv isio n o f H e a lth . Y o u r d a ta is very ' interesting. B ut, I w as w ondering when you w ere saying you are seeing a p attern o f disease, if you I could perhaps elab o rate on th at. It's very obvious th at o u r group has a p attern , but I w as w ondering I w hether y o u co u ld giv e a little m o re specific d a ta o n w h eth er w e ca n reco g n ize a p a tte rn in an in*d iv id u a l. W h at w ctc th e h allm ark s o f th e ab n o rm alities y o u saw ? D R . C A R N O W : T h e re a re a scries o f p ro b lem s. O n e is th e d o se , g en erally , th e d u ratio n and h e in ten sity o f e x p o su re . S econdly, is th e individual su scep tib ility o r sen sitiv ity based o n A H H inU u cib ility . So you are going to get som e variation in th e onset o f the sy m p to m s. G enerally, as 1 I p o in ted o u t, th e sy m p to m s th at w e saw -- and this is in a larg e g ro u p o f p eople now , th at w e have ex- | m ined, alm ost 400, 1 believe, involved headaches, fro n tal, bitem poral, to p o f the head headache, L a irly sev ere. D ep re ssio n w as very c o m m o n , g en eralized fa tig u e , v ery c o m m o n ; w eak n ess, less com - n o n ; loss o f libido in a lot o f people. These are sym ptom s, if you are looking fo r sym ptom s. D R A N D E R S O N : B ut, d o you get clustering o f th e sy m p to m s in th e sam e individual? If you l :t o n e , a re y o u likely to g et th e o th e r? ' . D R . C A R N O W : N o , gen eralized clu sterin g -- a g a in , you d o n 't fin d ev ery sy m p to m in every d iv id u a l, o b v io u sly . A n d you find m o re in so m e th a n in o th e rs . N u m b n e ss a n d tin g lin g o f the l l 21 fingers. P eople w h o d ev elo p ed ihis developed a n e u ro p a th y ; w o u ld have aching in their legs a n d in ih c ir a rm s , w h ich th e y w o u ld d e c rib e as a d eep a c h e . T h e y c o u l d n 't p u l th e ir finger o n it. A n d i t 's th e k in d o f th in g th a t k e e p s y o u a w a k e a t n ig h t o r w a k e s y o u u p at n ig h t. T h a t is classic n e u ro p a th y . A n d it m a y o r m a y n o t be a sso c ia te d w ith w e a k n e ss. W h e n y o u h a v e extensive n e u ro p a th y , you get foot d ro p an d wrist d ro p . But w ith a lot o f these people, there seem ed to be a sequence. The first th in g seem e d t o b e n u m b n e s s a n d tin g lin g . I f th e y re s te d th e ir a rm o n th e c a r w in d o w le d g e , it w ould fall asleep. If th ey crossed th eir legs, the legs w ould fall asleep fairly rapidly. All o f us have had th at experience a fte r a long p eriod o f lim e, but it h ap p en s to th em very rapidly. A nd a lot o f those people d o n 't have peripheral nerve conduction abnorm alities. S o th a t, in som e people, we w ould find the sym ptom s, they w ould have the sym ptom s, but we w ould find the abnorm ality. In som e people, we found peripheral n eu ro p ath y o r a slow ing o f conduction. A nd som e o f th e m d id n 't have n u m b n e ss a n d tin g lin g . But th e re is g en era lly a p a tte rn , a p attern w ith the cen tral nervous system fu n ctio n , in w hich w e found large n u m bers o f people related to atientional deficits, som e m em ory deficits. So, if you w ant to d o a quick and dirty you w ould d o a digit span. You read forw ard n um bers and b ack w ard num bers. T h ey can read fo rw ard n u m b ers, but they can only read a few nu m b ers backw ards. T h ere are o th er deficits in c o n c e n tra tio n -- in m em ory that we found. T hat seem ed to be a com m on p attern , the kind o f pattern that you sec in the diffuse cerebral dysfunction from toxic agents. N ot ail o f th em h ad general u rinary sy m p to m s. N o t all o f them had liver enzym e a b n o r m alities, but a large n u m b e r o f them d id . O ne o f the things th at I did not discuss was gastrointestinal dysfunction. A lot o f them had sym ptom s that sounded like ulcers. A nd a lot o f them had x-rays tak en . In m any, no ulcers w ere found. W hat was found, w ere diffuse inflam m atory changes. W e are not su re w hat the m echanism o f th at is. O f course, each o n e o f these sym ptom s an d every one o f these findings can be caused by a n o th er disease because th e b o d y can only react in a certain num ber o f w a y s . T h e d iffe re n c e -is t h a t y o u get a g r o u p o f th e se th in g s. I t 's a lm o s t lik e p ic tu re g am es w e p la y e d as children w here you w ould expose one eye, then the nose a n d ti^ to identify a person. Eventually, you say , O h !, th a t is F ra n k S in a tra o r J o h n W ayne, w h en y o u h a d e n o u g h in fo rm a tio n . D R . A N D E R S O N : T h a t 's w h a t I w as try in g t o g et a t . Is th e re s o m e -- t h a t 's -- o b v io u s ly , people have k an d p eople react in d ifferen t w ays. B ut in y o u r 47 people, w hich you characterized very carefully, werp there som e groups th a t were m uch m ore co m m o n and occurred together than the o th e rs? W as th e nerve c o n d u c tio n -- w as it sensory o r m o to r-- o r b o th ? D R . C A R N O W : It w a s m o r e m o to r th a n s e n s o ry , b u t w e s a w a fa ir a m o u n t o f s e n s o ry . It w as m edian nerve nero p ath y , diagnosed by orthopedic physicians as, carpal tunnel syndrom e, because it a f f e c ts th e n e rv e a s it g o e s th r o u g h a tiss u e tu n n e l. B ut y o u s e c , th e c a rp a l tu n n e l is w h ere th e m e d ia n nerve is co m p ressed a n d th e re fo re susceptible to d a m a g e . It is o u r experience th at w hen you have toxic d a m a g e to a n erv e, it is g o in g to o c c u r at th e p o in t w h ere th e n erv e is u n d er th e greatest tra u m a , b e c a u se d a m a g e w h e re a n e rv e is m o v in g th e m o st is w h e re it te n d s to be tra u m a tiz e d w hen it is d e fi c ie n t. T h a t is w h y p a in te rs w h o w ere exposed to le ad , w o u ld get w rist d ro p o f their w o rk in g a rm , because that w as the nerve that w orked the hardest, and the one that needed the m ost nutrition. A nd so we fo u n d th e carliecsig n s tended to be o f the m edian nerve in the carp a l tunnel. ^' M R . D IE S N E R : S en ato r D iesner from M in n eso ta. D r. C arn o w , you listed a w hole g ro u p of 'a b o ra to ry tests here as being ab n o rm a l. A nd 1 was w o ndering ab o u t the degree o f abnorm ality. Are l 22 \ (hese things b o rd erlin e ab n orm alities o r mild abnorm alities? D R . C A R N O W : W ell, w hen we say ab n o rm a l, w hat we are talking about arc two standard deviations from the m ean. So, w hen we are talking about som ething being ab n o rm al, we are not talking about one stan d a rd d e v ia tio n . W e a re ta lk in g a b o u t so m eth in g th a t is m o re th a n tw o . T h a t m a k es it a b n o rm a l. S o w hen you say m ildly a b n o rm a l, you a rc talking a b o u t so m eth in g th a t is a lre a d y beyond tw o sta n d a rd deviations. W e did not find th at a lot o f these people had gross abnorm alities-- som e did. For exam ple, triglycerides a re a b n o rm a l ab o v e 170. W e found so m e people w ith 900, 1,200, l ,400-- I had never seen a n y th in g like th a t b e f o r e . S o w e saw s o m e p e o p le w ith p r o p h y r ia . A n y u r o p o r p h y r in th a t is o v er 60 is v e ry , v ery h ig h . N o w , w e s a y th a t n o rm a l is fro m 15 to 6 0 . B u t, th e n u m b e r o f p e o p le th a t I saw w ith 60 o r 58 is ex tre m e ly lo w . S o , it is very h a rd to give y o u a n an sw er to h o w sever is severe. M R . D IE S N E R : M ay I use your term inology? D R. C A R N O W : Sure, go ahead. M R . D IE S N E R : H ow m any o f those w ere beyond three or four stan d ard deviations? D R . C A R N O W : 1 d o n 't k n o w . I c a n 't tell y o u th a t. M R . D IE S N E R : A few o r a lot o f them ? D R . C A R N O W : It depends on w hat tests you are talking ab o u t. M R . D IE S N E R : W ell, pick any. D R . C A R N O W : I d o n 't know . W e did n o t lo o k at it th a t w ay. M R. D IESN ER : Thank you. M R . M C C A R T H Y : F ran k M cC arth y , P resid en t o f the V ietnam V eteran A gent O range Vic tim s, and representing th e C onnecticut S tate C om m ission. D o c to r, w h a t w e a rc try in g to fin d o u t a t th is p o in t th a t is m o st c ru c ia l to us is trea tm e n t fo r the various sym ptom s a n d effects. N ow , the V ietnam veterans w ere all m edically scrutinized prior to g o in g to V ietnam . T h e y w ere considered m edically fit, physically fit a n d c o m b a t ready. W e have literally put som e o f o u r veterans in a blender. A n d w e realize th at there a re q u ite extensive variables w hich arc involved w hich are exposed to A gent O range, P inki P u rp le, W hite, D D T altheine, and vario u s o th er chem icals asid e fro m the illnesses fro m V ietnam . B u t th o s e o f u s w ith c h lo ra c n c -- n o w , th e V e te r a n s ' A d m in is tr a tio n is te llin g us th a t it's o f a te e n a g e -ty p e . A n d w e re a liz e th a t th a t is not tru e . B ut w ith y o u r tra c k w o rk e rs w h o w ere d efin itely d ia g n o se d as h iv in g c h lo ra c n e , is th ere an y tre a tm e n t being ad m in iste re d to these people o r d o you know o f any treatm ent? D R . C A R N O W : W ell, a lot o f people w ho have very severe ch lo racn e w ould have them e v a c u a te d . T h a t 's all th e y c o u ld d o . I f th ey d i d n 't e v a c u a te th e m a te r ia l, th e y w o u ld d e v e lo p this m aterial w hich has a terrib le, terrible o d o r. In severe chloracne they w ould evacuate them . A nd d er m atologists tried all so rts o f treatm ents; none o f them really w orked. In som e people, they go aw ay a f te r a y e a r o r tw o . A n d I sa id th e re w ere o th ers w h o h a v e h a d it n o w fo r 4 0 y e a rs. A n d th e ir w ives still squeeze o u t these bu m p s w hen they get bad enough. B ut 1 d o n 't k n o w th a t a n y tre a tm e n t h a s h e lp e d . S o m e o f th e se p e o p le h a d ra d ia tio n fo r th e s k in e a rly o n in th e 5 0 's . T h a t w o u ld b e ex tre m e ly h a z a r d o u s in m y v ie w . M R . M C C A R T H Y : D o c to r , la st q u e s tio n . W e h a v e b e e n to ld th a t th e T a t b io p sy is a w a y o f d e te c tin g d io x in w ith in th e fa tty tissue. In your o p in io n , is it n o t (ru e th a t d io x in co u ld have en tered / 8465 ihe system , d o n e th e d am ag e, and then left (he system w ithout leaving any residue? D R . C A R N O W : W ell, I think that we all agree (hat that m ay be the case. 1 think that there m a y still b e s o m e re s id u e , b ut i t 's d iffu s e d . Y ou a r e ta lk in g a b o u t a v ery sm a ll q u a n tity to begin w ith . Y ou th e n d iffu s e it b e c a u se i t 's fo u n d in the p a n c re a s , th e liv e r, th e a d r e n a ls , th e b ra in , th e k id n e y , and other organs, and the fat. In so m e cases, biopsies were d o n e and th e highest c o n c e n tra tio n s w ere found in the p ancreas, s o m e in th e liv er, a n d so m e in th e fa t. S o i t 's v ery , very d iffic u lt t o m e a s u re . Y ou w o u ld p ro b a b ly n eed a huge am ount o f fat because you are talking ab o u t a very sm all concentration, a very small concen tration o f m aterial. Such surgery w ould be som ew hat m utilating an d -- probably not a useful procedure. W hat we a r e d o in g is w e a r e g e ttin g access to th is a u to p sy m a te ria l a n d all th e w o rk e rs w h o w e re ex p o sed y e a rs a g o an d w ho a re d y in g . A n d w e will be doing m easu rem en ts in th eir tissues to see w h at levels we fin d . S o m e o f th e se p e o p le h a v e n o t been e x p o se d fo r 10 o r 15 y e a rs . A n d th a t m a y be v ery usefu l in f o r m a tio n . But until we h av e b etter in fo rm a tio n , I th in k th at if s o m e b o d y is ex p o sed , if th ey have this kind o f a s y m p to m c o m p le x o r a t least so m e o f the th in g s th a t w e fin d h e re , it seem s to m e th a t it w o u ld be re a s o n a b le a n d p r u d e n t to m a k e a ju d g m e n t th a t th e y w e re e x p o s e d a n d a f f e c te d . B ut a g a in , it depends on w hat you arc looking at. You are looking at m edical prudence. M R . O 'C O N N E L L : I 'd lik e to re tu rn a t 11:15 s o w e c a n g et o n w ith o u r la tte r p a rt o f th e m o rn in g . A t th is tim e I 'd lik e to th a n k D r. C a rn o w a n d D r. C a r ls o n o n a very in te re s tin g p r e s e n ta tion. (A pplause.) (W hereupon, a short recess w as had.) M R . O 'C O N N E L L : C o u ld w e s ta r t th e p r o g r a m ? Since w e began this m orning w e have h ad the arrival o f several o th er states. C onnecticut has arrived w ith F ran k M cC arthy. R uth Levcrctt fro m N ew Y ork arrived. H an k H ah n from C alifornia h as arrived. D r. A n d erso n , o f course, cam e in fro m W isconsin. So w e have a pretty good representa tio n . W e w elco m e o u r next sp eak er b ack to his h o m e to w n o f C h ic a g o . D r. M a rk T h o m a n is a g ra d u a te o f th e U n iv ersity o f M issouri School o f M edicine. H e is c u rre n tly th e p resident o f the A m erican A cad em y o f C linical T oxicology. H e is a Fellow o f th e A m erican A cadcem y o f P ediatrics, a n d a clinical fa c u lty m e m b e r a t D ra k e U niversity in to x ico lo g y a n d p h a rm a c o lo g y . T h is is to n am e but a few o f his m any qualifications. D r.'T h o m a n will discuss dioxin past, present, an d fu tu re w ith an em phasis o n fetal a b n o r m alities and on the effects o f dioxin on future generations. D r. T h o m an . D R . T H O M A N : T h a n k y o u . W e ll, i t 's g o o d to b e b a c k in th e h o m e to w n . I w ould like to bring us up to d ate and touch on som e o f the things that have already been discussed very ad eq u ately by D r. C arlson and D r. C arnow , an d not go over old g ro u n d . I think f o r brevity an d to give us som e tim e for questions at th e end o f th e session this m o rn in g , I w ould like to talk ab o u t a very basic thing. 1 w ould sim ply and initially talk a b o u t th e com plexities o f those o f us in clinical practice in clinical toxicology. T he A cadem y o f G in ic a l T oxicology has been aro u n d since 1968. S o i t 's a re la tiv e ly n ew s p e c ia lty . 1 g ra d u a te d f r o m m e d ic a l s c h o o l in 1962. A n d to x ic o lo g y a n d ecology w ere w o rd s th a t we h eard, but w e just d id n 't think w ere ever g o ing to be m u ch in the w ay o f s p e c ia ltie s . B u t th e n in rth e I9 3 0 's a n d 4 0 's ...f o r th o s e o f u s th a t w e re a r o u n d id th e e a r ly 3 0 's a n d 4 0 's, we grew up w ith the phrase " Better Living T hrough C h em istry ." I think that we are seeing one thing. u a n d th a t is w e e v e n tu a lly " p a y th e p ip e r ." I have g iv e n q u ite a n u m b e r o f p re s e n ta tio n s in reference to specifically, the chlorinated hydrocarbons. I'm going back to the PC B in fo rm atio n that cam e out so m e y ears a g o as it re la te d to th e so c a lle d c o la -c o lo re d b ab ies th a t o c c u rre d in Y u sh o , J a p a n a n d this is a chem ical cousin to the dioxin we arc talking a b o u t. But they have their ow n characteristic chem ical effects. N o w , le t's ta lk a b o u t h ow o n e g ets p o is o n e d . L e t's ta lk a b o u t b a sic to x ic o lo g y . Ed P ress in E vanston, Illinois, started the first poison center as a pilot study associated w ith the N orthw estern U n iv ersity . T h is w as p rim arily fo r o th e r d o c to rs w h o w o u ld call in say in g , " I 've g o t a child th a t's ta k e n g r a n d p a 's m e d ic in e .'' A n d th e p h y sic ia n w o u ld sa y w h a t to d o a b o u t it, a n d th e signs a n d sy m p tom s that you look for. P ed iatrician s to o k care o f th e children th a t w ould accidentally ingest toxins. They are big e n o u g h to get in to th in g s, b u t n o t big e n o u g h to k n o w a n y b e lte r. T h e to d d le r is th e o n e w ho is a m ain candidate for poisoning. This has now expanded. O v er th e y e a rs, w e d o n 't ju st h av e th e ac c id e n ta l in g estio n o f p o iso n in g by th e to d d ler, but we also have the intentional ingestion by som e people that w ant to get a high w ith certain chem icals. S o th e first w ay you gel p o iso n ed , o r m o st co m m o n w ay m o st o f us th in k o f is th e ingestion. S econd is in h a la tio n . A n d w hen w e talk a b o u t d io x in , we ta lk a b o u t n o t necessarily ingestion, b u t in h a la tio n . In h a la tio n is breath in g in th e m aterial. W h e n i t 's b r e a th e d in , it is sw a llo w e d w ith th e m u c o u s . It is o f te n c o u g h e d u p , th en sw a llo w 'd , hence, an indirect ingestion. T his is a cycle th a t o fte n in co rp o rates o th e r m e th o d s o f toxicity. W e ta lk ab o u t sim ple c o n tact o r sim ple inhalation. W e are often talking ab o u t a m ore com plex situation th an th at. But inhala tio n c a n be accid en tal a s it is in m ost cases in situ a tio n s w h ere th e re is an in c id en t o f a w o rk m an w o rk ing a ro u n d d ioxin, th e railro ad w orker w e talked a b o u t in th e previous stu d y . W e talked about lead poisoning and so o n . A n d this can cause the industrial toxic exposure. C o n ta c t is a real p ro b lem in th e ag ricu ltu ral sta te s, su ch as Illinois, M isso u ri, Iow a. A n d the co n tact w ith the organ o p h o sp h ates-- contact w ith this particu lar g ro u p o f toxins certainly has to be c o n sid e re d . T h e re a re situ a tio n s w here so m eo n e c a n a b so rb c h o u g h by c o n ta c t th a t it w ould cause o v e r t s ig n s a n d s y m p to m s w h e re it w o u ld h a m p e r f u n c ti o n ...t h e r e f o r e h a v e a to x ic e ffe c t. I'm ta lk in g a b o u t m a la th io n -p a ra th io n insecticides a n d h erb icid es. C o n ta c t is a ls o a p ro b le m w ith d io x in . Injectfn d o es n o t necessarily ap p ly h ere, b u t in jectio n is th e next w ay o ne gets poisoned. N o w , this could be accidental o r intentional. A ccidental w ould be so m eo n e inadvertently-- giving an in je c tio n -- th e w ro n g m a te ria l is given to a p a tie n t. T h e d e lib e ra te in je c tio n is w h e re so m e o n e is giving th em selv es so m eth in g to give th e m so m e kind o f a n e ffect; su ch is th e case in h e ro in ad d icts o r cocaine users. I w as d irecto r o f the heroin clinic fo r eight years in m y city. Finally, rad iation. A nd D r. C arlson had m entioned this earlier regarding the effects o f rad ia tio n . In fact, w hen we talk about the teratology o r the effect on the developing fetus, we really thought th a t th e fetus w as fairly safe, en cap su lated in a ro o m all its o w n , th a t isn 't a ffe c te d by outside w orld influences. * B ut in th e 1940's w e fo u n d o u t th a t ru b e lla ( o r 3 -d a y m e a sle s v iru s ) c o u ld c a u se c e rta in p r e d ic ta b le e ffe c ts in th e J e tu s . W e th o u g h t it w as a fairly u n iq u e c a p s u le u n til th e n . H ow ever, now w ith radiation an d with three-day m easles we know now that cataracts, c o n g e n ita l h e a r t d is e a s e , a n d c e rta in a b n o rm a litie s a r c p re d ic ta b le . A n d t h a t 's w h y (h e p a tte rn th a t D r. ; 6467 25 C arnow had m entioned regarding the profile o f those that had been exposed to dioxin rem inded m e o f a paper 1 h ad given in T o k y o in 1965 dealing w ith the first uses o f co m p u ters in poison centers. T h is went along with w hat we call the toxic profile. W hat I did in this particular presentation, was to take the signs an d sym ptom s that are fairly w ell-know n to the profile o f a particular toxin. Y ou w ould ask fo r, let's say in this case dioxin to give you the signs a n d sym ptom s a n d related incidents in a particu lar individual or g ro u p o f individuals; next w hat tests can be d o n e, the S C O T o r S G P T . Som e tests w ould be abnorm al, and give stan d ard deviations and references an d so fo rth . T he other function w ould be to put the signs an d sym ptom s o f the individual w ho has been poisoned against an unknow n toxin an d see w hat relative m atching that did w ith the profile o f the to x in in qu estio n . A n d I th in k p eo p le a rc going to have to accept th a t this is a real th in g . T h e p ro b lem th a t w e h av e in th e clinical p ro cess, is th at th e diagnosis a n d th e c o n firm a tio n o f th e o n b o a rd lo ad o f d io x in is very d ifficult. W orking w ith the VA H ospital, the surgeons an d the people in m y area, we can get a la b o ra to ry in o u r sta te that will give us figures u p to o n e p art p er billion w hich is n o t very close. W e need to get a lot clo ser th a n o n e p art p er billion because w e k n o w th a t o n e p a rt p er trillion w ould be better if we could do it, going back to our PCB experiences. A nd in St. L ouis, M onsanto has been u n a b le to g e t la b te sts f o r u s re g a rd in g th e P C B 's , a n d 1 n o t o n ly r e f e r to th e te r a to lo g y effects o f P C B and high doses fo r th e incident in the Y usho incident, but also the m others w ho w ere exposed fro m the o m n ip re se n t P C B b ecau se it n o t o n ly g o es to th e fetu s w hen th e m o th e r is ex posed to th is chem ical b u t it also affects h er system as w ell. It's fa t bound a s w e discussed e a rlie r, as is d io x in . A n d then it can g o o u t th ro u g h the breast m ilk if she breastfeeds her baby. A n d 1 th in k th a t y o u a re p ro b a b ly seeing a tre n d . In fa c t, v e ry d o s e to th is a ir p o r t is F ra n k lin P a rk , w hich is the h e a d q u a rte rs o f L a L ed ie L eague In te rn a tio n a l, w hich is a g ro u p o f m o th ers th a t the A cadem y o f P ediatrics in E vanston worked w ith and encourage nursing. It has helped to triple the p o p u latio n in the nursing m o th er population now as opposed to 20 years ag o w hen m ost o f them w ould use form ulas. ' S o w e h av e a w hole new a re a here, a n d th a t is th a t a m o th e r w ho is ex p o sed to a toxin b e t w een the 15th & 60th d a y follow ing conception, a n d as has been p o in te d o u t by D r. C a rlso n , is th a t if so m eth in g is atoxic en o u g h in th e early pregnancy o f the h u m a n o r an im al in this c a se , it will n o t be co n d u d v e fd r im plantation. It w ould cause a toxic reaction. A nd I am paraphrasing an d adding co m m ents to D r. C arlso n 's com m ents. Im plantation m ay not tak e h o ld , an d hence there is n o co nception. It is in fact, lost b ecau se th e m o th e r is so unable to be in a p o sitio n fo r n o rm a l im p la n ta tio n to ta k e p lace. I th in k th a t o n c e a b o u t 90 days is passed, a n d this is w h at w e call in m e d id n e th e first trim ester. T h is is th e tim e w h en w e a re w orried a b o u t chem icals co m in g in c o n ta c t w ith th e m o th e r eith er th ro u g h th e vario u s w ays I m entioned o r rad ia tio n , w hich is th e fifth to x in . T h e n o ne h as to be v e ry c a u tio u s . I t 's d if f ic u lt t o s a y th is is re la te d t o th is . I th in k th a t y o u h a v e b e e n a w a r e o f th e b e n d e c - tine problem s because there a re 1,311 cases o f bendectine w here phocom ejia o r o th e r abnorm alities, in d u d in g lim b defects have been rep o rted . Bendectine w as recently pulled o ff th e m a rk e t w ith th e idea th a t it w as very expensive to c a rry o n th e litigation. ' ' B ut n o w , theXTDC h a s ju st com e out this week statin g th a t th ere has been a causal re la tio n ship by an ep idem iological stu d y in a particular p ro b lem . A n d 1 h av e ju st the initial re p o rt, that th ere 26 \ have been a higher incidence in those th a t have been in d o u b le blind studies w here bendectine has in fact, caused co n sid era b ly m o re p roblem s w ith certain types o f lim b d efects th an in the controls. These are early studies, and o n e that litigation people are certainly interested in on the P la in t i f f s sid e . T h e D e fe n d a n ts d o n 't w an t to h e a r a b o u t th a t. B ut u p to n o w , w e h a v e n 't been ab le to g o b a c k -- an d if it w a sn 't fo r th e fact th a t p e d ia tric ia n s sat d o w n in th e e a rly 6 0 's an d fo u n d o u t th a t in G erm any there were a lot o f phocom elia cases, an d they w ere trying to figure out w hat the com m on denom inators w ere, they m ay not have picked up the fact that lhaJydom idc affected that early fetal developm ent. So I th in k if we d o n 't lo o k , we a re not g o in g to find o u t. A n d w e d o n 't k n o w . I think th a t at this point I w ould ju st like to say as the executive officer o f the A cadem y o f Clinical Toxicology, I w a n t to th a n k th e p e o p le w h o p u t th e p r o g ra m o n a n d M r. O 'C o n n e ll f o r g e ttin g s o m e o f us to g e th e r w ho have been feeling like we are the L one R angers o u t on the prairies o f Iow a and N ew York. But this gives m e an o p p o rtu n ity to -- and I have discussed th is-- to take this type o f in ter change and info rm atio n an d publish this in the jo u rn a l. I t 's c a lle d A a c tio n , A -a -c -t-i-o -n . I t 's th e A m e ric a n A c a d e m y o f C lin ica l T o x ic o lo g y N ew slet ter. A nd I have a nu m b er o f people w ho have w ritten m e letters w ho are m em bers o f the board o f trustees w ho say th a t this is n o th in g but a lot o f h y p e, a lot o f press h ype, w hich rem inds me o f so m e a rtic le th a t I c u t fro m th e p a p e r . I 'm s o rry I d o n 't h a v e it p r e p a r e d as a slid e , b u t let m e d escrib e it. It s h o w s N o a h 's A rk in th e b a c k g r o u n d in a c a r to o n . A n d o n th e fro n t o f th e p a p e r , th e re is a little w o rd S o x . A n d o n e sa id i f th e f lo o d 's o v e r, w h y c a n 't w e le av e th e a r k . A n d th e a n s w e r w as d io x in . S o it is w ith a n u m b e r o f things w e hav e seen in th e p ress, a n d w e have to b a la n c e this o u t. T he studies that have been done so far have been very helpful to m e. I have a large bibliography an d a file o n th is ch em ica l. 1 d o n 't h a v e th e sev eral th o u s a n d p ag es th a t m y c o lleag u e D r. C a rn o w has. B ut l d o have a num ber o f articles. A n d I think th at w ith this interchange o f in fo rm atio n we can all benefit. I t 's n o t a p r o b le m w e c a n ru n a w a y fro m . A n d I th in k w e c a n c o m e u p to o n e th in g , a n d th a t is th a t d io x in c e rta in ly is n o t g o in g to be c o n sid ere d a v ita m in . A t a n y ra te , sp e a k in g o f ru n n in g aw ay a n d w a n tin g to be b rie f so th e re is e n o u g h tim e fo r m y co lleag u e s a n d th e ir p re se n ta tio n s a n d q u estio n s, is th a t 1 recall a c o u p le fellow s th a t w ere sitting next t o th e fire at th e e n d o f th e w o o d s n e x t to th e la k e a n d th is g ig a n tic b e a r sh o w s u p . A n d h e is a b o u t 20 feet from them . A n d he com es to a point near them . A nd this one fellow looks at ^hc other, and he lo o k e d back at ^?e b ear. A n d this guy started tak in g his k n ap sack a n d he started ta k in g his running shoes ou t and started putting them on. So the guy asked him , you are putting on your running shoes? Y o u c a n 't o u tr u n th a t b e a r . A n d th e fello w said to th e firs t, I d o n 't h a v e to o u tr u n th e b e a r. I ju s t have to outrun you. D R . T H O M A N : T hank you very m uch. M R . O 'C O N N E L L : T h a n k y o u . D r. T h o m a n . Y o u a r c a b s o lu te ly rig h t a b o u t th e significance o f this se m in a r in th at th e tran scrip t will be av ailab le fo r o th e r researchers th ro u g h o u t the c o u n try . N ex t, w e h av e a n o th e r g en tle m a n w ho is m a k in g his seco n d a p p e a ra n c e at a n Illinois A gent O ra n g e C o m m issio n M ed ica l S y m p o siu m . D r. R o b e rt G in s b e rg is th e ,re s e a rc h d ire c to r fo r C itizen s fo r a B etter E n v iro n m e m based h ere in C hicago. D r. G in sb erg received his P h .D . in 'm o rg a n ic ch em istry from th e U niversity o f W isconsin in 1978. S ince th at lim e, h e has served as the research f 'O cia(e in the D ivision o f O ccu p atio n al-E n v iro n m e n tal M edicine at th e U niversity o f Illinois S chool I 27 o f Public H ealth. H e has been a technical consultant to O S H A . H e has been a m em ber o f (he M edical C o m m it tee o f the C hicago A rea on O ccupational Safety and H ealth. D r. G in sb erg will help us to d ay in draw ing certain parallels betw een the use o f A gent O ran g e in V ietnam a n d th e d o m e stic use o f dioxin. D r. G insberg. D R . G IN S B E R G : T h a n k y o u . It's a p leasu re to be h ere a g a in . U n fo rtu n ately . I w o n 't h av e the jokes that the previous speaker had, nor the w ealth o f clinical d ata that you heard earlier this m orning. I 'm going to present a slightly different perspective on the problem and discuss the w idespread use o f p esticides in this country*. Y o u m ig h t th in k i t 's so m e w h a t u n u su al fo r a p u b lic in te re s t/e n v iro n m e n ia ! g ro u p to b e h e re several tim es now , th ree tim es in the last year and a h alf, speaking before the Agent O range C o m m is sion and discussing A gent O range. B ut th e re is a very sim ple e x p lan atio n . P e stic id e u se in this c o u n try is u n b eliev ab ly w id e s p re a d , a n d th e p e stic id e s u se d a re very sim ilar to th o s e th a t w e re u sed in V ie tn a m . B ecause a few* o f th e p e s tic id e uses a r e so u b iq u ito u s (alm o st o m n ip re s e n t) th e p r o b le m is ig n o re d . I t 's alm ost in v isi ble. You rarely hear an y b o d y talking about the public health consequences. Perhaps as D r. T h o m an sa id , we a rc g o in g to p a y th e p ip e r fo r b etter living th ro u g h c h e m istry . A n d the piper will be p aid in the next few years. If you actually look at people from public health d ep artm en ts or agriculture departm ents at b o th state an d federal levels, y o u find in m ost cases a certain cavalier attitu d e tow ards the question o f p esticid es. T h e ir c o m m e n ts ra n g e fro m it is p erfectly sa fe to th e re is n o p ro b le m . T h e m o st recent ex am p le that com es in to m in d , is from M innesota w here they h ad a n o u tb re a k o f encephalitis. A n d very p ro p e rly , th e y w ere ta k in g s o m e a c tio n s, in p a rtic u la r a re a s p ra y in g w ith m a la th io n . B ut they w e re n 't . telling th e p u b lic th a t th e y s h o u ld be co n cern ed a b o u t th e m a la th io n as w ell; " M a la th io n is p e rfe c tly s a f e .'' T h a t's n o t e n tire ly w h at 1 w o u ld co n sid er a p ru d e n t a ttitu d e . I ag ree th a t o n e s h o u ld c o n tro l fo r encephalitis, but not to ignore o r dow n play the o th er problem s. P erh ap s a bit m ore extrem e exam ple c o n c e rn s a n u n n a m e d o ffic ia l in Illin o is w h o o n c e s ta te d a t a* p u b lic m e e tin g o n sp ra y in g fo r g y p sy m o th th a t w h en h elico p te rs w o u ld sp ray carbaryl, he co n sid ere d it to be so safe th at he w ould stick his to n g u e o u t a n d c a tc h th e d r o p s o n his to n g u e . O h , y es, h e is a liv e a n d still o p e ra tin g . H o p e fu lly it will have an effect on him o n e o f these days. H e & still w o rk in g w h ic h is o n e o f th e re a so n s h e re m a in s n am eless. B ut th a t a ltitu d e p erm eates m o st o fficial agencies a n d responses. M any p ro fessio n als will go to m eetings, on insect c o n tro l o r p la n t c o n tro l, a n d a tta c k m e b ecau se I 'm q u o te -u n q u o te a n e n v iro n m e n ta list. A p p a re n tly I have caused all th e ills in th e c o u n try that they perceive. T hey w ill b em o an the loss o f pesticides like D D T , to x a p h e n e , 2 4 5 T . A n d th e y will g o on in great len g th a b o u t h o w w e have destroyed the c o u n try , a n d h o w w e a r e g o in g to b e o v e rru n by in s e a s . I th in k th is is a n o th e r m isn o m e r. U nless I tru ly am th e a g e n t w h ich w ill c a u s e a b ib lical p la g u e . T h ey h a v e n 't u n fo rtu n a te ly q u ite lost th o se p esticid es. 2 4 5 T , is still a p p ro v e d fo r use in ran g e lan d , rice fields, a irp o rt ru n w ay s, industrial sites alo n g fencelines. T h e re a re a lo t o f u ses. S ilvex, re la te d to 245T , is still a p p ro v e d fo r ap p le s a n d p ears, su g a r c a n e , rice fields, an d range lands. D D T is still p r p d u c e d in th is c o u n try fo r e x p o r t. T o x a p h e n e still h a s a -n u m b e r o f-u se s---It still c a n b e u s e d in th e U .S . in a n e m e rg e n c y . It's used in P u e r to R ic o a n d th e V irg in Is la n d s . I t 's u sed o n 2 1 caitlc and sheep, too. So we still have a lots o f (oxaphcnc a ro u n d . A n d 1 can go o n with a list o f chem icals th a t w ere su p p o sed ly b a n n e d w hich we are still ru n n ing into p ro b le m s w ith . But this d is re g a rd fo r th e h a z a rd s o f p e stic id e s is a lso re fle c te d in the w h o le p ro b lem w ith A g e n t O ra n g e a n d th e a ttitu d e o f th e V e te ra n 's A d m in is tr a tio n a n d b y the ch em ic a l c o m p a n ie s. A c tu a lly , i t 's q u ite re a s o n a b le fro m th e c h e m ic a l c o m p a n y 's p o in t o f v iew . If it's p ro v e d th at in, fo r exam ple, en vironm ental situ a tio n s these pesticides an d h erb icid es will pose a problem in h u m a n h e a lth , it w o u ld b e very h a rd to d e n y it to th e v e te ra n s . I t 's q u ite lo g ic a l th a t th e y h av e a p r o b lem i f th e c o n v e rs e is tr u e , i.c . if w e h a v e p ro b le m s w ith v e te ra n s , i t 's a ls o g o in g to b e a p u b lic h e a lth problem . In that case, all pesticides use in (his co u n try w ould have to be reexam ined. W e have to exam ine very carefully what we are doing, and actually start looking for health effects an d d ev elo p in g th e p ro to co ls su ch as D r. C a rn o w ta lk ed a b o u t e a rlie r. T o say th a t cancer is th e o n ly end point o f co n ce rn is very m id lead in g a n d restric tiv e . T h e p o te n tia l p u b lic h ealth im pacts o f all tyi>es a rc stag g erin g . F ro m the chem ical c o m p a n ie s p o in t o f view , th e fin a n ic a l im p a c ts will be e q u a lly staggering. N evertheless, we must be very concerned about the w hole problem o f A gent O range ex p o s u re -- a n d i t 's m o re th a n ju s t A g e n t O ra n g e , a s d isc u sse d e a rlie r i t 's a lso a g e n t w h ite , ag ent b lu e , a n d agent p u rp le . T h e re is a w hole ra in b o w o f co lo rs th a t w ere d e sc rib e d a t a p re v io u s hearin g a n d to actually say w hat are the effects from these pesticides o r herbicides. U n fo rtu n a te ly ch ro n ic health effect d a ta in th is c o u n try is n early n o n ex isten t in p a rt, because th e re is not th a t m u ch research in to th e p ro b le m . I t 's f u r th e r c o m p lic a te d b y th e fa c t th a t a n y lo n g -te rm o c c u p a tio n a l s tu d ie s a n d e n v iro n mental studies are h am p ered by the unavilability o f g ro u p s o f people u n iq u ely exposed. F o r exam ple, .ry and find this country a group o f people uniquely exposed to D D T . It w ould be a very difficult task because o f o u r universal exposure to th a t pesticide. S o th ere is a virtual ab sen ce o f an y d a ta on the use o f pesticides, particularly in nonagricultural settings. I am b ased in C h icag o an d we a re co n ce rn ed a b o u t th e a m o u n t o f pesticides used in n o rth eastern Illinois-northw estern Indiana. A bout a year ago. C itizens fo r B etter E nvironm ent began a lo n g -term research p ro jec t to actually collect d a ta o n th e extent o f pesticide usage in n o n ag ricu ltu ral settings, particularly residential areas. In such circum stances m illions o f people are exposed to som e [ level o f pesticides. A n d we have no idea o f the extent. W e d o not co n ten d that these people are ex p o sed :q as m uch as the 60 o r 70 m illion pounds o f pesticide active ingredients applied annually to c o rn and soybean cro p s in Illinois. But substantial q u an tities a n d rates o f ap p licatio n a re occurring. [ T o o u r know ledge, there has been no such d ata previously collected in th e m idw est, o r in Illinois, o n p estic id e s usage. It is o u r a ssu m p tio n th a t o n c e y o u k n o w p e stic id e u s a g e , y o u c a n m a k e s o m e C lim a te s o f pesticide ex p o su re. T h e re fo re I will present so m e o f o u r p re lim in a ry d a ta a n d then discuss | io w th a t p ro b lem is related to veteran s-- as D r. C a rlso n d id e a rlie r w ith 2 4 D . Before proceeding, 1 am obliged to present several caveats fo r all this. T h ere are no official rcco rd s available in the state o f Illinois regarding pesticide usage o u tsid e o f th e ag ricu ltu ral setting. A ll | f o u r d a ta had to be collected from w hat I w ould call p rim a ry so u rc e s, sto res th a t sell pesticides, su rv e y s o f h o m e o w n e rs, surveys o f n u rseries, g o lf c o u rse s, c e m e ta ric s. A s y o u c a n im a g in e , th is is a som ew hat tim e-consum ing, labor-intensive operation. j We divided usage into three categories-- first, hom e professionals, i.e., stru ctu ra ljjcsi coh- l`io I , c o c k ro a c h e s a n d te rm ite s, a n d , a n ew p h e n o m e n o n , th e la w n c a r e p r o f e s s io n a l w h o g o es a r o u n d o ra y in g to m ak e y o u r law n green. T h e second cate g o ry is p u b lic a re a , i.e ., g o lf co u rse s, w hich .also 2V i hove to be green. cem c'.ancs. p o rk s m osquito abatem ent p ro cram s and forestry w o rk . A nd finally the th ird a n d la rg e st c a te g o ry is p e rs o n a l p u rc h a se s. T h is last c a te g o ry is b y far th e largest a n d p r o bably m ost u n co n tro lled source o f pesticides exposure in this co u n try . O ne can go to the superm arket and see th e row s a n d row s o f insect sp ray and w eed killers. T h ere is a trem en d o u s a m o u n t o f a d v e rtis ing that goes o n for pesticid es-- I w o n 't use p ro d u ct n am es. If y o u actually start read in g the labels th e vast m a jo rity co n ta in 24D . R arely will y o u find an y th in g co n tain in g 245T. B ut, in so m e o f the sm aller stores, you will still find old batches o f m aterial containing 245T. V e ry s im p ly w h a t w e h av e fo u n d is th a t ra te s o f a p p lic a tio n in re sid e n tia l a re a s a re o n th e o rd e r o f fiv e (5) to e ig h t ($) p o u n d s p e r ac re p e r y e a r. T h a t in c lu d e s av e ra g in g o v er a n en tire t o w n 's area. T ha: m eans streets get averaged in, sidew alks, your ro o f, w hich does not n o rm ally receive m uch pesticide. So that actually if you start looking at individual hom es or golf courses or a park, the totals tend to be three to fo u r tim es the a m o u n t. For co m p ariso n , I take the 1976 d ata on agricultural a p plication rates fo r co rn and soybeans. T h e rates are four p o u n d s per acre per year and two p o u n d s respectively. S o o n a n av e ra g e , we a re putting m o re pesticide per acre in o u r u rb an area s than we d o on our agricultural areas or our food crops. W e have been ignoring a potentially disastrous public health problem . N o w , I ju s t w a n t to ta k e a bit o f tim e to g o th r o u g h a n d d e sc rib e w h a t a c tu a lly is used a n d break it d o w n by so u rc e . W e find in -h o m e p ro fe ssio n a ls, th e p eople w ho co m e to th e h o u se or so m e p la c e else a n d s p r a y th e se m a te ria ls a c c o u n ts fo r a b o u t 15 to 20 p erce n t o f th e a c tu a l p e s tic id e use. T h e re a re v a ria tio n s, a n d I'm n ot going to g o in to th e d a ta here, b ased on eco n o m ic s ta tu s. G enerally, th e w ealthier the com m unity, the g reater the use o f such professionals. T hough oddly en o u g h , th e use o f law n ca re c o m p an ies is alm ost in d e p e n d e n t o f th e eco n o m ic sta tu s o f a c o m m u n ity . E ven in lo w er in c o m e a re a s, a p p a re n tly , th ey w ant to have g reen law ns. In term s o f p o u n d a g e , 2 4 D is th e m o s t w id e ly u se d c h e m ic a l b y h o m e p ro fe s s io n a ls . I t 's e ith e r u se d a lo n e o r in c o m b in a tio n w ith other herbicides, like d icam b a an d M C P P . A pplicatio n -rates vary from o n e o r two p o u n d s per acre for m ost com panies to one co m p an y w hich p u ts o n 16 p o u n d s o f 2 4D p er ac re . A p p licatio n s v a ry fro m o n e to fo u r tim es p er seaso n . W e are talking ab o u t phenom ina! rates o f application an d exposure. If the U .S. governm ent had put on A gent O ra n g e at th a t ra te in V ietn am . I 'm not su re a tree w o u ld still be s ta n d in g to d a y . F u rth e rm o re you have o th e r herbicides that go on at rates o f three to tw elve pounds per acre generally once a seaso n , b u t s o m e tim e s m o re . C le a rly a c tu a l p u b lic e x p o su re to th e se h e rb ic id e s, th e se ch e m ic a ls, is m u ch h ig h e r th a n it h a s b e e n th o u g h t previously.. A n d w e h a v e n o id e a w h at th e p u b lic h e a lth c o n s e quences are going to be. P esticid e use in p u b lic area s, has a sim ilar b reak d o w n as residential law n care . T h ree q u a rte rs o f all the g o lf co u rses, sod farm s, cem etaries in Illinois ap p ly herbicides to keep the w eeds d o w n . O f th o s e , a lm o s t 90/o e n tire ly u se 2 4 D a n d d ic a m b a . P e r h a p s i t 's th e u ltim a te re v e n g e o n th e c h e m ic a l com p an y executives w hen they go play golf; they are exposed to th e pesticides that they sold in th e first place. F inally, perso n al purchases account fo r th ree q u arters o f all the pesticides used in residential a re a s. G iv en th e p re v a ilin g a ttitu d e to w a rd s p esticid es in th is c o u n try , th e re is little re a s o n to believe that m ost p eo p le ap p ly the pesticides w ith proper p recau tio n s as the label req p ires.lt is-also unlikely that m ost p eo p le a re aw are o f the p o te n tial health effects. M o st people will have th e w orst ex p o su re th ro u g h in h a la ti o n , th r o u g h in g e stio n , a n d sk in a b s o r b ti o n . P e r h a p s th e g r o u p at g re a te s t risk is young children. T h e r e a r e very few s la te s -- a n d Illinois is not o n e o f (h e m -- th a t h a v e a n y re c o rd in g o f pesticide p o iso n in g . Illinois-- (here a re n o reco rd s (hat I can find a fte r 1973. C a lifo rn ia is th e o n ly state-- one o f the few states-- that actually keeps detailed records. A nd even that situation has m any problem s an d faults w ith the d ata. A ll o n e can re a so n a b ly c o n c lu d e , is th a t we have a vast a rra y o f h erbicides a n d pesticides used at w h a t I w o u ld c o n s id e r u n a c c e p ta b le levels. W e d o n 't k n o w th e real e x p o s u re s . W e d o n 't k n o w w h a t the p u b lic h e a lth e ffe c ts a re g o in g to b e . T h e o n ly d a ta on w hat m ight h a p p e n in th e U .S . is w h at has h ap p en e d to V ietn am a n d V ietnam v eteran s. It is the only d a ta we hav e to m ak e a p u b lic h ealth d eci sio n t h a t 's g o in g to a ffe c t m illio n s o f p e o p le in th is c o u n try . T h e re is a lm o st a c o n tin u u m th a t w e've d escrib e d -- T h e w o rk e rs, i.e ., th e ra ilro a d w o rk e rs, and the people in V ietnam , both the veterans a n d nonveterans w ho were exposed. W e m ust now take that d a ta a n d c a rry it th ro u g h to see w h at we are actually d oing to th e rest o f the pu b lic. T h a n k y o u . (A pplause.) M R . O 'C O N N E L L : W e will h av e so m e tim e fo r so m e q u e stio n s o f D r. T h o m a n an d D r. G insberg. (N o response). M R . O 'C O N N E L L : W ell th e n , I w o u ld like to ask a q u e s tio n o f D r. T h o m a n . Y ou had review ed the d ata d o n e by D r. C arlson o r as relayed by D r. C arlson o f the V iet n a m e se s tu d y o f c h ild 'c f f e c ts . Is th e re a n y th in g a p p ro a c h in g th a t ty p e o f te stin g t h a t 's b een d o n e in this country? D R . T H O M A N : T h e re is-- in clinical m edicine, a registry o f fetal a b n o rm a litie s th a t is b eg in ning. But n o b o d y has really correlated-- and perhaps som ebody here m ight have m ore inform ation on it. T h e -- th e re a re tw o p ro b le m s o n it, a n d I d id n 't get in to it. A n d I w o u ld like to say th a t g en era lly , w hen you think ab o u t the teratogenic effect o f a chem ical o r drug, you think about that period o f tim e in th e firs t tr im e s te r I-ta lk e d a b o u t . B u t th e re is a n o th e r e ffe c t w h ic h I 'm s u r e is w ell k n o w n b y m a n y h e re , a n d th a t is th e e ffe c t o n th e m a le , a s it w as p o in te d o u t in a n e a rlie r p r e s e n ta tio n . A n d th is is th e case in T im es B each th a t I h a d review ed last w eek. A nd this w as an individual w ho had the various signs and sym ptom s that w ere classically the m ore com m on sym ptom s described by D r. C arn o w . But in ad d itio n , th ere w as a 40 percent a b n o rm a l sperm co u n t. A n d th e sperm itself h ad these sm aller sperm head, the tail was too sh o rt, the enzym es w ere weak because o f the pathology o f the sperm itself w ould not be ad eq u ate enough at conception. A nd if so, then the dam age o f the fetus could be m uch h igher. A n d I a m sim plifying it because th ere are a lot o f things th a t g o o n w ith it, an d because th ere are things that we see th at go along w ith th e altered m orphology o f the sperm , the sperm count and so fo u rth . S o th e s e a r e o th e r m e a s u ra b le o b je c tiv e th in g s. A s f a r a s w h a t w e a r e d o in g to see if th e re is a c o r r e la tio n , I th in k i t 's a m a tte r o f g o in g b a c k . A n d u n f o r tu n a te ly , w e u sed to u se o u r re tro s p e c - to s c o p c r a th e r o f te n w h en it ta lk s a b o u t te rio lo g y . W e d o n 't d o d o u b le -c o n tro l s tu d ie s. W e a r e not ta k in g th is g r o u p a n d g iv in g th e m a c e r ta in a m o u n t o f c h e m ic a l e x p o s u r e , a n d sa y o k a y , le t's se e w h a t h ap p en s in th e next 30 y ears. ^- S o retro sp ec tiv e studies a re th e o n es we have to rely on in m ost cases. > ^ M R . O 'C O N N T X L : M a y b e D r. C a rls o n c a n jo in in th is a n s w e r . T h e e x p o s u re in V ie tn a m w as to th e w o m e n th e m se lv e s a n d m e n in m o st c a se s. In th e S ta te s h o w e v e r, it w as th e m en th a t w ere Jt 1 exposed, not the w om en. Bui we draw a distinction. D R . C A R L S O N : 1 th in k th a t is a n im p o ria m d istin c tio n b ecau se if m ales a re p rim arily e x L posed, an d w o m en a re n o i. th e o n ly en try for c o n trib u tio n to th e child is ih ro u c h ihe sperm . W hen a 1 sp e rm fertilizes a n e g g . it is th e sp e rm nucleus th a t e n te rs. T h e tail o f the sp erm d o es not en ter. T h a t m eans any dam age o f cytoplasm ic organelles, such as m itochondria, endoplasm ic reticulum and the i like w o u ld h a v e to b e c o n t r i b u te d fro m th e fem ale's eg g , n o t fro m th e m a le 's c o n trib u tio n . This essentially lim its m ale dam age to chrom osom al or gene dam age. The form s o f chro m o so m al o r gene d am ag e are lim ited. I m entioned th at fo r gene dam age, you w on't see m ost o f th a t. F or c h ro m o so m a l d a m a g e , m ost would a b o rt because an y ab n o m al excess or deficit o f c h ro m o so m e w o u ld be in c o m p a tib le w ith fetal developm ent o r em b ry o d evelopm ent. Very few get th ro u g h . T h at lim its o th e r types o f chrom osom al d am ag e that m ight get through o m ulti-break events. M ultiple-break events are detectable by studying a karyotype o f the chrom osom es. M y ow n feeling is th a t the birth defects th at veterans asso ciate w ith their ow n children a re unlikely to be associa;ed w ith herbicides. The possible erro rs that I have just described are also found am ong sp o n tan eo u s a b n o rm a l births for people w ho h av e never been exposed to any herbicide or pesticide. Five percent o f all births have some sort o f birth defect requiring m ajor m edical attention. i A lso , to sh o w th e d iffic u ltly o f th is p ro b le m , in a n e p id em io lo g ica l survey th a t is d o n e o n the v eteran s, o n e h as to re c o g n iz e th a t te n p e rc e n t o f all m arried c o u p le s (w h e th e r v e te ra n s o r n o t) a r e sterile. T h a i 's a high rate o f sterility. W h en y ou look at the cause o f sterility, ab o u t h a lf are due to male sterility. W hen von lo o k at th e causes o f m ale sterility, you find the d o u b le-h ead ed sperm , the tail w rapped a ro u n d the h ead , th e sh o rt tail, a n d oth er types o f ab n o rm alities. N o w , t h a t 's a m o n g y o u r n o rm a l o r u n ex p o sed s te rile m a le s. A lso c o m p o u n d in g th e d iffic u lty ? is th at o n e o u t o f every five w o m en in her reproductive lifetim e will experience a sp o n tan eo u s ab o rtio n o r m iscarriage. S om ew here betw een 40 and 60 percent o f all fertilizations have an abnorm al j,l c h r o m o s o m e n u m b e r to b e g in w ith . A n d m ost o f th e s e v ery e a rly e m b ry o s e lim in a te them selv es because they are in co m p atib le w ith life. N o w , t h a t 's y o u r c o n t r o l r a te . I f you a r e d e a lin g w ith a g e n ts th a t a r e w-eak m u ta g e n s , a n d th e y a re in c re a s in g , th e c o n t r o l ra te o f a b n o rm a litie s fro m 2 0 to 22 p e rc e n t, i t 's v e ry , very h a rd to m easu re this in a p o p u la tio n . Y ou w 'ould n eed h u g e sam ples an d very care fu l stu d ies. Y ou w ould need d o u b le-b lin d p ro c e d u re s . T h e re a r e s o m a n y c o n f o u n d in g variables th a t i t 's a f r u s tr a tin g p o in t fro m a n e p id e m io lo g ic a l perspective. / T h is is o n e re a s o n w h y an im al m odels, tissue c u ltu re m o d e ls, m icrogial m o d els a re so im p o r ta n t to d o c a re fu lly b e c a u se w*hen y o u fin d an ex p erim en tal sy stem th at y o u can c o n tro l, an d a b n o r m alities a re in d u c ed , y o u can suspect that these are a c tu a lly in d u ced . T h en you can zoom in on a 1 sp e c ific ty p e o f a b n o r m a lity . B ut it is a very difficult p ro b le m . M R . O 'C O N N E L L : A re th e re studies th a t c a n iso la te th e c o n tro l g ro u p ? A n d a re th e re ; L studies being done? D R . C A R L S O N : 1 th in k there are m any that can be d o n e. Som e are long range and som e are im m e d ia te . 1 th in k th a t th e stu d ie s th a t D r. C arn o w d e scrib e d w h ere he is h tte m p tin g to look fo r a sp e c ific sy n d ro m e o f to x ic e ffe c t is a n extrem ely v a lu a b le o n e , p a rtic u la rly b eca u se m a n y ag e n ts d o not have unique ab n o rm alities th e way thalom idc does. . > T h a lo m id c a ls o p ro d u c e d h eart defects a n d o th e r typical types o f a b n o rm a litie s . If h were'n i fo r the p e c u lia r lim b s, it m a y nev er h a v e been p ic k ed u p as te ra to g e n ic in a screen in g o f th e p o p u la tio n . S o th a t is a p ro b le m . Y ou co u ld fin d th e sy n d ro m e that sh o u ld be lo o k ed f o r -- an d I think this is likely. It will b e u se fu l fo r a d o w n -th e -lin e s tu d y o f w h o g ets c a n c e r. I th in k th a t p ro b le m is very im portant. T here arc som e epidem iological approaches that should control this. I think th at an y design o f a veteran s' q u estio n n aire on a n atio n al scale sh o u ld have a lot o f in put into its co m p o sitio n . A b n o rm alities th a t a re seen will h av e to be m atch ed against unexposed veterans. This requires a lot o f thinking and experience to do. M R . M C C A R T H Y : A re th e V ietnam ese doing a study o f the N V A w ho traveled dow n, left their wives like w e d id , traveled dow n th e H o C hi M inh T rail, cam e in to V ietnam , w ere exposed, w ent back and then saw their children w ith birth defects? D R . C A R L S O N : Yes. T hey claim they have these birth defects and they are higher than am ong the veterans w ho did not go to the so u th , w ho fought in the n o rth . But they also claim that these defects are n o t as freq u en t as in those w ho stayed in the so u th a n d m arried S outh V ietnam ese w om en. T h e y d o claim th is, b u t 1 fin d it very d ifficu lt to k n o w w h at th e causes w ould be. It w ould very difficult fo r m e to think o f a genetic o r a chrom osom al m echanism that w ould increase the fre q u e n c y o f c o n jo in e d tw in s . A n d I w o u ld n 't ru le o u t th a t m a y b e c o n jo in e d tw in s m a y b e a sso c ia te d w ith som e ab n o rm ality in the m em b ran e o f the sperm . T hese m onstrosities w ould be a one-tim e thing, they w ould not be passed on from generation to generation. M R . M cC A R T H Y : Please excuse m y academ ic ignorance on this question. N o w , I m a y b e w ay o u t o f lin e becau se I h a v e to a n s w e r it-- I h a v e to ask it b ecau se it w as b ro u g h t to m e. I f th e D N A m olecule is affected by dioxin, if, in fact, th e enzym es th a t create the d o u ble helix are a ffe c te d so th a t th e sp littin g o f th e d o u b le helix o ccu rs, yet th o se enzym es will n ot crea te th e d o u b le h elix a g a in , in th e sa m e w a y -- in o th e r w o rd s, in te rc e p t th e m essag e to th e fetu s, is th a t possible? D R . C A R L S O N : W h a t y o u a re describing, I p re su m e , is so m e ro u te fo r c rea tin g an a b n o r m al sequence o f n u cleo tid es, copying erro rs, o r th e like w hich will lead to m u tatio n s? M R . M C C A R TH Y : Yes. D R . C A R L S O N : A s I said, the chances that you w ould pick up an abnorm ality o f that sort a re very slim . F o r every h u n d re d changes in D N A th at y o u w o u ld in d u c e, you w q u ld only be able to pick up one as a dom inant m utation. N ow , ^certain d o m in an t m u tatio n s in a p o p u latio n a re relatively rare. T h e chances o f an ach o n d ro p lastic d w a rf being born are o n e out o f every o ne h u n d red thousand births. I w ould suggest th a t the U nited N atio n s, o r o th e r groups who have an o p p o rtu n ity , look at the d o m in an t m utation d a ta in V ietnam because th at sh o u ld involve a m illion o r m o re ch ild ren . T h at w ould be sufficient to look for disorders like retinoblastom a, achondroplastic an d o th e r d om inant m utations that usually arise from a brand new m utation. If they are being induced, they should be occurring w ith a higher frequency than the b a c k g ro u n d fre q u e n c y fo r th ese d iso rd e rs, w hich is well k n o w n fro m m a n y studies. I w ould suggest f o r a v eteran s' su rv ey th a t a list o f the severe, d o m in an t m u ta tio n s be included in such a stu d y , and th en those results can be co m p ared to th o se w ho a re not exposed-- such as veterans w ho did n o rg o to V ietnam . * - / M R . M c C A R T H Y : A n d th e la st q u e s tio n . I s n 't it tr u e th a t th e c h e m ic a l c o m p o s itio n o f d io - JJ Ir If * \n fils into th e DN'A m olecule, ihe d o u b le helix? O R . C A R L S O N : T h a i 's m u ch m o re d iffic u lt to tell. Y ou a re re fe rrin g to a n in te rc a la tin g agent. There a re co m p o u n d s-- douhlc-ringed-com pounds, that d o w ork through this m echanism . * T h ese p ro d u c e fram e shift m u tatio n s. M ost o f these will tu rn o u t to be recessive, and will not be picked up fo r the sam e reason that applies to m ost recessive m u tatio n s. T he induced m utation enf c o u n te rs th e n o r m a l c o rre s p o n d in g gen e a n d it w o n 't m a n ife st a n y d a m a g e to th e o ffs p rin g . T h e o n ly * w ay the v e te r a n 's o ffsp rin g will show d am ag e is if th a t g en e m u ta tio n p ro d u c e d by in tercalatio n o r a n y other m e a n s is d o m in a n t. i It h a s to b e th ro u g h a d o m in an t expression to sh o w so m eth in g system atic in the field. * M R . M cC a r t h y : A n d o n e fo r D r. G in s b e rg . Is it n o t tru e th a t N o rth w e st C o a litio n fo r th e U se o f P e s tic id e s -- I fo rg et th e n a m e o f it ex a c tly -- that th e y fo u n d d io x in , T C D D in 24D ? I D R . G IN S B E R G : 1 d o n 't kn o w o f an y studies w hich have fo u n d T C D D in 24D . T h ere have been several o th e r isom ers o f T C D D fo u n d in 24D sam p les. M S . W E S T : I h a v e a q u e stio n fo r D r. C a rls o n . I 'm H illa ry W est fro m th e Illin o is L eg islativ e l C o u n cil. 1 believe a fte r H iro sh im a an d N ag asak i, d id n 't th ey lo o k a t ch an g e s o f sex ra tio in th e o ffs p r in g , a n d w o u ld n 't th a t b e d o n e a n d m o re im m e d ia te ly tell th e e ffe c ts o f m u ta g e n s ? D R . C A R L S O N : T h e th in k in g b eh in d ch an g e s in sex ra tio is b ased o n earlier w o rk th a t w as i d o n e in fruit flies,- w here if y o u w ould ra d ia te a p o p u la tio n o f flies a n d you in d u ce m u ta tio n on the " X " ch ro m o so m e, the m ales that pick up an " X " ch ro m o so m e w ith som e induced lethal recessive vould m anifest it. W hereas, those m utations that are not an " X " chrom osom e w ould be protected. I If en o u g h " X " bearing eggs a re dam aged this will red u ce th e n u m b ers o f m ales in the population. T h e fem ale, how ever, has tw o " X s." If the m ale has a sperm w ith a defective " X ," the n o rm a l " X " c o m in g fro m th e fe m a le egg will p ro te c t th e d a m a g e d " X " fro m th e m a le . T h a t 's th e { thinking behind the sex ratio change. I I t 's e a s y to p ic k u p th is " X " c h ro m o s o m e in fru it flies w h e re th e " X " c h r o m o s o m e is 20 p e r c e n t o f th e to ta l g e n e tic c o n s titu tio n o f th e fly. U n lik e flies, w e d o n 't h a v e a c h r o m o s o m e n u m b e r o f ( 8. W e have a c h ro m o so m e n u m b e r o f 46. T h e " X " c h ro m o so m e is less th a n five p ercent o f the to tal genetic m a te ria l. So th e a m o u n t o f genetic d am ag e y o u a re p ro d u c in g in th e " X " c h ro m o so m e in th e j h u m a n is relativ ely m in o r c o m p ared to th e am o u n t o f d a m a g e y o u w o u ld be p icking u p in all the [ genetic m a teria l^ It becom es m uch m ore difficult, unless you have m assively high doses, to produce enough m utations on hum an " X " chrom osom es to show a dent in the sex ratio . T h e larger the am ount o f j g e n etic m a te ria l y o u h a v e 'fo r y o u r sex c h ro m o so m e , th e ea sie r it is to see-- usin g th e sex ra tio m e th o d . S o t h a t 's th e d if f ic u lty w ith h u m a n s . M S. W E ST : A nd no one has really bothered to look at th at? i D R . C A R L S O N : I doubt that you w ould find anything w ith studies o f A gent O range ex p o su re an d sex ra tio . Even w ith H iro sh im a an d N ag asak i victim s w h o w ere receiving doses o f 100 to 300 ro en tg en s, w hich is close to a m ean lethal d o se , th e re w as n o d e te c ta b le c h a n g e in th e sex ra tio . * B ut m a n y g en eticists w*ould h av e p re d ic te d th a t w e w o u ld n 't h a v e fo u n d it. D R . C O D A R I O : I 'd lik e to m a k e a p o in t in c la r if ic a tio n f o r th e la y m e n in th e a u d ie n c e , -par ticu larly the v eteran s. A n d Dr. C arlso n , you can c o m m en t o n this. In th e co u rse o f the d iscu ssio n s, \ye ia v e heard a lot ab o u t teratocenesis and m utagenesis. A n d in seeing p a tie n ts-- the veterans th at.I see. > l .u q u estio n is very o fte n ask ed o f m e: '`D o c to r, l h av e a c h ild . A n d I w as in V ietn am a n d exposed to A gent O ra n g e ." A nd for the benefit o f the laym en, we have to d ifferen tiate-- an d I want you to all u n d e rs ta n d w h at it m ean s w h en we say th a t so m e th in g is te ra to g e n ic a n d so m e th in g is m utag en ic. W h e n s o m e th in g is m u ta g e n ic , that m e a n s it c a u se s c h r o m o s o m e d a m a g e . A n ex a m p le o f th a t is as D r. C a rls o n p o in te d o u t, w e a r e b o rn w ith 4 6 c h r o m o s o m e s . A n a g e n t th a t is m u ta g e n ic is a n agent th at is g o in g to hav e us have 47 ch ro m o so m es o r 45 a n d a h a lf c h ro m o so m e s. A n a g e n t, o n th e o th e r h a n d , th a t is te ra to g e n ic , w ill c a u s e a n in d iv id u a l to be b o rn -- a s w e talked a b o u t-- w ith very sm all arm s, o r the absence o f an arm . T h a t m a y not be associated with an o b vious ch rom osom e dam age. N o w , h ere com es th e h u n d rcd -d o llar a n sw er. H ere is so m e th in g th at y o u hav e to u n d e rsta n d . It is v ery im p o r ta n t to u n d e rs ta n d in all th e stu d ie s th a t we d o . w e lo o k a t b irth d e fe c ts . But we a re ju s t beginning to scratch the su rface in term s o f finding out how th at cell gets from o n e sm all organism , o n e cell, to th e co m p lex ch em ical fa c to ry , if you w ill, th at th e h u m a n b o d y is. W e d o n 't ev en u n d e rs ta n d h o w th a t d e v e lo p s. W e d o n 't k n o w w h y . F o r e x a m p le , if yo u lo o k a ro u n d this ro o m , you will see 37 o r 40 different personalities. H o w d id that h ap p en . T hat happens, obviously, o n a chem ical level. T h ere are m any chem ical reactio n s th a t o ccu r in the body. W e d o n 't know how the bo d y goes ab o u t regulating those things. W h y d o tw o c h ild re n in a fa m ily -- o n e c h ild is six f o u r , th e o th e r is five n in e ? W h ere d o e s th a t c o m e f r o m ? O b v io u s ly , i t 's c o n tro lle d so m e w h e re in th a t g e n e tic c o d e . B ut w e d o n 't k n o w w h e re th a t c o n tro l is. A n d ju s t b ecau se w e d o n 't kn o w w h ere th a t c o n tro l is, w e a re ju s t in o u r in fan c y in looking into how agents like T C D D can cause problem s o f that type. M an y veterans com e up to m e and say m y child has m u ltip le in fectio n s. Is th at due to A gent O ra n g e ? T h e a n s w e r is w e ju s t d o n 't k n o w . W e re a lly d o n 't k n o w . W e a r e ju s t b e g in n in g to s c ra tc h the surface as to how the hum an body develops. I th in k in th a t resp ect. D r. C arlso n , dioxin is a lot s m a rte r th a n w e are. D ioxin know s how to d o it, b u t w e d o n 't k n o w h o w to d o it yet. D R . C A R L S O N : 1 share the im portance o f m aking that distinction betw een teratogenic and m u ta g e n ic e f f e c ts . I t 's v e ry d iffic u lt f o r m e to c o n c e iv e o f th e te ra to g e n ic e ffe c ts c o m in g o u t o f th e sperm o th e r th a n som e initial defect th at sets up ab n o rm al tw ins; so m eth in g that hap p en s alm ost im m e d ia te ly a t f e r tiliz a tio n . O n c e fe rtiliz a tio n is o n its w a y , i t 's h a r d to se c h o w th e s p e r m p la y s a n y ro le other than a m utagenic effect, rather than a teratogenic effect. O n tn e o th e r h a n d , in the eggs I can easily see how th e V ietn am ese exposed w om en can have th e s e h ig h fre q u e n c ie s o f m o le r p re g n a n c ie s b ec a u se th e eg g is a fa t f a c t o r y . I t's a b o u t a h u n d r e d to a th o u s a n d tim e s b ig g e r th a n a s p e rm , i t 's lo a d e d w ith y o lk m a te r ia l, w h ic h is lip id ric h . S o y o u d i f ferentially slack th e egg w ith herbicides which are fat soluble. I can u n d e rs ta n d h o w th a t can toxify th e d ev e lo p m e n t in th e eg g , a n d toss o u t th e nuclei in th e p o la r b o d ie s . T h a t m a k e s se n se . B u t i t 's very h a r d f o r m e to th in k o f a n y m e c h a n is m by w h ich th e sperm could do the sam e thing. M R . O 'C O N N E L L : O n b e h a lf o f th e Illinois A g en t O ra n g e C o m m is s io n , w e w ould like to invite ev e ry b o d y to lu n c h . W e will b e in th e ro o m next to us. A n d l w o u ld also like to th a n k D r. T h o m an and D r. G insberg. A nd again. D r. C arnow an d D r. C arlso n fo r their excellent presentations. (W h ereu p o n , a^uncheon recess was had.) M R . O 'C O N N E L L : C o u ld w e all tak e o u r seats, p lease? W e a re filib u sterin g right n o w until l 35 6477 If If \vc cel a lieu lic lu b u lb in th e c a m e ia . S everal o i m> co lleag u es o n ilie Illin o is A gent O ran g e C o m m is sion have arriv ed since o u r in tro d u c tio n this m o rn in g . S ta te R e p re se n ta tiv e L arry D iP rim a , w ho is th e if d e a n o f the Illin o is H o u s e o f R ep resen tativ es, a n d h as b een a s ta lw a rt re p re se n ta tiv e o f th e v eteran s in Illin o is is w ith us th is m o rn in g . H e is a m em ber o f th e Illin o is A g e n t O ra n g e C o m m issio n . A n d w e a ls o h av e B o b M iic h le r, w h o is not o n the C o m m is s io n , b u t w o rk s v ery earn e stly fo r th e Illin o is V eterans' A ssociation. il Jim K ing fro m A M V E T S is also a m em ber o f th e Illin o is A g en t O ran g e C om m ission a n d is w ith u s, an d has been an o u tsta n d in g m em ber o f o u r state c o m m issio n since its inception. J o a n M a im a n w ho h as b een w ith us is also a co m m issio n er. i, T he fo rm a t fo r to m o rro w will be to delay th e b re a k fa s t. In stead o f starting at 7:30. we will have a breakfast b u ffet at 8:15. 1 think w ith the size o f the g ro u p , we c in accom plish w hat we w ant to by starting the breakfast at 8:15. I, I th in k it w ill serv e as a g o o d fo ru m to e x c h a n g e id e as a n d p o ssib ly get som e d ire c tio n fo r o u r respective state co m m issio n s, an d to get som e ideas. I know we in Illinois-- our next project after this is to co m p lete o u r q u e stio n n a ire , w hich we have been w o rk in g o n fo r so m e lim e, an d w ould like to I, fin alize p re tty s o o n . S o w e w elco m e o u r o th e r sta te s' input o n th a t issue. W ell, o u r a fte rn o o n session will begin w'ith a p re se n ta tio n o n th e ad v an ces m ad e in d ia g n o sin g A g en t O ra n g e m edical co n d itio n s. D r. R o n a ld C o d ario o f P h ila d e lp h ia , was also with us a y ear a g o , a n d w e ap p rec iate his com ing back to 1 C h ic a g o fo r a r e tu r n v isit. D r. C o d a rio is a g ra d u a te o f H a h n e m a n n M e d ic a l C ollege, a n d is p re s e n tly on the teach in g s ta ff o f th ree P h ila d elp h ia hospitals. A n d h e is th e a d m in istra tiv e aide o f th e D ivision o f In te rn a l M ed icin e a t S t. A g n es H o sp ital. D r. C o d a rio is a lso th e d istin g u ish ed recipient o f th e 1981 I F reed o m F o u n d atio n A w ard at Valley Forge for his w o rk w ith V ietnam veterans. I 'd lik e to h a v e y o u jo in us in w elco m in g D r. R o n a ld C o d a r i o . (A pplause.) l D r. C O D A R JO : 1 w ould like to thank the Illinois A gent O ran g e C om m ission for being g ra c io u s e n o u g h to a s k m e to c o m e b a c k a g a in this y e a r. I t 's a lw a y s a p le a s u re to c o m e to C h ic a g o a n d to attend the Illinois A gent O range Com m ission m eeting. A n d I think that the com m ission has d em o n strated th at th ey are one o f the finest in the c o u n try . So I am certainly happy to be here. W h a t 1 w o u ld like to d o to d a y is to ju st give y o u a n o v e rv ie w as to som e o f th e c h a n g e s ( I 'd I, lik e to s a y a d v a n c e s -- 1 h o p e th e y a re a d v a n c e s) in d ia g n o s in g th is p e rp le x in g p ro b le m , a n d s o m e o f th e new er tests th at w e have com e up w ith that I hope will shed so m e light a n d m aybe give som e people so m e th o u g h ts in this ro o m ab o u t how we can go ab o u t lo o k in g in to this very perplexing problem o f diagnosing and proving that a lot o f the sym ptom s and signs that the veterans have are related to her bicides and their effect. T h is is th e c h e m ic a l s tru c tu re o f o u r friend te tra c h lo ro d ib e n z o p a ra d io x in . A s y o u can see th e chloride m olecules in the 2,3,7,8 positions. As already alluded to, there are 75 different isom ers o f this c h e m ic a l c o m p o u n d . I t 's a v e ry flat sy m m e tric a l m o le c u le th a t c o n v e n ie n tly d rifts in to th e cell m e m b r a n e . A n d th e n it b e g in s to w re a k h a v o c w ith th e b o d y c h e m is tr y . A n d t h a t 's w h ere th e fu n b e g in s. W e have to begin determ ining several years th ereafter w hat chem ical effects have taken place, l a n d w hat signs a n d sy m p to m s are related to this b io ch em ical d isa rra y . In the last year o r so , Pye. d e v o te d m o s t o f m y a t te n ti o n to lo o k in g in to tw o p a r tic u la r p r o b le m s . O n e is c h lo ra e n e aftd th e o th e r is th e sy n d ro m e o f n e u ro e s th e n ia . N ow , if you review th e m ed ical lite ra tu re a n d you sp en d so m e twite ( I .W, k I I looking at all the published reports on hum ans that have ingested these herbicides as suicide attem p ts a n d h u m a n s th a t h a v e b een ex posed as a resu lt o f in d u s tria l a c c id e n ts, o n e th in g is c e rta in ly clear--w h a t th e v e te ra n s a re co m p la in in g a b o u t is n o t s o m e th in g th a t h a s rec e n tly been d e s c rib e d . These sy m p to m s an d sy n d ro m e com plexes have been rep o rte d in civilians w ho have been exposed to 245T w ith its co n tam in a n t dioxin and 24D as well. So that these w hole hosts o f sym ptom s are not new in exposures. But as we m entioned last year, they are certainly characteristics o f hum an exposure th at you can pick out and say are reliably fo u n d in p e o p le th a t a re exposed to T C D D o r w hat we c o m m o n ly re fer to as dio x in . A n d as w e sa y , ch lo ra cn e is th e m ost co n siste n tly re p o rte d h e a lth effe c t. A n d as D r. C a rn o w m entioned, you do not have to have chloracne to have later d em o n strated side effects o f T C D D . O n e o f th e p ro b le m s with ch lo ra cn e is th a t it c a n ru n th e g a m u t fro m in n o c u o u s-lo o k in g b la c k h e a d s o n th e fa c t to r a th e r d isfig u rin g e ru p tio n s , as w e see h e re . N o w , th is is a n in d iv id u a l th a t had a skin biopsy th at h ad a characteristic finding o f ch lo ra cn e. A n d we are going to talk ab o u t th at in a m in u te . I w a n te d to ju s t c o n tra s t th is v e te ra n 's sk in w ith th is in d iv id u a l w h o is a n in d iv id u a l w h o h a s been exposed to polychlorinated biphenyls and n itro fu ran s. H e was in T aiw an, and exposed as a result o f an industrial accident there. O ne o f the big problem s with diagnosing chloracne, an d o n e o f the com m on m isconceptions is th a t y o u c a n d ia g n o s e it sim p ly b y lo o k in g a t it. A n d th a t s im p ly is n 't tru e . I f y o u lo o k at all th e pu b lish ed re p o rts by th e experts in th e field, p articu larly J a m e s T a y lo r o f C lev elan d C linic, D r. K en n e th C ro n e o f L o n d o n , E n g la n d . O n e o f th e key p o in ts th a t is m a d e is th a t a s k in b io p sy is c e rta in ly c ritica l in m a k in g th e d ia g n o sis. L e t's ta lk s a b o u t s o m e sk in b io p s y fin d in g s. N o w , th is is a s e c tio n , in essen ce, o f n o rm a l s k in . A n d f o r th e la y m e n in th e a u d ie n c e , th e skin is divided in to tw o g en eral areas, th e epiderm is a n d th e d e rm is . T h e d erm is is this d a rk e n e d , p in k area . A n d this is th e d erm a l a re a here. A n d the changes th a t w e see in ch lo ra cn e involved not o n ly th e epiderm is, but the derm is. W e see acanthosis or a thickening o f the epiderm is. W e see an absence o f b a c te ria a n d le u k o c y te s in th e d e rm is. C o n tra ste d t o a c n e v u lg a ris , o r th e a d o le s c e n t's a c n e , w h e re w e see a lot o f ro u n d cells in th e derm is and a lot o f b acteria in th e d e rm is, an d in th e h a ir follicles. A n d this is a h air follicle h ere, a n orm al h air follicle. W e see d isru p tio n o f th e n o rm al cells in the h air folli cle so-called sq u a m o u s m e tap lasia an d deposition o f k eratin c h lo ra c n e . A n d this is d e m o n stra te d h ere in this slid e ta k e n fro m a ra b b it ear. T h e re is a large a m o u n t o f k e ra tin d e p o site d in th e h a ir follicles, w ith the surrounding squam ous m etaplasia that has taken place. N ow , D r. C ro n e o f L o n d o n , E ngland, feels th at if w e a re a b le to see this ty p e o f e ru p tio n in tw o p articu lar area s, the eyelids as listed here, and th e groin a n d th e scro tal areas listed here, th at w e m ay be able to forego skin biopsy and m ake the presum ptive diagnosis o f chloracne. T he reason for th a t is th a t u s u a l g a r d e n v a rie ty o f a c n e v u lg aris ju s t d o e s n 't u s u a lly o r n o r m a lly o c c u r in th e se a r e a s . S o if you have a n individual that has eyelid involvem ent, you certain ly have scrotal involvem ent o r anal involvem ent, as we see here. You m ay suspect that the individual m ay have chloracne and forego the skin biopsy. N ow , these are slides that were provided to us w ith th e co u rte sy o f D r. R enata K im brow at th e C enters fo r D isease C o n tro l in A tla n ta . A nd these again a re T a iw a n e se people w ho w ere exp o sed to d ib e n z o fu ra n s. A n d j'O u can the disfiguring type o f eru p p 'o n s th a t have tak en p lace in this p a r ticular individual. But rem em ber, chloracne does not have to be a disfiguring eruption. N o w , J a m e s T a y lo r o f (he C leveland C linic is tre a tin g his p a tie n ts w ith v ita m in A d e riv a tiv e s, I a n d h as h ad s o m e su ccess in tre a tin g his p a tie n ts w ith th o s e su b sta n c e s I 'll h a v e to a d m it in m y clin ical practice. 1 have not been able to share that enthusiasm . T he patients I have given vitam in A to , I 4 h a \e n 'i been im pressed w ith th at agent as being rem ark ab ly helpful in relieving the sym ptom s o f chloracne. O ne o f the new er agents, accutane, which is a vitam in A derivative, m ay prove to be o f som e If b en efit in tre a tin g th e se p a tie n ts th a t h a v e c h lo ra c n e . B u t th a t c e rta in ly re m a in s to b e se e n . O n e o f th e p roblem s w ith a c c u ta n e is th a t y o u certain ly hav e to m o n ito r a n d w atch liver fu n ctio n very, very carefully. A nd as w as illustrated prior to this, m any o f these patients d o have liver involvem ent, if not l, from A gent O range o r dioxin per sc, perhaps on drugs o r other types o f chem ical substances that they may have been exposed to. S o 1 th in k a s o f th is tim e , 1 c a n 't really sa y th a t th e re is a n y re a l a c c e p te d tre a tm e n t fo r 1, c h lo ra c n e . V ita m in A h a s b een trie d b o th to p ic a lly a n d sy sie m ic a lly . U su a lly th e p a tie n ts d o not re s p o n d to te tracy clin e fo r so m e lay effects. D r. C ro w e uses d e rm a b ra s io n w h ich is literally scru b b in g the surface o f th e sk in , w ith so m e effectiveness, but certain ly a lot m o re research needs to be done in 1, th is p a rtic u la r a re a . O n e o f th e m o re fa sc in a tin g a re a s o f e n d e a v o r a n d an a re a th a t is really m y interest has been the post-V ietnam stress syndrom e, the delayed syndrom e. A nd the psychologists and psychiatrists 1, h av e c e rta in ly w o rk e d o u t a n ex ce lle n t clin ical d ia g n o s tic e n tity . T h e key q u e s tio n a n d o n e th at 1 th in k sh o u ld p e a k o u t in te re s t is w h a t is th e c a u s e o f this p o s t- tr a u m a tic s tre s s e n tity . It is re a lly ju st th a t it w as u n p o p u la r w a r , a n d th e v e te ra n s w e re n 't a c c e p te d p r o p e r ly w h e n th e y c a m e h o m e . T h e y m ig h t have a p re d isp o sitio n to d ev elo p in g psychological p ro b le m s. Is is ju s t a sim p le as th a t? O r m aybe is there an o th er factor? A n d that factor m ight be th at the chem ical them selves, either the herbicides o r dioxin or a com b in atio n o f the herbicides and dioxin m ay be playing the role and causing delayed - m e n ta l illn ess. I t 's a v e ry frig h te n in g a n d r a th e r p o ig n a n t q u e s tio n . I f y o u rev iew th e lite ra tu re , w e c e r ta in ly h a v e lo a d s o f ev id en ce th a t to x ic a g en ts c a n a ffe c t th e m in d . T h e classic e x a m p le is th e M a d H atter sy n d ro m e, th o se individuals that w ork in m ercury factories a n d have been exposed to m ercury an d develop th e m a d n ess o f th e h a tte rs w hen they used to use th e m e rc u ry to line th e h ats in the fac I, to r y . T h e s e in d iv id u a ls w h e n e x p o s e d to th a t s u b s ta n c e e v e n tu a lly b e c o m e m e n ta lly ill a n d in s a n e . T h e y a!! d e v e lo p e d th e sa m e ty p e o f m e n ta l sy n d ro m e . C ould we be seeing-- could this post-V ietnam stress d iso rd er be nothing m ore than a m anifestation ^ f herbicide poisoning? A n d with th a t in m in d , w ith th e aid o f D r. H erb ert Kaye o f S to n y b ro o k , w e have been able to d o certain specialized testing in V ietnam veterans w hich involves the use o f a com puterized electroencephalogram . N o w , th is p ic tu re is k in d o f a g rap h ic illu stra tio n o f w h a t 1 w as ta lk in g a b o u t. A n d I th in k a p ic tu re is w o rth a th o u s a n d w o rd s h ere. T h is w as a n article w ritte n in S e a ttle , W a s in g to n , by E ric Scigliano. A nd w ith the aid o f som e w ork given to him by D r. M alcom B arr o f A u stralia, he was able to w rite so m e in terestin g articles o n this p articu lar th e o ry . N ow , if y o u lo o k in the lite ra tu re , certainly as we said, this type o f neuroesthenia syndrom e has been described previously. W hat the veterans are c o m p la in in g a b o u t is n o t so m e th in g th a t does n o t h a v e a n y p re c e d e n t in th e lite ra tu re . It is in th e lite ra tu re . It is fo u n d th e re . T h e se a re n o t new c o m p la in ts . A nd getting back to w hat D r. C arnow was saying, I really believe that too. I have now looked a t 550 individuals. 1 a m 'n o t im pressed w hen 1 stand there and talk to an individual a b o u t-- this is,an :n d iv id u a l th a t is c o m in g in a n d t h a t 's b een c o a c h e d , th a t sp e n t o n e y e a r g iv in g his life in V ie tn a m a n d '' . l 6480 is n o w c o m in g to a d o c to r to try a n d g o ld b ric k a n d try to m a k e u p s y m p to m s , c o m p la in ts th a t in dividuals have been reported to have w ith Agent O range poisoning. A n d I th in k t h a t 's a n o v e rs im p lic a tio n . A n d I th in k th a t if y o u lo o k at th e lite ra tu re a n d y o u talk to the m en, you find that the sym ptom s a re peculiarly sim ilar: w eakness, fatigability, headaches. A nd I think one m isconception we all have as physicians and scientists, if we can 't prove som ething scien tific ally , it s im p ly m u s t n o t exist o r it m u st n o t b e sig n ific a n t. A n d t h a t 's a g ro ss o v e rsim p lific a tio n . I th in k i t 's a f a u lt in o u r s c ie n tific m e th o d . A n d th e b u r d e n is o n us to fin d o u t w hy th e s e gentlem en are having fatigue. A nd D r. C arn o w m ay have shed som e light on an interesting issue ab o u t the m uscular in volvem ent in the ab n o rm alities o f the m itochondria. A nd th at certainly has to be looked into. But cle a rly , w h e n a v e te r a n sa y s h e is c o m p la in in g o f fa tig u e , d e s p ite th e fact th a t we c a n 't p ro v e it th rough a b lo o d test, fatig u e has been rep o rted in the past, as well as the w eakness, the vegetative d y sfu n ctio n , m e n tal d ep ressio n , lack o f drive, lack o f sexual d riv e, by B asherov in the Soviet U nion in w orkers that w ere exposed to T C D D and herbicides. N o w , th is is b asica lly so m e e le c tro e n c e p h a lo g ra p h ic d a ta . A n d 1 w ant to give it to you as a n overview to give y ou so m e b ack g ro u n d as to w hat we are finding in these com puterized elec troencephalogram s. B asically w hen yo u d o an E E G , a stan d ard electroencephalogram , for the laym en in th e a u d ie n c e , i t 's k in d o f lik e th e E K G o f th e b r a in , if y o u w ill. W e a re h o o k in g u p electro d es to the b ra in , a n d we a re m e asu rin g b rain -w av e p attern s in d if ferent areas o f th e b rain . A n d there arc certain b rain w ave p attern s th at are norm al in particular areas o f the b ra in , a n d f o r p a r tic u la r types o f activ ity th a t a n in d iv id u a l is e n g a g e d in . A n d th e re are fo u r types o f w aves th a t w e sec in the stan d ard E E G ; a lp h a , beta, th e ta, a n d d elta. A n d they are all d e sig n ated b y th e n u m b e r o f b lip s o r c o u n t p e r se c o n d th a t y o u see w hen a n in d iv id u a l is h o o k ed u p to such a m achine. N o w , this is w h at th e sta n d a rd E E G lo o k s like. A n d these arc th e areas o f th e brain that c o r respond to these ab n o rm alities. N ow , w hat do we look at? W hat are we looking for when we look at w hat appears to be a lot o f chicken scratch up there? W ell, first o f all, the left side o f the brain and right side o f the brain have sim ilar patterns; th at is, the a m p litu d e o f the left side a n d the right side o f the .brain sh o u ld be the sam e. These deflec tions upw ard a n d d o w n w a rd sh o u ld b e th e sam e size in b o th sides o f the b ra in . In a d d itio n , we should see the deflections occurring sym m etrically. W hen the left cortex deflects, the right cortex deflects. So t h a t 's o n e a r e * th a t w e c a n lo o k a t. A nd this p h en o m en o n w here we look a t th e sym m etry, if you will, o f the w aves on both sides o f th e b rain is re fe rre d to ex actly as th a t, sy m m e try . C o n v e rg e n c e is re fe rre d to as th e ab ility o f the left side o f the b rain to co rre la te well w ith activities in th e right side o f the b ra in . A nd th e blips per second that we sec here are the n u m b er o f areas o r the areas o f the brain w here we are seeing this various type o f activity. N o w , it tu rn s o u t th a t d e lta w av e activity w h ich is very slo w w av es, th re e to eight cycles per s e c o n d , is fo u n d in a v e ry lim ite d n u m b e r o f c lin ica l s e ttin g s . W e see it in s q m e c h ild r e n , a n d w e see it in som e in d iv id u als th a t a re sleeping. A n d we see it in in d iv id u als th a t h av e b rain d a m a g e . N ow , the ncurom etricai uses m any m ore o f the standard electrodes and uses c o m p u te r to interpret the results. This com puter an d this technique has been used for over 50 years to look al the cause o f learning disabilities in c h ild re n . A n d w ith this technique, we have now stu d ied o v er 50 v eteran s. A nd we have jv been able 10 find som e in terestin g p a tte rn s, p attern s that as this tim e d o n 't in and o f them selves p ro v e so m eth in g . But th ey c e rta in ly in d ic a te to us that th ere is so m eth in g m o re th a t has to be in v e stig ated . W e are U ndine a large num b er o f delta wave activity. 84 percent o f the veterans that we have looked at have a b n o rm a l a m o u n ts o f d elta waves in their fro n tal lobe an d in their tem p o ral p arietal lobes indicating th at th e re is so m e ty p e o f b rain in ju ry . N ow , is th e re a n y type o f p recedent for this in the literature? Yes, there is. If y ou review the literature, on anim als that have been exposed to this substance and you do an EE G on an im als, you actually find that they have EEG abnorm alities, that they d o have delta wave ab n o rm alities. W hen you sacrifice those anim als an d you look at the brain under the m icroscope, you actually find that certain areas o f the brain, particularly what we call the pyram idal tr a c t, th at h as lost s o m e o f th e fat lining o f the nerv e itself. A n d th is p ro cess is k n o w n a s d ctu y elin a - tion. A n d i t 's a v e ry in trig u in g p ro c e ss b ecause p e rip h e ra l n erv e tissu e is lined w ith fa t. C e n tra l nerve tissue is lined w ith fa t. If y o u g o back an d you review th e lite ra tu re , this p h e n o m e n o n has also been described in nerve tissue. P erip h eral neu ro p ath y (dam age to the peripheral nerve) has been rep o rted in h u m a n s th a t h av e been exposed to herbicides, in h u m a n s th at have been exposed to T C D D a n d in an im als th a t h av e been exposed to T C D D an d exposed to herbicides. A n d th e p re c e d e n t h a s c e rta in ly b een set. W h a t a b o u t p e rip h e ra l n c ro p h a th v ? Is it s o m e th in g t h a t 's ra re ? It is n o t r a re . T h e r e a r c m a n y ty p es o f to x in s th a t c a n c a u se p e rip h e ra l n e rv e d a m a g e . F o r th e laym en in th e a u d ie n c e , p e rip h e ra l n eu ro p a th y is ch aracterized b y n u m bness in the h a n d s, n u m b ness in the feet. It m ay be ch aracterized in the later stages by u'eakness in th e m uscle. But the classic s y m p to m th a t th e p a tie n t h a s is n u m b n e s s . M a n y lim e s w h en w e g et a s ta n d a r d e le c tro m y o g ra m , i t 's m e asu re to design th e n erv e c o n d u c tio n in th e nerves. It m ay be n o rm a l. P hysical ex am in atio n m a y be n o rm a l. If c a re fu l a tte n tio n is n o t ta k e n to all types o f sensory stim u la tio n , p articu la rly vibratory- s tim u la tio n . S o p e rip h e ra l n e u r o p o th y is q u ite o fte n a m issed d ia g n o sis. I t 's n o t o fte n a se rio u s p r o b le m . I t 's n o t a p r o b le m th a t m a y c a u s e d e a th to th e in d iv id u a l. A n d as a d ia g n o stic ia n a n d as a p h y s i cian, 1 can tell you th at th e p erip h eral nerves are som ething th at are quite often m issed and glanced o v er w hen a physical exam is n o te d . N o n e th e le ss, w h en y o u lo o k at th e types o f p e rip h e ra l n e u ro p a th ie s , th e re a re tw'o g en eral types. T here are types th at cause d am ag e to the long sheath o f th e nerve in a segm ental fashion. A nd there are types o f nerve d am ag e that causes dam age to the end o f the sheath and the sheath then begins to d e te rio ra te in a b a c k w a rd fa sh io n . N erve tissue consists o f tw o types o f c o m p o n e n ts. T h e re is th e n erve cell b o d y , w h ich a c tu a lly lo o k s like a sta r, th e d e n d rite . E m a n a tin g fro m the s ta r th a t is a long co rd , the ax o n . A n d the toxins d am ag e the nerve by dam aging th a t axon. A nd there are all different w ays that an ax o n can be d am ag ed . All these different types o f chem icals cause d ifferen t types o f d a m a g e a n d p h e n o m e n a . A n d th e y c a u s e it in all d iffe re n t w ay s, lik e in te rfe rin g w ith th e b io c h e m is try o f that nerve, various enzym es, various vitam ins are interfered w ith. A rsenic, for exam ple, (one o f (he key ingredients o f agent blue) causes a peripheral neuropathy, a dying back neuropathy that usually responds to thiam in, a m ultivitam in. S o m e o f th e m e d ic a tio n s th a t a re av ailab le o n th e m a rk e t, lik e IN H , (w hich is u se d for tu b e r culosis) can cause peripheral neuropathy. -_ A nd strangely hough, o u r old friend porphyria carvcause peripheral lieu ro p ath y . A nd we h a v e h eard a b o u t p o rp h y rin d a m a g e in V ietnam v eterans. A nd last y ear. 1 talk ed a b o u t th e p o rp h y rin '. 4(1 8482 p roblem s th at we arc seeing in m any o f the veterans. O th er types o f d am ag e that a re caused directly by som e o f the agents that we m ay have heard about today, m any o f the pesticides, the o rg a n o p h o sp h o ro u s c o m p o u n d s fit in to this category. D ap so n e, w hich w as used in V ietnam as a p r o phylactic ingredient to fight m alaria, can also cause peripheral n eu ro p ath y . A nd strangely enough, we suspect that T C D D o r dioxin m ay fit in to this g ro u p th ree categ o ry . 1 will tell you som e in fo rm a tio n about that as we go on. N ow , the key q u estio n becom es a clinician w hen a p atien t co m p lain s o f num bness in th e peripheral nerves, how can we m ake that diagnosis o f peripheral neuropathy? W e said that m any tim es, the stan d ard E M G and nerve conduction study m ay be norm al. W ell, if the patient has p e rip h e ra l n e u r o p a th y , w hy is th a t n o rm a l? It m ay w ell be th a t th e E M G is not as sen sitiv e as it s h o u ld be o r can be. A very interesting p ap er was put o u t in the A rchives o f N eurology last sum m er by S ch au m b erg & A b ru si in N ew Y ork. A n d they d id fairly extensive w o rk on d iag n o sin g p eripheral neuropathies. A nd w hat they basically did was, they exposed a m onkey to an agent called acrylom ide. A nd acrylom ide causes this dying-back type o f neuropathy that we are taking ab o u t. They then w ent ab o u t doing tw o things. T hey w anted to find o u t how they can prove that this m onkey had a peripheral n eu ro p ath y , and th at was the best test, the best w ay to go ab o u t doing th at. A nd then, they sacrificed the m onkey and looked at the peripheral nerves, looked at the spinal co rd , looked at the b rain , and fou n d out w hat was happening on a m icrom olecular basis to explain their clinical findings. A v e ry in te re s tin g m o d e l, to lo o k a t p e rip h e ra l n e u r o p a th y . A n d h e re is w h a t th e y f o u n d . A n d th is is very im portant to the clinician. T hey looked at tw o types o f nerves, the perineal nerve and the m edian nerve. A g ain , fo r the laym en in the audience, the m ed ian nerve is o n e o f th e m ain nerves in the u p p er e x tre m itie s . T h e p e rin e a l n e rv e is th e n e rv e in the leg. A n d th e y w a n te d to fin d o u t if th e re is a n y d i f ference betw een the arm an d th e leg. A n d it turns o u t th a t th e re is a very significant difference. T h e perineal nerve seem ed to show m any m o re abnorm alities in term s o f th e degree o f d am pening o f th e re sp o n se , the s tim u lu s, a n d th e tim e p erio d that it to o k fo r th a t re sp o n se to be d a m p e n e d . W ell, big d e a l. W h a t d o e s th a t.m e a n ? W h a t it m e an s is th a t w hen we lo o k a t p e rip h e ra l n e u ro p a th y , m ay b e w e a r e m a k in g a n o v e rs im p lific a tio n to j u s t sa y this fello w h a s a p e r ip h e r a l n e u r o p a th y . L e t's ju s t d o th e u p p e r e x tre m itie s . O r th is fello w h a s a p erip h e ral n e u r o p a th y , l e t 's ju s t d o th e lo w e r e x tre m itie s . B ecause it tu rn s o u t th a t w hen y ou look at the perineal nerve, a n d yo u ta k e the so m ato se n so ry evoked p o te n tial, w hich for the laym en in the audience m eans the nerve co n d u ctio n as we go all the w ay up to the b ra in -- rem em b er, w hen you get a stim ulus in y o u r fin g ertip , you are able to sense that in you b ra in . A n d th e 're a so n y o u a re a b le to sen se it is b ecau se th a t stim u lu s g o e s u p y o u r a r m -- o r if it's th e p erin e al nerv e, it goes u p y o u r leg th ro u g h the spinal c o lu m n a n d in to y o u r b ra in . A n d it tu rn s o u t th a t if y o u lo o k at th e p erin eal nerve, w hich is the nerve o f th e fo o l, a n d y o u ch eck th e c o n d u c tio n o f th a t n e rv e a s it p asses th ro u g h th e cerv ical sp in e a re a , th a t th e a b n o rm a litie s a r e m u c h m o re sig n ific a n tly pronounced. This m eans that when you d o -- when you are attem pting to diagnose peripheral neuropathy on a toxic o r a toxin basis, w hich sh o u ld o r m ay well be very, very im p o rta n t to lo o k at not on ly th e upper extrem ity, but also the low er extrem ity, particularly the perineal nerve. But m ore im portantly, n o t o n ly th e p e rin e a l n erv e a s i: g o e s fro m th e foot to th e sp in a l c o r d , b u t up' th e s p in a l c o rd a n d in to the brain. Because the cervical spine area seems to be the area th a t's m u ch m ore sensitive to electrical p ic k u p . W e arc a b le to pick up th e ab n o rm alities m uch m o re sensibly in th e cervfcal sp in e area. N ow w h at they d id in this stu d y , w hich is very in te re stin g , th e y e x p o se d th e m o n k e y fro m 'd a y l ' , 6483 41 one 10 his su b stan ce w hich causes p erip h e ral n e u io p a th x . T h ey hen m easu red the electrical c o n d u c tio n a n d th e tr a n m is s io n o f this e le c tric a l s tim u lu s in th is n e rv e 12 d a y s a f te r a c rv lo m id e a d m inistration and 20 days after acrvlom ide ad m in istratio n . A nd as you can see, they saw tw o in teresting p h en o m en o n . T hey saw first o f all that the resp o n se w as d am p en ed . So that the nerve w asn 't able to co n d u ct the stim u lu s as w ell. A nd they also fo u n d th at th e re w as a o n e m illisecond d elay as tim e w ent on in c o n d u c tin g th a t im pulse, an a b n o rm a lity ; a w av o f p ro v in g that this in dividual has a peripheral neuropathy. They then did som ething that w as even m ore fascin atin g . T hey looked at the peripheral nerves. A nd they looked at the spinal c o rd . A nd they fo u n d th at the p articu lar area o f the spinal c o rd w here th e nerve fro m th e leg te rm in a te s h ad m u ch m o re sig n ific a n t n eu ro lo g ical d a m a g e ; d em yelination, loss o f fat. T hen the area w here th e m edian nerve term in ates. N ow , the perineal n e rv e te rm in a te s in a n a re a called the g racilis n u c le u s, w h ich is in d ic a te d right h e re . T he m e d ia n n e rv e te rm in a te s in th e c u n e a te n u c le u s, w hich is in d ic a te d h e re . A n d w h a t they fo u n d w as a la rg e a m o u n t o f Joss o f f a t , d e m y e lin a tio n in th e g ra c ilis n u c le u s . N o w , w h y is th a t? W ell, t h a t 's so m e th in g th a t is o p e n to d isc u ssio n . B ut it a p p e a rs as th o u g h th e s tr u c tu re o f th e g ra c iliu s n u c le u s is m uch m o re d iffe re n t th a n th e o th e r nu cleu s. W h a t d o e s th a t h av e to d o w ith th e V ietn am veterans? W ell, if in d e e d th is is tru e in h u m a n s , a n d o n c e a g a in , n o t o n ly d o we h av e a specialized te st f o r p ro v in g p e r ip h e r a l n e u r o p a t h y , b u t it h a s to b e d o n e in a s p e c ia liz e d w a y , a n d it h a s to b e lo o k e d at in a p a rtic u la r a r e a . W ith th a t in m in d , w ith th e a id o f C h e s tn u t H ill H o sp ita l in Philadelphia, we h ave n o w been lo o k in g at so m a to se n so ry e v o k ed p o te n tia ls in v eteran s. A n d I h o p e to have so m e very in terestin g fin d in g s a b o u t this in th e fu tu re a b o u t w hether this tech n iq u e will be effectiv e in lo o k in g a t h u m a n s. O n e in terestin g p a tie n t th a t we h av e had in p ractice th a t h o p e f u ll y w ill b e r e p o r te d s o o n , is a g e n tle m a n th a t s e rv e d in th e 111 C o r p s a r e a in S a ig o n f o r tw o years as a m edic. T his g e n tle m a n , sh o rtly a fte r his service in V ie tn a m , c o n tra c te d w hat w as listed as G uillain-B arre syndrom e. H e recovered from th a t, and eight years th ereafter, began developing n u m b n e ss in his h a n d s a n d In his feet. A n d has n o w p ro g re sse d to th e p o in t w here n o t on ly d o es he have sensory ab n o rm alities, but he has m uscular ab n o rm a lities as w ell, and he has a severe peripheral neuropathy. This gentlem an also has elevations o f c o p ro p o rp h y rin , u ro p o rp h y rin , an d interm ediate p o rp h y rin . A n d f o r tu n a te ly a n d th a n k fu lly , th e re is n o h is to ry o f d ru g a b u s e , th e re is n o h isto ry o f n e u ro lo g ic a l d ise a se in th e fa m ily , th e re is n o h is to ry o f a lc o h o l a b u s e . S o th e q u e s tio n is-w h at is cau sin g this m ixed neurological d istu rb an ce. Is it m u ltip le sc le ro sis th a t m a n y o f th e v e te ra n s a r e d ia g n o s e d a s h a v in g ? W e ll, w e d id a s p in a l ta p . A n d th e s p in a l ta p d id show* a n o lig o c h lo n a l b a n d th a t w e s o m e tim e s see w ith m u ltip le sclerosis. But his nerve biopsy d id not show w hat we see in m u ltip le sclerosis. A nd I w ant to p re sent the findings o f the nerve biopsy because they w ere very, very in terestin g . First o f all, w hen you ta k e a n erv e b io p s y , y o u d o n 't ju s t lo p o u t a n y s e g m e n t o f n e rv e a n d sen d it d o w n to th e D a th o lo g is t a n d s a y h e r e , (ell m e w h a t 's w ro n g w ith th is n e r v e . Y o u h a v e t o ta k e a c e r t a in le n g th o f h e n e u r o n o f th e n e rv e tis s u e th a t y o u w a n t. A n d i t 's u s u a lly s u g g e s te d th a t y o u t a k e th e s u r a l n e r v e , w h ic h is th e n e rv e m th e lo w e r e x tre m ity , th e le g . > I n te r e s tin g ly e n o u g h , it se e m s to be th e n e r v e o f c h o i c e b e c a u s e i f y o u lo o k at to x ic ex- , 6484 42 y p o s u re , p a r ti c u la r ly w ith S c h a u m b e r g 's d a ta , y o u m a y th in k a n d y o u m a y s u sp e c t th a t th e lo w e r extrem ities are affected before the up p er extrem ities. So certainly if a low er extrem ity nerve seem s to be th e n e rv e th a t y o u w a n t to lo o k a t , i t 's v e ry im p o r ta n t to p re s e rv e th a t n e rv e in p a r a f f in to g et a good long lo n g itu d in a l sectio n , as well as a cro ss-sectio n . T h e lo n g itu d in a l section should be stained properly so that you actually dem onstrate the areas o f nerve dam age and determ ine the type o f d am ag e th a t this individual has. M ost im p o rta n tly o f a ll, in a d d itio n to d o in g this sta n d a rd test, one m ust also exam ine nerve tissue w ith th e electro n m iscroscope. A nd th at w as alluded to by D r. C arn o w w hen he talks a b o u t lo o k in g at liver tissue in V ietnam v eteran s. A n d he talked ab o u t th e th ick en in g o f th e e n d o p lasm ic reticu lu m . B ecause it seem s as th o u g h to m a k e this d ia g n o sis, the toxin induced n eu ro p ath y , the electron m icroscope has to be used to actually d em o n strate it. T h is is th e s ta n d a r d se c tio n o f th e n e rv e tissu e. A n d o b v io u s ly , to m o st in d iv id u a ls, m a y b e all in d iv id u a ls , even m y s e lf, it lo o k s like a cro ss-se c tio n m a y b e o f a s a la m i. But th e se a re a c tu a lly b u n d les o f n erv e tissu e s. A n d th e re is a c tu a lly a set ra tio o f (he m y e lin e fibers to th e u n m y e lin a te d fib e rs. A n d th a t r a tio o f m y elin to u n m y e lin s h o u ld b e o n e to th re e . S o th e re is a set ra tio in n a tu re (hat we see. N ow w hen we looked at this individual, we found that this individual has a dram atic in crease in (h e u n m y e lin ated fib ers, th a t th e m yelin sh e a th a ro u n d th e n erve h ad been eaten u p an d d e stro y e d . N o w , w h a t we see in (he e le c tro n m ic ro s c o p e , is a n e rv e w h ich lo o k s like so m e fettu c- cini o r thin strip o f sp ag h etti. But if you look at th at strip o f sp ag h etti u n d er the m icroscope, you actu ally see th a t th e re are a lot o f nerve bundles in th e re . A n d we see som e very interesting and u n ex p lain ed p h e n o m e n o n in th a t n erv e. First o f a il, w e see th a t th e re a re a lot o f fib ers th at have lost their m yelin. A n d stran g ely and peculiarly e n o u g h , we see a lot o f d a rk g ran u le s in the cen ter area, the m edulla o f th e nerve. W e are n o t sure w hat these granules are. If you read th e literatu re on peripheral n eu ro p ath y , they describe d a rk g ran u les in this a re a , an d th ey talk ab o u t deposition and d eterio ratin g m yelin, d eterio ratin g fat tissue. W e ju st did not know w hat this p articu lar a b n o r m a lity c o n s t i t u t e d . B u t it c e r ta in ly is a p e c u lia r o n e in d e e d . A n d i t 's o n e th a t I th in k m e rits f u r th e r investigation. B ut nonetheless, if an individual has a p erip h eral n e u ro p ath y , an d you w ant to determ ine (he cause o f the peripheral neu ro p ath y , a special so m ato sen so ry evoked potential study is critica l in m a k in g th a t d ia g n o sis. A n d if th e re is c e rta in ly an y q u e stio n as to th e cause, o f th e p e rip h e ra l n e u ro p a th y , nerve biopsy certainly w ould give you an im p o rtan t in d icato r as to the cau se. W e talked ab o u t d ap so n e. W e said that d ap so n e can cause peripheral n europathy. 1 w ant to clarify th a t. I had an o p p o rtu n ity to review the lite ra tu re on d ap so n e because I got a letter from the D ow C hem ical C o m p an y sug gesting that d a p so n e w as the cause o f peripheral n e u ro p ath y . A nd I had an o p p o rtu n ity to call the co m p a n y and th e in d iv id u al w ho p ro d u ced d ap so n e. A n d th ey g racio u sly sent, m e all th e literatu re o n th e s u b s t a n c e . I t 's b e e n u s e d o n e le v e n m illio n le p e rs t h r o u g h o u t th e w o r ld to tr e a t le p ro s y . I t's u s e d in d o s e s e ig h t tim e s m o r e p o te n t th a n th e V ie tn a m v e te r a n s r e c e iv e d . A n d i t 's u s e d q u it e o f te n intravenously to treat leprosy. L O f the eleven m illion lepers, there have been eight rep o rted cases o f peripheral nerve d a m a g e s e c o n d a ry to d a p s o n e . S o I th in k it m ig h t b e a little b it p r e s u m p tu o u s to a ssu m e th a t a n y o n e w h o h a s p e rip h e ra l n e u r o p a th y h a s it o n th e b a sis o f d a p s o n e . B ut c e rta in ly , it's a n a g e n t [ th a t w as u sed. It w as sto p p e d in 1968 w hen there w ere eight re p o rte d d e a th s d u e to a g ra o u lc y td sis. w h ic h w a s a w ip e o u t o f frhe w h ite b lo o d c ells o f (h e v e te r a n s f h a t w e re g iv e n d a p s o n e , c h l o r a q u i p e . and quinine as a p ro p h y lac u c for m alaria. They no longer use iliat co m b in atio n . A nd ihev w eren 't really certain as to w hat agent caused th at. M aybe all three acting together m ight have cau sed it. B ut it d o e s n 't se e m a s th o u g h b> th e lite ra tu re th a t w e c a n e x p la in o r b la m e d a p s o n e fo r th e se p a r I,- tic u la r p h e n o m e n o n th a t w e are se e in g . T h e re is m u c h -- a lot h as been w r itte n re c e n tly o f m e lio id o sis, th e tim e b o m b o f m elio id o sis that is a c o n d itio n cau sed by p s e u d o m o n a p se u d o m a lic , a bacteria that w as p resen t in V ietnam . I, A n d o n c e a g a in , th e r e h a v e b e e n very few r e p o r te d c a se s o f m e lio id o sis sin c e th e w a r h a s e n d e d . T h e la st c o u n t-- th e re w ere 16 re p o rte d cases at th e c e n te r fo r d isease c o n tro l. T h e re a rc tw o la rg e s tu d ie s o f r e t u r n i n g V ie tn a m v e te ra n s in *67 a n d *68 d o n e b y th e A ir F o rc e w h e re th e y t, lo o k e d at 1750 re tu rn in g v e te ra n s, a n d did b lo o d tests fo r ex p o su re to this b a c te ria . A n d (hey found that 25 percent o f those returning veterans had elevated blood tests. But just because you have an elevated b lo o d test th at says you are exposed to th is, that d o e sn 't m ean you h ave th e i, d is e a s e , a n d it d o e s n 't m e a n th a t y o u a re going to d e v e lo p th e d ise a se . It ju st m e a n s th a t y o u w e re e x p o s e d . S o it d o e s n 't se e m a s th o u g h th e v e te ra n s a r e s u f f e r in g fro m m e lio id o s is . A n d it 's a n im p o rta n t point to k eep in m in d , how ever, because the disease can rem ain d o rm a n t fo r several y ears, I, a n d c a n r e a c tiv a te its e lf . A n d w h en it re a c tiv a te s , it p re s e n ts a s a b s c e s s e s in th e lu n g s , a b sc e sse s in th e p ro s ta te g la n d s , a n d ab scesses u n d e r the s k in . N o w , it's v ery im p o rta n t to u n d e rs ta n d th a t w h e n y o u h a v e m e lio id o s is , it is a v ery severe d is e a s e . Y o u d o n 't w alk a r o u n d w ith a c o u g h e v e ry i, su m m e r a n d see y o u r fa m ily d o c to r a n d he gives y o u an a n tib io tic a n d it goes a w a y . Y ou a re very severely ill. A n d if not d iag n o ses pro p erly , you go on to die in a reactiv atio n o f this d isease. So i, d o n 't th in k th a t if y o u h a v e a c o u g h e v e ry w in te r th a t y o u h a v e m e lio id o s is a n d i t 's b e e n g o in g o n u n d ia g n o se d fo r y e a rs. T h is is a very severe d e b ilita tin g illness asso ciated w ith v ery high fev ers. A nd the individuals are extrem ely sick. A nd fo rtunately, we have pow erful an tibiotics now that can cure this co n d itio n . B ut if a n y o f y o u a re p h y sician s in th e au d ie n c e o r p a tie n ts, to h av e V ietn am v e te ra n s p re se n t th e m s e lv e s a t th e h o s p ita l a n d h av e a b scesses c e rta in ly it w o u ld be v e ry im p o r ta n t to get m e lio id o sis lite rs. A n d it is very easily d o n e by sen d in g th em d o w n to th e C e n te r fo r D isease C o n tro l in A tla n ta . T h is is th e d a ta th a t w e p resen ted last y ear. W e h av e now g o n e ov er 550 V ietn am v e te ra n s. A n d a g a in , th e d a ta is p re se n te d not to suggest th a t th ese sy m p to m s p ro v e th a t th e se fellow s all >1 have A gent O ran g e e x p o su re, an d all the sym ptom s are related to the herbicides, b u t ra th e r to give you an idea o(w h a t th e fellow s are com plaining a b o u t. T hey all seem to be co m p lain in g ab o u t the sam e th in g s. P e rso n a lity ch an g es in 86 percent o f 300, fatig u e in 78 p ercen t. L oss o f c o n c e n tra tio n in 74 p e rc e n t. N u m b n e ss in 68 p erce n t. P h o to p h o b ia , w hich is a n in te re stin g a n d p erp le x in g p h e n o m e n o n . W e 've h a d a n o p p o r tu n ity to lo o k at se v e ra l v e te ra n s . O u r s u rv e y is n o w u p to 30 th at have this p h o to p h o b ia . A n d we have been unable to d e m o n strate w hy they have it. W e have been do in g visual evoked response tests. W e have been doing tests for the retin a. A n d right n o w , it still re m a in s an en ig m a as to w hy th e v e te ra n s h av e to w ear su n g la sse s w h en they g o o u t in th e li g h t. T h a t d o e s n 't m e a n th a t i t 's n o t o c c u r r i n g . It ju s t m e a n s th a t o u r level o f s c ie n tific s o p h is tic a tio n ju s t h a s n 't e x p la in e d it. D r. M a lc o lm B a rr in A u s tra lia c la im s th a t th e v isu al l e v o k e d re s p o n s e s in h is v e te ra n s a re a b n o rm a l, a n d th a t in d ic a te s rh a t th e re is re tin a l d a .m a g e .-B u i we h a v e n 't been a b le tc rp ro d u c e that in the U nited S ta te s. - ' T h e b ir th r a t e d e f e c t is 18 p e r c e n t, b u t i t 's a s k e w e d p o p u la tio n a n d c a n 't b e u s e d rig h t n o w to i prove anything one way or the other. T he interesting abnorm alities are (he clinical ab n o rm alities: 70 percent o f evidence o f p e rip h e ra l n e u r o p a th y . A n d I c a n 't e m p h a siz e to o s tro n g ly lo r th e p h y sic ia n s in th e au d ien ce th a t w h en a g e n tle m a n c o m e s to y o u c o m p la in in g o f e f f e c ts th a t he m a y feel a r c h e rb ic id e re la te d , i t 's very im p o rta n t in a d d itio n to ob v io u sly tak in g a very c a re fu l h isto ry , th a t a very careful physical exam m ust be d o n e, particularly w ith reference to the p erip h eral nerves. Test the individual for pinpricking, for cold an d tem p eratu re sensation, an d m ost im p o rta n tly , test th a t individual fo r vibratory sensation. In m ost o f the individuals that we have seen, they have an im pairm ent to vibration. This d o e s n 't m e a n th a t th e y c a n n o t feel a n y v irb ra to ry s tim u lu s . It m e a n s th a t th e ir v ib ra tio n sen se is im p a ire d . V ib ra to ry s e n s a tio n is te sted w ith a I2 5 E tu n in g f o rk . T h e in d iv id u a l is given th e tu n in g fo rk . D u ra tio n o f v ib a to ry sen satio n is m e asu re d . A 20-y e a r-o ld in d iv id u a l feels th a t tuning fo rk f o r f iv e 's e c o n d s a n d y o u as a 3 4 -y e a r-o ld c a n feel it f o r 25 s e c o n d s , th e re is s o m e e x p la n a tio n fo r that a b n o rm a lity . A n d that m ay be o n e o f the o nly clues th at the individual has to peripheral n e u r o p a th y . P o r p h y r in a b n o rm a litie s in 60 p e rc e n t. A n d a g a in , it is a s ta tis tic th a t is in te re stin g in th a t it h a s b e e n r e p o r te d b e fo re , b u t o n e th a t n e e d s m o re a n a ly s is . P o rp h y rin s are very interesting because as you know , they are building blocks to r h em o g lo b in th a t ca rrie s oxygen in th e red b lo o d cell. A n d th e fu n th in g a b o u t collecting p o rp h y rin s is th a t th ey a re passed o u t in the urine. So all y o u h av e to d o is get y o u r p a tie n t to collect his u rin e fo r 24 h o u rs . A n d if y o u get the lab to a n a ly z e th a t, y o u a re in b u sin ess. I f y o u m a k e a m is ta k e , if th e test is in v a lid , y o u can alw ays go b ack an d get so m e m o re u rin e at no co st to th e p a tie n t. O n e o f th e big p ro b lem s in getting p o r p h y rin s a n a ly z e d th e U n ite d S ta te s is th a t th e w o rld a u th o r ity f o r p o rp h y rin a n a ly sis is in M in n eso ta. A nd they have published an extensive b attery o f papers w ith w orld renow ned acclaim on porphyrin analysis. A nd fortunately, I was able to gel m y porp h y rin s at the N orthw estern H ospital. A nd there are som e people here from M in n eso ta . T o get these tests d o n e w ould be very m u c h a p p r e c ia te d b e c a u s e i f y o u re v ie w th e li t e r a t u r e , a n d D r. J o h a n S t r i k 's a n a ly s is o f p o r p h y r in is v ery im p o r ta n t in a s s o c ia tin g th is e x p o s u re to T C D D o r d io x in . If y o u lo o k a t all th e c h e m ic a ls th a t w ere s p ra y e d in V ie tn a m , th e re is o n ly o n e ch em ical that causes these sym ptom s, and that was dioxin. A rsenic caused p o rp h y rin problem s, but (hose s u b s e q u e n tly gfo a w a y . O n ly d io x in c a u s e s p e r m a n e n t p o r p h y r i n d a m a g e . S o if y o u h a v e a n in dividual that has porphyrin ab norm alities, you then m ust find ou t w hat o th er substances (hat in div id u al m ay h av e been exposed to in th e U nited S tates lh a y m ay have caused p o rp h y rin problem s. T h is is very , v ery im p o r ta n t. F in ally , th e P en n sy lv an ia M edical S ociety in c o n ju n c tio n w ith th e P en n sy lv an ia A gent O ra n g e C o m m is s io n is n o w p u ttin g o u t a text a n d I h a v e b een p riv ile d g e d to d o a lot o f th e w r itin g . I t 's g o in g to g o o u t to a ll p h y s ic ia n s in th e s t a t e o f P e n n s y lv a n i a . A n d w h a t th is (ext will in c lu d e (w h e n it fin a lly c o m e s o u t) is a rev ie w o f th e lite r a t u r e a s w e lh a s s u g g e s te d te x ts lo r d ia g n o sis. I m a y sug g est th a t in lo o k in g in to this p a rtic u la r p ro b le m , it's c e rta in ly very im p o rta n t to lo o k at all a s p e c ts o f liv er f u n c tio n s . Y ou a ls o g et th e G T T P . A ll o f th is i v e ry im p o r ta n t? In f a c t, th e G T T P is p o ssrt)ly th e m o st se n sitiv e in d ic a to r o f ^ d e r a n g e m e n t. next to th e u rin e p o r p h y r in . A n d i t 's v e ry im p o rta n t to u n d e rs ta n d th e im p o r ta n c e o l th is . y -is W h en y o u c o lle c t o u r p o r p h y r in , it has to b e in a c o n ta in e r t h a t 's p r o te c te d fro m th e lig h t. If it's not. then the p o rp h y rin s are going to be ru in ed . T he porp h y rin s are also very sensitive to te m p e ra tu re . T h e y m u s t be c o lle c te d o n ice a n d t r a n s p o r te d to th e l a b o r a to r y o n ice. S o t h a t 's very, very im p o rta n t. A n d re c e n tly -- n o w , in a d d itio n to th e o th e r b a tte ry o f tests th at in c lu d e C .T . scans o f th e h e a d , chest X -ray (if th e in dividual has p ro b le m s in th at area ) we are now d o in g th e tests to d e m o n s tr a te p e rip h e ra l n e u ro p a th y . T h e p u rp o s e o f th e E E G is to get m o re insight in to explaining why these individuals arc having their problem s. T h is slid e is a m o n g o n e o f th e m o st so b e rin g slides a n d p ro b a b ly o n e o f th e to x ico lo g ists th at had given th e talk p rio r h ad m entioned this p artic u la r p h en o m en o n . U n fo rtu n ate ly , the A gent O ran g e sto ry did n o t begin a n d end in V ietnam because acco rd in g to the U .S . D epartm ent o f A g r ic u ltu r e fig u re s th a t w e h a v e listed h e re , 5 0 p e rc e n t o f all 2 4 5 T th a t w as p r o d u c e d b e tw e e n 1961 a n d 1969 was sp ra y e d rig h t h ere in th e U nited S ta te s. O n ly 33 p ercen t w as sp ray ed in V ietn am . So th a t m eans that m o re 2 4 5 T w as d u m p e d here than w as in V ietn am . S o it w as a p r o b le m th a t w as n o t o n ly p e c u lia r to th e V ie tn a m v e te r a n s , b u t u n f o r t u n a t e ly , i t 's a p r o b le m th a t w e a r e g o in g to h a v e to c o m e to g rip s w ith a s tim e p a s s e s . I t 's v e ry , v e ry im p o r ta n t not o n ly to h e lp th e v e te ra n s th a t sto o d u p a n d fo u g h t fo r th e c o u n try , b u t i t 's g o in g to be very im p o rtan t fo r fu tu re g e n e ra tio n s th a t we d o all w e can to lick this p ro b lem an d try to keep an open m ind as we possibly can , and at the sam e tim e trying to m aintain o u r objective. T hank you very m uch for your attention. (A pplause.) M R . O 'C O N N E L L : J u s t as P h ila d e lp h ia h a s D r. C o d a r i o , C h ic a g o h a s D r. O r r is . O u r n e x t g u est is n o s tr a n g e r to th e Illin o is A g en t O ra n g e C o m m is s io n . H e a p p e a re d a t o u r h e a rin g at O 'H a re last y ear a lso . D r. P e te r O rris is c u rre n tly a m e m b e r o f th e s ta f f o f C o o k C o u n ty H o sp ita l, D ivision o f O c c u p a tio n a l M ed icin e, as well as being a sso ciated in a p riv a te m edicial p ractice. D r. O rris h o ld s a m a sters in public health fro m Y ale U niversity, an d a m edical degree fro m th e C h ic a g o M e d ic a l S c h o o l. A t C o o k C o u n ty H o s p ita l, D r. O rris is a s u p e rv is o r o f h o u se s ta f f in th e in te rn a l a n d o c c u p a tio n a l m e d icin e d e p a rtm e n ts . H e is a clin ical a ssista n t p ro fe s s o r at N o rth w e s te rn U n iv e rs ity S c h o o l o f M ed icin e a n d is a lso in v o lv ed in o c c u p a tio n a l a n d epidem iological research. I 'd lik e to p re s e n t D r. P e te r O rris . j, (A pplause.) D R . O k R IS : T h a n k y o u v e ry m u c h . I 'm g o in g to s p e a k fo r a few m in u te s to d a y to p o in t o u t a n u m b e r o f d e v e lo p m e n ts in th e lite ra tu re . S in ce y o u r p rev io u s h earin g s th a t I th in k b ear s o m e e m p h a sis. I w ill th e n sp e c ific a lly d iscu ss h o w a c lin ic ia n m ig h t e v a lu a te a .p a tie n t w h o is c o n cern e d a b o u t d io x in in to x ic a tio n , e ith e r d o m estically o r in V ietn am . T h is a p p ro a c h will a tte m p t to balance the need for indep th evaluation o f patient problem s w ith a concept o f avoiding subjecting a patient to a variety o f invasive testing that m ay show little result. N ow , by w ay o f an u p d ate, there arc (w o articles that I think are quite significant w ithin th e last y ear a n d a h a lf. T h e first article com es fro m P ra g u e . It a p p e a rs ip th e A rch iv es o f E n v ir o n m e n ta l H e a l t h , p u b li s h e d in (h e U n ite d S ta te s , in th e J a n u a r y / F e b r u a r y '81 is s u e ( V o l. 36, N o . I, P -5 -1 1 ). It is e n title d T h e D e v e lo p m e n t a n d P r o g n o s is o f 'C h r o n i c In to x ic a tio n b y *Tet- c h ro c h lo ro d ib e n z o p a ra d T o x in in M en. an d reco u n ts an e x p o su re o f w o rk e rs in a fa c to ry b etw een ^ 6 5 a n d 1968 o f w h ic h 55 w e re re e x a m in e d a f te r 10 y e a r s . ' 6488 46 i T h e sig n ific a n c e o f th e s tu d y is that it gives us so m e feelin g o f th e n a tu ra l h isto ry o f th is intoxication. T hey looked at people initially in the first m o n th , tw o m onths, three m onths afte r ex p o su re . A n d th e n a g a in te n years la te r. A n d w h at is fa s c in a tin g w ith in th is, is th a t th e n e u r o p sychiatric a n d p erip h eral n eu ro p ath ic diso rd ers m ost o f w hich show ed up in the first three m o n th s afte r ex p o su re, w ere in fact, m ore prevalent ten years later. T he o th er signs o f intoxication the c h lo ra c n e , th e liver d y s fu n c tio n , w ere b eco m in g less fre q u e n t ten y ears la te r. T h a t 's a v ery in teresting developm ent I think. T h e o th e r article ap p eared recently, 1982, in the A m erican Jo u rn a l o f In d u strial M edicine. (V ol. 3, N o . 2, P . 179-189). It reco u n ts an accid en tal ex p o su re at th e A ir F orce base in G erm any o n N ovem ber 17th, 1953, an d a m o rtality analysis 20 years later. W hen the prop o rtio n ed m ortality rates w ere com pared w ith the Federal R epublic o f G er m any as a w hole, as w ell as w ith those o f the im m ed iate area aro u n d the base, they discovered th a t th o s e p e o p le w ith e x p o s u r e h a d a m o r e d e a th s d u e to g a s tr ic c a n c e r th a n e x p e c te d . T h is is o n ly o n e report* yet it is sig n ifican t in th a t it m ay in d icate s an a sso c ia tio n w ith can c er o f o th e r o rg a n system s o th er than the soft tissue sarcom as and lym phom as that have been previously reported. I w ould com m end b o th o f those papers to you as significant new developm ents in the literatu re. C linicians m ay see p a tie n ts exposed to dioxin in V ietnam o r in th e U nited S tates. In the U n ited S tates a g ro w in g so u rc e o f ex p o su re is d ue to fires in electrical tra n s fo rm e rs. T h ese tra n sfo rm e rs often have oils com posed o f polycholorinated biphenyls and ch lo rin ated benzens. W hen these b u rn ab o v e 600 F d io x in s a n d fu ran s are p ro d u c e d . T h e fu ra n s a re m uch less u n d e rsto o d . Yet they w ould a p p e a r to beh av e very sim ilarly to d io x in s. W e a re c u rre n tly in v estig atin g incidents in M in n eso ta a n d C h ic ag o . T h e re w ere large fires th e re recen tly , as w ell as in S an F ran cisco an d N ew Y o rk . W h at d o es a clin ician d o ? I w ill give you m y a p p ro a c h . B ut l stress th a t th e re are m any d if- : ferent approaches. T h e m o st im p o rta n t th in g in these e v a lu a tio n s is to a ssu m e th a t th e re is re a lity to th e v ic t i m 's c o m p la in t s . A n d u n f o r t u n a t e l y , th e s y m p to m s a r c s o d if f u s e a n d s o c o n f u s in g , a n d o f te n v ery h a r d to d o c u m e n t th a t it o v erw h elm s p h y s ic ia n s , a n d th e ir re s p o n s e is o f te n th a t th is is psychiatric in o rig in . Y ou have all heard th at. T h e s e c o n d im p o r ta n t e m p h a sis -- a n d 1 th in k e q u a lly im p o r ta n t-- is th a t th e se s y m p to m s m ay com e fro m so m eth in g o th e r than a dioxin ex p o su re. T h ere m ust be the aggressive search for o th er causes. D iab etes, ch ro n ic liver disease, et cetera. A f te r ^ x c lu d in g o th e r cau ses, it is im p o rta n t to a tte m p t as m u c h as p o s sib le to d o c u m e n t th e su b jectiv e sy m p to m s. In d e p th w ork I th in k is clearly in d icate d w hen a p a tie n t has specific sy m p to m o lo g y , b u t 1 w ould n o t put a patient th ro u g h a b attery o f tests, w ith o u t the sym pto m o lo g y . A n d th a t is w h en p eo p le co m e in c o m p la in in g o f n u m b n e ss, tin g lin g , d iffic u lty h o ld in g pencils, clu m sin ess o f th e h an d s, a full indepth a n d p erip h eral n e u ro p a th ic stu d ies a re certain ly in d ic a te d . I f th o s e a r c n o t th e p re se n tin g sy m p to m s, it is n o t w o rth w h ile as fa r as l a m c o n c e rn e d to send everbody th ro u g h these tests. F u r th e r , 1 b eliev e it is n o t w o rth w h ile to s e n d p e o p le th ro u g h a v a rie ty o f te sts th a t h av e n o t been p ro v en o r w ell suggested by the literatu re as being asso ciated w ith dio x in in to x icatio n , u n less y o u a re p a rtic ip a tin g in a stu d y . Such th in g s as C .T . sc a n n in g 1 d o n o t feel is in d ic a te d in p atien ts w ith n eu ro p sy ch iatric com plaints or peripheral n eu ro p ath ic com plaints. N o w , a s f a r a s th e h is to r y is c o n c e r n e d , a c lin ic ia n m u s t get a c le a r im p r e s s io n o f rh e ex- 47 I I p o s u re . -lie f r e q u e n c y o f e x p o s u re , th e so u rc e o f e x p o s u r e . F or e x p o s u re s in V ie m a m th is is h a r d I 10 e e l. b u t ii m u s i b e e m p h a s iz e d a n d d o c u m c n ie d a s m u c h a s p o s s ib le . A g o o d in f e r n a l m e d ic in e p h y sic a l e v a lu a tio n is n e e d e d a n d l a b o r a t o r y tc s tin c in c lu d in g urine, an d b lo o d , tests to assess liver, kidney, card iac, g a stro in testin al, n eu ro lo g ic, an d pulm onarv I s y s te m s . M o re in d e p th te s tin g , o n c e a g a in is in d ic a te d o n ly w hen h is to r y a n d p h y s ic a l e x a m in a tio n I m a k e it lik ely to b e h e lp f u l. S p e rm a n a ly sis a n d c h r o m o s o m a l s tu d ie s : T o th is tim e , th a t h as n o t I been d o cu m en ted in th e lite ra tu re that m ale ex p o su re will cause rep ro d u ctiv e p ro b lem s. T o ju stify I th is testin g for m ales a h isto ry o f sp o n ta n e o u s a b o rtio n s in fem ale p a rtn e rs a n d o r co n g en ital ab- [ n o r m a l it ie s in c h i ld r e n s h o u ld e x ist. E x p o s u re o f f e m a le is c le a rly a s s o c ia te d w ith re p r o d u c tiv e I p ro b le m s th o u g h th e m e c h a n is m fo r th is effect is n o t c le a rly d e fin e d a n d th e re f o r e in v e stig a to rs in | this area are prim arily to define if any other ab n o rm ality exists. I U rin ary p o rp h y rin s: D ue to presistant re p o rts o f liver a b n o rm a litie s in the literatu re. I I believe q u an titativ e u ro and corprophvrins should be part o f a basic w ork u p . Fat and blood ( sam ples for T C D D levels: T hese are quite expensive, betw een S530 and S I,000 a sam ple. I think I b lo o d T C D D le v el a r c w ell w o rth w h ile in a n y a c u te in to x ic a tio n a n d t h a t 's a n y b o d y t h a t 's been ex- I p o se d to T C D D in th e last sev eral m o n th s. T C D D m a y be sto re d in th e fa t. B ut th e re is som e con- | tro v e rs v a b o u t th is . T h e r e f o r e fat levels m a y b e h e lp fu l as w ell. It s h o u ld be a d d e d th a t th e re a re I n o t firm ly estab lish ed n o rm a l b ack g ro u n d T C D D levels in the b o d y . T h e re fo re results o f these I tests m ay be h a rd to in te rp re t. T he la b o ra to ry m ust be able to id en tify the 2, 3, 7, 8. | tc ira c h lo ro d ib e n z o p a ra d io x in because th e re are m a n y o th e r less toxic d io x in s. | N o w , w h at a b o u t the V ietnam veteran w ith ex p o su re 11-15 y ears a g o . I w o u ld thin k th at I .s e s tu d ie s a r e a d v a n t a g e o u s i f o n e h ig h ly s u s p e c ts th e d ia g n o s is o f T C D D i n t o x ic a t io n . B ut it | o u st be pointed out th at the results are hard to in terp ret. | B ut 1 m o st c e rta in ly re c o m m e n d g ettin g th a t o n so m e b o d y th a t is h ig h ly su sp e c te d to be I in to x ic a te d , b e ca u se if it co m es b ack as 200 p a rts p er trillio n o r 300 p a rts p e r trillio n in th e fat, th a t I vill s u p p o rt y o u r o v e ra ll clin ical im p ressio n . W e a re c u rre n tly w o rk in g o n a c o n c e p tu a l a p p ro a c h I to the diagnosis o f T C D D intoxication at the D ivision o f O ccu p atio n al M edicine at C o o k C ounty j H o s p i t a l . W e a r e tr y in g to d e f in e e x a c tly w>hat c o n s t e l l a t i o n - o f s y m p to m s a n d s ig n s in d ic a te s I C D D in to x icatio n . A nd as w ith any other o ccu p atio n al or en v iro n m en tal exposures, the d i a g n o s i s is b a s e d o n th e th r e e leg s to o l o f a h is to r y o f e x p o s u r e , a p h y s ic a l e x a m in a t io n th a t is j ro n siste n t w ith th a t h is to ry , a n d la b o ra to ry tests su p p o rtiv e o f it. D ue to d iffic u lty in d efin in g ex- I o s u re s a n d la ck o f a n e s ta b lis h e d s y n d ro m e o f T C D D in to x ic a tio n it is h a r d e r in th is .s itu a tio n to , 'iiake th a t sto o l sra n d u p . W e are using a point a p p ro a c h , that puts to g eth er p o in ts to give relative w eights to j irio u s signs, sy m p to m s, h isto ry , and lab o rato ry tests as based u pon o u r analysis o f th e literatu re L .id c lin ic a l e x p e r i e n c e . A b o v e 15 p o in ts , w e c o n s id e r d e f i n i t e i n t o x i c a t i o n . T e n to f if t e e n , p ro - a b le in to x ic a tio n a n d six to ten p ossible. Below six we a re u n ab le to assess th e re la tio n sh ip , i W ith respect to the history, the m ost im p o rtan t part o f the history, if you can get a 1 .fin ite histo ry o f ex p o su re by a know n quantity o f T C D D . Few er p o in ts are given to a history o f sp o su re to a su b stan ce w ith a definite presence, but unknow n am o u n t to T C D D . A nd then wc L m e dow n to th e b o tto m , a h isto ry o f possible exposure to a su b stan ce w ith T C D D p resen t. As .4 u k n o w , th is la s t c a t e g o r y is w h e re w e at fo r m o st o f th e v e te r a n s .' I f th is is p u t . to g e th e r w rih I u ltip lc signs a n d sv m p td m s, w e feel that you can m ak e a -p ro b ab le or po ssib le d ia g n o sis o f , It l / -IK B490 T C D D inioxication, even ten years later. In the area o f physical fin d in g s: A cne beginning w ith in th ree m o n th s o f exposure a n d no p rio r h isto ry o f a cn e is very im p o rta n t. A cne b eg in n in g w iih in six m o n th s o f e x p o su re an d no p rio r h isto ry also has so m e significant w eight. A cne b eg in n in g w ith in six m o n th s o f exp o su re w iih a p r io r h is to ry o f a c n e w iih in th e last te n years w ith o u t a p r io r h is to ry h as less w e ig h t. T h is is th e a p p ro ach that we take to try to d ifferen tiate acne from ch lo racn e. H e p a titis o c c u rrin g w ith in th r e e m o n th s a f te r e x p o s u r e we th in k is v ery im p o r ta n t. P o r p h y ria c u ta n e a ta rd a o c c u rin g w ith in th re e m o n th s o f e x p o s u re is a lso very im p o rta n t. C h ro n ic h e p ta tic p o rp h y ria , th a t is a d e ra n g e m e n t o f p o rp h y rin m e tab o lism w ithin th re e m o n th s o f e x p o s u re w e th in k is also im p o rta n t. But fro m th e lite r a tu r e , less well a ss o c ia te d . P e rip h e ra l n e u r o p a th y , o n c e ag ain is im p o r ta n t, e s p e c ia lly w ith in th re e m o n th s o f e x posure. T he acute ncuropsychiatric disorder once again right after a significant exposure and p o ssib ly even d e v e lo p in g c h ro n ic a lly is given w eight as w ell. S o ft tissu e s a rc o m a , as ra re a s it is, a n d as d e fin itiv e a s th e a s s o c ia tio n is b e c o m in g to d a y , w e th in k is a ls o q u ite im p o r ta n t. I w o u ld call to y o u r a tte n tio n that in th e lite ra tu re , th e d e v e lo p m e n t o f (he soft tissue s a r c o m a tak es p la ce u su ally betw een 14 a n d 28 y ears a f te r e x p o s u re . S o be very c a u tio u s on in te r p r e tin g n e g a tiv e s tu d ie s a b o u t th e la c k o f th a t c a n c e r w h e n th e re is o n ly a te n -y e a r fo llo w u p o n th e p a tie n ts . W e see a lot o f negative stu d ies in the lite ra tu re to d a y . M ost o f them are eith er based on to o few people or too short a lim e o f observation. T he ly m p h o m as an d the gastric carcinom as are given less w eig h t. * W e believe th a t a carcin o g en in one o rg an system will p ro b a b ly be a carcin o g en o f a n o th e r o rg a n sy stem if it is d eliv e re d to th a t o rg an sy stem a t s u ffic ie n t q u a n itity at th e rig h t tim e . T h e re fo re , we believe the developm ent o f cancer in o th e r o rg an system s m ay also be found d u e to e x p o s u r e o f T C D D . A n d c e r ta in ly , t h a t 's b een fo u n d in a n i m a ls . N o w , w ith respect to the tera to g en ic e ffects, s p o n ta n e o u s a b o rtio n s in fem ales exposed h a v e been clearly d efin ed in an im als. T h e q u estio n o f w h e th e r c o n g e n tia l d efects in o ffsp rin g o f e x p o s e d m a le o r fe m a le w ith o u t o t h e r p r o b a b le e tio lo g y is d u e t o T C D D is a p o in t o f c o n s id e r a b le c o n tro v e rsy . G o in g to the la b o ra to ry tests, once again we p lace a lo t o f valu e on high levels o f T C D D in fat o r b lo o d . T h e nerve co n d u ctio n velocities are im p o rta n t as w ell. If liver enzym es, are elevated w ith in th re e o r f o u r m o n th s th is is g iv e n a lot o f w e ig h t. E le v a te d c h o le s te ro l a n d trig ly c e rid e s a re p erh ap s the m ost sensitive a b n o rm a lity .. E lev ate d u ro p o rp h y rin s in th e u rin e, is also given so m e w e ig h t. A nd fin ally , the increased frequency o f b reak s a n d g ap s in ch ro m o so m al an aly sis, w hich w as n o te d in o n e 'stu d y a fte r th e S eveso accid en t; we th in k sh o u ld be in the h o p p e r h ere, as w ell. T h e re fo re , I bring to you m o re confusion, to d a y . I'm a fra id , because I believe that (his is s u e is n o t w ell d e fin e d as y e t. I b rin g to you a feeling th a t w e a r e c o n tin u in g to s tru g g le w ith th is p r o b le m . B ut I d o n 't h a v e (h e m a g ic k e y , a n d I d o n 't th in k it e x ists y e t. T h a /ik y o u . (A pplause.) M R . O 'C O N N E L L : T h a n k y o u , D r. O r r is . O u r f in a l g u e s t s p e a k e r fo r (h is a f t e r n o o n is D r. G e o rg e A n d e r s o n , w h o is th e d ir e c to r o f th e T e x a s V e te r a n s ' A g e n t O ra n g e A s s is ta n c e P r o g r a m . D r. A n d e rs o n is a g ra d u a te o f H a rv a rd U n iv e rsity w ith a m a s te r 's d eg ree in p u b lic h e a lth . 1- > -IV H e is a lso a g r a u d a i e o f Y a le 's S c h o o l o f M e d ic in e . A f te r s e rv in g fo r 24 y e a rs a s a p h y sic ia n in th e U nited States A ir F o rce, D r. A nderson began a distinguished career w ith the Texas D epartm ent o f H e a lth , w h ere he h a s se rv e d in sev eral c ap a cities, a n d is c u rre n tly th e d e p a rtm e n t c o n s u lta n t fo r occupational m edicine an d toxicology. Please w elcom e from the state o f Texas D r. G eorge A nderson. (A pplause.) D R . A N D E R S O N : I 'm g o in g to ch an g e th e p ro to c o l a little bit h e re . 1 b ro u g h t a h u n d re d a n d tw enty five o f th e se h a n d o u ts. B ut each o f you sh o u ld have o n e o f each because I'm going to sp eak from them a n d th e n explain them to you as we g o alo n g . 1 w ant to give you a bit o f a ru n d o w n o n o u r p ro g ra m a s it in v o lv es th e legislature in th e s ta te o f T ex a s, back in th e sp rin g o f 1981. O u r v e te ra n s b e c a m e q u i t e c o n c e r n e d b e g in n in g in th e la te IQ's a s th e s itu a tio n b e c a m e k n o w n . S o o u r le g isla tu re in '81 p a s s e d in to a law a p ro g ram w h ich th ey g av e to th e T ex as D e p a rtm e n t o f H ealth as the ad m in istrativ e agency to develop a co o rd in ated program w ith the U niversity o f T exas system s, w h ic h .c o n ta in e d five m edical centers, to look at the problem an d to see w hat should be done. T h e law- h a s b e e n a m e n d e d . T h e last le g is la tu re in th e s p r in g a d d e d a n a d v is o r y c o m m itte e to the p ro g ram an d ex p an d ed the types o f studies w hich the U niversity o f Texas H ealth Science C enters are atte m p tin g to carry o u t. O u r legislature m eets only once every tw o years for a sh o rt p e rio d , arid th en th ey give us o u r m oney for a biennium . So w e live in a p o litical-free en v iro n m en t f o r p e rio d s o f a lm o s t tw o y e a rs a t a tim e , w hich m a k e s it n ice g e ttin g th e jo b d o n e . T hey gave us a h a lf a m illion dollars for the first b iennium , w hich we spent m ost of. A nd th e y gave us S588,000 fo r the second biennium to carry out th e p ro g ram fo r a n o th e r tw o years. So w e are now in o u r th ird year o f the program . T he first year o f th e p ro g ram w as a w in d u p , to get sta rte d , lo cate the v eteran s, th e o u treach , develop th e p ro to co ls by the university system , an d get th e ad m in istrativ e b a c k u p set u p , w hich brings m e to a sta te m e n t. E verybody needs som ething to c a rry h o m e w ith th e m . K n o w y o u r stren g th s an d w eak n esses, b o th in y o u r p ro g ra m a n d in y o u r . reso u rces. S tudy a n d d ev elo p y o u r program and keep the tenets o f epidem iology in m in d . I am basically an o ccu p atio n al physician. H ow ever, 1 function m ore as an epidem iologist th an anything else because w hen you d eal w ith this type o f thing, you are dealing w ith people and problem s. T he tenets th a t w e developed w ere first-- the n a tu re an d the extent o f the exposure m ust be d o cu m en ted . W e w ent to th e literatu re and we know th a t A gent O range w as used in V ietnam . Y o u h av e to ju s t get th a t b asic in y o u r thinking in th e b eg in n in g . S econdly, the ex p o sed p o p u la tio n m u st be precisely d e fin e d . T h ird , the disease and d y sfu n ctio n in th e exposed p o p u la tio n m ust be d ia g n o se d as well as po ssib le. A nd the relatio n sh ip betw een ex p o su re an d d isease m ust be e v a lu a te d w ith rig o ro u s sta tistic a l m ethodology in w hich a p a tie n t gives a resp o n se re la tio n sh ip , a n d t h a t 's a to u g h o n e . I d o n 't k n o w i f w e will e v e r g e t t h e r e . B u t w h a t y o u h a v e b e e n lis te n in g to t o d a y is th e ty p e o f b a c k g r o u n d th a t w e h a v e lo o k e d a t , o r w e a r e lo o k in g f o r. I t 's w h a t th o s e o f u s fa c e w ho are in th e m id d le o f th e problem dealing w ith the v eteran on a daily basis w ith his p ro b le m s in th e e v a lu a tio n p ro cess. A ll th a t y o u h a v e h e a rd to d a y fits. W e d o n 't w an t to lose an y o f this. T h e research p ra c tic a lity o f the physical ex am in atio n , we can argue back an d fo rth .fo r the g o o d , the b a d , the. so f o r th . B ut we h a v e to r m em b er o u r goal is all th e s a m e . W c a re a fte r th e facts. W e a re a f te r th e tru th . N ow , I w ould direct your atten tio n to the pilot studies. These were developed about tw o and a h alf years ago at the U niversity o f T exas and w ere approved by their independent research councils. They w ere not developed by the T exas D epartm ent o f H ealth. They w ere developed by the scientific staffs o f the U niversity. A t that tim e they had review ed the literatu re and decided th at they w ould co m e u p w ith six p ro to c o ls. 1 will tell you as we go along w hat has h a p p e n e d to each o f these protocols. F irst, o f c o u rs e , is th e m o rta lity s tu d y . In (h e D e p a rtm e n t o f H e a lth , w e have th e v ita l statistic tapes for th e state. T he death certificates are filed. W e had a m arker on our death c e r tificates. W e ran th e tapes th ro u g h the co m p u ter an d we can identify V ietnam veterans only up through 1979, b ecau se at th a t point in tim e, th e d e a th certific ate identifiers w ere changed. A n d sin ce th a t tim e , th e f r o n t o f o u r c e r tif ic a te o n ly sa y s w h e th e r th e y w e re o r w e re n o t a v e te r a n . It m u st be tu r n e d o v e r a n d th e n i t 's u p to th e c o r o n e r o r th e p h y s ic ia n to fill o u t a s to a v e te ra n o f w h a t; W o rld W a r 11, K o r e a , w h a te v e r it is. A n d in m a n y c a s e s , i t 's n o t filled in a t a ll. S o we fin d a co m b in atio n o f lack o f d a ta a n d in so m e cases m isin fo rm a tio n . F or in stan ce, m any o f the veterans w hen they died; we noticed (hat they w ere 60 years o ld . W e s a y , w ell, h e is p r o b a b l y W o rld W a r II. T h e n a g a i n , h e c o u ld h a v e b e e n K o r e a . H e 's p r o b a b ly not V ietnam , but he could be. W e h ad m a n y w ho h a d been in all th ree o r in tw o . A n d -- say back in 1975, they w ould o n ly list W o rld W a r II. B ut th e n w h en w e g o th r o u g h , w e a c tu a lly fin d o u t th a t he w a s in V ie tn a m ; he was a career m a n . S o th e statistics fell th ro u g h . W e finally realized th at we co u ld not get a go o d identifier. T hen th o se th at we did identify, we b ro k e out the cause o f d eath. A nd w hat did we find? W e found th a t they w ere d y in g fro m exactly th e sam e th in g s th a t their age g ro u p at that point in tim e was dying fro m . T h e first thing th a t the V ietnam v eteran d id w hen he got back from V ietnam w as g o o u t a n d get h im se lf a h ig h -p o w e re d s p o rts c a r, fill it u p w ith g aso lin e, gel o u t on In te rsta te 10, a n d he w o u ld b e k illed ju s t lik e a n y b o d y else in h is ag e g ro u p . So we lo o k ed at o u r hom icides and o u r suicides an d we found that we could not find a significant d iffe re n c e in lo o k in g at the n o rm al c a u se o f d e a th in th at age g ro u p . So w e d ro p p e d o u r m orality stu d y h o p in g th a t th e Feds in th eir m o rta lity stu d y w o u ld be able to pick u p w here we left o ff and do a m uch b e tte r jo b w ith it. T h e s e c o n d s tu d y e v a lu a te d b irth d e fe c ts in o f f s p r in g . T h is is a s tu d y th a t is at S o u th w e st M edical S ch o o l in D a lla s. D r. F rie d m a n is h e a d in g th a t o n e . W e h a d an o n g o in g b irth defect p r o gram in the Sjtate o f T ex as in w hich all ch ild ren w ith b irth d efects in the S ta te o f T exas a re re g is te re d . S o i t 's a r e tr o s p e c tiv e s tu d y in w h ic h D r . F r ie d m a n c a n g o b a c k a n d c h e c k w ith th e fa th e r a n d ch eck o u t w h e th e r o r n o t he is a V ie tn a m v e te ra n . T h is o n e has b een m oving a lo n g rath er slow ly. Ib e lie v e to d a te we have only fo u n d six in w hich we have a positive relatio n sh ip . P sy c h o g c n c tic te s tin g , o f c o u rs e , is lo o k in g fo r c h ro m o s o m e b re a k s . T h e re is a lo t o f c o n je c tu re w h eth er o r n o t (h is is g o in g to sh o w m u c h . B ut o u r p e o p le felt th a t since th e y h ad ex cellen t cap ab ility at th e M .D . A n d e rso n H o sp ital in H o u s to n th a t they w ould go in to th is. A nd to d a te 1 believe 44 o f o u r v eteran s have had th eir ly m p h o cy tes c h a ra cterized . T h e f o u r th s tu d y w as th e e ffe c t o n s p e rm . T h is is b ein g d o n e at th e M e d ic a l B ra n c h in G alveston under D r. L egator. T he sperm sam ples are sent there by federal express. H e cannot do a m otility study because o f (he distance they have to travel an d the tim e involved. H ow ever, they are d o in g a m o rp h o lo g y stu d y . A nd they arc looking fo r bodies. W e have not yet tak en any o l (he II II rep o rts of these stu d ies an d bro k en them out by b reak in g the co d e. W ith every v eteran that eocs into the study, we do have a m atch co n tro l. A nd I w ant to cover th at a little bit later. I T h e im m u n e e v a lu a tio n o f v e te ra n s is a ra th e r c o m p re h e n s iv e im m u n e p ro file . I believe w e a r e d o in g s o m e 15 d if f e r e n t p ro c e d u re s in o u r p r o f ile . T h e fa t tis s u e a n a ly s is w e h a v e v irtu a lly droppped out o f our p ro g ram . We found early that no surgeon w ould go into a belly and take out any fat, particu larly since o u r people w anted 60 g ram s, w ith o u t a very good reason to go in. II A nd we w ere to ld th at if we have a veteran in w hich he has ch ro m o so m e breaks, a co m prom ised im m une system , and a history o f the p ro p er sym ptom s, and he has a very definite ex p o su re , th en th e y m ig h t th in k a b o u t g o in g in an d g e ttin g fa t. O f c o u rs e , th e o th e r q u e stio n is h o w [ , w ould you ever find a co n tro l. N ow , we do have a double-blind study. T he individuals at the U niversity o f Texas w here the sam ples are sent d o not know w ho the veterans are from the co n tro ls. W e had a distance and 1, tim e p ro b le m in T e x a s . T h e y w a n te d th e sa m p le s w ith in 24 h o u r s . A n d 1 c a n tell y o u to get fro m u p in th e P a n h a n d le d o w n to G alv e sto n in 24 h o u rs ev en w ith fe d e ra l ex p ress it's to u g h . But w e d id pul out a contract w ith them and we have to date 44 veterans w ho have been tested. T he laboratory ll re s u lts a r e b a c k o n m y d e s k . I h a v e n o t yet b ro k e n th e c o d e to s e p a r a t e th e m o u t. W e a r e n ot p la n n in g o n d o in g th a t f o r s o m e lim e vet b e c a u se w e d o n 't th in k w e h a v e e n o u g h . W e d o n 't w a n t to co m p ro m ise th e studies at all until we are at a certain p oint in tim e. II W e d r a w - f iv e v ia ls o f b lo o d o n e ac h v e te r a n a n d g et a s p e r m s a m p le . A n d th is , o f c o u rs e , is sent by fe d e ra l ex p ress to th e th ree s e p a ra te la b o ra to rie s ; tw o in H o u s to n a n d o n e in G a lv e sto n . W e d o th re e sp e rm s tu d ie s; th a t m ean s th re e sa m p le s six w eek s a p a r t. A n d th is is ru n n in g in to a lot I t o f m o n e y . I t 's S23 e v e ry tim e w e s h ip a s a m p le . I t 's S15 to g e l th e s a m p le d r a w n . W e u s u a lly bet this d o n e th ro u g h either a local health departm ent o r clinic o r physician, anybody w ho has the capability o f draw ing blood. u Now*, y o u c a n see, I th in k , in th e sh o rt d e s c rip tio n s o f e a c h o f th e p ro to c o ls th a t a re a t ta c h e d . I d id n 't b rin g th e to ta l p ro to c o ls b e c a u se each o n e is a b o u t 25 to 30 p a g e s th ic k . I b rin g y o u r a tte n tio n to I, how- th e v e te r a n s c o m e in to o u r p r o g r a m . H e m u s t b e r e f e r r e d in w ith a m e d ic a l d ia g n o s is . T h e law I w as changed in th e last legislature. A veteran m ay refer him self d irectly in to the p ro g ram now , and th e n w e will fo llo w it u p w ith a m e d ical d ia g n o sis. W e like to h a v e b o th th e v e te r a n 's s y m p to m s as he secs it, his p resen tin g sy m p to m s, and then w hat a d o c to r says. W e also like to h av e an d get the V e te ra n s ' A d m in is tra tio n A g en t O ran g e physical. T o d a te , in T e x a s 4 ,5 0 0 h av e. W e h ave 470 in o u r p ro g ra m s o f a r . A ll b u t I th in k five o r six h a v e h a d th e p h y s ic a l. I 'd lik e to g et th e A g en t O ra n g e p h y sic a l fo r a v ery g o o d re a s o n . It d o c s g iv e m e a d d itio n a l in fo rm a tio n w h e n I review t m edical re c o rd s. N o w , if you w ill look at the listing o f how th ey c o m e in to o u r p ro g ra m . As so o n a s th e v e t e r a n 's r e f e r r e d i n -- w e se n d h im a q u e s ti o n n a ir e w h ic h Is "F iv e-p ag e q u e s t i o n n a i r e , w h ic h I, h e fills o u t a n d s e n d s b a c k to u s . W e re v ie w it, a n d th e n w>e s e n d to h im a u t h o r i z a t i o n f o r m s fo r release o f m edical records. A nd we go back an d get m edical records from th e-- both m ilitary V etera n s A d m in is tra tio n re c o rd s as well as all civ ilian m ed ical re c o rd s th a t he has h a d o v er th e last ten, fifteen, tw enty years. ; II W e th e n re v ie w th e se re c o rd s as th ey c o m e in . A n d t h a t 's w h e re I sp e n d m o st o f m y tim e is going over th em . Last week w hen we got m edical reco rd s in on o n e o f o u r v eteran s, fp u t a ruler i alo n g sid e o f th e m , an d they w ere nine inches th ick , just the m edical records (hat had accufh-l !I l L 52 > m ulaicd on him . N ow , once we have this. we also get his m ilitary p erso n n el reco rd s alo n g w ith his m ilitary reco rd s. 1 review his perso n n el reco rd s to verify w here he w as at in tim e, th e unit he belonged to . A n d w ith this in fo rm a tio n I 've g a th e re d , I can u su ally spot w h ere his unit w as at any point in tim e in V ietn am . S o th a t if he says he was w ith the 9 th In fa n try , 4 th B a tta lio n C o m p a n y D, I know he w as w ith the 25th D ivision up near T ay N ihn in 1967, w hich w as very h elp fu l. A ls o , I h a v e a n a d v a n ta g e th a t m a n y d o n 't h av e as I c a n p ick u p th e p h o n e a n d ask a n y o f these veterans a qu estio n concerning his unit. A n d if he says th at he w as sp ray ed on or that if he w as in a c e rta in a r e a at a c e rta in tim e , a n d th is a n d th a t h a p p e n e d , I sit d o w n a n d ta lk it o v er w ith him . I w ant to get a vivid description o f w hat the airp lan e looked like, how the spraying w ent, the s p e e d it w a s g o in g , th e d ir e c tio n it w as g o in g th a t d a y , b e c a u s e I h a v e th e ta p e s w h ic h I am w o r k ing w ith at the sam e tim e along w ith this to d eterm in e w hether o r not he w as w ithin the spray p a t te rn o r clo se to it. A n d in so m e cases, 1 even c a m e so clo se th a t M r. C h ris tia n , o f co u rse, w ho h e a d s th e A r m y 's T a s k F o rc e o n A g e n t O r a n g e -- c o u l d n 't b e lie v e , b u t o n e o f m y v e te ra n s to o k a p ic tu re o f a C -I2 3 -- actu ally tw o o f them in the p ic tu re , flying d o w n th e ro a d sp ray in g (rucks an d vehicles o n (hat ro a d w ith A m erican s in th e m . 1 w as ab le to give th e m issio n n u m b e r, the d a te , th e direction o f flight o f (hat aircraft, and the unit, the engineering co m p an y he belonged to and took that back to the A rm y and said, " H ow do you like th a t? " (L aughter) D R . A N D E R S O N : So things can be d o n e . W e can get p re tty close. W e can get dow n to w here we m ay be able som e d ay to get an estim ate o f w hat th e d o se w as on som e o f these fellow s. N ow , on th at guy we m ay be able because I think we can w o rk o u t the batch n u m b er o f the A gent O ran g e that was sprayed that day. W e are getting a little bit closer. S o a fte r i h ad gone that far, we keep on getting all th e records we can . A nd then I w ork o u t a n e x p o s u r e in d e x in w h ic h I h a v e n 't p u t in to n u m b e r s . I t 's o n l y h ig h , m e d iu m , o r p r o b a b le , o r p ro b a b ly possible, an d m aybe, o r som ething like th a t. I ta k e all this to the U niversity o f T exas, an d I sit w ith the selection com m ittee o f the researchers w ho a re d o in g the w o rk . A nd I m ean they are the ones that a re really doing the w ork. They are going to p ro d u c e the in fo rm atio n . W e select o u t v eteran s. N ow , we d o n 't select in, w e select o u t. If a v eteran says he cam e b a c k fro m V ietn am a n d h as b een e x p o se d , w e select h im o u t. H e c a n n o t be a c a n d id a te in o u r p r o g r a m f o r s tu d y in g if h e h as b een w o rk in g in a g r ic u ltu r e a n d h e h a s b e e n e x p o s e d to p e s tic id e s , he is se le c te d o u t. W e fin a lly n a rro w it d o w n to th o se th a t we h a v e d e te rm in e d h a v e a h ig h p ro b a b ility o f exposure w ith their unit and tim e w hen they w ere over th ere. A n d he has not since that tim e had an y ex p o su re o r an y th in g that w ould com prom ise the test th a t w e w an t to give him . T hen we look at his signs an d sy m p to m s. If he has a h isto ry o f a c n e o r in so m e cases m ay b e even ch lo ra cn e. in th a t c a s e , it m ig h t m a k e h im a b e tte r c a n d id a te . I f h e h a s p e r ip h e r a l n e u r o p a t h y , it m a k e s h im a g ood c a n d id a te . W c look at all o f signs and sy m p to m s. A nd then we review the A gent O range p h y sic a l. P a rtic u la rly , w e are in te re ste d in la b o ra to ry fin d in g s in s o m e o f his h o s p ita l a d m issio n s. S o m e o f th e m w e g o b a c k 15 o r 20 y e a rs to se e if s o m e b o d y d id j u s t h a p p e n to d o a c h o le s te r o l o n him at th a t tim e. In a few cases, we can find som e o f th e o ld c a re e r ty p es in w hich th ey did h ave so m e p ertin en t la b o ra to ry w ork d o n e during (hat very tim e p e rio d .'w h ic h m a j give u s-aJittlcb if o f a base line to co m p a re him currently w ith that period o f tim e. / O n c e h e h as g o n e th ro u g h this system a n d his b lo o d h a s b e e n d ra w n , a n d his sperm has 5J been a n aly zed a n d so f o r th , w hat h a p p e n s next? In th e m e a n tim e . G e o rg e , th a t's m e. H e is sittin g back at the h e a lth d e p a r tm e n t. H e is co lle c tin g d a ta . I'd lik e y o u to ta k e a lo o k at th e o th e r h a n d o u t . E v e ry m o n th I u p d a te th is, a n d it s h o w s 405 m ales in p ro g ra m s I th in k the o th e r day case n u m b er 4 1 1 cam e across my desk. T his w as as o f A ugust 31st. If y o u ta k e a lo o k at th e le ft-h an d c o lu m n , o n p ag e 2 you will sec th e age d is trib u tio n s . 1 d o n 't th in k a n y o n e in th is r o o m w o u ld d is a g r e e w ith th e fa c t th a t th is is w h a t y o u w o u ld e x p e c t to b e th e a g e d is tr i b u tio n o f V ie tn a m v e te ra n s ; r a n g in g fro m 29 to 6 2 . A n d it h a s th e p r o p e r d is trib u tio n . S o I th in k we a re in line. S o w hat 1 am say in g is o u r b ase line sta tistic s, d a ta th a t w e a rc a c c u m m u la tin g a s w e go a lo n g , is fittin g th e p ro p e r p a tte r s , w h ich is a very im p o rta n t item in an epidem iological type o f study. By sex-- a n d I h ate to have to say this-- but th e girls ju st a re n 't com ing into o u r p ro g ram . W e only have tw o . T h ey are b oth n u rses, and n either o f them has been selected for our study for o th e r re a so n s, b a se d p rim a rily o n th e ir m edical p ro b le m s th e m selv es. T hey ju st d id n 't fit th e p a t te rn . By race, we have the p ro p er d istrib u tio n , w hite, b lack , and hispanic. T his falls w ithin w h at w e w o u ld e x p e c t in th e s ta te o f T e x a s . By s e rv ic e , it a g a in falls in line. N ow , som e people m ay argue that the A rm y an d the M arines perhaps had a heavier ex posure as g ro u n d tro o p s. But we m ust rem em ber to lak e in to consideration the A ir Force R anch H an d ers, and th o se A ir F orce personnel that w orked w ith the C-123 and handled the dru m s o f A g e n t O r a n g e . S o th e d is t r i b u t i o n f r o m a serv ice p o in t o f view' c a n be lo o k e d a t se v e ra l w a y s . It d e p e n d s p r e tt y m u c h w h a t s e rv ic e y o u w<ere in a s to h o w y o u lo o k at it.- W e h a v e in o u r s tu d y th r e e o f th e R an ch H a n d e rs w h o w ere in th e A ir F orce stu d y . I c a n a ssu re you that at least tw o o f them h a v e h e a v y e x p o s u r e . T h e s e c o n d p a g e a s y o u c a n see is b y c o u n t y . T h a t is in th e r e b e c a u s e th e le g islato rs in o u r sta te w a n te d to know ' how m a n y fro m m y c o u n ty , w here l am fro m , a re in the program . So w e p u t th a t in . W c have ten veterans in o u r p ro g ra m w ho a re d eceased . A b o u t h a lf o f th e se-- an d d o n 't q u o te m e ex actly on th at n u m b e r-- h ave d ied sin ce they cam e in to the p ro g ram du rin g the last y ear. M ost o f them , o f course, have died from cancer. O ne was a heart atta c k , but c a n c e r is th e le a d in g c a u s e . W c h ad six rep o rte d in to the program w ho arc not eligible: these are o u t-o f-sta te rs. T he w ay th e law is yvritten, y o u m u st have en tered th e service fro m th e sta te o f T exas o r been a resid en t in the state of^T exas o n the 31st o f M arch , 1981. So a few are not eligible. W e have five w ho arc resid in g in o th e r sta te s a n d th a t gives us a problem if w e w o u ld like to bring them in to o u r studies because o f logistics. T h e nex t o n p a g e 3 is th e d u ty p e rfo rm e d b y th e in d iv id u a l. I d id n 't B reak th is o u t by se r v ice. W e ju st to o k w h a t th e v e te ra n h im se lf s a id , " T h is is w h a t 1 d id w hen I w as o v e r th e r e ," o n th e q u e s tio n n a ir e . Y o u c a n see th a t it h a s fallen in to s e v e ra l g r o u p s . A ir Crew- 2 3 , w h ic h in c lu d e s h elico p ter crew s as well as A ir F orce crew s; also several M arin e p ilots an d o th ers, th irteen w ere a r tille ry m e n . C o m m u n ic a tio n s s p e c ia lis ts , tw elve. I 'm ju s t re a d in g th e larg er n u m b e rs . In f a n tr y . 133. M e c h a n ic s, te n . A n y w h e re you w en in V ietnam th e re w ere vehicles, so y o u w o u ld expect to h av e a larg e n u m b e r o f m ech an ics in every u n it. Y ou n o tice w e ju st h ad tw o n u r s e s .J t's h a rd to d ecid e so m etim es w h e rfh e says I was a finance specialist w h ere he really was? H e co u ld have been clo ser to the ju n g le th an so m eb o d y else. SJ CjD T u rn to p ag e fo u r. W hat is he d o in g to d a y ? A n d it's interesting. If you m ove on d o w n to d isab led , m ed ically u n e m p lo y e d , 37. A n d then w e have a n o th e r over here on the next page, w hich is 1 believe u n em p lo y ed , 30. Now', these a re sep arate. W e sep arate them o u t. 37 are not w orking because they cannot w ork for m edical reasons. A nd m ost o f them are veterans w ho are already on som e form o f a pension. W e hav e 33-- a n d I th in k by now we p ro b ab ly have 34 veterans w ho are over in H u n t sville (state prison) serving tim e. W hen they com e into the program , we contact the authorities an d we get th e ir m e d ic a l h is to ry a n d th e ir p h y sic a l fro m th e in stitu tio n a n d t h a t 's a fairly c u rre n t o n e in s o m e cases. Som e have been there a num ber o f years, a n d they give them periodic physicals. So you can get a good idea o f w hat their cu rren t physical co n d itio n is. T hey are a g ro u p w here we alw ays know w here they are. Y ou d o n 't have an y tro u b le fin d in g these fellow s. N ow , we have had tw o released in the last two o r three m o n th s. W e do have a pro b lem w ith them in getting controls. For som e reason or o th e r, it's d iffic u lt to fin d a c o n tro l fo r a n in m a te . A n d w e d o n 't w an t to use o th e r in m a te s. I c a n 't th in k o f any good reason w hy n o t. But the researchers in the university do not w ant to use other inm ates. Y ou n otice there are six la w m en , m ost o f these are policem en. T hey were m ilitary police when they w ere in the service. N o w , o f the to tal o f 407, 89 h ad rep o rted that their wives or girlfriends h ad had m iscarriage or stillbirths som etim e since V ietnam , after their retu rn . A nd those reporting children with birth defects or m edical problem s present since birth, 90. W e have not gotten a good handle on this one yet as to w hat these birth defects really are because the study in D allas has not m oved ahead as rapidly as the o th e r th ree stu d ie s. But we will be lo o k in g in to th a t o n e. S y m p to m s o r initial c o m p lain t as re p o rte d by the veterans as they cam e in to the p ro g ra m on page 6. Y ou go dow n th rough here a n d you will find essentially w h at you have been seeing o n the screen all day. A nd you will see them p retty m uch in the sam e p ro p o rtio n s as yo u have been seeing them o n the screen. Y ou will see the high percentage o f d e p re s s io n s . Y o u w ill see th e p ro b le m s c o m in g o u t, 21 w ith c a n c e r, a n d 19 w ith b irth d e fe c ts . W e will lo o k la te r a t a listin g w ith th e p h y s ic ia n 's d ia g n o sis. T h e se a re w h a t th e y re p o rte d as th e p rim a ry reaso n for co m in g in th e p ro g ra m . T h is w as th e ir p ro b le m . S o m e h air toss, I d id n 't p ay m u ch a tte n tion to th at; y o u r secondary w as m ore im p o rta n t. H eadaches. 23 as the presenting sym ptom . N erve prob lem s, 19. N u m b n ess, 31. W e did sep arate those o u t an d p u t them together. W e realize that these w ere p ro b ab ly m any o f them , the sam e th in g . R ash, 89, w hich m eans a b o u t a third o f those in the p ro g ra m -- m o re like about a fifth o r a q u arter have rashes. T hey have that rash as their presenting sym ptom s today. T ingl ing in the extr ities w hich goes back to th e n eu ro p ath ies ag ain , nine. In th ext page, o f course, we get to the diagnoses as reported by the physicians w ho referred them into the program . A nd we began to find things that aren 't show ing up as a presenting sym ptom . T h e veteran will say th a t he has one th in g , an d the physician will d iagnose so m eth in g else. M an y tim es th e y a r e th e s a m e so m e tim e s n o t. A n d t h a t 's a m u c h lo n g e r list b e c a u se th e p h y sic ia n s h a v e a n a b ility , ju st d u e to v o c a b u la ry , to m a k e a m u ch lo n g e r list. S o th e n u m b e rs d o n 't beco m e q u ite as p ro n o u n c ed . But you will n o tic e as you go th ro u g h , th e re a re a n u m b e r o f c an c ers. A n d this is o n e w e a re really going to have to look at. A nd then as you look at the types o f cancers, adenocarcinom as o f the colon, basal cells, d iffu se bilateral ad en o carcin o m as m etastasis, giant-celled tum or;? o f the b o n e, H o d g k in 's disease w hich is a n in te re stin g o n e to be in h ere. In th e la ry n x , m e la n o m a s, tw o o f th e m . ^, W e a n tic ip a te a high instance o f m e lan o m as in certain ethnic g ro u p s, ofe-course, in T e x a s. W e h a v e a la rg e p o p u la tio n T )f n o r th e r n E u r o p e a n s . W c a lso expect a high a m o u n t o f s ki n c a n c e r #du<? to I t t being a Sun Bell state. We always have io lake this into consideration as a confounding factor. Con vulsive disorders. Three cases of physicians who actually said this man had chloracnc. which seems to me as a bit of a surprise because those of us who were physicians back in those Vietnam days didn't t really have chloracne in our vocabulary. We knew what acne was, but that was about it. Depression with anxiety, ten, confirmed by physicians. Depressive neurosis. For instance, we didn't even put diabetes, and diabetes mellitus together because we used the actual diagnosis of the doctor. Diabetes t mellitus, seven. Now, this can be when it is confounded with other symptoms. Hypertension, 13. I think we can expect that in number of veterans because of the age group we are dealing with. I pro bably want to take a little time later and go dow'n through and match these up with some of your ex i, periences. particularly those up here to see if the patterns that we are looking for of signs and symp toms are starting to evolve. Notice numbness in the extremities, 14. Just in that alone. Numbness, ulner aspect, upper extremits, one. i, I have not attempted as of yet to break these out and put them into proper categories so that we can say these are various symptoms or these are all skin conditions of these are all cancers. It's raw data. And no attempt at this point has been made to analyze it. We will be doing that shortly. I have to 1, let you know that my new computer is just arriving, and they are setting it up, and w-eMl be ready to start putting this into our computer. Then we will bring the laboratory data from the University of Texas, and we will start the matching program, breaking the code, and see what it begins to tell us. 1, Ten paranoid schizophrenics. And two more effective types of schizoid-tvpe disorders. These fellows, most of them have had periods of lime in the state hospital. They are true schizophrenics. There is no doubt about it. And one of them came in the other day and I saw him. He had some queer deas, but I enjoyed talking to him. He remembered everything that happened. The only thing was, he I, just couldn't put things in a proper time. And they were still after him. There was no doubt about that. And he was all right. 1had one call the other day, he said I am in jail. What can you do for me? I L just killed a guy down in the bar. It looks like I'm going to get a little time. This is the way of life when you are dealing at the grass roots level with the veterans and their problems on a daily basis. They come into the program, and we become another part of their medical care system. They look to us for help. And the law as written in the state of Texas says that we will assist the veterans by referring them 1 to agencies for assistance; medically, financially, in any way that we can to assist them. Which means tha: if necessary, 1 will end up in court testifying in his behalf if necessary, based on the medical records that we have developed in support of what his problem is. To date, 1 don't think we have 1, anything which^we can carry into a courtroom and say that we can relate this to his'exposure to Agent Orange. But we are building up to the point that we hope the day will come when we can start to bring the medical evidence in and the data in and put it together and start to make some sense out of this whole problem. On page 11 you might find it of interest, we were asked by the University of Texas to break out the types of cancer in the veterans. And they wanted those who were over age 36 and those under. Here we have case numbers. We have their age at the time they were diagnosed. And you will notice with the asterisk that a number of these individuals wore treated in Veteran's Administration hospitals. I have not yet been able to identify those cases that would be called a'soft tissue sarcoma or a lymphoma. We are only dealing with a small number, four hundred-and some. We are dealingjwilh sarcomas which is somcfhine that is very rare, and it may not have shown up. Perhaps if our program l 8498 li. goes to where we are up into the thousands, we may well find one. But a number have already died. I hate to have to say that. It happens. You can't save them all. On page 12 children with leg deformities. This is something that our cancer center in the Anderson Hospital asked us to have these listed hoping that we might be able to find some connec tions or at least have an incidence of how many among veterans there are. 62 of our veterans have cur rent rashes today. Last Wednesday, one of the veterans was in my office, and he was covered with a rash over his shoulders and his back and down his arms, which would be very suspicious. 1am not a dermatologist, and 1 would not attempt to really diagnose chloracne, but he does have an extensive rash. And the number of cases with tingling and numbness in the extremities--it's interesting to take a look at the year that they state that (his started. The diagnoses of these cases, most of them are rather recent. Some do go back to the time of Vietnam or the time they first came back. However, these are only those that have been diagnosed and confirmed by physicians. 101 veterans have the complaint. So we are always left in that bit of a dilemma between the veterans' and the physician's diagnosis. And it takes us lime to get it confirmed. On page 13 miscarriage and stillbirth. We have to take into consideration here what happen ed to the veteran as he came back from Vietnam. The first thought in his mind was 1want to get mar ried and have a bunch of kids. And you will note that there were a number that had the problem, or their wives had the problem. But it is pretty much throughout that whole lime period of the '70's up into the early '80's. I wish 1could give you a further insight into what this means. But it's going to re quire some analysis before that can possibly be done. On page 14 we get into the schizophrenics. Now, these are substantiated by medical records and competent diagnoses by physicians, psychiatrists. Look at the list of them. Now, does this mean that we have a problem of mental illness related to the veteran who served in Vietnam? Or does this mean that this is the kind of program that the schizophrenic likes? And he is going to come into it. Or is it that he has such a problem, and the physicians know about it; they have heard about this program and referred him in. We haven't been able to determine this yet. But we are going to have to answer these questions because in a program such as this in which it is self-selected individuals, we are always criticized by our peers when they review the data. First thing they say, " is it a self-selected study?'' Okay, it's not going to hold too much water. Your controls. Well, there is a problem there. You've got incomplete data here. There is a problem (here. Anybody that goes in a study like this is going to have to have a thiok skin and know how to ride through it because it's not a clean, straightforward-type of study. It's a ^ery complex study with incomplete information on which you base judgments. So it become a judgment evaluation in many cases as to the direction you are going as you move along. And I'm sure that the gentlemen at the table up here can agree with me that this is exactly the way it is. This is the real world. On page 15 (hen we took medical conditions that they listed which were not their primary presenting symptoms, and you can see that although some of them listed one, a lot of other things began to show up as a secondary. Some of them in large numbers. Gastrointestinal disorders, which didn't show up as a primary symptom, but as a secondary symptom. 140 said they had gastrointestinal problems. 127 have emotional problems. 137 have headaches as a secondary, which means we are get ting up in the high percentage of the totals, which began to fit the pattern on what you saw-on the screen today. * . . I 57 Q I I L \ 140 nerve problems, with 68 separaie oui from ihai as just numbness. I warn io give this lo vou (o gi\e you some insight as to the type ol data which is collected as the program evolves, and the information begins to pile up. We really came into existence in September of 1981. It took us about six months to get wound up to get everything going. The average time that it take us to get the medical records together, or I guess the case file you have to call it, because it contains more than medical records: ranges from three months if you are lucky to at least a year. In fact, we are still working and getting records together on cases which are well over a year old, but we don't give up. We keep right on going trying to get them. I thank you very much for listening to me so attentively. I didn't prepare it in a logical man ner. 1just gave it to you as I see it. Thank you very much. (Applause.) MR. O'CONNELL: Thank you. Dr. Anderson. At this time why don't we entertain some questions of the panel. DR. CARLSON: You mentioned that it's very difficult to get a control for a fat analysis. But many people carry an organ donor card. For instance, when a person has an organ donor card it could be modified to say for organ donation or for pathological examination, because then you would have autopsy material available from accidents for analysis to control tissues. DR. ANDERSON: There is no reason. Now. just out of interest, we do have one fat biopsy, autopsy specimen, which was collected on a Navy man that died from cancer. Unfortunately, we col lected it they put it in the deep freeze in Galveston. I w-ent through and did an exposure index on him, and I cannot validate his exposure. There is no way I can do it. He was in the wrong place at the wrong 1, time or the right place at the wrong time, whatever which you want to put it. But 1cannot say that this man had exposure, even probable exposure. DR. CARLSON: One other question 1wanted to ask on the cytogenetic analysis. There has been a recent technique. Jt's about a year old or so, in w-hich sperm can be used to fertilize hamsters. i l And the sperm fertilizes the hamster egg, but it eventually aborts. But the male chromosomes can the be studied. This technique yields beautiful male chromosomes obtained directly from the sperm. Since I, there seem to be so many testicular problems that have been identified with the herbicide exposure syndrome, this may be a very usable system to use. DR. ANDERSON: I will mention that when I get back.' I. MR. O'CONNELL: A question back there. A VOICE: I have a question for Dr. Codario of Philadephia concerning the central nervous system. The ventromedial nucleus of the hypothalamus. When you have a tumor, it's been known as Il occasions to come along there, not quite so rare, but every so often. 1don't know the exact numbers. But this causes very aggressive behavior if 1am not mistaken, and also, I believe, if I remember cor rectly, an insatiable desire for eating or drinking that you just can't seem to stop it. The question is: Does the TCDD--could that possibly ha\e an effect on the Vietnam vets, II and could that explain something as far as their aggressive behaviors? DR. CODARIO: What you are talking about is what we call satiety center. If you review the literature on all the animals, there arc not any case reports of central nervous system tumors occurring l in animals exposed to TCDD. All the literature deals with the association of pyramidal tract disease., dcmyelinization in the a^ca of the pyramidal tract in animals. There is one reported cause ol neural tube defects in animals that hasn't been substantiated scientifically to occur in humans.- But we do>fot t 1' , 6500 L SH 5 have any model to draw from in any of the animals in central nervous system tumors. Based on what we know about TCDD, just giving you an opinion, it would be difficult to say that a Vietnam veteran that had an abnormality in the satiety center that might be related to TCDD. It would be almost im possible to say because looking in the literature, the only thing that's reported in animals is demyelination in the central nervous system and in the peripheral areas. And so if an individual developed cen tral nervous system disorders--and this is a clustering in Vietnam veterans. We can't make that assumption scientifically. A VOICE: I have a question for Dr. Orris. I'm very concerned about the diagnosis for chloracne. In the various class action lawsuits, they have defined the various types of health effects that they feel are a result of their exposure to the dioxin. And they have listed 11 various effects of chloracne. Can anyone give me any understanding of that? DR. ORRIS: Well, I'm also not a dermatologist. And that's the critical expertise that you need with respect to chloracne. But it's our understanding from consulting the dermatologists that chloracne is diagnosed on the basis of the distribution--the history of exposure and the characteristic physical skin findings. If you just take one of those--and that is skin findings, even if you go to biop sy, it cannot to our understanding realiably be differentiated from vulgaris. There are several experts in the country with respect to occupational determatitis that could be solicited with respect to that. Dr. Adams in California, Dr. Birmingham in Michigan, Dr. Suskin in Cincinnatti. A VOICE: I have the Skin Diseases in Vietnam from '65 through '72, Volume of Military Medicine. And they state that the most common illness in veterans in Vietnam was, in fact, skin le sions. And they did an epidemiological study on one of the units. And one of the findings--one of the men is in El Paso, Texas. And they list all the various types of skin disorders that Vietnam veterans manifested. And chloracne was the highest. I'm just trying to get this straight in my mind. If a veteran had no predisposition of any acne throughout his lifetime, and he leaves Vietnam with chloracne. I'm trying to find out how we can discern if it was tropical acne or various other types of acne. DR. ORRIS: The history of exposure was there. If he developed it following that exposure, and if it is in a distribution that is characteristic of chloracne, and typical for chloracne vulgaris. We would be quite happy with the diagnosis of chloracne in that situation. And we have seen people who have chloracne who we believe got it from Vietnam when they were exposed. A VOICE: I have several veterans in our organization that have been diagnosed by seven dilferent dermatologists that it was chloracne. But the VA denies his claim. DR. CODARIO: Just as a point in elaborating the term chloracne, it was coined in IS98. It was felt--it was a condition that resulted from chlorine gas. It was only later in the late '50's that we began realizing that there were a number of chemicals that caused this type of eruption. At the last in ternational symposium on dioxin and related chemicals in Arlington, Virginia, in 1981; Dr. Kenneth Crowe from London, England, Dr. Renata Kimbrow from the Center for Disease Control in Atlanta. Georgia, presented two separate symposiums on chloracne in which they went into detail about discussing the pathological findings that we sec in acne vulgaris and we see in chloracne. And both of them specifically made the points, and this is of record jn the International Sym posium in Arlington, that there is a difference between acne vulgaris pathologically and chloracne. As true as Dr. Orris says, there are distributions that we sometimes see. These ^istributioos are-trrthe eyelid and in the groin? Those are (he areas at which chloracne tends to occur, as opposed 10 acne I II 1 vulgaris. The point is, that if you lined up ten individuals and looked at their skin you would have almost an impossible task differentiating chloracne from acne vulgaris. A skin biopsy may also have a hare :inn Jiflercntiating. And that may be because the in I dividual has chloracne and acne vulgaris. And in the biopsy, you'scc bacteria and the same informa tion you see in the dermis. But strictly speaking, there are criteria that are used for pathological dif ferentiation of chloracne by skin biopsy. And these are quite accurate in the criteria that 1mentioned. I Many of the Vietnam veterans might be very difficult to diagnose after all these years. But certainly, if there is any debate, the skin biopsy may be rather valuable in that determination. A VOICE: As far as for disabled veterans, what resources have we or do we have or what we I could do to get our children checked, because at this time the Veterans' Adminstration will not handle it. DR. CODARIO: Well. 1 think the saddest part of the entire Agent Orange story arc the t children of the Vietnam veterans, because we just have very little information other than just guesswork as to what's going on with the children. We are just going to look at the veterans themselves and as 1alluded to in my earlier discussion, we are just beginning to unravel the mystery of I the genetic code. And right now, if you take your children to any geneticist anywhere, he is going to be hard- pressed to give you an opinion as to whether or not the findings that you are seeking in your kids, be they frequent infections, learning disabilities, loss of an arm, heart murmur, heart defect, there is nobody on this planet that's going to be able to tell you yes, John Smith, your child has that learning disability because you were exposed to dioxin in Vietnam. I, And part of the reason for that is the scientific inadequacies of the past, and in a large part, in the scientific inadequacies that we have right now in unraveling the mystery of genetics. A VOICE: 1 see in my own child what they call cerebral dysfunction disorder, which has a I, neurological basis. Could that be transmitted let's say as far as--let's say my wife and 1made love and as a result of that our daughter was born. Could the Agent Orange that I was exposed to have an ef fect on the embryo? DR. CODARIO: That's a problem and very unfortunate one. l MR. O 'CONNELL: I might add that we have also with us Dr. Michael O 'Gradv from the I YA in Milwaukee, Wisconsin. I think you indicated that you would be willing to answer any questions of anyone. As to setting up the program format, we fell that it would be productive to have those II from the privat/sector and also our colleagues of the Texas Commission. But VATtas been involved in their willingness to answer any questions that we may have of them at this time. A VOICE: Is your commission planning to do any outreach for the veterans? [L DR. ANDERSON: Well, the law--1 know why you ask the question--did not include an outreach program in the beginning. In other words, the veterans had to come to us. Now, the legislature due to certain pressures this last time did put into the law an outreach portion by stating il. that the veterans contacting them. can now apply directly to the program, which docs not preclude our going out and And we are now in the process of sending out the VA Agent Orange Registry listing. We got the names and addresses from Washington just about a week ago, and we are in the process 1 now of mailing out 4400 brochures. Now, these are fellows that have already liad the VA physical, the Agent Orange physical. Now. beyond that we have already ordered .M3,000 brochures which we were- going to be putting into (Tie mail. We are working in developing our mailing list. <vhich vvhen you have ! Ml 6502 153,000 veterans to start with, it's a bunch. But we arc working primarily through the veteran's organizations and through the Veterans Affairs Commision hoping that we can reach the rest. And we have two or three very serious problems in Texas in just getting to people. What you send out in English also has to be translated into Spanish. So you have to pick and choose the areas. We also have a lot of sparsely populated areas. We have one county which is just about the size of Rhode Island in which only 67 people live. That leaves you a problem of locating a veteran among those 67. Now. we also have had the additional problem of being one of the Sun Belt states, of having a large immigra tion of Yankees. Is that what they called them? I was originally a Yankee. I came in and became a Texan. They are ineligible for our program. The law said, 31 March 1981, our population by 1980 will equal that of either Florida or New York. And shortly after that, Texas will be the second most populated state in the country. We are growing that rapidly. Austin, Texas, when I moved there nine years ago has doubled its population just in nine years. Houston is becoming huge. Everybody wants to go south and enjoy the nice weather. A VOICE: Doctor, are you using any of the data from the VA Registry in Washington for Texans? DR. ANDERSON: Only the names and addresses to contact the Texans. That's all. A VOICE: They won't give you any of that data? DR. ANDERSON: Oh, we have it all, yes. A VOICE: The name that the VA provided you from the Agent Orange Registry, did you ask for it? DR. ANDERSON: I asked for it last June, and it arrived a few weeks ago. N o w , I can ex plain that a little better. They have this prepared for any state that would like to go out to get it. It's just a matter of asking for it. And they were in the process of, at that time, getting it through their computers. A VOICE: Are you trying to get a list of just your names from the State of Texas? DR. ANDERSON: We have no such registry in the State of Texas because when a veteran comes home from the wars in Texas, his 214 is sent to the Veteran's Affairs Commission. And they immediately send it right on down to the county service officer, who then puts it into a file somewhere. So we have no central Texas file. So if we want to find our veterans, we have to go to each individual service officer by county. And you know how these veterans keep moving around. We are already 15 to 18 years behind the power curve. A VpiCE: Dr. Anderson, now let me say for 100 percent disabled veterans would the VA in the future initiate (he program for our children, because of different governmental payments, most doctors will not handle it. DR. ANDERSON: I am not VA. A VOICE: Maybe you have some input on that. DR. ANDERSON: Perhaps the good doctor here could better explain that. But I will answer the last half. The law- as it was amended last spring added the children of veterans who allege that they base children born to veterans with birth defects who alleged (heir problems related to exposure to Agent Orange. Now, it becomes part of our program and they will be referred for evaluation. They were already eligible for assistance in another way. But nobody is going to write them out a blank check. ' ^ --" A VOICE: Doctor. I'd like to add something but iir`ierms ol exposure to veterans, we ajf m <.i 6 5 0 3 this na;ion have come 10 believe that (lie majorits of spraying was done by Operation Ranch Hand. And this has become more or less the biblc to us. All I have been privy to see is some of the discovers' on (he Agent Orange class action lawsuit where the government has turned over 340,000 papers that they have on it. And, in fact, the spraying b\ this was much more intensive than the Ranch Hand. And perhaps I can tell you that I have discussed this with Mr. Christian, who heads the task force. We were looking at this about a year or so ago as a possibility because several of the veterans had said to me look, 1 don't know about those Air Force airplanes up there. But those choppers up there were doing a pretty good job of it. Then we have some of the fellows using backpacks and playing games out of spraying each other. But at any rate, there was a lot used in that manner. And Mr. Christian has assured me that they are now de\ eloping some data which will be useful in the determination. And I, of course, have been asking to get this as soon as it's been developed to start to apply it to some of the fellows in our program in which we have been unable to substantiate a good Ranch Hand spray. But he does give a history of it. This is particularly true with the 9th Infantry Division. They did a lot of their own spraying. MR. O'CONNELL: I'm going to remind the state commission officials that tomorrow we will be discussing the registry, and hopefully get into the key areas where we can exchange some in formation on that. J know that we in Illinois are most anxious in getting our questionnaire out. If there are no more questions. I'd like to announce that there will be approximately a one-hour long movie for anyone who wishes to stay. It is entitled The Secret Agent. It's a historical look at the use of Agent Orange. And anyone who washes to stay is welcome to do so. Before these gentlemen leave, I would like to thank both Dr. Orris and Dr. Carlson, and of course Dr. Anderson for the presentations this afternoon. I would like to commend our ex ecutive director of the Illinois Agent Orange Commission, Dave Weisbaum, who has put together a very interesting and a very productive session here today. He has been assisted by our secretary, Pat Lamsargis. And the public relations work for this project has been done by Joan Maiman of this commission. I think that we will all agree that the ultimate answer to the question of whether there is a causal relationship between exposure to Agent Orange and the problems that have been surfacing over the past decade, and will likely continue to surface, will be answered by medical rescun.il, uy the medical expertise that we have at our disposal. We think that today's symposium with the valuable and intelligent discussions that we have had transcribed will go a long way toward that cnH. And those of us who represent in the political and governmental spectrum the residents of our respective stales can ask no more of us than to do our part to elicit the facts, elicit the evidence that will hopefully quickly arrive at a very definitive answer to the question that we have been ask ing for a long time. Do we have something to worry about because we have served in Vietnam? And do our children have something to worry about because we served in Vietnam? So I want to commend ail of you for spending your Saturday--some of you coming long distances to share your day and your contributions with us, and to the overall effort in finding an answer. Those of you who are with the various states and do intend to stay tomorrow, please ad'ise me or Dave Weisbqum so we will haw a good idea as 19.how mans to evpcci tomorrow morn ing. We will spend approximately three hours exchanging information. 1understand there will be a press conference at 1:00 o'clock tomorrow afternoon. If there are no further questions, I will then thank you all and adjourn the meeting. (Applause.) / Printed by u id io aty of die Sure of Ulinoit Lep derive Council Service Unit Order 141)21 Mey 1PM - 5JO copici ' 63 _, 8505 %ir cp Ct> IO co i I ! I ii i  HrtJHn n t u v . f t k j ' D i o ^ i w ^ > w DRo m ( F F ?' I , 4 l ) J Ehvironmtnl! Toxin The Dioxin sy-u-u' ireme Researchersfind m ovefoohd _ Dioxin is one o the most i potent toxins known, but so | far the search for toxic j i fleets has vielded surpris" ingiv little. The reason. _ I a y s a team of Illinois doc^ M'S, is that physicians have TM oked at the wrong thing. _ 1 For 20 years, doctors j v<? considered a sudden TM uption of blackheads and t cne known as chiortcne | - - hallmark of dioxin con9 unation. But Drs. Bertram Camow and Shir1 nibear, of the Uni- ity of Illinois, say that V eruption occurs only i the time. More m ally, they find, there's n o ng list of variable signs symptoms that add up ~ue "dioxin syn- h ey include: generaitigue and weakness, t ty in holding hands head, severe head- i J Ur t i Qi 0Yy^,, _. , depression, irrita^ i memory k>ss. lack oL vj " `cerfike sym ptom s licers. And they Ct show up until two "y ears alter expoT~ tjsi e poison. r L o jxdan sy n d ro m e has I re alTaTonp u v " vd C onibear. But se\ : neurologic s are vague and ` xrtors often u o to o sy c h o lo u In fact, they j -- .i j ________ other firmas, Further, scratch the surface and there may be deeper signs: abnormal levels ol porphyrins, a " component of red blood cells, enzyme system s, hormones and muscle m elabotism; depression of the immune system: and mal function of fat m etabolism _ leading to extrem ely high H evels of triglycerides and elevated blood cholesterol. Absence n<chlorecr.e does not mean someone escaped the toxic effects of *3ioxin. Camow and LonT bear say. it just means the victim doesn't have the skin-eruption feature of the syndrome. Nfr more than 15'* of those exposed to hit;h concentrations of dioxin develop chtoracnc. Camow. professor and director of the Great Lakes Center for Occupational Safely and Health, and Conibear, an assistant professor of preventive and occupational medicine, have studied some 400 dioxin-exposed patients, 100 of them women and children. The syndromels not easy to pin down, it . v taxes 14 hours of tests, and costs a whopping $7,000. M any of these patients] afte r complaining to noTvail fo r y ears, have developed psychological problems. But, Cam ow says, neuro logical testing, along with a history of contamination. c an g et u n d ern eath live p sychological overlay down to the dioxin-caused physi ological dysfunction. 'Z'Z O nce the noison is in th e _ s y stem , th e re 's no wav know n to co u n teract it. Cam ow and Conibear con centrate on trying to pro tect sy stem s m ost likely to be affected: the heart. arteries, liver, skin. T hey prescribe special diets and lifestyle changes. -- G. V. 5^ ^2 CftRfOOuJ I Publiahcd al HO Flh Anur, N<~ 'l Z \i) c- A n m ran HtoM e n u a rflh 'throaty M / 6507 6508 .The W orld of ii i i, l> L -------------- --- -- I [ Encyclopaedia Britannica,Inc. t1 Environmental Health Dioxin, in undeairabi*byproduct inlh# manufacture a t herbicide.oinftlfrdliWt.and otherchemicals,isthe ~most toxic 01*all man-maae substances. Compared with me most powerful naturallyoccurring poisons, H ranks fourth,justbelow (hebacterialtoxinsrosponsibto (orbotulism, tetanus, and diphtheria. A portionofSe veso. an Italian town near Milan, has been cordoned offsince 1076. when a chemical-plant explosioncon taminated the area with dioxin. Recently more than a hundred sitesinMissouri have been found or aresus pected to have dioxin-contaminated soil. The most publicizedofthese locations,the smalltown ofTimes Beach, has been purchased by the U.S. government, and itscitizensofferedtheoptionofrelocation.Dioxin has also been detected infishand inriverwater from Michigan, inother U.S. communities, and inVietnam. The extraordinarytoxicityofthischemical,itshighsta bility,itsinsolubilityinwater, and nswidespread pres encemake theproblemo(protectingpeopleespecially serious and difficult. Wha t is di oxi n? Although the term dioxin has become a popular syn onym for one specific dioxin, 2.3.7,8-tetrachlorodi benzo-p.-dioxin.technicallyitrelerstoany pia group of chemical compounds called Oibenzo-p-dioxms. Siruc lurailvthe dioxins consist oi two oenzene rings con nected by a pair of oxygen atoms. Each of the eignt carbon atoms on the rings thatare notbonded tooxy gen can bind with hydrogen atoms or atoms of other elements. By convention these positionsareassigned thenumbers 1 through 4 and 6 through 9.The dioxins ofgreatestconcern carry chlorine (Cl)atoms at these positions. Theoretically. 75 possible combinations, calledisomers, can be formed by adding one or more chlorine atoms. There are 22 possible arrangements fordibenzo-p-dioxms thatcontain(ourchlorine atoms, these2 2 isomers constitutethefamilyoftotrachlorooi- bcnzo-p-dioxins (TCOD's). The most toxic dioxin isa m emberofthisgroup,withchlorineatoms atthe2.3.7. and 6 positions.Thisisomer, 2.3.7,6-TCDD,isextreme ly stable chemically even at temperatures as high as 700* C (1 ,290* F),possiblybecause ofitssymmetrical structure. Moreover, thisisomer isvirtuallyinsolublem water and inmost organic compoundstjufis sofuBle"in oils. Itis this combination ot properties that allows dioxinm soiltoresistdilutionwithrainwaterandcauses ittoavidlyseek and enter tattytissueinthebody ifitis absorbed. ~ Dioxinserves no useful purpose butisformed as an undesirable Dy-proouci ounng the synthesis of 2.4.5trichiorophenotand some otherusefulcompounds.For example, ifthemixtureofreactants used tosynthesize 2.4.5-trichlorophenolexceods 100*C (360*F).an oxo thermic (heat-generating) reaction occurs, ana some W hen E nvironm ental P rotection A fe n c y v o r k e rt te tttd the to il in T im e t B each. M o ., th e y fo u n d d ioxin levels to high th a t th e U S . {o v tr n m e n t o ffe re d to b u y the t o v n l SOO hornet a n d relocate its 2,000 friih ten ed residents. dioxin isformed. In fact,m any accidental releases of dioxin have resultedfrom suchoverheating, producing a runaway explosive reaction. 2 .4 ,`5 -trichtorophenol serves as a raw material for making the herbicides Silvex and 2 .4 ,S-T (2 .4 ,5 -trichlorophenoxyacetic acid). The latter compound is a major active inoredient of Agent Orange, a defoliantformerlyused inVietnam by th'e U.S. military and inthe U.S.on railroad,highway, and power-tine rights-of-way and intprested areas to killunwanted vegetation, 2.4,5-lrichlorophenol isalso used in the production of hexachlo/ophene. an antibacterialagent formerlyused indeodorants and soaps~ butpanned since 1972.If2.4.5-trichloroDhenoliscon taminated with dioxin during manufacture, then dioxin appears in these end products. The toxicity of dioxin rendersit capable ot killing some species ofnewborn mammals and fishallevels offiveparts pertrillion(orone ounce insixmillionions). Less than two millionthsofan ounce willkilla mouse. tstoxicproperties areenhanced by the factthatitcan pass mfo the b o d y through all major routes of entry, including the skin (by direct tontact). the lungs (57 inhalingdust,fumes, orvapors),orthrough themouth. E n try Ih r n ur/h anyn l theseroutesgonfnbutesftyihetola)body burden Dioxin may afteclthe skin upon^on- ^ taci, then enter the blood and move into the fat and laity tissue; ofm a n y o rg a n s A n a u to p s y ofa-resident C hJ- \A i'i ! Environment*! health of Seveso who died some months after exposure showed the highest concentrations in fat tissue, with decreasing levels in the pancreas. Cver. lungs, kidneys, and brain. In pmmals dioxin also appears to enter the thypmis pnft the adrenal nlanri. and it has been found~in human breast milk. W hat makes dioxin so toxic? A great deal Of scienl!firinformation on the marhiy. msms Of dioxin's fnyicilvhue haan natharart fppynm,. merous studiesoflaboratoryanimalsand human expo surevictims.One productiveapproachInthesestudies r hasbeen tolookatthewav inwhichriinxlnantamamil and what itdoes once itgets in. Contained in cell membranes are protein molecules, called rereotnrs1 thatnormallyfunctiontomove substancesintothecell. Dioxinavidlybindstothese receptors and, as areaiitx israpidlytransportedintothecvtoolasm and nucleusof thecell,where itcauses changes incellularprocesses. Experiments inanimals suggest thatafterenteringthe cell,dioxin afteclS tiny prureirtSfTanflfccalled smooth _ and rough endoplasmic relicula.Those structuresoarticipateinthe synthesis ofa largenumber ofenzymes that,m minu^ quantities, regulate important chemical reactionsinthebody,includingtheproduction convor _ sion.and storage ofproteins,carbohydrates, and fais Called mixed-function oxidases, these enzymes are also responsible (or the breakdown of some sex hor mones, drugs, and other substances, thus enabling theirremoval Irom the body. ktixed-lunclion oxidases are produced in many or gans of the body, including the liver, skin, kidneys. lungs,and those whitebloodcellscalledlymphocytes. . They appear only when they are needed and are _ "turned on" by the presence of various othpr rhnmi calscalledinducers. Dioxinisthemost potentenzyme inducer known. Ithas long been recognized that in creased production of some ofthese enzymes greatly increases the cancer rate In animals exposed to earrift- opens Another nntnt nzvme inducer, 3^thV^fchc"' lanthrene (3-MC1. hat bean used tor veer In eancef research became of Ha potency as an Inducer. Dlmrip is 30,000 timet more potent an Inducer than 3-MC. and . its effect is many times longer lasting--further reasons tor its extraordinary tnvtwty tn addition, the presence of chlorine atoms at key locations In dioxin's structure apparently protects Hfrom tome of the major biochemT ical breakdownprocesses by whichthe body disposes of toxins `-- The Hood of enzymes stimulated by dioxin leads to the malfunction of many organa and to the excessive destruction and excretion Irom the body of certain es sential chemicals such as estrogens. On the other .hand,chemical buildingblocks pileup inthebody be cause some basic processes cannot go forward to completion. For example,iron and compounds called porphyrins,bothofwhicharecomponents ofhemoolobin, may accumulate inthe blood and tissues. Significance o f animal studies Because informationabout thedirecteffectsofdioxin on people has been limitedprimarilytostudies of vic timsofinadvertentexposure,investigatorshave relied heavilyon monkeys, guinea pigs.rats.mice,and other laboratoryanimals togain a boner idea ofwhat dioxin does to the human body. While results from animals varysomewhat among variousspeciesbecause ofdif ferences in enzyme systems or inthe degree of en zyme induction, many common effects have been found Theseconsistenciesincreasethelikelihoodthat otherspecies,includinghuman beings,may be similar lyaffected. ____ In rnpst species,except incases inwhich,verylarge doses were administered, the effects of dioxin ap pearedonlyafterconsiderabledelay,possiblybecause of the lime needed forenzyme induction to occur. HT In the Sum m er o f 19S3. hift levels o f d io xin were discoverd in a hie w ork. N .J., neighborhood near a chem ical plant (hat once produced the deadly herbicide Agent Orange. A local swimming pool was closed because o f dioxin contamination. and agents fro m the.E P A went door-to-door collecting household refuse to be analyzed fo r the possible presence o f dioxin. > ( 2 ) 6511 l***" *UJ'- VI*, ' In 1976 an explosion co vered the lown o f Seveso, Italy, nth a tdxic dioxin cloud. T oday fo rm er Seveso residents continue to suffer fro m a variety o f skin disorders. every species studied, dioxin destroyed testicular tis sue and tissue of the thvmus gland Insome animals .theskin,liver,and kidneysandtheendocrine,gastroin testinal cardiac, and central and peripheral nervous systems were affected. In some animals the immune dtense system was suppressed, Oirthdefects,partic ularlycleft palate and neural lube abnormalities: em- bryotoxic ettects. including ahortion. miscarriage and resorption o( the tetus: and mutaoenic effects ap peared ina number ot species. Many species experi enced a strikingincrease incancer incidence,particu larly when dioxin was administered with chemicals .known tpfte cancer initiator: '' That dioxin'increases the chances ot cancer, birth defects, and genetic mutations in any soeciesls ot particularconcern. Itisoltendifficult,itnotimpossible, .--todetermine theleastamount olasubstancesufficient to cause genetic abnormalities because ol the tong _ latentperiodbetweenexposure andtheappoaranccol _disease Consequently, thequestionshiftsIromlindinq _a levelolexposure where no one isaffectedtofinding -- a socially acceptable level. 'Ihe Centers fordisease Control (COC) m Atlanta.Ga., has recommended that exposure todioxinbe limitedtolessthanone pan per billion,basedon an estimatethatagroupolone million people exposed tothisconcentration intheirlifetimes would experience one excess cancer death Human experience with dioxin Most people known to have been heavilyexposed to dioxinhave been the victimsofIndustrialmishaps in volving the explosion of areactor vessel ora blown safetyvalve.Workers inthevicinityatthetimeofthein cidentorwho came inafterwardtocleanupwereusu allyexposed forashorttimetohighconcentrations.In the past 30 years more than 200 such episodes have occurredworldwide.The firsthappened ataMonsanto plant inNitro.W.Va., In1849,when 220 workerswere reportedtohave been exposed followinganexplosion of a reactorvessel. Other accidents include those inthe BASF plantin Ludwigshafen, West Germany. In 19S3; the Rhone Poulenc plantinGrenoble, France,in1956 and again in 1966: and Coalite& Chemical Products Ltd.inDer byshire. England, in I860. Another such Incident oc curred at the Philips-Duphar plant in Amsterdam in 1963. Decontamination was apparently impossible at 'the BASF and Philips-Ouphar plants, which were dis mantled. put into ships, taken out into the Atlantic Ocean, and sunk. Inanother instance a plantwas diS: mantled and buried after more than two years of at tempts to remove the dioxin. Later a large stainless steel vat salvaged from that plant was installed at a new siteover a three-day period by two workers who had never entered the old plant. Both of the workers developed disease due todioxin, and the son of one worker acquired a severe skin disorder called chlor- acne. one ol the manifestations ofdioxin-caused dis ease. from wearing his father's scarf. O therworkersexposed tolowerlevelsofdioxinover longer periods of time-- ranging from months tomany years-- have been examined and also were found to 'have disease. They includegroups from the Diamond AlkaliplantinNewark, N.J.,aplantinSpolana.Czech., the Dow Chemical plant in Midland. Mich., and the Monsanto plant in Nitro.W.Va. A reportofdioxin-induced disease inthreelaborato ry workers in England was published in 1975. Their exposurewas onlytodioxin,andtheyknew ofitstoxic ity.In spiteofthe factthattheytoc^ Pfnrai`- tions, which included the use ofventilating frpnrl:and protective clothing, allthree developed yflriPP*<!Yfnn- toms and findingsassociated withdioxinexposure, in cluding abdominal,pain, excessive fatigue,decreased ability to concentrate, irritability, blurred vision, de- croasod muscle coordination, and excessive oilmess ot sovere acne olthe skin Inaddition, allexperienced elevated serum cholesterol levelsthat persisted (orat leastthreeyears.One showed no symptoms untilthree yoarsafterexposure, a delayalsonoted intome ofthe Czech workers. InJanuary 1979. 47 railroadwerkars senttocleanup ^ achemical spillinSlurgeon. Mo.,came incontact with- chemicals that included phenol, orthochlorophenol. and dioxm The dioxin was present in concentrations 8512 ; (3) f i . <n| li il 1 1 II l I l ! ranging from 2 2 to 36 parts pat billion and exposure ranged between 8 hours and 90 day. Severaleatenalve examinationovera three-vearperioduncovered disorders of allmajor organ systems. Laboratory ab normalities were timtlar to those lound in other ex posed groups, and again insome individualsdisease did not aooeaf until moro than two yoars alter . oxpqsum -- H - Perhaps the most publicized industrial accident in volvingdioxinoccurredin1976 nearSeveso. Italy.The ' V.iy source was a chemical lactorvbelonging toHollmanl_aRoche thatproducedtrichloroohenni An accidental riseintemperature ina reactorvesselcausedasafety valvetoopen, sendinga cloudofdioxin-contaminated trichlorophenol into (he air. Within three weeks 700 residentshad tobe evacuatedafterthousandsofsmall animals,birds,andinsectswere founddead.Morethan two-thirdsofthese people showed signsofdioxinpoi soning.Contaminated crops withina region extending five m iles south ol the plant were burned. The area aroundtheplantwas dividedintothreezonesbasedon thelevelsofcontaminationthoughttobe present.As of 1983 the most heavily contaminated zone remained fenced inand uninhabited. Of more imminent concern than the occupational exposures isthegrowingrealizationthatland sitesand entire communities have been contaminated by Ihe improperdisposalotchemicalwaste containingdioxin In 1971 waste oilwas sprayed m severe!horse arenas in eastern Missouri to keep down dust. Within weeks hundreds of rodents, insects, dogs. cats, and birds were founddead inand around thearenas. More than 80 horses thathad stoodorwere riddeninthearenas became ill, and within 16 months most developed multiorgan disease, became paralyzed, suffered ex traordinarywasimg. and died.Childrenand adultsalso appeared tobe affected. The oilwas eventually recognized as the source of the problem, and several inches of topsoil were re moved from the arenas. By thetimedioxinwas identi fiedasthetoxicagent(onearena showed aconcentra tionof33.000 partsper billion),some oftheexcavated soilhad beon used as landfillfor.homes inotherareas ofMissouri, inaddition,the same dioxin-contaminatedoilwas sprayedondustyroadsinTimes Beach andap parentlyhundredsototherareasinMissouri Itwas lat er tound that the waste oilhad been mixed with thick, oily,dioxin-contaminated sludge trom a plant thaihad manufacturedherbicideandhexachlorophcne in1983 Times Beach residents were toldIhatIheU.S.govern ment would purchase their800 homes from a "super fund" established in i960 lo finance toxic-waste cleanups. Dioxin has also been lound in soil and streams sur rounding a wasle-disposal plant in Arkansas and has been detected in (ish taken m pans ot New York and in fish and waier from the Tittabawasseo and Saginaw Environmental health rtvorsinMichigan. Highdioxinlevels continuetoplague theLoveCanalareaofNiagaraFalla,N.Y,,aresidential community built on (and used as a chemical-waste dump inthe 1940s and 1950s. In 1079 the U.S. Envi- f -y ^ . rn n m an tal PrgfertlnnAnarvyIrlAntlfler)91 citieswfviee C < chemicalindyfitHAc fcatym heanurceofdipxin- contaminaiod waste. Dioxin and Vietnam About 20 milliongalofphenoxyherbicideswere among those used lodefoliatevast areasottropicaliorestin Vietnam between January 1962 and September 1971 ,, inan operationcalled Ranch Hand. Various combina tions of the phenoxy herbicides 2,4-D (2.4-dichloro(N phenoxyacetic acid) and 2.4,5-T,thetattercontaminat ed with varying amounts ot dioxin, received names according to the color coding on the barrelsinwhich they were shipped. Approximately 276,000 gal of Agents Green. Purple, and Pinkwere spread over 2.5 millionac offorestbetween 1962and 1964.The mea suredlevelsofdioxinwere as highas 45,000 partsper billioninsome samples. From 1964 until 1971 the major defoliantused was Agent Orange and a modificationcalled Orange Two. Ouring thistime 11.250,000galofOrange were spread over five millionacres ofland. The stated militaryob jectives of forest defoliation were both offensive and defensive:toincreasevisibilityforairstrikesand moni toring of enemy troop movements and to clear land along highways, loading zones, and military bases used by U.S. and South Vietnamese torces. A third objectivewas todestroycropsinordertoreduce food sources in areas controlled by Viet Cong. About 2.6 million U.S. military personnel served in Vietnam between Jan. 1, 1965, and March 31. 1973, tholimeofhoaviestjuso ofAgentOrango. Those likeli est to have been exposed include crew members of helicopters used for spraying and those who loaded, unloaded, and serviced thecrafts.Inaddition,soldiers sprayingfrom backpacks,boats,and truckshad poten tiallyheavy exposure. Because of the persistence of Variationamong apeclotlethaldioxindoae animal was*; t LDy,(Mgper * kgbodywexjntr |3rfmak) .lal monkey labtki mouse dog txjtti'og hamster -*' 'LOv, moatanlainaiooia i 22 45 lessthan70 US 114 morethan300 j morethan500 5.000 i'-d A ****** fit 4 t fitiC tftO f *V. 1 'l (4) 6513 i Environmental health dioxin, personnel in camps where perimeters were sprayed and otherson tootandinvehiclesm forested areas that had been sprayed were also exposed. The affect of exposure to dioxin on the.health ol Vietnam velerans has vet 10 be adequately assessed. Various governmental agencies have been given re sponsibilityforcarryingout a study.Most recently this responsibility has shilled from (he Veterans Admims tralion(VA) (otheCOC. Meanwhile, more than 16,000 veteranshavetiledwiththeVA fordisabilitybenefitsfor health problems claimed tobe related toexposure to Agent Orange. Studiestoexamine the effectofAgent Orange on theVietnamese people are alsobeing car ried out. How dioxin a ffe c ts h um an health The first human health problem from dioxin to be noted was chloracne, a particularly unsightly form of acne with large whiteheads and blackheads, pustules, and sometim es abscesses. Although chloracne was initially thought to be an essential manifestation of dioxin poi soning. more recent studies in Seveso and of the Stur geon railroad workers revealed that only about 15*/ o f those affected developed chloracne. usually younger people and especially those with a history ol teenage acne. This condition can be very persistent: some vic tims ol the 194 9 Nitro accident who developed ch lor acne still had it 34 years after exposure. O ther skin effects include increased pigmentation and* increased facial hair. Skin cancer has also been reported. In the railroad workers, (or e xample. 15% developed one or more skin cancers within three years after exposure. The liverisa major organ forthesynthesis and pro cessing o( proteins, tats, and carbohydrate; It also playsa major roleindetoxifyingandremovingunwant ed substances from the body. For these reasons itIs particularly alfected by dioxin. Many studies have re vealed abnormal enzyme elevations resembling those seen in hepatitis; insome cases these abnormalities .persisted (or years. A disturbing finding in studies of both humans and otheranimals was the profound de rangement ol lipid metabolism with raised levels of triglycerides and cholesterol, both of which can be harmful. Also noted were decreases i~n high-rtensity lipoproteins, which are beneficialto the body. Individ uals with this lipid patiern are much more prone to atherosclerosis, or hardening of the arteries, stroke. .and heart disease Dioxin also seriously affects human reproductive or Cans and their (unction Although lew studies o>st of diQxm's effects on m ale reproduction some men, in cluding Vietnam veterans, have reported impotence and loss nf iihirtn. More than 40% ol the Sturgeon railroad workers were found to have abnormally low sperm counts and high percentages ol inactive sperm Eighteen ol the 47 worse's had abnormally low levels of testosterone, the male hormone responsible for libi do and secondary sex characteristics. Studies of the offspring of people exposed todioxin* containing herbicides in Vietnam and Australia re vealed increased abnormalities of extremities, particu larly fingers and toes; neural tube defects; and other birth abnormalities. Abnormal births have been report ed among the families of exposed U.S. Vietnam veter ans. One study of women exposed to herbicides in a town in Oregon revealed abnormally high miscarriage rales: 130 per 1,000 births, compared with 46 per 1.000 binhs for a similar town not exposed and used as a control. These rates peaked dramatically each June for six years, about two to three months after the spring spraying of 2.4.5-T In the area. InstudiesoftheSturgeonworkers,the genitourinary system also appeared to be affected.~5ome ot these" abnormalities might have bean relatedtothe toxicef fectsolphenol and nrihorhlnrnphflnnlprAcnntwiththe dioxin.Difficulties Included Inflammfltinn obstructed grme now iromtnebladder,and.Insome persons,loss q(sensation of the need to urinate. Studies carried out inSeveso and among (he Stur geon railroadworkers revealed suppression ofthe im mune system inboth groups. Ina large percentage of "Sturgeonworkers,activityofwhiteblood cellscalledTlymphocytes was particularly suppressed. T-lvmphocytesplaya m ajorpartinthedevelopment ofimmunity againstdiseaseand inpreventingcancerbydestroying newly formed cancer cells. The centraland peripheralnervoussystemsarealso major targets of dioxin. Many of the reports of expo suresdocument symptoms ofincreased and long-last ing irritability, severe headaches, profound fatigue. sleepdisturbances,and insomd~asesseizufeSVA m a jor symptom in these groups vtoc-deotession. which appeared to be chemically mediated and not of psy chological origin. Memory loss was also a significant findinginsome ot the studies.An extensive batteryol neurobehavioral tBStSQIV5n totherailroadworkers re vealed m any withcentralnervous system dysfunction" Effectson theperipheralnervous systemmanifested^ themselves as numbness-and tinolino in the finoers and toes. Nerve damaoerevidenced bv slowed and Impaired transmission of electrical impulses in the nerves,was foundinsome peoplealongwithabnormal reflexes and weakness of the extremities.. Joint stiffness and weakness of the muscles also werecommon inmany dioxinvictims.Loss ofmuscular strength, particularlyintne extremities, after briefwork suggested impaired energy transfer mechanisms, which are essential to muscle function. One compo nent ofthe cellaffected by dioxinisthe mitochondrion.~ a structurethathas responsibilityforprocessingchem icalstoprovidereadyenergytomuscles. Inexperimen talanimalsmitochondriawere ahown tobe swollenanj damaged alter exposure to dioxin, a finding that may 1 ( 5) 6 5 1 4 'Organ cycle m cym ptom c m dioxin-expocad railroad w o rker central nervous system general seizures and other serious symptom* sleep difficulties nervousness memory toss dizziness personality change (temper, irnUDiiity) depression cough shortnessofbreath benign tumors severe weight loss weakness headache latigue systemic urinary urgency unnary burning nocturia other urinary tract urnary frequency decreased kbkJo reproduction and sexual luncuon chest pam losso( hearing general gastrointestinal muscular skeletal eyes (including inlection, mtation. vision) numbness and tingling extremities mucous memorane (excluding eyes) Skm percent haln explain the reason tor muscular weakness__ Other organs and tissues affected bv dioxininclude the blood, heart, lungs, kidneys, and mucous memanes oftheeyes and nose. Insome exposed groups ancreatic tunction appeared tobe impaired,resulting in an increased incidence 9 !diabetes. Oioxirt also appears to be linked to an increased incidence o< cancer in exposed humans. One study carried out inVietnam showed an increase inprimary t livercancer. A significantincreaseinsoft-tissuesarco ma. a form of cancer, was found inSwedish workers exposed to2,4,5-T.An increaseincancerratosamong ^ 3ASF workers was alsonoted years aftertheaccident there. Because cancer frequently has a long latency period between the time ol exposure and the appearnee of disease. Iona-term observation of exposed l lopulationsisnecessary, particularlyinview ofanimat studiesshowing dioxin'spotency asacancerpromoter -nd itsabilityto suppress the immune system. I "he work ahead 1Dioxin's stability, toxicity, and potential for wide dis 3mmation inthe environment make docontammation 1 dillicult proQIpm. )wo provoQ methods, irradiation and incineration, are workable only under certain 0 1 | ".umstances. StoresofAgent Orange and Orange Two I atremained aftertheVietnamconflictwere eventual- i. taken toJohnstown Islandm thePacific,puton anm cmeralor ship, takenout tosea, and burned.This meth od was costly and was possible only because the chemical was in a reasonably concentrated, liquid torm. Incinerationisnot practicalfortreatingcontami nated water, buildings,ortons of soil.Chemical degra dation methods are being explored butare stillinthe laboratory stage. There iscurrently no good,,accept- able method fordisposing of or neutralizing dioxin in * most situation* - r Much more information needs to be gathered re garding nearly every facetof the dioxin problem. Ef fortsarebeingmade toidentifyothercommunities that may have been exposed to dioxin so that measures . canbetaken toprotectindividualslivinginthem.Inthe U.S..administrators and legislatorsatvariousgovern- mental levelsare underpressure totoughenInspection and enforcement programs aimed at the producers_ and transporters of hazardous waste and toimprove metnoos torloenurvinnsiteswhere dioxinislikelytobe - creator! __ A betterelaborationoftoxicpathwaysmavultimately.. enable modical researchers to block or nentralire riiOKinorromova ittrom the body. For example, ithas boon tound.that.animals placed on low-irondiets ap- poar 10 bo somewnat less atiecled than those with normal iron stores. Current treatment iaaupportrve and consists mostly of attempts to protect those organs thathave boon affectod ormay be affectocHn the fu- tuie Dioxinviclimshave boen advisedtostopsmoking andtoavoidexcessive exposure tosunlightinorder to iqwor ihoircancer risk Doctors have alsorecommeodad diets low m choiosterpi and triglyceride* tg reduce tholevelsol thoso lipidsiathe blood Such preventive medicmg issoon as a slooqan untilsuch time at mea- to block orromovo dioxin can bo developed. I : <T~ B o rtrM m W C s r n o w . M .D. ^ / Deaember 12, 1985 Mr. Phillip McMath MoMath Law Fina 711 V. Third Street P.0. Box 1^70 Little Rook, HR 72203 Dear Mr. MoMath: I am writing this letter to report to you the resulta and findings of ou r examinations on your twelve cllentsfthat took place in Chicago, Illinois in September and October, 1985. l Based on the medical and environ m e n t a l histories, physical e x a minations and laboratory and other medioal testing, it is my m edical opinion that these twelve individuals were exposed to and absorbed dioxins, inaluding 2 ,3 ,7 ,8 -tetraohlorodibenzo(p)dioxin, and other related compounds into their bodies through One or more portals of entry including through the skin, Inhalation, and ingestion. As a consequence, they are suffering from ohronio ohemioal poisoning involving multiple organs and organ systems with damage to them of a permanent and irreversible nature. The organs manifesting dysfunction and damage from these systemic poisons and the frequency of abnormalities found lnolude: Eyes In exoess of 6 0 % of persons examined had one or more complaints of visual difficulties or pain of various types. Five individuals had complaints of irritated, burning eyes, three had oomplainto of blurring of vision and four complained of watering of the eyes either now or when they resided in Jacksonville. / ^ '/ On physlaal, examination, two individuals exhibited evidence of ohronlc Inflammation ^of the membranes covering the eyes, the oonjunctiva. Two-thirds of thergroup had one or more symptomq of difficult with t their ears, including drainage, i-tohlng, and congestion. :<0 fTgreat ,* Mr. P h i l l i p McMath Page 2 December 12, 1905 concern were the findings 'in one third of the group of tinnitus (ringing in the ears), frequently a sign of eighth cranial nerve d a m a g e and, in more than *IOJi of the group (5 of 1 2 ), oompiaints of a decrease in hearing acuity. Four of the patients revealed some evidenoe of ear drum or other abnormalities on physical examination. Of great significance were the findings on hearing testing. A u d i o g r a m s performed on the group revealed eight individuals with abnormal findings. In six of them the abnormalities revealed hearing loss, most of them in the higher frequencies. This pattern of hearing loss suggests damage to the eighth cranial nerve. Adding to this concern is the fact that in all six individuals, the hearing loss was bilateral. \. Respiratory Tract There were a wide variety of c omplaints relating to the nose and throat and, to a s omewhat lesser degree, to* the lungs. Twenty-five percent of the group (3 of 12) complained of shortness of breath with the same number complaining of nasal discharge, nosebleeds, und sore, irritated, or dry throat. The most frequent symptom, nasal congestion, was found in almost half of the people examined. On phys i c a l e x a m i n a t i o n of the nose, 3 of 12 showed evidenoe of inflammatory ohanges and muaous membrane damage bilaterally. Cardiovascular S y m p t o m s r e l a t i n g - t o the heart included a b n o r m a l rhythms in 2 individuals and palpitations which also probably represent abnormal r h y t h m s in ^ of the 12. Two also complained of chest pain. On physical examination, 2 patients showed abnormal heart rhythm and one of those also had an abnormal pulse rate. Electrocardiograms taken on these individuals revealed that 5 of them had electrocardiographic tracings which were not completely normal. Gastrointestinal System Ten o f the twelve had *one or more c o m p l a i n t s relating to the gastrointestinal system. Those appearing most -frequently included epigastric (upper abdominal) pain or distress, nausea an<T generalized abdominal pain. These symptoms may represent inflammation of the upper Intestine or stomach or be a result of the prophyria which can cause severe abdominajL pain. The most c o m m o n s y m p t o m was diarrhea, a condition complained of by 5 of the 12 persons(examined ( H 2 % ) . Hr . P h i l l i p McMath Page 3 December 12, 1985 Liver The liver generally does not cause "symptoms." One individual, however, did have complaints of Jaundloe of the eyes and skin and his laboratory tests revealed an elevated bilirubin. Laboratory tests of the liver, a major target organ of dioxin and related compounds, revealed that all 12 had two or more abnormalities of this organ with k having five abnormal lab tests and one eaoh having six and seven abnormal tests. These generally reflected abnormal liver metabolism. Of great c o n o e m were the findings of abnormal porphyrin metabolism including porphyria, a normally very rare genetic disease. In this group, 8 had porphyria of one type or another. 7 of the 12 (5 8 f), an extraordinary number, had eoproporphyrinuria. Two of these also had porphobilinogenuria, and one had three porphyrins abnormal. While in a n o r m a l population this is a fare disease and these findings rare findings, they have been shown to be caused tjy exposure to dioxin and related compounds, which are known as porphyrinogenic agents. These abnormalities of porphyrins are a reflection of profound disturbance of major enzyme systems regulating body function. In addition, 11 of the 12 show e d high density lipoproteins (HDL cholesterol} below the l a b o r a t o r y 's normal range vhloh refloats abnormal lipid metabolism, d a m a g e also associated with exposure to dioxins. Seven of eleven i n d i v i d u a l s .had abnorm a l l y elevated prothrombin time which may r e present a bnormal bleeding and clotting damage, also shown to be associated with exposure to dioxin. Beoause of the large number with prothrombin time abnormalities this will need to be repeated since, occasionally, delay in testing of blood samples might cause this test to be ^ o m e w h a t abnormal. Genitourinary System T w o - t h i r d s of these individuals had difficulties relating to the genitourinary or reproductive system. Those symptoms found most frequently included frequency or increased urination; nooturla, that i s , frequent waking during .the night to urinate; and decreased libido, that is, decreased sexual desire in three of the twelve. -^ Central Nervous System The central hervocp 'system la one of the major target organa affected by systemic poisoning from dioxin and related ooqpounds. A wide range of symptoms referable to the system was present :In this group. Those complained of by two or more Individuals lnoluded episodes of a n ^ r , aphasia, difficulty in fconoentratlng, dizziness, and aloep dlfflewl^V Mr. P h i l l i p McMath Page 9 December 12, 1985 I n cluding frequent waking, d i f f i c u l t y In falling asleep and nightmares. Twenty-five percent of those examined complained of anxiety, decreased recent memory, depression and abnormal drowsiness or sleepiness. The two symptoms most commonly complained of were increased irritability in a third of the people questioned and headaches in more than 80* (10 of 12). In addition, a number of those examined showed one or more physical findings referable to the oentral nervous system including 3 with abnormal reflexes. Laboratory testing included a large battery of testa of neurobehavloral function. Forty-two peroent of those tested .(5 of 12) revealed some evidence of brain dysfunction and damage. Fifty percent also showed 'abnormalities of the Zung soale which is a measure of anxiety, and 3 `of 10 Individuals tested showed depression according to the Beck Depression Inventory. Peripheral Nervous System t Eight of those examined had one or more symptoms suggesting abnormality of the peripheral nervoi^ system. One of the most common complaints referable to this system was of tingling and numbness or pins and needles in the extremities. Six of the 12 individuals had this complaint. On physioal examination, 7 of the 12 had one or more a'bnormal physioal findings including ab n o r m a l response to touch and pinprick, the latter mostly in the upper extremities. Three showed abnormal reflexes of the type seen in peripheral neuropathy. The laboratory examination found 5 (^2 J) with abnormal nerve 'conduction. Two^bf the five had two abnormalities and one eaoh had three, four and five abnormalities of conduction reflecting severe peripheral polyneuropathy. Two of those examined had EMG abnormalities of the upper and lower extremities reflecting axonal degeneration of nerves, evidence of far advanced n e u r o l o g i c damage. Musculoskeletal System There were many complaints of musole and Joint difficulty. A number complained of spasms and bramps in the muscles with almost half (5 of 12) c o m p l a i n i n g of pain. Even m o r e had ooraplalnts relating to the Joints, inoluding swelling, and stiffness in the Joints i t i 5 0 i and, in two-thirds of those examined, Joint aohlng or pain. Three of twolvp had evidence of abnormal muscle metabolism with two having an elevated CPK and one, an abnormally depressed CPK. CPK Is an enzyme, which when abnormal, reflects muscle dysfunction. Mr. P h i l l i p McMath Page 5 December 12, 1985 Immune System All of the 12 Individuals examined had 3 or more abnormalities of the teat battery done to evaluate Immune funotion. Four had seven abnormal test results and one eaoh had eight, nine and ten abnormal results. Those with the greatest frequency included total lymphocytes and the percentage of total lymphocytes, a depression of "B" lymphocytes, abnormal numbers of OKT-8 cells (suppressors), oells percent of OKT-IO percent, and abnormal mitogen response with abnormal unstimulated CPH in 8 of the 12 examined. Male Reproductive Four .male patients had fertility analysis carried out. A variety of abnormalities were found in three including depressed sperm counts in two and an increase in the total number of abnormal cells found. Hematopoietic System Six of those tested have some abnormality of the red cell indices. Two of those had three and four abnormalities respectively. In three, the hematocrit was decreased, suggesting a smaller than normal number of red blood cells. i As you can see from this summary, these people have suffered damage to many organ systems as a result of chronic poisoning by dioxins and related chemicals. These Include particularly, 8th nerve damage r e j e c t e d in a hearing loss, multiple abnormalities of liver metabolism including an extraordinary number of individuals with abnormal porphyrins, normally an extremely rare disease in populations not exposed to porphyrinogenic agents, the oentral and peripheral nervous systems, the immune system, and reproductive system. This is not only reflected In the symptoms presented by this group, but in oorifirmatory physical findings and, particularly, laboratory findings of abnormal funotion and disease. We have examined hundreds of individuals who have been exposed to dioxins under sim i l a r or related circumstances, and find that the organ systems which have been damaged and* the type of dafiage which has been done to these organ systems in your ollents are those that we have seen in others similarly exposed. This is particularly true of those chronically exposed; that Is exposed over a period of time. People acutely exposed, for example, workers exposed ln explosions following a runaway exothermic reaction, loften will also develop t, Mr. Phillip HoMath Page 6 December 12, 1985 ohlo r one and o th er aoute symptoms and fin d in g s , and, during the aoute phase o f the d is e a se may show some d iffe r e n c e s from th is group u n t il ohronlo e ffe o ts aet In. I tr u s t t h is w i l l be h e lp fu l to you. Time c o n str a in ts did not permit me to c o m p le te ly oheok a l l o f my a d d itio n s. I b e lie v e the fig u res to be c o r r e c t ; i f th e r e are any c h a n g e s, I w i l l l e t you know. We, o f oourse, w i l l contin ue to a s s i s t in every way th at we can in providing m edioal ad vice and treatm ent fo r your o lie n t s . S in o e r e ly , V- CARMOW, CONIBEAR i ASSOCIATES, LTD. President, Senior S c ie n tist pWCrdp 8009-03 / > / t. 4 *5 6523 c MEMORANDUM TO: VERTAC CHEMICAL PLANT SITE FROM: ALISON PETTIETTE RE: LIABILITY ISSUES CONCERNING THE VERTAC CHEMICAL PLANT IN JACKSONVILLE, ARKANSAS DATE: July 29, 1986 I . Liability Against Dow Chemical Company, U.S.A., Midland, Michigan We have obtained a suitcase full of documents from the Area Supervisor for Vertac Chemical Company, who began working as an operator in 1971. Jerry L. Keister was the Area Production Supervisor at Vertac Chemical Company and retired in March of 1986. He produced the documents which substantiate the following testimony. In 1971 the plant site in Jacksonville, Arkansas, was purchased from Hercules Chemical Company by Transvaal, Inc. Transvaal, in about 1976 or 1977 changed its company name to Vertac Chemical Co. It is my understanding that Hercules Chemical Co. has its home office in Wilmington, Delaware, that Transvaal, Inc., and now Vertac Chemical Co. have their home office in Memphis, Tennessee. Hercules Chemical Co. was the author of a chemical process in approximately 1966 or 1967 to reduce the amount of dioxin contamination of their 2,4,5-T to less than 1 ppm. Hercules Chemical Co. attended a meeting in March of 1965, in Midland, Michigan, held by Dow Chemical Co., U.S.A., as a major manufacturer of phenoxy herbicides. These herbicides were used by the United States government as chemical warfare and as a way of clearing out the Vietnamese jungle. The major chemical companies met in Midland, Michigan in 1965 to discuss the problem posed by their manufacturing of a substance known as 2,4,5-T. The government's names for these herbicides were Agent Orange, Agent Purple and Agent Pink. Agent White was 2,4-D alone and Agent Blue had arsenic in the 2,4-D. The other colors had 2,4,5-T as a major component part. In 1969 and 1970, the United States government banned* the use of phenoxy herbicides in Viet; Nam. By 1971, all the major manufacturers hacl lost their contracts with the United States government to produce the chemical herbicide^ used in Viet Nam. It was at this point in time that Dow Chemical Co., according to Keister, began 6524 c II. providing shipments from Midland, Michigan, of crude benzene and trichlorophenol (TCP) and 2 .4.5-tetrachlorobenzene, which are used in the manufacturing process of 2,4,5-T. The documents provided to us by Keister substantiate each tank car and shipment from Dow Chemical Co. in Midland and other manufacturers of the raw materials used in the Transvaal/Vertac Chemical processes. From 1971 through and including- 1979, Dow Chemical Co., U.S.A., purchased the end product, 2,4,5-T with its contaminant, dioxin, from production in the United States totally. It was at this point that the manufacturing of 2,4,5-T was totally shut down at the Vertac Chemical Co. plant site in Jacksonville, Arkansas. One hundred percent (100%) of the crude benzene and 100% of the trichlorophenol was shipped in in tank cars from Dow Chemical Co., Midland, Michigan, and are verified by the production records produced by Keister. The 2,4,5-T end product was sold back to Dow Chemical Co. pursuant to a contract which we do not have access to at this point in time. However, the production records indicate purchases during the years 1971 to 1979 of pounds of Transvaal/Vertac 2.4.5- T by Dow Chemical Co., U.S.A. Christine Hilbert, a client and ex-employee of transaal, saw in her capacity as lab technician that Transvaal/Vertac's 2,4,5-T was labelled with Dow's label before shipping in Jacksonville. The supplier of inherently dangerous raw materials,who had knowledge of 1) what these chemicals are being usedfor, 2 ) the effective process being used by Transvaal/Vertac Chemical Co. and 3) the inherent risk of populations posed by these particular chemicals has an independent duty to provide such information to the employees of that corporation. Dow Chemical Co. provided no such information to anyone at Vertac or Transvaal. Secondly, the process that Hercules devised in1966 or 1967 to reduce their dioxin levels in their final end product 2,4,5-T was well documented and known to Dow Chemical in the early 60's. Hercules provides a process without Dow Chemical Co.'s help to reduce the dioxin contamination of their 2,4,5-T to less than 1 ppm if they kept manufacturing processes within certain limits. The process that Hercules used was to use a toluene wash on the 2,4,5-T end product in the Recovery Unit and remove all the solvent and waste contamination, including dioxin from their end product, 2,4,5-T. The waste product removed from theprocess left the waste in Jacksonville, Arkansas, on the Vertac Chemical Co. plant site. Hercules dumped open barrels into open pits in the 6 0 's while it was producing Agent Orange, as well as other phenoxy herbicides for the government. Hercules left dioxin*contamination when it let Arkansas in 1971. Liability Against Hercules Chemical Company I 6525 -2- n There are two theories of liability against Hercules Chemical Co. One, they sold a defective process to Transvaal/Vertac Chemical Co. in 1971. Hercules knew that its process left the majority of its waste contamination on the plant site and off the plant site where it had dumped its own waste -during the last- decade,. Secondly, Hercules knew that dioxin could not be biodegraded by 1971, "that it Was a poison "that would 'b'ioadcumulate in the human body. 2,3,7,8-TCDD is the worst poison ever made by man according to the United States EPA. It will be necessary to obtain the contracts where Hercules sold the plant site in Jacksonville, Arkansas to Transvaal, Inc., which later changed its name to Vertac Chemical Co. Vertac, at this point in time, wishes to close its own plant in Jacksonville, since it has had so much pressure from the governmental agencies and various lawsuits which have been filed against it by the citizens of Jacksonville. During the relevant years of Keister's employment, which include 1971 through and including March of 1986, various chemicals were purchased from other manufacturers. However, in and of themselves, those chemicals are not inherently dangerous except when given in acute and/or lethal doses. Vertac purchased many products from Diamond Shamrock, including chlorine and caustic. However, Diamond Shamrock, according to Keister, did not buy back the 2,4,5,-T end product. Therefore, the case against Diamond Shamrock is much weaker than that against Dow Chemical Co. Diamond Shamrock is one ,,of the Agent Orange defendants; however, since Diamond Shamrock did not buy back Transvaal/Vertac's end product, it would be harder to prove that they had actual knowledge of what this company was doing in Jacksonville, Arkansas, with their chemicals. Transvaal/Vertac bagged their acid (2,4,5-T) and shipped it to Dow Chemical Co. in Midland, Michigan. We have the production records from this era, 1971 through and including 1979. These are 55 lb. bags of acid. Ill. Operations Manuals and Lack of Warnings In addition, Keister has provided with the Operating Manuals for all the units on the Vertac Chemical Co. plant site, which includes 1) Chlorinator; 2) the Dechlorinator or Sputnik where they made Trichlorophenol (TCP); 3) the Acid Unit where they put molten Trichlorophenol and Proprionic Acid and made Silvex (2,4,5-T) or they would load 6,000 lbs. of Trichlorophenol with Monochloric Acetic Acid and 50% Caustic, reacted that and made the 2,4,5-T. They bought crude benzene from Dow Chemical Co. and 1,2,3 ,4-Tetrachlorobenzene and chlorinate^ it to make 2,4,5-Tetrachlorobenzene. At one time, they were using-so much benzene that they had to buy benzene from Dow Chemical Co. in orpler to keep up production, and to make their own tetrachlorobenzene; 4) in the early 7 0 's they had a Benzene -3- 6526 2 Unit to make their own benzene from the crude benzene that they purchased from Dow Chemical Co. They had a Benzene Grinding Room because benzene freezes in the winter months if it's not kept above a certain temperature and they would have to grind solid benzene in an interior room near the lunch room'- in border to put it in the reactor. They purchased Caustic -from Hooker Chemical Co. Until 1971^ they purchased all benzene from Hooker. Transvaal bought Trichlorophenol from Dow Chemical Co. and Caustic from Diamond Shamrock. Transvaal bought their Chlorine from Diamond Shamrock as well. They also bought from Tennessee Eastman and Celanese Corp. monochloric acetic acid. A. Chlorination Unit In the Chlorination Unit, Transvaal/Vertac (hereinafter referred to as the "Vertac process") used acetic anhydride and acetic acid in a 2,000 gallon tank filled with gas and introduced liquid chlorine vapors through sparger gas spickets at the bottom and heated this reaction to make either Monochloric Acetic Acid or Proprionic Acid. There were three heat exchangers cooling the water and reflux towers in the Chlorination Unit to make Monochloric Acetic Acid in the Chlorination Unit. Vertac made approximately 7.2 million pounds of Monochloric Acetic Acid from 1971 to 1976, which was used to make the 2,4,5-T in the Acid Unit. In the Chlorination Unit they also had the capacity to make Proprionic Acid by using a red phosphorous catalyst and a heated reaction to 90 degrees centigrade, which was combined with 2,4,5-T and Proprionic Acid to make Silvex (2,4,5-TP). Vertac made a half million pounds a year of Silvex from 1971 to 1976. The Chlorination Unit added chlorine to the reaction to make Monochloric Acetic Acid or Proprionic Acid. Between 1971 and 1981, production at the Vertac Chemical plant site was a dirty, nasty place and all operators were working 16 to 18 hours every day. Production was up. Cleanup was introduced in 1979 when OSHA and/or the EPA came down to begin monitoring this plant site. It was at this time that Vertac Chemical Company began being fined for the wrongful disposal of hazardous waste off plant site and on plant site, which up until that time had been dumped by tank trucks which were filled up at the various units with waste products and just dumped into the fields and open pits dug by the workers and lined with dirt only. Vertac started using visqueen and other clay liners in these pits after 1980. B . Dechlorination Unit (Sputnik) In - reactor tanks, Transvaal/Vertac put 1,2,3,4-Tetrachlorobenzene and loaded reactors from the top in 22 inch manways which were bolted down. Vertac put Tetrachlorobenzene into Methanol, methyl alcohol in a 750 gallon tank. The temperature was 150 degrees farenheit -4- 652 c( . under 300 pounds of pressure and 100% Caustic to make Trichlorophenol (TCP). The Acid Unit took the Monochloric Acetic Acid and the 2,4,5-Trichlorophenol and blended it together to make 2,4,5-T or it could make Trichlorophenol and Proprionic Acid in the Acid Unit and make 2,4,5-TP (known as Silvex, trade name). The Acid Unit could make 2,4-D as well, which is the other component of Agent Orange and causes' such things as neuropathy, and c a n "also be a 'cause of chloracne. There are three Recovery Units that were used during various stages of this process. Hercules had two Recovery Units. These were cooling ponds or a settling pond where they took the waste in a cooling pond and recovered the water and sent it through the system again. The recovery pond is now built up into Vertac Mountain which is a clay liner to contain the waste on the plant site. However, the clay is leaking because it is nonimpervious to dioxin contamination. In fact, dioxin will not photodecompose in sunlight, although, at one time Vertac had tried to dry out the dioxin in the sun light to photodecompose it. The Recovery Unit that Hercules devised and that was used by Transvaal/Vertac was devised by Hercules in 1965 to 1967, which used toluene washes in an agitator, which on the plot plan is symbolized by "A" to settle out the solvents and the other undesirables into a 2,000 gallon vessel; this waste was barrelled and dumped in open fields between 1971 and 1973 on the plant site itself; and later the company got a dump truck with a large tank on it which was filled up with waste everyday and on the night shift was dumped into the open field or pit by the workers themselves. C. Recovery Unit In the Recovery Unit, all the 2,4,5-T went through a system which had nine washes, three dirty washes and six clean washes of toluene in an agitator to drop out the solvents and the solids and distill them into a tank at the bottom of this reaction to take everything that was not supposed to be in their end product 2,4,5-T and dump it in the Jacksonville plant site area. Vertac buried these barrels in the fields in pits and then, without protective clothing, Vertac set the barrels in the fields on top of the ground at first and then later Vertac buried them after the EPA got out there in 1980. Vertac hauled 2,000 gallon vessels every day filled with dioxin contaminated waste and dumped them into large pits that the workers built in the field. Every twenty-four hours Vertac made dioxin waste. Vertac stored some of the barrels in storage sheds until the drums started leaking and in 1985 Vertao. capped the cooling pond, which at^one time was a Recovery Unit to provide cooling water to all the plant sites. Vertac had no rain suits. Vertac had cotton coveralls ? -a hard had and goggles and that was the only protective equipment that workers received for these : 6528 -5- cc operations. Workers had no respirators at all and they were not even required to wear respirators until the last year, 1985. Vertac had one chlorine gas mask available. The cotton coveralls provided were not chemically treated until after Pelton died in 1983. Workers did not know- until. James Cox died that Dichlorophenol was lethal when you got it all over you. James Cox poured himself a sample of Dichlorophenol and died. Cox was burned to death by the acid. This was in the Chlorinator Unit. Before that, two guys had been killed at the Dechlorinator Unit when there was a fire in the reactor. Marco Brolo has died. Mrs. Brolo, who Keister believes is a good friend o f CMackey Pierce^ The Dechlorinator Unit had an operator and the Chlorinator Unit operator was to help him. He was called the #2 Acid Man and he was to help the Dechlorinator Unit operator load the reactors in the Sputnik to make Trichlorohenol. Sputnik reactors had 22" manways. The Sputnik Unit had a floor and had three dechlorinator tanks with wooden staircases up to the platform of the tank and 22" or 24" manways at the top which could be unbolted. With a runaway reaction for the Dechlorinator Unit there would be these pipes with safety valves. When the reaction ran away there would be spewing black tarry stuff from the Sputnik reactors out of these pipes. When you opened the manways there was fire inside the reaction. The reaction was called "runaway" because at high temperatures the temperature was off the instruments and so was the reaction. There was no way to know how hot it was burning or at what,pressure. In the middle 7 0 's for one year Transvaal/Vertac had a joint venture with BASF to make a product called Dalapon for a short while and then it was banned. D . Benzene Unit The Benzene Unit had big dryers in it and Vertac brought their crude benzene in on conveyors; ground it; and put it into hoppers in order to use in the remaining process. If benzene gets cold it freezes. Keister believes that the people that own Vertac are the DeNore brothers from Italy via a holding company in New York called Didecon Investments. Keister believes that Transvaal/Vertac had a plant in West Helena, and in Mississippi. He also heard that Formenta was a Swedish company has bought Vertac. This is unsubstantiated at this time. With the documentation by Keister and the testimony by the ex-employees and current employees, even in 1979 and 1980 when M t . Sinai was paid by Vertac to come in and give employees physicals, the company's position was the dioxin can't-hurt you and you can eat it for breakfast. Doc Sidwell, who was instrumental" in devising the "Hercules process" with the toluene wash in 1965, did sample it with his nose and mouth in front of workers in order to show them that he could drink it for breakfast and still live. 6529 -6- (( Doc Sidwell is currently hired as a consultant by Transvall/Vertac Chemical Company and can go on the plant at will. There were five basic units at one time or another at the Vertac Chemical Company plant site. IV. Plot Plan We have obtained an'accurate plot'plan of this plant site in Jacksonville, Arkansas, which includes references to the old Hercules P & I.D. drawings, which were used by Vertac in its 1985 revision. It clearly shows where the Dalepon Unit, the Benzene Unit, the Chlorinator, the Dechlorinator, the Acid Unit, as well as the Recovery Unit, were located, which I have been referring to on the map. It also can be referred to to show where the barrels of redrummed contaminated waste are being stored presently on the plant site itself. As I have said, the entire place is contaminated, more so on the plant site than off the plant site. V . Statute of Limitations It is very important that we have " solvent" defendants who can be held negligent or strictly liable on the basis of Restatement of Torts, products liability and/or some other theory of law. It is equally important to find out what is the best forum to bring these lawsuits and whether that state has borrowing statutes which would make the choice of law an interpretation of Arkansas law. Arkansas compensation statute for death and/or occupational disease is strictly interpreted by the state courts of Arkansas. Basically, in order to avoid the Arkansas compensation statute on a negligence basis of any sort, v o n bavp to s h o w specific intent to kill each individual. This cannot be shown u n d e r t h e f a c t s a n d c i r c u m s t a n c e s of this particular case on behalf of the employees themselves. However, Arkansas has a product's liability statute as of 1973 (adopted Restatement of Torts 402 A & B and it would seem to me that we can avoid the workers' compensation statute by suing the manufacturers of raw materials who bought the end product, such as Dow Chemical Company, and equally sue Hercules Chemical Company for (1) using a defective process; (2) inventing and selling a defective process to a successor corporation; and (3) leaving there their dioxin waste in open pits and burying them all over the plant site itself. V I . Exposure In addition to the direct exposure for the workers, the wives and children had direct exposure to the chemicals and the waste on Vertac plant site because they were allowed at will to yisit their husbands. The wives brought family members on the plant site itself and strangers were - 7 - bA 0t ' A,/ (c permitted on the plant site at any time during the past fifteen years that Vertac has operated this plant. All the wives had direct exposures, so did the children. There may be property damage cases for the people that currently own homes in Jacksonville, Arkansas, or in a location which is south or southeast of the Jacksonville, Arkansas plant site. The EPA has published, as of July 15, 1986, that Off-ite Feasibility and Remedial Investigations concerning the off-site contamination of Jacksonville, Arkansas. Commercial fishing has been closed from Jacksonville south and southeast all the way to the mouth of the White River which flows into the Mississippi River. South of the Jacksonville plant site, the EPA and the FDA has closed commercial fishing from Rocky Branch Creek in and around Lake Dupree to Bayou Meto and to the mouth of the Arkansas River, which crosses Little Rock, Arkansas. The Arkansas River flows into the Mississippi River as well. We have obtained evidence from other plant workers of documents obtained from the plant site itself showing that in 1983 Vertac and Hercules entered into a consent decree with the Environmental Protection Agency. We must obtain the on-site samples taken by the United States EPA and the FDA from Region VI in Dallas, Texas and in Washington. All the sampling and the routes of exposure have been done by the EPA and published by the EPA, which was just finished July 15, 1986. Representatives from Washington, Atlanta and Dallas appeared in Jacksonville on July 15, 1986, and held a public hearing before the citizens of Jacksonville o tell the public that they were contaminated if they lived in the town of Jacksonville. After seven years of studying this plant site and doing numerous water and soil samples in the ponds and flood plains in and around Jacksonville, the EPA said that they should not eat any livestock, poultry, fish, etc., drink any water or use their toilets in Jacksonville, Arkansas if they lived anywhere from Vertac south or southeast all the way through Lonoake towards the Mississippi River. The EPA did not test upstream, even though the prevailing winds were from the south or southwest, which would cause the wind to blow contamination towards Cabot, Arkansas, where some clients live. Also, fish swim upstream and no fish samples were done upstream of Jacksonville. As far as residential contamination, I do not think we have any problem with anyone that has lived in Jacksonville, Arkansas while working for Vertac. VII. Medical Causation It became apparent from individual client interviews and review of available medical records that most of -our clients have reported their symptoms to 'doctors in and around Jacksonville and Little Rock. Many of them have "had surgery and had been diagnosed with chloracne, at least by M t . Sinai^. Many of them have nervous disorders, such as - 8 - 6531 (( peripheral neuropathy and other forms of neuropathy, which can be chemically induced. All of the chemicals which Vertac made, including 2,4-D and 2,4,5-T, can cause nervous disorders and have been known to cause chloracne. The combination, along with the dioxin waste, as noted by the EPA last week, is the most poisonous of all the chemicals and the most long lasting. The EPA said it would take 10,000 man years' for the amount of dioxin to biodegrade as found in the EPA Off- Site Investigations. The EPA did not mention their on-site investigation pursuant to the consent decree to keep all of this quiet. The On-Site Investigation I 'm sure reveals dioxin contamination was found on the lunch table in the break room ( locker room), in the shower stalls, it was tracked on shoes all over the place, it was seeping out of the ground, oozing a black tarry substance. It is running into the creeks and bayous and contained in the soil samples. Dioxin does not mix with water, but adheres and leaches to the soil through the waterways and is moved by the water. It can be blown by the wind. We need a Memorandum of Law concerning the laws in Michigan, Delaware and other states where Hercules and Dow Chemical Company do business, including Texas, and the choice of laws that would be applied by the various courts in any given state. We also need to look at the Arkansas products liability law to see whether the discovery rule applies. / -9- 8532 UL VITERBO V . DOW C H EM IC A L CO. 6357 Jules R. VITERBO, et ux, (Patricia Viterbo), Plaintiffs-Appellants, v. The DOW CHEMICAL CO., Defendant-Appellee. No. 8 6 -2 8 0 6 .------ "United States Court of Appeals, Fifth Circuit. Sept. 11, 1987. Individual exposed to chemical herbi cide and his wife brought action against chemical company to recover damages for alleged toxic effects of herbicide. The United States District Court for the East ern District of Texas, Howell Cobb, J., 646 F.Supp. 1420, granted chemical company's motion for summary judgment, and individ ual and wife appealed. The Court of Ap peals, E. Grady Jolly, Circuit Judge, held that information available to physician lacked foundation and reliability necessary to support expert testimony. Affirmed.1 2. Evidence <=555.2 Generally, questions relating to bases and sources _of expert's opinion affect weight to be assigned that opinion rather, than its admissibility and should be left for jury's consideration; however, in some cases source upon which expert's opinion relies is of such little weight "that jury should not be permitted to receive that opinion, such as when opinion is fundamen tally unsupported. Fed.Rules Evid.Rules 403, 703, 28 U.S.CJL 3. Evidence <=555.10 Sources upon which physician based opinion th at individual's exposure to herbi cide caused individual's physical and emo tional problems lacked foundation and reli ability necessary to support expert testimo ny and, therefore, opinion could be exclud ed; sources of opinion were individual's incomplete oral medical history, tests con ducted by physician indicating that individ ual suffered from some sort of toxic reac tion, but not implicating herbicide, and study concerning exposure of rats to chem ical in herbicide. FetLRules Evid.Rules 403, 703, 28 U.S.CA. Appeal from the United States District Court for the Eastern District of Texas. 1. Federal Civil Procedure =2545 Before WRIGHT,* GEE and JOLLY, Cir cuit Judges. District court may inquire into reliabili ty and foundation of any expert opinion to determine admissibility, in determining whether to grant summary judgment de spite party's producing expert to support its position. Fed.Rules Evid.Rules 403, 703, 28 U.S.C.A: E. GRADY JOLLY, Circuit Judge: In this case today we consider the ques tion whether it is so if an expert says it is so. Although the plaintiff's expert here said it was so, the district court excluded the expert's opinion and granted summary judgment in favor of the defendant, 646 * Circuit Judge of the Ninth Circuit, sitting by designation. Synopsis, Syllabi and Kev Number Classification _ - "COPYRIGHT 19S7 by WEST PUBLISHING^ CO. The Synopsis, Syllabi and Key N um ber CUssi/V cation constitute no part of the opinion of the court. i 6534 G35S VITERBO V. DOW CHEM ICAL CO. F.Supp. 1420 (E.D.Tex.1986). We uphold the lab before it could be analyzed. Addi the district court because the plaintiff's tionally, tests were performed indicating expert brought to court little more than his renal failure and hypertension, for wllier credentials and a subjective opinion. Y rerbo was already taking medication/ Fi- ' nally, an electrocardiogram, u a I' scan and I immune system studies all produced nor .From April to September 1981, Jules Vi mal results although allergy tests revealed terbo used Tordon 10K, a pesticide manu sensitivity to a variety of molds. factured by Dow Chemical Company (Dow), to eliminate tallow trees on a 700 acre tract of land in Jefferson County, Texas. On weekends he would pour the Tordon 10K pellets into a bucket and walk through the fields throwing the pellets on the ground. On Christmas Eve 1981, Viterbo experi enced his first alleged symptoms of expo sure to Tordon 10K. On that day, he cried, was nervous, and had itching on his arms and legs. The symptoms continued until April 1983, at which time he "felt [he] was The Viterbos mitiatecTTms action to re cover damages for the alleged toxic effects on Jules Viterbo of Tordon 10K. After discovery had ended, Dow moved for sum mary judgment on the ground that the Viterbos were unable to prove the neces sary causation and alternatively that the Viterbos' expert testimony was not admis sible under Federal Rules of Evidence 703 and 403.1 The district court agreed with Dow and granted summary judgment more or less out of the woods." At the time of his deposition in July 1984, he stat II ed that he still suffered from a rash and felt "about 80 percent mentally aware [as he] was before [he] got sick." Beginning in 1982, Viterbo saw a number of doctors, including psychiatrists. These doctors di agnosed a variety of ailments, including endogenous depression, depressive neuro sis, essential hypertension, and allergies. In granting Dow's motion for summary judgment, the district court concluded that the expert testimony of Dr. Johnson was inadmissible under Federal Rule of Evi dence 703. The district court examined the underlying data on which the experts' opin ion was based, and found them to be lack ing in reliability and probative value. ^Spe In April 1984, Viterbo was admitted to cifically. the district court held that Dr, Northeast Community Hospital where he Johnson Tacked objectivity in~tRat he diag underwent a battery of tests conducted by nosed viierpo's condition a5~resuiung from Dr. Alfred Raymond Johnson to determine exposure to Tordon 10K based onlv on the the source of his ailment. At that time, he pouenrs oral history and without the bene-_ was exposed to a diluted form of Tordon f!t of medical te^rs. Additionally, Dr. John 10K and showed no reaction. Blood tests son had no scientific Titeraiure to support revealed a high level of certain chemicals, his position and the tests which Dr. John including dieldrin, a herbicide. A fat biop son performed did not establish a' causal sy was also performed but misplaced by link between Viterbo's symptoms and Tor- 1. The district court also excluded the testi mony of another expert, Dr. Raymond Sing er, offered by the Viterbos. At argument, however, counsel for Viterbo withdrew him as an expert and conceded the district court properly excluded his testimony. We there fore do not consider the district court's rul ing on the admissiblity of his testimony. 6535 i V ITERBO V. DOW CH EM IC A L CO. 6359 don 10K. The district judge further noted that Dr. Johnson had no experience with Tordon 1QK and that none of the four of Viterbo's treating nhvsicians would diag^ nose Tordon 10K as the cause of Viterbo's condition. may still inquire into ihe reliability and foundation of any expert opinion to deter mine admissibility. Soden. 714 F.2d at 502-03; In re Agent Orange Product Lia bility Litigation, 611 F.Supp. 1223, 1239 (E.-D.N.Y.1985). [2] The district court should, initially, Ill approach its inquiry with the proper defer aueInpxp[opc1lrnr]uuodlpwiirnnihggaestetWthhoiehnenretthttthhehiesseerticmadasdisousmenmtryiiismscstoisabofrciylleoiDltuyyjrru.tddoeJgfepomrehreenenxddnspoetennirn.ttwasedabaionfiansfcsgpeeeercusantttteeohatsrhneaetdlrbhewetrthsuwoealjiueenuger,rhcnyiettqs'ssutcoaoeordsnobftmfileloeiiacsnantssasiinssbeigrigxletinhpltoayeeeptdriiatnna'ntsigrhodbnaoisstttpoh.eioornpuitAohiolnndesf | opinion evidence the trial court has broad be left for the jury's consideration. See discretion and its rulings must oe sustained . Dixon v. International Harvester Co., 754 unless manifestly erroneous! Crawford v. F.2d 573, 580 (5th Cir. 1985). .In some 'T/urLK, 44,T"F.2d 738, 745-41 "(5th Cir.1971); cases, however, the source upon which an Rodrigues v. Olin Corporation, 780 F.2d expert's opinion relies is of such linjp 491, 494 (5th Cir.1986). There is no dispute weight that the jury shouic not be permit here that Dr. Johnson was properly quali ted to receive mat opinion. Expert opinion " fied as an expert The dispute centers on testimony falls into this category when the source and basis of the expert opinion that testimony would not actually assist that he tendered. We first look therefore the jury in arriving at an intelligent and to Federal Rule of Evidence 703, which sound verdict See J. Weinstein &. M. Ber reads: ger, Weinstein's Evidence 702[1] (1985) The facts or data in the particular case (assistance of trier of fact is central con upon which an expert bases an opinion or cern of Federal Rules of Evidence regard inference may be those perceived by or ing opinion witnesses). If an opinion is made known to him at or before the fundamentally unsupported, then it offers hearing. If of a type reasonably relied no expert assistance to the jury. Further upon by experts in the particular field in more, its lack of reliable support may ren forming opinions or inferences upon the der it more prejudicial than probative, mak subject, the facis or data need not be ing it inadmissible under Fed.R.Evid. 403. admissible in evidence. See Barrel o f Fun, Inc. v. State Farm Although Rule 703 expanded the accept able bases of expert opinion at common law, see Soden v. Freighiliner Corp., 714 F.2d 498, 502 (5th Cir.1983), this expansion does not extend to "make summary judg ment impossible whenever a party has pro duced an expert to support its position." Fire & Casualty Co., 739 F.2d 1028, 1035 (5th Cir.1984) (evidence admissible under Rule 703 must satisfy Rule 403 which ex cludes evidence "if its probative value is substantially outweighed by the danger of unfair prejudice, confusion of the issues, or misleading the jury'"). Merit Motors, Inc. v. Chrysler Corp., 569 Against this brief background, we now F.2d 666, 673 (D.C.Cir. 197.7). The court turn to decide the case before us. As we 6536 > 6360 VITERBO V. DOW CHEM ICAL CO. are reminded by Soden: "Though courts ens this source as a foundation for Dr. have afforded experts a wide latitude in Johnson's expert Opinion. picking and choosing the sources on which to base opinions, Rule 703 nonetheless re B. quires courts to examine the reliability of Next Dr. Johnson relied on the tests he those sources." Soden, 71A F.2d at 505. "Those sources" here are 'VirprbnV p-?.L conducted. The tests, at best, support a conclusion that Viterbo suffers from some memcai history, tests conducted bv Dr..*IV sort of toxic reaction. The only supportive J ohnson, and a study of the effect of pic'lo- test results on which Dr. Johnson relies are ram on rats. We examine each source in those showing hypertension and renal fail turn. ure, both being characteristic of toxic expo sure. Neither these test results nor any IV test result implicates Tordon 10K as the A. basis for Viterbo's symptoms.3 Viterbo was, however, exposed to a small amount First Dr. Johnson relies on Viterbo's oral of Tordon 10K to which he showed no history given during his examination of reaction. Dr. Johnson explained that the Viterbo. Although a patient's oral history hospital board would not allow a patient to is generally considered reliable, see J. be exposed to a large amount of a chemical Weinstein and M. Berger, Weinstein's Evi to which they appeared to be sensitive, dence 703[2] (1985), t he history Dr. John even though there wras no evidence, except son used lacked reliability because it was Viterbo's subjective belief, that he was sen incomplete in a critical p.rpt\.2 -In forming sitive to Tordon 10K. Dr. Johnson further his opinion, Dr. Johnson was not aware explained that Viterbo adamantly refused that Viterbo had a family history of depres closer contact with Tordon 10K, even sion and hypertension, and that several of though, as noted by defense counsel, Viter his relatives had been hospitalized and bo brought Tordon 10K pellets to Dr. John treated for these symptoms. This omission son's office. In attempting to explain Vi is particularly damaging to the reliability terbo's failure to react, Dr. Johnson stated of Viterbo's oral history' because Viterbo that the amount was so small that he did was experiencing symptoms characteristic not expect a reaction; the fact remains, of depression and hypertension, and Dr. however, that Viterbo did not react in the Johnson admitted that hereditary traits slightest degree. However, blood tests did could cause symptoms similar to Viterbo's. reveal a high level of another, chemical, Thus Dr. Johnson's failure to take into dieldrin. which can cause depression: Dr. account this family history seriously weak Johnson recognized that the level was high 2. The district court rejected Dr. Johnson's reliance on Viterbo's oral history on the ground that Dr. Johnson formed his opinion before conducting any test. We agree that-' an expert who forms an opinion before he> begins his research is biased and lacking in objectivity: See Perry v. United States, 755 *F.2d 888 (11th Cir.1985). Because we reject Dr. Johnson's opinion on other grounds, it is not necessary to resolve this question. We would note, however, that this could be an additional ground indicating lack of reliabili ty o f his opinion. 3. Dr. Johnson himself admitted this at his deposition: "I have not had any scientific proof on a challenge that [Viterbo] is sensi tive to Tordon 10-KJ' ,_ 6537 VITERBO V. DOW CHEM ICAL CO. 6361 but ignored this chemical as a cause of evidence is clearly not sufficient to provide Viterbo's symptoms, based again on Viter a source of support for an opinion that bo's oral history that he had not been in Tordon 10K caused Viterbo's depression, contact with that chemical. According to nervousness, hypertension, renal failure Dr. Johnson, the dieldrir, test was merely and other ailments. an indication of Viterbo's chemical hyper sensitivity, but there was no explanation as to how the substance was in Viterbo's V blood. [3] In summary, then, Dr. Johnson's The significance of th lark of objective opinion rests on Viterbo's statements that evidence linking Tordon 10K to Viterbo's he experienced certain symptoms and that ailments is heightened dv Dr. Johnson's Tordon 10K was the only possible cause. admiccion that the sympmms could have a This opinion simply lacks the foundation number of causes. When asked to name and reliability necessary to support expert other potential causes o: these symptoms, testimony. As an unsupported opinion, it Dr. Johnson stated, "You know, you read does not serve the purposes for which it is the textbook of medicine, and any page you turn to, you will find those symptoms can be caused by any disease process." It is clear to .us,. as it was to the district court, that Dr. Johnson's reliance on these test results as a source of his opinion that Tor don 10K caused Viterbo's illness is un founded. offered, that is, objectively to assist the jury7 in. arriving at its verdict. We do not hold, of course, that admissibility of an expert' opinioh depend* Upon tne expert'^ disproving or discrediting every possible cause otner tnan tne one espoused bv him. _ Here, however, Dr. Johnson has admitted that Viterbo's symptoms could have numer- ous causes and, without support save Viter C. hn's o ra l gimnlv picks the cause Finally, Dr. Johnson relied on a study of *the effect of picloram on rats that showed that when exposed to large amounts of the chemical, the rats developed cancerous tu mors and died. He admitted that the ef fects of chemicals differ between humans and rats. Here, of course, there was no evidence Viterbo had been exposed to com parable amounts, nor that his symptoms that is most advantageous to Viterbo's claim. Indeed, Dr. Johnson's testimony is no more than Viterbo's testimony dressed up and sanctified as the opinion of an ex pert. Without more than credentials and a subjective opinion, an expert's testimony that "it is so" is not admissible. The dis trict court properly excluded and granted summary judgment for Dow. were similar in any respect. We then are The judgment of the district court is left to conclude that the study, at most, is therefore only evidence that picloram may produce some unidentified effect on humans. Such AFFIRMED. 6538, ! Adm. Office, U.S. Courts--West Publishing Company, Saint Paul, Minn. H1 y Curriculum V i t a e - M a r v i n S. L e g a t o r Page l CURRICULUM VITAE NAME: Marvin Seymour Legator, Ph.D. DATE: October,1987 PRESENT POSITION AND ADDRESS: Professor and Director Division of Environmental Toxicology Department of Preventive Medicine and Community Health University of Texas Medical Branch Galveston, Texas 77550 Office phone: 409/761-1803 BIOGRAPHICAL: Date of Birth: lace of Birth: Marital Status: Children: Home Address: Social Security Number: June 27, 1926 Chicago, Illinois Married Three 70 Colony Park Galveston, Texas 77551 348-16-3682 EDUCATION: 1948 Microbiology-Biochemistry 1948 Biochemistry 1951 Microbial Genetics-Biochemistry B.A. M.S. Ph.D. University of Illinois Urbana, Illinois University of Illinois Urbana, Illinois University of Illinois Urbana, Illinois > Curriculum V i t a e - M a r v i n S. L e g a t o r Page 2 PROFESSIONAL AND TEACHING EXPERIENCE: ^976-present Professor and Director 1972-1976 1968-1972 1962 - 1972 1952-1962 1951-1952 Professor of Genetics Professor (part-time) General and Medical Genetics Chief, Branch Genetic Toxicity Branch Head, Animal Health Program Senior Microbiologist 1948-1950 Instructor Division of Environmental Toxicology Department of Preventive Medicine and Community Health University of Texas Medical Branch Galveston, Texas Brown University Providence, Rhode Island George Washington University Washington, D.C. Food and Drug Administration Washington, D.C. Shell Development Company Modesto, California Julius Hyman Company Denver, Colorado University of Illinois Urbana, Illinois COMMITTEE RESPONSIBILITIES: UTMB Committees : University Cancer Center Committee (through 1982) University Appointment, Promotion and Tenure Committee (through 1980) University Fellows Grants Committee Department of Preventive Medicine and Community Health Executive Committee Department of Preventive Medicine and Community Health Steering Committee Department of Preventive Medicine and Community Health, Appointment Promotion and Tenure Committee Outside Committees: 1987 Member, Water Quality Advisory Committee,,Texas Water' Commission .Curriculum Vitae - Marvin S. Legator Page 3 1985 Member, Scientific Review Panel for the National Library of Medicine _ 984 Board Member, Committee for Responsible Genetics 1983 Member, Food and Nutrition Board's Committee on Food Chemicals Codex (expires October 31, 1987). 1983 Member, Board on Toxicology and Environmental Health Hazards' Committee on Epidemiologic Investigation of Air Pollutants (expires March 31, 1985). 1983 Member, Agent Orange Advisory Committee to the Texas Department of Health (expires January 1, 1988). 1983 Environmental Protection Agency Science Review Panel for Health Research 1983 Subject Selection Committee of the Texas Veterans Agent Orange Assistance Program 1980 March of Dimes Committee on Reproductive Hazards (Chairman) 1980 Environmental Protection Agency Research Grant Review Panel 1980 Environmental Protection Agency Criteria Document Panel 080 Environmental Protection Agency Committee Chairman, Gene-Tox Program (HMA) 1980 Science Committee of Food Safety Council 1975 Oversight Committee for Proctor and Gamble to determine adequacies of toxicological procedures 1975 Committee 17, Analysis of Methodology of Mutagenicity Testing 1973 National Academy of Science Committee on Biological Hazards^ of Low Levels of Radiation 1972 Member of Swedish Mutagenicity Testing Government Sponsored Committee on 1971 Japanese and United States Government Committee on Toxicology 1971 Member of World Health Organization Committee on Use of Hycanthone 1971 1970 Chairman of Government Hearing on Safety of Immunological Preparations r Member Steering Committee on industry-Academic, Committee on Toxicology ; 6542 .Curriculum V i t a e - M a r v i n S. L e g a t o r Page 4 1970 National Institute of Mental Health - Committee on Genetics Effects of Drug Abuse MEMBERSHIP IN SCIENTIFIC SOCIETIES: American College of Toxicology Co-Founder and Member, Environmental Mutagen Society New York Academy of Sciences Society of Occupational and Environmental Health HONORS: Honorary Health Advocate Award - "... awarded in recognition of outstanding contributions in health advocacy and promotion of the public's health to Marvin S. Legator." Health Policy Advisory Center, New York, New York, November 15, 1983. Food Safety Council 1976-1982 - "With deep appreciation for the tireless effort that Marvin Legator devoted to help the Food Safety Council achieve its goals. This experiment in concensus building has shown that representatives from industry and non-industry with different viewpoints can work together toward a better way for making food safety decisions." -.S. Environmental Protection Agency Certificate of Award - Presented to Marvin S. Legator in recognition of noteworthy contribution and special achievement for the U.S. Environmental Protection Agency, Cincinnati, Ohio Visiting Scholar Award at Western Michigan University 1980 Nominated for 1980 Distinguished Faculty Research Award F.D.A. Award of Merit - Presented to the Genetic Toxicology Branch (M. Legator, Chief), 1971 Key Lecture Award by the American Genetics Association for Outstanding Contributions on the Implementation of Genetics for Human Welfare and Improvement, 1970 U.S. Government Award - Technique Advance in Cell Culture, 1965 ADDITIONAL INFORMATION: Areas of Teaching and Research Competency: Mutagenicity ,, Cytogenetics ^ "productive Studies / I + ~ 6543 .Curriculum V i t a e - M a r v i n S. L e g a t o r Biochemistry Molecular Biology `ssue Culture (Post Doctorate Course, University of Wisconsin, Madison, Wisconsin) Page 5 Consulting Activities: Panel Member, Toxicology Panel on Psychochemicals, Commission on Life Sciences, National Research Council, National Academy of Sciences, 1983 Expert Witness, Texas Senate Subcommittee on Consumer Affairs, 1982 Expert Witness, U.S. House Subcommittee on Oversight and Investigations of the Committee on Energy and Commerce, 1982 Consultant, Hooker Chemical Company, 1980 Consultant, JRB Associates, 1980 Consultant, Toxi-Genics (Fabrizio), 1980 Consultant for Environmental Protection Agency, 1976-1980 Consultant for Lady Clairol, 1976-1978 Expert Witness, Committee on Science and Technology, 1975 Dow Chemical Company, 1974-1979 National Institute of Drug Abuse, 1973-1980 Consultant, Senate Committee on Public Works, 1970 Other Activities: Elected Member, Collegium Ramazzini, 1983 'amber of the Board of Directors, Committee for Responsible Genetics, 1983. .ember, Critical Issues Committee on Accreditation, Certification and Standardization, Environmental Mutagen Society, 1983-84. Co-chairperson, Workshops and Training Committee, Environmental Mutagen Society, 1983-84. Member of the Board, Texas Center for Rural Studies, Inc. The corporation is organized to provide research and educational services regarding the quality of life in Texas, including, but not limited to, the health, economic and environmental effects of pesticides and other chemicals; public policies effecting the rural economy; and the enhancement of the role of family farmers, farm laborers and rural residents in Texas agriculture, 1983, Austin, Texas. Co-Director of Workshop, Environmental Influences on Fertility, Pregnancy, and Development: Directions for Future Research, May 24-25, 1982 Cincinnati, Ohio Director of CME Workshop for Practicing Physicians, Recognizing, Diagnosing, and Treating Chronic Toxic Chemical Effects, July 16-18 1981, Galveston, Texas Director of Annual Genetic Toxicology Course, Galveston Director of Annual Genetic Toxicology Course, Hunt Valley Co-Director of Annual Toxicology and Law Course, Houston Director of Annual Workshop on Carcinogenicity, Mutagenicity . and Teratogenesis ,, , -' sponsored by the March of Dimes Birth Defects Foundation "acuity member of short course on Toxicology at Wayne State University,  C u r r i c u l u m V i t a e - M a r v i n S. L e g a t o r Page 6 1976-1979 Coordinator of Workshop on Occupational Monitoring for Genetic Hazards, March 27-29, 1975 visiting lecturer to Heidleburg University, Germany, 1971 Editorial Responsibilities: Editor, Journal of Teratogenesis, Carcinogenesis, and Mutagenesis Editorial Board, Journal of Environmental Mutagenesis (through 1981) Editorial Board, Toxicology and Industrial Health BIBLIOGRAPHY Published: A. Articles in Journals Legator, M.S., and Gottlied, D. 1954. The Biosynthesis of Chloramphenicol 1 Precursors Stimulating the Synthesis. J. Bacteriol. 2. Legator, M.S., and Racussen, D. 1959. Mechanism of Ally Alcohol Toxicity. J. Bacteriol. 2. Legator, M.S., and Withrow, A. 1964. Aflatoxin: Effects on Mitotic Division in Cultured Embryonic Lung Cells. J. Assn. Official Agricultural Chemists 47:1007-1009. lilds, V . A . , and Legator, M.S. 1965. Lactic Dehydrogenase Isozymes in Diploid and Heterploid Cells. Life Sciences 4: 1643-1650. Legator, M.S., Zuffante, S.M., Harp, A.R. 1965. Aflatoxin: Effect on Cultured Heteroploid Human Embryonic Lung Cells. Nature (London) 208:345-347. Childs, V . A . , and Legator, M.S. 1966. Induction of Thymidine Kinase by Aflatoxin. Life Sciences 5:1053-1056. Legator, M.S., Jacobson, C.B., Perry, M . , and Dolimpio, D. 1966. The Wooly Opossum -- A New Research Tool for Cytogenetic Studies. Life Sciences 5:397-402. Legator, M.S. 1966. Biological Effects of Aflatoxin in Cell Culture. Bacteriological Reviews 30:471-477. Wragg, J., Ross, V.C., and Legator, M.S. 1967. Effect of Aflatoxin B1 on Deoxyribonucleic Acid Polymerase of Escherichia Coli. Proceeding of the Society for Experimental Biology and Medicine 125:1052-1055. Kolbye, S., and Legator, M.S. 1968. Mutagenic Activity of Streptozotocin. Mutation Research 6:387-389. Dolimpio, D . , Jacobson, C . , and Legator, M.S. 1968. Effect of Aflatoxin on Human Leukocytes. Proceedings of the Society for Experimental / . C u r r i c u l u m V itae - M a r v i n S. L e g a t o r Page 7 Biology and Medicine 127:559-562. .gator, M.S., and Jacobson, C.B. 1968. Chemical Mutagens as a Genetic Hazard. Clinical Proceedings 24:184-189. Gabridge, M.D., DeNunzio, A., and Legator, M.S. 1969. Cycasin: In Vivo Detection of Associated Mutagenic Activity. Science 163:689-691. Gabridge, M.G., DeNunzio, A., and Legator, M.S. 1969. Microbial Mutagenicity of Streptozotocin in Animal-Mediated Assays. Nature 221:68-70. Gabridge, M.G., Oswald, E.J., and Legator, M.S. 1969. The Role of Selection in the Host-Mediated Assay for Mutagenicity. Mutation Research 7:117-119. Gabridge, M.G., and Legator, M.S. 1969. A Host-Mediated Microbial Assay for the Detection of Mutagenic Compounds. Proceedings of the Society for Experimental Biology and Medicine 130:831-834. Mayer, V.W. , and Legator, M.S. 1969. Production of Petite Mutants of Saccharomyces Cerevisiae by Putulin. J Agric Food Chem 17:454-456. Legator, M.S., and Mailing, H.V. 1969. Concepts in Mammalian Testing for Chemical Mutagens. EMS Newsletter 1:12-15. Legator, M.S., Palmer, K.A., Green, S., and Petersen, K.W. 1969. Cytogenetic Studies in Rats of Cyclohexylamine, a Metabolite of Cyclamate. Science 165:1139-1140. Legator, M.S., Kelly, F.J., Green, S., and Oswald, E.J. 1969. Mutagenic Effects of Captan. New York Academy of Sciences 160: 344-351. Mayer, V . W . , and Legator, M. 1970. Induction of N-Methyl-N'Nitrosoguanidine and UV Light of Petite Mutants in Aerobically and Anaerobically Cultivated Saccharomyces Cerevisiae. Mutation Research 9:193-198. Green, S., Palmer, K.A., and Legator, M.S. 1970. In Vitro Cytogenetic Investigation of Calcium Cyclamate, Cyclohexylamine and Trifluoropromazine. Food and Cosmetics Toxicology 8:617-623. Legator, M.S. 1970. Chemical Mutagenesis Comes of Age: Environmental Implications. Journal of Heredity 61: 239-242. Legator, M.S. 1970. Mutagenic Effects of Aflatoxin. Journal of the American Veterinary Medical Association 155:2080-2083. Legator, M.S. 1970. Host-Mediated Assay. EMS Newsletter 3:34. Legator, M.S. 1970. Chemical Mutagens in Man's Environment-- Book Review. EMS Newsletter 3:33-34. I 6546 - C u r r i c u l u m V i t a e - M a r v i n S. Legator Page 8 Palmer, K.A., Green, S., and Legator, M.S. 1970. Cytogentic Effects of DDT and Derivatives of DDT in a Cultured Mammalian Cell Line. Toxicology and Applied Pharmacology 17:276. Kelly, F., and Legator, M.S. 1970. Effect of N-Methyl-N-Nitro-NNitrosoguanidine on Cell Cycle and Chromosomes of Human Embryonic Lung Cells. Mutation Research 10:237-246. Zeiger, E . , and Legator, M.S. 1971. Mutagenicity of N-Nitroso-Morpholine in the Host-Mediated Assay. Mutation Research 12:469-471. Kelly, F . , and Legator, M.S. 1971. The Effects of N-Methyl-N'-Nitro-NNitrosoguanidine and Strepzotocin on Mammalian Cell Cultures. Mutation Research 12:183-190. Legator, M.S. 1971. Method for Detecting Chemically-Induced Mutations in Food Additives. Journal American Oil and Chemical Society 48:333A. Brusick, D . , and Legator, M.S. 1971. Utilization of Saccharomyces Cerevisiae in the Host-Mediated Assay. EMS Newsletter 4:31-32. Legator, M.S. 1971. Deficiencies in our Present Protocol for Chemical Evaluation and Possible Remedies. Annals of the New York Academy of Sciences 179: 508-513. Zeiger, E . , Legator, M.S., and Lijinsky, W. 1972. The Mutagenicity of NNitroso-Piperazines for Salmonella typhimurium in the Host-Mediated Assay. Cancer Research 32:1598-1599. Legator, M.S. 1972. Genetic Effects of Environmental Contaminants. Population and Pollution. Proceedings of the Annual Symposium of the Mutagen Society, 8th (1971), pages 95-99. Legator, M.S. 1972. Chemical Mutagens. Annual Review of Medicine 23:413428. Legator, M.S. 1972. The Need to Detect Chemically Induced Mutations in Experimental Animals. Mutagenic Effects of Environmental Contaminants, pp. 67-79. Legator, M.S. 1972. Indirect Indicators for Mutagenicity Testing-- An Overview. EMS Newsletter 6:10. Green, S., Palmer, K.A., and Legator, M.S. 1972. Effects of Cyclohexylamine on the Fertility of Male Rats. Food and Cosmetic Toxicology 10:29-34. Peterson, K . , Legator, M.S., and Figge, F.H. 1972. Dominant Lethal Effects of Cyclohexylamine in C57 B1 Fe Mice. Mutation Research 14:126-129. ^ > Palmer, K.A., Green, S., and Legator, M.S. 1972. Cytogenetic Effects of DDT in a Cultured Mammalian Cell Line. Toxicology and Applied I i Curriculum V i t a e - M a r v i n S. L e g a t o r Page 9 Pharmacology 22:355-364. Inter, K. A., Kelly-Garvert, F., and Legator, M.S. 1972. Methods for Preparing Anaphase Figures from Rat Bone Marrow. Mutation Research 16:111-112. IKelly, F., and Legator, M.S. 1970. Effects of Cyclohexylamine on the Fertility of Male Rats. Food and Cosmetics Toxicology 10:29-34. Petersen, K . , and Legator, M.S. 1973. The Dominant Lethal Results of Trifluoropromazine in Hybrid C3D2F1/J Mice. Mutation Research 17:8792. Palmer, K.A., Green, S., and Legator, M.S. 1973. Dominant Lethal Study of p ,p '-DDT in Rats. Food and Cosmetics Toxicology 11:53-62. Kelly-Garvert, F . , and Legator, M.S. 1973. Photoactivation of Chlorpromazine: Cytogenetic and Mutagenic Effects. Mutation Research 21:101-105. Kelly-Garvert, F . , and Legator, M.S. 1973. Cytogenetic and Mutagenic Effects of DDT and DDE in a Chinese Hamster Cell Line. Mutation Research 17:223-229. Green, S., Carr, J.V., Sauro, F . , and Legator, M.S. 1973. Effects of Hycanthone on Spermatogonial Cells (Cytogenetics) DNA Synthesis and Dominant Lethality in Rats. Journal of Pharmacology and Experimental Therapeutics 187:437-443. Green, S., Sauro, F.M., and Legator, M.S. 1973. Cytogenetic Effects of Hycanthone in the Rat. Mutation Research 17:239-244. Carr, J.V., and Legator, M.S. 1973. Hexachlorophene-Induced Alterations in a Metabolism of Cultured Human Lung Cells. Proceedings of the Society for Experimental Biology and Medicine 142:564-566. Kelly-Garvert, F . , and Legator, M.S. 1973. Cytogenetic and Mutagenic Effects of DDT and DDE in a Chinese Hamster Cell Line. Mutation Research 17:223-229. Legator, M.S., Palmer, K.A., and Adler, I.D. 1973. In Vivo Cytogenetic Analysis - A Collaborative Study. Toxicology and Applied Pharmacology 24:337-350. Legator, M.S., and Flamm, W.G. 1973. Environmental Mutagenesis and Repair. Annual Review of Biochemistry 42: 683-708. Legator, M.S. 1973. Procedure for Conducting the Host-Mediated Assay Utilizing Bacteria (Salmonella typhimurium). Agents and Actions - Swiss Journal of Pharmacology, Birkhauser Verlag, Switzerland S t i l us. . ' * " gee, P.N., Arrhenius, E., Holmstedt, B., Lawley, P.D., Legator, M.S., and l . C u r r i c u l u m V i t a e - M a r v i n S. L e g a t o r Page 10 Rylander, R. 1973. Importance of metabolism of environmental chemicals for mutagenic effects. Ambio, 3: 13-14. >.onnor, T . , Stoeckel, M . , and Legator, M.S. 1974. Niridazole, A Direct Acting Frameshift Mutagen, Not Affected by Microsomal Enzyme Preparation Which can be Detected in the Host-Mediated Assay. Mutation Research 26:456-457. Legator, M.S. 1974. Mutagenesis and Its Environmental Implications. Journal of Occupational Medicine 16(10):672-675. Legator, M.S. 1974. Relevance of Mutagenesis to Carcinogenesis. Proceedings of the Annual Conference on Environmental Toxicology 5th, pp. 293-308. Legator, M.S., and Williams, R. 1974. The Inadequacies of Submammalian Tests for Mutagenicity. Molecular and Environmental Aspects of Mutagenesis, Proceedings Publ Rochester International Conference on Environmental Toxicology 6th (1973), pp. 268-282. Legator, M.S., Stoeckel, M . , and Connor, T. 1974. Techniques for Isolating Mutagenic Substances from Urine and Blood of Treated Mammals Using Histidine Auxotrophs of S. typhimurium as the Indicator Organism. Mutation Research 26:456. Michel, T. M . , and Legator, M.S. 1974. Chromosomal Aberrations Induced In Vivo by DNA Repair Synthesis and Triethylenemelamine. Mutation Research 24:41-45. Weber, E., Bidwell, K . , and Legator, M.S. 1974. An Evaluation of the Micronuclei Test for Routine Cytogenetic Analysis. Mutation Research 26(5):461. Michel, T.M., and Legator, M.S. 1974. Comparative Study of Mutagens. Mutation Research 26(5):460. Legator, M.S., Connor, T . , and Stoeckel, M. 1975. Detection of Mutagenic Activity of Metronidazole and Niridazole in Body Fluids of Humans and Mice With Salmonella typhimurium. Science 188:1118-1119. Legator, M.S., and Zimmering, S. 1975. Genetic Toxicology. Annual Review of Pharmacology 15:387-408. Committee 17 of the Environmental Mutagen Society. 1975. Environmental Mutagenic Hazards. Science 187:503-514. Legator, M.S., and Zimmering, S. 1975. Integration of Mammalian, Microbial and Drosophila Procedures for Evaluating Chemical Mutagens. Mutation Research 31. Legator, M.S., Connor, T.H., and Stoeckel, M. 1975. The Detection'of Mutagenic Substances in the Urine and "Blood of Man. Annals o f ,the New York Academy of Sciences. M.S. Legator and A. Hollaender, ed., 1 > 6549 .Curriculum V i t a e - M a r v i n S. L e g a t o r Page 11 269:16-20. \dwell, K. , Weber, E., Nienhold, I., Connor, T . , and Legator, M.S. 1975. Comprehensive Evaluation for Mutagenic Activity of Dieldrin. Mutation Research 31:314. Gupta, A.K., and Legator, M.S. 1975. Chromosome Aberrations in Cultured Human Leukocytes After Treatment with the Fungicide Benlate. Proceedings of Symposium on Mutagenicity, Carcinogenicity and Teratogenicity. Chemistry, pp. 95-103. Stoeckel, M . , Weber, E., Connor, T . , and Legator, M.S. 1975. Failure to Detect Mutagenic Effects of Delta-9-Tetrahydrocannabinol in In Vitro and In Vivo Studies with Mice. Mutation Research 31:313-314. Weber, E., Bidwell, K . , and Legator, M.S. 1975. Evaluation of the Micronuclei Test using Triethyleneamine, Trimethylphoshate, Hycanthone and Niridazole. Mutation Research 28:101-106. Zimmering, P.H., Legator, M.S., and Weber, E. 1975. Effect of Pyrogen Treatment on Cytogenetic Response with Chemical Mutagens in Mice. Mutation Research 31:339-340. Drake, J.W., Abrahamson, S., Crow, J.F., Hollaender, A., Iederberg, S., Neel, J.V., Shaw, M.W. and Sutton H.E. et al. 1975. Environmental mutagenic hazards. Science, V o l . 187, ISS 4176, 503-14. ~een, S., Zeiger, E., Palmer, K. A . , Springer, J.A., and Legator, M.S. 1976. Protocols for the Dominant Lethal Test, Host-Mediated Assay and In Vivo Cytogenetic Test Used in the Food and Drug Administration's Review of Substances in the GRAS (Generally Recognized As Safe) List. Journal of Toxicology and Environmental Health 1:921-928. Nienhold, I., Kaplan, S., and Legator, M.S. 1976. Decrease in 3HThymidine Incorporation in Cells Derived from Systemic Lupus Erythematosus Patients Following Exposure to 4-Nitroquinoline 1-oxide. Mammalian Chromosomes Newsletter 217(1/2) :53. Connor, T.H., Stoeckel, M . , Evrard, J., and Legator, M.S. 1977. The Contribution of Metrinidazole and Two Metabolites to the Mutagenic Activity Detected in Urine of Treated Humans and Mice. Cancer Research 37:629-633. Kilian, D.J., Moreland, F.M., Benge, M.C., Legator, M.S., and Whorton, E.B., Jr. 1977. Collaborative Cytogenetics Study to Measure and Minimize Interlaboratory Variation. Mutation Research 44:97-104. Connor, T., and Legator, M.S. 1978. Method for Separation and Analysis of Body Fluids in Rodents and Humans for Mutagenic Components Using Salmonella typhimurium as the Indicator of Mutagenicity. Mutation Research 53:7,1-72. "''utino, R. , Meyne, J., and Legator, M.S. 1978. Cytogenetic Studies in - C u r r i c u l u m V i t a e - M a r v i n S. L e g a t o r P a g e 12 Chinese Hamster Ovary Cells With the Narcotic Antagonistic Naltrexone. Mutation Research 53:80. Kilian, D.J., Pullin, T.G., Connor, T . , Legator, M.S., and Edwards, H.N. 1978. Mutagenicity of Epichlorohydrin in the Bacterial Assay System: Evaluation by Direct In Vitro Activity and In Vivo Activity of Urine from Exposed Humans and Mice. Mutation Research 53:72. Kilian, D.J., Whorton, E.B., Jr., and Legator, M.S. 1978. Response to - Critique of Paper 'A Collaborative Study to Measure and Minimize Interlaboratory Variation'. Mutation Research 50:293-294. Meyne, J., Rinkus, S., and Legator, M.S. 1978. Distribution of Chromosomal Breaks Induced by Three Chemicals. Mutation Research 53:80. Molina, L . , Rinkus, S., and Legator, M.S. 1978. Evaluation of the Micronucleus Procedure Over a 2-Year Period. Mutation Research 53:125. Rinkus, S., and Legator, M.S. 1978. Deficiencies in the Microbial Activation System for Mutagenic-Carcinogenic Screening. Clinical Genetics 13:133-134. Troung, L., and Legator, M.S. 1978. In Vivo Determination of Alkylation of Amino Acids in Hemoglobin and Urine to Detect Potential MutagenicCarcinogenic Effects. Mutation Research 53:121. Nienhold, I., and Legator, M.S. 1978. Assessment of Unscheduled DNASynthesis in Lupus-Erythematosus (SLE) Patients. Clinical Genetics 13 (1):130. Biles, R.W., Connor, T.H., Trieff, N.M . , and Legator, M.S. 1978. The Influence of Contaminants on the Mutagenic Activity of Dibromochloropropane (DBCP). Journal of Environmental Pathology and Toxicology 2:301-312. Truong, L . , Ward, J.B., Jr., and Legator, M.S. 1978. Detection of Alkylating Agents by the Analysis of Amino Acid Residues in Hemoglobin and Urine. 1. The In Vivo and In Vitro Effects of Ethyl Methanesulfonate, Methyl Methanesulfonate, Hycanthone Methanesulfonate, and Naltrexone. Mutation Research 54:271-281. Rinkus, S.J., and Legator, M.S. 1979. Chemical Characterization of 465 Known or Suspected Carcinogens and Their Correlation with Mutagenic Activity in the Salmonella typhimurium System. Cancer Research 39:3289-3318. Legator, M.S., Kouri, R.E., Parmar, A.S., Zimmering, S., Putman, C., Latt, R . , Heicklen, J . , Meagher, J.F., Weaver, J., and Kelly, N. 1979. Mutagenic Testing of Diethylhydroxylaipine, Nitroethane artd Diethylamine Hydrogen Sulfite. Environmental Research 20:99-124. I : 8551 C u r r i c u l u m V i t a e - M a r v i n S. L e g a t o r P a g e 13 Connor, T.H., Meyne, J . , Molina, L . , and Legator, M.S. 1979. A Combined Testing Protocol Approach for Mutagenicity Testing. Mutation Research 64:19-26. Legator, M.S., and Zimmering, S. 1979. Review of the Genetic Effects of Caffeine. Journal of Environmental Science and Health, Part CEnvironmental Health Sciences 13(2):135-188. Moreland, F.M., Kilian, D.J., Palmer, K. A . , Springer, J.A., Green, S. and Legator, M.S. 1979. A Collaborative Dominant Lethal Study of Triethylenemelamine in the Rat. Toxicology and Applied Pharmacology 49(1):161-170. Trieff, N.M., Walker, R.D., Connor, T.H., Mackenzie, K. and Legator, M.S. 1979. Mutagenic Assessment of Air Particulate Samples of Houston, Texas USA. Fed. Proc. 38(Vol. 3, part 1):535. Infante, P.F. and Legator, M.S. 1979. Workshop on Methodology for Assessing Reproductive Hazards in the Workplace - Recommendations for Future Research - April 19-22. Environmental Research 20(1):217-223. Connor, T.H., Cantelli-Forti, G., Sitra, P. and Legator, M.S. 1979. Bile As a Source of Mutagenic Metabolites Produced In vivo and Detected By Salmonella typhimurium. Environmental Mutagenesis 1(2) :269-276. Legator, M.S. 1979. Chronology of Studies Regarding Toxicity of 1-2Dibromo- 3-Chloropropane. Annals of the New York Academy of Sciences 329:331-338. Sadagopa Ramanujam, V . M . , Made Gowda, N . M . , Trieff, N.M., and Legator, M.S. 1980. Ultraviolet Spectrophotometric Assay of pAminobenzenesulfonamides. Microchemical Journal 25: 295-300. Connor, T.H., Pullin, T.G., Meyne, J . , Frost, A . F . and Legator, M.S. 1980. Evaluation of the Mutagenicity of Normal-BGE in a Battery of Short-Term Assays. Environmental Mutagenesis 2(2):284. Connor, T.H., Meyne, J. and Legator, M.S. 1980. The Mutagenic Evaluation of Tetrakis (Hydroxymethyl) Phosphonium Sulfate Using a Combined Testing Protocol Approach. Journal of Environmental Pathology and Toxicology 4(1):145-158. Meyne, J . , and Legator, M.S. 1980. Sex-Related Differences in Cytogenetic Effects of Benzene in the Bone Marrow of Swiss Mice. Environmental Mutagenesis 2:43-50. Connor, T.H., Ward, J.B. Jr., Meyne, J., Pullin, T.G. and Legator, M.S. 1980. The Evaluation of the Epoxide Diluent, n-Butylglycidyl Ether, in a Series of Mutagenicity Assays. Environmental Mutagenesis 2:52153 0. Kapp, R.W., Jr., Benge, M.C., Picciano, D. J*., Kilian, D.J., Legator ,,'M. S ., and Jacobson, C.B. 1980. Monitoring Y Chromosomal Nondisjunction in I 8552 Curriculum V i t a e - M a r v i n S. Legator Page 14 Humans with the YFF Sperm Test. In: Proceedings of a Workshop on Methodology for Assessing Reproductive Hazards in the Workplace. DHHS (NIOSH) Publication No. 81-100. U.S. Government Printing Office, Washington, D.C. Legator, M.S. 1980. Human Exposure to Formaldehyde Monitored by Several Assays for Mutagenesis in Man. Toxicology Research Projects Directory 5(11). Made Gowda, N.M., Sadagopa Ramanujam, V.M . , Trieff, N. M . , and Legator, M.S. 1980. Assay of Thioacetamide and Thiobenzamide with ChloramineT. Analytical Chemistry 52:209-211. Rinkus, S.J., and Legator, M.S., 1980. An Evaluation of In Vitro Testing for Mutagens. DHHS (NIOSH) Publ. (U.S.):81-100, Proc. Workshop Methodol Assessing Reprod. Hazards Workplace, pp. 117-33. Albrecht, T . , Speelman D.J., Sadagopa Ramanujam, V . M . , Lund, H.W., Legator, M.S. and Trieff, N.M. 1980. Correlation of the Chemical Structure of 4-Nitroquinolines Inactivating Human Cytomegalovirus and established In Vivo Carcinogenicity Tests. Teratogenesis, Carcinogenesis, and Mutagenesis 1(2):161-169. Legator, M.S. 1980. Radiation Equivalents for Chemical Mutagens: A Critique. International Atomic Energy Agency, Vienna, pp. 87-90. Adams, P.M., Fabricant, J.D., and Legator, M.S. 1981. Cyclophosphamide Induced Spermatogenic Effects as Detected in the FI Generation by Behavioral Testing. Science 211:80-82. Ramanujam, V.M.S., Connor, T.H. and Legator, M.S. 1981. High Performance Liquid-Chromatographic Determination of Normal Butylglycidyl Ether. Microchemical Journal 26(2):217-220. Trieff, N.M., Ramanujam, V.M.S., Connor, T. H . , Made Gowda, N.M. and Legator, M.S. 1981. Mutagenicity Studies of Aromatic Amines. Environmental Mutagenesis 3 (3):322-323. Legator, M.S. 1981. Mutagenicity of Captan. Mutation Research 85(4):220. Speelman, D. , Li, J.L.H., Ramanujam, V.M.S., Legator, M.S. and Albrecht, T. 1981. Herpes-Viruses Inactivation by Chemical Carcinogens Differential Inactivation of Herpes-Simplex Vir u s e s .By 4Nitroquinoline 1-Oxide and Related Compounds. Environmental Mutagenesis 3(4):467-476. Rinkus, S.J., and Legator, M.S. 1981. Salmonella Revisited: A Reply to Ames and McCann. Cancer Research 41:4196-4203. Fabricant, J.D., and Legator, M.S. 1981. The Mutagenicity of Vinyl Chloride. Environmental Health Perspectives 41:189-. 'gator, M.S. 1981. Mutagenesis Test Systems - Development. Toxicology I J . C u r r i c u l u m Vitae - M a r v i n S. L e g a t o r P age 15 Research Projects Directory 6(10) ibricant, J.D., and Legator, M.S. 1981. Etiology, Role and Detection of Chromosome Aberrations. Journal of Occupational Medicine 23(9):617625. Frost, A.F. and Legator, M.S. 1982. Unscheduled DNA synthesis Induced In Human Lymphocytes By Butyl Glycdyl Ethers. Mutation Research 102:193200. Legator, M.S., Bueding, E., Batzinger, R . , Connor, T.H., Eisenstadt, E., Farrow, M.G., Fiscor, G., Hsie, A., Seed, J., and Stafford, R.S. 1982. An Evaluation of the Host-Mediated Assay and Body Fluid Analysis. A Report of the U.S. Environmental Protection Agency GeneTox Program. Mutation Research 98(3):319-374. Walker, R.D., Connor, T.H., MacDonald, E.J., Trieff, N . M . , Legator, M.S., MacKenzie, K.W., Jr., and Dobbins, J.G. 1982. Correlation of Mutagenic Assessment of Houston Air Particulate Extracts in Relation to Lung Cancer Mortality Rates. Env. Research 28:303-312. Adams, P.M., Fabricant, J.D., and Legator, M.S. 1982. Active-Avoidance Behavior in the FI Progeny of Male Rats Exposed to Cyclophosphamide Prior to Fertilization. Neurob. Tox. 4(5):531-534. Fabricant, J.D., Legator, M.S., and Adams, P.M. 1983. Post-Meiotic Cell Mediation of Behavior in Progeny of Male Rats Treated with Cyclophosphamide. Mutation Research 119(2):185-190. Meyne, J., and Legator, M.S. 1983. Clastogenic Effects of Transplacental Exposure of Mouse Embryos to Nitrogen Mustard or Cyclophosphamide. Teratog. Carcinog. Mutagen 3(3):281-287. Connor, T.H., Ramanujan, V.M.S., Rinkus, S.J., Legator, M.S., and Trieff, N.M. 1983. The evaluation of mutagenicities of 19 structurally related aromatic amines and acetamides in Salmonella typhimurium TA98 and TA100. Mutation Research 118:49-59. Legator, M.S., Kline, G . , Ramanujam, V.M.S., Cunningham, B . R . , Ward, J.B., Jr. and Gad-El-Karim, M.M. 1983. Presence of aflatoxin B1 in mould extracts used for immunotherapy desensitization. Lancet ii, p. 915. Whorton, E.B., Jr., Pullin, T.G., Frost, A.F., Onofre, A., Legator, M.S., and Folse, D.S. 1983. Dominant lethal effects of n-butyl glycidyl ether in mice. Mutation Research 124: 225-233. Connor, T.H., Ramanujam, V.M.S., Ward, J.B., Jr. and Legator, M.S. 1983. The identification and characterization of a urinary mutagen resulting from cigarette smoke. Mutation Research 113: 161-172. Ward, Jr., J.B.,. Legator, M.S., Chang, L.W. and Pereira, M.A.~ 1983. Evaluation of occupational exposure to" formaldehyde using a battery of tests for genetic damage. Abstracts 14th Annual Environmental Mutagen I 6554 - C u r r i c u l u m V i t a e - M a r v i n S. Legator Page 16 Society Meeting, San Antonio, Texas, Environ. Mut. 5: 433. dams, P.M., Shabrawy, 0., and Legator, M.S. 1984. Male-Transmitted Developmental and Neurobehavioral Deficits. Teratog. Carcinog. Mutagen 4(1): 149-169. Gad-El-Karim, M . M . , Harper, B.L., and Legator, M.S. 1984. Modifications in the myeloclastogenic effect of benzene in mice with toluene, phnobarbital, 3-methylcholanthrene, aroclor 1254 and SKF-525A. Mutation Research 135: 225-243. Fanini, D. , Legator, M.S., and Adams, P.M. 1984. Effects of Paternal Ethylene Dibromide Exposure on FI Generation Behavior in the Rat. Mutation Research 139: 133-138. Harper, B.L., Ramanujam, V.M.S., Gad-El-Karim, M . M . , and Legator, M.S. 1984. The influence of simple aromatics on benzene clastogenicity. Mutation Research 128: 105-114. Ward, J.B., Jr., Hokanson, J.A., Smith, E.R., Chang, L.W., Pereira, M . A . , Whorton, E.B., Jr., and Legator, M.S. 1984. Sperm Count, Morphology and Fluorescent Body Frequency (YFF) In Autopsy Service Workers Exposed to Formaldehyde. Mutation Research 130: 417-424. Legator, M.S. 1984. Concepts in genetic monitoring. 53rd annual meeting of the American Association of Physical Anthropologists, Philadelphia, PA, USA, April 11-14, 1984. AM J Phys Anthropol; 63(2):183 negator, M.S., Rosenberg, M.J.,Zenick, H. and Editors. 1984. Environmental influences on Fertility, Pregancy, and Development: Strategies for measurement and evaluation. In: Teratog. Carcinog. Mutagen, 1984; 4(1) 177. Anderson, D. and Legator, M.S. 1984. Practical issues in the evaluation of monitoring techniques: need for validation, quality assurance and establishment of baseline levels. IARC Sci. Publ. 59: 431-433. Gad-El Karim, M . M . , Sadagopa Ramanujam, V . M . , and Legator, M.S. 1985. trans, trans-Muconic acid, an open-chain urinary metabolite of benzene in mice. Quantification by high-pressure liquid chromatography. Xenobiotica 15(3):211-220. Heussner, J.C., Ward, J.B., Jr., and Legator, M.S. 1985.. Genetic Monitoring of Aluminum Workers Exposed to Coal Tar Pitch Volatiles. Mutation Research 155: 143-156. Rinkus, S.J. and Legator, M.S. 1985. Use and Regeneration of Amicon Ultrafiltration cones for deproteinization of microsomal solutions before chromatographic analysis. Letter to the Editor, Journal of Chromatography 342 (2):465-468. 4 Connor, T.H., Ward, Jonathan B . , Jr., and Legator, M.S. 1985. Absence of mutagenicity in the urine of autopsy service workers exposed to J" 6555 - C u r r i c u l u m V i t a e - M a r v i n S. Lega t o r Page 17 formaldehyde: factors influencing mutagenicity testing of urine. Int. Arch. Occup. Environ. Health 56:225-237. v^ad-El Karim, M. M . , Sadagopa Ramanujam, V . M . , Ahmed, A.E., and Legator, M.S. 1985. Benzene Myeloclastogenicity - A Function of its Metabolism. American Journal of Industrial Medicine 7(5-6):475-484. Hsu, L.L., Adams, P.M., Fanini, D. and Legator, M.S. 1985. Ethylene dibromide: effects of paternal exposure on the neurotransmitter enzymes in the developing of FI progeny. Mutat. Res. 147(4):197-203. Harper, B.L., Ramanujam, V. MS. and Legator, M.S. 1985. The effects of inducers and inhibitors on the micronucleus test with benzene benzo-apyrene and cyclophosphamide. 16th annual meeting of the Environmental Mutagen Society, Las Vegas, NV, USA, February 25-March 1,1985. Environ Mutagen; 7 (Suppl. 3). 54. Rinkus, S.J. and Legator, M.S. 1985. A Fluorometric Assay Using HighPressure Liquid Chromotography for the Microsomal Metabolism of Certain Substituted Aliphatics to 1,N (6)-Ethenoadenine-Forming Metabolites Anal. Biochem. 150: 379-393. Gad-El Karim, M. M . , Sadagopa Ramanujam, V.M. and Legator, M.S. between the induction of micronuclei in bone marrow exposure and the excretion of metabolites in urine of Toxicology and Applied Pharmacology 85:464-477, 1986. Correlation by benzene CD-I mice. egator, M.S. 1987. The Successful Experiment That Failed. Scientific Controversies: Case Studies in the Resolution and Closure of Disputes in Science and Technology. H.T. Engelhardt, Jr. and A.L. Caplan, eds., Cambridge University Press, pp. 465-486. Rithidech, K . , Au, W.W., Sadagopa Ramanujam, V . M . , Whorton, E.B., Jr. and Legator, M.S. Induction of chromosome aberration in lymphocytes of mice after sub-chronic exposure to benzene, Mutation Res. 188:135-140, 1987. Talaska, G . , Au, W.W., Randerath, K . , Ward, J.B. Jr., and Legator, M.S. The correlation between DNA adducts and chromosomal aberrations in the target organ of benzidine exposed, partially-hepatectomized mice. Carcinogenesis (in press). B. Other: Books/Book Chapters Ledley, R.S., Legator, M.S., and Wilson, J.B. 1968. Automatic Determination of Mitotic Index. Pictorial Pattern Recognition. B.C. Cheng, R.S. Ledley, D.K. Pollock, and A. Rosenfeld, eds., Thompson Book Company, Washington, D.C. Legator, M.S. 1969. Biological Assay for Aflatoxin. Aflatoxin Scientific Background, Control, and Implications. I. Goldblatt-/ ed. , pp. 107-149, Academic Press. /' 8556 `r - C u r r i c u l u m V i t a e - M a r v i n S. L e g a t o r P age 18 Legator, M.S., and Sperling, D. 1970. Selective Toxicity: Genetic Implications. Laboratory Diagnosis of Diseases Caused by Toxic Agents. F.W. Sunderman and F.W. Sunderman, Jr., eds., pp. 17-22, Warren H. Green, Inc., St. Louis, Missouri. Legator, M.S., and Jacobson, C.V. 1970. Detection of Cytogenetic Effects of Toxic Agents in Mammalian Systems. Laboratory Diagnosis of Diseases Caused By Toxic Age n t s . F.W. Sunderman and F.W. Sunderman, Jr., eds., pp. 23-31, Warren H. Green, Inc., St. Louis, Missouri. Legator, M.S. 1970. The Host-Mediated Assay: A Practical Procedure for Evaluating Potential Mutagenic Agents. Chemical Mutagenesis In Animals and Man. F. Vogel and G. Rohrborn, eds., pp. 260-270, Springer-Verlag, New York and Germany. Legator, M.S., and Mailing, H.V. 1971. The Host-Mediated Assay: A Practical Procedure for Evaluating Potential Mutagenic Agents in Mammals. Chemical Mutagens. A. Hollaender, e d . , Vol. 2, pp. 569589, Plenum Press, New York and London. Epstein, S.S., and Legator, M.S. 1971. The Mutagenicity of Pesticides. Massachusetts Institute of Technology Press, Cambridge, Massachusetts. Legator, M.S. 1972. The Use of Indirect Indicators for Mutagenicity Testing, Non-Psychiatric Effect of Drugs of Abuse. S.S. Epstein, e d ., p p . 171-176, Government Printing Office, Washington, D.C. _egator, M.S. 1972. Drugs as Potential Mutagens. Mutagenic Effects of Environmental Contaminants. E. Sutton and M.I. Harris, eds., Academic Press, New York. Legator, M.S., and Epstein, S. 1974. Environmental Mutations in Man. Environmental Problems in Medicine. M.S. Legator and S.S. Epstein, eds., Charles C. Thomas, Springfield. Legator, M.S., and Zimmering, S. 1975. Genetic Toxicology. Annual Review of Pharmacology. Annual Reviews Inc., Palo Alto, California. Legator, M.S., and Nichols, W. 1975. Mutagenicity Testing. Laboratory Manual, Plenum Press. Legator, M.S. 1975. Environmental Problems in Medicine. Mutagenic Effects of Environmental Agen t s . Charles C. Thomas Publishing Company, Springfield, Ohio. Legator, M.S. and Hollaender, A. 1975. Annas of the New York Academy of Sciences, Vol. 269. Occupational monitoring for genetic hazards. Ann N Y Acad. Sci.; 45 (reed 1976). ''gator, M.S., Zimmering, S., and Connor, T. 1976. Use of Indirect I 6557 - C u r r i c u l u m V itae - M a r v i n S. L e g a t o r Page 19 Indicator Systems to Detect Mutagenic Activity in Human Subjects and Experimental Animals. Chemical Mutagens and Principal Methods for Their Detection. A. Hollaender, ed., Vol. 4, pp. 171-191, Plenum Press, New York and London. Kilbey, B.J., Legator, M.S., Nichols, W. and Ramel, C. 1977. Handbook of Mutagenicity Test Procedures. Elsevier/North Holland Biomedical Press, Amsterdam. Legator, M.S., Rinkus, S.J. 1977. The Chemical Environment and Mutagenesis. Women and the Workplace. J. Wagoner and E. Bingham, eds., Government Printing Office, Washington, D.C. Legator, M.S., Pullin, T.G., and Connor, T.H. 1977. The Isolation of Mutagenic Substances in Body Fluid and Tissues of Animals and Body Fluid of Human Subjects. Handbook of Mutagenicity Test Procedures. B.J. Kilbey, M.S. Legator, W. Nichols, and C. Ramel, eds., pp. 149-159, Elsevier/North Holland Biomedical Press, Amsterdam. Kilian, D.J., Moreland, F. M . , Benge, M.S., Legator, M.S., and Whorton,E.B., Jr. 1977. Collaborative Study to Measure Interlaboratory Variation With the In Vivo Bone Marrow Metaphase Procedure. Handbook of Mutagenicity Test Procedures. B.J. Kilbey, M.S. Legator, W. Nichols, and C. Ramel, eds., pp. 243-260, Elsevier/North Holland Biomedical Press, Amsterdam. Butterworth, B.E., Longstaff, E . , Clive, D . , Pienta, R.J., Kuna, R . , Legator, M.S., Thilly, W.G., Ray, V . A . , Sheridan, W . , Williams, G.M., and Dunkel, V. 1979. II. Practical Guidelines for the Use and Interpretation of Short-Term Testing for Mutagens/Carcinogens. Strategies for Short-Term Testing for Mutagens/Carcinogens. B.E. Butterworth, e d . , CRC Press, Inc., West Palm Beach, Florida. Rinkus, S.J., and Legator, M.S. 1979. An Evaluation of In Vitro Testing for Mutagens. Genetic Damage in Man Caused by Environmental Agents. K. Berg, ed., pp. 343-362, Academic Press, New York. Legator, M.S. and Rinkus, S.J. 1979. Chemical mutagenesis and industrial monitoring. Genetic Damage in Man Caused by Environmental Agents. K. Berg, (ed.) New York: Academic Press, pp. 343-362. Rinkus, S.J. and Legator, M.S. 1980. The need for both in vitro and in vivo systems in mutagenicity screening. Chemical Mutagens Vol. 6, deSerres, F.J. and Holaender, A., eds. Plenum Press, New York and London, pp. 365-473. Legator, M.S. 1981. A Holistic Approach to Monitoring High-Risk Populations by Short-Term Procedures. Banbury Report 9: Quantification of Occupational Cancer. pp. 335-345, Cold Spring Harbor Laboratory. > Legator, M.S., and Rinkus, S.J. 1981. Mutagenicity Testing: Problems in Application. Short-Term Tests for Chemical Carcinogens. H.F. Stich C u r r i c u l u m V i t a e - M a r v i n S. L e g a t o r Page 20 and R.H.C. San, eds., pp. 483-504, Springer-Verlag, New York. ard, J.B., Jr., Rinkus, S.J., and Legator, M.S. 1981. Strategies for Overcoming the Deficiencies of Microbial Activation Systems for Detecting Chemical Mutagens. Microbial Testors for Chemical Carcinogens. I. Cecil Felkner, ed., pp. 167-186, Marcel Dekker Inc., New York. Legator, M.S. and Harper, B.L. 1982. Animal-Human Studies: An Integrated Approach to Identifying Hazardous Chemicals in the Workplace. Mutagens In Our Environment. M. Sorsa and H. Vainio, eds., pp. 181202, Alan R. Liss, Inc., New York. Harper, B.L., Rinkus, S.J., Scott, M.J., Ammenheuser, M . , Bang, K . M . , Lowery, M . , and Legator, M.S. 1982. Correlation of NCI and IARC carcinogens with their mutagenicity in Salmonella. Use of Human Cells for the Evaluation of Risk from Physical and Chemical Agents. a NATO Publication. Plenum Press, pp. 353-424. Legator, M.S. and Harper, B.L. 1983. From Bacteria to Man, The Evolution of Mutagenicity Testing. Use of Human Cells for Evaluation of Risk From Physical and Chemical Agents. A NATO Publication. Plenum Press, pp. 467-493. Ward, Jr., J.B., Legator, M.S., Pereira, M.A . , and Chang, Lina W. 1983. Evaluation in man and animals of tests for the detection of population exposures to genotoxic chemicals. Short-Term Bioassays in the Analysis of Complex Environmental Mixtures III. Waters, M.D., Sandhu, S.S., Lewtas, J . , Claxton, L . , Chernoff, N . , and Nesnow, S., eds., Plenum Press, New York and London, pp. 461-484. Legator, M.S., and Kapp, R. W . , Jr. 1984. Detection of Chemically Induced Y-Chromosomal Nondisjunction in Human Spermatozoa. Single-Cell Mutation Monitoring Systems. A.A. Ansari and F.J. deSerres, eds., pp. 265-277, Plenum Press, New York. Connor, T. H . , and Legator, M.S. 1984. The Intraperitoneal Host-Mediated Assay. Handbook of Mutagenicity Test Procedures. B.J. Kilbey, M. Legator, W. Nichols, and C. Ramel, eds., pp. 643-654, Elsevier Science Publishers, New York. Legator, M.S., and Ward, J.B., Jr. 1984. Personnel Monitoring with cytogenetic and other short-term bioassays. Synthetic Fossil Fuel Technologies. K.E. Cowser and C.R. Richmond, eds., pp. 303-321, Butterworth Publishers, Stoneham, Massachusetts. Legator, M.S., and Ward, J.B., Jr. 1984. Genetic Toxicology-Relevant Studies with Animals and Humans. Progress in Clinical and Biological Research, Vol. 160 (Reproduction: The New Frontier in Occupational and Environmental Health Research). J.E. Xockey, G.K. Lemasters, and W.R. Keye, Jr., eds., pp. 491-5^5, Alan R. Liss, Inc., New York. i C u r r i c u l u m V itae - M a r v i n S. Lega t o r Page 21 Legator, M.S., and Ward, J.B., Jr. 1984. Animal and Human Studies in Genetic Toxicology. Pregnant Women at Work. G. Chamberlain, ed., pp. 167-188, The Royal Society of Medicine and the MacMillan Press Ltd., London and Basingstoke. Kilbey, B.J., Legator, M . , Nichols, W . , Ramel, C. and Editors. 1984. Handbook of Mutagenicity Test Procedures. 2nd Ed. 860. Anderson, D. and Legator, M.S. 1985. Practical Issues in the Evaluation of Monitoring Techniques: Need for Validation, Quality Assurance and Establishment of Baseline Levels. Monitoring Human Exposure to Carcinogenic and Mutagenic Agents. A. Berlin, M. Draper, Hemminki, and H. Vainio, eds., pp. 431-433, IARC Scientific Publications No. 59, IPCS Joint Symposia No. 7, International Agency for Research on Cancer, Lyon, 1984. Legator, M.S., Harper, B.L., and Scott, M.J. 1985. The Health Detectives Handbook. A Guide to the Investigation of Environmental Health Hazard by Nonprofessionals. Johns Hopkins University Press, Baltimore, Maryland. Au, W.W. and Legator, M.S. 1986. Genetic Toxicology: In Utero Exposure to Genotoxic Agents. Drug and Chemical Action in Pregnancy. Fabro, S. and Scialli, eds., pp. 335-351, Marcel Dekker, Inc., New York, New York. Legator, M.S., Au, W . W . , Harper, B.L., Sadagopa Ramanujam, V . M . , and Ward, J.B., Jr. 1986. Regulatory implications of a mobile animal monitoring unit. Genetic Toxicology of Environmental Chemicals, Part B: Genetic Effects and Applied Mutagenesis. Ramel, C., Lambert, B. and Magnusson, J., eds., Vol. 209B, pp. 537-546, Alan R. Liss, Inc., New York, New York. Proceedings of the 4th International Conference on Environmental Mutagen Society. Stockholm, Sweden, June 24-28, 1985. Legator, M.S. and Harper, B.L. Mutagenicity Screening-In Vitro Testing - The End of an E r a ; Animal and Human Studies - The Direction for the Future. Presented at the Collegium Ramazzini International Conference, January 6, 1986. Legator, M.S. and Au, W.W. Need to reassess the Genetic Toxicology of Drugs of Abuse. Genetic and Perinatal Effects of Abused Substances. Braude, M.C. and Zimmerman, A.M. Academic Press, pp 3-26, 1987. Harper, B.L. and Legator, M.A. Tumor Promoters and Genotoxic Chemicals in Short-Term Testing for Carcinogenicity. Advances in Veterinary Science and Comparative Medicine. C.E. Cornelius and C.F. Simpson, eds., Vol. 31, pp. 1-19, 1987. SUBMITTED: > ^. > 'mmenheuser, M.M., Ward, J.B., Jr., Whorton, E.B., Jr., Killian, J.M. and I O p*' C u r r i c u l u m V i t a e - M a r v i n S. L e g a t o r P a g e 22 Legator, M.S. Elevated frequencies of 6-thioguanine resistant lymphocytes in multiple sclerosis patients treated with cyclophosphamide : A prospective study, 1986, submitted. Bibbins, P.E., Ward, J.B., Jr., Lipschultz, L.I. and Legator, M.S. Increased frequency of double fluorescent bodies in sperm in males with a varicocele, a possible indicator of germinal cell genetic damage, 1986, submitted. Ward, J.B., Jr., Sadagopa Ramanujam, V. M . , Talaska, G. and Legator, M.S. Development of a small laboratory inhalation exposure apparatus for low levels of carcinogenic or mutagenic agents, 1986, submitted. Legator, M.S. and Harper, B.L. In-Situ Genotoxic Monitoring of Chemical Mixtures by Relevant Animal Studies (Comb. Test Pro), 1986, submitted. Au, W.W. and Legator, M.S. The Use of Cytogenetic Assays In Vivo for Detecting Exposure to Genotoxic Agents, 1986, submitted. Moslen, M.T. and Legator, M.S. Advantages of a Combined Testing Protocol (CTP) with Multiple Endpoints: The Reverse Tier Approach, 1986, submitted. Legator, M.S. Artificial Sweeteners and Genetic Toxicology: Lessons from the Past and Future Potential, 1987, submitted. Harper, B.L. and Legator, M.S. Genetic Toxicology - A New Awakening, 1987, submitted to Adv in Modern Environ. Toxicol. Au, W.W., Ward, J.B., Jr., Sadagopa Ramanujam,V.M., Harper, B.L., Moslen, M.T. and Legator, M.S. Genotoxic effects of a sub-acute low level inhalation exposure to a mixture of carcinogenic chemicals, 1987, submitted to Mutation Res. Au, W.W., Bibbins, P.E., Jr., Ward, J.B., Jr. and Legator, M.S. Development of a rodent lung macrophage chromosome aberration assay, 1987, submitted to Mutation Research Letters. Bibbins, P.E., Jr., Lipschultz, L.I., Ward, J.B., Jr. and Legator, M.S. Fluorescent body distribution in spermatozoa in the male with exclusively female offspring, 1987, submitted to Fertility and Sterility. Patents Legator, M.S. 1961. Inhibiting Growth of Bacteria in Water Flooding Process. U.S. Pat. 2,987,475. Legator, M.S. 19.61. Slimicide. U.S. Pat.^ 3,006,807. > "ader, Legator. 1962. } Preservation of Foods. U.S. Pat. 3,044,884. 6561 Curr i c u l u m V i t a e - M a r v i n S. Legator -Page 23 Racusen, Legator. 1962. Soil Fumigant. U.S. Pat. 3,052,598. negator, Kreutzer, Soloway. 1963. Soil Fungicide. U.S. Pat. 3,080,274. Legator, M.S. 1964. Synergistic Antibiotic Compositions and Preparation. U.S. Pat. 3,126,318. Legator, M.S. 1964. Growth Promotant Substances. U.S. Pat. 3,148,988. Tieman, Legator. 1965. Trihalo-substituted Esters. U.S. Pat. 3,169,989. Fan, Rader, Legator, Dowding. 1965. Polyhydronaphthalene Biepoxides. U.S. Pat. 3,215,708. Haynes, Legator. 1966. Coccidiosis Control Compositions and Methods of Using Same. U.S. Pat. 3,234,087. Legator, M.S. 1966. Growth Promotant Substances. U.S. Pat. 3,240,605. Legator, M.S. 1966. Control of Microorganisms with Acrolein. U.S. Pat. 3,250,667. Legator, Page. 1971. Use of Certain Polyamines as Antimicrobial Agents. U.S. Pat. 3,567,420. I 1 HESE1 HRES . e*V -- _ / 6564 a NTICSETMESMMCH-IS. IMS / I tas is thefiist partof a thrce-partseries d v tic k s c n b e ^ e a u o lc o taminatni of a snail Ariauas cboiBaiity. I ia the s e n t hazantw s n t r srhatnryet knownh tee U^mdieserioas t e n those flat farcedevacuation of residents Iran Lew Canal, N.Y. m i Tine* Beach, Mo. Bailies are dying and adults arngnbingtD sudden disease in three neigtborhoods that bonier EPASvperftmd demnqi sites in Jacksonville, Aik. But the ramifications reach far beyond these sites. Jacksonville bolds a mirror to larger national questions surrounding tone wastes, incineration and the continued production of deadlycfaanicals. It also reflects neglect and mismanagement by federal and state governments. And the picture encompasses not only the Pentagon and its Agent Orange and rocketfuelcontracts,butthe hiddeninvolvementofmultinationalcorporations and foreigi entanglements. The Arkansas saga is a microcosm of a much bigger problem in an increasmgiy toxic America, for what has happened in Jacksonville is far from an isolated phenomenon. Particuiariy in the rural South, many similar com munities fitting for their economic survival have become dumping growth. Whilestate and localofficialsas weOas business leadersprotecttheirinterests, the impoverished suffer--and take on the struggle against greed and infiBerence. In dozens of areas, people Bke Arkansas' Patty Frase are running the gauntlet to fight the pollution affecting their homes. This ir their story, too. 0 ---- By Dicfc Russell iJACKSQVVIUf.AUK. u ITGAQUETSUrOAYAFhEltNOOrrft'nSCTrYOF nearly30,000residents 12milesnorth east o( the state capitalof LittleRock. PattyFrase turnsherstaboowagonoff the freewayand ontoRoute67leadinginto town,thensays,'Just don'ttouchthefood, drinkthewaterorevenwashyourhandsin Jacksonville.* Somelocalcitizensdon'tcalltheirhome townJacksonville.TheyrefertoitasUirninviUe,' and to the Arkansas Department at Pollution Control and Ecologyas the De partmentat Political CorruptionandEntfengermenL*Andwithgoodreason:thisArkan sascommunityisthesiteotthewontdanin contamination intheUS, withlevelsot the poisonfoundinlocalsoiltestingwellabove therangethatledtotheEnvironmentalPro tection Agency's'CD'A) 1983evacnatiooot TanesBeadi.Ua The peopleotJacksonvilleshouldhave longagobeengven the right toevacuate andreamedcompensationkrthenhomes* saysLotsGijt*.cirectorotthenationalCiti zen'CfearingKaae for HazardomWastes based inArlington, Va. The danension of to problem is jest outrageous--babies dying,wholeneigMaahoodiwithunbetievabie cancer rates. When I.was thesethree years ago, toy were faftfogabout dioaari beingorto drinkingwafersgiplywhileto federal Centers far DiseaseControt(CDC)^ . was sayng there wasno'one far alaon/ thetndhreallyhmauert on cyaaedt*'; Prasehrtbecnwortfagam^dthrctodT' sinceUKtoge*totndhdrt.Stosy*lto famerhrmirah,seggi nosnemopapnsinDjnQniaiK fait cancer-causfag' panentsreekingto faSVaocJfa fan. Us sfate hfaeancarfct 'faki>UQl Chambrr ot Cortame faaatil jpaip* calledJadoonviBePeopleWithPride. suaepartper. THiui fws fafit^iadfarfandrfat'rt TWttdi's brass': EversinceWorldWar b8Eoa^eftoagffwitlfal*wiitw>wr' hadred efftg i m toactfagtarec to kidshador tyn^feand* start* get D, three different chemical companieshad appard facompel 8m ERA to tipgfa luge,to doefatsrtto taretoMnrwewere mamdadlued a paving range ot tadc cleanup.JustoaejartferreBtonfa'tore- >i 1374myfetortad just vetoedhere afiergic to deodorant,* fare centrers chemicals here, the first plant, locally foe 1000timesmorekaic,feJacksrarfc to aiStaryat SIandwasfagootfshqre,* Whs,afterherother'sdeetkshefirstap ownedReasor-HSIChanicaLwasoriginally diaxfawasmeasuredfaabort2JB3tan*is fanesaysasshehratadoMacarthurRoad proachedVertacrtfchfem art abort the locatedonUtileRockAirForceBaseprop of 2,45-T herbicide waste stored at the towardVertac.Thenbewokeupooeacru- rhemjratodorfato air,Twasfatdfiat it erty. Alter moving m1948to the cvrent chemical siteat concentrations-high as fag.wortintoacomaandwasdeadttynoon. wasn'tcomingfromJacbonvffle.'tot Iwas plantsite, thecompanycontinuedfaman 111partspermfllim Theaveragewas 40 There was a major fire at to pfart right gndlmgthepspermiltsfafar Ikfff Iwent ufacturetheance-barmedDDT,aidrfaand potspermrHtoaSomeotthebandsof2.4-D beforefids,ablowoutwhento reactorYes' toto staleregulatoryagencies,hotnobody diekfrin pesticides and insecticides. Her wastewerediscoveredtobeleakingwhen setcautfitfireonenightftdestroyedevery there wouldgivemeanystraight to wers cules,Inc,whichtookovertbesitefa1961, the EPAmovedontotbe site in 1987and thingaroirel that area.Ahto oaks, every either.* producedat theplantnearly20percentof initialedre-&umamgandotherdearsup.Al hardwood practically rfauilrgralrtl over- Fraseslowsdownrehercarapproaches theAgent Orangeshippedoverseasfarde together,atleast30j000barrelsofhazardoiB nigbtThoeweredealdogs,dadsquirrels. tbe 140-aaeVertaccompound,its interior foliatingthejungles(hiringtheVietnamWar. materialsstillawaitdisposal. All to fishdiedinto dischargeareainto shielded by a fall chain-tiak fence and a AlterHerculessoldtheJacksonvilleopera Levelsofrfiodnhigherthanonepartper RockyBranchCreek. series of pine trees contracted bythecity tion, Vertac Chemical Corporation con billionhavealsobeenfoundintwosoilsam Doryearswe'dliveda fewblocksaway, aspartofa*beautificationprogram.*Point tinuedtomanufacturefordomesticuseboth . plestakenfromresidents'yardsnearVertac, andIhavenodoubtthat myfatherdiedot ingout thewindow,shesays,`Jacksonville oftheherbicidesusedinAgentOrange.They aswellasintheair,inthecitysewersystem chemical poisoning,*she continues. They wantstomakeitlookgood,sotheyhireda were 2,45,-T. banned as a cancer-causing andlagoons,inthesedimentsofthenearby (fidanautopsy, but couldn't findanything, company to put pines where all the agent bytheEPAin 1983.and2.4-D.alsoa Hoodplain,andinfishandwoodduds. sotoy decidedthathiscolonburst hardwoodsusedtobe.Thehardwoods'roots suspectedhumancarcinogen. TheJacksonvillechemicalplantcurrently "Mymotherstartedcheckingaroundthe aresolongthatthey'dgetintothecontami The result as described inone federal ranks 18thon the EPA'sSuperfund list oif area, and said, 'Everyone here is dyingof nationanddie* courtproceeding,hasbeena"witch'sbrew' nearly 1,000prioritytoxicwastecleanups. cancer. We'removing.' Rightaftertot she ERA'Sdaiayadreaction:Todayachem otcontaminationofairandwater,notonly AsauEPAofficialtestifiedata1984hearing, wenttotothehospitalwithlivercancer.She ical odorcontinues tolinger in to airlor inJacksonvillebutalsostretchingfarmiles evenifdioimwerenotpresent"thehighly hadjustturnedSO.andnobodyhadeverhad blocks arormd to Vertac site. Behindto alongtheBayouUetofloodplain.About20 toxic natureof theother chemicals would canceroneithersideatourfamily.Theday wall ottreesstandsawastemountaincon chemicalshavebeenmeasuredinJackson causeittobeincluded.* before she died she told me. `Goget 'em. tainingthehighestlevelsofdioxinevermea ville'sair.including12thatwerealsofound And tbe people of Jacksonville face Patty,andwatchout(oryourhealth." suredintheU3.Nobodyknowshowmany intestsat contaminatedLoveCanal,NY. another,evengrimmer,possibility.Atacourt So she did. Despite tier own mounting morebarrelswerelongagoburiedhereand Then there is dioxin, a contaminant by proceedingagainstVertacinLittleRocklast healthproblems.FraseorganizedtbeArkan elsewhere,ortheircontentssimplydumped productofAgentOrange.2.45-Tandpossi summer. US. District Judge HenryWoods sasChemicalClean-UpAllianceandeventu intotheRodcyBranchCreekthatcurisaway bly2.4-DherbicidesAccordingtoapublica reiteratedconcernshehadexpressedsince allywasnamedtotheGovernor'sTaskForce fromthesite toemptyinto the floodplain tionottheEPA'sOfficeofResearchandDe 1980thattbewastesarestoredintornado onHazardousWaste.Movingwithherhus andeventuallyto ArkansasRiver. Despite velopment titledDioxins, ft is reasonable alley.*AddedJudge Woods. Tertainly we bandTomm/TothetownofBenton,30miles C anm jrd on follo&nq pa$r topresumethatthelightesttraceof23.7-8- won't want aChemobyl-typedisaster with onto othersideotLittleRock,sht hadsix TCDD[themost lethal formofdioxin) inthe `miscarriages before finally conceiving a I V .- . CcMmd h m p n a i% page carry-overhornthesite'soriginal ok as a 1963 and spring ot 1985, lound the worst barbi'tbeenmanutactaredloryears. health complaints and reports ot massive WorldWarBordnanceplantTheDemocrat contaminationbelowtheJacksonvillesew Sincetheearly80sofficialsatthestate: fishkillsas iar backas the'50s,thedioxin reportedthataislespaceprovedinadequate agetreatmortplant'soutflowintotheBayou Game and FishCommissino have periodi threat wasnot brought topublicattention toperforminspectionsormaneuverequip Metofloodplain.Thecity'sentiresewersys callydiscoveredcontaminatedfishinArkan until 1379.Atthetime,followingcriticisms menttoremovetheleakingdrums.Notonly temwas deteriorating, filled with broken sas markets.Andin 1985officials inMem oitheEPA'shandlingo(theLoveCanalwaste werethebuildingsstructurallyunsound,the lines. For years after heavy rains, sewage phis.Term,complainedtoArkansasoffidat crisis--asituationtheagencyadmittedwas EPAfound, but also heavilycontaminated. overflowsoccurredregularlyintheresiden thatfishfromthefloodplainareareekedo tarlessseverethanJacksonville's--anEPA Onetankhadbeenleakingdioxinlorsolong tial areasouthottheplant.Anddurmgdry chemicalphenolicodon. spokespersontoldtheWashington Post that thatstalactitesandstalagmitesmadeotthe periods, theEPAnoted,chemicalstiketyfil DuringtheTiOs,thelateDr.RexHancock the agencywouldmovefasteroncleaning gummy chemical had krrmed under it A teredintotheshallowgroundwateratfiacent adentistinStuttgartArt,firstbegansound upVertacthanonanyprevioussite. similarsubstanceranregularlyintothefloor tothesewertines.Theaveragedkxdncon ingthealarmaboutfidiidUsandthebiolog ButwhiletheEPAdidconducttestinglor drainsleadmgtothesite'scentraldrainage centrationinthesewagecollectionsystem icaldestructionoftheBayouMetaHeana contamination,eightyearspassedbetonthe ditch.Oneotthelourditchesdrainsdnectly was215partsperbfflion(ppb),aiddimm same blends went to the chemical plant, agency sent a teamof workers in "moon intotheRockyBranchCreek. wasdetectedashighas200ppb--200times then ownedby Hercules, and tookphoto As'tobeginthecleanup.NotuntoVertac DiningtheCA's.first sixmonthsonthe theEPA'sactioolevellorcleanup. graphs dotianenting the ddfeente dis aid itcouldnolongeradordtocontinueto shelastyear,workersbutt twohugebarns Then there was the flood plain ftseU. charge ot chffldfah into Rocky Brant t-dnacorroshewastestheredidtheEPA to'house some at the drum and oected mostlyirrigated(urnland,lacedwithborin CreetAtthetimethousandsoitateraanc takeresponsibilityonFeb. I, 198Z. IOjOOOieetotiour-ioot-highfencingarotmd contarmrationafterheavyrains.Outat324 fishmnan signed petitions that were pie TheteamsenttoJacksonvilleiomrtttum thepertarier.Theagencyalsore-bunmed sodandsedimentsaeplq takenbytheEPA sealed to thegovemra, bat thestile too. afcy,*a large storage area with thousands no action apkut the rnrepaain to aub aftbeheavycorrodingbarrelsstackedthree- sequafttestsHancockconfectedwithFrase m . mviolationolfederalregulations.And "T h is is one o f the m ost serious public health inthestreamsaroundJacksonville,minnovr theylound*Vertacmountain,*whoe20JXM cubicyardsat <fiaxm-contaminaedsludge disasters in the U .S.," says Adrienne Anderson. "The put in the Ifcto water suvived nokwf: duntwosecondLUfer,Hancock,desperate (hedged tromold lagoons onthe site had number o f m ysterious S ID S (Sudden infant Death foraction,pouredoffishjuicesontothelac been piled aboitt 20 ieet high.Altogether, morethan lOOjOOOcidricyardsofcontana- Syndrom e) deaths is h orrifyin g." at ERAbaringotter, tefimgtank*0h don't worry,itdoesnTan* fertiiiqrprob uatedmaterials,enoughtocover20football leas.' Odds tfcaee-ieet deep, were discovered anarnageot 500to<00leakingbarrels a in a studyot ofl-sriepofiutioo, more tun RalphWjgpna.aIonitepilota^neiTj, within the pint's perimeter. Besides be met TheEPA,sC3on thesite today,baa aK-lbMcootaedTaXLdnim.hitestset HrmtieidipaBdnatsdfiglekjpttlieir Wring brass, sod was erwting, aBowmg authorizedS4J5affimi hr mamtmnce at fishtakenboathestemming alongte my-iy OjprTftjeantlytannedtheEPA contaminationtowashoilthesite. Vertac. Bat afterqn|ynine months, it tad Bayou lieto toed pia, TODO-Jruonmi shaftte tineheheomeshooedatdunp- Hatyotthebuddingsrrmtainrd"wafl-to- .alreadyqtent abaftt}mdfion. -.- defected*35tinestheFoodaodDrugAd- _iagtooftseaeektodwastoldbycompam wufl,ceiiog-to-cnlmgdrans,"dieEPA'soo- Thecrutaarnttotat (besite, however, ' jtanshatku'sacticulevel,wboonioifi 'hanitiienntilqnhjMAapriztlfer w cooninator,DavidWoodsGray,told artythebeginningotthe kmcdrnin. ft htSsh'aslarraflesdowstieam cafesbecame*wedentwantabigiili kii- theArkansasOemooa,oneotLiltieRock's Botta of tho borni: AsERAstiaiyto hotheVertacptaoLfio(fidatatabother. -todhe responsUe torit' Buttee fish tpttdrilynewspapers. Sameot the bums btrimiif.where(foxmandoihgrhnnirih ..P-Q-SBKSQ-sB.0n_B|.KJQia^-ui-C*J-f-DaOB.OKB* rilK. packed tijfit-in concrete taken, a tadmigrtordrdnnrhrtrdbetireofohKof cab,to m oi itfch, Be.thetamedTUT,! J9B5pta*waiterJnores Cat dfed-riurth ^cn'thhkSa-rPawia/XsgorrcBs, acifedreadaepfluStmoeiBt pSarc erfir,birdtipretiretanandataondfcrcd dftaaai pciannfeg SoroknowX sufier recoriega m anddmws sigmot feu- ketoa. Whftetfc SOOJBOnegligence suit ip* Varteciastfflpwfwlng_theAikansas FeeandPolicePensionReviewBoarddeniec Kona' requested AsabUftybeneitsTo De cember,whenitsphyudaostipulated that diaxmpoisoningcraddnot be proven. Wilcotoi tn cancar allay: hithenei|ft- borikmdborderingtheVertac facility,just anwd thecoruer bomatuninghomeand ahospital, not a soul seemstobestirring Theairisstill,but eyesareburning.Tour ears win ringafter a little while,*saysJack Ftefc,a23-yearresidentnowinhisearly60s. Park,whoworkedat theplantwhenitwas ownedbyReasor-Efift andwhoheadedthe wet^tjhoreresriksliibbli laboratory under Hercules, maintains that ' tatznTJfitimtf'Sotefetaat'MJU) -A S L -CV-. teesmoedewSybansodtaepasde, : ptaets sadf afT-fc teb td d si^ T : EarBar*.ttriERAptryuuudin Oe- somechemicalsusedtomakeAgentOrartge werebroughttoJacksonvilleinbulk.Hesays axnre(jutyuaedknTmitiocg%gt,and ; and itS ' ( t e qumpunente cT onbertoraaebyIf-kridthedaiyintake somecame bomHookerChemical inNew rimnt 580 teea more'tone (tan Orange), the wisw preservative pefi- of (kw But ft consldeskacceptable; York, the company responsible for Love iftytbiunL. Aod wide delate' persists oanrapoan m w in nm ci of basedonanewtbaftshriy.Itstatethat Canal. ever its long-term effects onbunan onidpri waste incmeratax. De^te tedtam maylactim a`promoter' Tie brought tetrachlorobenzene bom health,'theERAhedeemeditfeqmaalife Sons ot tana at production ot sack'' U other aacer-ansfef agrnri rather Hooker bythe traincarload.*hesays. The to establisharysale`acceptable*level wastesovera40-yearperiod,norestric Than being an iniSattr of cancerous, toxicchemicalwaslaterfoundinfishalong lorTCDD-dhzmtcontanunriion. tions wereputin placetab) 1980.The tumorsbecauseitdoesnotcasethemu thelocal Hoodplain. *Averysmall amount wifi lead to iU useat 2,<5-Tonrice fieldsandrange- tationat tenal cells. Alewyears ago Parksuffered a stroke. healthordeathinmanyarrimiispecies,* landswasallowedtftttflajmrago,when BarryCommonerattheCollegetorthe This is cancer alley," he says matter-of- says I>. Arnold Schecter, professor ot theEPAfinallyoutlawed aft usesat the BiologyolNaturalSystemsatNewYork's lactly. "Mynext-door neighbor isdyingol preventivemetficmeattheStateUniver herbicide.In1967itwasrevealedthatthe QueensCollegefindsthisoutrageous.Tn livercancerrightnow.Whensomeolusgot sityoiNewYavk'shealthsciencecenter. residues trampaper mftb also contain' (act, what .dioxin does is enormously testedbyDr.AubreyWorrell inPineBluff,! Soit is classified as a super-toxin by amountsofTCDOs. stimulate an enzyme that converts en had thehonorofhavingtile highest levels bothdemote andtoxicologists. Oneot Dioxincontaminationhas resulted in vironmentalcompoundsintoactivecar ol chemicals inmyblood. Igot a petition theveryfrighteningthingsisthatweare evacuations ot residents in the Love cinogens, makingthe bodymuchmore drawn up by a lawyer biend asking lor a recently fincfing surprisingly elevated Canal.N.Y.andTonesBeach,Mo.areas. vulnerable. The latest EPArisk assess healthevaluationdoor-to-door.Thatwas10 levels at tfioxins in ail the humans we Anddioxin exposure also prompted a mentshavenothingtodowithscience.' yearsago. It'sneverhappened." haveKokedatinindustrializednations.' lawsuitBedbymorethan259,006Viet -OR Hobbling outside with his cane. Park According to Schecter and other ex namveterans,whohavesufferedadverse pointsoutthespotswherehydrochloricacid 1 IN THESE TIMES MARCH J 1 5 . 1368 567 OnCar fMl' fAt*nMOamociM PattyFra(piguradheraddressingmwnbereofnvironoMrofgnny*):Mustdon'ttouchdiefood,dinkda nur ornanwahyourhandsinJadkaonvifte.* haseatenawaythecementinhadriveway. dumps.But theagencylakeraid thesere Toreverypoundofherbicide,theplanttool sits were niililu. because the swnpfes apoundofhydrochloricadd. kcameinby hidbeesrd*ifWrtallymfftammafrriAwrng the carload.' He picks tg>a grape plant laboratoryanalysis.Accortfingtosomelocal gnaried and twisted with mutation, and residents, dioxinmixedwithwastenilwas shakes hishead. sprayedonthennal roadstocontroldust, MozelleBergschneider,71,has livedtwo thesamesituation that forcedtheevacua blocks fromthe plant since 1946.Shehas tion of Tones Beach. In These Tunes was conducted her ownsurvey within a four- unabletoconfirmthespraying. blockradiusofherhome.Onherlist of50 Abie Glover, S3, lives rigit between the deathsinrecentyears,shesaysmostofthese two dump-sites and raised lour children werecancervictims.Another17people,she there.Twoofhersonsboughthomesnearby, says,areundergoingchemotherapyorother beforeanyoneknewaboutacontamination cancer treatment programs.Sincenostate problem.LastAugustshejoinedabout 100 orfederalstudyofthearea'scancerratehas otherresidentsinsuingVertac,Herculesand everbeenconducted,residentsaretheonly thecityofJacksonville,seekingunspecified monitors. damagesforpropertyandhealtheffects.The Bergschneidertellsoftunninghertongue citywasdroppedfromthecase.Vertacset around her mouth certain mornings and tled out of court withthecitizens, andon finding a sweet taste. That's dioxin.*she MarchIHerculeswasacquittedbyajuryin says.Theproblemiswehavesmelledit(or aLittleRockiederalcourt solongthat ourolfactoiynervesareabout ThecityownedandoperatedtheGraham gone.ThisIsadeadtown,notfitforhuman Road landfill, allowing the dumping of habitation, or animal. But Ihave noplace hazardous chemicals until 1973, when die else togo.That'struefor99percentofthe stateordereditclosedbecauseofthehigh peoplehere.' water table and poordrainage. A few miles from the Vertac facility, Nowhers to go: Nowthe EPA,whichfi sandwichedinamongaruralneighborhood nallyaddedbothdump-sites totheSuper ofhomes,aretheGrahamRoadandRogers fundcleanuplist last summer, is payinga Road dump-sites. Although both Hercules visitThreewomentomtheagency'sDallas andVertacofficialshavedeniedunderoath regional officesit around Glovers kitchen that anyof their products endedupat the table,seekingtodeterminetheextentofthe twolandfills,someoithesamewastesburied damage. at the plant sitewerefoundbytheEPAat Afewyearsback.Gloverrecallsbeingtold both, includingopendrums.TheEPAesti byanotherEPAofficial.*111wereyou.I'dget matesthatmorethan1.000barrelsweredis myfamilyoutofhere.*Butshetoldhimshe cardedatthelandfillsovertheyears.Dioxin, couldn'taffordtomove.Beforethecitydug herbicides.PCBsandnumerousotherchem ditcheslastyear,watertomthecreekbelow icals havebeendetectedinthesoil. theRogers Roadlandfill wouldstandinher The EPAalso reported findingone form yardloraweekor twoatatime. ol dioxin in a family's tapwater, and two "It wouldlloodover the barrels,*Glover differentformsinamunicipal wellnearthe says. *Wedidn't knowlor years theyhad anythinghadinthem.I'dpaythecityman What they witness is a house-to-house whoranthesite<2apiecefarthemtobin chronideofdisease--tornallagiesandre trashin. So(fida lot ofpeople. spiratoryproblems,tocancerandheartdis SeveraltimesIgotjustdeathlysick,'she ease,bothofwhichhaveaffectednumerous continues."Onetimeyrn'dhimyourfaucet peoplebeforetheyreachSO.Glovesdoesnot onandifdstinksobadyoucouldn'tstayin wishtotalkaboutherownhealthproblems, thekitchen.Wasn'tnosuchthingasopening onlytheallergyshotsthatherdaughter-in- upyour house insummertime, because of law and little granddaughter must take the odors. The cinders tom burning the weekly. trashdowntherewouldbealloverthecar. Ina 1985reportaboutthedump-sites,the Whentheyfinallyclosedthedump,theyhad EPAnotedthat"sevendeaddogswerefound thepigpenright there.* inthetwodrainageditches*and`itappeared TheEPAofficialsdonotfollowupGlover's that childrenhadplayedtherequiteexten laststatementYetinJuneof1985another sively.* fP \ crewhaddiscoveredsomepigpenssit It is, beyond a doubt, the children of tingwherethewastewasonceburned.The JacksonvillewhohavesufferedthemostAn pigs had been contracted out to a local informalsurveytakenin1985bytheArkan fannertoraisebytheTysonChickencom sasDemocratofchildrenlivingincloseprox pany, oneoi thelargest poultryproducers imityto thedump-sites (most ofwhomat inthe world, basedinSpringdale.Ark.The tended an elementary school in the same pigs, which wallowed regularly amid the area)found10ol18withserioushealthprob toxic barrels, were eventually sold to lems, including spina bifida (fluid on the slaughterhouseslormarket`goinginto*as brain), seizures, an infant witha hole be Fraseputsit "yourTVdinnersorbacon* tweenthechambersoftheheartandababy Sheadds.Thestatewastalkingaboutgiv bomwithpartofherbrainoutsidetheskull. ingthefarmerscompensationfortheircon Whilenodirectlinktodioxincouldbeestab taminatedpigslongbeforetheytoldpeople lished. some state health officials told the not to eat tom their gardens or-let their Democratthattheunusualsituationmerited children playoutside there* furtherstudy. DespitealetterGloverreceivedfromthe SomeofJacksonville'schildrenneversur state Health Department warningthat her viveat all. This isoneofthemostserious wellwaterwasunfittodrink,theJacksonville publichealthdisastersintheUnitedStates.* CityCouncilbalkedformonthsat pumping saysAdrienneAnderson,westerndirectorof apublicwatersupplytothearea.Nowthat the National Campaign Against Toxic residents have finally received citywater, Hazards. The number ol mysterious SIDS theirwaterbillsrunashighasS90amonth, (Sudden Infant DeathSyndrome) deaths is farbeyondwhatmostJacksonvillefamilies horrifying* an afford. Residents refer to a section of a local WhenGloiVeraskstheEPArepresentatives cemeteryas*babyiand*wherebabiesunder if they'd like to take a drive through the six months old whose parents can't afford neighborhood, theyreluctantlyagree. CgrAnuedon foUouJuqpose IN THESE TIMES MARCH 9-1S. 1908 11 I 8568 - v . J- *< * v :- * . w rr:-- r il i" -'.7V. 'S k. 1 -- n r -- r-* Continued Irom prrtrthnfpage exposure." gonnabatheherbabyinLysol.' calleda lab." toburytheminfamilyplotscanbeinterred InDecemberthehospitalreceivedthetest AlltheSheltons'couldfigurewasthatthe Dr.JohnLasiter.directoroftheTexaslab atnocostOfninebabiesknowntobeburied results. Levelsrangingashighas508parts chemicals might havegottenintoJoseph's oratory, would not comment on the con here, sevendiedin 1985.Oneoi themwas per billionofsixchlorophenols--theclass bodybomthe water that was mixed with troversy,sayingonlythathislabisCDCcer three-month-old Joseph Shelton, whose of chemicals used inthe manufacturingof hisformula.Or,asDr. Brewstersuspected, tified and that it is a "political situation.* mother hadgrownupnear thedump-sites 2.4.S-T,2.4-D,2,4-DBandSilverherbicides-- theycouldeasilyhavebeenpassedonduring LasiterhasservedontheEPA'sScienceAd and whose lamily was then living a lew werefoundintheSheltonbaby.Atleastthree pregnancy. visory Board longer than any current blocksaway.Thestoryofeventsloliowing ofthemwereknowntocausecancerinlab AVertacspokesperson,however,saysthe member. thisinlant'sdeathpaintastill-largerpicture animals,andonewasamutagenthatalters baby's death was mote likely caused by AskedwhytheCDCdaka-Tdoitsowntest ofgovernmentalindifference,evencover-up. cells' genetic material. Dr. Woodytoldthe burning treated wood in the family's ingontheSheltonbaby,Houkreplies:TVdl. Ignoringthevidence:OnSept.6,1985, Arkansas Democrat that theamounts were woodstoveor bypesticide traces state in whatareyougoingtotest?Youcannottest afterthethen-healthySheltonbabyreceived "aboveusuallevelsforurbanadults,"widing spectorsdetectedaroundthekitchensink. thetissuesbecauseoncetheyhavebeenin a 2 am. bottle feeding, theyoungparents that there are no "normal" levels ofsuch "Afterquitesometime.'saysDr.Brewster, formalin,noooeknowswhattheimpurities awoketofindhimdeadinhisaft. Aweek chemicals in the blood. Other chemicals, "thefinalanswerwegotbomtheCDCwas intheformalinarewhenyou'retakingabout later anotherchild, 17-month-oidJedShel pfaenoxyherbicides,werealsofoundintwo thatno.theywouldnotre-assaythetissues lowpartsperbillion.Likemtheearlydays ton. beganhavingseizuresandwasrushed urine samples taken fromthe mother, 19- or anybodyrise's either. The reason they of Legionnaire's Disease, before we knew to the hospital The director of pediatric year-oldBrenda. gavemewasthat theyhadsent an inves what it was, therewasalotofspeculation neurologyatArkansas' Children'sHospital, "Wethenrequestedthat theCentersfor tigatorandwerenotpleasedwiththequality becausethereweretraceamouXsofnickel Dr.RobertWoody,suspectedsomethingun DiseaseControl inAtlantautiliretheother control at theTexaslab."Besides,saidthe intheautopsytissues.Well,thesourcewas usualafteraninternruledoutspinalmenin half of [Joseph'sl tissue we had stored to CDC,theirscientistshadresearchedmedical reallynickel platingoftheautopsyinstru gitis. repeattheassay,"Brewstersays."Atthetime literature and had found no record of ments." HospitaltestsonJeflseemedtorevealthe we had stored approximately 100 other chlorophenols ever showing up in human As for dioxin contamination. Dr. Houk existenceofahigh-levelchlorophenolchem babies' tissuesbomSIDSdeathsthatcould liverandkidneytissues. adds. "Ourconcernabout thehunanhealth icalinhisblood.Thephysiciansthenclosely havebeenassayedsimultaneously.' AskedwhytheCDCwouldn'tpursueitany effects of dnonic low-dose exposure are examinedtissuesfromanautopsythathad When the story broke in the Arkansas way, Brewster replies. "I was very disap muchlessthantheywerein1980.Wehave alreadybeenperformedonJoseph, astan Democrat, citizens began todemandsome pointed at then approach. CDChas billed gottenalotofinformationthatappearsthat dardArkansaspracticeforSIDSdeaths.Dr. answersbomstateofficials.Atonegathering itselfasbeingthenation'spublichealthlab humansarenotassensitivetodioxinasthe Marge Brewster, whoheads the hospital's stateepidemiologistDr.TomMcChesney,a oratory,andwithaquestionofthistype,it's mostsensitivelaboratoryanimaLEverybody MetabolicLaboratoryandisinchargeofAr retired Air Forceveterinarian, commented reallytheonlyresourcewehavetogotofor inthiscountryhasTCDOintheirbody,iq> kansas'ReproductiveHealthMonitoringSys that theautopsyfindingshadbeen"prema ananswer.Ithoughtwehadallthematerial to18partspertrillkmmeasuredinfaLItis tem,thencontactedtheEnviro-HeaithSys turely released"andthat it was"most dif theyneededtogetsomeverydefinitivean nocauseforalarm." tems laboratoryof Richardson,Texas,one ficulttoassesswhattheymean."notingthey swers, and their excise doesn't make any Dr.Brewster,askedwhethershebelieved of the lewprivate labs in the US. that is were being sent on to the CDCHe then sensetome." theCDCsimplydidn'twant tocreateastir equippedtodofurthertesting.Asafavor,it suggested the chemicals may have come The ultimate dedsicc, Brewster says, over theSheltonbabyincident,comments: agreedtodoanunusualassay(analysis)of bomherbicidessprayedaroundtheShelton camebomDr.VernonHouk,directorofthe 1 thinkin general theCDCsattitudewith thedeceasedchild'sliverandkidneys,look home. CDCsCenterforEnvironmentalHealth.Ex regard to these toxicsquestions isone of inglorspecifictoxicchemicals. At another meeting of the city's sewer plainingthat decisionDr. Haft says. The skepticism.Theytendtowaitiat3 there's Tart of what we asked tor," says Dr. commissioners, Frase remembers, "Some [Texasllabislousy.Theirqualitycontrolis ampleevidenceofaproblembeforebringing Brewster."wasanassayforchtotopfienois, bodyhadthe audacitytosay, 'I wonder if notsufficient lorthemtodothethingsthey anybigguns to bear upon it That places thinkmgthatthoaebeingreleasedatthetme shewasbathingthatbabyinLysol'andthey saytheycftLftyhbtestingpartsperbiffion peopleinthesituationofgatheringthrirown throughtheJacksonvillesewersystemcould all hadabigchuddeabout1Thiswoman in autopsy materials that have been pre evidence, before the best set of erpntlir potentiallybewitatilizedandavailable for mightbepooranduneducated,butshe'snot served in formalin is not worthyof being getsintothepictureatalL' Backin1980Arkansas'healthdepartment Jocksonvfflc's dioxin disaster: a chronology director. Dr. BenSaltzman, had requested federalhelpaftercitizensconpbinedabout u m ifeytfkiT gfr by* ( & & * xri^riftrfei 3B ar>Ta|4riihrftl ill health. TheCDChadagreedto analyze data ooJacksonville chemicals. Up to that point the onlyother tests hadbeen con i.wrickbeginstoI itftxarMes WT. ftftft, rifrm. ax- . agftenea d a f t B v D w r i w f c i J r e "-riaefad ism eges fieldnetoteupen- -H hB M . . .VV TJ57-ifei**-HH starts pmdwfltow of " ThesriaequeetlytamedherbicideA5- ' 7, toadffitioutois otherHwlrah to- 'cfadtogtheherbicides 2,4-0ad Sivex. Morednas ateaddedtothefieldad treatedwastewateritdisdagedtrom the piad, riere i runs downhill into RockyBrachCreek. ntl-The plantisacquiredbytheHer cules chemical company. Theaid wale drums ate buriedinthesamearea. Her culesaddschlordanetoitschemicalrep ertoire anddischarges processedwaste waterintothecreek. 1967-68-Herculesmanufacturesthede foliantAgentOrangeforshipmenttoViet nam. 1172-HerculesleasestheplanttoTrans vaal. Inc Herbicide production, hatted brieflyin 1971,resumes. Burial ofdrums of concentrated waste continues until 1974. 1176-Transvaal and four other com paniesmergeintoVertac. 1978-Vertaccompaniesare under pro tectionof thefederal court duringbank ruptcy procedures. The company is brought out of bankruptcybynewown- Llfcela- itProtectionAgacy(En) re- ym a song atg ^to4Bpto permatonofifinrii lkrrky 'hackCreek,JackaaasfifchLritoDqprce dfieBayouMetearequarauttoed.Vfertacceases2.4JS-TpnxkictiouvokxXariy. IMt-TheFTAandArkansasDepartmes* ofPositionControlsodEcologysueVer tacandHercules, anda federal courtdersdeanupofbothtfaeplanailoff-site COOBHMOQ. TfC-Thechemical pilot site ispriced 18thon tfaeEPA'snational "Sigiatund" deatigr fist Negotiations continue among stake, federal government and chemicalcompaniesonthedeanuppfan. 1183-TheArkansas healthdirecta asks fa EPAhelpaltercitizenscomplainabout illhealth.TheCenterstorDiseaseControl agree to analyzeexistingdata onchem icalpollutioninJacksonville.Amufti-milUoo-dollar consolidated lawsuit is filed bycitizens against Hercules andVertac. Aformer Herculesworker identifiesthe old Jacksonville city dump as an area wherewastesfromdieplantwereburied. 1984-TheEPAreleases areportstating hazardous waste contaminationposes a continuinghealthdangertothearea.Ver tac, Herculesandthestate fight theEPA, seekingtoreducea 420millioncleanup planto$2million.Afederal courtjudge andeswerebaled. I9*-TheEPAi rowersystoms,withcostestimatesrang ingashighas 080ndfiou. Diaxtocon tamination is found in Arkansmwood ducks. The citizens'lawsuit against Ver tacissettledoutat courtVertacceases productionof2,4-Dandshutsdownthe plant 1987-Vertactransfersitsassetstoanew corporation,paysofiadebttoDowChem ical.andleavesArkansasandcleanupre sponsibilitiesbehind.Thefederalgovem- ment and the state take Vertac to court for fraud, namingDowin the suiLMore than 100residents near twodump-sites addedtotheEPA'sSuperfundlistfilesuit against Jacksonville and the chemical companiesinfederalcourtseekingdam ages and city water supplies. Interna tional Technologies. Inc- o(California is selected to incinerate (beVertac wastes on-site. -DA ductedon55formerworkersatthechemical plant by the Mount Sinai Medical Center, which found `effects of unknown signifi cance' onnerveconductionin46percent ofthem.Blood,fattissueandurinesamples weresent backtoNewYork,buttest results never came back. Arkansas itself doesn't evenhaveastatisticalcancerregistry,which canhelpastateidentifyunusualcancerclus ters inspecificareas. ACDCcovwr-up?EvenpoortotheShel tonbabyincident theCDChadhedged. De spiteastaterecommendationthat all toxics beconsideredintheCDCsinvestigation,the CDCexaminedoniytheQ'A'smeasureden vironmental dioxin levels in Jacksonville. TheninJulyof 1985theCDCdecidednot to undertake alatty-tissuestudyofresidents. Theirreasoning,whichwascontradictedby EPAstudies, was that Jacksonville'sdioxin problemwas not as badas Times Beach's. AftertheCDCturneddownfurthertesting oftheSheltonbaby.Dr.Brewsterpersonally contacted four EPA'CDClabs. Eachof them also tamed her down. Finally, a California labsaiditwouldexamine10unlabeledbaby assays,includingtheShelton's,fora$10.000 lee. Inthe interim, accordingto Brewster, the other 100 tissue samples of SIDSvictims beingpreservedbyChildrensHospitalwere thrown out. apparently by accident, by a morgueattendant. Tfeel nowthat Ishould havegathered themina sale." she says. 12 IN THESE TIMES MARCH 9-15. 1988 l 6569 *T-,,*.T-- -- -- r f -- . . 1 ITIT[ *-- in 11./v <. tJV* Finally, under prodding ironi Arkansas * thinkIdidsomethingtohelpsomebodyelse, Weinbergerpersonallyresponded:"ForDoD * ingloreverybodyonthebase,infad it'sa doctors and health officials, the (DC did ^ Twentyyearsagoittheyhaddealtwiththis (DepartmentofDefense!totakeonthedis hall-troth.Butthat'sthewaythemilitaryis." agreetodoastudytogaugechildren'sexpo- * problem, fact is myson might bewith us posalresponsibilitylorprivatesectorwastes * Ahealthy 25-year-old first lieutenant in sure level to chemicals, using "control todayandmaybeI'dhavesomehealthychil- wouldsimplyimposeonDoOsomeoneelse's , hissquadrondiedintheeariy'80s.according groups" of 100children fromJacksonville " dren." responsibilitytosatisfypermittingrequire- to the pilot. They sent himofftotheVA andConway,atown30milesaway.Thestudy Hepausesamomentthismanwhopaints * mentsandconditions forprotectionofthe Regional Center, and nobody knew. They didnot showsubstantiallyhigher levelsof " satellite dishes for a livingandnever had t environment" Besides, Weinberger added. , neverdidtell usexactlywhathappenedto . dilorophenols intheJacksonvillechildren, muchformaleducation,andsays:"Ourgov Pine Bluff wasn't technically equipped to him,otherthanheapparentlygotcancerof althoughsomedoctorsquestionedthewis- ernment,backinthe'60s.thesecompanies handlehighlytoxicdioxin. * theliver,likealotofpeopleinthistown." dom of comparing samples from com madetheAgentOrangefor'em.!figurethat's Robinsonfollowedupbysayinghewould Frasesays.1 knowthat alotofmilitary munities insuchclose proximity. probablygot a lot todowithushavinga seekanamendmenttoaDefenseappropria men(atthebase|who'vetakenillhivebeen Brewsterthenaskedstatehealthofficials hardtime.That'sthePentagon.That'swhere * tionsbilltorescindaiederairegulationthat senttoPennsylvaniatobetreated.Theydie iftheycouldobtaintheCDCssamplesfrom thepower'saL" binned themilitaryfromassuminganyre there,butthedeathcertificateneverreads the urine of the Jacksonville children, but Pentagon kaapi its dtaanca: For 20 sponsibility for civilian-produced waste. LittleRockAirForceBase." her request wasdenied.The reasongiven years,theLittleRockAirForceBasewasthe Addingthat beintendedtoraisequestions * Aphysicianat LittleRock'sVeteransAd bythe(DCwasthattheremainingvolumes military's primarylocationlorTitanDmis athearingsoftheVeteran'sAllairsCommit ministration Medical Center responds, "If of urine were toosmall to test' Brewster siles.whichwererecentlydismantledthere. tee. Robinsonsaid. This will allowme to anythinglikethat isgoingon.I'veseenno says. Frase's groupcontactedtheCDCand Outsideofthestalegovernmentthebaseis openaPandora'sboxaboutAgentOrange." evidenceofit Thebasedoesah-evacuatea askedofficialstocomply.ButtheCDCand the largest employer in Arkansas, which But Robinson never pursued the matter certain proportion of people who need thestate HealthDepartmentrefusedasec `competes'withMississippiforthedubious further.Thecongressmanisnowpushingfor surgery,whichwedon'thavehere,tomajor ondtime,because,accordingtoFrase,"they distinction of havingthe highest illiteracy mobile-basedMXmissiles onrailroadcars Teachinghospital'militarycentersinTexas." didn'twantChildren'sHospitaldoingquality rateandlowestincomelevelintheU.S.And tobestationedat thebase. Thephysiciansayshehas notnoticedany control on its own." Kaptinth*dark: Questionsremain.how unusual rate ofcancers that might be as 1worryalotaboutexposuretochemicals ever. especiallyabout possible large-scale sociatedwithtoxicchemicals,butaddsthat intheenvironmentbecauseIthinkit'squite chemicalcontaminationan thebase thebasehasarelativelyyoungpopulation. large."concludesDr.Brewster.The dioxin MaxPierce, now55and burdened with Yet whenawomanwhosehusbandwas issue is the unknown, and isextremelydif healthproblems,wasemployedduringthe onactivedutyinJacksonvillebeganraising ficult to test for. Weneedmotestudies of early'50sbyReasor-Hill Chemical.`Atone questionsaboutcontaminationat thebase, exposure that might affect theimmunesys tune there were two plants." says Pierce, atransfercamethroughtoabaseinMinot tem,betterepidemiologicalstudiesofhealth "andonewas locatedaboutwherethePX ND.Theywerecontinuallyharassedbythe effectsandmorevrorkonanalyzinglow-dose thecommissaryandtheNCOchibarenow. military," says Anderson of the National exposure to environmental chemicals. But Weused to get cars full ofbarrels oftox- CampaignAgainstToxicHazards."Wehave it could all be resolved ifthe money, and apheoe.Itwasnothingjusttolay'emonthe documentation ofother familieswhohave the politics, werethere toresolve it.' ground and chop 'em iq>. Wherever you sinceleftthebase,beenharassed,andwho Dr. Paul Connett a biochemist at New York'sSLLawrenceUniversityandfounder foundaspotyoujust(harped.Thosebarrels havenotbeengivenpropermedicalsupport were taken around different places where despite their dearlydocumentedcontami of the organization Workon Waste, is con thebaseis--2,4-D,cottondust diekirin,ail nation." vincedafteravisittoJacksonvillethat"poli different types of chemink Who thought Frasesaysthat "nopeopleshouldbeal tics'explainswhytheCDCcalledofffurther badethenthat this stuffcouldget intothe lowedtocometothebaseandexposeiheir investigation intothe sudden, inexplicable groundwaterandbeaproblem(orpeople?" familiesattheratethegovernmentisbring deathoftheSheltonbaby. Pierceaysbebelievesmuchofthewaste ingthan in. There are dump-siteson de Tm sure someone told them it's a ranoffintothenearbycreekandprobably base that need remedial action im- bombshell,*saysCornett. 'Becauseoneof intoaUkeonthebase.TmsureiftheEPA mediatety." the claims that the industryalwaysmakes or the state (fid some tests, they'd find Accordingto a source on the lose and isthatnoonehaseverdiedfromdioxinor thebaseisaplumthatneitherArkansasof kveipi substances stiff inthesoiLUIwas other residents, the Air Force has quietly related chemicals. And once that can be ficialsnorthePentagonwantstoseejeopar onthatairbaseandshoppinginthecommis takenafewotter steps. Nolongerwill the shown,it'sawholedifferentbailgame--for dized. saryorthePXit'dkindamakemewonder localVeteransArkninistratioo(VA)approve the Vietnam veterans exposed to Agent Someofthebasepropertywasoriginally whatliesunderthatground.' loansonhomesinparticularareasnearthe Orangeandmanyotherpeople." donatedbyReasor-Hill Chemical, the pre TheDoOhas testedfor some chemicals plantButfewpersonnelasktoomanyques *1ain't gonna lot up': M Shelton,the decessor of Hercules andVertac Mystery onthebase, but Fraseandothersay they tions when they are able to purchase a father ofJosephand Jeff, sits at a kitchen continues to shroud the relationship be neverlookedintherightplaces.Apilotstill 100.000homelor35,000.AVAspokesper table inside his small trailer. Jefl Jr, now tweenthebaseandHercules'contractwith on duty there, who requested anonymity, sondeniesbothallegations. three, ison medicationtocontrol his sei the government to manufachie Agent sayshe'sheardrumorsofmotetoxicsbeing When in 1984Frasediscussed the base zures. Alive-month-old dain^iter is on a Orange. The military used C-130 cargo buriedunderthebasegolfcourse. situation withan aide to Sen. EdwardKen heart monitor, just incase. planes totransport the defoliantoverseas. Foryearsmilitarypersonnelwerekeptin nedyinWashington,thestafferfinallythrew Rubbinga handoverhiseyes, thefather Thebaseisstillthecountry'smaintraining thedarkaboutthesituation.Recently,how uphishands."Utheyannouncedtherewere says, There wasababydiedalewhouses centerforC-130pilots,butthemilitarymain ever, due to escalating local pressure, the problems,'hesaid.Themilitarywouldhave downfromwhereoutsdid.acouplemonths tainsthatnoneoftheplanesbasedinArkan base'spublicaffairsofficeassignedsomeone topaythosemenhazardpaylorjustbeing after we moved. Started having breathing sas were used toshipAgent Orange. One to.assemble a one-page briefingsheet He there.Noway.Thegovernmentwilldoany problems, andbythe timetheygot himto reporterwastoldthatthecargoplanesdidn't wastoldtocontacttheEPA.thestatepollu thingto protect it andsowill thestateoi Children's, he was dead. But they haven't evenarriveonthebaseuntil 1971. tion agency and the Chamber-sponsored Arkansas." wantedtoget intoail this. ButFrase,whowaslivingtherewhenher JacksonvillePeopleWithPride. "Playedforfool*': Asthesunsetsover "Iprotested,wenttothegovernor'soffice fatherservedasactingbasecommanderin "Ithinkthefactsheetisbeingputtogether Jacksonville.Frasemaneuvershercaronto anddidsomethingsIregret"hecontinues. 1969.insistsshesawC-130satthetimeand becausethecriticismcouldeasilybemade the highway heading home. Shaking her There wasatimei tookacoffinupthere, wonders"whythey'redenyingthoseplanes that theAirForcehasdoneabsolutelyno head, she says sofdy. "Most peopleinthis to make a statement Ihadbeen tryingto were here for those couple ofyears." She thing to informits people of the problem community,withail theirmoneytiedupin get aholdofGovernor Clintona longtime, saysbaseengineerstoldherthattheytested there." says the pilot. "Alot ol men have theirhomesandchildren,don'twanttobe andwasgettingducked. I'dcall and they'd bayandcargoareas oi someoftheplanes comeandgone,andnever knewtheywere lieve that everything they've worted for sayhewasbusywithhiscampaign.Sothis andfoundthemhighlycontaminated. exposedtoanything.Nowthebaseisgonna might be useless. Weare played for fools wastheonlywayIcouldfiguretogettheir ThePentagonappears intentonkeeping saythatthebadnewsisthatyoudon'twant here,butthesepeoplehavenooutlet.Inall attention. Itrealtytoremeupinside.Myin its distance from Arkansas' dioxin con toget a house real close tocertain areas, theseyears,theEPAhasagreedtoholdonly tentionwastofollowhimaroundhiscam troversy.Latein1985ArkansasRep.Tommy butthegoodnewsisthat theEPAisgonna one public hearing. But alter all. whoare paign trail. Someof myfamilyagreedwith Robinson, a member oi the HouseArmed comeinand fixeverything. Their shield is you going to believe? Abunch of yelling it.somedidn't,soIneverdid.Diegovernor's Services Committee, asked the military to this hugegovernment agencywecansup housewives, or the EPA, the CDCand the stafftoldreporterstheyhadn'tforgotten,and takechargeofVertac'scontaminatedbarrels posedly relyon called the EPA. The com DepartmentolDefense?" wouldlet us knowassoonas theyinvesti anddisposeoithematArkansas'PineBluff manders won't say anything where they DidrRussall isafreelancewriterwhoseen gatedmore. That was twoyears ago.' Arsenal.Robinsoninsistedthatsincemuch couldgetcriticizedfromtheboysdowntown, vironmental reporting regularly appears in Sheltonplanstoreturnsoontohishome oftheproblemresultedfromthemilitary's thelocalChamberortherealestatepeople nationalpublications. town inIndiana, where an uncle says he'll Agent Orangecontract withHercules, they or the mayor. Nowwhen a reporter calls, hook himup wittwome attorneys. "I ain't boreequal responsibility. theycansayahighlyqualifiedofficerlooked (Next*week The cover-up inJacksonville, gonna let up." hesays. "Oneol these days Ina letter to Robinson datedDecember4 intotheproblemandputtogetherthisbrief and Arkansas Gov. Bill Clinton's pellmell maybefll beabletolaymyheaddownand 13. 1985. then-Delense Secretary Caspar rushto"bumtheevidence") IN THESE TIMES MARCH 9-15. 1988 IS ! I ih i cOeO; *71i IfIKSHNES VOL. 12. NO. 16 MARCH 1 6 -2 2 . 1 9 8 8 $ 1 .2 5 A Palestinian A new game Reshuffling Dems' deck PAGE 3 Spike Lee's School Daze A collegiate black comedy PAGE 20 W est Bank journalist H anna Siniora on building bridges to M ideast peace PAGE 16 6572 By Dick Russell I JW CSOHVim . A*X I INTHEWARTOFliecnYOF30inrH)Fl.T>E chemical plant that the Envraimental ProtectionAgency(EPA)hascalled `one oithe mod seriousuncontrolledhazard ous wastesites inthe US*isnowabandoned and secluded behind locked iron gates. In side theplant,some30,000barrelsofpoirai, including many containing xfiaann-laden waste from the cancer-causing herbicides, await disposal. Manyof l^ebagdb^gndgK to teak into tocto gqg idwtoc . The dty sewer system, creek adjacent to the plant,! hood plain,partsof thenearby Little Rock'Ak Force Base to two dty dump-sites have already been severely con taminated. TCDD dioxin has been detected here at the highest levels ever icuto in US. sod. An unwanted contaminant byproductofthe her bicide 2,45-T, it is the deadliest man-made chemical known--about 500 tunes more toxic than strychnine. Many residents who live near the chemical plant or the two dump-sites suffer severe health problems ranging from birth defects to cancer. The EPA has put all three contamination spots on its Superfund list of toxic site priority cleanups. Jacksonville used to be a quiet communi ty, a semi-suburban enclave of tree-lined streets only 12 miles from Arkansas' state capital ofLittleRock.The airbase and chem ical plant were considered among the hallmarks of the local economy.Shortlyalter World War D, Reasor-Hill Chemical began production of a wide range of pesticides, three ol which have since been outlawed due to their toxicity. In the '60s Hercules. Inc. took over the site and went on to make -percent ol the Agent Orangedefoliant that the Pentagon shipped to Vietnam. Vertac Chemical Corporation was the most recent plant owner, manufacturing Agent Orange's 'component 2,4,5-T and 2,4-0 herbicides for use indomestic agriculture.2,4,5-Thas since been banned by the EPA, and 2,4-D is now facing similar scrutiny for its damaging ef fects to human health. The powers that flee: In January 1987 Vertac declared itself unable to fulfill its fi nancial responsibilities for maintaining the corroding waste drums and left Arkansas be- hind, transferring its assets to a new Mem phis-based corporation. In federal court, the EPA, the Justice Department and the state of Arkansas are nowattempting to forceVer- money fromVertac,and that his relationship with Vertac's lawyers is his own business. Wilson alsoadmits toowning"ahalf-interest in 160 acres down the road bom or catty- viile residents went to the governor, who sent them to the pollution control agency, which referred them to the Soil and Water Conservation Commission. Eventually, their tac to follow through on its cleanup obliga comer to the old city dump [one of the EPA demand for city water was met--but the tions. The EPA and the state don't want to Superiundsites). We hope todevelop iteven water billsofthese low-income familieshave t saddled with a cleanup tab that the tually, but have no firm plans." If the extent since ranged as high as $90 a month, an agency has estimated could reach early thf the MX) ofSon. ; '/ SimuSanmudy.dbeEPAandthestatepoi- lotioo agency wt preparing to h** the .... hazardous wastes incineratWOlt=s^f1Jyra, "'dfretired air base commanderMacZumwalt, 'tfeafWp'Miance fouryears beforfflli!Wide private company with a dubious reputation founded an organization called Jacksonville group started up. and are planning to overturn a Jacksonville City Council ordinance and a peoples' ref erendum against incineration. The towns PeopleWithPride.Accordingto itsbrochure, As Jacksonville People With Pride set out the group's goal is "to foster a positive image tocounter the so-called "radicals" in Frase's for Jacksonville with regard to environmen Alliance organization, local publicity about people. along with many experts, are con cerned that the relatively untested incinera tion process will send more dioxin into the environment, even as it destroys most of the wastes. Yet the EPAand the state are ignor ing alternative technologies, adamant that incineration is the only viable solution. It isa tangled web indeed, with companies and governmentofficialsalike lookingto jug gle financial liabilities and come up with a quick fix. But it may only exacerbate the problem. The saga of this environmental dis aster shows that powerful corporate and military financial interests have long been appeased and protected by public reg ulators. Although local people began finding tal issues."Titled "The FactsAbout Jackson ville and Dioxin,' the 16-page booklet down plays the chemical dangers, insisting that Jacksonville is no more contaminated than any other industrial area. With backing bom the air base and the Chamber of Commerce, and with the assist ance of a public-relations person, Jackson ville People With Pride has blitzed the city with the brochure and brought in an array of speakers to lend it credibility. According to Wilson, the organization has about 1,000 members. In letters to the EPAand federal Centers for Disease Control (CDC), Wilson has urged the federal government to ease up on its standards for taking action on the chemical problems began to dry up. `A lot of people who were making noises suddenly stopped helping us," says Erase. Pride officials also worked hard to under mine the work of a crusading environmental reporter, Bobbi Ridlehoover, who writes for the Arkansas Democrat, one of Little Rock's two newspapers. Sitting in his lawofficerecently,State Rep. MikeWilsonshrugged away "the distortions, half-truths and outright falsities" dissemi nated about Jacksonville's contamination. In Wilson's eyes, all this pollution talk is bad for business in Jacksonville. "Sure," he added, "we could avoid a lot of environmen evidence of contamination in the '50s, not dioxin contamination. until 1979 did the full extent of the disaster In the spring of 1986, shortly after Vertac become public knowledge. Ever since, Ar ceased operation, citytests revealed thatthe kansas officials have sought to downplay the company had subsequently dumped some damage. While state officials repeatedly de of its remaining herbicide inventory into the layed efforts to address the problem, they city's sewers at more than 100times the al allowed chemical production to continue lowable level. For more than 40 illegal intilVertac itseUhaltedoperations in 1986. charges of chlorophenois and other But Jacksonville's dilemma has no easy answers. Arkansas ranks near the bottom of the nation's economic ladder. If state offi cals into the sewer system, Vertac was $1OjOOO.Thedty hassincebuiltanor to trial its-waste cials had squarely faced the problem, im At a news conference on the city's water poverished Arkansas would have risked los situation, the bank owner, Pat Wtlsoo--who ing not only its chemical industry and air also servesas head oftheJacksonvilleWater base, but also its herbicide-dependent ag Commission--commented: "Our water tests ricultural rice economy. Millions of dollars worth of property and other businesses might have been rendered worthless. Given these possible consequences, government and industry officials have given short shrift have shown no impurities. We're proud of our water and we drink it everyday."Simul taneously, Pat Wilson urged theJacksonville City Council not to approve pumping dty water to residents livingalongsidethe outly to local residents'well-being. Officials have ing dty dump-sites--even after the EPAhad used `cost-benefit analysis'--which pits found contaminated water in some wells. business "costs' against human "costs'--to The EPA had also found contamination at justify their stance. At best, they are guilty the dumps and in 1987 added both sites to of benign neglect at worst, callous greed. Only the people with nothing left to lose, like the low-income citizens whose homes its Superiund list for emergency federal cleanup. Sensingthat the local government was not surround the contaminated dump-sites, are going to act on their behalf, some Jackson- tackling the situation head-on. To them, it is a simple matter of being able to survive, for they have nowhere else to go. A family affair: "Charity," for the chemi cal companies and other business interests, begins at home--with Jacksonville's "first family," the Wilsons. Pat Wilson, owner of the First Jacksonville Bank, was bom here in 1919. In the mid-'50s, Wilson and a group of about 15 others donated part of the land to entice the Little Rock Air Force Base (today the state's second largest employer, with about 10,000 military personnel) to lo cate in Jacksonville. One of Pat Wilson's sons, Mike, briefly at tended the Air Force Academy, became a local lawyer and entered Arkansas politics. Today, at 43, he is serving his eighth term as the area's state representative. One member of the firm with which the younger Wilson's law practice was affiliated represents Vertac in Arkansas. Wilson says that arrangements withthe lawofficespecify that he shall never personally receive any tal problems by giving everybody 40 acres and a mule again. Wecan liveon a level with nature alright. But weas consumers demand plastics, and newsprint with colors in the ink, and nylon stockings. We demand ail sorts of things from industry and we ll pay a price lor 'em." iter,Wilsonwas nanyi feeAr t's Censervatioairt of fee ito successfullyprotecting6JW0 to hunting agfjtubfic on the office wall behind him is a duck that he bagged on the flood plain. A state Game and Fish Commission study found woodducks in that area withcontami nation levels of TCDD-dioxin five times higher than the limit established by the Food and Drug Administration for safe consump tion as food. That didn't seem to bother Wil son. "Yeah," he said, "that's my dioxin duck." and laughed. Wilson is a Democrat So is Gov. Bill Clin ton, one of the youngest governors in the country, a man with a populist reputation whoconsidereda run forpresident in 1988. Toxic trouble: The governor has tried to keep a safe distance from the Jacksonville situation. The links among the chemical companies, the military and the state's rice growers were a political hot potato long be fore his election in 1978. One-fourth of Agent Orange--the contro versial Vietnam defoliant--was made in Jacksonville until health-effects studies forced the military to suspend the com pound's use in 1970. But until a complete EPA ban 15 years later, 2.45-T herbicide-- . one of two components in Agent Orange-- was allowed to be used on American rice fields. Rice isArkansas' number-twoagricultural | | coanedty, so the bg> teweta. e lM S ft in. the soil continues to be causeTbr ffirfifln'--~ 1984 an Environmental Forum article re ported that 52 percent of Arkansas and ^ Louisiana soil samples taken after the her- r ~ bicide was sprayed in 1979 showed dioxin in concentrations ranging from 1.13to 13.01 parts per billion. Sixty-seven percent of rice samples from the same study contained 2.45-T--which would indicate the presence . of dioxin--in concentrations ranging from 3 to 227 parts per billion. "Some federal health agencies consider 1 part per billion of dioxin to be the maximum acceptable level for human exposure, al- - though many people argue that there is no acceptable level," wrote the article's author, EPA environmental counsel Richard Mays.. Continued on following page s certainlydii regional office i rate is in the middle of a any 2,45-T and dioxin on the rice is passed wayor another the whole time Iwas there-- Jacksonville citizens' meeting in 1985 that neighborhood." on to thepublicandconsumed withthe rice.' we were just sort of winging it. He would although humans should not breathe as At this point many residents decided to In his more than seven years as governor. back us once we explained things to him, much as one part per trillion of dioxin, it oppose the incineration plan.AldermanGary Clinton has done little to solve the state's but there was no real agenda." was possible that as much as 100 parts per Fletcher, representing the neighborhood ad looming toxic problems. Among southern Several other agency employees followed trillion could remain in the air if an in jacent to Vertac, said Gov. Clinton should states Arkansas still ranks a close second Blanz out the door. Many were concer d cinerator burned wastes as contaminated as be prepared "to call out the National Guard" behind Texas in the amount o other pes that Means, the man who had overseen lob the local plant's. to quell protests ifincineration wereallowed ticides applied annually; more than 20 mil bying on behalf of the state's nuclear power The burning of 2,4,5-Twaste itselfcreates to proceed. Three separate actions soon fol lion pounds worth were used in 1387. Yet plant, would be running the entire pollution dioxin, which then must also be eliminated lowed: the Jacksonville Gty Council, a Arkansas is one of only five states with no agenda. during the combustion. Even with the "six people's referendum and a subcommittee of program to monitor groundwater for pes SuchmovesbyClintonhaveangeredmany 9s" destruction capability, dioxin is so toxic , the Governor's Task Force on Hazardous ticide contamination. concerned about the Jacksonville situation. that the most minute amounts left behind Waste voted to ban incineration inJackson In 1986 the EPA undertook 100 enforce InFebruary 1986.30protestersgatheredwith can be extremely dangerous. ville. ment actions against Arkansas violators of picket signs outside the governor's office, 'Temporary operating problems could re Andupon takingoffice in 1987as pollution federal surface water pollution standards, irate that he had not attended any of the sult in very serious exposure," says Com control chief.Meansmade public assurances with only Texas receiving more (172 viola local residents' publicmeetings.Clintonhad, moner. "Suppose the flame goes out for a that no incineration would proceed unless tions). The 1988"State of the States" ranking however, foundtime toattend aJacksonville few seconds, and you are just biowing this local citizens agreed to it He told Jack on environmental protection by the Renew Chamber of Commerce luncheon honoring stuff right out the stack. It is very tricky, and sonvilleresidents that therewas noscientific Americaproject findsClinton'sArkansastied local industries, including Vertac. these things belong only in an isolated area reason why the chemical facility's wastes for 48th place with Mississippi, thesame two TIm governor's disposal proposal: with nobody living downwind. Doing this in couldn'tbe transported off-sitefordisposal. states that regularly "compete" for having Forseveralyears.Clintonhas beena staunch a residential neighborhood makes no sense But despite such rhetoric, neither Means the nation's highest illiteracyand percentage of population below the poverty line. When it comes to keeping up with pollut ers, the New York-based Council on Economic Priorities in 1986 gave Arkansas advocate of incinerationof the dioxin wastes and other chemicals still leaking at the Ver tac plant The incineration plan first came from Vertac, which In 1985 contracted the job to Ensco, anArkansas firmwithfinancial at all." The EPAdid successfully bumdioxinfrom contaminated soil in Missouri, but destroy ing contaminated barrels of such toxics in a populated area has never before been at nor the state has wavered from the inciner ation approach. Now Means is warning that ifJacksonville refuses to repeal itsanti-incin eration ordinance, his department will have to seek federal court action to force the a "O' for its laxity in punishing companies links to the governor's campaign and family. tempted. When the EPAconducted a series change. By law, federal and state authority that violate hazardous waste laws. But after Vertac last year declared itself un of dioxin test-bums at the National Center supersede local ordinances. "We have an extremely bad situation with our state legislature being maintained by special interests," says Bob Bland, organizer of a recently formed environmental group able to fulfill its financial responsibilities in Jacksonville, thestate pushed ahead with its own incineration plan. The EPA, along with many state govern for Toxicological Research, the first lour ef forts failed due to mechanical difficulties. Later experimental bums in Ensco's mobile incinerator were declared a success by the The last straw, as far as Frase's group is concerned, was a new law that zipped through the Arkansas State Legislature last spring, after being introduced by none other called the Arkansas Alliance. `And they have recently allowed hazardous waste operators to just roll over them." As for the governor, Bland says. "Clinton was a shining light during his first term [1979-80]."But Bland says that since his 1982 re-election, the governor has `done nothing but accommodate industry." Disappointing appointments: Evi dence to substantiate this charge came with Clinton's appointment of Dr. Ray Harbison ments, believes incineration is the best sol ution to the nation's landfill glut. And they like the fact that these "waste-to-energy" facilitiesgenerate electricitythat can besold to utilities. But the incinerators emit a host of air pollutants and generate some toxic ash (see In These Times, Feb. 11,1987). No one disputes the presence of some dioxin in mass-bum incinerator emissions, and ac cording to BarryCommonerofthe NewYorkbased Center for the Biologyof Natural Sys EPA,but these did not include dioxinwastes. Commoner adds. The only data I've seen on dioxin for an incinerator indicates that the emissions are on the same order as a not-too-well-operatmg trash incinerator." Th ash k^t over, hum the ndnention process, as consumer advocate RalphNader points out, is so toxic that "the government doesn't know what to do with it other than declaring it `non-hazardous' and storing it somewhere." That is precisely what Arkan than state Rep. Mike Wilson. It provides that any contractor hired by the state for a waste cleanup will not be liable for injuries, damages, death or economic loss resulting from the release of hazardous substances, unless negligence or intentional misconduct can be proven. Means'pollution agencypushedforthe legis-. lation, maintaining that it was needed to get companies to bid on the incineration con tract to the Task Force on Hazardous Waste, a state body formed in 1985 to deal mainly with the mounting Jacksonville outcry. Har bison, a toxicologist at the University of Ar kansas for Medical Sciences, is one of the tems, this makes incinerators `an inherently unacceptable technology." Opponents of garbage-burning say that preferable recyc ling programs are being given short shrift by the government sas has said will happen to the tons of toxic ash bom the Jacksonville plant which will be stored on-site permanently. Walter Hang, an incineration expert with the NewYorkPublicInterest ResearchGroup In mid-October, an outraged Ralph Nader paid a visit toJacksonvilleand called a news conference. 1 have not seen such a bill any where else in the country," he said, noting that there would be no standard against US. chemical industry's favorite expert wit nesses. But critics charge that he has consis tently contradicted himself in government testimony. The man will say whatever he's paid to say," charges Dr. Samuel Epstein, a re nowned expert on hazardous chemicals at the University of Illinois Medical Center. Environmentalists also cite another Clin ton appointment as evidence of acquies cence to bigbusiness interests. Lastsummer the governor chose Paul Means to be the new chief of Arkansas'Department ol Pollu tion Control and Ecology (ADPC&E). Before the appointment.Means worked forsixyears as an executive for the state's major utility, Hazardous waste tike Jacksonville's can not be recycled, of course. And there is a major difference between trash incineration and the high-temperature burning methods proposed for hazardous waste disposal. Trash-burners synthesize a mixed stream of refuse in the cooler parts of the incinerator while hazardous waste incinerators feed the material directly into the furnace. But this process isnotfoolproof.Thequestion ishow much dioxin and other chemicals may be released into the environment? The EPAhas set a `six9s" destruction and removal efficiencyforsuch materials, mean ing that 999999 percent of the waste must (PfRG), adds: "Neither the EPAnor state au thorities have demonstrated an understand ing of the long-term hazards posed by in cinerator ash. On paper, these hazardous in cinerators look great they're bii-tech, state-of-the-art. But you're looking at the prospect of learning on the job, and such a facility has to operate at peak effectiveness all the time because oftheextraordinarytox icity and persistence of these compounds if they're released into the environment Any kind of fire, explosion or leakage could have extremely far-ranging implications." Hm paopi* spaak: InDecember 1985au thor Lewis Regenstein, another expert on which to measure the company's actions, since how could any people harmed "try to prove the state of mind of the contractor?" Returning to Washington, Nader received a letter from Clinton. In it, the governor In sisted that the law protecting cleanup con tractors "is modeled on federal law which gives EPA the authority to hire contractors to complete remediation ofSuperfund sites." Without it, Ginton said, potential contrac tors would justifiably fear that they might be held liable "for releases from conditions that existed before they began work at the site." Congress had passed a similar bill in 1986. but Arkansas was the first state to follow L O Arkansas Power and Light. suit. Nader wrote to Clinton on October 31 I s But nowMeans cannot administer his own JLQ department's National Pollution Discharge f ^ Elimination Systempermit programbecause of a federal regulation forbiddingformer em ployees of industries and municipalities that his `concyn in the statute was the de lation of any strict liability (liability without fault) in tort What is left is a negligence standard /liability with fault) which is a greater obstacle to any community litiga holding such permits from doing any crfer- ' tion." sight in government service for two years. Commenting on his visit with Jacksonville Asubordinate has been granted the permit citizens. Nader concluded his letter to the ting authority. i governor this way: "Among other things, it Robert Blanz, deputy director ofthe pollu is a feeling that their government is not rep tion control agency, resigned when Means' resenting them so much as it is reflecting appointment was announced. Blanz. who led corporate pn >rities and demands--some whatever charge the state had mustered say ultimatums (eg., either give us this or aiainst the Vertac Chemical Corporation for we won't do the job)." J*< *sS$n * $ & * '* & * ^ ^ c^ ouso^ insoluble pn dons. Nader recently recelv? Arkansas State Rep. Doug Wood, who toic the story of his efforts to enlist American Fuel and Power Corporation, the first com mercial licenseeof anexperimental technol ogy that would destroy the wastes under a closed system that allows no venting of chemicals into the air. A large, clay-lined trench would be dug in the ground on the plant site, the barrels placed inside it and electricity used to melt the wastes into a substance similar to boiling lava. The high temperature would destroy most of the dioxin. When it cooled, a huge black glass monolith of obsidian-like rock would be ajl that remains. Therefore, it does not have the excessive xficemissions ol an incinerator and it does leave an ash for further treatment or disposal," wrote Wood. Though untried on dioxin wastes, the process has worked suc cessfully on petroleum wastes at several Texas sites. And. according to Wood, an EPA lab verified that contaminated soil samples from Vertac have also been tested by the company and achieved a destruction and re moval efficiency of "seven 9s"--"fullv an rDa - a_ spokesperson" would cost about one-thind c ton incineration price tag.) In dismay, Wood added that the state and federal agencies won't `let American Fuel and Power do an on-site test at full scale because of prior commitments by EPAoffi cials to incinerate the first phase of the pro ject.This isabsurd!"Woodlatertold/n These Times, "Any new technology doesn't have a chance because the EPA'sregulationsare so heavily skewed toward incineration. The greatest irony is that the citizens ofJackson ville accepted this other technology but are still fighting incineration." Wood's disposal alternative is one of sev eral options other than incineration. Rollins Environmental Services, a company based in Deer Park. Texas, offered last year to have the waste shipped there, where it would be burned inanunpopulatedarea.The proposal was not warmly received by the state of Ar kansas or the EPA.so the companywithdrew its bid. Another largely unexplored option is a chemical solidification process that would John Schofield, senior vice president of ITC, told the Arkansas Democrat that his company previously worked "under con tract' to Vertac at the site, but would not disclose any specifics. ITCalso served as an PAcontractor on some initial groundwater ntainment and cleanup at the plant. The : firm completed a $29million EPAcon t r a c t in 1985 for incineration of dioxin-con- laminated soil and clothing at a farm site in Verona, Mo. Yet ITCs past record is anything but en couraging. Last April it received a $20-mil- Iion-pluscontract fromthe Pentagon to bum munitions-contaminated soil and pollution from leakage at the Comhusker Arsenal in Grand Island, Neb. Using a mobile in cinerator similar to the one now slated for Jacksonville, an accident occurred during a shutdown for routine maintenance after the first test bum in October. Twoworkers were severely burned when hot ash fell on them from an upper chamber. ITCs mainstay has been land disposal of hazardous waste,' says Will Collette, pro gram director at the Citizen's Clearinghouse for Hazardous Wastes in Arlington, Va. It has operated three landfills in Californiaand for die past several years has had nothing but trouble at those facilities. In April 1987 it was levied the highest fine against any company in California history--$32 mil lion--for violating state regulations. Even with the lax enforcement there by the Deukmejian administration, it has been or dered dosed and allowed to re-open twice. 1am told it has announced plans to divest its entire California landfilling operation.' A 62-year-old firm that evolved from a marine cleaning business. ITCcurrently has global sales of $237 million. Last May the Justice Department filed suit against the company, charging it had violated regula tions on its hazardous waste storage. Also last year an ethics commission found ITCin violation of ethical standards. Citing the downplaying toxic bidonville: the real less comforting. company lor purchasing land while doing a feasibility study for an incinerator, and for hiring an employee who had worked for the state agency that awarded the contract, Louisiana's Ethics Commission ordered the company to return the $375,000 it had re nist at New York's St. ceived from the state. ITC has challenged f a nationally recog- the finding in a state court expert, offered still If a company has shown it can't handle when he came to its main line of business, that doesn't inspire Jacksonville lasPJyear. Expressing alarm much confidence in its ability to handle about the incineration plans, Connett said something entirely new,' says Collette. "But the best approach would be `secure holding Arkansas and the EPA say there's no cause in concrete bunkers" that would be built for alarm, the situation is well in hand and until a safe disposal method can be found. anybody who says otherwise is an environ `I'm scared stiff about [the incineration) mental kook or hysterical housewife.' being a money-making operation," Connett In recent weeks Arkansas pollution offi said in a later interview, "especially if the cials have not been able to get ITC to agree operators have any kind-oftrack record that to all the safety and testing requirements makes them dubious." f- that must be met before a contract can be Dubious buck record: Unfortunately, signed. And this is not the onlyproblemstate the company that Arkansas chose for the job officials face. More than half of the $10 mil has just such a record. Late last October the lion needed to do the incineration was sup state, under an EPA permit procedure, posed to come out of a trust fund that Vertac selected the International Technology Cor established before transferring all of its as poration (ITC) of Tqrrance, Calif., to receive sets into a new corporation and leaving its a $9.7 million contract to incinerate Vertac's Jacksonville plant behind last year. But now wastes on-site. According to Means, once the trust fund is tied up in federal court liti negotiations and tests are completed, the gation proceedings. The state has also been company would be able to complete inciner unable to collect another $4 million through ation of nearly 30,000 drums of waste in a letter of credit in a Swiss bank that Vertac about seven months, although environmen- supposedly set aside (or the incineration. Dioxinville Continued from page 13 In addition. Means says Vertac kept such poor inventory records that some barrels contain unidentified solid substances that may have to be destroyed differently from the dioxin-contaminated drums. Now state officials say that not even a test bum on the waste can occur before next fall at the ear liest. Meanwhile, ITC is rumored to be on the edge of insolvency due to its other en vironmental liabilities. So Arkansas isrepor tedly negotiating once again with Ensco--a firm with an equally dubious record--to eventually handle the incineration. "Explosive situation'': Despite the delay, the concerns of Jacksonville citizens have not abated. "If there is a malfunction out there,' says Frase, "it could cause cancer through the whole community. During the incineration, they are not going to do any secondary monitoring (monitoring alter the incineration takes place). Yet dioxin would show up as a secondary chemical, because it's formed in the combustion. The other ter rible thing is that the turn-around period for sending in lab samples is six weeks, so if there is a problem and dioxin is pouring out, we won't know until much later.' Hazardous-chemicals expert Epstein be lieves "the only real way to cope with this issue is to have a high-level congressional inquiry that would investigate not only the role of the chemical industry, but also the EPA,thestate and the industry'sconsultants. You are dealing in Jacksonville with an al ready tragic, and potentially explosive, situ ation.' Incineration expert Cornett adds, 1 am really distraught by the whole Jacksonville phenomenon. Ibelieve those people; they're not giving me a soag-and-dance about what they've been through. You hear story after story of health damage done to people of all ages. To me, it's outrageous that this 'anec dotal' information isdismissedasbeingnon- sciendfic and therefore irrelevant, when clearly it demands an answer. If these agen cies don't get their act together pretty soon, noone is goingto believe anythingthey do.' In Jacksonville, where the people talk about "cancer alley" and wear T-shirts read ing "Hostage ofVertac and Ointon,' it is the 11th hour ina tragicmicrocosmofAmerica's toxic time-bomb.And ifthe federal and state governments eventually do get their way on incineration, the people of Jacksonville can only hope that it won't cause an apocalyptic high noon. ' Dick Rucsal is a freelance writer whose en vironmental reporting regularly appears in national publications. (Next week: In Part 3 of fit These Times' in vestigation into the Jacksonville imbroglio, the interlocking ties among the chemical companies--including Dow Chemical and other nxiltinationais--are revealed.) 5 ^t i I mr* I-  jS c . ,6578 The Jackson fa c to r in election '88 PAGE 3 !/TKSETHES VOL. 1 2 , NO. 17 MARCH 2 3 -2 9 , 1 9 8 8 $ 1 .2 5 .0 DlOX INVILLE part th re e :v THE T R A IL tracking down the corporations responsible for the w o r s t d i o x i n d i s a s t e r in the U.S.  < i The conclusion o f In These Times'th ree-part investigation into the The intricate maze iftstrates bow bigger companies use smaller ones--Ife Jackson -raw u m a i dioxin contam ination o f Jacksonville, A rk , focusses on the chemical com panies involved. In unveiling the hidden ow nership behind Vertac ville's Vertac Chemical Corporation--to 1i bdan she-jpiin keep up production of lucrative, but poten tially deadly, products. Then, when push wastes at tire chemical plant and "restora Chemical Corporation, it is revea led for the first tim e that the city's toxic disaster ex te n d s ou tw a rd to e n v e lo p tw o o f th e nation's largest multinationals. Their connections to an obscure an d once quiet comes to shove over liability tor the toxic hazards posed by these chemicals, the com panies sometimes square oil to implicate each other. AIthou#] they often publicly ap tion' of off-site pollution areas may cost dose to MOOmillion, h has detected TCDDdkmn, a byproduct of herbicide production and the most lethal distance produced by community pose troubling questions that go far beyond Arkansas. pear to be corporate "enemies,' theycollude humans, at the highest levels ever found in behind the scenes to tie the hands ofgovern soil and barrels of toxic waste. Many scien ment regulators, lawmakers and citizens. tists say that there is no sale human expo By Dick Russell Employing small armies of attorneys, they sure level for this form of dioxin. |7 CKSn V1U6. ARK. -- , | are able to stall remedies and avoid product But Jacksonville residents were not even f V' Tras 5 ASTORYOFCORPORATEINTRIGUE and manipulation,ajourneythrough the labyrinthine worldof the makers of toxic chemicals. Itattempts to an swer this question: who bears the ultimate restrictions indefinitely. Employingsophisti cated public relations staffs, they are able to stay out of the national limelight. Legacy of neglect: Jacksonville, a city of 30,000 people, is a case study insuch corpo informed until 1979 of the pollution prob lems that had abounded lor about 30 years. Before chemical production ceased in 1966. toxic wastes were systematically spewed into the city's waterways, sewer system and 653Q * responsibility for thousands of leaking bar rate maneuvers. Its pollution woes far sur several landfills, severely contaminating the rels of dioxin-laden chemicals and other pass those of the Love Canal landfill near area and causing numerous health problems poisons in this Arkansas community--a NiagaraFallsand ofTunesBeach,Mo, where for local residents. During what a former place that can justifiably be called the most in both places residents were evacuated by plant supervisor calls "runaway chemical serious hazardous waste area in the U.S.? the Environmental Protection Agency (EPA). reactions," and3n explosion in the mid-'60s, J AnIn These Timesinvestigationhas tracked a corporate maze extending far beyond the contaminated chemical plant in Jackson-ville, 12 miles from the state capital of Little Yet except fora 1980 story publisfid inLife magazine, the major media have ignored the Jacksonville situation. Aformer Vertac pub lic-relations employee, David Simmons, ad vast quantities of dfozin were released into the air. Dozens of residents maintainthatover the years they have suffered everything from < Rock. It includes not only a network that mits that "when inquiries came (from major miscarriages and birth defects to Sudden In stretches into five other nations--Panama, media outlets], generally the Ideal stories fant Death syndrome and cancer. More than Italy, Switzerland, Sweden and Japan--but had enough holes in them that they were 100Jacksonville residents have sued two of also hidden ownership and shady deals. It discreditable." the three companies that since 1948 have points to the quiet involvement of the for YettheEPAfoundJacksonville's toxic saga run the chemical plant, allegingpersonal in i mer chief executive officer of the Diamond very credible indeed. In recent years it des juryand wrongful death.Since 1986portions Shamrock Corporation and the potential lia ignated three different areas for Superfund of both lawsuits have been settled out of br\i_li_ty/Xo.f_o_ne:_ofithechemical industry'sgiants, cleanup. The agency estimates that disposal 4L. --_L. WWWI ej K*<*rr4me court for undisclosed sums. Th* mwetvm nrffutur# lUhalitv for the cnn> D IO X IN V IL L E I I I : THETOXIC TRAIL tamination. however, is now tangled up in federal courts. The two companies that are supposed to share cleanup costs with gov ernment agencies are at each other's throats. Vertac Chemical, which has run the plant for the past 16 years, is suing its predecessor, Hercules. Inc., which manufactured 25 per cent of the Agent Orange used to defoliate the Vietnamese jungles. Vertac is claiming that Hercules should be held responsible for all future liability. In turn. Hercules, as well as federal and state agencies, are hounding Vertac in other court proceedings. In a seeming attempt to duck its legal ob ligations, Vertac last year suddenly transfer red its remainingassets intoa series ofnewfy tried corporations and left Arkansas. It rer informedgovernment officialsofthese moves. A friend in need: This is where Dow Chemical enters the narrative. Headquar tered inMidland. Mich, with 50.000employ ees worldwide, the multinational was for years Vertac's main supplier of herbicides and the formulas for them. In December 1986. two months before Vertac pulled out of Jacksonville, company officials held a series of meetings with Dow executives in Great Britain, Washington, D.C, and Michi gan. At the time Vertac was feelingconsidera ble heat fromthe governmentAlthough ithad ceased operations inJacksonville in February 1986. the companywas beingsued bythe Jus tice Department (on behalf of the EPA) for continuing to discharge contaminated waste water into a creek adjacent to the plant site. The department wasseekinga 510,000-a-day ' fine. Vertac wanted out from under--and in a complex and back-handed way, Dow was about to provide the opportunity. Dow. which contracted trademarks and products to Vertac. privately informed its 'supply partner" that the smaller company had breeched one or more of their agree ments. Thus. Dowdeclared Vertac indefault, with a debt of 553 million owed Dow for goods sold and delivered. Vertac could cover the debt, but its money was tied upina trust fundand letterofcredit' the company had earlier agreedwithgovem-n t agencies to set aside 511 million for al on-site cleanup at the Jacksonville pi<tnt. After consulting with Dow. Vertac quietly established three new companies in Memphis, Term., where Vertac's corporate headquarters were located. Then, on Jan. 31.1987. Vertac President J. Randal Tomblin called representatives from the EPA. the state of Arkansas and Hercules to a meeting in Dallas. Without mentioning Former DiamondShamrockChief ExecutiveOfficerWilliamBricker: was helinkedtoVertac? T8S9 Contnoerffrompnading page Vertac's meetings withDowor Vertac's new ly formed companies, Tomblin said that the company could no longer meet its legal obli gation to maintain the corroding waste drums in Jacksonville. He seemed to be im plying that Vertac was broke. But it wasn't fine days laterVertac trans ferredall ot itsassets (which it claimedwere 1117 million) into bter-Ag, under the um brella at the two other newiy formed com panies in Memphis. The next day inter-Aggave DowChemical nearly$1.7ntiffionofthe moneyVertacowed the cbaektl giant Dowalso reeeiwd dam to both the mfexest payments bom the Jacksonville cleanup trust fund and any uncontarainated equipment fromthe Arkansas plant And Dow took title to the remainder of Vertac's inventory, alongwith all product formulasand trademarks.Thiswasa strange him of events, because Dow had sokl those three areas of its 2,44) herbicide business to Vertac back in 1963. ` Evidence of fraud*: What was going on? The EPA and Justice Department soon hauledVertac intoUA DistrictCourt inLittle Rock to try to find out last July Vertac's lawyers argued that the company hoped its business dealings with Dow would provide it with enougi money to defray `environmental expenses.' Further testimony revealed that those 'expenses' were hardy `environmental.' They included m e.Jhaa 4400JN0 far keep ofVfgac's Menphis office and abort ffiOBjj6Wpr !depteriaiion and lawyers' lees.* it also came out that a Vertac employeewasseen mowing documents from the plant to a private stor age area. Although Judge Henry Woods did not hold Vertac in contempt oi court, he ordered measures toassure no moreunauth orized removal of documents. In handing down his ruling in September 1987Judge Woodssaid, *fhe evidence of fraud is dear and compelling. The present manage ment of Vertac has demonstrated its willing ness to manipulate numbers and corporate assets to facilitate non-performance of Ver tac's environmental responsibilities under various court orders.' The transfer ot assets into inter-Ag, he added, was simply`aneffort to put them beyond the reach' of environ mental agencies--a deal that involved "fic titious considerations" rather than lair mar ket value. The judge agreed with the government that the state should appoint a receiver to take over Vertac, an arrangement that he ruled would extend to inter-Ag as well. Ver tac officialsare currentlyseekingtooverturn the decision in the US. Court of Appeals in SL Louis. Meanwhile, the Justice Department de manded that Dow give the EPA the money it had received fromVertac, as well as assign over to the federal governmenttheherbicide trademarks that Vertac had returned toDow. When Dow refused, the EPAand the Justice Department filedanother suit This time, the government said that not only Vertac's top officers and successor corporations but also Dowshould be held liable for Vertac's caortordered share of the Jacksonville cleanup costs. Dow immerfiatHy filed a countersuit in AdeatagrttrtjUtnpbis.Doioim. USAnma.time thte.any leffiirt proceerfingt should be held there, not is little Rock. In the suit, which mdudes Vertac and the Fust Tennes see Bank (where the cleanup trust fund is arbmnistered), Dow claims it is entitled to the net income fnA the bust fund as part of Vertac's remaining debt to iL Enter the corporate mazo: Why is Dow, with $11 billion in global revenues in 1987, quibbling so vociferously over a compara tively paltry $53 million? "The Vertac-Dow relationship is definitely a deep pocket to look into,' says Robert Blanz,who dealt with the Vertac situation for seven years as dep uty director oi Arkansas'Department of Pol lution Control and Ecology. T don't think anyone understands all the dealings that went downbetween them.Butyou don't take Dow on lightly with inexperienced govern ment lawyers, because they wit) come in loaded lor bear.' Vertac, with its new name, Inter-Ag, con tinues to this day to conduct business out of Memphw ,Motions toart tae-triefej: tien are expected to be^itied .la te r Ibis year. Meanwhile, under a separateruling by JudgeWoods,thegovernmenta g so es have tried tocotiectan a $4million letter ol credit that Vertac in 1985 agreed to set aside at a The chronology of o toxk coverup: Dow, the EPA and cBoxki 'W i e n i e * * - -- ChemkarffiDWthit ex- --* t.te-<; E?j$jT3s registered..ijprleUS-DcpartmentefApicBl- ? J 'lR jtsthefirstmdustriaiJtiddertinmtv- c.^dk^dcoaEsa^ltiansaCtoChcrnicai; StudyMb Bgbcrto- ot tiB7-4?fcgialsidentifiedbysrfenlhfas . Hdeoeer U fiveraacecriportaneouB 1 an unavoidable contamment i> 2,43-T. .abortions and baft jfrfcrte to. fg p t i f : U5fi-FmdiDgs pomt to-tbe-preseace oi r&amge. -::- -Iser dateem <jexm aaiheB^idh' J*7i-A explosion atmcbemical plant. a x exposed to 2,45-T.- - ' ^ HnSereso, Italy,Messes sewralpomds , MO-Oefcliarts containing'2A3-T are . of ffingm in a densely populated area, tatused mVietnam.Do*starts making -LocalresideatsareartinlorDedtoragbt je&d gasotine that Ufa tea afterhuxhedsofanimalsharedted -parttofiriy painful wq,faMpffitasyuse jttibradredsofpeoplearehospftafeed. ~1n-VietaBL- .Chronichealthefledsensue. ' -^C-Tlmfcrtagon contract wittiDow lf77-5oldiers wild served as Yfetmffi and ether US. cfaemical:cnmp*nini to ; Se^approachingflKVeterawAitainis- ' banwfacture Agert 0ran^e t5Q percent' -tHiioft(VA)withvariousheatihprobleo comprised of 2,43-T and 50percent 2,4- -theybefieveare retefedtoAgentOrange T)}farok inVietnam.Ataseaet meeting exposure. it Dow's headquarters, manufacturers 1978-The EPAaiers evidence based on are told that 2,43-T has negative health testing of laboratory animals that 2,43-T effects. and dxmn cause cancer, birth defects lV7t-After suppressed 1966 studies are and fetal deaths. The Love Canal area of released firridpg 2,43-T to birth defects Niagara Fails,where 21300 tons of chem inrodents. the Pentagon susnends itsuse. ical wastes including dioxin are buried, &Dgoaider ciscoirwg w ts x r f c o c j p t t ' .cy_ fwtataeabdfe.?" " idaCnj3i^|~ - M XMorartedJSMdBS^ GXVKtnfap ffie massive dassnactioostAagahst ' ` ' .......... and ffie- Lakesfisharehigh enooghtircausesit-:.. the U&jav-/ afficart create.ktrtsw taiesansdag IKh-The Canadian government pres-, p u re s te U3. tokm stigate the sourpe C rtlM lto u B levels iaund ip the Great Lakes-JbeEPA considers Dowthedfief snspeat far (fimdn contamination of fish downsireamfrom itsMichiganheadquar- - ters. The company issues a report sug gesting that dioxins are a natural product of afl combustion sources, present in the environmentsince`Prometheus stole fire .fish, the Food and,I _ _ j asaei a Mr.red itavrHMvfMiiyCte af--jictedstrtesreoommendfag Jurtted fish ; jconstmpfioa Ayepattby tiie EPA'sktid- vest regioal . office tmoes the Great lakes (fionn to Dow's doorstep, but is -dsdrtanitaBy revised by order i f Dr. to n e s and his depu^, John Hernandez. Vietnani vets fife iu t against tbeVA and Department of Defense. 1M2-When a severe contamination problem in Tunes Beach, Mo, comes to light-resulting from the illegal dhposal oi dioxin-laden waste oil 11 years be- Swiss bank for the Jacksonville cleanup. But the bank, citing problems with certain "pro cedural requirements," has so far refused to turn over the money. For now. the EPA--whichspent more than 55million lastyear re-drummingleakingbar rels of waste at the Jacksonville plant--and the state are left holdingthe bag. UnderSuper fund. Arkansas is supposed to provide 10per cent of the total funds to restore Jackson ville's polluted environment. But the state's economy is already one of the country's most depressed. Coming up with 10percent of a potential 5400 million cleanup tab "might well be impossible." says Phillip Deisch. a Little Rock attorney and former counsel to .Arkansas' pollution agency. "Ar kansas is vitally Interested in getting to the private pockets who are really responsible for this mess." Those corporate private pockets, how ever. so overlap each other that proving lia bility may be impossible. To understand why. the origins ofVertac must beexamined. The real ownership behind the company has long been a mystery. Sources in and out of the government remain reluctant to discuss what they know. Evenwhentheyweresimply confirming information that In These Times had uncovered, many of them requested anonymity. Who own* this firm, anyway? Vertac Is an acronym for the names of lour chemical companies that merged in 1976 (Vicksburg, Eagle River.Transvaal and Agricultural Chem icals). At the time. Transvaal was leasing the Jacksonville site from Hercules. Vertac. ac cording to an ex-official, was initially set up by some former executives ofUnion Carbide --the chemical company responsible for the 1984 disaster in Bhopal. India. In addition to its Jacksonville operation. Vertac owned chemical plants in West Helena, Ark., and Vicksburg, Miss. But. says the source, "the Union Carbide people did not understand that there were limits to expense accounts." In 1978 Vertac declared bankruptcy. Not long after, the company re-emerged intact although its new owners were un known. They had registered Vertac under the aegis of three offshore holding compan ies in Panama. Says Reed Newman, a former Justice Department lawyerwho investigated the company for the EPA, "Panama is some what ofa haven forpeoplewhowishtoincor porate or have a significant interest in com panies, but not have a lotof folks knowabout it in terms of [US. government] reporting requirements. We ran into a brick wall as farasfindingout whoreallyownedVertac." Over the past year or so, however, the mystery surrounding Vertac's owners has started to unravel. In These Times was able totracemajorityownership toa wealthy Ital ian named Vittorio de Nora. This was con firmed by several sources. Nowage 76 and living in Geneva, Switzer land, de Nora made his fortune in the elec trochemical segment of the industry. At a Milan-based company that he and a brother established more than 50 years ago. he pioneered in the 70s a process used in mak ing chlorine. Chlorine is the basic building block ofchlorohydrocarbon herbicides pro duced by both Dow and Vertac. To protect themselves from possible pa tent lawsuits, the de Noras "set up com panies all over the place that could be finan cially isolated,' says Colonel Dillmore, a lab oratory researcher with PPG Industries, an American company that previously worked closely with de Nora's Italian firm. Parts of the de Nora operation were regis tered in Panama. "Vittorio is a man of the world," Dillmore adds. "He used to have his own private jets, and spent most of his time outside Italy. He was deeply involved with the Diamond Shamrock company, and used to own a substantial block of their stock.' The Diamond Shamrock connection: Diamond Shamrock, for years one of Amer ica's "big five' chemical giants, was a major producer of herbicides, including Agent Orange, for the Pentagon. Vittorio de Nora's relationship with Diamond executives dates back to the '50s. By 1973hesat on Diamond's board of directors. But because de Norawas trying to do business with competitors, fel low directors convinced him not to stand for re-election the next year. Hewasa longtime friendofWilliamBricker, then in charge of bolstering Diamond's agri cultural chemicals business. In 1976Bricker was appointed chief executive officerof Dia mond. That same year Diamond spent more than 550 million to acquire de Nora's Electronor Corporation that was registered in Panama. De Nora remained in Italy as chair man of Electronor. In later 1979, Bricker reportedly intro duced de Nora to Vertac's owners and Continued on folloainf page 6583 on dioxin to a one part per biffion level of concern.' 1983-Attempting to defuse a mounting scandal surrounding misconduct and mismanagement at the EPA, the agency offers to buy the entire town of Tunes Beach and evacuate residents. John Her nandez becomes the EPA's acting ad ministrator after the scandal forces two top officials to resign. Hernandez soon also steps down in disgrace after Con gress uncovers that he had intervened personally to allowDowto alter the draft report on Great Lakes dioxin contamina tion, at the same time that Dowwas refus ing to give the EPAinformation on dioxin problems at its plant. The altered report had also eliminated all risk information on dioxin-tainted fish, a damaging scien tific appraisal of 2.4JSTs health effects in Alsea, Ore., and any mention of Agent Orange. Congress appropriates 54million for an EPA study of dioxin nationwide^ Reagan appoints William Ruckelshaus to restore the EPA's image. Ruckelshaus calls for "risk-benefit analysis" to replace the "margin of safety" laws. Part of an EPAstudy showing the severity of dioxin contamination in Alsea, Ore., is re leased--pages that the agency had claimed to a federal court did not exist. The EPA asserts a "mix-up," maintaining that the highly contaminated samples were not really gathered in the sediments of Oregon drinking water supplies, but inside Dow's Michigan manufacturing facility. Dow and the EPA are privately negotiating an agreement to allow wider use of 2,4,5-T,.permitting resumption of some applications banned in 1979. But in the faceof anotherpotential scandal over the "mix-up,"Dowand theEPAsimultane ously announce the cancellationofall re maining registrations on 2,43-T. 1984-Interagency working groups on dioxin are now coordinated bom the White House by Maj. Alvin Young, an Air Force scientist who had a key role in de veloping Agent Orange as a weapon. The day before the Agent Orange trial is to begin, Dow orchestrates a 5180 million out-of-court "settlement"--over the ve hement objections of many veterans in volved--to be paid by seven chemical companies. Thus, the manufacturersavoid l a precedent-setting court decision--as well as having to reveal what they knew about Agent Orange and when. Referring to the suppressed Oregon study and to "widespread fraud" in herbicide health testing, an appeals court judge bans fed eral use of all herbicides in the Alsea study area until they are adequately oesmH noun cdgcb. 198S-Aveterans'attempt to sue the gov ernment over Agent Orange is initiated, butdenied on grounds of federal immuni ty.All domestic usesof 2,45-Therbicides are finallyoutlawed bythe EPA.Fishsam plescollected downstream frompulpand paper mills consistently reveal dioxin contamination. 198C-A new study of Missouri residents bythe federal CentersforDiseaseControl (CDC) reveals that exposure to relatively small amounts of dioxin in the environ ment appears to lead to a higher risk of immune-system damage. A privately funded medical study finds that nursing infants in the US. may be imbibing dioxin in mothers' breast milk at levels 1300 times those considered acceptable bythe CDC. Agroup ofVietnamveterans, scien tists and members of Congress announce research results showing a biological "fingerprint" left in veterans' blood Jjy dioxin." 1987-Anappeals court upholds the chem ical companies' settlement in the Agent Orange case. The CDCand the Congres sional Office of Technology Assessment agree that no large-scale study on the effectsofAgentOrangecan be conducted because too fewtroops were actually ex posed to the chemical. The Air Force an nounces results of a 20-year Agent Orange study that it says has failed to uncover any unusual health problems inveterans. Overtheprotest ofsevenchemicalmanu facturers, the Supreme Court lets stand an appeals court order that the compan ies allow Vietnam veterans to see re search documents on Agent Orange. Aprivately funded medical study finds dioxin present in the breast mk of all 50 American mothers tested. A federal ap peals court absolves Monsanto Chemical - of knowingly exposing seven workers to dioxin. The paper industry reveals that traces of dioxin have been detected in a wide range of its products, but says that there is little risk to human healtit The EPAannounces that dioxin-contarainated soils are less prevalent than feared. The EPA unveils a new draft study sharply lowering its estimate of the cancer-caus ingpotential ofdioxinbysixteeniold.Dow Chemical, now embarked on a major ad vertisingcampaign to fostera "good-guy" image, finallyshuts down the world's last 2.4,5-T production facility, in New Zea land. ATexas jury holds Dow liable for 51S millionin thedeathofa forestservice worker whosprayed its 2,4-Dproduct, on grounds that the herbicide had caused his cancm. 1988-The Supreme Court denies an ef fort to overturn governmental immunity in the Agent Orange litigation. Dr. Barnes, who has held control of the government's dioxin information for nine years, is pro- ` moted to chairman of the EPA's Science Advisory Board. -D.R. Continued hum preceding page the idea ol acquiring the company. It must have seemedan attractive businessopportu nity to de Nora. After all, herbicides were a muttimillion-dollar international business. De Nora could use his own electrochemical pro cesses to make chlorine (which he did. espe cially at another Vertac outlet in Vicksburg, Miss.), and then save money by using the chlorine in his own herbicides. When he bought Vertac. Jacksonville's environmental problems had barely begun to surface. In These Times could not determine whether Bricker took part ownership in Ver tac. supposedly a competitor ol Bricker's company. Diamond. But "if that is what hap pened." and il Bricker was privately involved with two competing companies, says staff attorney Robert Hausman of Trial Lawyers lor Public Justice in Washington, "the lack of a technical violation of the anti-trust laws does not make it less scandalous." This much is certain: two of Diamond's executives left the company and went to Ver tac.AmeObel.president ofBricker's Interna tional and Diversified Technology unit-- which oversaw the newly acquired de Nora firm in Italy--set up the main holding com pany for Vertac in Panama. Obel then be came Vertac's chief executive officer and was. according to company officials, "the liaison between the management andowner ship" of Vertac. Ray Guidi, who had been an executive at Diamond's NewJerseychemical plant, became the Jacksonville plant's oper ations manager. The relationship between Diamond's top executive Bricker and Vertac's de Nora con tinued over the next several years. In 1982 their companies established Eltedi Systems, a newjoint venture to makechlorineproduc tion equipment. Two years later Diamond sold its interest todeNora. ADiamond attor ney told Business Week magazine that this buyout came about because "the chemical industry was flaton its back."Fora company that other sources told Business Week was a "guaranteed money-maker," de Nora paid $13million less forEltechSystemsthan what Diamond thought it was worth. Bricker kept his ties to de Nora as an unpaid director of Eltech. By 1982 de Nora's Vertac venture was al ready coming under heavy fire in Arkansas. The EPAwas suing Hercules and Vertac, try ing to force the companies to split the initial cleanup costs at the Jacksonville plant The extent of the off-site contamination, which stretched for miles across a flood plain and onto several landfills where the companies disposed ol their wastes, was beginning to be discovered. Perhaps de Nora wanted to unload a potential albatross. And Bricker seemed willing to help him out. The puzzle widens: Diamondhad under taken withaJapanese firmanotherjointven ture in the early '80s. The U-S.-based com pany was called SDS-Biotech. the initials of Showa DenkoDiamond Shamrock. Besides Vertac. SDS-Biotech was America's only other majormanufacturerofwidelyused2,4Dherbicide products. At a board meeting in 1984, a source told Business Week, Bricker demanded thatSDS-Biotech'sJapanesepart ner either agree that SDSBiotechbuyVertac or the partnership was over. But the Japan ese refused. Whywas Brickerapparently so interested in incorporating Vertac into a subsidiary of his own company? Was he trying to comer the market on 2,4-D? Or was it part of a long-range planto helpde NoradumpVertac one way or another? The latter seems an equally logical explanation. Shortly alter the Japanese arm of SDS-Biotech turned Bricker down on Vertac. Diamondbought out the Jap anese and took sole control of SDS-Biotech. But someone else was interested in SDSBiotech. In the fall of 1985 Bricker and de Nora travelled to Stockholm. Sweden, to meet with Refaat el-Sayed. owner of the Fermenta biotechnology company. El-Sayed had previous business relations with de Nora, dealing him Fermenta stock options in exchange lor an Italian pharmaceutical company that de Nora owned. Nowel-Sayed was interested in acquiring SDS-Biotech. But according to Hans Undberg, Sweden's chief prosecutor who later investigated the transaction. Diamond's Bricker and de Nora insisted on a "package deal." Ifel-Sayedwant ed Diamond's subsidiary, he would have to buyVertac aswell.Atthe time,however, more and more of Jacksonville's environmental troubles were being uncovered. El-Sayed's It is unclear who w ill eventually have to pay the cleanup costs in Jacksonville. Every company involved w ants off the fma.Ticia.1 hook. advisers "looked into Vertac," Undberg says, "and said he should not buy the Jacksonville plant, only the other Vertac chemical com panies." Otherwise the deal was off. Trust fund set up: In October 1985 Ver tac'smanagementcalled a meetingwith rep resentatives of the EPA, Justice Department and Arkansas' pollution agency. The idea, at least as it was represented to us, was that a foreigncorporation hadapproached theboard of Vertac seeking to acquire certain of its assets," says Reed Newman, then with the Justice Department. Fermenta AB was de scribed to the officials as "a giant holding company with a multinational participation in its capitalization." Vertac's officials told the Justice Depart ment that the Swedish company would ac quire only the plants in West Helena, Art, and Vicksburg, Miss. It was a `spinoff pro posal, whereby "Vertac would reincorporate those other entities as Cedar Chemical, which would then be acquired by [elSayed'sj Fermenta through a stock deal," says Newman. Vertac's owners would get a large chunk of Fermenta stock. According to Newman, the government was concerned about whether the deal would leave Vertac with enough capital to maintain its responsibility for the Jackson ville cleanup. The government wondered whether the deal was part of a Vertac plan to walk away from Jacksonville completely. Newman says that the Justice Department considered legal action to prevent the deal, butsettled instead lorwhatappeared a legiti mate resolution. Vertac's management proposed that the owners of the company, alongwith the poten tial buyers, establish a $7 million trust fund and an additional $4 million letter of credit tobeassigned later forspecific cleanup tasks at the Jacksonville plant. Vertac was also ordered to spend a dollar on environmental cleanup forevery one it spent on operations. The deal was struck and the letter ol credit wgs drawn on -a Swiss bank in the Italian language. At the time theJustice Department did not knowwhohad approved the transac tion on Vertac's behalf. On Dec. 18. 1985. the Wall Street Journal reported that Fermenta had purchased SDSBiotech and a Vertac unit. Reincorporated as Cedar Chemical, the Vertac spinoff would be managed by SDS-Biotech. now owned by el-Sayed. A shutdown and a scandal: Two months later Vertac shut down its Jackson ville plant. This move coincided with an an nouncement hv Arkansas environmental ol- * i that the company was being fined Vw.500 for violations of a 1982 court-or dered cleanup decree. Vertac. the state claimed, wasstill discharginglevelsofchem icals up to 10 times the allowable level into adjacent Rocky Branch Creek. The company was not reporting monitoringof these chem icals as required, and was also violating bar rel storage requirements. On Feb. 28.1986. Vertac laid off 50 of its 80 Jacksonville employees, keeping the rest, it claimed, to start cleanup at the plant. Four days later, the company settled out ol court with 71 nearby residents who had filed suit against it. Details of the settlement were not revealed. That same week Diamond an nounced plans to sell its J820-mil!ion-a-year chemical division to Occidental Petroleum. De Nora had come out of the SDS-Biotech Vertac deal with S44 million in cash and $30 million in Fermenta stock. He had also un loaded most ofVertac, includingother plants besides Jacksonville that had potential en vironmental liabilities. Meanwhile, the Swedish government had launched an investigationof Fermenta's cor porate dealings. The resulting scandal, one of Sweden's biggest in years, led to Fer menta's expulsion from the Swedish stock exchange and el-Sayed's resignation as chairman of the company's board. Swedish prosecutor Lindberg did not bring any indictments in the affair. But he ' in These Times that he believes the SDS.dvVertac deal may have involved mil lions of dollars' in stock kickbacks from de Nora to el-Sayed. Could those kickbacks have been compensation for el-Sayed taking most of Vertac off de Nora's hands? Following the scandal in Sweden, Fer menta's stock value dropped by 90 percent. With de Nora's investment in Fermenta nearly wiped out. and SI1million of Vertac's moneybottled up intheJacksonville cleanup trust fund and letter of credit, he needed a way out of the Jacksonville imbroglio more than ever. A backroom deal? Late in 1986. a year after de Norasold most ofVertac to Fermenta. Dow suddenly called in its chips on Vertac's debt for its herbicide supply contracts. The question that arises through in These Times' probe of the various corporate maneuvering is this: did de Nora, or perhaps Bricker. work out a behind-the-scenes deal with Dow--al lowing Vertac to use the debt payment as an excuse to transfer all of its assets into Inter-Ag and bolt from Jacksonville? In These Times was unable to determine the extent of de Nora and Bricker's possible involvement in the Vertac-Dow dealings. Neither could be reached for comment. But In These Times did trace a probable de Nora connection to Dow. The chemical giant was--and still is--involved in a joint venture with the Italian electrochemical* company that de Noraoriginally formed with ' brother Oronzio. Bricker. as head of a ir chemical company like Diamond, was aiso likelyacquainted withDowexecutives. In an unrelated incident. Bricker was forced tostep downat Diamond in December 1986. Hereportedly had been under pressure from Diamond's board for alleged misuse of company funds. In telephone interviews with In These Times. Justice Department investigators re fused to comment on their probe of Vertac's ties to Bricker and Diamond. But if Bricker was aware of a government examination of his relationship to de Nora--and his own possible liability fortheJacksonvillecleanup --it mayhaveseemed asensible idea tohelp unload what was left of Vertac. The links between Dow and Vertac have always been curious. They can be traced to 1978, when Vertac was brought out of bank ruptcy by de Nora and Diamond executives. In retrospect, it appears that Dowwas using the smaller company as a kind of "shell" to handle some of Dow's more controversial products. On paper, the twocompanies were competitors. Both, for example, made sub stantial quantities of 2,4-D herbicides-- which recent studies have linked to cancer. But even though Dowcontinued to manufac ture 2.4-D. itsold in 1983allofits registration rights, inventories, formulation recipes and marketing data to Vertac. `Dowknew2,4-Dwasa dirty business,with a lot of environmental hazards associated." says Vertac's former publicist David Simmonp. "So they wanted Vertac to take front line responsibility for it." About the same time, Vertac received per mission fromthe EPAto put some wastes that were classified as containing TCDD-dioxin back into its 2,4-D products. Some of these wastes may have come directly from Dow. "Among Dow employees.' says Paul Merrell. co-author ofa report on dioxin pollution when till plant changed hands. It was, Ver tac's lawyers said, "a deliberate transfer of technology" that resulted in "continuing the manufacturing and waste disposal methods practiced byHercules, with no disclosure by Hercules of the associated hazards and risks." While this may seem a ludicrous exercise in buck-passing, the bet remains that the courts found Hercules, along with Vertac, equally liable for the Jacksonville cleanup. Back in 1965, at a secret meeting called by DowChemical at its Michigan headquarters, Hercules, Diamond Shamrock and other chemical companies learned that the Agent Orange ingredient 2,4,5-T caused adverse health effects. Dow and Hercules, using dif ferent competing formulas, then attempted to remove dioxin from the finished Agent Orange,resultinginarelatively"clean" prod uct Both were fairlysuccessful in getting rid of the impurities, but in Hercules' Jackson villeoperation this process left behindabout three tons a week of the highly concentrated dioxin wastes. These wastes were then placed in 55-gal lon drums at the Jacksonville plant. Accord ing to former plant workers who have tes tified under oath, Hercules' dioxin-filled drums were either buried in unlined pits at the plantsiteorcarted toa nearbycitydump, where unwitting residents sometimes bougit them from the dump's manager to bum trash in. Some of the Agent Orange waste was simply hosed into Rocky Branch Creek, which ran into aneighborhood to the south. _ That, afterthe Pentagon'ssuspension of its I Agent Orange contracts and with the con- J troversyover 2.4J5-Tmounting, Herculesde cided in 1971 to move on to other ventures. Today, the company is a major aerospace contractor with 26,000 employees, head quartered in Wilmington, Del. But the Jacksonville plant still technically published by Greenpeace, "the scuttlebutt belongedtoHerculesuntil 1976,althoughfrom was that part of its dealings with Vertac in 1971 to 1976 it was under lease to Transvaal, volved transferring a bunch of Dow's 2,45-T Inc Transvaal then merged intoVertac. which (dioxin] waste to the Jacksonville plant." took over the site later that year. The herbicide supply contract between Vertac attorney Rick Beard recently tes Dow and Vertac has now been terminated, tified in federal court that Transvaal had in according to Vertac officials.AlthoughJudge the early '70s discovered dioxin on the site Woods found"clear andcompellingevidence" and reported it to the EPAand Arkansas of of fraud in Vertac's transfer of assets into ficials. Some wastes containing dioxin were Inter-Ag, it remains an open question whether then taken at a cost to the company of the company's move was part of a scheme 1250,000 to "a place approved bythe govern between Vertac's owners and DowChemical. ment." according to Beard. That question is. perhaps by design, now AHerculeandilemma: But whether Her mired in the federal courts. cules. as Vertac alleges in its lawsuit, is more Passing the buck: Adifferent court pro culpable than Vertac for the Jacksonville ceeding, however, may answer some other mess is not really the point. The fact is. lingering questions. everyone involved wants off the financial Dow. along with Vertac and its Jacksonville hook. predecessor Hercules, was named in a law So Vertac is suing Hercules, the state and suit filed by 183 former wbrkers at the chem federal governmentsare suingVertac andHer ical plant agd their families. They maintain^ cules, Dowis suing the government and Ver that Dow. through its ongoing supply of her tac. and Vertac's promised letter of credit for bicides to Vertac despite full knowledge of cleanup costs is still being held by the Swiss their potentially detrimental effects, shares bank. While all this is going on. the EPAand the guilt for health problems that the work the state--if they can retrieve the court-or ers have suffered. In the legal dispute over dered cleanup funds--are planning to go cleanup obligations among the chemical ahead with a controversial plan to incinerate companies, Vertac $ nowpittedagainst Her the Jacksonville wastes at the plant site (see cules. In These Times. March 16). Last June Vertac petitioned the court that Thus, noonecurrently knows forsure who Hercules should be held responsible for all will bear the Jacksonville cleanup burden. future Jacksonville cleanup liability because In Vertac's case, the law is unclear about no dioxin contamination was disclosed back Continued on poge22 6585 Dioxinville Continued from page 13 whether a corporation that has transferred its assets can ultimately be held accounta ble.Arecent ruling ina Michigancourt found that acompany can be, but most otherstates have been reticent about making such a de termination. Whether Vittorio de Nora can be impli cated by US. authorities is another matter. As Vertac's apparent majority owner, he might bear responsibility for the company and its environmental liabilities. But de Nora may be out of reach, since he resides in a foreign country. The way things now stand under an international treaty, US. courts must rely on local courts in each country to serve any legal papers. A case currently before the Supreme Court, how ever, isexaminingwhether plaintiffs in prod uct liability cases can drag foreigners into US. coirtrooms. Then there are the legal questions sur rounding the roles of DowChemical and Di amond Shamrock. Yet another corporate courtroom drama--either in Little Rock, if the government has its way, or in Memphis, ifDowwins the jurisdictional dispute--isex pected to imfold later this year. Looming questions: It is conceivable that the Dow-Vertac debt exchange could - backfire o r both companies. Several ques tions may be decided by the courts. Will Dow be forced to turn over the money and goods it retrieved fromVertac to the govern ment agencies? Will Dow be ruled at fault in the pfariT workers' lawsuit for having supplied Vertac with the toxic herbicides in the first place? Finally, will possible invotve- ment ofthede Norafamilyor Bricker betack led by investigators, amid the tangle of cor porate shufflings? And when it comes to big companies, are there ramifications of Bricker's possible dealings with Vertac that might also apply to Occidental Petroleum? The Armand Ham mer oil giant absorbed Diamond Shamrock Chemical back in 1986. Occidental, because of its ownership of the Hooker Chemical company that polluted LoveCanal, was held liable in February by a federal judge for un determined millions in cleanup costs sur rounding that situation. Meanwhile, Diamond's ex-chief executive Bricker and Vittorio de Nora apparently re main travelling partners. Asource in [Has says the men were recentlyobserved paying visits toseveralAmericanchemicalcompan ies, looking to strike up more business ven tures. All these questions mid considerations could perhaps only be unravelled by a fullscale concessional investigation into be powers behind the nation's worst hazardous waste disaster. Some of those powers may already be worried about such a possibility. Diamond is still based in Dallas, where its legal counsel--Gardere and Wynne--is con veniently located in the Diamond Shamrock Tower. The same law firm is representing Inter-Ag--and Vertac'assets--in the battle against the government According to Arkansas' Patty Frase--who lor the past seven years has led the fight to expose the chemical companies behind Jack sonville--somebody in Dallas apparently wants to knowwhat the environmental move ment knows about be chemical compani*' deafimp. A few months ago Frase says she r .-. . i--- received a visit from a private investigator. Hesaid he was with the Fred Meyersagency in Little Rock, but had been hiredbya client in Dallas whom he would not identify. He brought with him a list of names of environmental activists, including one who has long battled DowChemical in Michigan, and wanted to knowwhat information Frase might have about them. Frase says she re fused to speak to him. Lonely victims: But Frase will continue to speak out about Jacksonville's unpre cedented toxic tragedy. So will many other residents, despite a reversal in federal court on March 1that surprised even the judge. It was a jury trial, in which about 100 people living near the two dty dump-sites had charged Vertac and Hercules with contam inating their property and damaging their health. Vertac settled with the citizens out of court, for an anfisdosed sun, as b e pro ceedings began. Then, after de&enting lor two days, a Little Rock jury fond Hercules innocent of negligence in its operation of the pianL About fiftyof the citizensstageda demon stration in Jacksonville tiaee days later, gathering more water samples near the plant site hi an effort tofurtherdoasaent ongoing contamination. But unless the machinations of thechemical companes areprobed further by federal investigators and environmental lawyers;the people ofthis snuff comBHinty in Arkansas are--andwiSremain--be lonely victims of governmental ntfiBcrence and ! corporate manipulation. ; The corporate ante tewfihgtoJadksonvfile brinfp to mmd a scene bom the 1976 movie Network Init, Mr.Jensen, the hithertounseen power behad thetnegncutpceitron. stands at the end ofa longcutereuce latte addressing - hantS^wre*onlyone *wiJiteiwwmi,- interacting, niiBivaried,muJtin*iGOil domin ion of dolais," Mr. Jensen goeson about the *naiurai order of tbimp today. There is no America. There isno democ racy," he says. There is only EM, ITT and AT&T, and DuPont Dow, Union.Carbide and Exxon--The world is a college o( corpora tions. inexorably determined by the immut able laws oI business." And so it goes in Jacksonville. Q Dick Russali s a freelance writer whose en vironmental reportingrgulait/appears inna tional publications. I 4 ^ V __________________________________ - - w -- 6.587 > S* -- .. Chapter 9 Biological Issues in Extrapolation aymond S. II. Yang1, James IIufT1, Dori R. Germolec1, Michael I. Luster1, Jane Ellen Simmons1, and John C. Seely1 i National Toxicology Program, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709 lealth Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 3Pathco Inc., P.O. Box 12796, Research Triangle Park, NC 27709 Approximately 41* (26/63) of the pesticides evaluated in the chronic toxicity and carcinogenicity studies of the National Toxicology Program (NTP) showed varying degrees of careinogenicity. Since those chemicals nominated to the NTP for carcinogenicity studies usually represent a sampling of potentially "problem" chemicals, this ratio (i.e., 41%) does not implicate the actual percentage of carcinogenic chemicals among all pesticides. In general, results from epidemiologi cal studies are of limited value in prevention and have been done on few pesticides. Furthermore, it is - impossible to conduct chronic toxicity/carcinogenicity studies in humans. Therefore, laboratory animals must be utilized as surrogates, at least for the foreseeable f u t u re . T o assess potential risks of chemicals to humans, extrapolation of the findings in laboratory animals to possible health effects in humans is inevi table. Several important biological issues must be considered in such, a process; these include extrapola tion between doses, species (including strain and sex), routes of administration and exposure regimens Ce.g., intermittent vs constant rate). While there is no per fect surrogate for humans in the evaluation of car- . cinogenic potential, and other toxicities of chemicals and other agents, nodents still represent the best models. Any imperfction in such a process (i.e., hazard identification and risk assessment of any given chemical or other agent) must be taken into con sideration during extrapolation. The state-of-the-art technique or tools, such as physiologically based pharmacokinetics/computer modeling, should be con sidered and utilized judiciously to minimize the CD 0097-6156/89AM14--0142J06.50/0 o 1989 American Chemical Sociely Ut GO 9. YANG ET AL. B iological Issues in E xtrapolation intrinsic imperfections in the process. The continuing refinement and Improvement of the entire process (from selection of chemicals for testing, experimental design and conduct, i n t e r p r e t a t i o n a n d analysis of data, interpolation and extrapolation, to risk assessment) is essential as scientific advances are made in these areas. Other important issues related to hazard iden tification and risk assessment include multiple chemi cal exposure as well as multiple route exposure; these must be incorporated into the process as Information and tools become available. 143 In a recent review article (U, the Council on Scientific Affairs of the American Medical Association reported their findings on the cancer risk of pesticides in agricultural workers. Their conclusions were: (a) The primary h a z a r d o f pesticide exposure is the development of acute toxic reactions as a result of dermal contact with or inha lation of a relatively large dose. The effects usually are mani fested within minutes or hours of contact; (b) Epidemiological studies offer only limited evidence at best that pesticides may be carcinogenic; (c) Alarge number of pesticidal compounds have shown evidence of genotoxlcity or carcinogenicity in animal and in vitro screening tests, but no pesticides -- except arsenic and vinyl chloride (once used as an aerosol propellant) -- have been proved definitely to be carcinogenic in man; (d) With few exceptions, the long term (e.g., carcinogenic) effects of pesticides on human health have been difficult to detect. Perhaps the health risks are suf ficiently small that they are below the power of epidemiologic stu dies to detect. But 1t is also possible that there are very few effects to humans at all. While a comprehensive review of the epide miologic studies conducted world-wide on pesticides, fertilizers, and/or agricultural practices (e.g., poultry, hog, dairy production) yielded conflicting results, the limitations of epidemiologic studies were also given (_1) as shown in the following quotation. "Epidemiologic analysis of data in man often fails to yield conclusive results because the size of the study group is too small (statistical power is inadequate to detect a difference), exposure data are lacking, concomitant or prior exposures to other known or suspected carcinogens may interact with the compound(s) in question and confound the analysis, or a proper control group cannot be identified. Then, too, some well-defined studies in different groups under different circumstances may yield totally conflicting findings." Even if there were no such limitations, epidemiologic analysis Is retrospective study; it cannot be depended upon for the detection and prevention of potential health hazards to the public. In com parison to epidemiologic studies, animal bioassays are short in dura tion, relatively inexpensive, easily perfomed under controlled conditions, and are reliable predictors for known human carcinogens. Therefore, from the point of view of identifying and preventing public health hazards, animal bioassay is an invaluable tool. 144 CARCINOGENICITY AND PESTICIDES As of April 1989, the National Toxicology Program (nTP) and the National Cancer Institute (NCI; up to 1981), have completed chronic toxicity/carcinogenicity studies on 385 chemicals (2). Of the chemi cals studied, 63 were considered pesticides (GeneraT or Unclassified) (Tables I and II). Approximately 41X (26/63) of the pesticides eva- Table I. NCI/NTP Carcinogenicity Study Results for Pesticides: Carcinogenic Pesticides Under the Experimental Conditions Chemcial Name CarcinogenicIty Results TR No. Route 'Mr Er FM Aldrin Captan Chloramben 021 015 025 Feed Feed Feed EEP N NNP P NNE P Chlordane 008 Feed N N P P Chlorobenzilate 075 Feed E E P P 3-Qhloro-2- methylpropene Chlorothalonil 300 041 Gav Feed CE CE CE CE P P NN Daminozide 083 Feed N P E N 1,2-Dibromo-3- chloropropane 028 Gav PPPP (DBCP) 206 Inh PPPP 1,2-0ibromoethane (EDB) 086 . Gav PPPP 210 Inh PPPP 1,4-Dichlorobenzene 319 Gav CE NE CE CE 1.2- Dichloropropane 263 Gav NE EE SE SE 1.3- Dichloropropene (Telone 11) 269 Gav CE SE IS CE Dichlorvos 342 Gav SE EE SE CE Dicofol 090 Feed N N P N Ethylene oxide 326 Inh CE CE Heptachlor 009 Feed N E P P Mirex 313 Feed CE CE Monuron 266 Feed CE NE NE NE Nitrofen 184 Feed N N P P 026 Feed IS P P P Piperonyl sulfoxide 124 Feed N N P . N Sulfallate 115- Feed P P P P Tetrachlorovinphos 033 Feed N P P P Toxaphene v 037 Feed ` E E P P 2,4,6-Trichlorophenol 155 Feed P 'N P P Triflural in 034 Feed N N N P TR = NTP Technical Report; Gav = Gavage; Inh = Inhalation; MR- Male rats; FR = Female rats: MM- Male mice; FM= Female mice For experiments evaluated by the NCI or the NTP prior to June 1983, results are reported as "positive" (P), "negative" (N), "equivocal" (E), or "inadequate" (IS). In June 1983, the NTP adopted the use of "categories of evidence": two of the five categories correspond to positive results ['tcleaV evidence" (CE) and "some evidence" (SE) of carcinogenicity], orite is for uncertain findings ["equivocal evidence" (EE)], one is for negative studies ["no evidence" (NE)], and one Is for studies that cannot be evaluated because of major flaws ["inadequate studies" (IS)]. 9. YANG ET AL B iological Issues in E xtrapolation 14 Table II. NCI/NTP Carcinogenicity Study Results for Pesticides: Non-carcinogenic Pesticides U n d e r the Experimental ,Conditions Chemcial Name TR No. Route Carcinoqenicity Results MR FR MM FM Aldicarb 136 Feed N N N N Anilazine Azinphosmethyl 104 069 Feed Feed N E N N N N N N Calcium cyanamide 163 Feed N N N N 2-Chloroethy)tri- mthylammonium 158 Feed N N NN chloride Chloropicrin 065 Gav IS IS N N Clonitralid 091 Feed N E IS N Coumaphos 096 Feed . N N N N Oiazinon 137 Feed N N N N Dichlorvos 010 Feed N N N N Diel dr in 021 Feed N N E N 022 Feed 1 N N 1,2-Dichlorobenzene 255 Gav N N NN Dichlorodiphenyl- dichloroethane (TUE) 131 Feed E N N N Dichlorodiphenyl- trichloroethane (DDT) 131 Feed N N N N Di(p-ethylphenyl) dichloroethane (DDD) 156 Oimethoate Dioxathion 004 125 Feed Feed Feed N N N N N N N N N E N N Endosulfan 062 Feed IS N IS N Endrin Fenthion Fluometuron Lindane Malaoxon Malathion 012 103 195 014 135 024 Feed Feed Feed Feed Feed Feed N N N N N N N N N N N N N E N N EN N N N N N N 192 Methoxychlor 035 Methyl parathion 157 Mexacarbate Parathion 147 070 Pentachloronitrobenzene 061 325 o-Phenylphenol 301 Phosphamidon 016 Photodieldrin 017 Picloram 023 Piperonyl butoxide Rotenone 120 320 2,3,5,6-Tetrachloro-4- 114 Feed Feed Feed Feed Feed Feed Feed SP Feed Feed Feed Feed Feed Feed N N N N 'E N E N N N EE N N N N N E N E N E N NE N N N N N N N NE N N N N NE N N N N N N NE NE N N N N NE N nitroanisole Triohenyltin hydroxide 139 SP = Skin paint; For all other Feed N abbreviations, see N Table 1[ foNotnotesN 146 CARCINOGENICITY AND PESTICIDES luated showed varying degrees of ca-cinogenicity in animal studies (2); these carcinogenic pesticides and those found to be ncncarcinogenic in the test systems are presented in Tables I and II, respectively. The criteria used to determine whether a pesticide is carcinogenic are according to the NTP or NCI convention; that is: one or more of the four experiments (i.e., male rats, female rats, male mice, female mice) showed "clear evidence", "some evidence" of car cinogenicity, or was ruled to be "positive" for carcinogenicity (3,4). Acaution must be made here that the percentage (i.e., 41%) for pesticides tested positive as carcinogens does not mean that the same percentage will hold true for all pesticides or all chemicals. The fact that these chemcials were nominated to the NCI or NTP for testing means there was concern that these chemicals could be poten tially troublesome; thus the sampling is slanted toward potential carcinogens. AS shown in Figure 1, the primary efforts of the NTP center on chemical nomination, evaluation of the existing Information, study design and conduct, data analysis and interpretation, and finally the preparation, public peer-review, and publication of technical reports. However, the information presented in the NTP Technical Report is frequently used world-wide for hazard identification and risk assessment, often leading toward regulatory decisions and actions. Even though the NTP is not directly involved in the regula tionrythepsreocpersoscees,ssethse. data generated at the NTP play an important role NTP Nomination Evaluation of Existing Information Experimental Design Study Conduct and Monitoring >'I , Technical Report Regulatory Agencies Risk Assessment Figure 1. Flow chart of*, the functions of the NTP in the toxico rloeggiuclactohrayraacgteernicziaetsi.on of chemicals and its role In relation to 9. YANG ET AL. B iological Issues in E xtrapolation 147 Once a chemical Is demonstrated to have carcinogenic activity In laboratory rodents, extrapolations from "animal carcinogen" to "human carcinogen" and from "high dose" (l.e., the dose used in animal stu dies) to "low dose" (l.e., the dose humans are exposed to) are inevi table In the risk assessment process. Many biological issues are automatically brought Into the limelight. At least some of these Issues had been "locked in" as early as the experimental design stage. Those Issues most often discussed are species, strain, sex, dose, route, and to some extent exposure scenario. Though important in the risk assessment process, the issues of toxicological interac tions and the health effects of chemical mixtures have received com paratively little attention. In this paper, we will only discuss the current thoughts on a few selected issues with a special emphasis on toxicological interactions and chemical mixtures. Species Extrapolation Are rats and mice good models for humans toxicologlcally? This is an age-old question and opinions continue to be varied. But "Is a human a good model for humans?" Assuming there are no ethical and moral considerations and we, as a society, could perform toxicological stu dies including carcinogenicity bioassays in humans, would there be arguments? The answer is most likely a yes!, because there are so many environmental and life style differences (e.g., dietary pre ference, smoking, coffee drinking, alcohol Indulgence, exercise, etc.) among individuals that the outcome of the results may easily bt influenced. Assuming further that we built "human cages" with exer cising machines, formulated "NIH-07 Human Chow," and completely eli minated all environmental and life style variables, would we then be more comfortable? The answer is no because there are known human pharmacogenetic differences such as fast acetylators and slow acetylators, and other biochemical and physiological diversities. There will always be arguments such as "Why didn't you use a different subpopulation?" The point is that there is not and will never be a perfect system and that we have to settle for less than perfect. The right question to ask then Is "Given the fact that there is no perfect system, how good are rats and mice as models for humans in toxicology?" Reviewing the literature regarding the development of the carcinogenicity bioassay, one finds such discussion as the one given by Shimkin (5) who proposed a general set of criteria for the selection of test animals in carcinogenicity studies: (a) availabili ty; (b) economy; (c) sensitivity to carcinogens; (d) stable as to response; (e) similarity to human in regard to metabolism; (f) simi larity to human in regard to pathology responses. When all these criteria are considered realistically, not too many laboratory anima species.may be used for carcinogenicity studies. Other examples in the literature on the selection of species for carcinogenicity bioassay include Sontag (6) and Weisburger and Weisburger On the basis of certain criteria, Sontag (6) suggested that the only l 4 g CARCINOGENICITY AND PESTICIDES species suitable for large scale, long term carcinogenicity bioassays are the rat, mouse, and hamster. Weisburger and Weisburger (7), on the other hand, indicated that when specific questions are asied of the bioassay rather than the simple endpoint of the increases of neoplasms, a variety of species can be used. Thus, the NTP Ad Hoc pane) on Chemical Carcinogenesis Testing and Evaluation suggested examples where the specific relationship of a highly defined genetic background and the induction of neoplasms in animals harboring few oncogenic viruses may lead to the use of fish or insects (8 ). In our opinion, considering tihe scientific as well as practical issues, laboratory rodents are still the best models available to provide information regarding the potential toxicological consequences of chemicals in question. As responsible scientists in the public health arena, we do not have the luxury to ignore the results from animal studies even if they are less than perfect models for humans. For instance, in recent years, there has been higher prevalence of fin rot, tumors and other lesions in Winter Flounders caught in the Boston Harbor (9). Are we to take such findings as a valid warning fromnature and consider them as the results of a "natural bioassay" on the pollution in the area, or simply ignore it on the basis that a fish is not a human? There is abundant debate in the literature about the use of laboratory rodents as models for humans; a recent example appeared in Statistical Science (10-16). Some scientists considered rodents very good surrogates for humans in predicting carcinogenicity; for instance, of the known human carcinogens, 86Xto 100X (depending on the data base used) were shown to be animal carcinogens (12,17-19). Others (10), apparently using the same data base but only the "sufficient evidence"^category as defined by the International Agency for Research on Cancer (1ARC) (18) in their calculation, considered rodents to be poor models for humans because the concordance was poor (59%). At-issue though is not whether or not the concordance is 100% or 59%between human and,animal models because even a selected sample of humans probably do not have 100%concordance with the rest of the human population. We know laboratory rodents are not perfect surro gates for humans but they definitely provide valuable scientific information regarding the intrinsic biological activities of chemi cals. It is important fer scientists in toxicology to recognize the imperfection of the animal bioassays and to try to continually deve lop better scientific methods to minimize the differences in the extrapolation between species and between high and low doses. As a case in point, the incorporation into the risk assessment process of physiologically based pharmacokinetics/computer modeling which takes into consideration physiological constants (e.g., body size, organ and tissue volumes, blood flow, and ventilation rates), biochemical constants (e.g., metabolic constants, partition coefficients for blood, tissues and air),, and mechanistic factors (e.g., target tissues and metabolic pathways) of various species, including human, represents a major scientific advance in recent years (20). * CD ... y y te.-C\ to 9. YANG ET AL. Biological Issues in Extrapolation 14 The Importance of continuing refinement and.Improvement of the hazard Identification and risk assessment process based on newly developed scientific information may be Illustrated by another example using a pesticide, EDBor ethylene dibromide. Critics of c a n c e r risk assessment based on animal bioassays frequently make reference to a paper by Ramsey et^ 1.. (2U. In that paper (21), Ramsey and coworkers questioned the validity of the EPA's esTTmate < 100Xlifetime incidence of cancer to be expected in humans exposed i a concentration of 0.4 ppm (3.1 mg/m3) of EOB for 40 years. As pointed out by Ramsey et^ _ak (21), the reliability of such a predic tion is dependent upon the validity ofi the carcinogenesis model (one-hit model in this case) as well as its'extrapolation from rat bioassay data to human population. To test these hypotheses, Ramse et al. (21) compared the incidence of cancer predicted by the EPA one-hit carcinogenic model with that observed in a group of 156 workers employed in the production of EDB. While the one-hit model predicted a total of 85 tumors above the normal background incidenc (2.2 tumors expected based on a comparison with the U. S. white mal mortality rates) in this group of workers, the actual t u m o r inciden r a t e of 8 tumors was observed (j^l). Ramsey et al. concluded that u of the one-hit model appears to result in "highly exaggerated" risk estimates. Their results and conclusions have been cited as eviden that extrapolations from animal bioassays to human real-world expo sures are implausible. Amore recent attempt by Hertz-Picciotto et al. (22), however, has provided counter arguments. When cancer rls for 08 among the cohort of workers u s e d b y R a m s e y et al. (2 1) w e n estimated by fitting several linear nonthreshold adBltive models t< data from gavage and inhalation animal bioassays (22), the predict upper bound risks were within a factor of 3 of the observed cancer deaths (Table III). Thus, Hertz-Picciotto et al_. (22) concluded tl the previous overestimate of risk to workers occupationally expose< to EDBwas due to failure to consider their age at start of exposur when extrapolating from an animal bioassay with an exceedingly shot latency period. In the quotation from Hertz-Picciotto et ak (22) below, the spirit of continuing Improvement and refinement of the hazard identification and risk assessment process is elegantly reflected: "The field of carcinogenic risk assessment Is in its infancy. The primitiveness of methodology echoes the lack of a clear theory of carcinogenesis. However, the gaps in knowledge and the uncertainties in methods do not constitute sufficient justification for abandoning efforts to provide the public with plausible upper bounds for cancer risks due to environ mental chemical exposures. For a large number of such expo sures, these estimates will necessarily be based on animal data. When quantified human exposure data are available and are related to cancer risk, these data can be useful either as a basis for extrapolation or as a standard for assessing the plausibility of risk estimates based on animal data alone." o -- <0 1/1 i- T3 at 0 5 g4- *-> m a to at 3 3 0 c 4- c 4-> o *0J1 at 0 H- <*-o* 4-1<* 0 at gat <T3 X) o c a> 2: -- 0W<0 4- 4-* ,, CARCINOGENICITY AND PESTICIDES O Ol 30 ^CVJN < N J lO K * r cnj v o Table III. Total Cancer Deaths; Predicted by Several Models for EDB-Exposed Workers *o at *o HUtU) rs ^ rH g -- at *- E ldaV03/lt x UJ rs. m f\j E CaL. 01 o ISaoo* -o*M- Xi.J ol *l il SI V t XJ at k. vi >i_ aot *j ' 'Cain?ot cmu -a6t I ; ran oim o VO CO C O H Ol CO CM W> covnco *oe-- to c-ri**u~) x o a> i--at 2*:- O> OKK *Hr** i(--Vi| om mor*s* ^ p s in CMHn VO CM CO lO'fO in n oi P! o o u u Q. 9. YANG ET AL. Biological Issues in Extrapolation 151 MaximumTolerated Dose (MTD) Since quantitative risk extrapolation Is presented 1n another chapter, we discuss briefly here the Issue of maximumtolerated dose (MTD). Actually "maximum tolerated dosp!' is a rather nebulous term without specific qualifiers. Agenerally accepted definition does not exist. The definition for MTD, given in one source (8 ), is "...this dose is determined by prechronic studies which aid in the identification of a dose level which, when given for the duration of the chronic study as the highest dose, will not Impair the normal longevity of the treated animals from effects other than the induc tion of neoplasms. Such dose should not cause morphologic evidence of toxicity in organs other than mild changes such as slight hypertrophy or hyperplasia, inflammation or slight changes in serum enzymes..." In a second source (23), MTD is attributed to be the result of "...the simplistic approach of the National Cancer Institute's Bioassay Program, which is to conduct a 3 month range finding study with enough doses to find a level which suppresses body weight gain slightly, i.e., 10X. This dose.is defined as the maximum tolerated dose (MTD) and is selected as.the highest dose." In a third source (24), MTDis defined as "...a predictive dose obtained from analysis of subchronic study doses In the oncogenicity study, the MTDshould elicit toxicity without substantially altering the norma) life span of the test species from effects other than tumor formation." In this case, it is of course really an exercise after the fact (i.e., after the completion of the chronic toxicity study) to evaluate if the doses selected were reasonable. Examples in such an evaluation for determining a MTD include body and organ weight effects as well as clinical and anatomic pathology (24). Thus, MTD must be considered 1n the context of the toxicologicTT endpoints measured. , In the estimation of MTDand setting doses for chronic toxicity/carcinogenicity studies, one often hears advice against selecting any dose within the range of "saturation kinetics" (or "nonlinear kinetics"). The underlying reason for such advice is tha' we, the experimenters, should not "overwhelm" the animals' capacity of handling chemical Insults. This is once again debate or argument resulting from nebulous terms. If one considers that any toxicity o> toxicological response(s) is a manifestation of the disruption of homeostasis, then somewhere in the body there must be a system(s) (e.g., sites of action, transport mechanisms, metabolic pathways, binding sites, repair mechanisms, etc.) being overwhelmed. In fact, 1t has been suggested that toxicology is nonlinear pharmacokinetics (25). Therefore, at the stage of selecting doses for chronic toxi- cTty studies based on prechronic toxicity data, it is very difficult to talk about nonlinear pharmacokinetics or saturation kinetics without defining precisely what parameters are involved. As to the debate on the use of estimated MTDin chronic toxicity/carcinogenicity studies, recent information may be found in two letters by Abelson (j!6 ) and McConnell (27). Abelson suggests that the public has been misinformed througft~"a media barrage" by th results of chemical carcinogenesis studies in animals, particularly In rodents (26). One of the criticisms from Abelson was the use of "massive doses" (i.e., MTD) which, 1n his opinion, "vastly exceed those to which humans are likely to be exposed" (26). McConnell CARCINOGENICITY AND PESTICIDES _7. n the other hand, pointed out that, in at least three impor tant instances (asbestos, benzene, and 1,3-butadiene), past occupa tional exposures are not different from the levels used in laboratory rhnents. Further, McConnell (27) defended the use of MTD in car cinogenicity studies because animals are able to detoxify chemicals much faster than humans do, and to get an equivalent dose to the target tissue in such a case would require much more of the chemical In animals. He illustrated his point by using cigarette smoke as an example; it takes an unusually high exposure of cigarette smoke to cause cancer in laboratory antumaIs as compared to humans (27). McConnell asked that if cigarette smoke were an "unknown," would one assume tobacco was safe because the dose to animals was higher than the average human receives? (27). Toxicologic In te ra c tio n s Toxicologic interaction has been defined as "a circumstance in which exposure to two or more chemicals results in a qualitatively or quan titatively altered biological response relative to that predicted from.the actions of the single chemicals independently. The multiple-chemical exposures may be simultaneous or sequential in time, and the altered responses may be greater or smaller In magnitu de" (28). While most if not all of the known examples of toxicologic interactions concerning pesticides (29) involve respective chemicals at concentrations far above levels o7~environmental contamination, recent findings have uncovered toxicologic interactions at low enough concentrations to be relevant to environmental pollutions. Table IV illustrates an example of toxicologic interaction other than the classical instances of insecticide synergism (e.g., pyrethrin and piperonyl butoxide). Mingensmith and Mehendale (30) and Mehendale (II) reported probably the first case where a pesticide, Kepone, at an environmentally realistic level (i.e., 10 ppm) caused a dramatic increase (67-fold) in the acute toxicity of carbon tetrachloride. Although this synergistic effect of Kepone is rather specific in that close structural analogs such as mirex and photomirex do not share this property (31), one wonders whether other chemical(s) or chemical mixtures, at environmentally low levels, might cause similar synergistic toxicity. Indeed, the NTP has obtained some preliminary experimental results (presented later) which may shed light upon this question.' ' ` Toxicologic interactions may occur in chronic toxicity and car cinogenicity studies. For instance, Wong and colleagues (32) demonstrated a profound enhancement of mortality, tumor Incidences and the shortening of latency period for neoplasms of a well-known fumigant, EDB, by disulflram (antabuse) In a chronic toxicity study. As shown in Table V, the numbers and the types of tumors increased significantly when EDBand disulfiram were given together. Of course, the reason for such a synergistic effect was due to the Interference of metatjol 1o degradat ion of EOBby disulfiram (32). The j relevance of this study, as was the original purpose for the-Tnvestl- I gallon (32), is the concern of the potential synergistic hazard for |>people occupationally exposed to EOB (e.g., production workers, pest !j control applicators) who might be simultaneously participating in an i alcohol control program using antabuse as a therapeutic agent. 6593 9 . YANG ET A l. Biological Issues in Extrapolation 153 Table IV. Enhancement of Acute Toxicity of Carbon Tetrachloride by LowLevel Dietary Pretreatment of kepone Dietary Pretreatment 48-hr LD50 (ml CC14/kq) Increase in Mortality Control diet 2.8 Kepone (10 ppm) diet 0.042 67-fold Condensed from K1ingensmith and Mehendale (30) and Mehendale (317 These examples above demonstrate y e t another area of uncertainty in the extrapolation of animal toxicityistudies to the hazard iden tification and risk assessment of humans. Since the data base In this area is extremely limited, particularly at chemical con centrations which are environmentally realistic, major endeavours in this area are urgently needed. > Table V. Major Histopathological Findings in Rats Exposed to EDBor EDB/Disulfiram (EDB+DS) in the EDB/Disulfiram Interaction Study " DB 1 Male Female No. of Animals Examined "46" 48 Liver hepatocellular tumors 2 3 Mesentary or omentum hemanglosarcoma '0 0 Kidney i adenoma and adeno- carcinoma 3 1 Thyroid fol1Icular epithelial adenoma 31 Mammary all tumors -- 25 Lung all tumors 30 EDB+S Male Female ~ W 45" 36* 32* 11* 8* 17* 7* 18* 18* --" 13* 9* 2 No. of Rats with Tumor No. of Rats with Multiple Tumors 25 29 io 8 45* 45* 37* 32* * P<0.05 Condensed from Wong et al. (32)~ Disulftram was given in diet at 0.01 and EOB inhalation exposure was at 20 ppm. The control and DS alone groups (not shown here) had, in general, very low or no tumor inci dence with respect to these organs; the only exception was that the DS alone group had statistically higher Incidence in mammary tumors than did the control group. 154 CARCINOGENICITY AND PESTICIDES Toxicology of Chemical Mixtures Human exposure to chemicals, be it occupational or environmental, is rarely limited to a single chemical. Even in a strictly controlled situation such as a production plant for a single chemical, the expo sure of workers to a variety of other chemicals in food, drink, per sonal hygiene, etc. is part of daily life. As illustrated very clearly in a recent government publication on human health and the environment (33), "...Each of us is exposed daily to multiple chemi cal substances in our environments. The food we eat is a complex mixture of chemical substances. Our drinking water contains hundreds of chemicals, even when it is obtained from a municipal "purification" facility. The air we breathe and the things we touch likewise conta-in a variety of chemicals with an almost limitless range of compositions. Moreover, our habits and lifestyle may add other chemical exposures. Tobacco smoke, for example, contains thousands of substances. Additionally, the American public spends between $4 billion and $8 billion per year on self prescribed and self-administered drugs for self-diagnosed illness..." In the last few years, the NTP has been interested in the toxi cology of a mixture of 25 frequently occurring groundwater con taminants derived from hazardous waste disposal sites. The diagram in Figure 2 is a summary of the projects completed or ongoing at the NTP and neighbouring institutes. The genesis of such a program, the formulation of a 25-chemical (19 organics and 6 inorganics) mixture in deionized water, and the analytical and initial animal toxicology work have been reported (34-41). In most of our animal studies, the highest dose level, as shown in Table VI, contains individual chemi cal concentrations close to those detected in the groundwater samples near hazardous waste disposal sites. When this mixture is given to female B6C3F] mice for 14 or 90 days, suppression of immune function was seen in 3 of the parameters examined (38); the results are sum marized ,i.n. Table VII. First, the suppression of bone marrow stem cell proliferation, as expressed by the number of colonies formed of the granulocyte-macrophage progenitor cells is presented. Note the lack of response in the paired-water control group in the 14-day stu dy; this finding suggests that the immunotoxic responses seen had little, if anything, to do with the reduction of water consumption in the treated groups. Aclear-dose-response relationship was demonstrated- in the 90-day study results on the suppression of bone marrow stem cell proliferation. The second immunological endpoint affected is the suppression of antigen (sheep red blood cel 1)-induced antibody forming cells (Table VII); similar results as discussed above for the stem cell suppression are also evident for this end point. Three host resistance assays following challenge with infec tious agents (Listeriafmonocytoqens, PYB6 syngeneic tumor cells, or Plasmodium yoeTTI) were investigated (38). Altered resistance, as expressed by % pafasitemia, occurred in the group challenged with Plasmodium (Table V11)^ These results collectively suggest that long-term exposure\to NeaviTy contaminated groundwater may represent a risk to the immun system (38). In another experiment (Figure 3), a collaborative effort between the EPAand the NTP, we examined the effects of pretreatment with the ,25-r.hi-mical mixture of groundwater contaminants for 14 days on the BJpatotoxicity of carbon tetrachloride in male Fischer 344 rats (39). 9. YANG ET AL. Biological issues in Extrapolation i 155 Chemistry Development and Support Health EKeels Subchronic and chronic studies Toxicological Interactions 1 Immunotoxicology %%%\ \ Reproductive and %S%% Developmental Toxicology 'N %%% i ' / 0000 0000 00 0* Biochemical Toxicology Principal Mutagenicity 0 Investigator % 0000 %S%* S .' 000004 %\ \% Pharmacokinetics Neurobehavioral Toxicity 1 1 1 a1 Myelotoxicity Hepatotoxicity/ Nephrotoxicity Figure 2. Aprogram of toxicology of complex chemical mixtures of groundwater contaminants at the NTP. CARCINOGENICITY AND PESTICIDES 5* t . i, yj# comparison of Concentrations of the Components of the 25 Chemical Mixture Dosing Solution with EPA Survey Results*8 _f Ave EPA Survey ppm High Dose Concentrations (ppm) Ratio B/A Acetone 6.9 53 7.7 Arochlor 1260 0.21 0.01 0.05 Arsenic Benzene Cadmium 1 30.6 5.0 0.85 9 12.5 51 0.29 2.5 60 Carbon tetrachloride 0.54 0.4 0.74 Chlorobenzene-1 0.1 0.1 1 Chloroform 1.46 7 4.79 Chromium 0.69 36 52.2 DEHP l,l-01chloroethane 0.13 0.31 0.015 1.4 0.12 4.52 1,2-Dichloroethane 6.33 40 6.32 1,1-Dichloroethylene 0.24 0.5 2.08 1,2-trans- Dichloroethylene 0.73 2.5 3.42 Ethylbenzene 0.65 0.3 0.46 Lead 37.0 70 1.89 Mercury 0.34 0.5 1.47 Methylene chloride 11.2 37.5 3.35 Nickel 0.5 6.8 13.6 Phenol 34.0 29 0.85 Tetrachloroethylene L 9.68 3.4 0.35 Toluene 5.18 7 1.35 1,1,1-Trichloroethane 1.25 2 1.6 Trichloroethylene 3.82 6.5 1.7 Xylenes ,4.07 1.6 0.39 3 chemicals > 10X Average EPA Survey Concentration 14 IX - 10X 8 < IX As Table VTII demonstrates, the deionize^ water control group and the drinking water chemical mixture alone group showed no histopathologlcal changes In the liver. While the CCI4 alone group showed a mild centrilobular vacuolar degeneration at the dose level applied (0.075 ml/kg), the m1xture/CCl4 group showed. In addition to the mild centrllobular'vacuolaf degeneration, minimal centrilobular hepato cellular necrosis (Table VIII). The necrotic changes In the liver In the m1xture/CCl4 group also coincided with the elevation of serum aspartate aminotransferase (177X of controls) and alanine aminotrans ferase (273Xof controls). We are currently conducting an experiment to determine the effect of prior exposure to the 25-chemlcal mixture on the CCI4 dose-response curve and to determine the Influence of the observed decrease In water and feed consumption on the apparent enhancement of CCI4 hepatotoxlcity. 9. YANG ETAL. Biological Issues in Extrapolation I Table VII. Immune Functions in B6C3Fi Mice Affected by Exposure to a Chemical Mixture of Groundwater contaminants123 Exposure Level (X Stock) 0 0 .2 2 .0 20.0 Paired water 0 1.0 5.0 10.0 CFU-GM PFC/Spleen / 10l cel 1si (X 102)2 14-day study 59.8 + 6 .0 172 + 16 57.2 + 1.3 231 + 16 55.4 + 3.2 157 + 24 37.8 + 0.4** 96 "+r 16** 50.5 + 1.3 172 + 17 1 3-month study l 55.3 + 2.1 189 + 49 52.6 + 2.9 120 + 19 43.5 + 4.6* 144 + 21 29.6 + 1.7** 93 + 15 P. yoelii X parasitemia. 14.2 + 1.2 9.2 + 1.0 19.8 + 2.9 22.1 + 2.9* N.O. 10.1 + 1.5 9.4 + 2.9 12.7 + 1.9 20.8 + 2.9* 1 The CFU-GM, granulocyte-macrophage colonies, were assayed by incubating femoral bone marrow cells in the presence of mouse lung conditioned medium as a colony stimulating factor at 37C 5%CO2 for 7 days. Colonies of >50 cells were enumerated using stereomicroscope. Values given represent mean + SE of CFU-GMp lo' cells for at least five mice per group. 2 The antibody response to sheep erythrocytes was determined by enumerating plaque-forming cells (PFC) in splenic lymphocytes 4 days after primary immunization. Values given represent mean * SE of PFC per spleen for at least five mice per group. 3 Infection with the malarial parasite P. yeolli was determined b quantitating the percent parasitemia on days 10, 1?, and 14 following injection of 10 parasitized erythrocytes. Only peak day, day 12, of infection Is shown. Values given represent mea i SE-of eight mice per group. N.O. not done; ** Significantly different from control at P < 0.01; * Significantly different from control at P < 0.05 Source: Data are from ref. 38. 96S9 3 r* -- a c ifi nCicoLrraOr<e*.f r.cC-eio , 3 r-r r(ZeD m iD 3 X na^* oj n i*r--0e 3* 3* 3 ^ ---re re < 01- O3--f 3r* t roe.&-- -- . 3--xrr.air--./Qe> C-J 3 re o ao<> rconr3e*. r* CO "1 OX O --' cn 3o CL -- .Or*r-ej*t-tno*o+. n3 O 3 rr*e- ar+ *&1 3 a3 o3 l (A O o o 3 a ? < 5 Xn 2 O wn 2 > 2 O O 5 B YANG ET AL. Biological Issues in Extrapolatioi 4 Table VIII. Enhancement of Carbon Tetrachloride Hepatotoxicity in Male Fischer 344 Rats by Prior Exposure to a Mixture of 25 Groundwater Contaminants Treatment^ Groups Control/ Control Low Mixture/ Control High Mixture/ Control Control/ CCI4 LowMixture/ CCI4 High Mixture/ CCI4 No. Animal Examined 4 4 4 4 4 4 Clinical Chemistry Parameters Liver Histopatholoqy (No. Rats with Lesion) AST2 ALT2 Normal Vacuolar Degeneration Cellular Necrosis 52.8 + 4.3 35.0 + 4.1 4 0 0 46.5 + 2.6 32.8 + 1.7 4 0 0 53.8 + 6.2 39.0 + 2.2 4 0 0 55.0 + 3.9 47.0 + 7.5 1 ' 52.5 + 4.0 .. 41.2 + 7.4 0 0 4 4 0 0 93.5 + 36.5* 95.5 + 49.7** 0 4 3 ^ The rats were given deionized water (Control) or 1* (LowMixture) or 10X (High Mixture) mixture stock for 14 days and then dosed by gavage a single dose of corn oil (Control) or CCI4 at the rate of 50. 07 ml/kg in corn oil; the animals were then sacrificed 24 hours later. AST * Aspartate aminotransferase; ALT * Alanine aminotransferase **Sienificamlv different from the ComroUComrol grouo. the Hieh Mixture/Control eroup. and the Control/CQ^ 160 CARCINOGENICITY AND PESTICIDES The primary hazard of pesticide exposure is acute toxicity resulting from dermal contact with or inhalation of a relatively large dose (_1). However, the toxicology of chemical mixtures at the level of environmental contamination will probably not involve acute toxic responses. It is most likely an insidious effect(s) disrupting the homeostasis of the organism. The exposed animals may appear totally "normal" clinically or based on conventional toxicological endpoints. However, such a subclinical state may provide a basis for enhancement or potentiation of otherwise mild toxic responses from an acute exposure(s) ofchemical, physical, a n d / o r biological agents. In this sense, the concept of a generic "promotor" or "enhancer" for any possible toxicity may be advanced for the potential toxicologic consequence Trf a mixture of environmental pollutants. These findings also raise the possibility for synergistic interaction between a background long-term, low-level chemical mixture exposure and an sub sequent acute dose resulting from accidental exposure or drug intake including alcohol abuse. All these issues are not only relevant but very important in the extrapolation between animals and humans. Concluding Remarks Two years ago, in the ACS symposium on "Pesticides: Minimizing the Risks", the utilization of physiologically based pharmacokinetics/ computer modeling for dealing with the complex issues of extrapola tion, toxicological interaction, and chemical mixtures was suggested (42,43). As shown in Figure 4, the Stage 1 effort has already been Physiological Pharmacokinetics/ Animal Scale-Up Bischoll el al (19)1) Dedrick (1973) Application of Special Computational l- Technology lo Toxicology Clewell and Andersen (1986) STAGE STAGE II CO: or: CD STAGE III Risk Assessment Extrapolation between Routes Species Single and Multiple Doses I\ Extrapolation between Young and Old Healthy and Disease Slates Acute and Chronic Toxicity Administered and Delivered Doses Single and Multiple Chemicals I PREDICTION 7 Figure 4. A suggested approach utilizing physiologically based pharmacokinetics and computer technology for the extrapolation and prediction of various situations in toxicology. (Reproduced from ref. 42. Oipyright 1987 American Chemical Society.) 9. YANG ET AL Biological Issues in Extrapolation I In progress. Some scientific activities are also evident for the effort of Stage II and beyond (44-49). In the last two years, a great deal of progress has been made in this area Including a Workshop on "Pharmacokinetics in Risk Assessment" organized by the National Research Council which resulted in the publication of volun 8 of the Drinking Water and Health series (20). However, like any other new technique, the computer modeling of physiologically based pharmacokinetics and its application to risk assessment is going through an evolutionary phase. Much debate and controversy have bet appearing in the literature. As a case in point, EPA's adoption of physiologically based pharmacokinetics in their risk assessment pro cess and the related criticisms and debate reflect the current state of flux (48,49). Nevertheless, all these activities and debates wil inevitably help to improve and refine this approach. Eventually, th asscsieesnsmtifeinct mcoemthmoudn.ity and the public at large will have a better risk Acknowledgements Some of the work mentioned in this report was supported in part or whole by funds from the Comprehensive Environmental Response, Compensation and Liability Act trust fund by interagency agreement with the Agency for Toxic Substances and Disease Registry, U. S. Public Health Service. Many colleagues in NIEHS and EPAhelped in the studies mentioned in this paper; their effort and devotion are gratefully acknowledged. We thank Drs. E. E. McConnell (retired Julj 1988) and M. P. Dieter of NIEHS and Or. D. M. DeMarlni of EPAfor reviewing the manuscript and for their helpful suggestions. Disclaimer*123456 The research described in this article-has been reviewed by the Health Effects Research Laboratory, U. S. Environmental Protection Agency and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agenc nor does mention of trade names or commercial products constitute endorsement or recommendation for use. Literature Cited 1. Council on Scientific Affairs, American Medical Association. JAMA1988, 260, 959-66. 2. Chemical Status Report. National Toxicology Program, April 5, 1989. 3. Huff, J. E.; McConnell, E. E.; Haseman, J. K.; Boorman, G. A.; Eustis, S. L.; Schwetz, B. A.; Rao, G. N.; Jameson, C. W.; Hart L. G.; Rail, D. P. Ann. N. Y. Acad. Sci. 1988, 534, 1-30. 4. Haseman, J. K.; Huff1, J. E.; Zeiger, E.; McConnell, E. E. Environ. Health Perspect. 1987, 74, 229-235. 5. 5hlmkin, M. 6 . In Carcinogenesis Testing of Chemicals; Golberg L., Ed.; CRC Press Inc., Cleveland, OH, 1974, p. 1$. 6 . Sontag, J. M. In Origins of Human Cancer; Book CHuman Risk Assessment. Hiatt, H. H.; Watson, J. D.; Winsten, J. 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M.; Eds.; Academic Press, New York, 1978, ppi 119-141. 26. Abelson, P. H. Science 1987, 237, 473. 27. McConnell, E. E~ Science 1987, 238, 259-60. 28. Principles of Toxicological Interactions Associated with Multiple Chemical Exposures, National Research Council, National Academy Press, 1980. 29. Murphy, S. 0. lh Casarett and Ooull.'s Toxicology; The Basic Science of Poisons, 3rd Edition, Klaassen, C. 0.; Amdur, M. 0.; Doull, J.; Eds.; Macmillan Publishing Co., New York, 1986, pp. 519-581. 30. K1ingensmith, J. S.; Mehendale, H. M. Toxicol. Lett. 1982, 11, 149-154. 31. 32. Mehendale, H. M. Fundam. Hong, L. C. K.; Winsteon, AJ.ppMl..;THooxnigc,olt.. 1984, 4, 295-308. B.; Plotnick, H. Toxicol. Appl. Pharmacol. 1982, 63, 155-165. 33. Human Health and the Environment Some Research Needs, Report of the Third Task Force for Research Planning in Environmenta1 Health Science, 0. S. Department of Health and Human Services, N1HPublication No. 86-1277, 1984, pp. 147-164. 34. Yang, R. S. H.; Rauckman, E. J. Toxicology 1987, 47, 15-34. 6598 9. YANG ET A L Biological Issues in Extrapolation 1(3 35. Yang, R. S. H.; Goehl, T. J.; Brown, R, D.; Chatham, A. T.; Arneson, D. W.; Buchanan, R. C.; Harris, R. K. Fundam. Appl. Toxicol. 1989, In press. 36. Yang, R. S. H.; Goehl, T.; Jameson, C. H.; Germolec, D.; Luster, M. I.; Chapin, R. ; Morrissey, R. E.; Schwetz, B. A.; Harris, R.; Chatham, A.; Arneson, D.; Moseman, R.; Col1insworth, N.; Bigelow, D. The Toxicologist. 1989, 9, 216. 37. Chapin, R. E.; Phelps" J. L.; Schwetz, 6. A.; Yang, R. S. H. Fundam. Appl. Toxicol. 1989, In press. 38. Germolec, 0. R.; Yang, R. S. H.; Ackermann, M. F.; Rosenthal, G. J.; Boorman, G. A.; Blair, P.; Luster, M. I. FundamAppl. Toxicol. 1989, In press. 39. Simmons, J. E.; Yang, R. S. H.; Seely, J. C.; Svendsgaard, 0.; McDonald, A. The Toxicologist 1989, 9, 58. 40. Schwetz, B. A.; Yang, R. H. In Proceedings on the Symposium on Experimental and Epidemiologic Applications to Risk Assessment of Complex Mixtures, Espoo, Finland. May 14-17. 1989, In press. 41. Shelby, M. D.; Tice, R. R.; DeMarini, 0. M.; Yang, R. S. H. In Proceedings on the Symposium on Experimental and Epidemiologic Applications to Risk Assessment of Complex Mixtures, Espoo. Finland. May 14-17, 1989. In press. 42. Yang, R. S. H. In Pesticides. Minimizing the Risks; Ragsdale, N. N.; Kuhr, R. J., Eds.; ACS SymposiumSeries 336, American Chemical Society: Washington, DC, 1987, pp. 20-36. 43. Yang, R. S. H. CHEMTECH1987, 17, 698-703. 44. Research to Improve Health Risk Assessments (RIHRA) Program. Environmental Protection Agency, June 1088. ' 45. Connally, R. B.; Reitz, R. H.; Clewell, III, H. J.; Andersen, M. E. Toxicol. Lett. 1988, 43, 189-200. 46. Connally, R. 6.; Reitz, R. H.; Clewell, III, H. J.; Andersen, M. E. Comments Toxicol. 1988, 2, 305-19. 47. Selected Issues in Risk Assessment. Drinking Water and Health Vol. 9, National Research Council, National Academy of Sciences, 1988. 48. Perera, F. Science 1988, 239, 1227. 49. Moore, J. A. Science 1988, 240, 1125. R eceived June 28,1989 Reprinted from ACS Symposium Series No. 414 Carcinogenicity and Pesticides: Principles, Issues, and Relationships Nancy N. Ragsdale and Robert E. Menzer, Editors Copyright * 1989 by the American Chemical Society Reprinted by permission of the copyright owner A: i: f:- .JL KEISTER y. DOW - Attachment to Memo of 1/28/91 (Exhibit List of Documents) CTj 05 LO CO ft ATTACHMENT TO MEMORANDUM OF NOVEMBER 28, 1991 (KEISTER V. DOW) EXHIBIT LIST 1. 3/20/47: United States Patent 2,509,245 ''PREPARATION OF 2.4.5TRICHLOROPHENQL" by the Givaudan Corporation of New Jersey. Comment: This describes a process where 1,2,4,5-tetrachlorobenzene is subjected to alkaline hydrolysis in the presence of ethylene - or propylene glycol. This is accomplished by stirring in the ingredients at elevated temperatures between 160 C and 200 C. The reaction mixture is cooled and then acidified with hydrochloric acid. NOTE: It is this heating above 160 C that produces the deadly dioxin 2,3,7,8-TCDD. The benzenes are the key to all this. 2. 1/24/55: United States Patent 2,799,713 "METHOD OF MAKING TRICHLOROPHENOLS FROM TETRACHLOROBENZENES" by The Dow Chemical Company od Midland, Michigan. Comment: Dow changes the process in exhibit #1 where they can do the same thing faster and less expensively on a mass production scale by further heating the above mixture to between 225 C and 300 C under a pressure of 400 to 1500 P S I . The result is more dioxin contaminant since any temperature above 160 C will produce it. These higher temperatures and pressures later led to several chemical plant explosions around the world, thus releasing the deadly dioxin into the atmosphere and exposing workers in the plant with high concentrations of dioxin. But, Dow made more money faster with this process! 3. 8/2/62: Hercules Powder Company Jacksonville, Arkansas Operations Booklet. This booklet gives information on the chemistry, equipment, method of manufacture, etc. for 2,4-D and 2.4.5- T. Note: Hercules later made these herbicides for Dow Chemical under contract and distributed them under the Dow Label, including Agent Orange. This particular plant was especially contaminated with the TCDD dioxin impurity. 4. 1962: "Toxicology of Herbicides" by Mikkelsen et al of the Dept. of Pharmacology and Toxicology, Royal Veterinary and Agricultural College of Copenhagen, Denmark. Comment: This report reviews the acute effects of 2,4-D and 2.4.5- T mostly in animals and shows CNS disorders. It states "Many of the toxicological data underlying assessments of the risk involved by using them in practice originate from confidential, non-published reports placed at the disposal of the authorities concerned. Such data has not been included in the present survey." 5. 5/2/63: Confidential inter-office correspondence between Diamond Shamrock employees on Chloracne being a potential hazard to anyone working with chlorophenoxy herbicides, especially 2.4.5- T . They point out it is an inherent danger with all companies 2,4,5-T products.lt states " Dow has had this problem on and off in their plants in past years." A handwritten note at the bottom says "This problem is more likely to occur when using 2.4.5- T than when using 2,4-D. In fact, some people cannot work with 2 .4.5-T." No is: Other literature shows that a person with chloracne is a proven exposure to the dioxin 2,3,7,8-TCDD. Dow Chemical knew 2.4.5- T had the TCDD dioxin since at least 1957 based on correspondence they received from their German chemical company friends as BASF. The literature first identified chloracne in 1897! All these chemical companies know that a person with chloracne is a walking advertisement of dioxin exposure. 6 . 2/24/65: File memo from R. Kelly, M.D. on his talk (phone?) with V.K. Rowe of Dow stating that Dow has 20 cases of Chloracne in the plant. Dow found a contamination level of 3 - 10 ppm in a sample of 2,4,5-T sent to them by Dr. Kelly. Rowe says "Dow has been receiving complaints from their customers . . . on chloracne problems" Dow says "The PMS is looking into this problem and has contacted some of Dow's customers concerning the occurrence of chloracne." Rowe wants to have a "crash meeting with all the producers to try to reach some specification level in order to eliminate this particular contaminant before the PMS got into the act. " 7. 3/24/65: *** Dow Chemical Company confidential internal letter from L.Q. Silverstein to V.K. Rowe of Dow's Biochemical Research Laboratory on "Report of the Chloracne problem meeting on 3/24/65". They talk of 60 to 70 cases of individuals at Dow with chloracne and the emphasis of clinical studies on liver function tests in these individuals. Hooker Chemical related chronic exposures that are there 30 years after exposure! They showed slides of TCDD tests run on the ears of rabbits and discussed the pathology in detail at the meeting. They said if exposure occurs for very long, washing does little good. The group said no level of TCDD is safe, but they are trying to hold it to less than 1 ppm in their products. They admit the significant factor is the dose, the number of exposures and the days on exposure to the subjects. The tested level of response ranges from: none to extremely severe! It then states " the group then proceeded to the Toxicology Laboratory to view some of the test animals. They were shown responses of varying intensity and these were described. This demonstration appeared to have considerable i m p a c t ." 7. - 8 . 6/24/65: ** Dow confidential letter from V.K. Rowe to Ross Mulholland of Dow Canada on "2,4,5-Trichlorophenol, the T Acids, and Associated Acneqens." Rowe says "as you well know, we had a serious situation in our operating plants because of contamination of 2 ,4,5-trichlorophenol with impurities, the most active of which is 2,3,7,8-tetrachloro-dibenzodioxin. This material is exceptionally toxic: it has a tremendous potential for producing chloracne and systemic in-jury. If it is present in the trichlorophenol. it will be carried through into the T acid and into the esters and hence into formulations which are to be sold to the public. One of the things which we want to avoid is the occurrence of any acne in consumers. T am particularly concerned here with persons who are using the material on a daily, repeated basis such as custom operators mav use it. If this should occur, the whole 2.4.5-T industry will be hard hit and I would expect restrictive legislation, either baring the material or putting very rigid controls upon it." (Note; Systemic means to affect the entire organism or bodily system!) The letter ends with a P.S that says "Under no circumstances may this letter be reproduced, shown, or sent to anyone outside of Dow." 9. 11/18/65: Hercules internal memo from their medical department to their synthetics department of "The investigations we contemplate on chloracne possibly associated with 2,4,5-T esters." They discuss various ways to test their products for dioxin (TCDD) contaminants before they reach the customer. 10. 6/13/66: Hercules internal memo from their analytical division to their medical department on "DIOXIN FORTIFIED SAMPLES FOR BIOASSAY TESTS." Most are "spiked" samples of added dioxin from 2 to 20 ppm. One sample is a plant grade 2,4,5-T with known dioxin of 3 ppm contamination. It states they are storing their contaminated batches used in tests at the rate of 2-3 drums per day. 11. 2/15/67: Dow letter from V.K. Rowe to M.S. Buckley, Technical Director of Thompson Chemical Company on "How to deal with their chloracne problem that resulted from a chemical accident during production." Rowe refers him to an article called "Clinical Observations About The Origin of Chloracne" by W. Braun published in Germany in 1959. Rowe then writes an internal memo to Dixon in the Dow Bioproducts Department on this conversation (See attached memo of 2/15/67) where he refers to a phone conversation he had with Mr. Dixon on 2/7/67 and says "I told him that under certain circumstances, which I did not describe, the caustic insoluble oils could contain considerable amounts of a very highly toxic substance which we had identified as 2 ,3,7,8tetrachlorodibenzodioxin. I indicated to him that this material was not only extremely toxic systemically, but it was also an extremely potent chloracnogen." Rowe later states "Dr. Holder (of Dow) indicated to him (Mr. Dixon) that he must take extreme precautions, including the use of rubber suits and gloves and respirators." (i.e. to clean up their chemical spill at the Thompson plant) NOTE: No one at Dow ever told a user of their - 3- product to do this! They certainly never told a user their product was contaminated with a known deadly dioxin called 2.3.7.8- TCDD! 12. 6/30/67: Hercules confidential memo to their Jacksonville plant saying their were 5 cases of chloracne in Columbia from contaminated 2,4,5-T that entered the sales channels in 1963 and 1964. "No prior cases of chloracne outside of manufacturing operations have come to our attention . . be on the alert for abnormal operating conditions" 13. 9/26/67: Dow letter to the USAF Directorate of Air Force Aerospace Fuels from A.P. Beutel, Dow's Director of Government Affairs on "Request for Dow's Bid on the Design, Conversion, and Operation of an 8.000,000 Gallon per Year "Orange" Plant at the Government Owned Chemical Plant at Weldon Spring. Missouri." Dow asks to be withdrawn from this process because they consider it too high of a risk for them due to the location of the Air Force Plant near the University of Missouri Experimental Farm and the August Busch Reserve. Dow says any accidental release of these products into that particular environment is a risk Dow will not take. "The chloracne problem is one of human health which Dow has had to combat in the design of its own plants at its Midland operations." Dow says they are already engaged in the production of 2,000,000 gallons per year of "Orange" at their own plant. 14. 10/16/68: From Industrial Hygienist Emil Christofano to V.K. Rowe of Dow on "Hercules attempts to develop a bioassay technique to simplify detection of dioxin in herbicide formulations." He states they have not been successful on the tests that measure liver function changes after feeding their rabbits with 2,4,5-T. 15. Late 1960's: Abstract on "Influence of Dioxin on Liver Functions in the Rabbit" by M.L. Keplinger et al of Industrial Bio-Test Laboratories in Northbrook, Illinois and Hercules, Inc. which simply states that some rabbits show liver damage when fed 2.3.7.8- TCDD and some don't. Hence this test is not a positive indicator of proving contamination levels. 16. 3/17/70: Dow Press Release on "DOW RESEARCH ON 2.4.5-T BLAMES BIRTH DEFECTS ON IMPURITY." Here Dow tries to convince the public that it is a contaminant in 2,4,5-T and not 2,4,5-T itself that caused birth abnormalities in a recent test animal study by Bionetics Laboratories, under contract to the National Cancer Institute. Dow says they analyzed the Bionetics sample used and found a contamination of 27 ppm dioxin TCDD. Dow says they have kept their contamination to 1 ppm of TCDD since 1965 and hence their product is safe to users. V.K. Rowe of Dow says we simply proved again what we already knew. 2,4,5-T is a material of low toxicity while the dioxin is highly toxic." Comment: Dow has already told other chemical manufactures that any level of TCDD dioxin is too much, but a contamination of 660 : 1 ppm is what they try to maintain at Dow. Only a few companies in the world could even test for a contamination below 1 ppm at this time. It was very expensive to test even one sample and Dow knows that few people outside of the major chemical companies can afford to do this, even if they have the equipment. It has later been proven that 1 ppm is an acute dose level. and not even Dow admits testing for long term chronic exposures to users. Private studies have shown that even a few parts per billion on a chronic basis are deadly to certain people. What Dow does in this press release is what they have continued to do until this day - namely claim that 2,4,5-T is safe and focus on levels above 1 ppm on TCDD which are readily detectable at many labs today. The point is, no one's 2,4,5-T can be produced without the TCDD contaminant, and long term chronic exposures will cause serious health effects, including many forms of cancer! Don't forget that Hercules and Vertac made these herbicides under the Dow label for years and had a hard time keeping their TCDD contamination at 1 ppm. 17. 3/19/70: Hercules internal memo from J. J. Ford, Analytical Division to Dr. M. A. Taves, Synthetics Research Division on "ANALYSIS OF 2,4,5-T ACID FOR "DIOXIN" CONTENT." Here they say samples of their 1965 production yielded "dioxin" values of 1.3 to 3.5 ppm. They claim a dioxin level of less that 0.2 ppm from their 1967 to 1970 production. 18. 3/24/70: ** National Agricultural Chemicals Association letter from K. K. Krausche, Director of Technical Services to J.O. King of Diamond Shamrock Chemical. ""Possible Industry Public Relations Value in Publicizing The Full Dioxin Story." They say that the consensus of the member companies most closely involved with this problem is that they will handle it on their own, but the next time the " Phenoxy Herbicide Task Force" gets together, he will bring it up again. Comment: They handled it like Dow did in their press release and later advertisements - namely that 2,4,5-T is perfectly safe, it is only the dioxin that will kill you! 19. 4/27/70: Article entitled "GOVERNMENT STEPS UP PRESSURE ON PESTICIDES". C&EN publication. The government suspended and cancelled consumer and food crop uses of 2,4,5-T and halted its use in Vietnam. The order specifically suspended use of liquid formulations of 2,4,5-T around the home, near lakes and ponds, and on ditch banks and cancelled use of non-liquid formulations around the home and on apples, blueberries, barley, corn, oats, rye, rice and sugar cane. Not restricted were uses for weed and brush control on range, pasture, forest, rights-of-way, and nonagricultural land. Use of a 2,4-D and picloram were allowed to continue (agent white). This action all came about because of a dioxin contamination of between 16 and 27 ppm in a Diamond Shamrock sample of 2,4,5-T taken in 1965 and found to cause birth defects (teratogenic) in rats by Bionetics Research Laboratories. A joint Agriculture- 5- - 6604 Interior-HEW announcement said that "nearly pure 2,4,5-T was reported to cause birth defects when injected at high doses into . . . pregnant mice, but not in rats. No data on humans are available." Further evidence was presented by the FDA that chick embryo studies and preliminary hamster data indicate that current production 2,4,5-T with 0.5 ppm of TCDD was teratogenic and embryotoxic. 20. 1972: J. Aar. Food Chem. ,Vol 20, No 2., 1972 by Woolson, E. et al, "Survey of Polychlorodibenzo-p-dioxin Content in Selected Pesticides." The article explains that dioxin TCDD occurs when the reaction temperature for making 2,4,5-Trichlorophenol from tetrachlorobenze exceeds 160 C. If too much heat is applied, these various dioxins will form, including 2,3,7,8-TCDD, It is important to note that the other dioxins formed can be just as deadly as TCDD, it just takes more heat to produce them and their impurity levels can be combined to be just as deadly as the TCDD. Of 129 samples of the 17 different pesticides derived from chlorophenols that were examined for PC D D , 9% contained seriously toxic levels of this dioxin (PCDD). Comment: There is just as much hazard in the other forms of dioxins as there is in TCDD, it just takes a higher manufacturing temperature and more of them to kill you! Remember the Dow patent to produce their 2,4,5-T at temperatures between 225 C and 300 C under pressures of 400 to 1500 PSI because it was faster and cheaper that the earlier patent by their competitor! This makes for major dioxin contamination, but it doesn't show up as readily in acute doses, which is the only regulated area that is tested. It is the long term chronic exposures that kill most workers. 21. 11/72: Chemical manufacturing process of 2,4-D and 2,4,5-T in their "technical acid" and "technical Butyl Ester" forms as produced at the Jacksonville, Arkansas plant by Transvaal, Inc. (Contained in the Vertac Operations Manual). 22. 7/8/74: ** Confidential Dow memos where D.D. McCallister tells Marguerite Leng that Dow must not send to the EPA certain of Dow's residue tolerances on TCDD levels, and she tells him that "it seems to me that our not informing the government about TCDD in 2,4,5-T is what got us in all this trouble in the first place. Withholding information at this time (which they know we have) can only make them think we are still trying to hide something from them." 23. Jun-Nov 1976: Chemical manufacturing process of 2,4,5-T from the Vertac Operations Manual on its various "technical ester" forms. 24. 10/15/79: Presentation by Marion Moses, M.D. of the Mt. Sinai School of Medicine Environmental Sciences Laboratory at CUNY on "2,4,5-T, Agent Orange and Tetrachlorodibenzo-p-dioxin ? Evolution of the Problem." This presentation was made by slides which give a well rounded picture on this whole problem to include contamination levels of TCDD in Vietnam of between 1 and 50 ppm of TCDD. It shows all the chemical formulas and health effects of these exposures. 25. 12/15/79: Research Paper on "DETERMINATION OF TCDD RESIDUES IN HUMAN MILK. BEEF LIVER. FISH, WATER, AND SEDIMENT." This study confirms that it is the high temperature, high pressure conditions of 2,4,5-T manufacturer that produce the condensation which causes a reaction that results in the formation of TCDD. It says that for chemical companies to even discover the presence of TCDD, the detection technique used must be ultra sensitive and also highly specific because of the required low ppt (parts per trillion) detection limits. EPA laboratories have had to be able to detect TCDD in the 0.02 - 100 ppt concentration to isolate and confirm the presence of TCDD in our human milk, beef liver, fish, water, and sediment extracts. Under a section entitled SAFETY PRECAUTIONS. it is stated "TCDD is toxic and can pose grave health hazards if used improperly. TECHNIQUES FOR HANDLING RADIOACTIVE AND INFECTIOUS MATERIALS ARE APPLICABLE TO TCDD. Only qualified individuals who are trained in laboratory procedures and familiar with the dangers of TCDD should handle this substance. Females of childbearing age should not work with this material. A good laboratory practice involves routine physical examinations and blood checks of employees working with TCDD. Also, facial photographs using oblique photoflood lighting should be periodically taken to detect chloracne. which is an early sign of overexposure." 26. April 1980: Dow Chemical Publication Booklet on "PUBLIC CONCERNS ABOUT 2.4,5-T". by Wendell R. Mullison, Ph.D. He is a retired Dow employee of 32 years experience in agricultural research with a degree in botany. With these "qualifications", he has been asked by Dow to tell the public that 2,4,5-T is safe. Dr. Mullison states that "Human cancer generally develops over a latency period of many years and usually is a disease of old a g e !" He discredits testimony of Dr. Ton That Tung of Vietnam on the horrors observed there as a result of spraying agent orange and says the Vietnamese have poisonous molds in their jungles which cause their problems of liver cancer. He further debunks all other claims regarding actual human experience and relies instead on "nine long-term carcinogenic studies with rats and mice where the authors conclude that 2.4.5-T was not a carcinogen." This kind of twisted logic reveals the whole thrust of Dow's defense on their product. They misdirect everyone by boldly claiming that 2,4,5-T is safe and fail to add that it is the deadly 2,3.7.8-TCDD is all 2.4.5-T herbicides which is a carcinogen! Since few labs in the world can detect the presence of TCDD at levels below 1 ppm, Dow further states that their 2,4,5-T has less that 1 ppm dioxin and hence must surely be safe! Then Dow privately tells their fellow manufacturers that any level of TCDD is deadly and you have to wear rubber suits, rubber gloves and respirators to even be around it. The final logic presented to the public is that "SINCE THIS CHEMICAL HAS BEEN IN PRODUCTION AND USE FOR OVER 30 YEARS. THERE HAS BEEN AMPLE TIME 7- - 6606 FOR CANCER TO APPEAR IF IT WERE A PROBLEM. THUS. THE LIMITED HUMAN DATA AVAILABLE ARE IN AGREEMENT WITH THE EXTENSIVE ANIMAL DATA AS TO THE NON-CARCINOGENIC EFFECTS OF 2.4.5-T." Maybe people like Greenhill, Davis, Moyer, Rice and all the cancer cases around Jacksonville, Arkansas would like to dispute this claim by Dow with their double-speak about 2,4,5-T being so safe, while failing to mention the TCDD that all these herbicides contain. Dow later contradicts themselves and admits that chloracne is the first visible symptom of human over-exposure to TCDD! In a forum where punitive damages are awarded, this one booklet by Dow could be used as a basis for proving criminal liability on the public at large. If you want to see how Dow will currently defend its herbicide litigation, this booklet is their blueprint. They conclude their booklet by stating "2,4,5-T is a safe, efficient, and selective herbicide to control weeds and brush and its use has not caused cancer, birth defects, or miscarriages. 2,4,5-T with its trace contaminant TCDD can be and has been used safely and effectively without harm to people, animals, or the environment." 27. Jan-Feb 1981: Pazaderova-Ve jlupkova', Jana M.D. et a l , "The D e v e l o p m e n t and P r o g nosis of Chronic Intoxication by Tetrachlordibenzo-p-dioxin in Men", Archives of Environmental Health. Vol. 36, No.l, pp. 5-11. The authors were on the Faculty of General Medicine at Charles University in Prague, Czechoslovakia. This report states that during 1965 to 1968, 80 workers who had been engaged in the plant production of 2,4,5-T became ill due to exposure to 2,3,7,8-TCDD. These doctors observed 55 of these 80 patients on a long-term basis over 10 years. It is an excellent study and shows that these patients ended up with a wide variety of health affects including almost all patients having had chloracne. The others varied from c o m b i n a t i o n s of medical lesions, neurological lesions, psychiatric changes, skin lesions, and 1/3 had liver lesions. Two patients died of bronchogenic lung carcinoma. This study contradicts almost all claims made by Dow on how safe 2,4,5-T is to humans. 28. 5/81: Vertac Operations Manual on "PROCEDURE FOR DETERMINATION OF MONO-,DI-.TRI-. AND TETRACHLORO DIBENZO-PDIOXINS IN 2.4.-D ESTERS." NOTE: THIS IS TCDD IN THE HERBICIDE 2,4-D! All manufacturers claim it cannot be present in 2,4-D because the heating mixtures of production do not exceed 160 C. Comment: These tests were done by the Mass Spectrometry Laboratory in the Food Production and Inspection Branch at Agriculture Canada. It finds significant quantities of several different dioxins in 2,4-D including 2,3.7,8-TCDD! It took a very sophisticated piece of test equipment in a governmental lab in Canada to find this, but it resulted in the banning of 2,4-D in Canada. 29. 1/82: EPA Handbook on "Recognition and Management of Pesticide Poisonings." This is a good overall reference book by - S'- Donald P. Morgan, M.D., Ph.D. at the University of Iowa Medical School under contract with the EPA. It is a general listing of all pesticide products including the herbicides 2,4-D and 2,4,5-T (see Ch. 6) that lists all manufactured brand and trade names of these products and gives their chemical formulas and a brief reference on their toxicity. While not an in-depth study on herbicides, it does serve as a good overall resource. 30. 3/83: Article by Dunagin, Wm. G. , M.D. on "Dioxin Effects on Human Health", Vol. 80, No. 3, pp. 127-131 at Columbia University. This paper concludes that the evidence on long-term health effects is conflicting and seems to depend on the dose received. It admits to some people dying of cancer, but states others do not. It says "the thymus is particularly susceptible, and the problem may be decreased immune surveillance." Note: Based on several hundred studies I have looked at, the reason why some people get cancer and others don't is because the dioxin is really attacking the immune system of the body and creating different reactions with different degrees of exposure. These studies say that the dioxin is soluble in the fat cells of the body through skin absorption and breaks down the immune system so as to allow all kinds of disease to enter the body undefended by the natural immune process. 31. Summer of 1983: "The Agent Orange Case: An Overview." This is mostly for information on how the whole case was started and developed by the various lawyers. It is good background on this subject. The author is obviously one of the lead attorneys, by no specific name is given. 32. 7/6/83: *** News article from "The Arkansas Democrat", an Associated Press release dateline Uniondale, N.Y. entitled "FIRMS KNEW DIOXIN EFFECT, MEMOS SHOW." This article summarizes the key memos which show the collusion between these chemical companies, especially Dow in attempting to cover-up the known problems they had with their contaminated products. A 1957 document to Dow from a German chemical manufacturer (BASF) refers to a 1955 accident at their plant where there were "severe cases of chloracne, including some suspected facilities." That document includes among the entries for effects in humans: "Usually not disabling, but may be fatal. "liver injury" and "long-term - two to five years to recover." The news article also states "According to the federal Centers for Disease Control at Atlanta, a maximum safe exposure to humans is just one part per billion." NOTE: This document is a continuous quote of all the damaging memos found by plaintiff's attorneys, many I have copies of, but not all of them. Read in its entirety for the story it tells, this is a major smoking- gun document. 33. 8/3/83: A Business Newsletter Article in Chemical Week publication entitled "VERTAC BEEFS UP IN HERBICIDES." This states that "Last week, the privately-held firm acquired the U^S. cl ~ rights to Dow Chemical's 2,4-D trademarks." It further states "Vertac gets the registration rights, inventories, formulation recipes and marketing data for the phenoxy herbicides." Comment: This was in the time-frame when the EPA had formally banned 2,4,5-T for domestic uses and several countries either had banned or were considering banning both 2,4,5-T and 2.4- D. Reading between the lines here, it appears Dow is doing this partly to escape future legal liability for their 2,4-D herbicide. The Greenhill v. Dow litigation had just gone all the way to the U.S. Supreme Court and they upheld the verdict which said that 2,4-D caused cancer in Greenhill. 34. 8/10/83: Article in Chemical Week entitled "DOW SELLS ITS 2.4- D TRADEMARKS." This article says that while Dow has sold its trademark to Vertac, they will still supply technical 2,4-D to herbicide formulators, including Vertac, and that Dow is not reducing its capacity to produce 2,4-D. They have simply decided not to take it all the way to the distributor. The only other remaining U.S. maker of 2,4-D is SDS-BioTech, a 50-50 joint venture of Diamond Shamrock and Japan's Showa Denko that has taken over Diamond's 2,4-D production and marketing. 35. 1/21/84: News article entitled "International Study Is Urged of Agent Orange in Vietnam" by Phillip M. Boffey, Special to The New York Times Congress is calling for this study to determine whether Agent Orange had caused harm to the Vietnamese who were exposed to it. Congressman Don Edwards just returned from Vietnam and said "We can't resolve the problem here, . . It just doesn't make sense not to go where the living laboratory is." While there he was told of a high rate of cancer of the uterus and of abnormal births among these women. Note: Attached to this news article is a Fall 1982 publication entitled "BULLETIN: U.S. COMMITTEE FOR SCIENTIFIC COOPERATION WITH VIETNAM". Vol. 1, No. 2. See page 5 on "In Memoria: Professor Ton That Tung (1912-1982)" and the article written by him on page 6 entitled "Vietnam, Seen From America", on his 1979 visit to the United States. Page 8 has an article entitled "The Question of Dioxin Levels in Vietnam, Then and Now. " 36. 2/84: EPA Study entitled "Ambient Water Quality Criteria for 2,3,7,8-Tetrachloro-dibenzo-p-dioxin." This document was prepared under contract at several research locations in the U.S. This study shows that TCDD is only one of many trace contaminants found in chlorinated industrial products, especially the h e r b i c i d e 2,4,5-T. It names the others i ncluding the polychlorinated dibenzofurans (PCDF's) found in 2,4-D. 37. 2/27/84: Expanded summaries of key Plaintiff's Government Causation Witnesses in the Agent Orange litigation on their: Qualifications; Subject Matter; Scientific Principles; Substance of Opinions; and Grounds for Opinions. These experts are: A. Dr. Deborah A. Barsotti, a toxicologist expert. 6609 -to- B. Dr. Alastair W.M. Hay, a lecturer on Chemical Pathology. C. Dr. Herbert Kaye, an expert psychologist. D. Dr. Alan Scott Levin expert on the immune system. E. Dr. Marvin A. Schneiderman an expert statistician and epidemiologist, particularly in the area of the determination of cancer causation. Comment: All these experts have made a special study of the health effects of 2,4,5-T in humans. This gives a good summary on how to present a logical presentation of the proof of causation from these herbicide's exposure. 38. 3/16/84: Letter from attorney Margie T. Searcy to attorney Tom Henderson with copies to lead Agent Orange counsel. She presents suggested posters to show scientific causation for the Agent Orange case. These posters depict the: NERVOUS SYSTEM; NERVE CELL; HOW DIOXIN IS FORMED;HOW DIOXIN ATTACKS THE LIVER AND CREATES HARMFUL ENZYMES; THE MAJOR STEPS IN MANUFACTURING AGENT ORANGE; WAYS OF EXPOSURE; and HOW DIOXIN TRAVELED IN THE ENVIRONMENT. Comment: This presentation, or something like it would be very good for large trial exhibits to a jury. 39. Spring 1984: ** PLAINTIFF'S MEMORANDUM ON CAUSATION, In re: "Agent Orange" Product Liability Litigation, MDL #381, U.S. Dist.Court Eastern District of New York. This document gives the whole line of Medical Causation and concludes on how it caused an array of adverse health effects in the nine representative Plaintiffs, including cancer. 40. Spring 1984: ** Key Plaintiff's expert witness Dr. Lennart Hardell summary of his QUALIFICATIONS; SUBJECT MATTER; SCIENTIFIC PRINCIPLES; SUBSTANCE OF OPINIONS; and GROUNDS FOR EACH OPINION. Comment: This testimony is primarily based on Dr. Hardell's epidemiological studies he conducted in Sweden plus personal cancer patients he has seen in his own clinical practice regarding herbicide exposure. Since this time in 1984, he has gone on to become a world authority in this field and Dow Chemical in particular has done everything possible to find ways to discredit his studies, including manufacturing "rigged" studies on their own. 41. Spring 1984: ** Key Plaintiff's expert witness Dr, John A. Garofalo summary of his QUALIFICATIONS; SUBJECT MATTER; SCIENTIFIC PRINCIPLES; SUBSTANCE OF OPINIONS; and GROUNDS FOR EACH OPINION. Comment: This testimony pertains to the field of immunology and the effect dioxin has on the human immune system. 42. 5/84: Proceedings from the "First National Aaent Orange Medical Symposium", hosted by the Illinois Agent Orange Study 6610 -ti- Commission with cover letter from the Chairman John T. O'Connell. The purpose of the symposium was to allow physicians and r e searchers familiar with herbicide exposure and its physiological ramifications to have a forum which they could speak. Dr. Bertram Carnow, a professor and then current director of Great Lakes Center for Occupational Safety and Health of the University of Illinois School of Medicine was a key speaker. He pointed out that 2,3,7,8-TCDD is the most potent toxic agent ever produced by man. It has shown that it will kill a young guinea pig at a concentration of approximately five parts per trillion. This symposium was filled with experts telling h*\ and why this dioxin was so deadly to humans and is excellent reading for preparing a trial in this field of law. 42a. Jan-Feb 1984: Article from American Health on "Environmental Toxin: The Dioxin Syndrome" by D r s . Carnow and Conibear. This article is very strong on the health effects of TCDD dioxin and says "Once the poison is in the system, there's no way known to counteract it." (Note: a better copy should be ordered for a trial exhibit by calling 212-242-2460 who is the publisher of this magazine) 43. 1984: E n c y c l o p e d i a B r i t a n n i c a , "The W orl d of Medicine Environmental Health - What is Dioxin?" written by Dr. Bertram W. Carnow, M.D. The publication says that "animal studies have shown dioxin's potency as a cancer promoter and its ability to suppress the immune system." C o m m e n t : This is an excellent overview and easy to understand summary in six pages of what dioxin is all about. 44. 12/12/85: Letter from Dr. Bertram W. Carnow, M.D. to attorney Phillip McMath on the results and findings of his examination of the twelve clients that were done in October and November of 1985. All 12 had abnormalities to their immune system functions. This was due to 2,3,7,8-TCDD exposure detected in the patients bodies and the conclusions were that "they are all suffering from chronic chemical poisoning involving multiple organs and organ systems with damage to them of a permanent and irreversible n a t u r e ." 45. 7/29/86: Memo from attorney Alison Pettiette re: "LIABILITY ISSUES CONCERNING THE VERTAC CHEMICAL PLANT IN JACKSONVILLE. ARKANSAS" The memo refers to Dow's liability in Keister v. Dow and explains the horrors found at the Vertac Plant in Jacksonville. It is an overview of Dow's attempt to hide or cover-up any evidence of their involvement. 46. 9/11/87: Fifth Circuit Opinion of Viterbro v. The Dow Chemical Co., at pp. 6357-6361. Here Dow won on appeal because plaintiff's expert admitted that the symptoms of Viterbro could have numerous causes and simply picked the cause that was most advantageous to the plaintiff Viterbro's claim. The doctor failed to specifically link the herbicide used to the plaintiff's l Z- - 6611 medical condition and admitted on cross examination that the symptoms could have a number of causes. Comment; This case shows how not to try a toxic tort exposure case in the courtroom! 47. October 1987: Curriculum Vitae of Dr. Marvin S. Legator who has been the key expert witness in several successful cases on herbicides. He is Professor and Director of the Division of Environmental Toxicology at the University of Texas Medical Branch in Galveston, Texas. He was the expert in Davis v. Dow; Keister v. Dow; and Newman v. AT&T. All of these cases settled just prior to trial. 48. March 1988: Lead news articles from In These Times telling the entire story of the dioxin exposures in Jacksonville, Arkansas and labeled "The Site of America's Worst Toxic Contamination." A. March 9-15, 1988 edition: "WELCOME TO DIOXINVILLE, ARKANSAS" part one of three p a r t s . B. March 16-22, 1988 edition: "DIOXINVILLE.ARKANSAS: PASSING THE BUCK AND BURNING THE EVIDENCE" (part two of three parts). C. March 23-29, 1988 edition: "DIOXINVILLE III: THE TOXIC TRAIL." (Part three of three parts). 49. 1989: American Chemical Society Symposium Series No. 144, "Biological Issues in Extrapolation". Chapter 9 by Yang, Raymond S. H . , et al National Institute of Environmental Health Sciences, Research Triangle Park, N.C. This report debates the issue of: "Given the fact that there is no perfect system, how good are rats and mice as models for humans in toxicology?" They conclude that "The field of carcinogenic risk assessment is in its infancy. The primitiveness of methodology echoes the lack of a clear theory of carcinogenesis." They claim that "it is impossible to conduct chronic toxicity/carcinogenicity studies in humans.... While there is no perfect surrogate for humans in the evaluation of carcinogenic potential and other toxicities of chemicals and other agents, rodents still represent the best m o d e l s ." Comment: This is the kind of industry supported logic that one faces when trying to show that any given person got cancer from a particular chemical or in this case 2,4-D and 2,4,5-T. Until someone admits the causes of cancer and defines what it is, the game will go on! - S3 ~ 6612