Document 85qdqNXoDVMR90kY9gdMwNz45

I ** -ti!. ( \ 111,:1 MIDLAND February 19, 196? 2159 CONFIDENTIAL - SUBJECTTO INJUNCTION' V ' E.D. Ml. 4-4-78; DOW/EPA AGREEMENT9-79 O O 0 01 00 CO WDIltni G. Dlaon iildpraducta Department LF<. cei V. U CorUn, DPC D, . Pletcher, Bi*C J. H. Cowell, BPC V. 2, M covf BPC 1'/. C. holder, M.D., 607 z Ni Vi tvs 00 9 TH O iviPBr.ii C !. > .a C A i. C :-M P A N Y , ST. L j UIS, M IS S O U R I C t 1 tbruary , 196?, V . J. McCoy inform ed me that a Mr. m , 8 , Buckley of T tom piso ( b em ltal bad called L'ow indicating that they had had an accident aeaoctatad 1th Ct manufacture of trU h lorophonal* and that they had aom s men U h hat thay thought was chloracne. Thay \adared If wo could advise them lo regard to m edical practice. I contacted Dr. holder, who then called Mr. CucfcJcy and dlecuaaed with him m odicnl a ep eett of the problem , ll ie toy understanding from i)r. holder that Mr, Buckley tteo started talking about the chem istry of Ikle m ats r ia l, end Lr. holder ug*atad that he contact me in regard to anything along Shia lin e. ;o or about February f Mr. Buchley callad oa to cao b l vo h 53 bcot chloracne causad by cotdoe itb otatertalo aeeociatod wUb ^31 ccd. GSD tha pianofctore cf tflcblercpheool from tetrachlotobaaseoo, 1 GL3 " toid bim that nadar certsia circomataorac, whUh I did oot describo, $& s 11-"'J. r^aj c r,,, tha caoctic iAcdaUa olla could c talo cacaldarabio amoanta o a very idghly todc sohsaace whlcb vo Cual Khctlflif fio 2 9*V#8 tetrachlarodibeaccdloalc, KUdlcated to blm that thlo malaria! as . ' C`il. 1JL cCaJdZa e a |a a n no3 oajy es&reissiy tala oystfimlcaUy, bol o a i tico fio atrccoely potas! cbloraccogofi, fa Indicaled that thay fcad becn diatUUcf oaaa olio or taro coafaiaiog antalas boa tha oparctloa gol c3 o costrol, and cha e a la r i libar pillad or apiaesod o& a ta i encoclar. Ha the%g3tt that Uto to ta s fiad vaporo cS tho misles k d csasad thslr fU I c d l;. I told Uq t d!4 no) thlfik Ua a c u a i cacsad by Uto anislas, bel atibar by ochar matarais ymsaat la tha aaiaolae. V Vf \ \ i A VV >? * } V J i i ir.. r i. 742 - <rT- t h s D O iv January 19, 1962. ccy -too M A R K E T 3TnitnT CA M D RN a. N 1W JB R R SY 2182 MNt) 732 80 -r. Jonn Dan Co, Sordoni Construction Company Kingston, Penna. bcc : J ,;i#W:ilIbor5'-AC^-7 w.j.iicCcy-ACij-/.?.!! P.ri.lUtry-.ACS-^B V.K.ncrrj-B.i . 1 rol Dear Mr. Denta; We have discussed vour employee's claim of Tracheitis due to chemical inhalation, with our Biochemical Re* searcn Department. In our opinion, it is nighly un* likely that a man spraying a Kuron-water mixture would develop tracheitis. On the other hand, one can never say that such an irritation could not occur if an in dividual had an excessive exposure to heavy mists. It would be our opinion, however, that even if this happened, the throat irritation would clear up very promptly upon cessation of exposure and there would be no further con sequences. It is also our opinion tut if this man is a heavy smoker, particularly a cigarette smoker, that this could well-account for his chronic ccugh. We believe there is adequate medical history to show that:smoking can result in a chronic cough. ' We would be pleased to be kept Informed of the develop ments of this casew^C: Please contact us if we csn be of any further.s e r v i c e ^ ; ; ; - ''r '"V : Sincerely youri ----- -- '4 \ D. L. Agrlcul ;Industrial y - ,;yy .:'YV' -T, y V.yy Vf.V i'' , ; .'U-v mm mmm m% ' mf g 'V.v=y - r- n m & m m m t m - M m mmmm-m :;:*." > ' !" " ' -i ';1i-.'- ' v y y ; n :y v ,', : >: k ';:v . ' '1:...iv..'" '' 7 ?. 3d - W M. H . T M U N , m i i i d < nt WM. N lK IM U tO O C . M onroe C ounty E -l e c t r i c m . MU1'*. Cooperative, Inc. 22l DOW 075280 Biochemical Research Dept. The Dow Chemical Company Midland, Michigan Dear Sir: Thank you for your letter dated September 1, 19511- giving us information with reference to the effect of Eeteron Brush Killer on skin and lung tissues. We note that this information covers cattle, whereas our request addressed to the Dow Chemical Company in St. Louis, Missouri, dated August 2lj., 195>Ut requested the same in formation with reference to the effect on human beings. We would appreciate receiving this information at your earliest convenience. Thanking you for thi3 courtesy, we are Yours very truly, MONROE?BnO<UNTY ELBCTR-& COOPERATIVE, INN'^ / / , Manager CMD:MP :} ^ 16745 L:r . V . Ho-.a. , .... v:;I'Mill . .THE'.-DOW "CHEMICAL':- COMPANY . 6 l5 : O live Street.: '.'St .Louis , Miss turi-. August v.(, , 08ZE20N W r- c , c C 0 M a m Louroo County..Electric Cooperat-ive , i-ic . >"afc<;rluo .'. ' '. ^ . Illinois .. .v .:- v t t e n t l o t i o f . M r . ' C ; ;11. ;I> o vi.g:I n c , : la e a g e r .D e a r L r . ; D o u g l a s Thla :wlil--->cknotfl2ge:4^our; letter of August 24th in vihiuii; you requested information r3 to whether the drift o f '. -'LL Eateron Brush Killer .during application would be- injurious : .to skin or lung tissue. It- is your understanding that the ;spray does not inJure 1skin or lung tissues but you would like to have a'confirmation of this. :S v,;e .*'1 quite sure-' that your a'>3u~;ption' Is'correct:in that this spray does not injure the ekiri or lung tissues, how- over, we are asking our T!r. V. K . fiouo of our 'Biochemical Rose arch Lub at our Hc-no Office in Lidland, Michigan to ; .. advise you ulroct regard ing thin as bo has been .''working with 2,^-D type product.', irosi a toiviaolngisal. viewpoint and will be in a position to give you t;hi latest iru'oreati on on these materials. L L- -''V-l -c -i'er,y truly. yours .. R b A . Cra.idall . Agricultural_.-Chemical Division .RAC ;ava SENT BY:CLARK, DRIMIIE, & CO. ll-19-92 ; 3:18PM ; 506 459 6720;# 2/ 6 me V: / r/ THE DOW CHEMICAL COMPANY Abbott Head Building Midland, Michigan February 16, 1969 I 2 8 (Vvyo F. H. Riley, Special Chemical Sale, ARB J. C. Tucker, Industrial Chemical Sale, ARB R. N. Sm iley, International Sales, ARB Xjwfci k cc: J. W. H arris, Chemical Sales, ARB L. B. Grant, Sales Administration, 47 Bldg. H. W. Feinaner, Chem icals Department, ARB C. O. Hutchenreuther, Organic Chem icals Prod." Dept. 2S8 Bldg. E. C. Staehling, Organic Chem icals Prod.' Dept. 172 Bldfr Cl. S . O tis, Bioproduct D ept,, Bioproducts Center L. Silverstein, Biochem ical Research Lab., 1701 Bldg. Subject: 2, 4, S Trichlorophenol The 2 ,4 , 5 trichlorophenol courently being manufactured has been found to contain 2 ,3 ,7 ,8 tetra chloro dibenzo-p-di-oxin and is suspected to contain 2, 3, 7, 8 tetra chloro dibenzo furan. It is known that both the 2 ,3 , 7,8 tetra chloro dibenso-p-dioxLn and the tetrachlorcdibenzo furan can produco chloracne. ! i 1* The concentration of these im purities has been found to be le ss than 0 .5 ppm of the 2 ,3 , T, 8 tetra chloro dibenzo-p-dioxin and approximately 20>2S ppm of the tetrachloro dibenzo furan if the present VPC analysis is correct. A nalysis of retainer sam ples shows that these concentrations are very clo se to the impurity lev el in the trichlorophenol we have shipped in the past. Up to our recent in-depth studies of our trichlorophenol and its im purities, we did not know that they were present in our product. Consequently, we do not have animal experience which indicates this impurity level is consistant with safe handling. We do know; however, that we have had no chloracne problems in our own operations in the handling and processing of these m aterials, and we have not heard form ally that any of our custom ers have. We are presently making animal studies to determ ine what the safe lev els for these im purities are. _e While the current product is essen tially the sam e ae past m aterial, we feel it is im perative that our custom ers know this new Impurity and concentration information. They should, if they decide to accept our SENT BY:CLARK, DRLMdlE, & CO. Jll-19-92 ; 3:19PM ; a- - 506 459 6720;# 3/ 6 F e b r u a r y 16, 196$ D O W 048516 m aterial with this new knowledge, be cautioned to ex ercise care in handling and processing this m aterial to avoid human exposure, r As I indicated before, we are carrying out animal tests to determine safe levels, and if needed, additional handling precautions. When this work is completed, we w ill make it available for you to pass on to your custom ers. Meanwhile, your custom ers should be informed of this information before any m aterial is shipped to them. 7 1 fustic i f. D. Doedens Chemicals Department ARB \ \ 4 " ^irUvJOJO *MCULTUiTAL P"0:)C7S SPECIFICATION NUMBER DATE 87523 2/13/70 THE DOW CHEwu- l .u m .-ami agricul tu? i l pr d i;:; s o c P a : is o l a n o . michigah a m SUPERSEDES NUMBER DATE 87523 2/27/69 U ET H O O O F A N A LY SIS 87523 2, 4, 5 -T R IC H L O R O P H E N O X Y A C ETIC ACID 2, 4, 5 - T r ic h lo r o p h e n o x y a c e tic acid, m in im u m Freezing point, minimum 2, 3, 7, 8 - T e t r a c h l o r o d i b e n z o - p - d i o x i n 98. 0 % 148.5 C < 1 ppm confidential - sueject to injunction D.C., E.D. 4 -4 -7 3 ; D O W / EPA A G R EEM EN T 9 -79 C T H E P O L IC Y OF T H L 0 0 * C H I'M 1 C A L C O M P A N Y iS OHE O F C O N T IN U L D IM P R O V E M E N T S a r R E S E A R C H A N O M A M lj r A C TU ftIN C W IlC K C v r -R P O S S IO L C TO A S S U R E A S T I L L F I N E R P R O O U C T . H E M C t . SP t L H -IC A 1 IO N S ARC S U O iE C T TO C H A N G E W ITHOUT N O T IC E. FORM C-1W70 f M M It D IR U.S.A. H U C t 16749 DOW 275096 18.473 ---------wQ-<yTi?i.} o<> THE SEVES ACCIDENT: ITS NATURE, EXTENT AND CONSEQUENCES January, 1979 * E. Homberger , G. Reggiani , J. Sambeth , H. Wipf x- ro o v -Ni oo Introduction In July 1976 a runaway reaction during the production of trichlorophenol in a subsidiary of the Givaudan company, the Icmesa plant in Seveso, Italy, resulted in the discharge of products containing TCDD (2,3,7,8tetrachlorodibenzodioxin) over an area of about 2.8 km 2 (700 acres). This report covers the past two years and gives an account on the nature, the extent and the consequences of the accident. * Givaudan Research Company Ltd. ** F. Hoffmann-La Roche & Co.Ltd. 16750 DOW 27509V 2 1. Conditions of the accident Trichlorophenol was produced in this factory only for the manufacture of hexachlorophene, a local antiseptic active against grampositive bacteria. When designing the installation for this production the chemists and engineers were aware of the previous accidents in the chemical plan-ts manufacturing this chemical. To avoid a chemical process under pressure and the formation of dangerous amounts of TCDD, the unwanted highly toxic byproduct of the reaction of 1.2.4.5-tetrachlorobenzene with alcali especially at temperatures above 170-180 (Fig. 1) and to prevent uncontrollable exothermic reactions which can start above 230, special attention was given to the ci O N a Cl OCHjCOjNa Cl c h 3 o h Cl N aO H CI ClCHjCOjNa 5 " Cl l2 r4 ,S - f lr a - chlorobnnzcn* 2>4^-frich/oroph*noJ 2,4,3-T rI TCDO FIGURE 1 Formation o f 2J , 7;3-trachlarodibcnio-f>-dioxin (TCDD) as a by-product in the jynthes o f 2,4^-T. 16751 DOW 2 7 5 0 9 8 3 choice of the solvents (ethylene glycol instead of methanol), of the heating system (steam instead of hot oil) and of the cooling system (flushing of cold water through the same heating coils and quenching the reaction mixture with a large volume of water in a matter of minutes). During the premanufacturing laboratory and pilot phase of production as well as during the later phase of routine manufacture no exothermic reaction which would elicit a runaway temperature rise,increased TCDD formation and explosive discharge, ever occurred. In order to abide by the regulations of the USA, where the trichlorophenol was delivered for the production of hexachlorophene, the quantity of the TCDD formation was carefully controlled and kept within the limit of 0.1 ppm recommended by the Advisory Committee to the Environmental Protection Agency Administrator on May 7, 1971 (16). The working and handling conditions in the Icmesa TCP plant were adequate with respect to hygienics and exposure of the plant operators. 16752 DOW 275099 4 Chloracne, the indicator of TCDD exposure, was never observed either in the workers of the Icnesa factory or in those manufacturing hexachlorophene in the USA and Switzerland. On the day of the accident the production of sodium trichlorophenate in the reactor was completed and some IS % of the ethylene glycol had been removed. When the heating was switched off the final recorded temperature was 158 C. The workers night shift left the plant shortly after 6.00 a.m. and nothing happened until 12.30 p.m. when the accident occurred. 2. The causes of the accident The task of assessing the causes of the explosion has been given to several groups of scientists in- and outside our laboratories. It was assumed that the temperature increase which led to the accident was provoked by a slightly exothermical reaction proceeding very slowly already below 200 in alkaline surroundings and which had been unknown so far. Preliminary tests examining all conditions at which an exothermic reaction might have been provoked, i.e. long-term heating at 16753 D W 2 7 5 1 0 0 critical temperatures, thermal behaviour of the reaction mix when exposed to air, accidental presence of metals, copper etc. and checking all materials used for the reaction and the operating procedures at the plant have led to the following reconstruction of the possible mechanism of the accident. At the beginning a slow exothermical reaction of as yet unknown nature may have taken place in alkaline environment raising the temperature of the reactor over several hours to approximately 250 with slow decomposition and with formation of gas. Possibly due to an obstruction of t:_i pipe that connects the reactor with the outside, this slow formation of gas may have caused a pressure increase inside the reactor greater than the one allowed by the rupture disc, thus .leading to the escape of gases together with glycol and other organic products. The chlorodioxins produced at the higher temperature in the reaction and particularly TCDD proved to be, under the conditions of the accident, much more volatile than one would have expected from known scientific data and foreseen on the basis of their physical properties. Further investigations and experiments are needed to prove that this explanation of the mechanism 16754 DOW 2 7 5 1 2 4 28 of spontaneous abortions in the Seveso population for the years 1976 and 1977 (19, 20, 59, 60) was substantially similar to that found in the previous years 1973-1974 and 1975 in the same region and which fluctuated between 9.0 and 10.3 % (Table 11). For the Lombardy region, where Seveso is located, the rate of spontaneous abortions has been indicated to be in the-'range of 12-15 % (13) and world-wide an overall ratio of 15-20 spontaneous abortions per 100 pregnancies has been estimated (68) . This rate of pregnancy wastage seems to be common for all mammalian species which are said to rarely lose less than 30 % of their fertilized eggs (8). Tabla 11 f s tillb ir th * * spentaneeue and Indues* i k r t l m ru ts per nuaeer / calculate* prtcncnftle* Tim m MP r , ____ 0*U K*<* Im M im * 9.41 15.5* 4 .1J 10.79 1*7* * 10.1* 13.*3 3 . 7.1* 1973 % a.lx 13.31 3-70 11.13 197 % .15 8.91 9.00 U .lb 1977 .01 U-5* 4.70 u .c Mmd 10.3* 31 10.2} 33 u .o * Iit m s Im W rl*la lo u N Vev* X. i n * M 4.14 .* l.aa 1 1 .5 23-* 13.1 10O0 5. 3 11.03 1.13 13.7* 13.03 11.09 9.09 4.12 lb . 41 1.37 .11 11.72 15 U .31 a . r 12.42 1-3* U .17 13.31 a . 73 7.02 3-03 11-31 5-15 U .3 1 12.4* 12.07 10.3 iT m o .*1 9.40 .03 .3 u . i * I s e e c t r**laa *J .33 .> 57 10.1* ( c e l* cl *## 13 20 % t u s n i t y r eb o rn 12 13 %) 16755 OtfT/.Z M n n --y A closer analysis of the chronology of the fetal losses for the months which immediately followed the accident and in correlation with their geographical distribution in the zones with and without contamination shows that (Table 12) Table 12 INCIDEK2 Of SfOITAREOUS ABORT!OfO |.i me U TCWSMPS Of JUTE PCR 4UK8ER Of CALCULATED PREGMnCIES SEYESO ZONE ?S0a JULY 1976 TO *UT 1977 kM O T IO M ! auM TW L37S s iL iv n i 1 auM T U 1377 M U T IS M a u M ru 137S X U V U IIS 2 a u M T tt 1977 m t i m l 4 a u /u rru 1977 H U V tllU 3 auM T IR 1377 m u t is m 2 a u u r u 1377 S IL JV U IU 4 sw um * 1377 mm 5 s! CZSAMQ itv n o 0 (1 (0 NCSA 3 * l i TOTAL IS 12 S 12 s <12 a M U S S IN A M V t l l Q UXTATI 11 i 3 W U IO : i NOVA 55 a s UM M o3 m w VAJtCDQ s 7 1 14 12 4 TOTAL so o o n 38 49 38 34 313 2S 38 35 e 37 129 44 23 21 9 13 3 S8 (1 7 a 3 5 17 21 7 4 62 U 4 a 78 35 93 S3 272 11 28 35 64 73 US 31 353 14 7 24 9 4 (1 4 a 9 9 17 15 23 10 33 o s a 102 52 104 68 324 8 35 41 64 71 95 38 351 10 U 17 10 8 (14 a 7 10 7 13 IS 6 S3 (1 3 a 96 21 105 75 237 3 38 2 34 73 117 48 334 during the third quarter of 1976 the incidence of abortions for the 4 townships embodying the contaminated zones was 12 % and for the remaining townships of the territory under health surveillance was 10 %. The 16756 DOW 27512U incidence increased in the fourth quarter of 1976 to 17 % for the contaminated and to 14 % for the non contaminated part of the territory. At first sight the figures could be interpreted as showing a relation between incidence of abortions and degree of contamination. Yet if the analysis is extended to the following months, i.e. the first quarter of 1977, there is drop to 14 % for the contaminated townships and an increase to 19 % for the townships without contamination. In the second quarter of 1977 the values sure 14 % and 13 %. The fluctuations observed are therefore likely to be related to factors other than TCDD. Besides it should be noted again that the frequency of abortions in the contaminated area remained well within the normal incidence in Europe. b) Congenital malformations The same can be said for the frequency of congenital malformations. For the population of the western countries, the ratio of defective children reported when no special diagnostic procedures are used is of 2-3 % (21, 58). It increases to over 7 % of malformations if the cardio vascular system, respiratory tract, gastrointestinal tract and genitourinary system are considered (26, 66). 16757 In Seveso the number of malformations notified to the provincial health officers shows an enormous increase between 1976 and 1977 from 4 to 38. The number of malformations reported during the first quarter of 1978 is 5. However if these numbers are related to the number of live-births that occurred in the corresponding periods of time (Table 13), the only possible explanation for the discrepancy is that the notification data on birth defects are incomplete. A previous survey (17) on the incidence of malformations in' the same territory based on data of better quality had revealed a ratio of 2.9 per 100 live-births. O O K, on hto Table 13 Tmiwr *uUmatlMa - mm .(1141*crlu) T i* r im m iM la iittr 1177 U aaaOa 1*7 n m (u n ir Jtsu * t a a lfa m tiM U par loo ftt ta n t i af l.j3 A 17 ( a . a *) 35 - U .M *) M - 10 in 5 (3.7* *1 l - ZO 16768 ) 'y AAOO The polymorphism of the malformations observed (Table 14) Table 14 <M U>1 aairnatla la Sam t Tjrpa M f i m n 1774 i w 1774 nm qaartar Pttlaonw ip i u i i iM fteepftalia i i V M l t 9f IUAi1U7 I M tU X CancwiLtal arlapathgr * T n ita l M topit l <Jajtrlani lu tro p Jtr X X ftm vpM ly X i l n w p M l i - XapiapaOla aa AMMlnal u U o im U m a taai u U m u l i a X faaaila aalfaraattaa 10 Xenlncoeele X iiaaplaala a D tiN I M llH O M ll i Own a ' a Sm taatyly 3 Clan palasa - OU pfenpA tii lu n U * a X i X Ira i * 3 3 in the newborns of the Seveso region is another element in favour of the assumption that there is no causal relationship between the malformations registered and the chemical. Morphological heterogenicity of anomalies scarcely supports the presence of a single causal agent. Even in the groups of congenital cardiopathy (8) and pedalic malformations (10) it corresponds to the normal distribution of congenital spontaneous anomalies. The 16759 ? M '-NH H 7, morphological differences of these anomalies is from this point of view convincing. A further aspect examined, the geographical distribution of the mothers of the malformed children in the zones contaminated by TCDD compared with those outside the contaminated communities shows that the malformed children were equally distributed among the two groups (Table IS) Table 15 a m r plm l d iau ltn U an a t ( u U M H t lm Olatrlata Cana* IU4. Oh I s Ml (* fatal taalaaalm k n it letU k *uSle Jfev* XU. Itrtp * TatU OrM tM l 197 2&4 SBMtcr a l a 0 l a i a i 1 0 0 3 4 1977 i 3 u 2. n 0 3 i 1 l 7 3 U 3* 197% la* quarter 1 0 1 1 3 0 0 9 9 1 1 9 2 3 c) Neonatal growth Growth retardation, decreased survival and smaller size at birth have been observed in experimental animals under the effect of TCDD (12, 33, 40). The examination of about 16780 'ISAS MOa 2000 newly born infants of the Seveso region have revealed no abnormalities in respect of the somatic and psychic development of the child. d) Embryomorphological studies O Embryomorphological studies were performed in LQbeck on 34 cases of abortions. In 30 cases the pregnancy had been interrupted at the gestational age of 5/6 to 15/16 weeks. In 3 cases a spontaneous abortion followed an intrauterine death at the developmental stage of 8, 13 and 18 weeks respectively. In a 4th case of spontaneous abortion no embryo was found (49). Direct examination and radiophotography did not detect any gross or clear signs of abnormal development. Histological examination and morphological evaluation of the lymphatic and other visceral systems did not provide any sign of damage brought about by the action of an exogenous agent. The cases of spontaneous abortion showed different morphological alterations obviously due to a variety of causative factors. 16761 DW 275131 35 5. Cytogenetic studies Induced abortion was sought by women of the communities most affected by the TCDD release in the second half of 1976. Chromosome analysis of maternal peripheral blood/ amniotic fluid cells and fetal tissues were performed for numerical and structural chromosome variations. No significant change in the chromosome number nor an increase in the frequency of aberrations was found in the blood samples.. There was a higher number of aberrations in the fetal tissues than in the blood samples or fibroblasts from adult tissues. However, the frequency of these aberrations was not greater than that expected in cultures of comparable cells (52, 57). Chromosome analysis have also been performed on the blood of people belonging to the group of acute (145) and chronic exposure (69), of the Icmesa plant workers (73), on children with (14) and without (15) chloracne and on a control group (87) . The average frequency of gaps, breaks and structural rearrangements found were within the accepted standard frequency (30, 66). 16782 DOW 2 7 5 1 3 2 6. Immunological studies Immunosuppression and decreased resistance to infections due to TCDD have been observed in several animal species (51, 61). Immunocapability was therefore examined from September 1976 to March 1978 at 4 months intervals in 45 children belonging to the zone at maximum level of exposure, of which 20 children had chloracne and concurrently on a comparable group of 44 children who had not been exposed to TCDD. The age range of the children was 3 to 7 years. The serum z immunoglobulins, the circulating level of complement, the ability of the lymphocytes'subpopulation T and 3 cells to react to non-specific mitogens were examined, ilo significant difference in the immunoresponse of the three groups has been so far detected. 7. Occurrence of infectious diseases The number of notifications for infections diseases submitted in 1977 to the provincial health officers of the 11 townships looked after by the medical commission shows a clear increase compared with that of the previous year, rising from 435 to as many as 1219 (30). 16783 DOW 2 7 5 1 3 3 37 This fact seems to contradict the results of the immunological investigations referred to above. In fact it has to be attributed to a better compliance to the mandating notification of the prescribed diseases during 1977. Indeed (Table 16) Table 16 U u i o f l a c l d a n c a o f L o f a c tio u a d l a a a a a a p u r 10 000 p o p u l a t i o n u a l e a Z a fa c e io u a d lsaaeea U O nfaeal ttM U IlM lO a Jala o n alla L ai*0*1000 aj typhoid itv a r tel a c h w aalaM M llo u a vj_eU h a p a u . u a - H lio e y o lie la 2) A ira o ra o tr in -- la eio n - o ip n th aria - I c a s l a tmrms Mllia^OCOCTC t i sa n la fltla - N rc a siia OVMAlpO (4) c o v u rtn * coBgM iinecod V I* 1974 1977 to tm a h lp a (7) o u tald a co a taaiaatad area 117 1977 nutr& y eoM ualey v itd p opulation 220 000 197* 1977 fro ria a a of x ila n 1 720 OQO 117 1177 lo o n a rd y la q io a 1 900 000 1974 1977 0 a47 1 .0 2 .0 0 1 .0 7 1 .0 2 .2 * 0 0 .4 * 1 .1 2 2 .7 4 0 1.29 0 .2 2 1.20 2.5 3 .2 4 0 4 .3 0 0 .2 2 2 .7 2 4 .0 9 0 1 .7 9 1 .9 2 4 .4 2 0 1 .0 l.U 4 .1 7 0 1 .1 1 .9 7 4 .7 2 0 0 .7 9 1 .7 7 4 .4 2 0 0 0 0 0 0 0 0.009 0.002 0.009 0.00 2 .9 2 .7 0 .2 4 0.9S 9 .7 4 .4 9 9 .9 0 4 .1 9 4 .2 * 2 .7 7 0.2 0 0 0.17 0.04 0 0 .0 7 0 .1 0 0 .0 9 0 .0 * 1 .4 0 .4 7 0 .7 7 1.29 2.21 1 .2 2 2 .0 0 .9 7 2 .4 9 1 .1 7 the increase affects 'mainly the infections for which the notification is normally made with greater frequency as for example viral hepatitis, salmonellosis, meningitis, scarlet fever, and pertussis. Furthermore, the increase 16764 DOW 2 7 5 1 3 4 - 38 - affects to a lesser extent the inhabitants of the more highly contaminated zone. Finally it does not involve poliomyelitis and diphtheria, diseases where vaccination is currently performed, thereby confirming a normal immunological reaction of the population to antigen stimulation. If compared with the incidence of a nearby community of equal population, of the Province of Milan and of the Lombardy region the infective pathology of the Seveso zones does not exceed the average of this part of Italy. 8. Birth rate and mortality The demographic trend recorded by the health statistic in the Seveso zone is caracterized by a constant decline in births. During the period 1975-1977 in the districts under consideration the birth rate fell from 17 % to 12.5 %. The fall was more pronounced in 1977 and affected particularly the four communities most involved by the accident (Table 17) J.S7B5 Table 17 ta t* a# t i r r a . la ts a J n c n (11 d a - t r l a n ) '.ITI - 1777 S lra lit 1971 3I rta * C<m m Xad. Oaaia iu a 3tM bua larjiu lm tarlala la u ta Mela Ber* X. Sarau Tna Ararara laraaa radon lj.* 7 1 7 . 17. CO ia .n 16.7% U .oj 17.03 19.3? it.io 17.CO j.i li. 17.37 137 31rs&* fa 11.3* 13-70 17.7* ia .it 17. J4 13.7 li. l i . 32 17.34 H .1J u .ia 14. 14.9 17.1J 137J sirju fa u . i l i . 17 14.33 13.4 O j.-* li.io 13. ai l i . 43 14.23 1 7 . 14. 7 * l i . 4 li.U J IJ.J* 1774 U ras fa 1.J7 1 3 . IJ.17 13.44 13.1* 12.3* 12.04 i a lf 13.4* li.* 0 13 . t * 1. 13.37 i* .io 1977 31r a a ita 13.92 12*34 I4.C1 U.OJ 12.13 11.33 11.3* 13.*4 ' 13.17 13-31 12*33 1 2 . 12.9? 12.33 275135 c c * The fact may be attributed to psychological factors associated with the abortion-seeking phase of the period of time immediately after the accident; to the use of contraceptive methods recommended as a preventive measure at technical level; to the advice to abstain from sexual intercourse. It may also suggest that there is a reduction in fertility in the population although this relationship must still be regarded as hypothetical and in need of further study. An examination of the statistical data relating to mortality shows an overall increase in the eleven districts in question, particularly pronounced for the year 1976, 16766 HU - when the death rate rose from 7.62 % in 1975 to 8.24 % in 1976. The rate went down again to the current figures in 1977 (Table 18) Table 13 lac9t 4*clula Ue Una ism perUQ9 popwietieaiu DIr t r l r t Cm m U-*. S ta la >W U laara -- U a ^ a a ta rla la la n tu K H a s m !.. t n 4 a iT m ntm l i r m taaa rrmmtamm m t U lan Leader*? recto* 1973 4.24 I.H I.U 9 .U 9.14 3.99 i.i* 9.47 4.94 4.34 i.n 4.74 7.44 7.9* 197* 4.44 1.14 7.44 7. *3 7.i7 10.49 7.47 7a 71 4-30 3.44 9.*0 .*1 7.44 7.44 1.29 9.30 1974 .S3 3.30 1.2* 4.79 7.47 7.47 4.33 9.29 3.71 3.47 9.33 7.70 7.!- 7.42 1974 4.34 9.03 4.17 9.33 4 .J2 7.*3 4.24 10.43 4.90 4.44 9.39 7.41 4.14 4.2 9.39 9.43 9.44 J.94 1977 4. 3* 7.44 4.44 7 . 4* 7.41 7.09 4.44 9-34 9.*4 4-7* 4.41 7 . l 7.90 7.75 C c n c K Cu, A breakdown by the place of residence of the death cases (Table 19) shows striking high values for the district of Seveso and at first sight the increase appears to be specific to the more highly contaminated zone. Table 19 ilatrlautlM mt iaataa an* 4rata rat* la nra il.trt.t* ./ oa Ira#* lana ZM A 1 1 O utside J ovom 1974 1977 Asce 4 c lu ster Asce 4 C itte X*4. 1974 1977 Cluster l i t . 4a Cluster Xta <e 7 10.37 A 4 7.94 4 7* 9.04 47 7* 10.0* 3 3.47 7.94 4.43 7.44 : 94 123 J.l* 3-73 7.37 1* 91 109 4.34 4.07 4-91 14* 9.3a 13* 7.4* 222 4.1* 21* 4.34 16787 U U W 7^137 4j. - A monthly breakdown of the death rate for the township of Seveso where the increase was the highest (9.54 to) shows that in fact the increase occurred during the first semester of that year, i.e. prior to the accident and therefore related to other factors (Table 20) Table 20 Ua ta u u p um a la tin l i n n U ia in January ftferu i7 U lU JIM ia iu l l^tM W 6eta*#r J w n lir Daanaaar i m X97* 1975 1974 1977 IS U X3 19 uU 999 u X* U 20 12 12 7 12 10 1 < 7 X3 9 u xo X 5 u 9 u 10 u 7 10 < 10 7 10 u 12 1 1 X3 X3 1 12 u 9 1* 1% X7 15 X* X3 X* n t X15 103 X3* Taken as a whole the death rate has always remained within the frequency of the province of Milan and of the Lombardy region. 16768 l hj w 275138 42 CONSEQUENCES ON THE ANIMALS 1. The period immediately following the accident The first deaths among domestic animals and some wildlife in the area occurred about three days after the accident. Small animals were most severely affected/ particularly rabbits but also guinea pigs and domestic poultry and other birds. Whereas the birds appeared to die quickly and without specific symptoms/ rabbits and other small animals showed anorexia, apathy and later also gastrointestinal hemorrhages, pulmonary oedema and wasted away with a complete depletion of the fat stores. The first animal deaths occurred in the immediate vicinity of the factory, but the zone became progressively larger in the following days. The dying of the animals was there fore the second element, after the results of the chemical \ analysis of the soil and vegetation samples, which was used for completing the map of the contaminated zones, which had been set up by the Givaudan laboratories and submitted to the Italian authorities with the request of the evacuation of the population. In fact the map based 18769 n r to i - 4J - on the deaths of the animals which was later compiled by the Regional Veterinary Service, working from animal death patterns and TCDD levels in surviving animals (24) corresponded rather closely with the analytical map originally composed by the Givaudan laboratories. The analytical and veterinary data were then used in the definition of the contaminated area and in .-.its subdivision in zones with different levels of contamination. When approximately four weeks after the accident, some animals died at a still greater distance from the factory, a further zone of protection (Zone R) was created which covered several square kilometers and had only a few 2 sporadic spots with very low levels of TCDD ( < 5 ^ug/m ) . l 2. Conditions two months later a) Domestic animals It has been reported that during the two months following the accident over 2000 animals had died, predominantly rabbits. Probably not all these animals died because of TCDD. Some emergency slaughtering had in fact taken place 16770 i u x il U 44 because of the evacuation and other animals had been sacrified by the Regional Veterinary Service for examination. Table 21 Vmrtnllty < 4cM txli animal lurin* the first tso saatfta (petition<m lOtftSeptember1776) tmm Animal aount before iota ;i/ 197 "i 3*000 10*000 t u . to'eo Tatal aertallty a. i i.t i <v * SafeUt M ro U ty **.1% 3.7 * Wk 1 f Table 21 shows the mortality of domestic animals in the three zones up to September 10, 1976. By this time the number of spontaneous deaths had for various reasons substantially declined and it was possible to draw a first balance. It was clear that only a minority of animals had been directly affected by the aerosol cloud on the actual day of the accident with the possible exception of birds and some poultry and rabbits. The most severely and most i kj x 4 JL -45- rapidly affected animals were the herbivorous which had ingested with the food relatively large amounts of the-chemicals sprayed on the vegetation with the cloud and of TCDD as it was later confirmed by the levels found in their organs. The site where the animals were kept was obviously of lesser importance than the source of the fodder. Small animals succumbed to the toxic effect of the chemicals and of TCDD more rapidly than large ones. Sheep and goats were affected later than rabbits and cattle and horses last. Table 22 shows the deaths among large animals. Table 22 no ** i Ur* U ln a la taa* A. 1 m l 1 u tu l Sami* iw ii / Om Out* Ur* w l u l tacal Anlial lire a iota 1974 ** u ** nj m 4*taa (1.7 *1 l <*.i *) (0 %) 1 <2 i) 3 <1.3 *} 12 <1.2 *) ( 16772 (H T P i y -46- It is difficult to tell how far these deaths could be related to TCDD alone. The aerosol that escaped consisted chiefly of trichlorophenolate which was also the cause of the chemical burns in human subjects. Undoubtedly there have also been harmful effects on freely moving animals. Cats and dogs for instance had inflamed sites and wounds chiefly on the extremities. Whereas some cats died of the wounds or of the systemic toxic effects caused by licking, the dogs recovered. The chemical burns found in the pharyngs of rabbits and cattle can also be explained by the caustic properties of trichlorophenolate. Animals which had from the beginning been fed on uncontaminated grass came to no harm, and many animals which had been taken off the contaminated food showed no toxic effects although some, on their subsequent slaughter, were found to have traces of TCDD in the liver. b) Wildlife To prevent the entry of TCDD in the food chain all the larger animals of Zone A 'were exterminated. Although the vegetation showed no external changes with the 16773 47 exception of minute phytotoxic damage on old acacies foliage, at the beginning of September, there was still 30 % of the total TCDD to be found on the vegetation, where virtually the entire aerosol had been deposited originally. The acute danger to herbivorous animals was past only when the old grass died down in September/ October due to the wet season. After that virtually all TCDD was to be found in the upper most layer of the soil as the new growth vegetation was practically not contaminated apart from traces resulting from dust. In autumn some wildlife still remained in the Zone A. Many birds populated the area and behaved normally. Insects, snails, slugs and earthworms were clearly unaffected. Lizards, mice and rats were thriving without visible impairment. No dead animals were found. Dogs continued to roam and poultry and rabbits released into the wild were seen time and again. T G L Z A\ r\ C - '43 3. Precautionary slaughter On our request the authorities of the Lombardy region had banned the consumption of vegetables, dairy products and meat from the Zones A and B in order to keep TCDD out of the human food chain. They also banned the use of products of the zones for animal feeding purposes. Sick animals and those which could no longer be cared for as a result of the evacuation had to be slaughtered. Slaughtering operations were later extended to all animals because officially uncontaminated feed were in short supply and it became difficult to enforce the official measures. The last animals were killed at the beginning of 1978. A few animals have been kept alive for research purposes or for the study of the effects of TCDD on the animal body. i\I -V CP I-- According to the final report on the action (Table 23) the original death toll was approximately 3300, a figure which inlcudes many slaughtered under emergency conditions; the animals slaughtered as a prophylactic measure numbered nearly 78000. 16775 ( - 49 - Table 23 S m m m rf t4 # s n la # l # # r Zona* A, 3 to d X p o s i t i o n an }QtA J u a # 1978 0 rl(lA * l ftuo#r 3l#4 a f ta r th S t i l l In (lO ta Ju ly 1988) aa14snt*) tn# ton# r*uat4 (l4 u n u r* a ,ro* far study purpose# 3ior 30.0.137 8m U u ila a U CtU* I n n a / OoniMT* 3lM Mm * / (M U 0O*3O 3 '*7 m n 3*m 71 i 3 9 i -* 3 3 1- 3 77*07 !H V, 207 u :> u j tl'U l (100.4 %t y tv ( i ..i *) ) I p w t i m w 4#atba o r s*#rt*nay tlau<A t* 3 (9 .0 *> U (0.1 ) 77*714 (3.0 *1 4. Analysis of tissue samples It is known that TCDD accumulates chiefly in the liver and fatty tissues. The veterinary service of the Lombardy region secured therefore a large number of livers from animals which had died or had been slaughtered. The chemical analysis (limit of detection: 2.5 ug/kg = 2.5 ppb or 2500 ppt) demonstrated TCDD in the lives of some of the dead animals but not in all of them. TCDD has been detected in 71 out of 113 rabbits, 3 out of 3 goats, 2 out of 3 hares and 2 out of 27 chicken, but the organs of 6 ducks, 16776 .9 * T O / 7 aa 3U ~ 2 hens, 1 cat, 2 guinea pigs and 1 peacock did not contain TCDD (1, 22). Tabla 24 Qlexln level In the liver f r v O it Im / a i m ctauf * ( 1J -MO* i n / o) / * /dim * < 1 - 1 3 w /* 1) / dim * / dim * ( * J / dim a to m / um Cm r*l / ilw itu n d - La TCSO la tk a in MC'fc* fLpit r* 3* ; la? : 3 1 "J ! 34 * < 4*3 la (i*> n ( j) ' (13) 1) 1 )) U <) 13 ( 3) ( }) r ty n ae u m* rm * ire I The levels found in the rabbits' liver are shown in Table 24. The amount of TCDD detected in the animals that died ranged between 50 and 200 ^g/kg in the livers, but levels of the same magnitude have also been found in clinically healthy rabbits. Of 14 rabbits, collected in the Zone A, which had rather large amount of TCDD in their liver (up to 300 ^ug/kg), all were apparently normal, - JX had normal serological, hematological and enzymatic values and only 5 showed histologically hepatic lesions when sacrified three months after the accident (1 ). Consequently analytically measurable amounts of TCDD in the liver or in the fat do not necesserally correspond to anatomical or functional lesions. There is certainly an accumulation of TCDD in the liver and in the fatty tissues, but there is also an elimination from the body. The half-life of TCDD in the rat (43, 50) is approximately three weeks and'a steady state is reached after approximately 80 days. If doses of 0.01 j i q / k q TCDD are administered daily to the rat for a life time, the steady state level in the liver and fatty tissues is 20 respectively 50 yug/kg without prejudice for the animal. As soon as the rats are withdrawn from the contaminated food, the body TCDD level falls exponentially. The same applies to other animals (47) especially cattle, for whom the elimination rate (half-life) is in the region of 100 days (Figure 5) and to smaller animals (guinea pigs, 9. **9 c 3 rcoo oaspAnoN imm i * ICOUMCTIO OATAJ tooi* 16778 5 52 a ^ sheep, monkeys) for whom the half-life is similar to that j- for rats, i.e. 3-4 weeks. Animals which have grazed on or have been fed with TCDD contaminated food would therefore c V i \ no longer have any measurable tissue concentrations of TCDD after a corresponding feeding time with uncontaminated food. In fact, even affected animals have been known to recover after having been exposed to levels of TCDD much higher than those found in Seveso. At least six horses of the Arena B in Missouri (10), which had been ill, had recovered. The TCDD levels in.this arena as measured 3 years after the incident in the removed soil was 0.5 ppmr i.e. 100 times higher than in the zone at highest contamination in Seveso. The original contamination in the arena may well have been 10 times higher yet. Our own measurements with liver samples from animals slaughtered in Seveso (Table 25) in the last months of 1977 have revealed levels which are at most one thousandth of those measured in rabbits in 1976. Table 25 CM tialaiUM atf u l M l i La uia t tana La Savaaa (IM 1177 / !winaln4 1771) Animal* ne etn lt lin n S u ti sum coo*mitra ilon la ta . lir La */* la rrt < 0.31 0.0* 0.0 3.13 < 10 *0 90 130 18779 '- 'W 75149 This may to some extent be referred to a lower original exposure but also undoubtedly to the elimination of TCDD from the body. In due time, virtually all the liver samples would no doubt have been negative, despite the low detection limit of 1 0 - 2 0 opt reached in our laboratories. Table 25 shows also the difference between animal species in relation to the food. Swine, as non herbivorous, show no measurable traces of TCDD, whereas cattle, horses and goats appear to have been more exposed. Table 26 represents a cross section of TCDD concentrations found in healthy and unaffected wildlife and domestic animals in the OSA. The living organism examined by Young et al. (70) in Florida seem to tolerate soil concentrations of between 1000 and 1500 ppt without discernible damage. Commoner (11) shares the view that 5QQ ppt in the soils represents a tolerable level for the fauna. In Seveso the TCDD levels found in the soil after the vegetation had died out, i.e. in late autumn 1976 were of 150-20000 ppt for the Zone A which had been fenced in, 54 of 50-150 opt for the Zone B and 0-50 ppt for Zone R. ** After the Zone R and B had been ploughed in the spring 1978, the TCDD surface concentration was below 10 ppt throughout. 75150 O .O ro Tabl 6 26 * 5 l m l i la h ea lth y d o ee rtle m i s a le snd w ild life la the S i Ca m at e e o t a a l a e t l o a Old a l l t m t u o t a f s e l l te M ai dues (susfeexaa) State X laeeurl w itt ll 7CSS ebeeeape etnitrsmsuteiosa La ea. 23- 90 ?yl la ths f it lit. 1977 S erbleide tfflle s tle a i ta ;e e t u r e ( t i l e ( M a i Lai C iltii 5 7f t l a t a a r a t 1971 C(sluesapteccatledi)n d u s try I?xrtpcerrsl--a en tafl hthaar t LUSdLnc arl ?arta. U lla API 1941-1970 sell seAtsslAsUea la-ijoo fie rid a Pisa fleets U rsa S turnaU a u t u Zeoaidura see* ra m mi .le trs fia hypsela p ta n s Osafluflis i f f l r u s l a p a u punetatue X eptlles ChaaLdorae Islla estu a le d easts fereayseua p e ll onetua 13- 20 9ft 1979 ** ?9* 130-13359P7fMt La La th e th e Uw lite r tad ra t 12 ppt la turn kmtt 12 ?pt la taa Stay I j ppt la u * put :6 0 7f t La th e b e d ? 197*/75 197*/75 1J7V 7J 1973/7 1973/ 7 1973/7 197V 7* 2 0 -13 0 0 7f t l a th e L iv e r 1973/7 16781 - 33 - CONSEQUENCES ON THE CROPS AND THE LAND 1. The situation after the accident It should be remembered that the summer of 1976 was rather hot and dry in Lombardy. This was reflected in the condition of the crops at the time of the accident. The grasslands were ready for the second cutting and the cereals which had ripened slightly prematurely due to the drought, were nearly ready for harvest. The aerosol cloud which settled down southeast of the factory after the accident had practically no effect on the flora. Phytotoxic damage (Figure 6 ) throughout the affected area was confined to a few broad-leaved plants in the Immediate vicinity of the factory. Most of the damage was due to the high temperature and high alkalinity of the mass that escaped from the reactor and consisted in a drop like perforation and in a brownish change of the green colour of the leaves. There were no discernible changes anywhere in the remaining areas, either to crops or to shrubs in numerous little copses or to ornamental plants. 16782 Z v o L 'o Z 00 It was the sampling of the vegetation and the chemical analysis of the samples which made possible the location of the areas which had been severely or slightly contaminated and those which had escaped. The map (Figure 7) ---- - ---- j ` Ny a t J k--H-if Him m .*&*i k . ' ,, '/ D t*lq ?v--iO/'*^l-' ' P W LW S ffi& l& T lft M n t^ - p ^ t i / ,t`!k*X i` ` ! r ,,/'i j e 7 j / r t f / - a s a w--- / oso v< o L k . * ^ 9 .o ^ f e . <3 '^Ai U OI D t/o O V OI D (OO Ve5/^eO/?tQ3 i i i i . jp% _V t>4 VI >< 7 i* * ] U t m O iz> -* o 1-1 * \^ O -vs >r - 57 (O i r J 6 represents the results of our sampling and of the chemical analysis of the Givaudan research laboratories and this map was the determinating factor for the decisions on all protective and preventive measures later taken by the Italian authorities. In respect of the crop and rangeland of the contaminated z o n e , an absolute ban on cultivation and grazing was issued for all three zones and the same regulation prohibited the use of plant products. At that time (August 1976), measurements showed 80 % or over of the total TCDD traced to adhere to the vegetation (foliage, grass, crops). This TCDD location : would have been highly favourable for the decontamination work as will be related later.' It changed however rather rapidly toward the autumn. Heavy rains flattened the standing grass and overripe cereals and pressed them with the adherent TCDD to the ground. Young grass and weeds grew up and covered what remained standing. Consequently the TCDD adhering to the vegetation was transferred to the ground and by the activity of the rain as well as of the micro- and macroorganisms living in the soil, it was shifted to the upper layer of 1 to 2 cm. This made it more difficult to take rapid and effective measures of decontamination as by that time immediate removal of the pOW ^ 53 contaminated soil and its safe disposal were the only actions that promised a reasonable degree of success. The autumn storms, the heavy rainfalls which followed further complicated the situation created by the leaf fall rendering the TCDD penetration to deeper layers of the soil virtually inevitable. 2. The behaviour of TCDD in the environment At the time of the accident data on the TCDD behaviour in the environment - unlike those on animal toxicology were sparse as in previous accidents contamination had generally been restricted to the production buildings of the chemical industry. The only available findings from investigations of incidents comparable with that of Seveso were those obtained by the CJ.S. Air Force in connection with the use of "Agent Orange". On the basis of the references in the literature and of the data obtained by ourselves we can make the following comments on the effects of TCDD on ecology: TCDD is not mobile in the soil. Rain at most causes TCDD to be washed out and transported with simultaneous erosion of the soil. There is accordingly no risk for the ground-water (7, 27, 29, 32, 33, 34, 36, 70). ZLZ m o q 59 TCDD is transported within plants in only negligible amount or not at all. There is no accumulation of TCDD in the vegetation (14, 15, 16, 27, 29, 33, 34, 70). TCDD is broken down in the soil under natural environmental conditions. Unless the breakdown is speeded up by additional measures, the half-life ranges from 200 days to one year (10, 27, 32, 33, 34, 69, 70). d Ol 3. Field and greenhouse trials The environmental behaviour of TCDD as outlined above were confirmed by a trial under controlled conditions in a greenhouse; by a field trial in Zone A and by sampling from various areas of the three zones. Leachability of TCDD was measured in soil columns with Mltscherlich containers using Seveso soil and showed that even at high TCDD levels and simulation of heavy rain precipitation (downpour of 200 mm in 20 minutes equivalent to am extremely heavy thunderstorm) no TCDD could be demonstrated in the percolated water. 16787 9QTS/..Z m o - 60 - Systematic measurements of soil samples taken from different depths carried out in the course of a field 2 trial in Zone A (520 ;ug/m ) in spring 1977 showed that there was no leaching beyond a depth of 20 cm. The breakdown of TCDD corresponded to the findings reported in the literature. In our greenhouse trials (Table 27) the breakdown was measured on the" crops 2 obtained from the Zone A (520 /ug/m ) and transferred to greenhouse pots. The breakdown rate ranged here from 21 to 52 % for a nine months period. Table 27 4M w t l n t n M aun la tn . 6trial u i m tram ptxa in W (Mil fnm Son* A) (320 it*/**) X Satunlly <mei tit IX Cunts UX lsw XT itumU)r g w T X30 la pM ter 1177 M m run at tut Ceeeafrer. 1977 i Aeduetlon 4.1 2.77 27.1 2 .1 1*32 <H.2 2.5 1.12 35.2 3-a 1-53 M .3 T K t u t U y p m 2 .1 1.72 a.i TX lUllT Ul TttStl 3-5 1.25 TO tssissss I.) 1.77 rtn CatnstM aot Mtwtafcl m y ietmtaAie 52.1 32.1 * 27515 bi - In the field trial (Table 28) carried out in the Zone A (62 iig /m ? ) the reduction occurred during December 1976 and May 1978 ranged from 28 to 49 %. The breakdown was therefore more rapid in the greenhouse than under field conditions. This difference may be largely attributed to the increased activity of the soil living organisms in the greenhouse where the mean . temperature was approximately 20C and there was no winter season with frost and arrest of growth. Table 28 I i t e c t l at t e a La Sana A (42 tM l 4TM i 2 3 IM I O H S M r ITT* *73 j n 294 * 17 * 2M JUr 1979 U 99 iaj UJ 1*9 * 49 3 IS oc Examination of the croDS from the three different zones , showed that there was no detectable TCDD in the Zone R (Table 29) and B. Table 29 7680 la v a l* eeAur*4 la ri(iutiM u srp l im a * I tn4 X (a u tw a 1977) SpM laea 7688 c o n c e n tra tio n la j 7683 onaentrm tlan la th e s u r r o u n a l A C s a i l ] -,t.w p l a n t i p e c i a e n S nfM FU tM Tw u m ]< iM *p. ( > O r** C tM ifi tu lk t SLUM Iw eury e n iitr.m r C auU A am r l w C klm ty c im f L u a e tn a A w aM n e . 200 9f t i t . 200 ppt 3 p p t 2 ppt TP* a * 1 JQ 7 9 U . 200 79* 2 pp* 3 PP 10 TV* 10 ? p t 10 TV* 10 ppt 3 TP* 13 PP* not e e e e e e e U n it of leteaU on < 9 .2 ] pp* < I . J PP* < 0.3* ppt < 1 .3 pp* < 1 . pp* < 2 ppt < 0. ppt < 0 .9 79 < 3 PP* * l PPt <1 < 3-3 <0.7 < 1.7 PP PP* ppt ppt < 0.* ppt The crops collected from a highly contaminated part of Zone A (1000 ^g/m^) contained small amounts of TCDD. In this connection it was interesting to note that TCDD was contained on the surface areas of.the crops, i.e. in the skins of the fruits, the spathes of the corncobs etc. (Table 30). Table 30 7689 ^ 9 t j m r lo M plant fre e * la tfta e^reXjr ee n te a tn a tw tone A ____i^iooa14/021 61*90 7 9 7638 lA th e 1 1 79 7680 la ta# p lan ts la % of so il e a n ta a ir.a tio n Mif IfA SM tnxn* 10*000 < 1.3 < 0 .0 < 0. 01} < 0.CC4 iP P lM PMI riM . 10*000 137 < 2 .3 l.JT O < 0.02) Fun pi flo o a 10*000 79 < 0.3 0 .7 9 0 t 0.00) 7eonea JCiA floo* 10*000 102 < 0.4 1 .8 2 0 < 0.004 A pntota Ala f t v t t 10*000 9 0.09 P lu o * 1 i n i to 10*000 7 0 .0 7 o O ^ CJ1 00 1S790 -63- Thi3 finding suggests that TCDD found in plants was chiefly derived from fine contaminated local dust deposited on the surface of the crops. The greenhouse trials seem to support this assumption because even where plants were grown in soil with high levels of TCDD, only 0.04 to 0.2 % - depending on the crop of the TCDD soil level could be found in the plant (Table 31) Table 31 C a n tM ln a tla a f p la n t* fro w i in tn# craafiftouaa an ontanlAAfaft t a i l nut (Naan iro n 4 p atal ta r if f (aarat Va4a c ra m f r a . M p ra a a a i Ui u i t u l la U iiiu (Jtifftim a cfttlrm j ppa TCDO In taa ta il i.i U.i lf t . a ppa 7CS0 1 c u c u i I n iAa p U n t a liilu 9.0104 0 .1 3 o .o c ftr 0.0ft b alav 4*t*at**la lia it - U .i o .c a a o 0 .1 4. Decontamination methods A rapid collection and storage of the vegetation under safety precautions on the basis of the analytical tests carried out during the first days would have permitted the disposal of the major part of the TCDD. A second possibility would have been the spraying of an H doner and the utilization of the UV part of the August daylight. 1G 791 DOW 2 7 5 1 0 0 The photochemical reaction would have resulted in a relatively rapid breakdown of TCDD. Corresponding experiments had been carried in our laboratories (63) shortly after the accident. Food quality olive oil was used as H donor (Table 32) . Other agents proved equally active but had been shown in preliminary tests to be less tolerated by the plants than olive oil. A limited field trials carried out in Zone A confirmed the laboratory findings. Tatle 32 I r u U m o f SS3 t t U r lU n o il o m a m ru t hh0iOnUwQvItUi*lientorUW O40r0leirlo1 tui luil/in*a-*l ih tm iH SCSO I * l la 24 fi ft r 44 ii it * r 26.i 16.9 9.6 19-1 xa.s 10.7 . U.J 1S.J X4.4 XeldaM ti%aiK * j.i 9 A decontamination program for the houses, gardens and land of the less contaminated part of the Zone A was worked out and operated by ourselves. The in- and outside of the houses were cleaned with special vacuum cleaners, 16 DOW washed and finally repainted. In the gardens 10 to 20 cm soil were removed, followed by a fresh layer of humus. The entire network of streets and paths was renewed and either paved with asphalt or stone slabs. Analytical tests after the cleaning operations failed to detect any TCDD and the evacuated residents were allowed to return to their houses. 2 The core of Zone A with TCDD levels of 150-5000 ;ug/m is still sealed off and behind fences. Moreover, it has been used as dumping ground for waste from other zones. The natural course of the TCDD breakdown will take, in the light of our present knowledge, 6 to 8 years. The area could, be make accessible by removing the contaminated soil layers and burying them in a concrete pit. The process would have the advantage of eliminating TCDD from the environment completely and rapidly. c h C 16*733 Conclusions Two years after the most publicized Seveso accident, when products containing the highly toxic TCDD descended on the surroundings of a chemical plant, an attempt can be made to summarize what happened. It is still not yet possible to explain the--,accident. The nature of the possible exothermic reaction which should have brought about a rise in the temperature in the reactor during the production of TCP with slow decomposition of the reaction mass, formation of gas and increase of the pressure, is #still unknown. Further experiments are needed to explain the mechanism of the accident. It was the chemical analyst who supplied the data for the assessment of the amount and location of the hazard. The detection of the TCDD and the measurement of its amount in our laboratories led to the definition of the contaminated territory and of the importance of the contamination. Neither the injuries on the humans nor the effects on the animals, on the vegetation and land would have been sufficiently relevant for the preventive and protective measures taken for the population and the territory. M ^3 Ol cn ro 16794 DOW Z 7 s ! u d - 67 - The harm induced by 7CDD on the health of the population either during the acute high level exposure of the first two weeks or during the lower level chronic exposure of the following 24 months shows the following main features: Chloracne, the-striking clinical feature which is suggestive of a TCDD exposure appeared in a very small percentage of the most sensitive group of the population involved. The manifestation was not limited to the first days after the accident but held on during the following months and is still lingering in the environment. The t skin lesions were rarely severe, mostly mild or extremely mild and always inclined to rapid and complete healing. Recidivism of the symptomatology was rare and occurred practically only in cases with mild or very mild lesions probably originated from low level and short duration of exposure. The incidence of chloracne and its degree of severity persistently decreased and has now reached a rate which is very close to the frequency of chloracne in the surrounding provinces. This fact suggests that the level of TCDD exposure has also decreased. The TCDD contamination of the environment has not affected neither the incidence nor the degree of severity of the puberty acne nor the current skin pathology of the region. One is inclined to 1S7SE Mon 63 assume that in these cases the skin lesion is the manifestation of the presence of TCDD in the environment more than a sign of the toxic effect of the substance on the human organism. The systemic effects of the TCDD exposure which have been reported in over 50 % of the chloracne cases occurred after occupational exposure in the past, have not been observed here. No laboratory evidence of significant hepatotoxicitv or deranged porphyrin metabolism, no abnormal neurologic findings have been observed in these cases. As for the other samples of the population (adults evacuated from the Zone A, inhabitants of the Zone B, plant workers of the Icmesa factory, decontamination parties) no prevalence in the current neurological and hepatic pathology of the region could be correlated so far with the exposure. The rata of abortions and malformations, the growth of newly born infants, the immunoresponse, the chromosome aberrations, the reaction to infectious diseases, the morbidity and mortality have not been affected by the amount of TCDD exposure. 16796 -63- i JiOi) In the wake of the accident a number of wild and domestic animals died in the contaminated zones. Affected were mainly small herbivores,- while only 1.7 % of the larger animals died. A small number of the surviving animals were evacuated for study purposes (8 6 ) while the rest (77 716) were slaughtered preventively in order to keep them out of the food chain. Chemical analysis of liver samples from dead animals confirmed TCDD in 78 of 158 samples collected immediately after the accident, at the original detection limit of ^ 2.5 jug/kg (highest values in the order of 300 ;ug/kg) . However, measurable amounts of TCDD in the liver do not necessarily imply anatomical or functional lesions. Apparently healthy rabbits with normal body functions were also found to have as much as 300 ^ug/kg TCDD in their liver. Many originally affected animals have recovered, consistent with other observed recoveries of horses in a Missouri mishap, where much higher TCDD concentrations occurred. This is due to the elimination of TCDD from the body. The elimination process has been studied in the laboratory. The half-life of TCDD in the body is 3-4 weeks for smaller animals (rats, guinea pigs, sheep, monkeys) and approximately DOW 27516(3 .. .. J. - 70 - 100 days for cow3 . If contaminated animals had been fed with uncontaminated feed sufficiently long, they would no longer have shown measurable TCDD concentrations in their tissues. Actual liver concentrations in the domestic animals slaughtered at the end of 1977 were at least three order's of magnitude less than in the rabbits in 1976. In many cases they were even below the new detection limit of 1 0 - 2 0 ng/kg (ppt). The study of the effect, persistence and mobility in the environment has shown that the cloud of chemicals which settled down southward of the plant had very little effect on the vegetation of the fallout area. About 80 % of the TCDD ejected with the reaction mixture adhered to the foliage, grass and crops for several weeks until it was transferred to the soil by the rain. Our field and greenhouse trials have shown that in Seveso TCDD does not leach vertically beyond a depth of 20 cm in the soil and that it disappears slowly by a natural degradation process and half of it is lost after 9 and 12 months. Plants do not take up significant amounts of TCDD. Only fractions of the quantity in the soil can be found in the vegetation and in a * the fruits growing in the contaminated area. A useful method for removing large quantities of TCDD from the area could have been applied immediately after the accident either by collecting and disposing of the vegetation or accelariting the natural process of degradation by spraying a suitable hydrogen donor. Today the remaining part of Zone A (115 acres) which is still fenced in could be made accessible by removing the contaminated soil layers and burying them in a concrete pit. The natural process of degradation would take 6 to 8 years. Reprints to be requested at the following address: Dr. G. Reggiani Research Department F. Hoffmann-La Roche 4 Co. Ltd. 4002 Basle Switzerland References 1. Abbruzzl, R. et al..: Identification and quantitative determination of 2 . 3 . 1 . 8-tetrachlorcdibenzo-para-aioxin in animals from contaminated areas. 4th International Symposium on Mass Spectrometry in Biochemistry and Medicine, Riva del Garda, Italy, June 20-22 (1977) G ? 2. Adamoli, P. et al.: Analysis of 2,3,7,S-tetrachlorodibenzopara-dioxin in the Seveso area. Ecological Bulletins No. 27, Lund 1978 3. Allen, J.R., Barsottl, D .A : , Lambrecht, L.K., Van Miller, J.P.: Reproductive effects of halogenated aromatic hydrocarbons on nonhuman primates. Int. Conference on Health Effects of Halogenated Aromatic Hydrocarbons. New York Academy of Sciences, New York, June 24-27 (1978) 4. Baughman, R . , Meselson, M.: An improved analysis for tetrachlorodibenzo-p-dioxins. Adv. Chem. Series No. 120, 92-104 (1973) 5. Bleiberg, J . , Wallen, M . , Brodkln, R. , Applebaum, I.L.: Industrially acquired oorphyria. Arch. Dermatol. 89, 793-797 (1964) 6 . Buser, H.-R.: Analysis of polychlorinated dibenzo-p-dioxins and dibenzofurans in chlorinated phenols by mass fragmentography. J. Chromatography 107, 295-310 (1975) 7. Calvin, M . ; Oral communication. Summing up of TCDD Workshop, Milan, Oct. 23-24 (1976) 8 . Carr, D.H.: Detection and evaluation of pregnancy wastage. Handbook of teratology,vol. 3, 189-213. New York, London: Plenum Press 1977 16800 DOW 27516) 9. Colombl, A.M.: Relationship between present volunteer research by scientific and technical popular ccmitee of_ Seveso and porphyrin and porphyrin pattern assessment on urines of TCDD exposed people in Seveso run by the Toxicological Department of the Agricultural University of Wageningen. Paper presented at the Thena Colloquium on "Chronic Hepatic Porphyria in humans" Agricultural University, Wageningen, The Netherlands, May 10 (1978) 10. Commoner, B., Scott, R.E . : Accidental contamination of soil with dioxin in Missouri: effects and countermeasures. Center for the Biology of Natural Systems, Washington University, St. Louis, Missouri, Sept. 29 (1976). Dioxin information project, Scientists' Institute for Public Information, New York N.Y. 11. Commoner, B., Scott, R.E.: US Air Force studies on the stability and ecological effects of TCDD (Dioxin): an evaluation relative to the accidental dissemination of TCDD as Seveso, Italy. Center for the Biology of Natural Systems, Washington University, St. Louis, Missouri, Nov. 13 (1976). Dioxin information project, Scientists' Institute for Public Information, New York N.Y. 12. Cunningham, H.M., Williams, D.T.: Effect of tetrachlorodibenzo-p-dioxin on growth rate and the synthesis of lipids and proteins in rats. Bull. Environm. Contamination a Toxicol. 7 (1), 45-51 (1972) 13. Dambroslo, F . ; Violenza, coscienza, aborto. Sapere No. 796, 85-90 (1976) 14. Dloguardl, N.: Critical considerations two years after the accidental pollution of Seveso "July '76 - July '78". Paper presented at the Press Seminar, Milan, July 2 (1978) 15. Doss, M . : Diagnosis and therapy of porphyrias. Springer-Verlag, Berlin, 1978 16. Editorial; Pesticide programs. Rebuttable presumption against registration and continued registration of pesticide products containing 2,4,5-trichlorophenol and its salts. Environmental Protection Agency, Federal Register 43 (149), August 2 (1978) Part IX 17. Fara, G.M., Marublnl, E . ; Monitoring birth defects: an Italian project. 3rd Conference of the European Teratology Soc., Helsinki, June 3-6 (1974) c C *5 18. Fara, G.M.: Introductory report on the epidemiological aspects. In Proceedings of the Expert Meeting on the Problems Raised by TCDD Pollution, pp. 39-46, Milan, Sept. 30 and Oct. 1 (1976) and Rapporto preliminare sullo stato di salute nella zona inquinata da TCDD. Quaderno di Documentazione 28.5.1977 19. Fara, G.M. : Seveso: Studies on teratogenic and otijer chronic effects of chemical pollutants following an accident in a chemical plant. Symp. Detection of t Teratogens, Montreal, August 21 (1977). A special Symposium held in conjunction with the 5th Int. Conf. on Birth Defects. 20. Fara, G.M.: Experiences of the accident in Seveso. European Teratology Society, 6 th Conference, Budapest, September 4-7 (1978) 21. Fraser, F.C.: Relation of animal studies to the problem in man. Handbook of teratology, voi. 1, 75-96. New York, London: Plenum Press 1977 22. Frlgerlo, A.: Identification and quantitative determination of 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD) in animals from contaminated areas: the Seveso case. 26th Congress of the International Union of Pure and Applied Chemistry (IOPAC), Tokyo, Sept. 4-10 (1977) 23. Garattini, S .: TCDD DOisoning at Seveso. Biomed. 26, 28-29 (1977) 24. Gianotti, F.: Chloracne au tetrachloro 2,3,7,8 dibenzo-pdioxine chez les enfants. Ann Dermatol Venerol 104 (12), 825-829 (1977) 1S802 25. Glovanardl, A.: Introductory report on decontamination problems. In Proceedings of the Expert Meeting on the Problems Raised by TCDD Pollution, pp. 49-50, Milan, Sept. 30 and Oct. 1 (1976) 26. Helnonen, O.P., Slone, D., Shapiro, S.: Birth defects and drugs in pregnancy. Publishing Sciences Group, Inc. 1977 o O 27. Helling, C.S., Isensee, A.R., Woolson, E.A., 'Ensor, P.D.J., Jones, G.E., Pllmmer, J.R., Kearney, P.C.: Chlorodioxins in pesticides, soils, and plants. J. Environ. Quality 2 (2), 171-178 (1973) 28. International Agency for*Research on Cancer. Monographs on the evaluation of the carcinogenic risk of chemicals to man. Chlorinated Dibenzodioxins 15, 41-102 (1977) O <1 Cl <1 t-- - 29. Isensee, A.R., Jones, G.S.: Absorption and translocation of root and foliage applied 2 ,4-dichlorophenol, 2,7dichlorodibenzo-p-dioxin, and 2,3,7,8-tetrachlorodibenzo-p' dioxin. J. Agr. Food Chem. 19 (6 ), 1210-1214 (1971) 30. Italian Parliamentary Commission. Report of inquiry on the release of toxic substances occurred on July 1976 in the Icmesa factory. Rome, July 1978 31. Jirasek, L . , Kalenskv, J., Kubec, K., Pazderova, J., Lukas, E .: Chlorakne, Porphyria cutanea tarda und andere Intoxikationen durch Herbizide. Hautarzt 27, 328-333 (1976) 32. Keamev, P.C., Woolson, E.A., Ellington, C.P.: Persistence and metabolism of chlorodioxins in soils. Environmental Science & Technology 6 (12), 1017-1019 (1972) 33. Kearney, P.C., Woolson, E.A., Isensee, A.R., Helling, C.S.: Tetrachlorodibenzo-dioxin in the environment: sources, fate, and decontamination. Environ. Health Perspect. No. 5, 273-277 (1973) 13803 34. Kearney, P.C., Isensee, A.R., Helling, C.S., Woolson, E.A., Pllmmer, J.R.; Environmental significance of cnlorodioxins. Adv. Chem. Ser. 120, 105-111 (1973) 35. Kocfba, R.J., Keves, D.G., Bever, J.E., Carreon, R.M., Gehrlng, P .J . : Long-term toxicologic studies of 2,3,7,8tetrachlorodibenzo-p-dioxin (TCDD) in laboratory animals. Int. Conference on Health Effects of Halogenatad Aromatic Hydrocarbons. New York Academy of Sciences, New York, June 24-27 (1978) 36. Matsumura, F. , Benezet, H.J. : Studies on ..the bioaccuraulation and microbial degradation of 2 ,3 ,7 ,8-tetrachlorodibenzo-pdioxin. Environ. Health Perspect. No. 5, 253-258 (1973) 37. Matthlaschk, G . : Survey about toxicological data of 2 ,3 ,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Dioxin: Toxicological and Chemical Aspects. TCDD Workshop, Milan Oct. 23-24 (1976) 38. Moore, J.A., Gupta, B.N., Zlnkl, J.G., Vos, J.G.: Postnatal effects of maternal exposure to 2 ,3,7,8 -tetrachlorcdibenzop-dioxins (TCDD). Environ. Health Perspect. No. 5, 81-85 (1973) 39. Moore, J.A.: TCDD toxicity. Symposium on Chlorinated Phenoxv Acids and their Dioxins; Mode of Action, Health Risks and Environmental Effects. The Royal Swedish Academy of Sciences. Stockholm, February 7-9 (1977) 40. Murray, F.J., Smith, F.A., Nltschke, K.D., Humlston, C.G., Koclba, R.J., Schwetz., B.A.: Three-generation reproduction study of rats ingesting 2 ,3,7,8 -tetrachlorodibenzo-p-dioxin. Tox. appl. Pharmacol. 41 (1), 200-201 (1977) 41. Neubert, D., Dillmann, I.: Embryotoxic effects in mice treated with 2 ,4,5-trichlorophenoxyacetic acid and 2 ,3,7,8 -tetrachloro dibenzo-p-dioxin. Naunyn-Schmiedeberg's Arch. Pharmacol. 272, 243-264 (1972) 42. Neubert, D., Zens, P., Rothenwallner, A., Merker, H.J.: A survey of the embryotoxic effects of TCDD in mammalian species. Environ. Health Perspect. No. 5, 67-79 (1973) IS 804 43. Piper, W.N., Rose, J.Q./ Gehrlng, P.J.: Excretion and tissue distribution of 2 ,3,7,8 -tetrachlorodibenzo-pdioxin in the rat. Adv. Cherti. Ser. 120, 85-91 (1973) 44. Pocchlarl, F .: Accidental TCDD contamination in seveso (Italy): Epidemiological aspects. In long-term hazards of polychlorinated dibenzodioxins and polychlorinated dibenzofurans. International Agency for Research on Cancer. Internal Technical Report, Lyon, June 1978 -jj CH T'' 45. Pocchiari, F.; Human health effects from accidental release of TCDD at Seveso (Italy). International Conference on Health Effects of Halogenated Aromatic' Hydrocarbons. New York Academy of Sciences, New York, June 24-27 (1978) 46. Poland, A.P., Smith, D., Metter, G., Posslck, P.: A health survey of workers in a 2,4-D and 2,4,5-T plant with special attention to chloracne, porphyria cutanea tarda, and psychologic parameters. Archives of Environmental Health 22, 316-327 (1971) 47. Private communication. Dow Chemical USA, Midland, Michigan 48. Reggiani, G.; Toxic effects of TCDD in man. NATO Workshop on Ecotoxicology, Guildford, England, July-August 1977 49. Rehder, H . , Sanchlonl, L., Cefls, F., Gropp, A.: Pathologisch embryologische Untersuchungen an Abortusfllen im Zusammen hang mit dem Seveso-Ungliick. Schweiz, med. Wschr. 10 8 (42) , 1617-1625 (1978) 50. Rose, J.Q., Ramsey, J.C., Wentzler, T.H., Hummel, R.A., Gehrlng, P.J.: The fate of 2,3,7,8 -tetrachlorodibenzo-pdioxln following single and repeated oral doses to the rat. (Toxicology and Applied Pharmacology 36, 209-226 (1976) 51. Sharma, R.P., Koclba, R.J., Gehrlng, P.J.: Immunotoxicologic effects of 2,3,7,8 -tetrachlorodibenzo-p-dioxin in laboratory animals. Tox appi Pharmac 45 (1), 333 (1978) W V ( Ji. f i 52. Slmonl, G . , Larlzza, L ., Sacchl, N. , Della Valle, G., Dambroslo, F., De Carli, L . ; Chromosome lesions in amniotic fluid cell cultures. Paper presented at the Symposium of the European Society of Human Genetics, Oslo, May 14-15 (1977) 53. Smith, F.A., Schwetz, B.A., Nltschke, K.D.: Teratogenicity of 2,3,7,8 -tetrachlorodlbenzo-p-dioxin in CF-1 mice. Toxicol. Appl. Pharmacol. 38 (3), 517-523 (1976) 54. Sgarschu, G.L., Dunn, F.L., Rowe, V.K.; Study of the teratogenicity of 2 ,3,7,8-tetrachlorodibenzo-p-dioxin in the rat. Food & Cosmetics Toxicology 9 r 405-412 (1971) 55. Schwetz, B.A., Norris, J.M., Soarschu, G.L., Rove, V.K., Gehring, P.J., Emerson, J.L., Gerbig, C.G.: Toxicology of chlorinated dihenzo-p-dioxins. Environ. Health Perspect. No. 5, 87-99 (1973) s 56. Strik, J.J.T.W.A.; Porphyrins in urine as indication for exposure to chlorinated hydrocarbons. Int. Conference on Health Effects of Halogenated Aromatic Hydrocarbons. New York Academy of Sciences, New York, June 24-27 (1978) 57. Tenchlni, M.L., Glorqi, R . , Crlmaudo, C., Simoni, G., Nuzzo, F., De Carli, L.: Approaches .to examination of genetic damage after a major hazard in chemical industry: preliminary cytogenetic findings on TCDD-exposed subjects after Seveso accident. Paper presented at the Symposium of the European Society of Human Genetics, Oslo, May 11-13 (1977) 58. Tuchmann-Duplessls, H . : Drug effects on the fetus. Monographs on drugs, vol. 2, ADIS Press 1975 5 9 . Tuchmann-Ouplessls, H.: L'accident de Seveso; donnes actuelles sur le dveloppement pr et post-natal. Bull. Acad. Nat. Md. 162 (5), 389-394 (1978) 16806 60. Tuchmann-Duolessls, H . : Pollution de 1'environnement et descendance. A propos de l'accident de Seveso. Mdecine et Hygine 36, 1753-1766 (1978) 61. Vos, J.G., Moore, J.A.: Suppression of cellular immunity in rats and mice by maternal treatment with 2,3,7,3tetrachloradibenzo-p-dioxin. Int. Arch. Allergy 47, 777-794 (1974) { f re c-na 62. Vos, J.G.: TCDD effects, mechanisms. Symposium on Chlorinated Phenoxy Acids and their Dioxins; Mode of Action, Health Risks and Environmental Effects. The Royal Swedish Academy of Sciences. Stockholm, February 7-9 (1977) 63. Vos, J.G., Kreeftenberg, J.G., Engel, H.W.B., Mlnderhoud, A., Van Noorlejansen, L.M.: Studies on 2,3,7,8-tetrachlorodibenzo- p-dioxin-induced immune suppression and decreased resistance to infection: endotoxin hypersensitivity, serum zinc z concentrations and effect of thymosin treatment. Toxicology 9, 75-86 (1978) 64. Waldenstrom, J.G.: The porphyrias as an inborn error of metabolism. American Journal of Medicine 22, 758 (1957) 65. Wassom, J.S., Huff, J.E., Loorleno, N.: A review of the genetic toxicology of chlorinated dibenzo-p-dioxins. Mutation Research 47, 141-160 (1977/1978) 6 6 . Wilson, J.G.: Embryotoxicity of drugs in man. Handbook of teratology, vol. 1, 309-355. New York, London: Plenum Press 1977 67. Wlpf, H.K. et al.: Field trials on photodegradation of TCDD on vegetation after spraying with vegetable oil. Dioxin: Toxicological and Chemical Aspects. TCDD WorkshOD, Milan, Oct. 23-24 (1976) 6 8 . World Health Organization Technical Report Series: Programmes of analy3 i3 of mortality trends and levels, No. 440, 1970; Spontaneous and induced abortion, No. 461, 1970 69. Young, A.L., Arnold/ E.L., Wachinski, A.M.: 2,4,5-T, 2,5-D. Presentation to the Weed Science Society of America, Las Vegas, Feb. 13 (1974), Abstract No. 226 70. Young, A.L., Thalken, C.5., Arnold, E.L., Cuoello, J.M., Cockerham, L.G.: Fate of 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) in the environment: summary and decontamination recommendations. United States Air Force Academy, Colorado 80840, Department of Chemistry and Biological Sciences, USAFA-TR-76-13 16808 DOW C H E M IC A L U.S.A. AN O ^C rfA I lN lj UN IT O P TH O O W C l-ltM IC A l C O M P A N Y MIDLAND. MICHIGAN 48640 SALES SPECIFICATION 2,4-DICHLOROPHENOXYACETIC ACID 2,4-Dichlorophenoxyacetic acid, minimum --'W u m ' b 'e r i O O ~ t BTE- 20683 7-9-'. NUMBER SUPERSEDES date 20683 1-17- M T H O O r a F - 4 N A L Y 5 I 5 --------- 20683a o O 99.0% O QD C DENOTES CHANGE The p o lic y of The D ow C h e m icoi C om pany is one of confirm ed im provem ents by rese arch ond m anufacturing w herever p o s s ib l e to a s s u r e a s t ill lin e r p ro d u c t H e n c e , s p e c ific a tio n s are su b ie c r to c h a n g e w itho ut n a n c c__________ ________________________________________________ FQPm 20780 PRIN TED R.J.74 Fo r a m ore com plete d e scrio rio n of th is product, includ ing ove ra ge p h y sic a l properties, p le a se refer to the a p p ro p ria te D o w t e c h n ic a l d o ia b u lle t in A l l sh ip m e n ts w ill be ac co m p a n ie d b y m inim um m a rk in g s w hich in c lu d e p rod u ct ide n tificat.cn . lot or patch num ber, net contents, com pany name ond ad d re ss, ond such pre c a u tio n a ry la b e lin g and other inform ation a s jeem ed a p p ro p ria te for th is prod uct SENT BY:CLARK, BRUMMIE, S 00. ;11-19-92 3:20PM ; 506 459 6720;# 4/ 6 2230 :\1 iV # * rj :o g | g r-; I c i I J t'jj- --- vflC rss n-^.TvJ-v-w.. (j 2fi * ,-t <"g V.* 1V--*- -V&>.'Jt6*'-.'-.*s.-.-:*"?>?,:**:*.y*.-;- y. tio . >V '.=::>i & C -i-'* '?\:'V-.L < ' * * -n . ^ / *: **.;, ** ;* -v_vT_ IMTsVij-^t.WURll-j*' -Vv.'&Lto.k:J* Imw~-If':*#*/ ps^v-rJ 16B1* 2296 DOW CHEMICAL U.S.A. POST OFFICE BOX 1706 MIDLAND. MICHIGAN 48640 June 27, 1973 b c c : D. D. McCollister/Action File M. L. Leng Mr. Richard F. Mountfort R. F. Flannery L. R. McCutchen Fungicide-Herbicide Branch L. Southwick Registration Division Environmental Protection Agency South Agricultural Building E. E. Kenaga o O 12th & Independence A v e ., S.W. Washington, D. C. 20460 as o oo CP- Dear Mr. Mountfort: Ul 04 04 cc VO Subject: HURON Weed and Brush Killer C3 EPA Reg. No. 464-162 Your letter of May 1, 1973 For convenience in review a copy of your May 1, 1973, letter is enclosed. We will discuss your comments by their numbers in that letter. Comment No. 1. At our May 31, 1973 meeting on Phenoxy Labels, Mr. Robert J. Taylor discussed our HURON label application of March 13, 1973 . In accord with that discussion and your letter we have deleted the recommendation for a tank mix of HURON and TORDON 101 Mixture for Forest Site Preparation until we have the phytotoxicity data requested concerning planting of conifer seedlings. To make your files more complete, we are enclosing copies of two brief research reports and a brief letter report indicating the general efficacy of such a tank mix for over all brush control. Notes on transmission line brush control test near LaPlace, Louisiana, 1972 by H. A. Nation March 1973. Report to The Dow Chemical Company. Notes on power transmission line brush control test near St. Francisville, Louisiana, 1972 by H. A. Nation March 1973. Report to The Dow Chemical Company. West Tree Service Inc. Letter report of October 6, 1972 to Mr. W. G. Wright, The Dow Chemical Company. A N OPERATING UNIT OF THE D O W CHEMICAL C O M P A N Y Mr. R. F. M o u n t f o r t -2- June 2 1 f 1973 comment N o . 2. We had previously changed the statement (page 10) to read " .... along the shorelines of ponds and similar aquatic areas ...." We believe the use of the word "of" rather than "in" is a non-substantive change and that the sentence as written expresses the idea you had in mind. Under Comment No. 2 - a request for additional bird toxicity data, if available. We have no additional bird toxicity data to supply. This' matter was -discussed between our E. E . Kenaga and your A. J. Duvall in a phone call of-May 8 , 1973. It is my understanding that there were no further questions raise;;. I also understood from Mr. J. W. Akerman at the May 31, 1973 conference previously mentioned that if he wished further information he would contact Mr. Kenaga. Five copies of labeling for this product revised in accord ance with the above comments are enclosed . We believe this label therefore is acceptable to you and look forward to receiving such official notification. Sincerely, O O 02 r ont o Wendell R. Mullison Registration Specialist Ag-Organics Department Enc. cah 1S812 SENT BYCLARK, DRIMIIE, A CO. ;11-19-32 ; 3:22PM ; 506 459 6720;# 5/ 6 WUD LIST tWiii Ctmmmi WMNMO WEED AG3D BRUSH KELLER =5=2=35=5 ^MipZ|*^*"^2 ia M b *N r N i#b i *M CAUTION io ru v n im m c tO M AwUC|>M with h * . IN md Cttirm b t f Om **71* I n * ^ CMfa* r a f t 6NXQU1NO CERTAIN HERBACEOUS WIEDS, WOODY PLANTS ANO AQUATIC WEEDS f mmm frtenAspisMMIftewftUMtfrhin rfMni M V n A M NUMMlwr I S TOWNOT M CMIOM W--iU-gA*-Tii*fa^Aiiiiull MW" I N ( M 4 tCi M M M w h M . . ___ __ M<M>A l mu _ ______ JLMh CAUTION o r our or mach Or cmuw in mICMfilBiafamnwaW mwwl 1 0SUON p a t i ni*' MMM -- * ' *-- i l l MB * "* Ml IMMMr i >4*1 M ''H u 1 rfew,, Ik IM JN VE 'fi1.'*! or*>i*92 m u r a tk p .s a . a u w m 19*7 V m u a s sn ctrxx u m jt-io si m in e s is s o m a n . 1*S. M B JULX. U t l . u ttiic s s ncuoE ; n i a s m e te m i m os m m IM M K T SOI H i m "USED ABB B U S n i n ( 2 > MuWaaPISrCasUoHsEeEa5TtAuTrUaOEiIcT.ue( I) is uB TnIsOuDmU.M w y r n . X-J''-'1?.U'!'1 U>5 ZC o c f t o a CAUTION r or *ucm or o m i- I CA liO N SiEiu:* i-d- /I l i p * - 1* M H ---W'* * * * ! * 'm . Ut *irJH. duhchms ktlH lM H p i* W f I l * t f k tfM W . w 1 I M * b t > - I w * m M l * * * * M * r * MwMwMfr*<t fi J-->himmh-u7mo >wmm mtmmi W T IM T M H I,C i MaCCMmMINVM tm* - M r 4* M i gw-- M M , l M > M < ft H ^ M >I -- N I|^I A f W*I w < M w f M.M WMp*>-- -- - m u N t i t r w r n i w M w M 4 -- l| Wlfcf *M>k Uu * p- >> r p |* * satiraeinam i^ > i .M n w w tM U M M M p M m - ! M W < . l r t M * * J M w P < H < l W I M w H l WM h w NHf. i p y H >iM tiifc * )WM <aw M r w ku w i i p H w 'n M il m t W M W ik USE JIECOMMfNDMIOM* IN SUGAI CAM KOtito m *I r*/r m w M - M H M D r w WMHMA M l i m c i t a V I ta n a p p u M f H H . M W W p i (, >W P M W t , 4M* * M *^ M i m i iKlw n * H W pw m >m >n r w n - w w M * - i m M l M h fc m ) r * M r t M i m i N m m M M m * W M m k w - M m M w i> M m u f tJ U - M m i r m m ii - M rw i n M l p m i l <m i i Ih mmw . m H *M | m i m m p -- m wm M * -m m W n L H y i l M i l W l W m w - m r n <w% tfM M -- i M . m - m . U m M 1 I f m i - w rM ifM p m f c m M M M M p m i u lr < m A M M M IU I *mW *m r iP ia iw M w t iiir H p m *^ flM --------m ' i --------r --i ~ r i r ~j i m u -r r* i i- v r * n - | m u f t i i n i 11 i p i m m i i i u m h i M m i f . M 11m pur y -- -- f U n t ^ h p - im . -- > -- p p r* ni M -- 40 16814 UUrtiUZ't T-- ( O CO CQ A c tiv e In g re d ie n t Silv cK I 2 ' 12.4.5 -T ric h lo ro p h c n o a y pro p io n ic A c id |. P r o p y le n e G ly c o l B u t y l E t h e r E it e r t . . . . . . 67.9% S ilve s I 2 - * 2 ,4 ,5 -T ric h lo ro p h e n o a y l p ro p io n ic A c id I, E q u iv o lc n t 4 5 , 0 % In e rt In g re d ie n ts . . .. ....................... ......... 3 2 . 1 % U .S.O .A . R c g iitro tio n N o. 4 6 4 .1 6 2 C o n t a in ! 6 .0 P o u n d s per G a llo n of L o w V o la tility E ste rs of Stlvex S IL V E X A C ID E Q U IV A L E N T 4.0 P O U N D S PER G A L L O N BRUS tf*N o w R e c o m m e n d e d f o r 4 A Q U A T IC W EED C O N T R O C ^ Submerrggee*! Agwaa*ti<t Wferft (in Foendi *4 0O>ikir*tr Still Wet*: -To ec>o>n'"0ol< cerrtoomn tub rrw'ft'j'jffnnli iwrreric1lt\ nH>x(hh 4ot\ wggiir> irTmhJlHlloil,. Ilogntw*og<ili t>)leor1i<tr><wwnnrffl aond o lr'w frd , u>mf QtuMQ'fMl of Kww/'rnirnt peir (XtT Ilroxoit of woor'err (IA n ocrtee lI "i1f' nofi g imr f >1 >f koctre *>n or* oOnoidJ one footl d fufop Thu\ on oc'rr of woo''*e* 5 left decerp will rterKh/ititrfr 55S QQoOort%% of HH* C 25 goitont * Apt>l, .n ro>i> m x i h f i wo'e* n ,np iio iw 'r it above SO F ood weedt o t r oDP'oochmg the w iif i w f o c r To oopfv piooerly. f'tt dlui* the Kwroo with rno^Qh w a in lor uniform dwtnbuton over the water twrfocr with the ipr0y etjuiflmenl Of hood ApoliCOtrOo roov fllVI bo mode Wrfh prOOfrly C0l*b'0fd proportioning rqi/ipmeni which .oufcmoticoHy m>>ei Kwron ood pood water >o the pt/mp NOTE Do nqi freol How og wo*fr with Kuifln Ponjf with o %fght current con be t*eo'e>l if the woir* lrcf coo be lowered vo the will be no Overflow lor of Irot 3 doyt ofter lreo,mrnt However, control will be lei\ around tport where uoireoted woter Hrwt mto he pond In Ireotmg thoreime of lo*>et or forge ptodt, ihrr wH be tome d^ufion coused hv 'he woter in the unirroted center oeot of 'h e bond. ihv* fore. > it betf to freot on o*eo at leo\> 200 tee* touore (M e ry iM Aewefic Weedir Tu confml r m r 'g f " ' weedt tucli ot wh.ie wafer lil*. parrenmet pictpreiwecd orrowheod etc . ute On* gofl'm of Kw un m 10 0 rja'li'n-. i i wo'er Apply ot a writing tpov ro 'ro rt and ilrm j when teoe> ore fully ili'\clnped otvr the waterline Br.o eai at nncrttorv Special Freiawiiant ter Ue it* A * r W eed C m ln l: Apply onl m o t c n ig '- c r with troie and locol lewf and fgutoiwm governing chrm'col treatment ot buO*et of water tor control Of w ftdt To OvOid injury. da rvU ute Huron where pond water it being uved for trr>gat>On in cluding rce production i. lor og'<Cuffuro( tprovt. domettic water tupply or fo' bvetrock woiermg W hen uted Ot recommended ObOvt. Huron it not ordinarily hormlul to aouo'ie on-mcm. but tome lith Vill moy occur, rtpeciolly m ihodow covet where uniform oppice'on it diM'Cult. Aooly Kurcei when water level i\ irw. to ct to keep ot o minimum the e>potue n I dptiioo'e ig* eto'ion along the tftorelme Since tnev nxjy coute interference with the act.n of Huron qq not opply olgoculet tuch at copper wllate lor J doyt before or alter ooo'vmg Cyron Here: T*0f pond edget or (ok thorcim* firtl to fith will not be trooped m tholiow pockety or mien. KEEP OUT OF REACH OF CH ILDREN Read Complcfe Precautions on Rear Panel uuntJz 4/ HURON BRUSH KILLER FOR CONTROLLING CERTAIN HERBACEOUS WEEDS AND W OODY PLANTS P articu la rly P o ll O o k , B lackjack O a k, an d N orthern O a kx tuch as Pin O ak, Red O ak. W h ite O ok and Scrub Oak DIRECTIONS geilonv of wOler per o<rr H.gh, a .Lviirl up tu I PO noMrvis oer Ode mo Ire Uted IO m inimiic tirili h o ta 'J A,.ui* m iiit ro'* sp'm g ot h.-1 -wroihrr u v n o * touve reces Kwfn lol.oor heit*tid* *s used >n controlling ceno* wcodv ond herbottout plants growing ,n poviw'et. rqngrioodt, l i 'H f rows, iiglii*ol<*ovi< and on ai<hbonkt sive damane <o lori 0 * nr aa<T i* irle*leras rette u d kent. I m v 4 . t4 St. Awgvitine. or la * tari at ny vanefy. Kii'O n > m controlling -- block,ock ook mopfet. such a red, northern ipm, red. sugar, end big 1* 0 h u e K iu b 1 oofci mqplr ground **v nfvjtiil poison >*v p io cerio* bioed'lr e v H r r d t u e b at -- piM m offd Curly mdigO <it^ ifhur lomb t'Q M rlrrt Croton f f i l Mexico t*lfd pokeberry post Ook lend thinnyty ook wild biockbevry yucca ragweed tali cedar tun I lower N O T I: Da not uve Kuron- for ih control of Oth P R E P A R IN G T H I S M A Y : Add half the required omount el * o 'r r iu the spror lonk. then 0,4,1 Kwin w.iK og.iptHn K u 'o forms on emuluon *n wafer ond tendt to settle out on piMi.wvqeil \la*!>ng Provide 0gi*0 " 0n lo prevent tuch sePO'Olton Ond mure uniform maaiurr <n (hi* tproy lonli FO LIAG E T R E A T M E N T : Sproy woody growth up to 6 or 8 eel toll ofier the folaogc it luliy Orek>oe<l. using o tproy conloming 3 to 4 QuoMS o Kuron per 10 0 goIIont o< woier. W ith tentative pecidi, toller broth or tree* rryjy be controlled i! oltoge it odrqupitly COetrd On paiiutn tty end biomplft tuch Ot wild blackberry, ute 2 ouortt of Kuron per 100 gallons ol woier Spray hawM drench ail plant peril m ly d w f In *i and item. Delay tpravmg new to'ciuls from recently cul turn* until they hove rnade appreciable growth Unler good growing conditions. applications mode up to three weeks before foU fritvl ore usually eMecibve. tproytng after (eaves hove lost ihetr normol green color ond vigor moy not gave SOl'tfoClory control Less effective control moy retufl during hot dry weather when i W p >oil nynvlure is deficient Utuolfv o Srngle oppftcolton in ony one year ts suffi cient if new (wih develops, repeat oPpiKanons may be necettory m succeeding years. A IR P L A N E A P P L IC A T IO N : for control of post and bfockiock ookt, ute 2 Ouorit of Kuron in I go'lon of J ir u l 0<l ond 2 ' j 10 3 ' l golhms of water, or 2 Quarts of Kurin m 3 ` i to f1/ goffnns o il'evel o*l per octe Apply alter folioge *s fully developed l usually m M ay or June* An additional tproy u un g I to 2 quorrs Of Kuron mgy be necettory the second or third year These oDpl'COtiuns will effectively control brood-leaved weeds in iproyed oreos. SPOT T R K A T M C N T : for tn o d tot1 Of>ol'CO*'n of Kuron. mia ' j cupful m ) gollons of wo'er. Wet oil lolioge thamaoghly W H O C O N TRO L IN ILAW NS A N O G O Lf COURSES-. for control ol b'ood-teoved plon* tom. buckhorn, common ch<kweed, mouse-cored Chickvveed. dondelmn. ond legumes such Os white clover ond block medic tn estobbshed turf, apply I 1j Q uo'tt of Kuron m 25 to 40 C A U T IO N : To OvOid domo<j f I I uf. iti noi spray in oy n o ''n( '' whach will oute eaCrtUve dntoges AvriaaJ overlooing enrl doubl CnvriOQe whrn bockmg up ond ol lu m i Avoid spreymg whyn oil-av ond boom ore noi rtvavang. >u<K ot **hfi* cleomng Or irstmg n e illr s Use 0 privi., ,|u.<v vhwI'Oll volvc On boom tproymg coummenl W IE D C O N TRO L IN RICE: Trro< 4 R .celai ofirr emergrr*<e of Ihc ncc W herr tluooed, teof between 7 od *t c ri ofirr terdmg, whrn pionls bove emergrd Ctrove water end leovet ore tiO'Hfing errai (J'e I 1/ io 3 p*ni\ o Kurnn m ihr o no u i'i ol water needed far pvfr ditlubuuon fin many vig o in n v 2 pinti per oce 't QilrquOlC Where Wsrdt lend IO be revtlonr barou-r Ol tpeCiC, oge or growlh condilMjn, uo I " 3 pini wilf givf b e lli' Control Treaimi-ni e iifr llooalmg i| usuafly tale' Ihon bifore floodmq Convoli yOur Slore fip rn n y iM Stoiirn m E.irm w n Service for tpecdic loco! recommendouont rOR C O N TRO L O f YU C C A A N O SAN O SH IN N C R T O AK : Use * P>m to 1 Quo of Kuron in > golfo diesel mi, ond water io moke 4 galluns loiol pe' ocre T * o to thrre opplicoiions qs necestary >n succrss-ve yeors moy be needril Apply ofirr fofioge fulfy deveioped Consoli com prim i locai ouihomies for inlormoi>on on besi tele ond bevi lime for appl'CO'ion locai ceedilM may eflect iKt wte a kribnidri, State africwllaral avlkeiiliei in many state ino ra<omme4ofini le fil locai tondifiont. USE R E C O M M E N D A T IO N S IN SU GAR C A N E F 1 0 R I0 A for oost emergence conrroi of regweed. dog lennel. ground <hry, purdone. wild feMucr. nighivhode od oihrr toscrp'ibfe b'Ood-fravra werdt. ooply * in I 'j ciud'i ni KURON in 20 io 40 gollons of *oter oc* n o e os brooJcos' tofoy MaVe ihr **st aopi>:o'">n alirr Ihr Cone emrrget Ot toring growlh ond whrn wreits oe growmg laorously. bui befo'C ihev send up teed tloiWt A tecond applaCei'on con be mode fot loie cmr>gmg weadv NOTE: Do noi opply oller Ihe con is 3 lo 3 ' ; fer ioli LO U IS IA N A for Ihe COnlruf ol <<obgrott bornyord grotS ond Jnhnvon* giost terdtings m tugoi con, OPOfy on* quon ef Kuron m IO gollamv of woier per ocre nn Ih * row loooroeimglrly onrIhrad of ihe loto oreoi thortlr (flore ihr teedt ore eapecicd lo germano! Il con* is thovfd ond oft-borrcU. eoi immed>oirfy loHnwmg ibis npcioiion follow ihe cori* Ucormenl wh*n necettory wiih 2 poundt of Oowpon* grotv killer per ocre, epplied Over Ih* greti m ih * row (oooroatmoirly one-ihird ef ihe tuia! oreo> Tu cirnl w iM U'Mocr Curlnf iVck, onJ nihrr wi'vils ove "ne ol ihe Inllowmg procedure whrn ihe werdv no* i/y iu-|v ]c ru-4i ' f 'iM vm iy w Creane Aepliart*n : U'.e t u ua " <rf K u im m I ro*li w*-. i.l w o'i lf' or rt- i h i >'-i" row OMiroumptrl >-ny ih n j ul in* toOl 0>rO- A M 'f-nd OW-MOImn I L> n**ijed On no m as* ouoikouu o n co*e ' i * 3 1r t io*l M ove a w l x d " ' 5 rwinrni Itrliirp hn'vrvl 't*n j - t oor Irosi 'tA ir A a o l x a l a a * : U I a iu O Ol K u r o n p e ' o c 'e m n v w j h w o ' to r i r v l v r w A p p l K o i v o c o n be amie u p ift r w v a ih v lir li u ,* h o ' r ' l HAWAII fai |r.rn y<jrn (r (ip .Ii , ni h o "* C'Ul.g'OV' *e'- * l" lo ,,, ri<hoailvmaio a.rr^.r.l lyth r 0"0O"lh. (Lu o I pO"'*b'W-h luaiglr u rr |*U-IO"r O"! '( j r o n H oaduon M-OO (0"C OM)1* 4 li* 'i aiuo'iv Kua.ni pr> 0C*I' ,n ''I " 1 )olk"*s i l v j l " O O l i i 'O-HO'i sire rvwnvdiaielv OHrr plqninH) IQr^aoning twf>re Cone emvigence f-* cv-si *"> cv Contro! pi weeds ocr cours h0e emerged od.! ! ' . *' > pounds &>wp,v* pe* q<e tu ih* toroy of Kuron in ruder ip cnnirol gaotves ond vproy Ih,- inifitanf soocr *<lhl vpaOv*ng Ihe con* darecily This Opotacolion con b* mode Up lo Ihe firn* ol **Clalvmg m ' tapi rant levi ihon 5 months before horesf Do nyf mo*e more hon U o OOOf'COlaons u* 5 UuC'tv eoch of Kurnn tu ony One C'Dp LuCOl COnd>laOn\ mus o*Cl Iha* uM "* h fb 'C 'd l't S '0'e ognCwllU'Ol OpafVja.i^v .n mqny Sio ln issue recummcndolaunv f0 fa* lOCOi conditions Dn noi oppi Ku'Rn dirrc'l *0 or iihrrwive perm.i | to corri* ,nlv conioc* w.lh o " C " o pioni nr r.inonynlo' D'onf 'inclotlang t-ul ami limiteli la) peonott. SOvhv'onv t u o "* pnOV. l'tmoinev l'4aot( ai cralinn, nsfliy**, vro m re i pntotnes, peppers. C rU 'v nwerv .a*a- m, aatol*. Q'OIarv, alee><lu>tu'. O'wl n*m,|, <>ilu -u. l'o 'l larfs 1 Onal 1 rv .1 permi, Npir) m.- r t -m. tO'nnag Kurnn In (fili ,u-lii Ihrm i.mce m.n,,ip q uon'.lif, n o , (OHM t-.rrp .temij-* durarvi |vlh griiwmg oivl .(.rmflnf |,a> I, ( o i y i (ko ,', o h ' Ir., M i 1, Appli- lin| ky irptane, ground rtgs nd kand iipcmcr ihauld he m ef al ly when irr* il n h **i4 lrm dnft. 0 nat apply by arpione in Ihe vicinar* f ny et<rki* pi *r prnmraiafi mcludany tkaie fiifed eknv*. A i elevate! irm iu ro 'uaev *oia>'(Oiiur* " e * Cfluse iniury in suvct'piiblc plonlv qa> wang nco<l>v io n -yOr* nn* u v e K u 'la n On la e v h lv v e rd a 'd l o > " i p O 'lw 'e v u r 'o n d u n l i l Q ovs h o v b r< >mc SVflI f s lo lll a s h r if Da* rsaal CIV'IO m in Q le ir r a ijn la i'n . |. t c l , i n i vO>r u -I I * 11 m n v l- f f,uitp-**V D o m s tu r e n*O I I v r l a U jr a v v r r j lv m v * C lir V v l u ''g * ( '!*> T - >n-.u,v I. .Obif p i o n l s alo n o i v ln r e , h ija n llr *' O M 't* 'k i 'i p'*i< .aliai'O l rh * m i r i t i , w iv . i n , v o - f < - - i o .......... Or rOu'pmenl OM'd fi Kiliaci D * ! u -r Kaa- *> 'l'io * "*0 ,.|Uap''iani ; i>aom.->Vj,r i| .ih 2,4 .0 at th 2.4 .0 all **H'ii'x ihr hacoM i .l<-.a.oi>l>' (.)*^ fic iure (hot m e o f th ii produci co n fo rm i to o li opplieobie rcgulofrons. M A Y CA U SE S K IN IR R IT A T IO N A v o id C o n foct w ith Eyes. Sk in ond C lo th in g Keep O ut of the Reoch of Children N OTICE: Seller motet nn *orao>>iv ..I >*.. i Ol (has produci 0u*rr o "1'* OH aavk ,.l uv direci'Ons nr not U K r : h o n a l'a n g . w hrr*.-a o < t - ' JO 1* T P --*** DOH2022542 directions tn *>*. >* #.*'!. .............. .. , . , . . . 1 1 . - 9 . . , . ,, I. . 1 tl ** W*ki. len/e '** " .9 W .Ql.-r0 y P 'o" H " P O ,' >" ' v iti .?d H oikbfrry. ............. .. k...V l . . ,, J - . . V . . h a . . . k l . b u . , .o n wood. curly ,ni,9,. lo r"b , ........... ............ .. ,, , , d . . . i . b c . n , . < o ~ . d . c o ll d o . , t u n l l o w . r . NC'f 0' '** <** < v '* U be <! ih . :h ( IMAT A,H nil is* n -* * rd s # v f l ' 9 I w ote* 0 be p ray to n k . b eo o d d X v io " ~ ,,K .. r . . , . ,,.- 0 in .aie p n d ten d to out on p ro lo n g ed tto n d .n g , N o*d* .................. f , . , . , . . 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M in. * I l lN f l l f 0 * . j ** fo n d ;i,* w*# ***^*'* d , ipAdt r* rh * # f p*odr* * -- - i**ot - v m 1 ' rik o f a n y v ih j * a oato-oW y <****< iil07.0l0 3 U s. f t *a ` MO. 00 vH CD CO. s-\ 2302 U .. D EP A R T M E N T OF AGR ICULTURE AGRICULTURAL RESEARCH SERVICE P E J T I C I O E S REGULATION DIVISION WASHINGTON. D.C. 20200 APPLICATION FORIaMENDEDI REGISTRATION OF ECONOMIC POISONS (Under the Federal insecticide, Fungicide, and Rodenticide A ct) form approv ed BUOO I T BU RE A U HO. AO-FU7A6 1. D A T E O F A P P L I C A T I D h IMPORTANT* r e Ao i n s t r u c t i o n s on r e v e r s e October 17, 1973 "> 2. n a m e o f e c o n o m i c p o i s o n (Must be same product name as on label--do not list active ingredients J KURON 3. N A M E M A I L I N G A D D R C I I O F R E G I S T R A N T ( I n c l u d e Z i p C o d e ) ' Dow Chemical U.S.A. . r P. 0. Box 1706 Midland, Michigan 48640 REG ISTRATION HO. 464-162 C PROPOSED EFFECTIVE DATE OF CHANGE ^ Attn: Fred lloerger O/ As soon as possible. Q ! _____________ -- 6 , n a t u r e o f r e v i s i o n (Check applicable item and give details in item 7, when required J GENERAL REVISION OF LABELING Q CHANGE IN FORMULATION Q ] (Give description of exact change in item 7) OTHER (Specify m item 7) ADDITIONAL USES ADOED TO LABELING C ] (List new recommendations in item 7) CHANGE IN P R O D U C T NAME I I (Give old name and new name in item 7) ' :-i 1 7, d e t a i l s r e o u i r e o BY r e v i s i o n c h e c k e o i n i t e m (Attach additional sheets i f more space is needed) For a number of years, Louisiana has recommended the use of KURON [2-(2,4,5-trichloro- phenoxy) propionic acid propylene glycol butyl ether esters1 herbicide in combination with dalapon, sodium TCA, and 2,4-D for control of a variety of weeds in sugarcane. Each of the herbicides is currently registered for use on sugarcaneein Louisiana, but the current labels do not bear specific directions for the combination treatments as recommended by Louisiana. . ..... - This application therefore consists of a supplemental labeling brochure to cover the combination treatments. The brochure is intended to augment the individual product labels and pepresent too much printed material to include on each product package label*. Based on state recommendations, the combination treatments have been used commercially for a number of years. We believe that Federal registration would bring these practices ttithin the intent of the Federal Environmental Pesticide Control Act of 1972. The attached volume "Technical Information on Tank. Mixtures of Dow Herbicides for Louisiana Sugarcane" provides data supporting the practices. It also seems noteworthy that commercial field experience has been extensive with satisfactory weed control and no indication of adverse problems. - I I CONTINUED ON ATTACHMENT 8 . T H E F O L LO W IN G M U S T B E S U B M IT T E D W ITH T H IS A P P L IC A T IO N F iv e (5) co p ie s of re v ise d lab eling, in clu d in g any printed or graphic m o lt*' .which may accom pany the s a le p i th is product. C o p ie s m ust be c le a rly legible and identical. A t l l O C l l C u v If o change in form ulation is involved, five (5) co p ie s of o statem ent or revised formula show ing the p re cise name ond precentoge o f each a ctive end each inert ingredient, (This information is treated confidentially) B WVi,n o pp ro prio te, th ro . (3) copia of SuppoM Ing Dolo.Attachcd 9 . SIGNATURE OF AUTHORIZED FIRM REPRESENTATIVE ^r RINEGAINSYT RCAOTRIORNE SNPOO*NIDNEINTCEME O4 N, ATBHOISV PR E. O O UC T REFER TO TITLE 11, DATE SIGNED Sr. Registration PR FORM 9-198 MAT 1969 SEWXpILIeSLTcBINiEGaUlSiSTsEODtCKU NOTFIfLtPeERtXoFHObARaUMcST9E-11D978. (A1U9G7. 3(9681- APPLICANT'SCOPY exhibit c (CONTINUED) Do W o a 3 OO :;URON registration file including communications with 1SDA and EPA 1963 - 1974. 30. Application of July 17, 1970 21. Application of November 10, 1964 22. Application of May 15, 1963 23. Application of October 17, 1973 '4. Label of September 19, 1966 and Application of July 12, 1966 25. Label of November 24, 1965 .-5. December 1964 revisions - Florida Sugarcane 2 7. Revisions of early 1964 38. Getzendane.r, RESIDUES OF SILVEX AND SILVEX ESTER IN SUGAR CANE RESULTING FROM AERIAL APPLICATIONS OF KURON' 29. DETERMINATION OF TRACE AMOUNTS OF 2,4,5-TP AND THE PROPYLENE CLYCOL ISOBUTYL ETHER ESTERS OF 2,4,5-TP IN SUGAR CANE PULP (April 9, 1963) 30. A RESIDUE STUDY OF KURON IN SUGAR CANE 31. DETERMINATION OF TRACE AMOUNTS OF 2-(2,4,5-T)-PROPIONIC ACID OF THE PROPYLENE CLYCOL BUTYL ETHER ESTERS OF 2(2,4,5-T)- PROPIONIC ACID IN SUGARCANE PULP (Sept. 24, 1959) 32. DETERMINATION OF TRACE AMOUNTS OF PROPYLENE CLYCOL BUTYL 16821e t h e r e s t e r s o f 2-(2,4,5~t ) p r o p i o n i c a c i d in s u g a r c a n e r' JUICE (August 13, 1959) I 7?OW O a 99 3 0 0 c 33. K U R O N U S E R E C O M M E N D A T I O N S IN S U G A R C A N E 34. COMPARISON OF SILVEX AND DCMU WITH OTHER COMMONLYUSED HERBICIDES FOR PRE-EMERGENCE WEED CONTROL 35. COMPARISON OF SIMAZIN AND OTHER NEWER HERBICIDES FOR PRE-EMERGENCE WEED CONTROL 36 RECOMMENDATIONS FOR JOHNSON GRASS SEEDLING AND JOHNSON GRASS CONTROL IN SUGARCANE by Ernest R. Stamper and S. J. P. Chilton 37. REPORT OF THE DEPARTMENT OF PLANT PATHOLOGY TO THE AMERICAN SUGARCANE LEAGUE FOR 1958 16822 <Cooc6 * C o 38 . EXHIBIT D HURON specimen labels dated: May 20, 1974 January 21, 1974 November 16, 1971 January 12, 1971 October 3, 1969 May 29, 1969 August 1967 June 1967 August 1966 39. Miscellaneous labels i 16823 t 3 O C ? C i K 0 /wo <C 40. EXHIBIT E KURON Complaints: 1. E. L. Hand - Lake Jackson, Texas 2. John Norton - Glendale, Arizona i i J /fZ* A* / .Z) ^ EXHIBIT C 23 u3 KURON registration file including communications with USDA and EPA 1963 - 1974. DOW 2 8 9 2 1 8 MN 0 2 2 7 7 ? 16325 MNO 2 7 509 2307 /Z i- < 5 1 0 ,5 .0 AG RICU LTUR AL PRODUCTS DEPAR TM EN T -9001 Midland, Michigan 48640 COPIES TO: INDEX 18 R. CHARLTON M. NORRIS W. MULLISON A. WATSON S. VRANISH B. SCHWETZ W. CRUMMETT T. HAAGSMA K. WATSON' E. BLAIR R. MOFFAT E. LANING H. VERSCHUUREN D. McCOLLISTER J. SCRIVEN M. TUCKER J. WESELOH M. LENG R. MAIN B. McCREDIE M. WINE O. WOLCOTT F. TSCHIRLEY u: JOHN H. DAVIDSON 517-636-4826 16826 DOW 1664268 KO.IOVKOLOflV \ND ENVIRONMENTAL SAFETY4.96-102(IVb'Ol PANEL REPORT Panel tNoewDisYcoursksCthitey, EJpuildye1m0i-o1lo1g, y19o7f92,4,5-T Chairman: Dr. F r ed er ic k C o u l st o n Rapporteur: D r. E u g e n e J. O lajos Received October 19. 1979 MEMBERS Dr. R. C o D rM. eFd. icCaol loClkos.ltlEeogpnei,.dPeAmrlobifoaelnsosygo.irsNta.enDwdoDY.'oirCrekchte(omCrh,icaianirlsmtUiat.unSt).e.Ao..f Midland. Michigan. Comparative and Human Toxicology. Albany DrO. rFeg. oDn.e c k e r . Associate Professor. Atmospheric Sciences. Oregon State University. Corvallis. DrM. iPc.hiJg.anG.c h r in c . Director. Toxicology Research Laboratories. Dow Chemical U.S.A.. Midland. DrY. oEr.k.CN. eHwa mYmorokn. d . Vice President, Epidemiology and Statistics. American Cancer Society. New D rC.liRni.caHl aPrhbairsmo nac.oAlosgsyo.ciVaatendPerrboifletssMoredoicfaPl hCaernmtearc.oNloagsyhvainldle. Biochemistry. Tennessee. Division of Pediatric MsN.eMw. YHoartkc. h . Division of Epidemiology, School of Public Health. Columbia University. Ne York. Dr. J. Kline. Research Associate. Gertrude Sergievsky Center. Columbia University. New York. New York: and Research Scientist III. New York State Psychiatric Institute. DDDrrrAM... lbeEEId.a.. incMJSyi.nerOeMla.ilekkM.da.oijCocfoaufhsln..atC1nRScoDeeilsnillerleaoaegircreStc.oEhcArhm.lAobeosEralsinntiosuyvtfs.iar.nMNoUtneenmwPdiievrcnoYeirfntoeasersil,ktsyoNS(rocRe. ifwaeIpCnnpYcsatoeloiisrtfrutoketrLu.enraNio)ba.ef.owrCDaoatYomvoriprysk.a.rCaanatdilvifeoPrarnnoidafe. sHsourmaonf Toxicology, Community D rY.oSr.kS. t e l l m a n . Chief. Computing and Biostalistics. American Health Foundation. New York. New Dr. Z. Stein. Professor of Public Health. Division of Epidemiology. School of Public Health. Columbia University. New- York. New York: Director. Epidemiology of Brain Disorders Department. New York State Psychiatric Institute. REPRESENTATIVES OF OTHER ORGANIZATIONS Ms. Ms. M r. M. P. L. RMForabarenkrkteWsn.i-bnEeenr.vciK.r.oirEnkmnlaveninrdtoan<lSm:PeErnlolttiaesl.ctPWio-.naostehAciglnieugntt:ocnyA..gDWen.Cacsy.hinWgtaosnh.inDg.tCon. . D C. 1. INTRODUCTION This report contains the collective view-s of a group of experts who participated in a Panel Meeting to " Discuss the Epidemiology of 2,4.5-T," held in New York City on July 10 and 11. The purpose of this meeting was to discuss the epidemiologic 1In attendance on Day 2 only. OM7-65I3*0010046-075.02.000 Copyright *' iv*u hy Academic fYes\. Inc Ail nuftiN of reproduction m in> form reserved 96 PANEL REPORT 97 methodology and data used by the Environmental Protection. Agency in its recent action suspending the use of 2.4,5-T because of the possibility that spontaneous abortion rates increased in the Alsea basin area of Oregon. Dr. Coulston. in his opening comments, stated: The EPA is to be commended for its desire to insure the health of the public by removing any possible environmental hazard. The position of this meeting should not be forgotten. We are here not to judge whether 2.4.J-T is safe for use around man. Or. Barbara Blum. Deputy AptBholdauitmnmttishn:eeimrsntearpmwahtaaeoslsryiazo,neftdhtihnavtecertErheyaPesrAecead.wriinenaftscuhiladelyepdnroaconcebudlomefImesqnp, utothonoattfetaMna"ceaWcorocuehrsdaa1irnb,ego1r9ntt7ooi9otinnpssfraoeiyrnsimenangactteeitdorhtnaaatitnnhtuheamerEebhaPeeAroafolhtOfhairsneetrfgeTeorceenecs.titvsDi_enirdng. humans are positively proven, or that 2.4.3-T should never be used again. What we are saying is that there is sufficient evidence to stop further exposure to the chemical until the issues can be resolved." What was the evidence EPA used? Was this good evidence in the sense that it follows good scientific, epidemiologic procedures? Had the EPA acted too quickly? The Panel considered the following points: (1) Whether the Control and Study areas were indeed comparable? (2) What was the true spontaneous abortion index? (3) What was the actual individual exposure and what other contaminants may have been present in the Study area? (4) Was the analysis of the data a correlative one and if so. does this relate to causation? (5) What kind of definitive study should be done to settle this controversial problem, namely, did 2,4,5-T indeed increase the spontaneous abortion rates? Available to the Panel were all pertinent reports from the United States as well as foreign countries on the subject of 2,4,5-T and spontaneous abortions. Most of the discussion related to Alsea I and II, but other documents were also considered in light of the experience of other epidemiologists and scientists from different geographic areas. The documents are listed in Appendix I. 2. SUMMARY OF FINDINGS 2.1. A lsea I R eport The Alsea I report was based on an extensive health questionnaire administered to nine women who had experienced 13 early spontaneous abortions in the Alsea. Oregon, area from May 1973 to March 1978. In general, the study design was adequate; however, several flaw s characterize the study: (I) A major flaw in the study w'as the failure to define the array of miscarriages that were distributed among the women reporting spontaneous abortions. Therefore, the possibility exists that at least a number of these miscarriages were experienced by miscarriage-prone women. (2) There was no attempt to identify specific causes for any of the miscarriages: for example, exposure to other pollutants and contaminants, advanced maternal age. prior history of abortion, heavy smoking, alcohol use, and chromosomal or morphologic abnormality in the embryo or fetus. (3) There w-as no documentation of exposure to 2.4.5-T. 2.2. A lsea II Report The Alsea II report was a follow-up to the Alsea I study where it was noted that 12 of the 13 miscarriages reported by the original nine participants were for terms DOW 1 664269 16828 oiz/?9dTnoG. 98 PANEL REPORT under 20 weeks. In the Alsea II report, the investigators compiled the rates of hospitalized early spontaneous abortions (less than 20 weeks term) in three areas of Oregon: (1) a Study area, which centered around the Alsea basin including additional contiguous areas: (2) a nearby Urban area (Corvallis): and (3) a Control area, a distant inland rural region located in eastern Oregon. Although the objectives of the Alsea II study were valid, the study was poorly conceived and designed. Indeed, even taking into account the aspects of confidentiality and public pressure, the study design was still inherently very weak. Numerous shortcomings, invalidities, and biases characterize the Alsea II study. A number of the most apparent deficiencies are described below. 2.2.1. Collection of Data and Data Input a. Only hospitalized spontaneous abortions were reviewed with no consideration of clinic data. This resulted in a significant bias when one compares the Urban area with the Study and Control areas. Spontaneous abortions were treated in hospitals in the Study and Control areas, whereas in the Urban area they were treated in hospitals and in clinics. The lack of data for abortions treated in the clinics in the Urban area seems to account for the notable difference in the overall spontaneous abortion rates among Study, Control, and Urban areas. b. The investigators of the Alsea II study examined the rates of spontaneous abortions in a Study area and compared those rates in a comparable Control area. In no manner are the Control and Study areas comparable: the Alsea II investigators had not determined whether real differences existed in demographic and geographic characteristics that could affect the rate and seasonal pattern of spontaneous abortions. The two areas are not compatible with regard to socioeconomic and population parameters such as: (1) life-styles: (2) emplpyment practices: (3) ethnic and racial makeup; (4) health care delivery systems: (5) medical practices: (6) environmental pollutants and infectious agents: and (7) additional background factors within the two populations. The demographic characteristics including occupation and ethnic composition may influence the use of medical services between the Study and Control areas, particularly, if related to season, may produce spurious results. More importantly, the Alsea II study had not analyzed the comparability of the Study and Control areas with respect to variables known to be associated with spontaneous abortion, namely, maternal age. cigarette smoking, and alcohol usage. c. The Alsea II investigators intended to compare only those abortions occurring within (he endogenous populations of the Control, Study, and Urban areas. The abortion and/or birth rates may have been significantly altered by the inclusion of abortions of seasonal residents in the Study area, which may experience an influx of population during the summer. The summer transients within the Study area coupled with the exodus of people from the Urban area would maximize me difference in the abortion rate that occurs during the summer months. d. The documented spray areas represented only a small proportion of the Study area, which in turn was defined by zip code. The question which immediately comes to mind is where in the area did the people live in relation to the 2.4,5-T-sprayed areas? Furthermore, the unjustifiability in using zip codes is also apparent when one considers the possibility that a summer transient hospitalized for an abortion in the 00W 16642V! PANEL REPORT 99 Study area could have given her summer address at the time of hospitalization, and perhaps be classified as a resident of the area. Only those women who were living in the area at the time of spraying could have provided the necessary data base relatively free of variables. e. The Alsea II authors used two types of variables: the effect measure (hospitalized early spontaneous abortions/live births) and exposure data (acres or pounds of 2,4,5-T). As they stated in their report: Thus, the data from the Alsea basin illustrate a pattern which may be considered as representative of the Study area. The above quote refers to the spray data and represents their justification for extrapolating the pattern of exposure from sampling 2,4,5-T usage in the Alsea basin to the entire Study area. The investigators of the Alsea II study have correlated exposure in a small area with outcomes in a larger area, and it is essential that they discuss how representative the Alsea basin spray data is of the use patterns in the entire Study area. One may question if the amount of 2,4.5-T acreage, and timing of the sprayings are similar; therefore one must know exactly to what extent they may differ. f. There was no attempt by the Alsea II investigators to estimate variability. 2.2.2. Ascertaining Reproductive Effects a. The overall incidence of spontaneous abortions as reported in the Alsea II study was as follows: (a) Study area (8.1%); (b) Control area (6.5%); and (c) Urban area (4.4%, unusually low). In a gener. ; discussion pertaining to the spontaneous abortion rate, it had been stated: We have estimates of the rate of spontaneous abortion (all recognized spontaneous abortions). Take the one good prospective study in Hawaii: maybe estimate that 1/4 of the pregnancies diagnosed after 4 weeks from the last period will abort. The highest we would estimate is that 1/4 of the pregnancies that you know exist at 2 weeks post-conception would abort. People estimate all the way be that 1/4 of all recognized pregnancies wupill10ab9o0r%t. but we think a sensible estimate would It was the consensus of the panel that the hospitalized abortion rates reported in the Alsea II study were low. Estimates of hospitalized spontaneous abortion rates in the United States generally range from about 8 to 15%. It is not known whether this range reflects real differences between populations in the rate of spontaneous abortion or whether it reflects differences in patterns of service use. Estimates of the rate of spontaneous abortion from obstetric histories are usually somewhat higher, ranging from about 12 to 18%. The hospitalized abortion rates reported in the Alsea II study are on the low end of the spectrum when compared to other hospital-based studies. Since spontaneous abortion indicates a strong association with maternal age. evaluation of these rates should consider the maternal age distributions of the populations as well as the possibility of differences in service use as an explanation for the somewhat low rates. b. The study was not based on a cohort of women all concei ving at the same time. The importance in examining the outcomes in a cohort of women conceiving at the same time is that for reproductive health effects (as opposed to other types of 16830 100 PANEL REPORT effects) the timing of exposure is critical: for example, with radiation the conceptus is sensitive to particular outcomes at some stages of gestation and not at others. c. The gestational age was determined by the date of abortion and in some cases was not well defined. One must distinguish a preconception from a postconception effect, the miscarriage must be analyzed by date of conception or last menstrual period, and not just by date of abortion. The manner in which gestation was estimated varied tremendously from hospital to hospital: therefore, the possibility exists that women may not have conceived at the time of purported exposure to 2.4.5-T. d. The extracted hospitalized spontaneous abortions (HSA) were not identified with individual women: therefore, a small number of chronic aborters in the area could have significantly biased the results. e. The live birth database was collected in a differential fashion between Control, Study, and Urban areas. f. A serious bias was introduced in the computed hospitalized abortion indices (HSAI: HSAl = spontaneous abortion data/weighted live birth data). The weighted live births were derived from gestational ages aggregated over the entire 6 years, these weights were somewhat unrelated to the gestational ages of the monthly spontaneous abortions found in the numerator. The weighted aggregate method would potentially smooth out the denominator data which would make the index more dramatic in monthly peaks. A more serious error is noted in the weighted live birth data (denominator). The authors of the Alsea II report stated, and we quote "The computed monthly births for the six-year interval were divided equally between the two periods." This assumes that the births were relatively stable for all areas over the entire 6 years. The raw data provided by the EPA subsequent to the emergency ban clearly indicate that the above assumption was not valid. The births rise slightly in the Control area during the last 3 years, but more dramatically in the Study area. The equal division of births produces an artificial rise in the HSAI of the Study area for the second period. 2.2.3. Documentation o f Exposure and Exposure Levels The EPA assumed a dose-response effect in the absence of validating exposure. The failure to examine the data with respect to exposure is unfortunate since it is absolutely critical in demonstrating that 2.4.5-T or any other compound was associated with or had caused an increase in the sDontaneous abortion rates. Normally, one. tries to establish the use pattern, occurrence, and the levels of whatever chemical agent is being examined in order to determine a correlation with a biological event. It is very disturbing that the authors of the Alsea II Study had not: a. provided data on human and animal exposure :o 2.4.5-T as well as providing an estimate ot the levels of 2,4,5-T in the aborted pioductx of conception (no attempt was made to determine the individual exposure or to ascertain whether any other contaminantts) was present in the Study area): b. attempted to identify an independent source of data existent, so one could cross-check exposures; c. concentrated on the time relations of the raw number o! abortions in the Study area (the lime exposure is absolutely critical, the data had not been examined in the above manner). C~i CO cU {C C TC 36231 DOW 1664273 PANEL REPORT 101 3. CONCLUSIONS After reviewing all the documents and the data presented, including the Alsea I and II repons, the Panel expressed the following conclusions: a. The new evidence (Alsea II) did not demonstrate an effect or the absence of an effect. Neither cause nor even association of the use of 2,4,5-T to the incidence of spontaneous abortion had been demonstrated. b. There was no evidence to establish a causal relationship between 2,4,5-T exposure and spontaneous abortion. c. There were no data of individual exposure to 2,4,5-T or to. any other contaminant or pollutant in the Study area. d. With respect to 2,4,5-T exposure and spontaneous abortions, the majority concensus of other panels and expert reviewers of the Alsea II study was that no relationship exists. e. The overall spontaneous abortion rates reported in the Alsea I and II documents (8 to 14%) are well within the background spontaneous abortion rate of the general population. f. The Study and Control areas of Alsea II study were too diverse to be considered comparable. The abortion data for the Urban area cannot be properly compared to the abortion data for the Control and Study areas. In fact, the data base obtained from the Urban area should be dismissed completely. g. Only those women living in the area at tne time of the spraying of 2.4,5-T should have been used for the data base in the Study area (Alsea II study). h. The Panel could not draw valid conclusions from the cluster of 13 cases in the Alsea I study because the data base was derived from a very limited sample size. 4. RECOMMENDATIONS a. Both the Alsea I and II studies could be made more informative by reanalysis of the data and additional data. Pivotal to such a reanalysis would be the utilization of established cohorts, the uniform definition of gestation age. and the collection of complete spray data. However, even with such improvements a crucial problem would still exist; namely, that the population in the area is too sensitized in connection with collecting additional information. o. A comparison study in another area where 2,4.5-T is known to be used is essential. c. To settle the controversial problem as to whether 2,4.5-T is responsible for spontaneous abortions, and following definitive study is recommended by the Panel: One would design a prospective, long-term, dose-response epidemiological study with a clear understanding of the problem, appropriate modeling, and accessibility and control over the data. A study that goes beyond the level of an ecological study which permits hypotheses to be tested on an individual basis. The study would consist of a sufficiently large cohort of women of reproductive age. with a record of reproductive experience on every single woman in the defined cohort, utilizing reltively simple endpoints to determine reproductive effects. Also, the incorporation of reproductive history by interview of the population in the Study and Control areas that is solid, complete, and unbiased. The reproductive history is the truest estimate of pregnanes' history that can pros ide information os er and 16832 io: PANEL REPORT above that which comes to medicai attention. One would also establish gestational age based on a uniform definition of gestation, establish a baseline level of abortion rate, and acquire a control population that is virtually the same without exposure. Finally, definition of the exposure areas must be established using reliable measures of dosages and exposure. Validation of exposures to 2.4,5-T must be done through blood, urine, fat tissue analyses of the human and animal populations as well as tissue analyses of abortices. APPENDIX I: DOCUMENTS AVAILABLE FOR REVIEW OF 2,4.5-T DATA /. EmSetragteenmceyntAbcytioEnPAto DSelpouptySpArdamyiinngistoraf ttohre BHarebrabriacidBelsum2..4E.5P-AT, aWndasShiinlvgetxon, Press D.C. Conference 2. Forest Spra\ (Alsea I). E\lPisAc.arWriaasgheinIngtvoens.tigDa.tCio. ns. Alsea, Oregon: Questionnaire Evaluation and Study Plan 3. 4. RCreiiOpPntiorrqroeTutggherooraonefmefAA".OsrRHsereeaeusgpsmsooimnnartneRAoneHrftleAaeoatassifslotaeinhnsF-stREomieeiFellledanoctrtItiesonosnvftM.eats2ooFt.ni4igFie.taSolodtr-riTeoIinsnnStgvp2oeBr.sfa4rtSiy.agSin.Pa-vdTteissYoS.tneipBcaroireadnfSyeSepsfPi!oixtrA-nsaYltcasaetnenaiadcereoISFsIup.)i"se.olnEdAEtPbaSpAontirdue.tedoiWomuiensasiosARhDlobiaignovtigericsttsaiiooolInnnnS. tRDTOuha.dPCrtiDeee.ses. OTS. EPA. 5. 6. 7. FAAuonAssDattlnreiyvairsmilisLisaiaoenoltnstf,.eCErDPo.PomoAOrwmtflfDauiCcennechdiioeq.smfuiOoeDinrc.ieast.PleoraCeDssoees.c,MSlaMtoarneitdeitalmoanrneiEndn.tgmMbaenyrigdctehhCn.eocynMtSrinuoilss.ptDeenrespoiaofrnHtmoeeafnl2tt,h4o..f5C-HTaunambsearRnreaRl.aeAtseoudusttrorcaeSlista,u.Hdieeasltihn 8. 9. 10. 11. 12. 13. 14. 15. IS. BSMXDLHDlaiuoaueashwlnnmnweadcntaerehRlstnyleheedRRveRvReeeiereRreevvvvwieRiRieieve.eewewiwwvevE...iwi.PeeFEE,EwwA.PPPPE,.,AAAAEPEW,..AP.PWWaWA.WAsah,aW.aasissWnWhshahhgiisinaniatnhnosghggihgntntstotoi.iognonnnntDngg.o.,t,tn.oDoCDD.Dnn....C.DC.,CC.D..D.C. ..C.C.. Raw Data Provided by EPA on 14 March 1979, Live Births. EPA. Washington. D C. 17. Coo1k97R9.evDieowws C15h)ewmiitchalPrCinot.o, uMtsidolfaSndp,onMtaicnhe.ous Abortion Data as Provided by EPA on 14 March 18. 19. ACmoSoekunsdRpeeednvsieLiowinveoHfBAeiamrrthienngDd--eadt9aLAiPvpreroilBvii1dr9teh7d9D. baEytPaEA, P,DAWowaWsChitihnneegmstsoicna(.DlDuC.nCoc..a, nM) iodnlanLda. sMt iDcha.y of Emergency 16833 2 ' s '. j THE DOW-CHEMICAL COMPANY .-o , .nI. BIOCHEMICAL RESEARCH LABORATORY 2311 ** P .y J Z JL CHLORACNE STUDY CONDUCTED ON HEXACHLORODIBENZO-p-DIOXIN filBC T 36,25-84763-3 k50 K84763 CHG. 0 1 2 1 2 - 0 0 0 - 0 2 9 ref. FDA-F9 IT source A E P o h la n d sub, by O A n ilin e 4 REP-T. by J M N o r r i ^ j ^ CH ECK ED BY PJGehrjng n DATE 1 2 / 1 1 / 7 0 m vo rti co I in (N VmO CJ m IA tOuC . I N F O R M A T I V E SUMMARY WITH C O N C L U S I ON J - B A S E O ON T H E S A M P L E R E C E I V E D . A O O I T I O N A L I N F O R M A T I O N I N C L U D I N G T h e E F F E C T S O F R E P E A T E D E X P O S U R E MAY B E R E Q U I R E D AS S P E C I F I C U S E S ANO F O R M U L A T I O N S A R E D E V E L O P E D O R I F process chances occur- A sample of hexachlorodibenzo-p-dioxin (95% pure) was received from A. E. Pohland of the FDA and submitted to the Biochemical Research Laboratory for evaluation as a chloracnegen. Two 0.005% solutions of the test material, one in dimethoxyethane and the other in chloroform, were" prepared. Each solution was ap plied to the inner surface of 3 rabbit ears, 5 days per week for 4 weeks at a dose of 0.1 ml/day. Both test solutions produced d chloracne responses. All skin contact with the test material should 3* be avoided. U8 o w 31 CO CO O ro CO *JL- CORPORATE J. E. Johnson H. H. Melntyro C. E. Kirnnol MeL. K. Frovol O.D. Col listar (2) 0. Aniline, B. E. Burgort H. L. Gordon, MQ E.H. Blair A.J. Schwarz, MD S.M. MocCutchoon 1710 DISTRIBUTION W ESTERN DIVISION D.H. Clogg B . H. Lloyd, MD L. Pltchlorlh C . A. Goring Rx PHARMACEUTICALS V. B. Robinson TEXAS DIVISION MIDLAND DIVISION B. Holdor, MO Don Mors* Z a L c.l l FORM 41740 PRINTED RI-70 D. Kilian, MD J. Barton ds r_rfE5TRICTEb FOR USE OF DOW EMPLOYEES ONLY 16835 CRUS) DOW C H E M IC A L U.S.A. (J_jj ( ' 34 O March 21, 1979 -- " .....fiR 0 u i.ir B EN N ETT B U ILD IN G : 2B3f>C^W, M ID LA N D . M ICH IG A N 48640 | | ! STATE DEPARTMENT OF AGRICULTURE ' -o i ON. D. (. SUPPLEMENTAL LABELING 2 ,4 , 5 - T AND SILVEX PRODUCTS The enclosed s t i c k e r s are being used on DOW products that are the sub j e c t o f the Emergency Suspension Orders by The Environmental P rotection Agency on 2 , 4 , 5 - T and Si 1vex. The Agency has chosen to handle t h i s as a compliance program independent of the in d iv id u al r e g is t r a t io n actions so our conmunication' with you i s to allow your f i l e s to r e f l e c t the O most c u rre n t la b e l in g f o r these products. I t i s our in t e n t that the O products l i s t e d below be moved in your S t a te with these s t i c k e r s a p p lie d . * ESTEROrr Brush K i l l e r VEOMK 245 Weed and Brush K i l l e r KUROf!R Brush and Weed K i l l e r ESTERON 245 Herbicide VERTONR 2T Herbicide Since only p a r t o f the r e g is t e r e d uses have been suspended, the use of these s t i c k e r s on c o n ta in e rs with non-suspended uses i s intended to c la r if y the statu s o f the remaining accepted uses fo r these products while the Emergency Suspension Order i s in e f f e c t . Th is procedure has been reviewed by the Agency, i s c o n s is t e n t with t h e i r programs, and is being implemented f o r compliance purposes by making s t i c k e r s a v a ila b le to d e a le rs who own sto ck s of these products and p lacing s t i c k e r s on DOW owned sto c k s p r io r to shipment. * CD Z C3 O K) Dl CZ ^ a\ Vj>4 I -N - O' J1 You are undoubtedly aware th a t several a d d it io n a l leg al a ctio n s are underway regarding t h i s Order and the implementation of t h i s program fo r compliance purposes i s not to in d ic a t e t h a t The Dow Chemical Com pany has waived any r ig h t s o r recourse to challenge t h i s actio n on the part of the Adm inistrator. I t is l i k e l y that legal actions w ill again a lt e r th is subject in the near future. T h is program would a ls o apply to 2 ,4 ,5 - T products re g is te re d to deplete stocks in your S t a t e . I f you have any questions in t h i s m atter, please do not h e s i t a t e to co n ta ct me. Sincerely yours, & A. T. T a l c o t t , Manager Product Safety Compliance Quality Assurance jh Enclosures: 2 , 4 , 5 - T and S i l v e x S t i c k e r s EPA Compliance P o lic y AN OPERATING UNIT OF THE OOW CHEMICAL COMPANY 16836 NOTICE The following uses for products containing 2.4.5-T have been suspended by the United States Environmental Protection Agency. All uses in forests, right-of-ways and pastures. Do not apply this product on any of the areas listed above. THE DOW CHEMICAL COMPANY. MIOIANO. Ml UMO NOTICE The following uses for products containing Silvex have been suspended by the United States Environmental Protection Agency. 1. All uses around the home and recreation areas. 2. All uses in.forests, right-of-ways and pastures. 3. All aquatic uses. Do not apply this product on any of the areas listed above. THE DOW CHEMICAL COMPANY MIDLAND. Ml *36*0 o co CP ro / en CJT ro 18837  2 2 7 6 VfleaJus&bu (Snaa___uae-ftgt1& Stale Warning on 2,4-D Herbicide Exposure issued *T BOWALDB.TATLOB lb the first hazud alert of its kind, the state Department of Health Ser* ileai a warningthpublictoday that sp an to the herfatade 2.4-0 mar causa lasting nerve damage, as wail as canceror birth defects. The unusual wanting, basedon ex pert aarmnatlnn of seven persona who tagged nerve damage; is ex pected to set offanother controversy over theconnoted useofsoch pbenn ry hartaicidea. Dt MareLapp, chiefoftheHealth Services Department's hazard alert system, said six of the people were exposed while working as pesticide applicators, theseventh waaawoman whoknelt down in her gardenan sod nakedwith herUdde. Two weeksafterexposure, thesev en people reportedly developed tinring or numbness in their toes and fingtn. Mowedby weakness oftheir ansa and lege. Sane suffered "vir tually ccmpteia arm and leg paraly se." Lappsaid. Hernadae tike 2.4-0 and the no banned 2.4J-T bam been widely used in faresa; on farms and along, pubhe rights of way to till weeds, crush and unwanted trees. In combination, these herbicides werecalled Agent Orange andwere used to den ude the jungles of Southeast Asfe duringthe Vietnamwar. Along California's north coast, in PlaaasTun to Page IS, Cal. i c C cr a ex Oc HERBICIDE A LER T i-DUfip the timbercountryofOregonandthe w(p4antt of Homans, groups of concerned citizen and doctors con tend. 2.4-D Is causing birth defect* and miTjrnig amoog women who havebeenespoeedtopesticidssprays. However. EPA offldaie told The : Times the previous toxicology data i was iucrmdusive. tfaat.it neither proved nor disproved anything aad the chemical companies'were being asked to donew studies; Such studies couldtake hornana to three years to Lapps said the hazard alert report is behifses&out toworkers anddoe- ton in an effort to warn them that 2.4-D has caused cancers and birth defects in laboratory animats- and nervedamagein humans. AccordingtoLapps; "Currentwork practices (in the forests and on formal a^sim pavrme Hiniiadneequuroatceositcoity.p"rotect. The timber hamating companies, backed by the 05. Forest Service, argue that the use of phenazy herbi cides are critically needed if timber harvests are to b e sustained. They contend 2.4-D is a relatively mild pesticide and that there is noproof it Pis"Pha*rtimy.ful to human;s .wh__e_n_used Lapp sail that while affltiatty the hazard alert system was established to went workers of health problems, he was also concerned about home gardeners because one of the seven . victims had been exposedto the her* btide in herzarden. .. Lapp explained the state wag is- ; ' suing the unusual warning because thesnvironmemai Protection Agen cy hadfoiledtoact. HetoldTheTimes."Thereis apol icy vacuum in EPA. an absence at leadership. So we had tor move on . tha." n 16838 Foreward. AN EVALUATION OF 2,4-D DATA j >n Oi < The phenoxy h e r b ic id e s , in c lu d in g 2 ,4 -D , have re ce iv e d co n sid e ra b le a tte n tio n during th e l a s t decade in t h e ,p r e s s , in p u b lic h earin g s and by groups which have campaigned a g a in st the continued use o f these h e rb ic id e s fo r c o n t r o llin g unwanted ve g e ta tio n in f o r e s t s , on r ig h t s - o f - way and on c e r t a in cro p la n d s. The groups a g a in s t the continued use o f J h e rb ic id e s have sp ent co n sid e ra b le tim e and e f f o r t p rep arin g l i t e r a t u r e , p re ss r e le a s e s , m a ilin g s and in p a r t ic ip a t io n a t p u b lic h e a rin g s. The prim ary message o f th ese groups is th a t the use o f phenoxy h e rb icid e s w i l l in c re a s e b ir t h d e fe c ts and cause m is c a r r ia g e s , ca n ce r o r o th er p h y s ic a l ^ e f f e c t s . V arious s c i e n t i f i c stu d ie s as w ell as a r t ic le s from the p re ss are CD ro CD used to support t h e ir a lle g a t io n s . Very freq u en tly only those po rtio n s of the data in a given study which support the a lle g a tio n are c ite d . The r e lia n c e upon data from s tu d ie s conducted in anim als to estim ate the e f f e c t s in humans has a ls o been debated. However, anim als are the o n ly s p e c ie s p h y lo g e n e t ic a lly c lo s e to humans which can be used f o r t e s t in g . T h e re fo re , i t i s n e ce ssa ry to c o r r e la t e data from animal s tu d ie s w ith the p o te n tia l f o r human exposure under w orst ca se co n d itio n s and d e fin e a safety factor. In most s t u d ie s on l i v i n g organism s the data a re n e ith e r com pletely p o s itiv e nor com pletely negative but re q u ire the e x p e rtise o f knowledgeable sc ie n tists for in terp retatio n . H e re in , data and c o n c lu sio n s a re subm itted which are intended to p resen t an unbiased review o f the t o x ic o lo g ic a l i^ u u ie s on 2,4-D which have been conducted to date. 16839 MW /249298 1. What i s 2,4-D? 2,4-D (2 ,4 -d ic h lo ro p h e n o x y a c e tic a c id ) i s an h e rb icid e which s e l e c t i v e l y c o n tro ls many b ro a d le a f weeds, c e r t a in hardwood tre e s and brush on crop and ran g e la n d s, r ig h ts - o f- w a y , and on t u r f and law ns. 2,4-D was f i r s t introduced in the U .S . f o r use by farm ers in 1946 (P e te rso n , 1967). I t performs i t s co n tro l fu n ctio n by a lt e r in g the normal growth o f s u s c e p t ib le weeds and woody p la n t s . The m ajor use o f 2,4-D i s c o n t r o llin g b ro a d le a f weeds in c e re a l g r a in s . I t does not k i l l most g ra sse s. 2 ,4 -D i s u s u a lly a p p lie d a t the r a te o f k to h pound a c t iv e in g re d ie n t p er a c re f o r c e re a l g r a in s . H igher r a t e s a re often used on r ig h t s - o f way. 2,4-D i s u s u a lly form ulated as amine s a lt s o r e s t e r s j 2 . How t o x ic i s 2,4 -D to a n im als? 2 .4 - D i s m oderately t o x ic to mammals. The th re e routes o f p o ssib le human exposure a r e : in g e s t io n , dermal c o n ta ct and in h a la t io n . The s in g le dose o ra l LD50 (dose determined to be le t h a l to 50% o f the tre a te d s p e c ie s ) f o r 2,4-D a c id i s g re a te r than 350 mg/kg o f body weight in r a t s , m ice, guinea p ig s and ch ick e n s (NRCC, 1978). In .th ese same sp e c ie s the acute o ra l LD50 f o r v a rio u s fo rm u latio n s o f 2,4-D s a l t s and e s t e r s ranges from 75 to 2000 mg/kg (Weed S cie n ce S o c ie ty o f A m erica, 1979) (IRAC, 1977). In a ca se o f a s u ic id e by a 23 y e a r old stu d e n t, the to ta l amount o f 2 .4 - D in the body was estim ated to correspond to a dose o f 80 mg/kg. (N ie lso n e t a l . , 1965) No adverse e f f e c t s were reported in a man who x. jk 500 mg 2,4-D o r a l l y d a ily fo- 0 weeks (approxim ately 8 mg/kg/day) (IA RC, 1977). When 2,4-D was used as a treatm ent in a p a tie n t w ith 16840 249299 term inal stag es o f d issem inated co ccid io m y co sis, no sid e e f f e c t s were observed fo llo w in g 18 in traven o u s doses o f 15-37 mg/kg o f body weight over 33 days (Seabury, 1963 in IARC, 1977). Dermal exposure i s perhaps the most freq uent route by which man becomes exposed to 2 ,4 -D . Kay e t a l . (1965) stu d ie d the e f f e c t s o f repeated sk in a p p lic a tio n o f the dim ethylam ine s a l t , is o o c t y l e s t e r and the butyl e s t e r o f 2,4-D on in t a c t and abraded ra b b it abdominal s k in . Skin ap p licatio n of te s t m a te ria ls, prepared as d ilu tio n s in water or o i l o r both, was made 7 hours p er day, f iv e days p er week f o r th ree weeks w ith no s i g n if i c a n t sy ste m ic e f f e c t s , noted. S k in ab so rp tio n s tu d ie s were conducted on the shaved sk in o f a lb in o r a b b it s . The butyl e s t e r and the diethanolam ine s a l t o f 2,4-D were not absorbed in t o x ic amounts up to 3,980 mg/kg (th e h ig h e st r a te t e s t e d ) . For the butoxy ethanol e s t e r , ^the^ac ^ e sk in absjjBign_LD50 in ra b b its was c a lc u la t e d to be 3980 mg/kg (Unpublished d a ta , The Dow Chemical C o .) --------------------- -- ------ -- There have been se v e ra l ca se s reported in the l i t e r a t u r e in which sp ray a p p lic a t o r s and production workers e x h ib ite d v a rio u s symptoms as a r e s u l t o f exposure was dermal c o n t a c t , in h a la tio n o r both. . However, a re ce n t re p o rt (O tt e t a l . 1978 and IARC, 1977) on workers exposed in a m a n u fa c tu -\ rin g p la n t t o 30-40 mg/day o f 2,4-D fo r p eriod s ranging from 0 .5 -2 2 y e a rs in d ic a te d no d if f e r e n c e s in h e alth param eters from a co n tro l group of workers. DOW 1 2 4 9 3 0 0 Men (248) and women (44) engaged in the manufacture of the amine s a l t or the butyl e s t e r o f 2,4-D w ith exposure p erio d s ranging from under 5 / y e a rs to 6-10 y e a rs ( f o r 194 and 98 persons r e s p e c t f u l l y ) ; were screened /-- -- ------ and 63% o f th ese w orkers rnmpllin e d nf weakness, rapid fa tig u e , headache o r v e r t ig o . About 20% had d istu rb a n c e s o f the c a r d io v a s c u la r system (m ain ly hypotension and bradyc a rd ia 1 and o f t he d ig e s t iv e organs -- (d y sp e p tic symptoms and g a str i t i s ) . The v a rio u s l i v e r d y sfu n ctio n s t h a t were found were more pronounced in wor k e r s w ith lo ng er exposures to the ^--- -- - --- ---------------------- " h e rb ic id e s. (IARC, 1977) x *~ ` Feldmann & Maibach (1974) stu d ie d in man the ab so rp tio n through the s k in o f 4yg/cm2 llfC - la b e lle d 2,4-D d is s o lv e d in a sm all amount o f acetone. 1I*C a c t i v i t y was measured in u rin e o ver a 5-day p eriod and compared w ith th a t in u rin e a f t e r i . v . a d m in istra tio n o f the compound : ur in a r y e x c re tio n o f' 2^4-D a f t e r i . v . jadmini s t r a t i on was 100% o f the dose in 120 hour ^ w h ile 'J e x c re tio n a f t e r t o p ic a l a d m in istra tio n was 5.8% o f the dermal dose- Kohli et a l . (1974) ad m in istered 5 mg/kg body weight o f pure 2,4-D in a g e la t in ca p su le w ith w ater to 6 h e a lth y male v o lu n te e rs , aged 22-30 y e a r s ,/ None o f the s u b je c t s complained o f any i l l - e f f e c t s , no changes in blood p re ssu re , p u lse r a t e , hemoglobin content or to ta l o r d if f e r e n t ia l w hite c e l l counts were o b served . 2,4-D was absorbed f a i r l y r a p id ly . The h ig h e st c o n ce n tra tio n in blood was reached in 7-24 ho urs. In u r in e , 2.4-D was p resen t as e a r ly a s ?...hnnr<: a f f p r in g e s t io n , and more than 75% was ex creted in 96 hours w ithout undergoing tra n sfo rm atio n in the body. In 5 male vo lun teer given a s in g le o ra l dose o f 5 mg/kg body w e ig h t, the h a l f - l i f e in the plasma was 11.7 h o u rs, and e lim in a tio n in the u rin e 16842' DOWJ 2 4 9 3 0 1 occurred w ith a h a l f - l i f e o f 17.7 hours. About 82% was ex creted as such and 12.8% as a conjugate (S a u e rh o ff e t a l . , 1976). From the above s tu d ie s i t appears th a t 2 ,4 -0 i s r e a d ily absorbed from the g u t. Some ab so rp tio n through the sk in may o c c u r, but a p p ro p ria te precau tio n s w ill adequately minimize exposure during the tra n s fe rrin g , m ixing, / and a p p lic a t io n o f the h e rb ic id e . Long term s t u d ie s conducted in la b o ra to ry anim als have been evaluated by se v e ra l eminent s c i e n t i f i c groups who have concluded th a t 2,4-D does not cause can cer . In 1969, a Report o f the S e c r e t a r y 's Commission on P e s t ic id e s and T h e ir R e la tio n sh ip to Environm ental Health was p u blished (Mrak, 1969). In th a t re p o rt the s tu d ie s conducted by Innes e t a l (1969) in two s t r a in s o f mice r e c e iv in g 4 6 .4 or 100 mg 2,4-D /kg/day by stomach tube from day 7 to 28 o f age follow ed by in g e stio n o f d ie t co n ta in in g 149 and 323 ppm o f 2,4-D f o r 18 months were review ed. Even under these r ig o r ous c o n d itio n s th e co n clu sio n w as, "2 ,4 -D ich lo ro p h e n o x y a ce tic A cid (2 ,4 -D ) and f iv e compounds c lo s e ly re la t e d to i t s t r u c t u r a l l y were found to be nontum origenic :in the te s t circum stances". The Food and A g r ic u lt u r a l O rg a n iza tio n o f the United Nations World H ealth O rg a n iz a tio n 's Working P a rty o f e x p e rts on p e s t ic id e re sid u e s a ls o reviewed the Innes study and concluded, "There i s no s ig n if ic a n t in c re a s e in tumors between the c o n t r o ls and the groups given the two le v e ls o f 2 ,4 -D " . (FAO/WHO, 1971). 18843 DOW J249302 Hansen e t al (1971) adm inistered 2 ,4 -0 in the d ie t s o f r a t s fo r two y e a r s a t 0 , 5 , 25, 125, 625 or 1200 ppm. While the number o f r a t s employed in t h is study would not be adequate by todays sta n d a rd s, the authors concluded t _?.4-D was not a c a rcin o g e n . A rk ip o r and K o z lo ria (1974) s t a t e th e re was no s ig n if ic a n t in c re a s e in tumors in r a t s o r mice from d ie ta ry o r sk in p ain tin g a d m in istra tio n o f 2 ,4 -D . B jo rk lan d and Erne (1966) adm inistered 2 ,4 -0 in the d rin k in g w ater o f r a t s f o r two y e a rs a t le v e ls up to 1000 ppm and observed no in c re a s e in tumors. 4 . Does 2,4 -D cause b ir t h d e fe c ts in humans? T e ra to lo g ic a ! s tu d ie s (stu d y o f b ir t h d e fe c ts ) have been conducted w ith . 2 ,4 - 0 as the a c id and as c e r t a in e s t e r s in r a t s , m ice, ham sters and sheep. There are d if f e r e n c e s among s c i e n t i s t s in d e fin in g t e r a t o lo g ic a ! responses to tre a tm e n ts. In t h i s d is c u s s io n we w i l l c i t e the d e f in it io n s o f the N ational Academy o f S c ie n c e s' (1974) and t h e i r ex p lan a tio n o f each. "Prenat a l development i s d ivid ed in to the embryonic stage ( e a r ly ) when the organs are form ing, and the f e t a l stag e ( l a t e r ) when the org anism i s ma t u r in g d uring gest a t i o n . However, the d iv is io n i s not c le a r - c u t and the p ren atal organism w ill be re fe rre d to in t h is d is c u s s io n as an embryo even i f i t i s t e c h n ic a lly known as a f e t u s ." "An agent o r chem ical i s consid ered as te ra to g e n ic when i t causes develop mental d istu rb a n ce s in the embryo r e s u lt in g in co n g en ital m alfo rm ations. I f an agent k i l l s the embryo i t i s sa id to be e m b ry o cid al, and i f i t 16844 produces t is s u e damage (not n e c e s s a r ily r e s u lt in g in m alform ation) i t i s em bryopathie. The term em bryotoxic w i l l r e f e r to any harmful e f f e c t on the embryo." DOW 1249303 "The harmful e f f e c t s o f b io ch e m ica lly a c t iv e compounds vary w ith the dose of the compound, the route by which i t i s g iv e n , the g e sta tio n a l stag e a t which the embryo i s exposed, and the g e n e tic c o n s titu tio n o f the , exposed mother and embryo." * "In g e n e r a l, the embryo i s more s e n s it iv e than the mother, and te ra to g e n ic doses a re l i k e l y to be lower than embryopathic doses w hich, in tu rn , are low er than em bryocidal d o ses. However, th e re i s a good deal o f o v e rla p , and much v a r ia t io n in t h is re sp e c t between d if f e r e n t compounds. For in s t a n c e , th alid o m id e i s te ra to g e n ic in pregnant women a t low doses but i s not t o x ic to the mother a t ve ry high d o ses. For many o th e r agents a terato g en ic dose a lso in cre ase s the reso rp tio n (embryonic m o rta lity ) r a t e , but t h i s i s not always so . S t i l l o th e r agents may not be te ra to g e n ic even a t doses th a t k i l l many o f the embryos, a t le a s t in some s p e c ie s . F i n a l l y , th e te ra to g e n ic e f f e c t may vary w ith the route o f a d m in is tr a tio n . Vitam in A, f o r in s t a n c e , may be te ra to g e n ic when given o r a l l y , but i s not when given in tra m u s c u la rly . In g e n e ra l, acute doses are more te ra to g e n ic than ch ro n ic exposures, p o ssib ly because repeated exposure allow s the form ation (in d u c tio n ) o f enzymes which degrade the p o t e n t ia lly te ra to g e n ic compound. " " It is important to recognize that sp ecies d if f e r w idely in t h e ir su sc e p ti b i l i t y to te ra to g e n s. An o utstanding example i s thalidom ide which i s h ig h ly te ra to g e n ic in man and the New Zealand grey r a b b it , but has only a very low le v e l of t e r a t o g e n ic it y in the mouse and r a t . C o rtiso n e 16845 DOW 12 4 9 3 0 4 causes c l e f t p a la te in the mouse and the ra b b it , but not in the r a t . We s t i l l do not know i f i t i s te ra to g e n ic in man. Thus, one cannot e x tra p o la te w ith any assu ran ce from o n e ,sp e c ie s to a n o th er, or even one s t r a in to a n o th er, and one cannot rig o ro u s ly prove an agent i s te ra to g e n ic in man from data on experim ental a n im a ls--o n ly from data on human b e in g s ." " I t must be emphasized th a t a g re a t many agents are te ra to g e n ic in e x p e ri mental a n im a ls, p a r t ic u la r ly ro d en ts. IMany drugs have demonstrated t e r a to g e n ic it y : vario us a n t ib io t ic s , amphetamines, a n tih ista m in e s, a n tic o n v u lsa n ts, b a rb itu ra te s , c a f f e in e , clomiphene, c y c liz in e , LSD, th alid o m id e, tolbutam ide, and v a rio u s tranqui l i z e r s . M etals (cadmium, c a lc iu m , le a d , m ercury)', hormones (ACTH, a d re n a lin , androgenic hormones, a n tio v u la t o r y compounds, e s tro g e n s , g lu c o s t e r o id s , i n s u l in , s e r o t o n in ), * , and se v e ra l o th e r k in d s o f ch e m ical, p h y s io lo g ic a l, and environmental agents (maternal dehydration, maternal s t r e s s , carbon monoxide, n o is e , and hypoxia) have a ls o been shown to be te ra to g e n ic in la b o ra to ry a n im a ls. For s e v e ra l o f these there i s good evidence o f low o r no t e r a t o g e n ic it y in man ( e . g . , c y c l i z i n e ) , but f o r most o f them the p o s s i b i l i t y o f low l e v e ls o f t e r a t o g e n ic it y has not been rule- ) u t , and i t would be very d i f f i c u l t to do so . Only f iv e have been c l e a r l y im p lica te d as humans terato g en s (d ip h en ylh yd an to in , androgenic p r o g e s t in s , o rg a n ic m ercury, r a d ia t io n , and th a lid o m id e )" (NAS, 1974). "Much le s s work has been done on the t e r a t o g e n ic it y o f 2 ,4 -D . One study ( B io n e t ic s S tu d y, see Mrak R ep o rt, 1969) suggested th at the b u t y l, i sopropyl and is n n c t v l e s t e r s o f 2,4-D may be teratogens o f low pote n cy . Schwetz e t a l . (1971). f i n i n g tho f r CO p|r -jH propylene glycol butyl e th e r e s t e r and the is o o c t y l e s t e r a t le v e ls up to 8 7 .5 mg/kg/day-- 16846 DOW 1 2 4 9 3 0 5 the maximum tolerated level-- on day 6-15 of pregnancy, found symptoms of em b ryo to xicity (edema, delayed o s s i f i c a t i o n , e t c . ) but no genuine t e r a t o - - -- ' -- - -- 1" -- lo g ic a l e f f e c t s in r a t s even a t the h ig h e st dose. The h ig h e st le v e ls of --------- ' /. ~ " ' -- the e s t e r s decreased v ia b il ty and la c t a t io n in the mothers but had. no e f f e c t on the growth and development of the o f f s p r in g . Khera and M cKinley --I (1 9 7 2 ), working a ls o w ith r a t s and using fo u r samples o f 2,4-D and one .i each o f the b u t y l, i s o o c t y l, butoxyeth ano l, and dim ethylam ine d r i v a t i v e s , found s im ila r a b n o rm a litie s as in t h e i r experim ents w ith 2 ,4 ,5 - T and d e r iv a t iv e s , a t th e same dose le v e ls (100 mg/kg and ab o ve). C o llin s and W illiam s (1971) found in the progeny o f hamsters tre ated w ith three samples o f 2,4-D some in c re a s e in m alform ations but th e re was no dose- e f f e c t r e la t io n s h ip and the d iff e r e n c e s were not s t a t i s t i c a l l y s i g n i f i c a n t . 11 "An agent may be consid ered a potent teratog en i f i t has t e r a t o lo g ic a ! le v e ls f a r below the dose le v e ls th a t are le t h a ly to x ic to the mother. By t h i s c r it e r io n 2,4-D would be consid ered to be a r a t h e r weak teratog en in experim ental an im als. In view of wide d iffe re n c e s between sp e cie s in te ra to g e n ic s u s e p t i b i l i t y , one cannot e x tra p o la te t e r a t o lo g ic a ! r e s u lt s from exp erim entis anim als to man." (N .A .S . 1974) 16847 Is 2 ,4 -0 a Mutagen? F i r s t , a mutagen i s a m a te ria l th a t i s capable o f producing g en etic damage which can be in h e r it e d by fu tu re g e n e ra tio n s. 2,4-D has been evaluated in a number o f m u ta g e n icity s t u d ie s . I t has been demonstrated th a t 2 ,4 -0 i s not~a mutagen in a v a r ie t y o f m icro b ial s t u d ie s as w ell as in male f r u i t f l i e s (D ro sp h ila m elanoqaster) . (Vogel - Chandler, 1974). E p ste in e t a l (1972) found th a t a t o t a l o f 75 mg o f 2,4-D/kg o f body w eight given o ver a f iv e day period did not in c re a s e dominant le t h a l r mutations in m ice. Treatm ent o f in v it r o c u ltu re d human lym phocytes w ith 0.0 2 mg/ml. 2,4-D in cre a se d th e number o f chrom atid a b e rra tio n s and to a l e s s e r e x s te n t, chromosomal a b e r r a t io n s . In m ice, t o x ic co n ce n tra tio n s (100-300 mg/kg/body weight) of 2,4-D adm inistered as a sin g le o ral dose s ig n if ic a n t ly increased the frequency o f aberrant metaphases (2-4 fo ld ) in lym phocytes; sin g le fragments were the prim ary a b e rra tio n (P ilin s k a y a , 1974, c it e d in IARC, 1977). 2,4-D had no e f f e c t on c u ltu re d c e l l s nor on bone marrow a f t e r i t s o ra l a d m in istra tio n to r a t s ( S t y l e s , 1973 c it e d in IARC, 1977). There was no in c re a s e in the m icro n u cle i in e ry th ro c y te s o f mouse bone marrow a f t e r in je c t io n o f 100 mg 2,4-D /kg/body w eig h t. Exam ination o f chromosones o f w orkers employed in the production o f 2,4-D in d ic a te d no changes (Johnson, 1971). The Royal Swedish Academy o f S c ie n c e s arranged a co n feren ce in Stockholm in Feb ru ary , 1977 organized in to f iv e working groups com prising c h e m istry , p la n t p h y sio lo g y , t o x ic o lo g y , g e n e t ic s , and ecolo gy w ith econom ics. The co n clu sio n reached by the group o f in t e r n a t io n a l e x p e rts reg ard ing the m u ta g e n icity o f the phenoxy h e rb ic id e s was as f o llo w s . 16848 DOW 1 2 4 9 3 0 7 "The only s t a t i s t i c a l l y s i g n if i c a n t dem onstration that phenoxy a cid s induce m utations t r a n s m is s ib le to the o ffs p rin g was obtained in the r e c e s s iv e le t h a l t e s t in D roso phila m elan o g aster. Work on m icroorgan- / isms su sta in s the co n clu sio n th a t the phenoxy a cid s are mutagenic under the t e s t c o n d itio n s used. Two in v e s t ig a t io n s on 2 ,4 ,5 - T and one on 2 ,4 -D , both using pure a c id s , showed an in cre a se d number c f r e c e s s iv e le t h a ls in D ro so p h ila . From a t e n t a t iv e comparison o f the ra d ia tio n %J dose th a t would g ive a s im ila r e f f e c t ,_ t h e mutagenic e f f e c t s o f 2 ,4 ,5 - T and 2,4-D were concluded to be weak. Som atic m utations have been observed in D ro so p h ila , and chromosomal a b e rra tio n s have been shown to be induced in p la n ts and mammals. The re levan ce o f th e se l a t t e r fin d in g s to a r is k o f mutation from phenoxy a c id s (a s s o c ia te d o r not w ith h e r it a b le damage) re q u ire s f u rt h e r s t u d ie s . O bservation in one study o f a p o ssib le ro le o f the e m u ls if ie r and/or s o lv e n t show the n e c e s s it y o f in c lu d in g th ese c o n s titu e n ts o f phenoxy acid form ulations in fu tu re stu d ie s ." (Ramel, C. 1977). 6. Are there "dioxins" in 2,4-D ? The g e n e ric term "d io x in " i s o ften used in c o r r e c t ly to d esig n ate one member o f the f a m ily , 2 ,3 ,7 ,8 te tra c h lo ro d ib e n z o -p -d io x in (TCDD). There a re 75 p o s s ib le p o ly c h lo rin a te d b en zo -p -d io xin s w ith a m illio n fo ld spread in the dosage le v e l required to k i l l lab o ra to ry anim als. Trace amounts o f p o ly c h lo rin a te d d ib e n zo -p -d io x in s can be formed during the manufacture of chlorophenols under a lk a lin e conditions at elevated tem peratures and high p re s s u re . Trace amounts o f the h ig h ly t o x ic TCDD a re formed during the m anufacture o f 2 ,4 ,5 - t r ic h lo r o p h e n o l by a lk a lin e 16849 DOW 1 249308 h y d ro ly s is o f 1 ,2 ,4 ,5 te tra ch lo ro b e n ze n e . Any TCDD so formed can be c a r r ie d through in to products made from 2 ,4 ,5 - t r ic h lo r o p h e n o l, such as 2 ,4 ,5 - tric h lo ro p h e n o x y a c e tic a c id ( 2 ,4 ,5 - T ) and hexachlorophene. in 2,4-D (Ramel, C. 1977). v--------------------- No TCDD i s-----f---o---u---n--d-- The expected 2 ,7 -d ic h lo ro iso m e r i s not formed by condensation o f 2 .4 - dichlorophenate under the a cid co nd itio ns used in i t s manufacture by c h lo rin a tio n o f phenol. Of 28 samples o f 2,4-D te ste d f o r content o f c h lo ro d ib e n z o -p a ra -d io x in s, one was reported to contain le s s than 10 mg/kg (/of7f/H hexachlorodibenzo-p- d io x in . (Woolson e t al 1972, c it e d in IARC, 1977) 7 . What E f f e c t Does 2,4-D Have on The Environment? The environment i s composed o f many compartments in c lu d in g s o i l , a i r , w a te r, man, b ir d s , a n im a ls, p la n ts and i n s e c t s , e t c . 2 ,4 -D , when used as d ire c te d on the l a b e l , e x e rts i t s e f f e c t on a s e le c t p o rtio n o f the p la n ts in the environm ent. A p p lic a tio n o f 2,4-D by means o f sp ra y in g , e it h e r by ground o r a i r , p ro vid es the p o te n tia l f o r contam ination o f the other compartments. Fate in Soil In s o i l , in the presence o f m o istu re , even a t low l e v e l s , the e s t e r s o f 2 .4 - D a re hydrolyzed to the a c id form. The p e r s is te n c e o f the is o o c ty l e s t e r of 2,4-D was stu d ie d under f i e l d co n d itio n s by B u rca r et a l . (1966, c it e d in NRCC 1978) who noted the complete breakdown o f the e s t e r to the a c id in two weeks.. The fre e a c id s a ls o have a r e l a t i v e l y 16850 DOW 1 2 4 9 3 0 9 sh o rt l i f e in s o i l . Klingman (1961) s t a t e s th a t when used a t normal r a t e s , from 0 .5 to 3 Ib / a c r e , 2,4-D d isa p p e a rs from s o il in 4 . to 5 weeks. M icrobial degradation a lso p lays a s ig n if ic a n t r o ll in 2,4-D breakdown. I t has been shown th a t repeated use o f an a g r ic u lt u r a l chem ical i s lik e l y to in cre a se the population o f s o il microbes which can degrade i t . 2,4-D does not b u ild up in the s o i l , and treatm ents can be ap p lied to . cropland year a fte r year without accum ulation. * Fate in Water D e te ctab le re s id u e s o f 2,4-D do not appear in su rfa ce w aters u n le ss i t i s added d i r e c t l y to the w a te r o r f a l l s th e re in c id e n ta l to spraying a d ja ce n t a r e a s . In p r a c t ic e , re sid u e s in stream s o r la k e s r e s u lt in g from range and f o r e s t uses a re le s s than 0.1 ppm (Newton and Norgren, 1977). In the United S t a te s the maximum p e rm is s ib le co n ce n tra tio n o f 2,4-D in w ater which i s used f o r p u b lic su p p lie s i s only 0.1 ppm. Once intro duced in w a te r, 2,4-D undergoes r e l a t i v e l y rap id decom position. In 1971 over 7,000 a c re s in the Loxahatchee N ational W ild lif e Refuge, F lo r id a were sprayed w ith the a c id e q u iv a le n t o f 4 pounds 2,4-D per a cre to control w ater h yacin th . The hig hest 2,4-D residue le v e l measured in w ater was 0.037 m g / lit e r found on the day a f t e r tre a tm e n t.. The h ig h e st le v e ls in h y d ro so l, 0.005 mg/kg, o ccurred 3 to 15 days a f t e r treatm en t. M u lliso n (1970) has review 150 s tu d ie s .o n the E f f e c t s o f H e rb icid e s on Water and I t s In h a b it a n t s . T h is review dem onstrates th a t 2,4-D breaks down in w ater q u ite r a p id ly . The r a te o f breakdown i s dependent upon 16351 HOW 1 2 4 9 3 1 0 tem perature, pH, presence o f org an ic m a tte r, s u n lig h t and m icro b ial f lo r a . At the la b e le d r a t e s o f a p p lic a t io n , 2,4-D would not be d etected in most a q u a tic environm ents 30 days a f t e r in t ro d u c t io n . T o x ic it y s t u d ie s w ith f is h have been review ed by M ullison (1 9 7 0 ). In g e n e ra l, under n a tu ra l co n d itio n s most f i s h sp e c ie s can t o le r a t e 2 ppm 2 ,4 - 0 . Sp rayin g 5 pounds 2,4-D per a c re in w ater about one fo o t deep would approxim ate 2 ppm. Under n a tu ra l c o n d itio n s f is h could u s u a lly swim away from a re a s o f high c o n c e n tra tio n s . Fate in A ir Form ulations o f 2,4-D are applied as aqueous emulsions o r so lu tio n s in o i l s by ground sp ra y e rs o r by a i r c r a f t . During a p p lic a t io n , some o f th e m a te ria l may d r i f t from the t a r g e t s i t e before being in te rc e p te d by the t a r g e t . The q u a n tity which may d r i f t i s dependent upon d ro p le t s i z e , wind v e lo c i t y , tem perature and h u m id ity , v is c o s it y o f the formu l a t i o n , d is ta n c e from a p p lic a t o r to t a r g e t , and perhaps the most im portant f a c t o r , the p re ca u tio n s e x e rc ise d by the in d iv id u a ls perform ing the a p p lica tio n according to the la b e l. 2,4-D fo rm u latio n s d i f f e r in t h e ir ra te o f v o la t iliz a t io n from the ta rg e t s u rfa c e . The amine s a lt s are le s s v o la t ile than the e s t e r s . Proper s e le c t io n o f th e fo rm u latio n and o b se rv a tio n o f the c lim a t ic c o n d itio n s recommended on the la b e l can m inim ize v o l a t i l i z a t i o n from the ta rg e t s i t e to a d ja c e n t a re a s where damage may o c c u r. IS 8 5 2 DOW 1 249311 req uired on the l a b e l . Subchronic o r le s s than one h a lf the lif e t im e s tu d ie s in c lu d e : 90 day d ie t a r y in r a t s , s i x month d ie t a r y in dogs, t e r a t o g e n ic it y in two s p e c ie s , two generation rep ro d uctio n in r a t s and metabolism in two s p e c ie s . Chronic ( e s s e n t i a l l y lif e t im e ) d ie t a r y s tu d ie s a re conducted in r a t s and mice to determ ine a no e f f e c t le v e l to a s s i s t in e s t a b lis h in g to le ra n c e le v e ls and p o s s ib le oncogenic (tumor producing) e f f e c t s .- These comprehensive stu d ie s re q u ire a t le a s t fo u r y e a rs to complete. During t h i s same tim e p eriod samples of the t a r g e t crop which has been tre a te d w ith the chem ical a t the maximum la b e l r a t e a re c o lle c t e d from v a rio u s geographical a rea s and analyzed f o r p o s s ib le r e s id u e s . R esidue s t u d ie s a re a ls o conducted in cows and ch ick e n s to determ ine i f re sid u e s which might be p resen t in the food o f these anim als i s c a rr ie d in to m eat, m ilk o r eggs which humans might consume. The EPA then e v a lu a te s th ese data tog ether w ith the data which d e sc rib e the fa te , and e f f e c t s in the environment and o n ly a f t e r d e t a ile d a n a ly s is may grant * Residue to le r a n c e . The to le ra n c e g ra n tin g procedure i s very d e t a ile d and not taken l i g h t l y by the EPA nor the in d u s t r y . By the time a to le ra n c e i s granted an ex cess o f f iv e y e a rs have ela p sed s in c e the in i t ia l data gathering. There may be t r a c e q u a n t it ie s o f 2,4-D in the food we e a t but an e x te n siv e review of the data a ssu re s us i t is a q u an tity which w ill not cause harm. The FDA market b aske t samples fo r 1974-1975 (PEMJJAA) which a re comprised o f c o lle c t io n s in 20 c i t i e s which range in pop: ' ' ions from le s s than 50,000 to more than one m illio n showed no re sid u e s o f ch lo ro p h en o x ya cid s. DOW 1 249312 A rkhipov, G.N. & K o slo va, I.N . (1974) The study o f the carcin o g en ic p ro p e rtie s o f the amine s a l t o f 2 ,4D . Vop. Pi t a n . , 5_, 8384. B jd rklund , N .-E . a Ern e, K. (1966) T o x ico lo g ical stu d ies of phenoxya c e tic h e rb icid e s in anim als. Acta vet, sc a n d ., 7 _, 364390. C o llin s , T .F .X . & W illiam s, C.H. (1971) Teratogenic studies with 2 ,4 ,5 - T and 2,4-D in the ham ster. B u l l , environm : Contam. T o x ic o l., 6 , 559567. ~5 ~ FA0/WH0, 1971. 1970 E v a lu a tio n s o f Some P e s t ic id e Residues in Food, AGP: 1970/M /l2 /1 . Monograph. IARC, 1977 - In t e r n a tio n a l Agency f o r Research on Cancer Monographs on the E v a lu a tio n o f the C a rcin o g e n ic R isk o f Chem icals to Man, V o l. 15, August, 1977. Johnson, J . E . (1971) The p u b lic h e alth im p lica tio n s of widespread use o f the phenoxy h e rb ic id e s and p iclo ra m . B io s c ie n c e , 2 1 , 899905. Kay, J . H . , e t a l (1965) Subacute Dermal T o x ic it y o f 2,4D . A rch . E n v iro n . H ealth - Vol I I , . Nov. K hera, K .S . & M cK in ley, W.P. (1972) P re - and p o stn a tal s tu d ie s on 2 ,4 ,5 - t r ic h lo r o p h e n o x y a c e t ic a c id , 2 ,4 -d ic h lo rp h e n o x y a c e tic a c id and t h e ir d e riv a tiv e in r a t s . T o x ic o l, ap p l. Pharmacol. , 22, 14-28. Klingm an, G .C . (1961) Weed Control as a S c ie n c e . W ile y , New York. Mrak, E .M ., chairm an , 1969. Report o f the S e c r e t a r y 's Commission on p e s t ic id e s and t h e i r r e la t io n s h ip to environm ental h e a lth . Dept, of H e a lth , Ed ucation and W e lfa re , Government P rin t in g O f f ic e , Washington, D.C. M u llis o n , W.R. 1970. The s ig n if ic a n c e o f h e rb ic id e s to nontarg et organ ism s. P ro c. 24th Annual M eeting, N o rtheast Weed Control C o n f ., pp. 111147. N ational Academy o f S c ie n c e s , U .S .A . (1 9 7 4 ). Committee on the E f f e c t s o f h e rb ic id e s in Vietnam. The E f f e c t s o f H erb icid es in South Vietnam. P a rt A. Summary and C o n clu sio n s. Newton, M ., and Norgren, J .A . (1977) S i l v i c u l t u r a l chem icals and pro te ctio n o f w ater q u a lit y . U .S . Environmental P ro tectio n Agency Rpt. 910/977036. N ielso n e t a I . (1965) F a ta l P oisoning in Man by 2,4-d ich lo ro p h en o xy a c e t ic acid ( 2 ,4 - D ): determ ination of the Agent in Fo ren sic m a te ria ls . Acta Pharmacol. T o x ic o l., 22, 224-234. f DOW I 249313 MRCC, 1978. Phenoxy Herbicides - Their E ffe c ts on Environmental Quality. 'N a tio n a l Research Council Canada No. 16075. PEMJJAA - 1977, P e s t ic id e and Other Chemical Residues in Total D iet Samples ( X I) P e s t ic id e Monitory J o u r n a l, V o l. I I , No. 3. P e te rso n , 6 .E . 1967. The D isco very and Development of 2 ,4 -D . A g r ic . H ist. 41: 243-253. Ramel, C. 1977, C h lo rin a te d Phenoxy A cid s and T h e ir D io x in s, E c o lo g ic a l B u lle t in s No. 27. Report from a conference arranged by the Royal Swedish Academy o f S c ie n c e s , Stockholm , Sweden, 7-9 February 1977. i S a u e rh o ff, M.W. e t a l . 1976. The Fa te o f 2,4-D ich lorp henoxy A cid (2 ,4 D) Follow ing Oral Admi ni s t r a t i on to Man. T o x ic o l. Appl. P h arm aco l., 37, 136-137. Schw etz, B .A ., S p a rsch u , G .L . & G eh ring , P . J . (1971) The e f f e c t o f 2 ,4 d ich lo ro p h e n o x y a ce tic a c id (2 ,4 -D ) and e s t e r s of 2,4D on r a t embryonal, fo e ta l and neonatal growth and development. Fe Cosmet. T o x i c o l ., 9 , 801-817. Weed S cie n ce S o c ie t y o f A m erica, 1979, H e rb icid e Handbook, 4th ed. 16855 DOW O 3.^0 J BIOCHEMICAL RESEARCH DEPARTMENT THE DOW CHEMICAL COM PANY MIDLAND M ICHIGAN DATA SHEET OF PROPERTIES, HEALTH HAZARDS, AND PRECAUTIONS FOR SAFE HANDLING OF MATERIALS M O LECU LAR FORMULA M O LECU LAR WEIGHT INDUSTRIAL HYGIEN E STANDARD CHEM ICAL NAME M-2121 SYNONYMS S T R U C TU R A L FORMULA - OR COMPOSITION Silvex acid Silvex, Potassium salt 8/15 AA RVM Attaclay to contain 50% Silvex equ. 25% 2 8 .5% 46.5% BOILING POINT EXPLO SIVE LIMITS f * B Y V O L. IN A IR ) C mwH. CORROSIVENESS (T s C m Urtale) CHEMICAL R EA C TIV ITY STA RILITT (T . ,H O . .., H n , Ll^ | FLA SH POINT IGNITION TEM P. M ELTING POINT VAFOR P R E U U R C -- Ha 2 J*C f . c c PHYSICAL STA TE COLOR solid white ODOR (iMclud* C m c b w w I m la Air) ess., none O CO O O TYPE OF CONTACT EYE SKIN S UA. DUST OR XOP- MIST I VAPOR CLASSIFICATION OF TOXIC PROPERTIES May c a u e ao n i p e o i e or ao a m than m y slig h t to slig h t transitory pain sod/or slig h t tra n sien t caracal injury a a d /o r irritation of the ey elid s. May caoae id f i c ic o t injury to the eye to re soli ia lo s s of tia e (to o work. (This iacludes damage to the cornea which heals or oeaxljr heals ia s week s a d /o r coasiderah lc conjunctival in ita tio a wirb p H rin^ _ -------------------------- May c so se some perm anent lo se of vision (th is ia d a d e s damage to cocoes or iaieraal iajory which is incom pletely healed ia a e w eek.) Vapor exposure way cao ae sev ere pwta, lacrym acioa or seriows iajtvy to the eyes. Siagle proloaged expos ure (hours) causes oo c ifc c t Several re- B peated prolonged cxposorca way or a i y nor cause cbe develop' weor of s o a r alight irritation. Single abort expoore (minores) may c a u se co n sid erab le trrixwoa aad/or single proloaged er frequently repeated abort expoores ca u se a b u n aad /o r way cause system ic injury, even death. ) Single proloaged exposure way caoae some reddening of the skin. Repeated prolonged contacts way cause appreciable irritation, possibly s wild burn sa d /a r way cause appreciable systemic iiijiiy due to absorption. Ao esposare rapidly canses se re te h u u aad/or serious syseemic injury, even death. No syeccwic injury expected. No irricatioo co ao se aad throat ia dusty or wisry atmospheres. Throat aad aose icritatioo ia a dusty or misty atmosphere is painful btx aoc intolerable aad /o r prolonged or repeated e r posurcs may caoae systemic injury. Dusty or misty atmosphere painful ta uose aad throat (intolerable to moat people) aad/or exposure smy cause serious systemic injury. Shan esposare (m iaates) may cau se death or serious systemic injury. Exposures do ncc cause any effects oebet than some very slight tsitacio o or pain to the eyes or respirato ry p a s s a g e s at the most Single exposures exceeding 1/2 boar, or frequently repeated e r p o sares of shorter duration, may ca u se slight aaestfaesia and/bt alight system ic injury, a a d /o r ca u se ap p reciab le, bte ooc iato lersb lc, isriratioa of respiratory p a s s a g e s . E sp eso res may cau se extreme ^ o w s ia e s a , a a d /o r seriomv sysrem ic iajury, aad/or may cau se intolerable itricarioa te th r respirasary possages. Shoct e sp o sares c-xy csao e uncoacioesw esa, s a d /o r seri o s syscewic iajury, iw l'd ia i A a tk Even eery short expona will cause scriou systemic injury or death. INGESTION XMMENTS (1) Amouots which may be swallow ed incidenta l to industrial hand - m Uag will nor cause injury. Amounts which my be swallowed incidental re in d u strial hardi ing aad c te may cause i r r i s a iajury. Applies when wet and confined under a bandage 16856 tins toMod K PRECAUTIONS (SEE CODE BELOW) DEGREES OF EXPOSURE RELATED TO TYPES O r OPERATION EYES INHALATION* m if T nm '"1ST VAPOR INGES7N 1 NO CONTACT II % MINOR CONTACT C haracterised by remote operation with cquipmeoc iso la ted from th e work area. T h e p erro n s enter ing iso lated areas w ill require th e personal protection outlined for IV below. Q u a c t c u i t d by closed system s with equipment vented outside the work area; instrum ent control; mechanical handling of m aterials is bulk. Examples are; continuous reactor, stills and filters; enclosed conveyors; veotilaceu packaging. A A A A A A ' III r IV OCCASIONAL C haracterised by manual handling of m aterials in p ac k ag es such a s b ag sydrums and fiberpnka. DAILY CONTACTS V cntiiauoo may be provided for sp ecific jo b s. Many b atch o p erations fall in to th is category. GROSS CONTACT C haracterised by hand operation. Examples ares Emergency repairs, cleaning cquipmeoc, cleaning filters, taking care of sp ills, packaging volatile or dusty m aterials without ventilation, wheeling LIKELY and tray drying. A B A A EYE CONTACT A No eye protection M td e i B U ae safety|1umi ichoat aide abielda. C Uae safety glaa se a with side shields. D Use chemical workera goggles. E Use g ss dghc goggles or s full face g a s s a d . A U L* SKIN** CONTACT DUST OR MIST : < A A bach and clean cloches ooce per week alo o f with the usual v u h i f l | ax mealtim es abo old be adequate precautions. G rossly contaminated clothing aod shoes most be removed nor later fi th a a th e cad a4 the work period so d m ost be thoroughly cleaned before re-aac. _ Require s b o v o sx che cad of th e work period aod clcao clothing from ** che H" m the s ta rt of each work day. No respiratory protection. No protection required for expo sore of th irty mia. daracioo o r le s a co obviously dasry atmosphres. Expoeorcs of longer dorados will require che oac of a dust respirator bearing che approval of th e U- S. Buresu of Nines for the use with toxic dusts. A No precautions n ecessary . O o th ia g should be changed sad skin washed promptly upon any detectable 0 contact. Each use will require special co o tid ersd o a to determine suit able protective devices sad standards of personal cleanliness. Impervious clothing such s s rub b e r b oots, n b c r aprons, sad rubber E gloves will be required. Specific item s will be diesseed as required by circumstance. Any exposure to obviously dusty atnioapbcres w ill require a dust reap0 rater bearing the approval of th e U- 5 . B ureau o f Mice* for use with toxic ousts. Any exposure * duary atm ospheres will require th e e s c of an airline E respirator, blower mask, or Cbemox mask. No precato io o a ac cessa ry for sin g le ex p o su res of no more chan tea minutes. Longer exposures citb et sin g le o* repeated, w ill require g as su n k or resp irato r equipped arich a^ivoprince ca n ister. VAPOR No precautions A ccessary for single exposures of le ss chan 1/2 hour. B Longer single c lo s u r e s , or frequently repeated exposures will require a gss mask or respirator equipped with appropriate canister. 0 G as mask with appropriate canister required a t a ll tim es. Evacuate area at once and ester only with airline napita u r , blower mask or Cbemox mask. INGESTION COMMENTS A No unusual procedures required. . Food aod tobacco should not be present in the work area. H ands aod face should be washed before smoking aod eating. GOOD PRACTICE REQUIRES THAT GROSS AMOUNTS OF ANY CHEMICAL BE REMOVED FROM THE SKIN AS SOON AS IS PRACTICAL SUITACLE GAS MASK CANISTER dust respirator (l) Avoid confining to the surface particularly if moist or wet. SIGNED DATE K. J.O P.0. 12- 27-61 CHECKED DATE H.R.Hoyle 16857 *\ ~r js & 2 U i: w4 4.^-1 v; 1. i s 'Y v fs- T >'- i.r f n . - : . r k* * V HEH23. 1*1-11-2(3) A u th o r: R. W. Bohl ; .*yar -i" :- *:k:.! . S-i J* * **;J COMPREHENSIVE SURVEY OF EMPLOYEES* EXPOSURE TO AIRBORNE CONTAMINANTS IN THE MICHIGAN DIVISION 2,*-D PLANT, 489 BUILDING, OCTOBER, 1977-MARCH, 1979 INDEX NO. 9053 i -ii -'fi '' -V r - .* ,-r- -..V : .* rf -- ru r '<T*(r.*r::v v t .. : ic' . . ' 'i ; v.i . . i. > '. -5. > i-? *-',>T . '.W'.v4 v r \ /i - ' 4' ^ ..;^ ^ v . j: J ' l i -T ; i ... > -- .*# v :rr..*- -;-' ; . . ;h v - .Vi--1, ... i7>- .r i-* */ i .* ; ..V..-.i .,, r S :}r. f -T^. .# ... . ` a i '. - - 'j 'V . I;: -i. , - ? . . V.V- ' \ : i* ' i'. i (1*A... :I . . 1' ' *>' .- 4 Vi " `T i f t . ' V*SJ\ .. . . i i-Sr' .. ' ! rv^.-8V-- , * <: * * i* > 'r t *>' < A 1." y .S \ < r - :* . .. ,1 c * ' y rVi '..\ ' - , - ; '; ;;L" * .. ' '.. ' ' i .. * 4-; . .. . .jf- ' b? ' <" C3 j v # v- $ or <7 4 oo CD'. - s i' r.> ^ j */ ; ; v " . ; 'V <o in 'O in ' 'x:l/. . > '*. . in o ,^ * ' * yi. h-. v. 4 . V;. k *. r-* 1 ..*",s -i:.v5- ..- .'.2 ? r'.: . ^T-.r -- 7-.V. r t*" vv -i ~ ' '--"lit ^ '.-L-ti.fy ~ y . ; f-V- r vi . ^ ri -* A f -- **, . .X** . > *. . A * i .. '4 . ." ' v- < S ' . 5 i ' 4; .. A JVve:" j/ i - % '* . S*> jr i' i . r -j OFFICE COPY ICAL U.S.A. L 9053 HEH23.1 4 - 1 1 - 2 ( 8 ) June 21, 1979 ACCOUNT N O .IV R O B LK M N U M BS 9084000 OYEES' EXPOSURES TO AIRBORNE CONTAMINANTS IN THE T , 489 BUILDING, OCTOBER, 1977-MARCH, 1979 K. F . Davey or y .o o CO vl cnr. h o m e contaminants were evaluated during operation of [:he packaging lin e s . Eight-hour time-weighted average :B , Dowanol P IB , is o o c ta n o l, amnonia, dichlorophenol h s t e r , carbon monoxide and MCPA were measured fo r [ith the highest potential fo r exposure to each. A ll h e . The p o te n tia l fo r overexposures to Dowanol EB in the [ind Dowanol PIB in the " a c id " e s t e r area was co rre cte d [ i s t high le v e ls of DCP were lowered to acceptable ' clo su re through v e n t ila t io n Improvements made p r io r to igh ammonia e x cu rsio n s in the a c id e s t e r area w i l l be a n t , 489 B u ild in g 489 B uild ing S e c t io n , 834 B u ild in g l i s t r a t io n , 834 B u ild in g 834 B u ild in g i l s R esea rch , 1710 B u ild in g il Department, 607 B u ild in g jie n e S e r v ic e s , 607 B u ild in g .a b o r a t o r ie s , 574 B u ild in g invironm ental S c ie n c e s , 1603 B u ild in g jp /S ilv e rste in /S c h n e id e r * 18859 94.68^9 l MOO 2 PURPOSE An ev alu a tio n o f 2,4-D P la n t employee exposures was completed as part of t h e ir a c tiv e on-going in d u s t r ia l hygiene program. Survey work of the 2 ,4 -0 Acid operatio n reported by M. F . Stevenson in 1976, HEH23.141 1 -2 (6 ), found exposures to dichlorophenol in two job c l a s s i f i c a t i o n s to be in excess o f h e a lth g u id e lin e s . New v e n t ila t io n in the en clo su re area had been in s t a lle d and exposures were re e v a lu a te d . The l a s t employee exposure data to the a lco h o ls used in the two e s t e r production areas were reported by G. H. F lo re s in 1973, in rep o rt NBH2.1 -1 -5 3 (2 ). Process changes were made in the in te rv e n in g y e a rs and new employee exposure documentation was re q u ire d . E v a lu a tio n s during t h i s survey were a lso made in the packaging areas and when methyl chlorophenoxy a c e t ic acid was being handled. CONCLUSIONS AND RECOMMENDATIONS 1. New Chemical and P h y sic a l Agent In v en to ry sh e e ts were prepared for a ll job c la s s if ic a t io n s . 2. Employees' exposures w h ile working in the 2,4-D acid enclosure area were reeva lu ated p r io r to e a r ly shutdown in 1978. a . The C r y s t a l l i z e r O perators' and A s s is t a n t O perators' 8-hour TWA exposures to dichlorophenol (DCP) and 2 , 4-dichlorophenoxy a c e t ic a cid (2,4-D a cid ) were w ith in accep tab le li m i t s . b. The re a c tio n equipment was scheduled f o r removal. The packaging op eratio n of the p ro cess was s ta rte d again (on 2,4-D acid ) in the f i r s t quarter o f 1979. 3. For the 2,4-D "acid" e s te r operation a rea : a . The E s t e r O p era to rs' and Form ulation O p erato rs' 8-hour TWA exposures to Dowanol EB, Dowanol P IB , iso o cta n o l and ammonia were w ith in accep tab le lim it s . b. T ra n sie n t co n ce n tra tio n s o f ammonia next to the r e a c t o r s , j u s t a f t e r the E s t e r Operator m anually added `V > in to an open manhole, o c c a s io n a lly exceeded the ex cu rsio n l i m i t . Although the o p erato r was able to avoid exposure by stepping away, t h is p o te n tia l fo r exposure w ill he e lim in a te d in 1979 w ith the i n s t a l l a t i o n o f a d ir e c t add ition method. c . C o ncentratio ns o f alco ho l next to the open s lu r r y ta^k were the highest measured in the e s te r process area and`occasion a l l y were above recommended g u id e lin e s . T h is p a rt o f 't h e process was changed to a clo se d system to e lim in a te t h is source of exposures. Ml* I 548977 5 4. For the d ire c t e s te r area: a . The D ire c t E s t e r O perators' (two o p erato rs per s h i f t ) 8-hour TWA exposures to Dowanol EB, Dowanol PIS and Esteron 245 were w ith in accep tab le lim it s . b. C o n cen tratio n s o f Dowanol EB in the "high Bay" area were o c c a s io n a lly above the a ccep tab le ex cu rsio n l i m i t . The p o te n tia l f o r overexposure was reduced w ith the i n s t a l l a t i o n o f an improved tem perature c o n t r o lle r a t the decanter and by pip in g the s t r ip p e r column overflow to an o u tsid e sump. (EB and w ater phases in v e r t over a narrow temperature range and EB often was d ischarg ed with w ater in to an open tre n c h ). c . R valu atio n o f p o te n tia l exposures to Dowanol EB in the "high bay" i s recommended fo r 1979 survey work. 5 . C on cen tratio n s o f a irb o rn e 2 ,4 ,5 - T PIB e s t e r in the work area o f the M a te ria l H andlers a t the one g allo n can f i l l i n g machine area did not exceed 0 .0 0 4 mg/ra , which was judged a cce p ta b le . 6 . The Lo ad e r/C h e ck e rs1 and M aterial Hanglers* 8-hour TWA and peak exposures to carbon monoxide (CO) in the drum f i l l i n g area and warehouse were w ith in accep tab le l i m i t s . A new continuous area CO monitor was i n s t a l l e d . P e rio d ic c a lib r a t io n i s to be c a r r ie d O out by the Instrum ent Department. 7. The C lerk/Tank C ar U n lo a d e rs' estim ated 8-hour TWA and peak exposures to methyl chlorophenoxy a c e t ic a c id (MCPA) were w ell w ith in a cce p ta b le l i m i t s . The lo c a l exhaust v e n t ila t io n hood over the bag dumping hopper was a ccep tab le f o r the co n tro l o f dust from t h is l o t o f MCPA. An average hood fa ce v e lo c it y o f approxim ately 150 f e e t per minute i s reconmended i f a d u s t ie r product is handled in the fu tu re. 8 . V e n tila t io n to the drum f i l l i n g lin e s was in e f f e c t iv e and high t r a n s ie n t c o n c e n tra tio n s o f ammonia were n o ticed during the f i l l i n g o f drums w ith amine fo rm u la tio n s. A new exhaust v e n t ila tio n system w i l l be in s t a lle d in 1979. 9 . No data e x is t s f o r the Form ulation O p erato rs' exposure to dim ethylamine, and an e v a lu a tio n o f these exposures i s recommended fo r 1979. C 16861 i DOW. '548978 l, PROCESS AND JOB DESCRIPTIONS ,- N o 16862: S168PSI 5 2 ,4 -0 11A cid" E s t e r P ro cess . . * > 1 u m I 548980 <J3 CO CD SO sH! 7 The 2,4-D acid process was d iscontinued e a r ly in 1978 as the new produc tio n p lan t came on stream . Packaging and Warehouse Packaging and warehouse op eratio ns were contained on two f lo o r s with two can f i l l i n g machines on the second flo o r and two drum f i l l i n g lin e s on the f i r s t f lo o r . These lin e s were operated by M a terial H a n d le rs, Set Up Men and Loader/Checkers. Very l i t t l e v e n t ila t io n was in s t a lle d which allow ed a n o ticea b le odor when DMA form ulations were packaged. New v e n t ila t io n for the drum f i l l i n g lin e was planned fo r 1979. In 1978, two g a so lin e powered f o r k l i f t s were being operated and carbon monoxide fumes were generated. A continuous a n a ly z e r was in s t a lle d in the ce n te r of the drum f i l l i n g area to monitor carbon monoxide. The a n a ly z e r was found to be in accu ra te and was replaced in 1979. Methyl Chlorophenoxy A c e t ic A cid (MCPA) MCPA production was a form ulating p ro je c t f o r about one to two months each y e a r . Purchased bags o f s o lid or g ra n u la r MCPA were opened by hand and m anually dumped in to a hopper in a room e a s t o f the warehouse. A lo c a l exhaust v e n t ila t io n hood covered the hopper to co n tro l dust evolu t io n . The re st o f the work o f the Clerk/Tank Car Unloaders who performed t h is job was located o u tsid e o r in o th er low exposure a re a s . v Formulations ) Form ulations work was performed by the Form ulations O p erator. This o p e ra tio n , asid e from when amine form ulations were made, had a low exposure p o te n tia l and was not e x te n s iv e ly in v e s tig a te d . The Formula tio n s Operator spent most o f h is time in an a i r cond itioned control room o r a t o u tsid e equipment. He did have to e n te r the 2,4-D o r "acid " e s t e r p ro cess area and was th e re fo re evaluated f o r exposures r e la t e d to th a t p ro c e s s . P o te n tial exposures to dimethylamine w i l l be in v e stig a te d in 1979 and the process d escrib e d in th a t re p o rt. The o th er job c l a s s i f i c a t i o n s l i s t e d in Appendix 1 th a t have work in process areas (p o te n tial exposure areas) were the A n a ly tic a l T e ch n icia n s, P la n t Mechanics and Foremen. The Spares covered fo r the absence of o th er c l a s s i f i c a t i o n s . The remaining c l a s s i f i c a t i o n s had p r im a r ily a d m in istra tiv e and o f f ic e or c l e r i c a l fu n ctio n s which req u ired in f r e quent e n try and sh o rt exposure time in the process a re a s . / 548981 23* Vf>1. C 8 15 4 8 9 8 2 o EVALUATION CRITERIA Dow In d u s t r ia l Hygiene Guides (IHGs) a re co n ce n tra tio n s o f airborne substances to which n e a rly a l l employees may be re p e a te d ly exposed throughout a working lif e t im e w ithout adverse e f f e c t . IHGs are e sta b lis h e d by the h ealth p r o fe s s io n a ls o f the Dow In d u s t r ia l Health 8oard fo r chem icals (raw m a t e r ia ls , in te rm e d ia te s, b y -p ro d u cts, w a stes, and products) handled w ith in The Dow Chemical Company. P u b lish ed exposure c r i t e r i a a re a v a ila b le f o r many in d u s t r ia l c h e m ic a ls; examples in clu d e the Threshold L im it Values (TLVs) of the ACGIH (Am erican Conference o f Governmental In d u s t r ia l H y g ie n is t s ) , the ANSI stan d ard s o f the American National Standards I n s t i t u t e , and the OSHA stand ard s o f the Occupational S a fe ty and Health A d m in istratio n o f the United S t a t e s Department of Labor. For most o f these ch e m ic a ls, the In d u s t r ia l H ealth Board has adopted the published exposure c r i t e r i a as the Dow IHGs. In a few in sta n ce s the IHG s e t by the In d u s t r ia l H ealth Board d i f f e r s from the published exposure c r i t e r i a . In e s t a b lis h in g IHGs f o r chem icals which lack published exposure c r i t e r i a , the In d u s tria l H ealth Board considers to x ic o lo g ic a l in fo rm atio n , o ccu p atio n al exposure d a ta , and medical experience. In d u s t r ia l Hygiene Guides do not rep re sen t fin e lin e s between sa fe and dangerous exposures. As the name in d ic a t e s , IHGs a re p ro p erly used as guides fo r p lan t design and fo r e v a lu a tin g o ccu p atio n al exposures-. IHGs fo r gases and vapors are u s u a lly expressed in p a rts p er m illio n (ppm, volume/volume); fo r d u s ts , fumes, a e r o s o ls , and m is t s , IHGs are u s u a lly expressed in m illigram s o f contaminant per cubic meter of a i r (mg/nr). Most IHGs are time-weighted average (TWA) co n ce n tra tio n s f o r an 8-12 hour workday and a 40 hour workweek. Lim ited e x cu rsio n exposures to co n cen tratio n s exceeding the IHG are p erm itted , provided th a t the TWA exposure fo r the e n t ir e work day i s accep tab le and the consequences o f exposure, w ith in the excursion l i m i t , are minimal and r e v e r s ib le . For most c h e m ic a ls, excu rsio n l i m i t s a re c a lc u la te d from the IHGs and the excu rsio n fa c to rs recommended by the ACGIH. C e ilin g IHGs a re assigned to those m a te ria ls which cause s ig n if ic a n t or ir r e v e r s ib le e ffe c ts at co n ce n tratio n s exceeding the IHG. Fo r these c h e m ic a ls , no excu rsio n exposures are allow ed. The fo llo w in g exposure c r i t e r i a c u r r e n t ly apply to the airborne contaminants measured during t h is su rvey: Compound o r M aterial Dowanol EB Dowanol PIB mix Isooctyl alcohol Dimethyl amine IHG 50 ppm 25* ppm 75 ppm 10 ppm Excursion 1 75 ppm 110 ppm , 2 0 .ppm *Not e s ta b lis h e d by the Dow In d u s t r ia l H ealth Board, 25 ppm used as a temporary g u id elin e. r~ V PRRRfrcf Off 9 Compound o r M aterial 2 ,4 -D ich lo ro p h e n o l Methyl chlorophenoxy a ce tic acid IHG 1 ppm 5 mg/m^ Excursion Lim it 3 ppm 10 mg/m^ 2 ,4-Dichlorophenoxy a ce tic acid 10 mg/m^ 20 mg/m'* 2 ,4 ,5 -T ric h lo ro p h e n o x y a c e tic acid 10 mg/m^ 20 mg/nf* Ammonia 25 ppm 35 ppm Carbon monoxide 50 ppm 400 ppm When the r e s u lt s o f an in d u s t r ia l hygiene su rvey in d ic a t e a need to reduce exposure, co n tro l measures should be implemented. T r a d it io n a l engineering co n tro l methods in clu d e containm ent, is o la t io n , s u b s t i t u t io n , lo c a l exhaust v e n t ila t io n , g eneral v e n tila t io n and change of operating procedure. A d m in istrative control -- lim itin g exposure time through remote c o n tro l o r jo b r o t a t io n -- may a lso be e f f e c t iv e . P ersonal p r o t e c t iv e equipment may be used to p ro tect employees o n ly as a l a s t a lt e r n a t iv e when none o f the preceding co n tro l methods i s f e a s ib le o r u n t il c o n tro l measures can be e f f e c t e d . i i ~'\ 10 AIR SAMPLING AND ANALYSIS Airborne Dowanoi EB (2-butoxy ethanol) Dowanol PIB-T [mixed (mono, d i , t r i ) propylene g ly c o l isobutyl e t h e r ] and iso o ctan o l were c o lle c t e d on commerical adsorber tubes packed with 800 mg o f s i l i c a g el. Each tube was connected to p o rtab le b a tte ry operated personal monitoring vacuum pumps, c a lib r a t e d before and a f t e r sampling and operated a t about 0.1 l i t e r s per minute (LPM). The pumps and tubes were worn by operators to c o l l e c t personal breathing zone samples or placed in s p e c if ie d work a re a s to c o l l e c t area samples. The sample tubes along with tubes prepared with known co n ce n tra tio n s were l a t e r desorbed with car6on d i s u l f i d e with 1% methanol or with methanol and then analyzed by gas chromatography and flame io n iz a t io n d e te ctio n (GC/FID ). A n a ly t ic a l work was performed by R. G. Melcher (AL 77-51116 and AL 78-50450), L . Nauer (AL 78-50170), J . Warren and P. K a stl (AL 79-50107). Airborne dichlorophenol and 2,4-dichlorophenoxy a c e t i c acid were c o lle c t e d with both a c t iv a t e d alumina adsorber tubes and midget impingers containing 0.1 N sodium hyd ro xid e. A i r sampling was completed using c a lib r a t e d personal monitoring pumps operating a t about 0.1 LPM fo r the tubes and up to 0.5 LPM f o r the impingers. Both the tubes and the impinger s o lu t io n s were e x tra cte d with a 50/50 hexane/diethyl eth e r solution and methylated with diazomethane. A nalyses were performed by L . Nauer by GC/EC (gas chromatography/electron capture d e te c tio n ) (AL 78-50015). In an attempt to document exposures to airborne 2 ,4 ,5 - T Dowanol PIB e s t e r , a i r samples were drawn through midget impingers containing reagent iso o cta n e . A i r flow r a t e s and volumes in the beginning were 0.3 LPM with up to 10 l i t e r s o f a i r c o l l e c t e d . Breakthrough at the higher contaminant l e v e l s was common. A i r flow r a t e s were lowered to under 0 .2 LPM and volumes under s i x l i t e r s f o r l a t e r samples. Impinger s o l u t io n s and knowns were analyzed with GC/EC techniques by R. G. Melcher CAL 78-50449) and L . Nauer CAL 78-50170 and AL 79-50029). Ammonia was estim ated on s i t e using Bendix Gastec No. 3L ammonia detection tubes with an expected accuracy w it h in 25%. Carbon monoxide was estimated on s i t e using Bendix Gastec catalog number ILa and IL L d e te c to r tubes and Draeger 50/a-L extended time d etecto r tu b es. A n a l y t ic a l accu ra cy has been determined to be within 25%. Airborne methyl chlorophenoxy a c e t i c a cid (MCPA) i s a s o lid at room temperature and was c o lle c t e d on 0 .8 micron membrane f i l t e r s using c a li b r a t e d a i r monitoring pumps operating a t over 3 LPM. The weights were determined g r a v i m e t r i c a l l y as t o t a l MCPA by R. W. Bohl. ..if. ,, M W 154898-1 11 DISCUSSION OF RESULTS Table 1 i s a summary o f employees' exposures to chemical and physical agents by va rio u s job c l a s s i f i c a t i o n s . The degree o f exposure, hazard r a t in g and e v a lu a tio n r e s u l t s are shown fo r those p o te n tia l contaminants with a hazard rating of 1 to 3 for any job c la s s ific a t io n . The four r a t in g s f o r the degrees o f exposure are the same as the one defined on the back o f the I n d u s t r ia l Hygiene Data Sheets. DEGREES OF EXPOSURE RELATED TO TYPES OF OPERATION C h a ra cte riz e d by remote operation with equipment is o - I NO CONTACT ^a t e d from the work a re a . The persons entering is o la te d areas w ill require the personal protection outlined in iy helow. MINOR I l rnwTft C h a ra cte riz e d by clo se d systems with equipment vented o u tsid e the work a r e a , instrument c o n t r o l, mechanical handling of m a t e ria ls in bulk. Examples a r e : continu ous r e a c t o r s , s t i l l s and f i l t e r s , enclosed conveyors ventilated packaging. OCCASIONAL I I I DAILY CONTACT C h a ra c te riz e d by manual handling o f m a te ria ls in packages such as bags, drums and fib e rp a k s. V e n t ila t io n may be provided f o r s p e c i f i c j o b s . Many batch opera tions fa ll into th is category. GROSS IV CONTACT LIKELY C h a ra cte riz e d by hand o p era tio n . Examples a r e : emergency r e p a ir s , cleaning equipment, cleaning f i l t e r s , taking car o f s p i l l s , packaging v o la t ile or dusty m a t e r ia ls without v e n t i l a t i o n , wheeling and t r a y drying. The degrees o f exposure, as rated by p la n t su p e rv isio n and reviewed by the in d u s t r i a l h y g i e n i s t , were based on normal operating c o n d itio n s. Each was based on r e g u la r o b servations o f the operating procedures and work p r a c t ic e s employed by operators in the s p e c i f i c job c l a s s i f i c a t i o n . The hazard r a t in g found in Table 1 i s defined as fo llo w s : 154898 CT 16089 A numerical r a t in g ranging from 1 (high) through 5 (low) which estimated the p r o b a b il i t y that an i n j u r y or overexposure w i l l occur in a given s i t u a t i o n or environment. I t i s based on the degree of exposure and the p h y sical and t o x ic p ro p e rtie s o f the chemical. The degree o f exposure i s influenced by the type o f process (open v s . closed system) and the type of operation req u ired (manual v s. automatic). The i n d u s t r i a l h y g ie n is t has the r e s p o n s i b i l i t y f o r s e t t i n g the hazard r a t in g s based on h i s observations o f the p la n t , the degree of exposure and the a b i l i t y o f the m a te ria l (o r p h y sic a l s t r e s s ) to cause i n j u r y . The hazard r a t in g s were unique f o r each jo b c l a s s i f i c a t i o n . Within any given p l a n t , the hazard r a t in g fo r a chemical may be d i f f e r e n t fo r the various job c la s s if ic a t io n s because of a varying degree of exposure. The ev alu a tio n r e s u l t s may include measured TWA exposures f o r each job c l a s s i f i c a t i o n o r a p ro fe ssio n a l judgment that given exposures would be acceptable based on past exposure data or other data th a t would In d ica te a low p r o b a b il i t y o f overexposure. Tables 2 and 3 show an in c re a se in the l e v e l of exposures by the D ire c t E s t e r Operators to Dowanol EB over a one y e a r period . Concentration in the d i r e c t e s t e r high bay area were, at tim es, i r r i t a t i n g and o c c a s io n a lly exceeded the e x cu rsio n l i m i t . Water from the decanter and s t r i p p e r column o c c a s i o n a ll y contained e x ce ssiv e Dowanol EB due to a water/alcohol phase inversion which occurred within a narrow temperature range. In 1979, a new temperature c o n t r o l l e r f o r the decanter and piping of the s t r i p p e r overflow d i r e c t l y to an outside waste water sump has decreased odor l e v e l s . A r v a lu a tio n of exposures was reconmended and scheduled for 1979. No o th e r a l c o h o l s , e i t h e r r e s id u a l from previous runs or recycled from c u rre n t operations of the "acid" e s t e r p r o c e s s , were detected in the d i r e c t e s t e r area . Table 4 shows the r e s u l t s o f monitor ing at the d i r e c t a c id process f o r Dowanol PIB and the r e la t e d 2 ,4 ,5 - T e s t e r . While IHG's had not been e s t a b lis h e d fo r these two m a t e r i a l s , PWA co n cen tratio n s o f 25 ppm f o r PIB and 5 mg/nr f o r the 2 ,4 , 5 - T e s t e r were co n se r v a tiv e vaues used as interium g u id e lin e s . [The lowest IHG fo r any-Dowanol (Dowanol EM) i s 25 ppm and the IHG f o r 2,4-D a c id is 10 mg/m . ] Exposures were well below these values and no health ahzard would be a n t i c i p a t e d . Tables 5 , 6 and 7 show the r e s u l t s o f monitoring f o r p o t e n t ia l Dowanol EB, Dowanol P IB , is o o c t y l alcohol and . J exposures in the 2,4-D "acid" e s t e r process a r e a . Eig h t-h our TWA exposures to a l l four were well w ith in a ccep tab le l i m i t s . The E s t e r Operators were p o t e n t i a l l y exposed to e x c e s s iv e ammonia when adding through an open manhole in to the r e a c t o r s . Operators were observed to step back away from the fumes to minimize actual exposures. A d i r e c t a d d jtior method i s scheduled f o r i n s t a l l a t i o n in 1979. The open s l u r r y - t a n k ' a l ^ . - c o n tributed a p oten tial excursion exposure as seen in Table 6. Th is tank was clo sed to e lim in a t e the source. 13 While no hazard was expected, data on airborne 2 ,4 ,5 - T e s t e r s was req uested , and the r e s u l t s o f monitoring at the one gallon can packaging area are shown in Table 8. Work area concentrations were very low, and the M aterial Handlers' exposures were judged to 6e well w ith in acceptable 1i r a i t s . G a so lin e powered f o r k l i f t s were in use in the warehouse and drumming a re a s through 1978. Carbon monoxide exposures were evaluated and found to be w ith in acceptable l i m i t s , as shown in Table 9. The f o r k l i f t t r a f f i c pattern and the a i r sample lo c a t io n s are shown in Fig ure 5. The fu tu re conversion to e l e c t r i c o r l i q u i f i e d petroleum gas powered equipment should minimize both carbon monoxide and odor l e v e l s . U n til t h i s re p la c e ment o c c u r s , new continuous carbon monoxide analyzer located between the drumming l in e s should be maintained and c a lib r a te d r e g u l a r l y . The new a n a ly z e r manufactured by Dynamation has operated in an acceptable manner s i n c e i t was i n s t a l l e d the f i r s t q u a rte r of 1979 to rep lace an old er Dynamation model which c o n t i n u a ll y l o s t c a li b r a t i o n . The h ig hest exposure to methyl chlorophenoxy a c e t ic a cid (MCPA) encoun tered by the Clerk/Tank Car Unloaders occurred while opening and pumping purchased bags at the hopper fo r the mix tank. Exposures were well under acceptable l i m i t s as shown in Table 10. Also no skin i r r i t a t i o n was reported. The MCPA f la k e used was reported to be l e s s dusty than m a te ria l purchased one y e a r ago when sk in i r r i t a t i o n was experienced. The lo c a l exhaust v e n t i l a t i o n hood over the hopper was evaluated and the a i r flow measurements are shown in Fig ure 6. For the dust l e v e l s observed, ) the hood was a cce p ta b le . For hig h e r dust l e v e l s , dependent on the co n d itio n of the purchased MCPA, the a i r flow into the hood should be in cre a se d to an average hood face capture v e lo c i t y o f a t l e a s t 150 fe e t per minute. The 2,4-D acid process was operating in 1977 and was to Be phased out as the new 2,4-D acid p la n t a t 948 B u ild in g was brought up to c a p a c it y . I t was expected th a t t h i s operation might continue well in to 1978. Th erefo re, exposures to dichlorophenol (DCP) and 2 ,4 - 0 ac'H were evaluated to a ssu re th a t the m a rg in a lly e x c e s s iv e concentra,. jns o f DCP measured in 1976 had been reduced through the i n s t a l l a t i o n of a new v e n t i l a t io n system in 1977. As shown in Table 11, exposures were w ith in acceptable l i m i t s . The production process was shut down at the s t a r t o f 1978 and the r e a ctio n equipment scheduled f o r removal. The packaging end of the p rocess was kept on stand-by co n d itio n and was sta rte d again in 1979 to package 2,4-D a cid produced at the new p la n t. In developing a new Chemical and P h y s ic a l Agent Inventory (Appendix 2) w ith exposure and hazard r a t in g s f o r a l l job c l a s s i f i c a t i o n s , the Formu l a t i o n s Operators' p o t e n t ia l hazard to amines was not well e s t a b lis h e d with d a ta , and i t was reconrnended th a t exposures to dimethyl amine and p o s s ib ly diethylamine be evaluted in 1979. ' ... . - `tr *. i* A n o is e survey completed by the ACPD s a f e t y re p re se n ta tiv e ( 0 : Bugg) found employees' TWA exposures were acceptable A report o f t h i s survey i s kept at the 2 , 4 -l r i a n t s u p erin te n d e n t's o f f i c e and in the In d u s t r ia l Hygiene Laboratory's f i l e s . 1548987 cr 1687 1548988 14 Four sealed sources used in process instrum entation and in a n a lt y ic a l equipment were surveyed and wipe tested tw ice in 1978 by J . M. Bronson and R. W. Bohl of the I n d u s t r ia l Hygiene L a b o ra to ry . A ll sources were found to be in acceptable co n d itio n . Documentation i s kept at the Health Physics section of the Industrial Hygiene Laboratory with copies mailed to each plant superintendent. % .>. . :1 16872 ^ Table ., ) {) SUMMARY OF DEGREE OF EXPOSURE RATINGS, HAZARD RATINGS AND EXPOSURE EVALUATION RESULTS BY JOB CLASSIFICATION IN THE MICHIGAN DIVISION 2,4-D PLANT, 489 BUILDING, OCTOBER, 1977-FEBRUARY, 1979 Material IHG Dowanol EB (2-butoxy ethanol) 50 ppm Dowanol PIB Mix (72% mono, 22% d i , 4% trip ro p y le n e glycol isobutyl ether) NE* Direct Ester Operator DE HR E 3 3 2.5 3 4 1.0 2,4-D Ester Operator DE HR EE 3 4 1.5 3 4 1.9 Formulations Operator DE HR JtT 2 4 0.4 Clerk-Tank Car Unloader bE HR E 1 5 JA 2 4 0.5 1 5 JA Loader-Checker DE HR " I T 1 5 JA 1 5 JA Isooctyl alcohol Diinetiiylamine (DMA) 2,4-Dichloropheno.l (DCP) Methyl chlorophenoxy a c e t ic acid (MCPA) 75 ppm 34 JA 3 4 0.5 2 4 0.1 1 5 JA 1 5 JA 10 ppm 1 5 JA 1 5 JA 2 3 JA** 3 3 JA** 1 5 JA 1 ppm 2 4 JA 1 y JA 1 5 JA 3 3 JA** 1 5 JA 5 mg/m3 1 5 JA 1 5 JA 1 5 JA 4 3 0.07 2 4 JA 2,4-Dichlorophenoxy acetic acid (2,4-D acid) 10 mg/m3 1 5 JA 2 4 JA 4 3 JA*** 3 3 , JA*** 1 5 JA 2 ,4 ,5-Trichlorophenoxy 10 mg/m3 3 4 0.2 1 5 JA 1 5 JA acetic e ste r (Esteron 245) / 1 5 JA 3 4 0.001 Ammonia 25 ppm 1 5 JA 3 3 0.5 1 5 JA (e s t.) 1 5 JA 1 5 JA Carbon monoxide,. 50 ppm 1 5 JA 1 5 JA 2 4 JA 3 4 15 3 3 15 Sodium hydroxide 2 mg/m3 2 4 JA' 1 5 JA 1 5 JA if. *NE - Not esta b lish ed **To be measured in 1979 ***Prim arily a potential skin contact hazard 3 3 JA*** 1 5 JA DE - Degree of exposure HR - Hazard rating EE - Exposure evaluation JA - Judged acceptable 16873 Table 1. CONTINUED Material Dowanol EB (2-butoxy ethanol) Dowanol Pill Mix ( 7 2 % mono, 2 2 % d i , 4! trip ro p y le n e glycol isobutyl ether) Isooctyl alcohol Dimethyl amine (DMA) 2 ,4-Dichlorophenol (DCP) Methyl chlorophenoxy a c e t i c acid (MCPA) 2 ,4-Dichlorophenoxy acetic acid ( 2 ,4-D acid) 2 ,4 ,5-Trichlorophenoxy a c e t ic e s t e r (Esteron 245) Ammonia ? Carbon monoxide - Sodium hydroxide,, IHG 50 ppm NE* Material Handler DE HE EE 1 5 JA 1 5 JA 75 ppm 1 5 JA 10 ppm 1 5 JA 1 ppm 1 5 JA 5 mg/m^ 3 3 0.07 10 mg/m^ 3 3 JA** 10 mg/m^ 3 4 0.001 25 ppm 1 5 JA 50 ppm 3 3 15 2 mg/m^ 1 5 JA Set-Up Man DE HR EE 1 5 JA 1 5 JA 2,4-D Enclosure P rio r to Shutdown C r y s t a l l l 2 er Operator (Not a ctiv e in 1978) DE HR EE Assistant (2,4-D) Operator (Not a c tiv e in 1978) DE HR EE 1 5 JA 1 5 JA 1 5 JA 1 5 JA 1 5 JA 1 5 JA 1 5 JA 3 3 0.07 3 3 JA** 2 4 JA 1 5 JA 3 3 15 1 5 JA 1 5 JA 1 5 JA 3 3 0.05 1 5 JA 2 3 0.09 1 5 JA 1 5 JA 2 4 JA 2 4 JA 1 5 JA 1 5 JA 2 4 0.05 1 5 JA 3 3 0.07 1 5 JA 1 5 JA 2 4 JA 2 4 JA *NE - Not esta b lish ed **To be measured in 1979 Note: Exposures by a l l other job c l a s s i f i c a t i o n s l i s t e d on Appendix 1 to a l l chemicals above and l i s t e d in Appendix 2 were judged acceptable. 05 MOOS 0 S 6 8 T S / . O Table 2. AIR MONITORING FOR DOWANOL EB AND DOWANOL PIB-T IN THE DIRECT ESTER OPERATION DURING PRODUCTION OF DOWANOL EB ESTER OF 2,4-D (DOWANOL PIB ESTER BEING PRODUCEDI IN 2,4-D ACID ESTER PROCESS), IN THE MICHIGAN DIVISION 2,4-D PLANT, 489 BUILDING, NOVEMBER, 1977 Description Personal Samples (Approximate Hour TWA Exposure) Personal breathing zone of the D irect E s te r Operator for the high bay process area Personal breathing zone of the D irect E s t e r Operator for the high bay process area Personal breathing zone of the Direct E s te r Operator for the high bay process area Personal breathing zone of the D ire ct E s t e r Operator fo r the low bay area Personal breathing zone of the D ire ct E s t e r Operator fo r the low bay area Personal breathing zone of the D ire ct E s t e r Operator fo r the low bay area Date 10/24/77 10/26/77 10/28/77 10/24/77 10/26/77 10/28/77 Concentration (ppm) Dowanol EB Dowanol PIB* 0.6 . 0.8 2.7 0.5 0.4 4.5 ND** ND ND ND ND ND Area Sampling 1 Control room., D ire ct E s t e r Process A D irect Eisfer, high bay, f i r s t level 'r 10/26/77 10/28/77 10/24/77 10/26/77 10/28/77 0.8 0.7 23 28 17 ND ND ND ND ND From acid room **ND - Not detected at a n a ly t ic a l s e n s i t i v i t y of <0.3 16875 T668FS| Table 2. CONTINUED J Area Sampling Description D ire c t E s t e r , high bay, 2nd level ' (Odor i r r i t a t i n g ) Direct E ste r, high bay, third level D ir e c t E s t e r , low bay, f i r s t level D ire c t E s t e r , low bay, second level Inside the 2,4-D acid enclosure Open a re a , north end of 409 Building between D irect E s t e r and Acid E s t e r rooms In sid e 2,4-D a cid e s t e r room Industrial, Hygiene Guide Excursion Limit *From a cid room **ND - Not detected at a n a ly t ic a l s e n s i t i v i t y of <0.3 ***ND - Not detected at a n a ly t ic a l s e n s i t i v i t y of <0.2 o CO Date Concentration (ppm) Dowanol EB Dowanol PIB* 10/24/77 10/26/77 10/28/77 10/28/77 10/28/77 10/24/77 10/28/77 10/24/77 10/26/77 10/28/77 10/28/77 10/28/77 6.8 10 16 38 6.3 0.4 0.9 0.6 0.4 1.1 0.3 0.5 ND*** 50 75 ND** ND ND ND 0.4 ND ND ND ND ND 0.2 ND 0m r* /J Table 3. AIR SAMPLING FOR DOWANOL EB AT THE DIRECT ESTER PROCESS DURING PRODUCT OF DOWANOL EB ESTER OF 2 ,4 -D , 2,4-D PLANT, 489 BUILDING, JANUARY, 1979 Description Personal Samples (Approximate 8 Hour TWA Exposuire) Personal breathing zone (BZ) of D ir e c t E s t e r Operator (operating high bay) Personal BZ of D ir e c t E s t e r Operator (operating low bay) Area Samples Control room, D ire c t E s t e r Process High bay, f i r s t f lo o r High bay, second f lo o r High bay, .-3rd f lo o r High Bay, fourth f lo o r (Odor very strong) (Odor very strong) (Odor very strong) Date 1/18/79 1/20/79 1/18/79 1/20/79 1/15/79 1/17/79 1/18/79 1/18/79 1/20/79 1/15/79 1/17/79 1/18/79 1/19/79 1/20/79 1/15/79 1/17/79 1/18/79 1/19/79 1/15/79 1/17/79 1/19/79 Dowanol EB (ppm, voi; 5.0 3.4 3.5 2.8 1.8 2.9 1.5 25 27 59 5.4 64 26 61 47 55 77 44 44 49 44 18877 MOO C668PS| Table 3. CONTINUED Area Samples Low bay, f i r s t f lo o r Low bay, 2nd f lo o r Description In d u s t r ia l Hygiene Guide Excursion Limit V-> <S> \+*. J Date Dowanol EB (ppm, vcil/vol) (Minimal odor) 1/17/79 1/18/79 1/17/79 1/18/79 1/20/79 3.0 5.5 3.3 5.4 5.2 50 75 O fable 4. O RESULTS OF AIR MONITORING FOR DOWANOL P1B-T AND ESTERON 245 AT THE DIRECT ESTER PROCESS DURJN? PRODUCTION OF DOWANOL PIB ESTER OF 2 .4 ,5 - T IN THE MICHIGAN DIVISION 2 .4 - 0 PLANT, 489 BUILDING, FEBRUARY-MAV, 1978 Description Personal Samples (Approximate 8 Hour TWA Exposure) Date Dowanol PIB-T (PPm) 2 ,4 ,5 - T Jster (mq/m ) Breathing zone of D ir e c t E s t e r Operator for High Bay Breathing zone of D ire c t E s t e r Operator fo r Low Bay 2/24/78 2/24/78 1.0 1.0 Area Samples - D ir e c t E s t e r Area High bay, f i r s t f lo o r High bay, second flo o r Low bay, second f lo o r Control room il i1 ^ 2/20/78 2/24/78 5/01/78 2/20/78 2/24/78 2/24/78 5/01/78 5/01/78 2/20/78 2/20/78 2/24/78 5/01/78 2/24/78 2/24/78 5/01/78 - 10.0 - 3.9 4.5 7.5 - - _ 1.9 3.7 - 0.3 1.1 - 0.3 0.6 0.1 0.3 0.3 0.2 0.2 0.3 0.4 0.5 0.6 0.2 In d u s t r ia l Hygiene Guide C alcu la ted 8 Hour TWA Exposures: D irect Este r Operator (fo r high bay) D ire ct E s te r Operator (fo r low bay) (Assume both spent 702 of time 1n control room, NE* NE I 1n process a re a , 152 out of area) 0.2 0.2 *NE - Not e sta b lish e d CO ZC 668 H I & 3 Table 5. RESULTS OF AIR MONITORING FOR DOWANOL EB, 2,4-D "ACID" ESTER PROCESS IN THE MICHIGAN DIVISION 2,4-D PLANT, 489 BUILDING/MAY, 1978 Date 5/01/78 D escription of Samples Personal SampHnq Personal breathing zone (BZ) of 2,4-D E s t e r Operator on re g u la r work (loaded two r e a c t o r s ) , sample time 6.3 hours, approximate 8 hour TWA exposure Dowanol EB (ppm) 1.5 5/04/78 Personal breathing zone (BZ) of 2,4-D E s t e r Operator on re g u la r work (loaded two r e a c t o r s ) , sample time 6.1 hours, approximate 8 hour TWA exposure 1.4 5/01/78 Breathing zone of 2,4-D E s t e r Operator while making up two r e a c to r batch es, 52 minutes 0.9 5/01/78 Breathing zone of 2,4-D E s t e r Operator while changing S p a rk le r f i l t e r at f i r s t f l o o r , 20 minutes 21.0 5/01/78 Personal BZ of Formulations Operator on r e g u la r work o f which one hour of h is 8 hour s h i f t was spent in the 2,4-D e s t e r room, sample time 6.3 hours and t h is approximates n is 8 hour TWA exposure 0.3 5/04/78' Personal BZ of Formulations Operator on re g u la r work of which one hour of h1s 8 hour s h i f t was spent in the 2,4-D e s t e r room, sample time 6.1 hours or approximate TWA exposure 0.4 Area Sampling 5/01/78 ' , 2nd f lo o r , center next to north a i s l e near r e a c t o r s , stro ng est odor le v e l In 7.3 1 - room at the time, sample time 6.3 hours 5/Al/7 8 ' r> 5/01/78 2nd f lo o r , south a i s l e , south of r e a c t o r s , sample time 6 .3 hours, odor j u s t noticeable * 2nd flo o r west, sample time 52 minutes 0.8 0.9 R R R P tC l O' Table 5. CONTINUED 0 O Date 5/01/78 5/01/78 5/04/78 5/04/78 Description of Samples Area Sampling 1st f lo o r under r e a c t o r s , sample time 53 minutes 2nd f l o o r , center next to north a i s l e near r e a c t o r s , sample time 29 minutes 2nd f l o o r , center of north a i s l e 2nd f l o o r , center of south a i s l e on control panel ' In d u s tria l Hygiene Guide Excursion Limit Dowanol EB (ppm) 1.0 2.2 2.8 0.7 50 75 I Vj O O 05 h* GBSfSI 1 MOU 1 jble 6. Jo RESULTS OF AIR MONITORING FOR DOWANOL PIB-T AT THE 2,4-D ACID ESTER PROCESS DURING PRODUCTION' OF DOWANOL PIB ESTER OF 2,4-D IN THE MICHIGAN DIVISION 2,4-D PLANT, 489 BUILDING, OCTOBER, 1977 AND FEBRUARY, 1978 Description Personal Sampling (Approximate 8 Hour TWA) Personal breathing zone of 2,4-D E s t e r Operator Personal Sampling (Short Term High Exposure Job) Personal breathing zone of 2,4-D E ste r Operator while charging a ll four reactors (h1s highest potential exposure p e r io d ) , 56 minutes Date Concentration 1n ppm (v o l/ v o l) Dowanol PIB Ammonia 10/24/77 10/26/77 10/28/77 02/24/78 1.2 2.0 3.0 1.4 10/28/77 4.9 Area SampHnq - 2,4-D E s t e r Room Work areas on second f l o o r , near r e a c t o r s , during production of 2,4-D PIB ester Work areas on second f l o o r , near re a cto rs during reacto r changes Next to s l u r r y ta n k , 2nd f lo o r (hig hest odor le v e l 1n room) Wor areas on f i r s t f lo o r North end'bf 489 Bu ild in g between d i r e c t e s t e r room and lunch room Between th d i r e c t e s t e r and a cid e s t e r rooms Between the acid e s t e r room and lunch room Inside 2,4-D enclosure 10/24/77 10/26/77 10/28/77 10/28/77 02/24/78 10/28/77 10/24/77 10/26/77 10/28/77 02/24/77 10/28/77 02/24/78 10/26/77 10/28/77 0.9 0.9 1.7 3.2 7.6 83 0.7 0.5 1.0 5.4 ND(<0.20) ND(<0.30) ND(<0.20) 0.2 MO MO M MO ND*(<0.5) ND(<0.5) In d u s t r ia l Hygiene Guide NE** 25 *ND - Not detected at a n a ly t ic a l s e n s i t i v i t y indicated In parentheses **NE - Not e sta b lish e d cp ce 3 n p o n t n i MOO \ u O Table 7. AIR SAMPLING FOR ISOOCTYL ALCOHOL IN THE 2.4-D ACID ESTER PROCESS OF THE MICHIGAN DIVISION 2,4-D PLANT, 489 BUILDING, OCTOBER, 1978 Personal Monitoring Description Personal breathing zone o f 2,4-D E s t e r Operator during production o f iso o cty l e s t e r of 2,4-D , approximate 8 hour TWA exposure Personal breathing zone of Formulations Operator, approximate 8 hour TWA exposure Isooctyl Alcohol _________ (ppm) 0.5 0.4 Area Monitoring* At desk on 2nd l e v e l , west of south a i s l e of acid e s t e r room Nexf to No. 4 r e a c t o r , 2nd f lo o r e a st Nex'w to s l u r r y tank, 2nd f lo o r about s i x fe e t from open manhole in work area Near f i l t e r s , northeast on f i r s t f lo o r Walkway four feet o f f f lo o r and running east-west under reacto r area In d u stria l, Hygiene Guide * % 0.3 0.3 0.5 0.5 0.5 75 Noticeable odor permeated the room which was considered by operating personnel to be ty p ic a l and normal. M W m sK I m GO o Table 8. AIR MONITORING FOR AIRBORNE ESTERON 245 IN THE WORK AREA OF THE ONE GALLON CANNING LINE DURING PACKAGING OF ESTERON 245 (DOUANOL PIB ESTER OF TRICHLOROPHENOXY ACETIC ACID) IN THE MICHIGAN DIVISION 2,4-D PLANT, 489 BUILDING, FEBRUARY, 1978 Description Next to M aterial Handler at can f i l l i n g machine Next to M aterial Handler at can f i l l i n g machine Next to Material Handler at capping machine Next to Material Handler at capping machine Near two Material Handlers loading empty cans onto the conveyor Near two Material Handlers loading empty cans onto the conveyor Near M aterial Handler loading p a ll e t s with f i l l e d cans and working near canner 2 ,4,5-T/PIB (mg/nr) ND* ND 0.001 0.002 ND ND 0.004 In d u s t r ia l Hygiene Guide ( NE** t 1 *ND - Less than the lower detectable l i m i t of 0.001 mg/m3 with a 10 l i t e r a i r sample **NE - Noticestabl 1shed MOOGO oooGf'Si O Table 9. JO RESULTS 0F AIR SAMPLING FOR CARDON MONOXIDE (GASOLINE ENGINE FORKLIFT EXHAUST) IN THE WAREHOUSE AREA OF THE MICHIGAN DIVISION 2,4-D PLANT, 489 BUILDING, NOVEMBER, 1978 Date Description* Carbon Monoxide (ppm) 11/02/78 Between drumming l i n e s , 1st f lo o r warehouse area (one f o r k l i f t operation) 11/02/78 Next to ea st drumming (one f o r k l i f t operating) 11/02/78 Next to west drumming l in e (one f o r k l i f t operating asc lo se as 20 f t away) 11/02/78 Between drumming l i n e s ( l a t e r in day) 11/02/78 Between drumming U n e s about 10 minutes a f t e r a l l f o r k l i f t operations had ceased 11/12/78 West of drumming l i n e s 1n warehouse during f o r k l i f t operation 1n building 11/08/78 .A isle w a y south of 5 gallon f i l l i n g lin e 11/21/78 Between drum f i l l i n g l i n e s (one f o r k l i f t operating in area) 11/21/78 Between f i l l i n g l i n e s ( l a t e r ) next to continuous monitor which indicated 45-75 ppm (maintenance work was ordered) 11/21/78 Next to f o r k l i f t during drum removal from 55 gallon l i n e (near operator of f o r k lif t ) 11/21/78 Between drum f i l l i n g U n e s (one f o r k l i f t operating) 11/22/78 Between drum f i l l i n g l i n e s by a nalyzer with 2 f o r k l i f t s operating (analyzer reading approximately 250 ppm) 11/22/78 Storage area (west) random times 11/08/78 Personal breathing zone sample o f Loader/Checker while working at drum ' ' f i 1in g l 'ines (S nour sample) , l l / 0 8 / 7 8 : Personal breathing zone sample o f Loader/Checker while d riv in g f o r k l i f t (5 hour sample) "ft In d u s t r ia l Hygiene Guide Excursion Limit 35** 20 50 10** 5 5 15 25 25 30 15 45 5 14 16 50 400 *Area samples unless otherwise noted **These values were over 253! lower than the continuous analyzer value. The continuous analyzer was positioned between the two f i l l i n g l i n e s and about 25 feet from the warehouse o f f i c e (Instrument Department evaluation was scheduled). T006TS] MfifI 15085 Table 11. RESULTS OF AIR MONITORING IN THE 2,4-D ENCLOSURE DURING DICHLOROPHENOL AND 2,4-D ACID PRODUCTION IN THE MICHIGAN DIVISION 2,4-D PLANT, NOVEMBER 11, 1977 Description Personal Samples Personal breathing zone sample of the C r y s t a l l i z e r Operator (approximate 8 hour TWA exposure) Personal breathing zone sample of the A s s is t a n t Operator (approximate 8 hour TWA exposure) Dlchlorophenol _______ (PPm). 0.049 0.049 Dichlorophenoxy Acetic Acid (PPm) Trlchlorophenols (ppm) 0.087 0.069 0.093 0.073 Area Samples 2,4-D a cid f i l t e r wheel a re a , 4th f lo o r South of f i l t e r wheel a re a , 4th f lo o r Packaging a re a , 1st flo o r Next to bulk tank manhole, 3rd f lo o r . In d u s t r ia l .Hygiene Guide 0.083 0.11 0.065 0.059 0.008 0.005 0.015 0.014 1.0 0.084 0.12 0.038 0.094 0.007 0.011 0.047 0.013 1.1 , (.10 mg/nr) 0.32 0.37 0.19 0.14 0.007 0.019 0.034 0.036 1.0 C006S | FIGURE I. DIRECT ESTER PROCESS IN THE MICHIGAN DIVISION 2,4-D PLANT, 489 BUILDING ' (549004 `\ FIGURE I I . ACID ESTER PROCESS IN THE MICHIGAN DIVISION 2,4-D PUNT, 489 BUILDING Os J 549005 O FIGURE 3. 489~BUILDINGR0CESS ^ THE MICHIGAN 0 IV IS 0 n 2,4-0 PLANT, j]0 iy : ' 1 5 4 9 0 0 6 16819 FIGURE 4(a). PLANT AREAS IN THE MICHIGAN DIVISION 2,4-D PLANT 489 BUILDING Dfljafj 5 4 9 0 0 7 LOCATION A B C D E F G H I J K L M N 0 P Q R S T U V w X Y Z AA BB CC FLOOR 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 3 3 3 PROCESS AREA DE low bay OE high bay S h ift foremen's o ffice Coffee room Shop Lab 2.4- D 2.4- 0 enclosure 2.4- D reactor Acid ester DMA 55 and 30 gallon packaging line 5 gallon packaging Warehouse o f f i c e Warehouse Tank car house De low bay DE high bay Lunchroom 2.4- D 2.4 - D enclosure 2.4- D reactors Acid ester DMA Warehouse Offices DE high bay 2 . 4 - D - ~ .. *. 2.4- 0 enclosure N jURE 4 ( b ) . FIRST FLOOR OF THE 2,4-D PLANT IN ' __MICHIGAN DIVISION, 489 BUILDING s-> CO t o OOGi'Si 'M W FIGURE 4 ( c ) . F-.fONSECOND FLOOR OF THE 2 ,4 - 0 TM E MICHIGAN DIVISION, 489 BUILDING IV lOC 6006-2 I ^0(1 FIGURE 4(d). THIRD FLOOR OF THE 2, ^ ( Q aNT IN THE MICHIGAN DIVISION, 489 BUILDING 0T06S I FIGURE V. WAREHOUSE TRAFFIC FLOW AND SAMPLING POINTS FOR CARBON MONOXIDE IN THE MICHIGAN DIVISION 2 ,4 -0 PLANT, 489 BUILDING CONVEYORS T T 0 F^ r* Mflw A V\ ( V ) = SAMPLE POINTS = TRAFFIC PATTERN FOR GAS JEEP DURING SAMPLE PERIOO ib i % K aron foliage herbicide it used . in controlling ccd o in woody ond herbaceous piontt grow ing on posture ond ronge londt. ditch bonk*, fence rows ond right-of-w ays. D IR E C T IO N S P R E P A R IN G T H S P R A Y ; A d d h o lf the reguired om ouni of water to the ip ray took, then odd Kuron with ogitafion. K uron forms on em ulsion in w oler ond tends to settle out on prolonged stand ing. Provide og<>otion to prevent such seoorotion ond ensure uniform mixture in the spray tank. FO LIA G E T R E A T M E N T : Spray woody growth up to 6 or 8 feet toll a lte r the fo liage is fully d e v e l oped, using a sproy containing 3 to 4 quarts of K uron per 100 gallo ns of woter. W it h sensitive species, toller brush or trees m oy be controlled if folioge it adequately covered. O n poison ivy ond brom bles such o s.w ild blockberry, use 2 quorts of Kuron per 100 gallons of water. Sproy should drench all p io n t port in c lu d in g leave o nd item . Deloy sproying new sprouts from recently cut stumps until they hove mode appreciable growth. U nder good grow ing conditions, in hum id areos, opplicotions m ode up to three w eeks before foil frost ore usuoNy effective. (A p o lic o lio n in lote Summer ond foil in Texos and O klaho m a is not recom m ended.) Spraying offer leoves hove lost their normoi green color and vigor m oy not give satisfactory control. Less effective control m ay result during hot. dry w eather w hen deep soil m oisture is deficient. U su ally a single ap plicatio n in ony one yeor is sufficient. If new grow th develops, repcot ap p licatio ns m oy be necessary in Succeeding yeors. A IR P L A N E A P P L IC A T IO N : For control of past ond blockiock ooks, use 2 cuorts of Kuron in I go H o n o f diesel Oil o n d 2 V x to 3 V x g o llo n s o f woler, or 2 quarts of K u ron in 3 V x to 4 V x g a llo n s of diesel oil per acre. A p p ly offer folioge is fully developed (usually in M a y and Ju n e ). A n a d d i tional sproy u sin g I to 2 quarts of Kuron m ay be necessary the second or third year. These a p p licotions w ill effectively control brood-leaved weeds in sproyed o'Cos. SP O T T R E A T M E N T : For knopsock application of Kuron, m ix Vx Cuoful in 3 gallons of water. W e t oil folioge thoroughly. W EED C O N TR O L IN L A W N S A N D GOLF C O U R S E S : For control o f brood-leoved plontoin, buckhorn. common chickwecd, mouse-eared chickweed, dondehon, and legum es such os w hite clover ond block medic in established turf, opply 1 Vx quarts of Kuron in 25 to 40 gollons of w ater per ocre. H ig h e r volum es, up to 10 0 g o llo n s per acre, m o y be used to m in im iz e drift hozord. A p p ly in fall or early spring os hot-w eother use m ay cause excessive dom age to turf. D o not opply to tta lo nifoiou g r o iic s lu c h a bent, B erm uda an d St. A u g u ilin e or to now turf of ony vorioty. C A U T IO N : To ovoid dam oge to turf, do not sproy in ony monner which will couse excessive dosoges. A void overtopping ond double coveroge w hen bocking up, ond ot turns. Avoid sproying when nozzles ond boom ore not m oving, such as w hen Cleoning or testing nozzles. Use a positive quick shut-off valve on boom sproying equipment. W E E D C O N T R O L IN RJCC: Treot 4 to 8 w eeks ofter emergence of the nee. W h e re flooded, treot between 7 ond 9 w eeks after seeding, w hen plants hove emerged obove woter ond leoves are stan d in g erect. U se I V x to 3 pints o f K u ro n in the om ount of woter needed for even distribution. For m ony situations, 2 pint per ocre Is odequate. W h e re weeds tend to be resisfont because of specie, oge or grow th condition, up to 3 pints w ill give better control. Treatm ent offer flooding is usuolly sofer than before Hooding. C o nsult your Stole Experimental Station or Extension Service for spe cific loco! recom m endations. FOR C O N TR O L OF Y U C C A A N D S A N D S H IN N E R Y O A K : Use I pint to l quart of K u ron in I gallo n of diesel oil, ond w ater to m o ke 4 g o llo n s total per ocre. T w o to three opplicotions as necessary in successive years m ay be needed. A p p ly after foliage is fully developed. C o nsult competent local authorities for inform ation on best rote and best tim e for application. USE RECO M M EN D A TIO N S IN SUGAR CANE FL O R ID A For post em ergence control of rogweed, dog fennel, ground cherry, purslane, w ild lettuce, nightshade an d other susceptible broodleoved weeds, opply I to 1 Vx qu a rts o f K U R O N in 2 0 to 4 0 g o llo n j o f w a te r per acre os b ro a d ca st sproy. M a k e the 1st ap plication after the cane em erges as spring grow th ond when weeds ore grow ing vigorously, but b e fore they send up seed sloiks. A second ap p lica tion con be m ode for lote em erging weeds. N O T E : L O U ISIA N A For the control of crobgrass, bornyord gross ond Johnson grass seedlings in su go r cone, op p ly 1 quort o f K uron in 15 gallo n s of w ater per acre On the row (approxim ately one-third of the total areo) shortly before the seeds ore expected to germ inate. If Cone is shaved ond off-barred, treot im m ediately follow ing this operation. Follow the early treatment w hen necessary w ith 2 pounds of D o w p o n A per acre, ap plie d Over the g ra ss in the row (opproxim otely one-third of the total areo). T o control w ild lettuce, curled d ock.^ond otherr " w eeds use one of the follow ing procedures w h enN -- . O the weeds are grow ing vigorously. Ground A p p lica tio n : Use 1 quart of Kuron in 15 gallo n s of woter per ocre applied over the row (approxim ately on e-lh ird of the total ore ol. A second application con be m ode if needed. D o not m oke application offer fan p .n 4 A ir A p p lica tio n : Use iasu u E tx o f K uron per o cre In en ough w ater for uniform coverage. A p p lica tio n con be made up before harvest. H A W A II For pre-em ergence control of hairy crobgross, yel low foxtoil, richordsonia, fireweed, slender a m a ranth, Flora's pointbrush, jungle rice, purslone an d w iregross In H o w o ilo n sugor cone, opply 4 to 5 (Continued on Side Panel) 5 6 238 9 oo ? i\D CO CD CO W EED LIST K u ro n ( effective In co n tro llin g -- post o ak , b lo c k jock oak, ground ivy, northern (pin, rod, whito, le ru b ) ao kt, mosquito, mopl (su ch os red, su ga r, and big leaf m aple), poison ivy, sand shinnery oak, yucca, w ild blackberry, also certain broad-leaved woods such os bcoom waed, cocklebur, croton weed, curly Indigo, lo m b 'tquerters, M exican wood, pokeberry, ragw eed, salt cedar, sunflower. N O T E : Do net use Kuron for tho control o f eih. H A W A II -- Continued quorts Kuron per ocre In 2 0 to 4 0 ga llo n s of w oter os o broodcosf sproy Im m ediately ofter planting Of rotooning ond before Cone emergence. For post-em ergence control of weeds ofter cones have em erged, o d d 2 Vx lo 5 p o u n d s o f D o w p o n per ocre to the spray of K uron In order to control grosses, ond sproy the interline space without sproying the cone directly. T h is o pplicotion co n be m ode u p to the tim e of "c lo s in g in " but not less th o n ^ n w iiilx before harvest. D o not m oke m ore Ihon two opplicotions of 5 quorts each of Kuron to ony one crop. Loco! conditions m o y affect the use of herbicides. Stote ogriculturol authorities in m any slates Issue re co m m e n d a tio n s to fit locol co n ditio n s. W ARNIN G D o not a p p ly K u ron d irectly lo, o r oth erw ise pe r m it it lo com e Into co nta ct w ith , a n y crop p la n t or ornam ento! plonl (in clu d in g but not lim ited to peonuts, soybeans, beans, peos, tomotoes, tobacco, cotton, m elons, okro, sweet potatoes, peppers, celery, flowers, ornom cnfols, gropes, deciduous ond nondeciduous fruit trees! and do not perm it sptay m ists containing Kuron lo drift onto them, sine* even m inute quantities m oy couse severe dam oge during both grow ing ond dorm ant periods. Coarse sproys are less likely to drift. A p p lic a tio n s by a ir plane, ground rigs and Hand dispenser should ba cantad out only when there is no h a ta rd from drift. Do net apply by airplane In the vicinity of any desirable crops or ornam entals including these tilted above. A t elevated tem peratures vapo r ization m oy couse injury to susceptible plants grow ing neorby. D o not use Kuron on freshly seeded (owns, p o s ture or ronge lands until gross hos become well established- D o not contam inate irrigation ditches or w ater used for dom estic purposes. D o not store near fertilizers, seeds, insecticides or fungicides. T o ovoid injury to desirable plants, do not store, handle or opply other ogriculturol cherm cols w ith the some containers or equipment used for Kuron. D o not use Kuron in spraying equipm ent con ta m i nated w ith 2 ,4 -0 if the 2 ,4 -0 w ill increose the hazard to desiroble plants. Ba sura that usa af this pradwet conform s to all applicabla regulations. C A U T IO N -- M A Y CA USE S K IN IR R IT A T IO N A vo id Contact with Eyes. Skin and Clothing Kaap Out af Tha Reach af Children "86--l-03L2^Prlnced la U.S.A. In November 1 9 6 5 -- ' REPLACES SPEC Ei~ao_-J.09.2-PRTFTDIN APRIL 1065 THE REVISION IS INJlTUi-SECTl~uUSE^RECOMMENDATIONS IN SUCAR^ANS-r"-- AMONG T1IE CHANGES WS~Th OS-THE"RECOMMENDATION FOR USE IN FLORIDA. Proposed Revisions - July 11, 1966 1. Substi tu te : - "within 60 days 2. Add: - "morningglory, tievine 3 . Add: - "broadleaved" 4 , Substitute: - "within 60 days 5. Substitute: - "2 to 3 pints" 6. 7. Substitute : - "60 days tt Substitute: - "60 days ft of harvest" cypressvine" of harvest" 16885 . THE GLOBE AND MAIL Thursday October 30, 1980 2 3 d ia > DOW ; 0 5 0 4 7 9 Employers withhold truth about toxics, MD warns workers By ROBERT STEPHENS Workers exposed to toxic and carci nogenic substances are little more than guinea pigs, and their employers . Dr. Epstein said one of the favorite strategies of industry was to "blame 1 the cancer victim himself" by linking are purposely withholding Informa tion about the very real risks of indus trial cancer, a expert on occupational health has warned. his disease to smoking, diet, and even ' his genetic makeup. " Industry tries to ' deny the evidence for occupational 1 cancer." Dr. Samuel Epstein, professor of . occupational and ' environmental medicine at the University of Illinois, ' told a conference In Toronto yester- day that workers who are exposed to He said industry also frequently resorts to the argument that the costs of complying with exposure regula tions will result in plant shutdowns ' and higher unemployment. hazardous substances "are the throw away segment of society." He'condemned the governments of the United States, Canada and Britain for failing to regulate toxic substances In the workplace. While regulations controlling the use of seven designat ed substances were proposed in Ontar io more than two years ago, these : regulations are yet to be passed. Dr. Epstein said the incidence of cancer is increasing among the gener al population at an alarming rate that reflects the huge growth in the pro duction of synthetic organic chemi He said chemical companies in the United States had fought regulations on vinyl chloride (or years, and that their spokesmen had claimed the costs of compliance would be JSO-billlon and 2.2 million lost jobs. "But when BF Goodrich came under the regulations in the spring of 1975 -- its cost was $35-million -- it actually began to make money on the recovery of vinyl chloride, and then, complaining of unreasonable govern-, mcni interference, it had the nerve to raise its prices," Dr. Epstein said.. i cals beginning 30 years ago. One of the delegates at the confer He said the worker is being sacri ence asked what workers could do to ficed by government and Industry ' protect themselves.from exposure to because "they believe that economic dangerous substances in the absence growth is paramount." And he of government regulation, and Dr. charged that industry was engaged in Epstein replied: " if you have an op a massive coverup to keep its employ- tion. I'd say get the hell out of hazard ees ignorant of the risks of cancer in . ous workplaces." the workplace. ,< 2 ^ 0 : COMMUNICATIONS 2 4 0 9 TO: CHARLTON RE: STEVENS STUDY I KNOW. I THOUGHT I TOLD YOU ABOUT THE KINGSLEY STEVENS PIECE. THING IS, I CAN'T FIND AN EASY WAY TO MOVE BETWEEN PARTS PER AND mg/KG. HAVE TO TALK WITH DAVTDSCN ABOUT THAT. IT'S A SKILL I'LL BE NEEDING FOR THE NEXT TWO YEARS. ONCE I'VE LEARNED HOW TO DO THAT, I CAN REALLY MAKE USE OF THE STEVENS PIECE. FROM: GARRY HAMLIN 2020 Dow Center 636-1325 i O <)i oo; PUBLIC AFFAIRS DOu/ 2 fi G04 0 7 <5.6. / U m u M 'U r W S S r P$. 3 0 ^ S M ^ j --- s 73 yw f i-- i r c ( 4 - 0f - # F-- \ ~ [tp b - p e A c tfe b 3WGie Fccefc." P G c n & J zrMmettr W f t . M7ibi& O U U H t T t o p / y m S v m 7^ ^ M ft& rn w - 'R p r v fr l f r o m -. V [ U t > 7 z> BOB CHARLTON 636-9303 IM wz F f *-- ST EF. F e e - 1 6 8 S8 E1. UV- 0 G H 9 J Z f^OQ Human Toxico/.(19Sl),l,31-39 Agent Orange Toxicity: a Quantitative Perspective Kincslev M. Stevens Department of Medicine, State University of New York at Stonv Brook, Stonv Brook, New York 11794, USA 1 The minimum toxic dose of tetrachloro-dibenzo-p-dioxin (TCDD) for man has been calculated from monkey and human data to be 0.1 Mgkg"1. 2 The amount of TCDD which man takes in from his environment is about 1/2050 of that present in one square metre of his immediate environment. 3 The average concentration of TCDD present in Vietnam immediately after spraying Agent Orange was S Mgm~:. 4 A soldier directly sprayed would attain an internal body concentration of 7 x l0 _iMgkg"1 or 1/1750 of the minimum toxic dose; soldiers moving through previously sprayed areas would ingest much less. 5 Tnese quantitative aspects indicate that the dioxin sprayed with Agent Orange in Vietnam cannot have caused systemic illnesses in Vietnam veterans or birth defects in their children. Introduction To evaluate the probable toxic effects of the dioxin in Agent Orange upon Vietnam veterans requires three steps. First, the minimum toxic dose (MTD) of 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) must be established for man. Sec ond, the fraction of the TCDD which is actually transferred into humans, within a unit area, must be estimated. Using these figures, the known amounts of TCDD which contaminated the Agent Orange sprayed in Vietnam can be converted into fractions of the minimum toxic dose. Minimum toxic dose of TC D D in man The herbicides 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5trichlorophenoxyacetic acid (2,4,5-T) composing Agent Orange have very low mammalian toxicity but the 2,4,5-T was contaminated with TCDD producing an average concentration of TCDD in Agent Orange of 2 p.p.m. (Young era/., 197S). Whereas the herbicides contain a single benzene ring, the dioxins are one of a large group of polychlorinated aromatic hydrocarbons with two rings. There is a very wide range in the toxicity of these compounds but the pathology produced in a given animal species is the same once the toxic level is reached (McConnell &. Moore, 1979). Hence quantitative data on poisoning by one compound can be 014-1-5952/81/010031-09 S01.00 , Macmillan Publishers Ltd 19S1 8 D Haj 32 KINGSLEY M. STEVENS convened to TCDD equivalents if the comparative toxicity of that compound to TCDD is known. One way to estimate the MTD of TCDD in man is by extrapolation from primate experiments. When rhesus monkeys were fed small amounts of TCDD in the daily food ration, they showed puffy eyelids, loss of facial hair and scaly skin after a cumulative ingestion of 1 figkg- ' (Allen et al., 1977). Minimal signs must have appeared earlier, thus 0.5 fig kg-1 should approximate the MTD. The number of monkeys was small and this value as the MTD for man must remain suspect because of basic differences unless supported by more direct data. Human data to determine the MTD are available from the Japanese studies of Yusho or oil disease (Kuratsune et al., 1972). In 1968 an oil made from rice bran was contaminated with a commercial polychlorinated biphenyl (PCB) which contained trace amounts of the highly toxic 2,3,7,S-tetrachloro-dibenzo-p-furan (TCDF), the furan analogue of TCDD. D ie structures of TCDD and TCDF appear below. Iiii CO CO CO t I TCDD TCDF The contaminated rice oil contained between 5 p.p.m. (Nagayama, Masuda &. Kuratsune, 1975) and 2p.p.m. (Bowes etai, 1978) of polychlorinated dibenzofurans of which about 30% was TCDF (Nagayama et al., 1975). Taking 30% of the mean of 3.5 p.p.m. yields TCDF of 1 p.p.m. or 1 fig ml-1 of rice oil. This oil was incorporated into a commercial chicken mash which caused illness in 2 million chickens wiih death in 400,000 of them. The oil was also marketed as a home cooking oil and consumed by about 2500 people over a period of several months. About two-thirds of those people who ingested the oil became ill. Frequent signs and symptoms in males were eye discharge (89%), chloracne (88%), oedema of upper eyelids (72%), asthenia (5S%), and transient visual disturbance (56%). Gastrointestinal symptoms were less common with vomiting in 24%, diarrhoea in 19% and jaundice in 11%. Serum chemistries showed very few changes, the most frequent being increases in cholesterol and triglycerides. Severe cases developed anaemia and elevated alkaline phosphatase (Kuratsune, 1972). In the following decade there were 51 deaths among the 1665 patients, the first being about a year after the onset of symptoms (Urabe, Koda &. Asahi, 1979). Several early deaths were associated with pericardial disease (Kikuchi &. Masuda, 1976). There have been two deaths from malignant lymphomas which will be discussed later. Thirteen babies were delivered of mothers who ingested TCDF. Most babies showed some of the signs of Yusho found in adults. Some babies were small at birth and grew more slowly but later resumed normal growth rates (Yoshimura &. Ikeda. 1978). There were no birth defects. Of two stillbirths, one was autopsied; it showed minor signs of Yusho but death was due to asphyxia from a rwisted umbilical cord (Kikuchi etal., 1969). ( ( ] V a n . tl rr u se fl: w di. ha he ha he (R wh ex; 16900 AGENT ORANGE TOXICITY 33 Of 141 patients with Yusho whose dietary intake of oil was carefully studied, only two adults had ingested less than 200 ml of oil when they first developed signs or symptoms (Hayabuchi, Yoshimura &. Karatsune, 1979). Their oil intake was 2.1 and 3.0 ml k g '1respectively or 2.1 and 3.0 fig k g '1of TCDF. SinceTCDD is 20 times as toxic as TCDF (McConnell & Moore, 197S), the minimum-toxic dose of TCDF of 2 fig kg"1is equivalent to 0.1 fig k g '1of TCDD. Humans can describe symptoms while monkeys cannot, hence one would expect the true MTD for man to be lower than that obtained by extrapolation from monkey studies. The agreement between 0.5 fig kg"1 from monkey studies and 0.1 fig kg"1 from the Yusho studies in man is good. The value from the human studies of TCDD of 0.1 pg k g '1will be used as the cumulative minimum toxic dose in man. Intake transfer factor Chloracne can be caused by TCDD acting externally at local sites (Crow, 1971) or by systemic TCDD. The major concern of Vietnam veterans is not with chloracne but with other possible long-term systemic effects. Hence one must determine what fraction of TCDD present in a unit environmental area is introduced into a human in that environment; the intake transfer factor is the ratio of the intake of TCDD to the environmental TCDD. This factor w'iil be estimated from two accidents which dispersed TCDD. In May and June of 1971, TCDD contaminated waste oil sludge was sprayed for dust control on one outdoor and two indoor horse arenas in Missouri.'The sludge contained waste from the purification of 2,4,5-T; its TCDD content was 330 fig g-1 (330p.p.m.) and a soil sample from one covered arena contained 3 2 fig g '1 (Kimbrough e: aL, 1977). TCDD does not leach into soil even from oil (Wipf etal., 1978), thus most of the TCDD would remain in the top centimetre of soil. If the soil surface is equated with the top millimetre, then a square centimetre of soil would contain 3.2 fig of TCDD or 32,000 figm '2. Of 85 horses exercised in the arena, 5S became ill and 43 died. There were 26 known abortions in horses and many foals died young. In the second covered arena 12 out of 25 horses died; in the open arena 7 out of 40 horses died. There were hundreds of deaths of birds, many cats and a few dogs. Despite this extreme animal toxicity no human illness was associated with the open arena. Two three-year-old boys who played in the second arena developed chloracne only. A six-year-old girl played daily on the floor of the arena with 32,000 fig m '2 of TCDD from May 26 until mid-August when she developed mild chloracne (Reggiani, 197S), nosebleeds, headaches, diarrhoea and bloody urine. Examination revealed an acute nephritis and haemorrhagic cystitis. Within a week after removal from contact with the arena her symptoms had disappeared. Cystoscopy 3 months later revealed punctate haemorrhagic areas of the bladder but no haematuria. Her ten-year-old sister and her mother also entered the arena frequently. They developed very mild chloracne (Reggiani, 1978), abdominal pain, diarrhoea and intermittent headaches, all of which promptly subsided when arena contact stopped. Five years later, extensive examinations of all three revealed only normal findings (Beal e: a!., 1977). 34 KINGSLEY M. STEVEN'S This six-year-old girl had an unparalleled opportunity to take in TCDD from her daily environment. It was during summer so her clothing was light. Systemic toxicity can occur from TCDD applied to large skin areas (Schwetz et al, 1973). She played on the floor where TCDD was easily available to hands and thence to mouth and vet she became less ill than the average case of Yusho. That average case ingested 6S8 ml of oil (Hayabuchi, Yoshimura &. Kuratsune, 1979), equival ent to 34 pg of TCDD or 0.7 Mgkg"1. Hence the symptoms shown by this girl would be consistent with a cumulative intake of not more than 0.7 MSkg-1 of TCDD; for her 20 kg weight this would be 14 Mg. The ratio of 14 Mg to 32,000 Mgeq' : is 1 :2300, the intake transfer factor based on this incident. About noon on July 10, 1976, a factory north of Milan which produced trichlorophenol had an explosion which released boiling reagents into the atmos phere. Most of the cloud settled on a 110 hectare (1 ha = 2.47 acres) area in the town of Sevaso where it deposited about 2 kg of TCDD. This area was designated Zone A and a larger,'more distant area of 269 ha which received only 20 g of TCDD was designated Zone B. The 733 residents of Zone A were evacuated 2 weeks after the explosion. The 4800 residents in Zone B were not evacuated but were prohibited from raising or using produce from either Zone B or the surrounding 1430 ha Zone R. These amounts of TCDD would produce average concentrations of 1800 and 7 Mg of TCDD per square metre in Zones A and B respectively. Analyses carried out days to weeks after the explosion showed a very' spotty distribution with a range in Zone A from 5447 Mg per square meter to not detectable (Pocchiari, Silano &. Zampieri, 1979). Actual concentrations on vege tation and soil shortly after the explosion were undoubtedly higher than these recorded values. Birds began dying in Zone A a few days after the explosion. Birds preen their feathers regularly. The surface area of the feathers is many times that of the skin surface so even a small bird must have at least 0.1 m3of feather surface. If the feathers held the average concentration of 1800 Mgm':, then 180 Mgwould be present on a bird weighing only 30 to 100 g. Thus the bird could ingest 1000 Mgk g '1, about ten times the acute LDJ0 for birds (Young el al, 1978). Rabbits which ate fresh vegetation from local fields died next. A 1 kg rabbit consuming vegetation from an area of one square meter would take in at least 1800 Mg, over ten times the LD50for rabbits. More cats than dogs died since cats both groom frequently and eat birds. Later a number of sheep and cattle died; most livestock in Zone A was destroyed. In Zone B, however, birds and rabbits would consume TCDD in the order of 7 Mgk g '1(below the acute toxic dose) and here few of these animals were found dead. The early toxic effects in man were not due to TCDD but to other chemicals, for example sodium hydroxide. Chloracne has been the only prominent effect found to be caused by TCDD; 193 cases have been diagnosed with 50 cases in residents of Zone A. The diagnosis in the 143 cases outside Zone A is confused because these were found by screening 49,000 people for an incidence of 0.39c and this percentage is reported to be the incidence of chloracne in more northern industrial Italian cities not involved in the accident. How-ever, in Zone A the incidence of chloracne was 79c : 23 times this base rate. In addition, about 10% of the Zone A population showed either minor clinical signs of polyneuropathy or laboratory co CO <cn CD i f ( 1 ut ro a m .a s AGENT ORANGE TOXICITY 35 evidence of slowed nerve conduction times. Transient changes in liver enzymes were noted in a few' cases. There have been no deaths, no serious disease, no immunological changes, no birth defects, no increase in spontaneous abortions and no chromosomal changes attributable to TCDD (Pocchiari et al., 1979; Rehder et al., 1978; Reggiani, 1978, 1979; Tenchini et al., 1979; TuchmannDuplessis, 1977). Cases of chloracne outside Zone A were probably due to external contact with transported TCDD. The overall pattern indicates that the mean concentration of TCDD in Zone A w'as below the minimum toxic dose but the spotty distribution produced minimal signs and symptoms in about 10%. Since most clinical findings were in children under age 12, 30 kg will approximate the average weight. To reach the MTD of TCDD of 0.1 pgkg-1 would require an intake of 3 pg. The mean concentration of TCDD was 1800pgm ': which must have been considerably lower than the level needed to provide the MTD. It will therefore be assumed that the 10% affected were exposed to about three times this mean value or 5400 pg m"J. The intake transfer factor for Seveso would then be 5400/3 or 1:1800. .TCDD is most toxic for guinea pigs and least for dogs. The acute toxicirv for chickens, mice, rats, cats and monkeys are all within a proportional order of magnitude, and chronic toxicity in man, monkeys and rats is not very different (Young et al., 1978). Hence the reason that human toxicity was low in Missouri and Seveso while animal toxicity was high, related not to innate differences in sensitivity but to a very much lower intake of the environmental TCDD. Humans w'ear shoes and clothing, they do not groom w'ith their mouths, they wash themselves and their food and they do not eat vegetation in bulk. These features account for the intake transfer factors of 1:2300 calculated from a single individu al for whom accurate measurements of environmental TCDD and of the duration and type of exposure were known, and of 1:1800 calculated from the signs and symptoms of about 75 individuals with less accurate TCDD measurements and of their exposure. The agreement is good and the average value of 1:2050 wall be used for the intake transfer factor. Industrial cases and animal studies Tnere have been at least eight industrial accidents w'hich would have released TCDD (Young et al., 1978). The explosion at Seveso differed from the others in that the reagents were released to the atmosphere instead of within the plant. Although TCDD levels were not measured in earlier accidents, it is obvious that the plant levels attained would have been much higher than those found in Zone A at Seveso (Reggiani, 1978). About S00 cases of chloracne w-hich developed from explosions and other industrial contact have been followed, some up to 30 years. The largest group, consisting of 121 workers who developed chloracne after an explosion in 1949, have been followed for 30 years and showed no increase in overall mortality rates nor in cardiovascular or neoplastic death rates (Zack &. Suskind, 1980). From the rather sparse details available, persisting morbidity from Yusho appears greater than that from industrial poisoning by TCDD. CD CD NO <~n co NO 160Q3 26 KINGSLEY M. STEVENS TCDD produces fetal deformities and cancer in rodents in cumulative doses over 1 pgkg"1, It has not produced either of these effects in monkeys (Young etal., 1978). TCDD caused abortions in monkeys after 7 months of daily feeding, and depression of spermatogenesis after a year (Allen et ai, 1979). Treatment of male mice with doses of TCDD which caused fetal abnormalities in pregnant mice (Lamb, Moore &. Marks, 1980), caused no changes in the libido of the fathers nor abnormalities in their offspring. Vietnam Agent Orange is an oily liquid composed of equal volumes of the n-butyl esters of 2,4-D and 2,4,5,-T. TCDD, present in Agent Orange in an average concentration of 2p.p.m., is extremely insoluble in water but-readily soluble in Agent Orange. Tne herbicide was delivered as a coarse spray with droplets of 320-350 (im diameter (Young et al., 1978). While gases readily enter the lungs, only droplets which are less than 10 fim can enter (Walton, 1971), thus Agent Orange could not be absorbed from the lungs. Each gallon of Agent Orange contained 10.7 lbs (4.9 kg) of total herbicide (Young er a i, 197S). One acre is 3660 m: so the spraying rate of three gallons per acre converts to metric mass units of 4.1 gm -3. Since the mean TCDD concentration in Agent Orange was 2 p.p.m., the delivered amount of TCDD would be 8 fjgm-3. The average concentration of TCDD in Zone B in Seveso, where the people were not evacuated, was 7 fxg m ': (Pocchiari et ai, 1979). The conditions for destruction of TCDD in Vietnam were almost ideal. TCDD is very stable in the dark but is photodecnlorinated in position eight. The resulting 2,3,7-TriCDD is 10,000 times less toxic (McConnell &. Moore, 1979). Photodechlorination requires light, an organic hydrogen donor (Agent Orange works well) and the reaction proceeds three times faster at 30C, the mean annual daytime temperature in Saigon, than at 23eC (Liberti et ai, 197S). When Agent Orange is applied to leaves in full sunlight, the half-life of the contaminant TCDD is only 2h (Crosby &. Wong, 1977). Grass receives less light and some TCDD reaches the soil; the half-life of TCDD applied to turf is about 6 days (Young etai, 197S). Since spraying was done in early morning (Young etai, 1978), a single day of full sun would decrease the TCDD on the leaves from 8 to 0.3 pg m~:. About 9 0 % of Agent Orange was sprayed on forests and only 6 % of that reached the foresi floor (Young et ai, 1978) to yield 0.5 ug m ': of TCDD. Hence under forest cover, troops passing through, even under direct spraying, would receive less than l( ig m ': in their environment. For the 109c not sprayed on forests, the early morning concentration of 8 m? m '3would be less than half of that by evening. For most soldiers who had any exposure to Agent Orange, that exposure would consist of walking through vegetation which contained no more than 1 pg m '3of TCDD. Using the transfer factor of 1:2050, the soldier would take in 5 x 10'4pg of TCD~D. For a 70 kg soldier this represents 7 x i0"<'pg kg` 1 or 1/14,000 of the minimum toxic dose of O.liigkg"1. On rare occasions soldiers were probably exposed to direct spraying from aeroplanes. The intake would still be only 1/1750 ! ; i : t ` j ! ; j | ; j >. ; i AGENT ORANGE TOXICITY 37 of the MTD. Even if a soldier were exposed to 8 pg m '5each day of his one year tour in Vietnam and each day was treated as a new exposure, his cumulative intake would be only 1.4 pg or 0.02 pg kg"1of TCDD. Since it would take about 5 years of daily close contact with Agent Orange to reach toxic levels of TCDD, claims that illnesses in Vietnamese (Tung eial., 1971, 1973) and Americans (Bogen, 1979) were due to Agent Orange are without merit. However, certain workers in forest industries have been exposed to 2,4,5-T over many years. Although the present concentration of TCDD in 2,4,5-T is < 0.1 p.p.m., it w'as considerably higher than 2 p.p.m. before the 1960s. Commerdal spraying rates were usually less than 3 gallons per acre but higher TCDD concentrations could lead to toxic cumulative intakes after several years. Two patients with Yusho have died from lymphomas and recently six cases of lympho ma of histiocytic type were reported in patients w'ho had an average of 8 years exposure to 2,4,5-T in years past (Hardell, 1979). Hence the possibility that cumulative intakes of TCDD above the MTD may have increased the inridence of lymphoma must be further investigated. References ALLEN, J. R.. BARSOTTI, D. A., VAN MILLER. J. ?.. ABRAHAMSON, L. J. &. LAUCH, J.J. (1977). Morphological changes in monkeys consuming a diet comaining low levels of 2,3,7,Stetra-chlorodibenzo-p-dioxin. F ood C osm et. T a x.. 15, 401-410 ALLEN, J. R., BARSOTTI, D. A., LAMBRECHT, L. K. &. VAN MILLER. J. P. (1979). Reproductive effects of halogenated aromatic hydrocarbons on nonhuman primates. A n n . AY. A c a d . Sci., 320, 419-425 BEAL, M. G,, SHEARER, W. T,, KARL, M. M. < ROBSON, A. M. (1977). Long-term effects of dioxin exposure. L a n cet, 1, 748 BOGEN, G. (1979). Symptoms in Vietnam veterans exposed to agent orange. J. A m . m ed . A cs., 242,2391 BOWES, G. W,, MULVTHILL, M. J., SIMONEIT. B. R .T ., BURLINGAME. A. L. & RISEBROUGH, R. W. (1978). Isolation and identification of chlorinated aibenzofurans from polychlorinated biphenyls and from Yusho rice oil containing PCB. In D io xin : T oxicological a n d C h e m ic a l A sp ec ts, pp. 79-98. New York: Spectrum CROSBY, D. G. & WONG. A. S. (1977). Environmental degradation of. 2.3.7.8tetrachlorodibenzo-p-dioxin (TCDD). Science, 195,1337-1338 CROW, K. D. (1971). Chloracne. T rans. St. J o h n 's H asp. derm . Soc.. Lond., 56, 79-99 HARDELL, L. (3979). Malignant lymphoma of histiocytic type and exposure to phenoxyacetic acids and chlorophenols. L a n cet. 1,55-56 HAYABUCHI, H.. YOSH1MURA, T. & KURATSUNE, M. (1979). Consumption of toxic rice oil by `Yusho-patients and its relation to the ciinical response and latent period. Food C osm et. Tox., 17.455-461 KIKUCHI. M- HASH1MOTO, M., HOZUMI. M., KOGA. K , OYOSH1. S. e NAGAKAWA.M. (1969). An autopsy case of stillborn of chlorooiphenyls poisoning. F u k u o k a A c ta m ed., 60, 489-495 KIKUCHI, M. & MASUDA. Y. (1976). The pathology of Yusho. In P C B P oisoning a n d P ollution, pp. 69-86. New York: Academic Press KIMBROUGH, R. D.. CARTER, C. D., LIDDLE ,J. A.. CLINE. R.E. 4: PHTLLIPS. P. E. (1977). Epidemiology and pathology of a tetrachlorodibenzo-dioxin poisoning episode. A rc h enuir. H ltk. 32, 77 - 85 KURATSUNE. M. (1972). An abstract of results of laboratory examinations of patients with Yusho and of animal experiments. E n vir. H h h Perspcct., 1, 129-136 t* 00 c' ri _ (*0C1 38 KINGSLEY M. STEVENS KURATSUNE, M., YOSHIMURA, T.. MATSUZAK, J. & YAMAGUCHI, A. (1972). Epidemiologic study on Yusho, a poisoning caused by ingestion of rice oil contaminated with a commercial brand of polychlorinated biphenyls. E n v ir H ith PerspecL, 1, 119-128 LAMB, J.C.IV, MOORE, J. A. MARKS, T.A."(19S0). Evaluation of 2.4-dichlorophenoxyacetic acid (2.4-D), 2,4,5-trichlorophenoxyacctic acid (2,4,5-T), and 2.3,7,8-tetrachlorodibenzo-pdioxin (TCDD) toxicity in C57BL/6 mice: reproduction and fertility in treated male mice and evaluation of congenital malformations in their offspring. N a tio n a l T oxicology R e p o r tN 1f- 8 0 ~ 4 4 , Research Trianale Park, N.C. 22709 LIBERTI, A., BROCCO. D.. AJLLEGRINI, I.. CECINATO. A. St POSSANZINI, M. (1978). Solar and ultraviolet photodecomposition of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the envi ronment. Set. T o ta l E n vir., 10, 97-104. McCCNNELL, E. E. <Si MOORE, J. A. (1978). The toxicopathology of TCDD. In D io xin : T o xico lo g ica l a n d C h e m ic a l A sp ec ts, pp. 137-141. New York: Spectrum McCONNELL, E. E. St MOORE, J. A. (1979). Toxicopathology characteristics of thehalogenated aromatics. A n n . N . Y. A c a d . ScL, 320, 138-150 MOORE, J. A., McCONNELL, E. E,, DALGARD, D. W. St HARRIS, M. W. (1979). Compara tive toxiciry of three halogenatcd dibenzofurans in guinea pigs, mice and rhesus monkeys. A n n . N . Y . A c a d . ScL , 320, 151-163 NAGAYAMA, J., MASUDA, Y. & KURATSUNE. M. (1975). Chlorinated dibenzofurans in Kanechlors and rice oils used by patients with Yusho. F u k o u k a A c ta m ed., 66, 593-599 POCCHIARI, F.. SILANO, V. St Z.AMPEERI, A. (1979). Human health effects from accidental release of ietrachlorodibenzo-p-dioxin (TCDD) at Seveso, Italy. Ann. N .Y . A cad.. ScL, 320, 311-320 REGGLANI, G. (1978). Medical problems raised by TCDD contamination in Seveso, Italy. A rc h . T ox., 40, 161-188 REGGIAN1, G. (1979). Estimation of the TCDD toxic potential in the light of the Seveso accident. A r c h . Tox. (suppl) 2, 291-302 REHDER, H,, SANCHIONI. L,, CEFIS, F. St GROPP, A. (1978). Paihologisch embryoloeische untersuchungcn an abortusfallen im zusammer.har.g mit dem Seveso ungluck. S ch w eiz, m e d W sckr., 108,~1617-i625 SCHWETZ. B.A., NORRIS, J. M,, SPARSCHU, G. L., ROWE, V. K., GEHRING. P. J., EMERSON, J. L. St GERBIG, C. G. (1973). Toxicology of chlorinated dibenzo-p-dioxins. E n vir. H lih P erspecL, S, 87-99 TENCHIN1, M. L., CRIMAUDO, C., SIMONI. G,, DE CARLl, L.. GlORGl, R. St NUZZO, F. (1979). Approaches to the evaluation of genetic damage after a major hazard in chemical industry: preliminary cytogenetic findings in TCDD-cxposcd subjects after the Seveso accident. In G enetic D a m a g e in M a n C a u se d b y E n v ir o n m e n ta l A g e n ts, pp. 301-316. New York: Academic Press TUCHM ANN-DUPLESSIS. H. (1977). P^oblimes embryologiques posds par l'accident dc Seveso. C oncours m ed . (Paris), 99, 6SS9-6397 TUNG, T. T., TUGEN, T. K. A. B. Q., TRA, D. X. St HUYEN. N. X. (1971). Clinical effects of massive and continuous utilization of defoliants on civilians. V ietnam ese Studies, 29, 53-81 TUNG,T. T.. AN, T. T,, TAM, P. H., PHEET, N. N.. BANG, N. N,, BACH.T.T,, Va N SON, H. St SON, D. K. (1973). Le cancer primaire du foie au Vietnam. Chirurgie. 99, 427-436 URABE. Hi, KODA, H. St ASAHI. M. (1979). Present state of Yusho patients. A n n . N . Y . A c a d . ScL. 320, 273-276 WALTON. W. H. (cd.) (1971). In h a le d P anicles. Old'Wokinc. Surrev: Gresham Press WIPF, H. K.. HOMBERGER. E,, NEUNER, N. St SCHENKER. F. (1978). Field trials on photodegredation of TCDD on vegetation after spraying with vegetable oil. In D io xin : T o xico lo g ica l a n d C h e m ica l A sp ec ts, pp. 201-217. New York: Spectrum YOSHIMURA, T. k. IKEDA, M. (1978). Growth of school children with polychlorinated biphenyl poisoning or Yusho. E n vir. R es., 17, 416-425 YOUNG, A. L.. CALCAGNI. J. A.. THALKEN, C. E. St TREMBLAY, J. W. (1978). The toxicology, environmental fate, and human risk of herbicide orange and its associated dioxin. TO CO ID CD 1690S AGENT ORANGE TOXICITY 39 U S A F O E H L T ech n ica l Report, 78-92, available from the i'.'ational Technical Information Service, 52S5 Port Royal Road, Springfield, Va. 22161 ZACK, J. A. &. SUSKIKD, R. R. (19S0). The roonality experience of workers exposed io tetrachlorodibenzodioxin in a irichiorophcnol process accident. J. occup. M ed., 22, 11-14 (Received A pril 10, 1981; accepted July 1 3 ,1 9 8 1 .) NJ OP o~ CO CP 18807 AN EVALUATION OF 2,4-D DATA /i '> Foreward. yv The phenoxy h e r b ic id e s , in c lu d in g 2 ,4 -D , have re ce iv e d c o n sid e ra b le a tt e n t io n during the l a s t decade in the p r e s s , in p u b lic h earing s and by groups which have campaigned a g a in s t the continued use o f th ese h e r b ic id e s f o r co n tro l-lin g unwanted ve g etation in f o r e s t s , on r i g h t s - o f - way and on c e r t a i n cro p la n d s. The groups a g a in s t the continued use of h e r b ic id e s have spent c o n s id e r a b le time and e f f o r t preparing l i t e r a t u r e , p re ss r e l e a s e s , m a ilin g s and in p a r t i c i p a t i o n a t p u b lic h e a rin g s. ^ 0 \ 551081 The primary message o f these groups i s th a t the use o f phenoxy h e rb ic id e s w i l l in c r e a s e b i r t h d e f e c t s and cause m i s c a r r i a g e s , ca n ce r or o th er p h y sic a l e f f e c t s . Various s c i e n t i f i c stu d ie s as well as a r t i c l e s from the press are used to support t h e ir a lle g a t io n s . Very frequently only those portions of the data, in a given study which support the a lle g a tio n are c it e d . The r e l i a n c e upon data from s t u d ie s conducted in anim als to estim a te the e f f e c t s in humans has a ls o been debated. However, anim als are the only s p e c ie s p h y lo g e n e t ic a lly c l o s e to humans which can be used f o r t e s t i n g . Therefore, i t i s necessary to c o r r e la t e data from animal stu d ie s with the p o t e n t ia l f o r human exposure under worst ca se c o n d it io n s and d e f in e a safety factor. In most s t u d ie s on l i v i n g organisms the data are n e i t h e r com pletely p o s it iv e nor completely negative but req u ire the e x p e rtise of knowledgeable scien tists for interpretation. H e re in , data and c o n c lu s io n s are submitted which are intended to present an unbiased review o f the t o x ic o lo g ic a l s t u d ie s on 2,4-D which have been conducted to date. U U W 1 551082 1. What i s 2,4-D ? 2 . 4 - D (2 ,4 - d ic h lo ro p h e n o x y a c e tic a c id ) i s an h e rb ic id e which s e l e c t i v e l y c o n t r o ls many b ro a d le a f weeds, c e r t a i n hardwood t r e e s and brush on crop and rang eland s, r ig h t s - o f - w a y , and on t u r f and lawns. 2,4-D was f i r s t introduced in the U .S . f o r use by farmers in 1946 (P e te rso n , 1967). I t performs i t s co n tro l fu n ctio n by a l t e r i n g the normal growth o f s u s c e p t i b l e weeds and woody p l a n t s . The major use o f 2,4-D i s c o n t r o l l in g b r o a d le a f weeds in c e r e a l g r a i n s . I t does not k i l l most g r a s s e s . 2 . 4 - D i s u s u a l l y a p p lie d a t the r a t e o f h to h pound a c t i v e in g re d ie n t per a c re f o r c e r e a l g r a i n s . Higher r a t e s a re often used on r i g h t s - o f way. 2,4-D i s u s u a l l y formulated as amine s a l t s o r e s t e r s . 2. How t o x ic i s 2,4-D to anim als? 2 . 4 - D i s moderately t o x ic to mammals. The th ree routes of p o s s ib le human exposure a r e : i n g e s t io n , dermal co n ta ct and i n h a l a t i o n . The s i n g le dose oral LD50 (dose determined to be l e t h a l to 50% o f the t re a t e d s p e c i e s ) f o r 2,4-D a c id i s g r e a t e r than 350 mg/kg o f body weight in r a t s , m ice, guinea pigs and ch ick en s (NRCC, 1978). In these same s p e c ie s the acute oral LD50 f o r v a r io u s form ulations o f 2,4-D s a l t s and e s t e r s ranges from 75 to 2000 mg/kg (Weed Scien ce S o c ie t y of America, 1979) (IRAC, 1977). In a case o f a s u i c i d e by a 23 y e a r old stu d e n t, the t o t a l amount of 2 . 4 - D in the body was estimated to correspond to a dose o f 80 mg/kg. (N ielson e t a l . , 1965) No adverse e f f e c t s were reported in a man who took 500 mg 2,4-D o r a l l y d a i l y f o r 3 weeks (approxim ately 8 mg/kg/day) (IARC, 1977). When 2,4-D was used as a treatment in a p a tie n t with 16809 /Men (248) and women (44) engaged in the manufacture of the amine s a l t or the butyl e s t e r of 2,4-D with exposure periods ranging from under 5 y e a r s to 6-10 y e a r s ( f o r 194 and 98 persons r e s p e c t f u l l y ) ; were screened and 63% o f these workers complained f re q u e n t ly o f weakness, r a p id f a t i g u e , headache o r v e r t ig o . About 20% had d istu rb a n ce s o f the c a r d i o v a s c u l a r system (mainly hypotension and b rad y card ia) and of the d i g e s t i v e organs ^ j (d y sp e p tic symptoms and g a s t r i t i s ) . The v a rio u s l i v e r d y s fu n c t io n s th a t - I were found were more pronounced in workers w ith longer exposures to the ^ \ h e rb ic id e s. (IARC, 1977) Feldmann & Maibach (1974) stud ied in man the ab sorp tion through the s k in o f 4yg/cm2 ^ C - l a b e l l e d 2,4'-D d is s o lv e d in a small amount o f acetone. 1!*C a c t i v i t y was measured in u rin e over a 5-day period and compared with t h a t in u rin e a f t e r i . v . a d m in is t r a t io n o f the compound: u r in a r y e x c re t io n o f 2,4-D a f t e r i . v . a d m in is t r a t io n was 100% o f the dose in 120 ho u rs, w h ile e x c r e t io n a f t e r t o p ic a l a d m in is t r a t io n was 5.8% o f the dermal dose. i Kohli e t a l . (1974) adm inistered 5 mg/kg body weight o f pure 2 ,4-D in. a g e la t in capsule with water to 6 healthy male v o lu n te e rs , aged 22-30 y e a r s . None o f the s u b je c t s complained o f any i l l - e f f e c t s , no changes in blood p re s s u re , pulse r a t e , hemoglobin content or to ta l or d i f f e r e n t i a l white c e l l counts were observed. 2,4-D was absorbed f a i r l y r a p i d l y . The h ig h e st co n centration in blood was reached in 7-24 hours. In u r in e , 2,4 -D was present as e a r l y as 2 hours a f t e r i n g e s t i o n , and more than 75% was ex creted in 96 hours without undergoing tra n sfo rm atio n in the body. In 5 male vo lun te ers given a s in g le oral dose o f 5 mg/kg body w e ig h t, the h a l f - l i f e in the plasma was 11.7 hours, and e lim in a t io n in the u rin e Hansen et al (1971) adm inistered 2 ,4 - 0 in the d i e t s of r a t s f o r two y e a rs at 0 , 5, 25, 125, 625 or 1200 ppm. While the number o f r a t s employed in t h i s study would not be adequate by todays sta n d a rd s, the authors concluded 2 ,4 - 0 was not a ca rcin o g e n . A rkipor and K o z lo r ia (-1974) s t a t e there was no s i g n i f i c a n t in c r e a s e in < tumors in r a t s o r mice from d i e t a r y o r sk in p a in tin g a d m in is tr a tio n o f 2 ,4 -D . Bjorkland and Erne (1966) adm inistered 2,4-D in the d rin k in g w ater o f r a t s f o r two y e a r s a t l e v e l s up to 1000 ppm and observed no in c r e a s e in tumors. 4. Does 2,4-D cause b i r t h d e f e c t s in humans? T e r a t o lo g ic a l s t u d ie s (stu d y of b i r t h d e f e c t s ) have been conducted with 2,4-D as the a c id and as c e r t a i n e s t e r s in r a t s , m ice, hamsters and sheep. There are d i f f e r e n c e s among s c i e n t i s t s in d e f in in g t e r a t o l o g i c a l responses to treatm ents. In t h i s d is c u s s io n we w i l l c i t e the d e f i n i t i o n s o f the National Academy o f S c ie n c e s ' (1974) and t h e i r ex p lan a tio n of each. "Prenatal development i s d iv id e d into the embryonic stage ( e a r l y ) when the organs are forming, and the f e t a l stage ( l a t e r ) when the organism i s maturing during g e s t a t io n . However, the d i v i s i o n i s not c l e a r - c u t and the prenatal organism w i l l be r e f e r r e d to in t h i s d is c u s s io n as an embryo even i f i t i s t e c h n i c a l l y known as a f e t u s . " "An agent or chemical i s considered as t e r a to g e n ic when i t causes develop mental d istu rb a n c e s in the embryo r e s u l t i n g in cong enital m alform ations. I f an agent k i l l s the embryo i t i s s a id to be em b ry o cid a l, and i f i t -1-16911 causes c l e f t p a la t e in the mouse and the r a b b i t , but not in the r a t . We s t i l l do not know i f i t i s te r a t o g e n ic in man. Thus, one cannot e x tr a p o la t e with any assurance from one s p e c ie s to another, or even one s t r a i n to a n o th er, and one cannot r ig o r o u s l y prove an agent i s t e r a t o g e n ic in man from data on experimental a n im a ls - - o n ly from data on human b e in g s ." " I t must be emphasized t h a t a g reat many agents are te r a t o g e n ic in e x p e r i mental a n im a ls, p a r t i c u l a r l y rod ents. Many drugs have demonstrated te ra to g e n icity : various a n t ib io t ic s , amphetamines, antih istam in es, an tico n vu lsan ts, b a rb itu ra te s, c a ffe in e , clomiphene, c y c liz in e , LSD, th a lid o m id e , tolbutam id e, and v a rio u s t r a n q u i l i z e r s . Metals (cadmium, c a lciu m , l e a d , m ercu ry), hormones (ACTH, a d r e n a l i n , androgenic hormones, a n t io v u la t o r y compounds^ e stro g e n s, g l u c o s t e r o i d s , i n s u l i n , s e r o t o n i n ) , vitam in A, and se v e ra l o th er kinds o f c h e m ic a l, p h y s i o l o g i c a l , and environmental agents (maternal dehydration, maternal s t r e s s , carbon ^'monoxide, n o is e , and hypoxia) have a ls o been shown to be t e r a to g e n ic b in la b o ra to ry a n im a ls. For se v e ra l o f th ese th ere i s good evidence o f low or no t e r a t o g e n i c i t y in man ( e . g . , c y c l i z i n e ) , but f o r most o f them the p o s s i b i l i t y o f low l e v e l s o f t e r a t o g e n i c i t y has not been ru le d o u t , and i t would be v e ry d i f f i c u l t to do so. Only f i v e have been c l e a r l y im p lica te d as humans teratogens (d ip h en y lh y d a n to in , androgenic p r o g e s t in s , org anic mercury, r a d i a t i o n , and th a lid o m iJ - ' " "Much l e s s work has been done on the t e r a t o g e n i c i t y of 2,4 -D . One study ( B io n e t ic s Stud y, see Mr'jajk Report, 1969) suggested th a t the b u t y l, isopropyl and i s o o c t y l e s t e r s o f 2,4-D may be teratogens of low potency. Schwetz et al_. (1971), feeding the free a c id , the propylene glycol DOW 1 551090 Is 2,4-D a Mutagen? F i r s t , a mutagen i s a m a teria l th a t i s capable o f producing g en etic damage which can be i n h e r it e d by fu tu re g e n e ra tio n s. 2 ,4-D has been evaluated in a number o f m u tagenicity s t u d ie s . I t has been demonstrated th a t 2,4-D i s not a mutagen in a v a r i e t y o f m icro b ial s t u d ie s as well as in male f r u i t f l i e s (D ro sp h ila melanogaster) . (Vogel - Chandler, 1974). E p ste in et a l (1972) found th a t a t o t a l o f 75 mg of. 2,4-D/kg o f body weight given over a f i v e day period did not in c r e a s e dominant le t h a l mutations in mice. Treatment o f in v i t r o c u ltu re d human lymphocytes with 0.02 mg/ml^ 2,4-D in cre ased the number o f chromatid a b e rr a tio n s and to a l e s s e r e x | t e n t , chromosomal a b e r r a t io n s . In m ice, t o x ic co n ce n tra tio n s (100-300 mg/kg/body weight) of 2,4-D administered as a sing le oral dose s ig n if ic a n tly increased the frequency of aberrant metaphases (2-4 fo ld ) in lymphocytes; sin g le fragments were the primary a b e rra tio n ( P i l i n s k a y a , 1974, c i t e d in IARC, 1977). 2,4-D had no e f f e c t on c u ltu re d c e l l s nor on bone marrow a f t e r i t s oral a d m in istra tio n to r a t s ( S t y l e s , 1973 c it e d in IARC, 1977). There was no in c re a s e in the m icro n u clei in e ry t h ro c y t e s o f mouse bone marrow a f t e r i n j e c t i o n of 100 mg 2 ,4-D/kg/body weight. Examination o f chromosomes of workers employed in the production o f 2,4-D in d ic a t e d no changes (Johnson, 1971). The Royal Swedish Academy of S cie n ce s arranged a conference in Stockholm in February, 1977 organized into f iv e working groups comprising ch e m istry , i p la n t ph y sio lo g y , t o x ic o lo g y , g e n e t i c s , and e ' " ' -- w i4-^ r r - -- 13 ? fiO T c ;S f h y d r o ly s is o f 1 , 2 , 4 , 5 tetra ch lo ro b e n ze n e . Any TCDD so formed can be c a r r ie d through into products made from 2 , 4 , 5 - t r i c h lo r o p h e n o l , such as 2 , 4 , 5 - t ric h lo ro p h e n o x y a c e t ic a c id ( 2 , 4 , 5 - T ) and hexachlorophene. No TCDD i s found in 2,4-D (Ramel, C. 1977). 1 'L 'if a - iJ 1 The expected 2 ,7 - d ic h lo ro iso m e n / i s not fonpecT'by co n d en sa tio n "o r / 2,4-dichlorophenate under the acid>oflnditions used in i t s manufacture by c h l o r i n a t i o n o f phenol. -dJf 28 samples o f 2,4-D te s t e d f o r content o f c h lo ro d ib e n z o - p a ra - d io x in s , one was reported to co n ta in l e s s than 10 mg/kg~ hexachlorodibenzo-p- d io x in . (Woolson e t al 1972, c i t e d in IARC, 1977) ..o 7. What E f f e c t Does 2,4-D Have on The Environment? The environment i s composed o f many compartments in c lu d in g s o i l , a i r , w a te r, man, b i r d s , a n im a ls, p la n ts and i n s e c t s , e t c . 2 ,4 - D , when used as d ir e c t e d on the l a b e l , e x e rt s i t s e f f e c t on a s e l e c t p ortion o f the p la n ts in the environment. A p p lic a t io n o f 2,4-D by means o f s p r a y in g , e i t h e r by ground or a i r , provides the p o t e n t ia l f o r contam ination o f the other compartments. Fate in Soil In s o i l , in the presence of m oisture, even a t low l e v e l s , the e s t e r s of 2,4-D are hydrolyzed to the acid form. The p e r s is te n c e o f the is o o c ty l e s t e r of 2 ,4 - 0 was studied under f i e l d c o n d it io n s by B u rcar et a l . (1966, c i t e d in NRCC 1978) who noted the complete breakdown of the e s t e r to the a c id in two weeks. The f r e e a c id s a ls o have a r e l a t i v e l y pH, presence o f org anic m a tte r, su n lig h t and m icro b ia l f l o r a . >;ed ra te s o f a p p l i c a t i o n , 2,4-D would not be detected in most , : rcnments 30 days a f t e r in t r o d u c t io n . : . : i e s with f i s h have been reviewed by M ullison (1 9 7 0 ). In - natural" c o n d itio n s most f i s h s p e c ie s can t o l e r a t e 2 ppm :ng 5 pounds 2,4-D per a cre in water about one foot deep --ate 2 ppm. Under n a tu ra l c o n d itio n s f i s h could u s u a ll y - areas of'high concentrations. "f 2,4-D are applied as aqueous emulsions or s o lu tio n s in s p r a y e r s 'o r by a i r c r a f t . During a p p l i c a t i o n , some o f the '' f t from the t a r g e t s i t e before being in te rc e p te d by - q u an tity which may d r i f t i s dependent upon d ro p le t "ty, temperature and hum id ity, v i s c o s i t y o f the formufrom a p p l ic a t o r to t a r g e t , and perhaps the most important itions e x e r c is e d by the i n d i v i d u a l s performing the ''ing to the l a b e l . d iff e r in t h e ir rate of v o l a t i l i z a t i o n from the target r salts are le ss v o la t ile than the e s te rs . Proper '"'-nation and o b serva tio n o f the c l i m a t i c c o n d it io n s :'<el can minimize v o l a t i l i z a t i o n from the t a r g e t ' where damage may o ccu r. req uired on the l a b e l . Subchronic o r l e s s than one h a l f the l i f e t i m e s t u d ie s in c lu d e : 90 day d i e t a r y in r a t s , s i x month d i e t a r y in dogs, t e r a t o g e n i c i t y in two s p e c i e s , two generation reproduction in r a t s and metabolism in two s p e c i e s . Chronic ( e s s e n t i a l l y l i f e t i m e ) d i e t a r y s t u d ie s are conducted in r a t s and mice to determine a no e f f e c t l e v e l to a s s i s t in e s t a b l is h i n g to le ra n c e l e v e l s and p o s s ib le oncogenic (tumor producing) e ffe c ts. years to complete. These comprehensive studies require at le a s t four r or or o CO CD V.3 Aa j During t h i s same time period samples o f the t a r g e t crop which bds been tre a te d with the chemical a t the maximum la b e l r a t e are c o l l e c t e d from v a rio u s geographical areas and analyzed f o r p o s s ib le r e s id u e s . Residue s t u d ie s are a ls o conducted in cows and ch ick en s to determine i f re s id u e s which might be present in the food o f these animals i s c a r r i e d in t o meat, m ilk o r eggs which humans might consume. The EPA then ev alu a tes these data tog ether with the data which d e s c r ib e the fa te , and e f f e c t s in the environment and only a f t e r d e t a i l e d a n a l y s i s may grant a resid u e t o le r a n c e . The t o le r a n c e g ranting procedure i s very d e t a ile d and not taken l i g h t l y by the EPA nor the in d u s t r y . By the time / a to le ra n c e i s granted an excess of f i v e y e a rs have elapsed s i n c e the in it ia l data gathering. There may be tra c e q u a n t i t i e s of 2,4-D in the food we eat but an e x te n s iv e review o f the data assu res us i t i s a q u a n tity which w i l l not cause harm. The FDA market basket samples for 1974-1975 (PEMJJAA) which are comprised of c o l l e c t i o n s in 20 c i t i e s which range in populations from l e s s than 50,000 to 1 X . f'.v: Ow" ' NRCC, 1978. Phenoxy H e rb icid e s - T h e ir E f f e c t s on Environmental Q u a l i t y . National Research Council Canada No. 16075. PEMJJAA - 1977, P e s t i c i d e and Other Chemical Residues in Total D iet Samples ( X I) P e s t i c i d e Monitory J o u r n a l, V o l . I I , No. 3. /5&1U96 P e te rso n , G .E . 1967. The D isco very and Development of 2,4 -D . A g r ic . H ist. 41: 243-253. Ramel, C. 1977, C h lo rin a te d Phenoxy A cids and T h e i r D io x in s , E c o lo g ic a l B u l l e t i n s No. 27. Report from a conference arranged by the Royal Swedish Academy o f S c ie n c e s , Stockholm, Sweden, 7-9 February 1977. . Sa u e rn o ff, M.W. e t a l . 1976. The Fate o f 2,4-D ich lorphenoxy Acid ( 2 , 4 D) Following Oral A d m in istratio n to Man. T o x i c o l . A p p l. P h a rm aco l., 37, 136-137. Schwetz, B . A . , Sparschu, G .L . & Gehring, P . J . (1971) The e f f e c t o f 2 ,4 d ich lo ro p h e n o xy a cetic a c id (2 ,4 -D ) and e s t e r s of 2,4D on r a t embryonal, f o e t a l and neonatal growth and development. Fe Cosmet. T o x i c o l . , 9 , 801-817. Weed S cie n ce S o c ie t y o f America, 1979, H erb icid e Handbook, 4th ed.  O A j '< ANALYTICAL REPORT .___________ ____ DOW CHEMICAL U.S.A. MIDLAND A N A L Y T IC A L LA BO R A TO R IES M. B. Chenoweth, 607 , EL L. Garfield, 607 TO Jk. S W. L, H. Leng, 9QQ8 Braun. 1R03 L. P. McCarty 1701 & 607 J, H, Saunders, 607 W, B, Crunjmett, 574 aL nRH5TRICTED REPORT AL 78-50668 Ac c t . tluM tlH .U FUNCTION 8004 LAB. NO. PROBLEM NUMBER July 28, 1978 T.TLC DETERMINATION OF PHENOXY HERBICIDES IN URINE a n d b l o c D SAMPLES FRQM_,2.4.5-T PT.ANT PERSONNEL - II. INTRODUCTION Human urine and whole blood samples were obtained from personnel working at the 2,4,5-T production facility for a determination of 2,4-dichlorophenoxy acetic acid (.2,4-D), 2-(2 ,4,5-trichlorophenoxy) propionic acid (.glyexl, and 2,4,5r trichlorophenoxy acetic acid (2,4,5-T). * -c* no ^ ^ O' EXPERIMENTAL The samples were prepared by extraction, hydrolysis, mthylation with diazomethane, and silica gel column clean-up prior to analysis by gas chroma tographyr-mass spectrometry (GC-Mg) . The experimental procedure used is detailed in Report ML-AL 78-50252. The silica gel column used was changed slightly. The column used was packed with 1.5 grams dry silica gel 11 cm x 6 sun i.d, glass). The column was eluted with 60/40 methylene chloride/ hexane. The first 2 ml were collected and discarded (waste fraction), The next 13 ml of eluent were collected for analysis. Then an additional two ml were collected to check for recoveries, (extra fraction). The collected fractions were evaporated to dryness. Prior to analysis, the sample residue was dissolved in 50 jjl benzene. Validation data for this procedure are detailed in MLf-AL 78-50252. RESULTS AND DISCUSSION Results are detailed in Table I , Pigure 1 shows a typical standard ion chromatogram and GC-MS conditions. Figure 2 shows typical GC-MS data for a urine sample from a 2,4,5-T plant`worker, >918 iig n a tu *~- . . a y / Marsha L. Landrhorst Data Book AL 1207 p. 118 O R M M 60 940 PHONE auiLO iN s OATE FINISHED HOURS RPHESOUNLETDS 6-6207 574 7/13/78 37 h DOW 1512709 J u l y 28, 1978 -2- AL 78-50668 Figure 3 shows typical GC-MS data for a blood sample from a 2,4,5-T plant worker. The presence of Silvex was asked to be confirmed. It was questioned whether Silvex could have an interfering com pound by GC-MS six-ion monitoring or whether Silvex or an interference could be created from 2,4,5-T during the sample preparation or analysis. To check the creation of an interference during sample preparation, a urine and blood sample were spiked with high levels (1.85 jig/gm sample) of 2,4,5-T. The sample was pro cessed through the usual procedure and analyzed. No peaks were found other than 2,4,5-T. See Figure 4. To check if the ethyl ester of 2,4,5-T might interfere with the methyl ester of Silvex, (both have parent ions by MS at m/e =* 282) by GC-MS, A sample of 2,4,5-T was ethylated with ethanolic HC1. The sample was analyzed by GC with electron capture detection and found to elute at a different retention time than Silvex. Therefore, it could not interfere by GC-MS and produce a response interpreted as Silvex. In addition, to check if any ethyl ester of 2,4,5-T is formed during methylation, a relatively high concentration of 2,4,5-T was methylated. No peaks were detectable except the methyl ester of 2,4,5-T, This evidence is shown in Figures 5 and 6 . The identify of Silvex in urine and blood samples is confirmed by retention time, ions in the mass spectra, and ion abundance ratios (.282/198) , 16919 DOW 1 512710 J u l y 28, 1978 - 3 AL- 7 8 - 5 0 6 6 8 REFERENCES 1. Marsha L. Langhorst, "Determination of Phenoxy Herbicides in Human Urine and Blood Samples - (Validation Data)", ML-AL 78-50252. 2. Marsha L. Langhorst, "Determination of Phenoxy Herbicides in Human Urine and Blood Samples (RESTRICTED REPORT)" ML-AL 78-50405, 3. Marsha L. Langhorst, "Determination of Phenoxy Herbicides in Human Urine and Blood Samples from 2,4,5-T Plant Personnel, (.RESTRICTED REPORT)" ML-AL 78-50489. td 1&920 DOW 1 512711 J u l y 28, 1978 AL 78-50668 TABLE X RESULTS PHENOXY HERBICIDES IN 2, 4y5WT PLANT PERSONNEL. Sample Concentration found Cng/gm Sample1 NO, Person Type 2,4-D Silvex 2,4,5-T U-l Amble Urine U-2 Crivac Urine a- 3 Falkowski Urine U-4 Swogger Urine B--1 Amble Blood B-2 Crivac Blood B-3 Falkowski Blood B-4 Swogger Blood 380 520 510 270 2.0 8.6 9.3 3.8 21 4.1 23 11 N . D . (1) N.D. (1) N . D . (1) N.D. (1) 540 220 310 170 8.7 5.6 7.9 2.4 SPIKED SAMPLES FOR RECOVERIES Sample No. Type Spiked with 2,4,5-T Cone found (ng/gm) % 2,4-D Silvex 2,4,5-T Recovery U-l Urine 1850 ng/gm urine N.D. (1) N . D . (0.5) B-l Blood 1850 ng/gm blood N . D . (2) N.D. (1) 1540 1400 83 76 NOTES: N.D. = Not detected with minimum detection limits shown in parentheses. Minimum detection limits (MDL1's) are: Compound in ng/ml in nq in ng/gm urine in ng/gm blood 200 10 1 2 Silvex 100 5 0.5 1 2,4,5-T 100 5 0,5 assuming 50 yl final volume assuming 10 gm urine sample 1 asstaming 5 gram blood sample 1 Methods are validated down to 3 ng/gm urine and 5 ng/gm blood. to 1 D  i . 11^ ; : T ..-j C lT j..-V - - G h>~, ' `f l Gu ie ; . STA N PARO ' ' C - :i L hbLil DATA ~' '" *: i i . *' 0 ri ; I L F b. - : . F :f: : i R R u c . h V r : ' _ F 2 _ 2 INSTRUMENT.1 HcultH -facarzi S W Z G-c-M S Cc u im n : H ' X Z m * cL^hss/ 3 7 SP '240l n ,<JO/i3<7 F O R R I J M tf 0 . 00 SX V v' TEM P/ 9 0 .0 T IH C I r a te S O : t i e r m cX f TEM P 2 9 0 .0 T M E 2 50. G - O . Z . Q Z.O 2 0 .0 1000 . .,* . i .. .' ; ; .' k- " ! , _ i j. * f ! . ' r . i : ... r .: . o t : U ? < ..l = r ` M ..' : . o b .o t o 2 3 S . t t 1 8 8 . 0t i-!F3 O : . ; . 0 8 5 0 . t 5. 0 l iM DOO F I J O = 0 . 3 03 'F3'i5802; u.. 0j o .32'53; 03.t.0*te0so 132u5F(t.8i.tc.itnt. i i MO o . : : ; :' I ri J E C T E I : - 2 .0 0 STANPftg-P Um-/; 2 . 3 ( ju a / sU ^ 4 -~ P US^/r- 2jl3ylAfy 2,4,'S'*T b T'i j F M O N I T O R & I O N F u l I 3c a le = 100 . *Lr-fV?-ts i-7 s ;. V O L T f C E =28tt i? 4 * .' 3 ) I S a !i5- -.4 - : - . u'"*5I3J3B 0 a y 13 J 4' fieUN DfiH C E S ION 2 3 4 .0 0 Full Seals = Sfc " i**' ir^ C a s m dW j* ste fs}- 50 , , -------------------- i ^g S 3 j S ^s a : Q*s 1: a.. *-i fH1 ak Hi sIsi :i S ' li, S a 3f 1 ';3 a 3 2 3 2 S S 3 9 " *a ---------- S-^ P^ agiB? 7 SILVER ll3aaBaaa.. JJ = j4 *x7>' a :i ! --~ **i 5:5 3i *rW -r ! S*3:"J.:SM; J: 'j1 - - o :^ ^ i* ^ ^ 5 | i r ^ a y a a 3 3 ^ .*--- } ro:H >- . 2 ':::i --*TM * r" ' ii/-. i "v'L i tfUt-. --1000 3 3 4 . OU ribUMli'-i-io-c Vq * 7 o I * 2 .;it . 0 I i `7 ? . 1 fc 282.00 175.85 2 3 3 . t 03 cJ cO-cJ . --J -I? t` 2b 3 . O0 2 0 2 * 2r 0- '' - - . J H F ' L E i r'_ i' 0. z T. i j r* 0 d i r*: . i .l \ i 0' T t-* O <1 r y . O03 d.i.tOi.' TV 19 7 8 ro HcHJiiijrO-L 34.00 3bt. w 2 i . tt obo?, t t i'ro.Oo 3 jt . to -2_.!J OC . 00 r . C..1 20 y o 350.00 e; r sr - -J.j .j .-_`i 2 So . 0303 3 b03. t t TOTRL T:-: 2 3 4 . ;* i4 * RnjUb" r JECTED = 2.003 = 2 3 6 . - -t G N 1 9 8 0.1 3 :J i-t = 2 9 2 . 0 0 IO N = 2 3 3 . 8 0 i:. 1 8 F' FS = ION = 6 8 . 0 0 Kj2. I''. ii :- \s ! i. \ I1 i!; i S\ i 11 J :i ) l -- jfc i1 1 II ^ ______________ 169 M ol 3,^1 . r ,,` Ui' 1 - r : : ft! : hu! ' r- 11i. ftPL - U RGrE Z ` ! S A P P L S -- FA Ufi OV^^K.1 . ;! ; r!i. fC ' 'ir 0 !...Fl _l_ :-L F krit; L' r_ ' ' .- 1 r. - j >n r * -; '.ft ''S ; l u f f ; , 4F l .4 ".1 ' F j . 0 s.. . `r -r t* i' 7 4 ,,KIM ill.VT f'/EN Mfi ,0 10,3 RUH TIME 2 G. 3 . 1 r>T 4. .1Hrat iru : `;H:v' . _ 3 T, 0 US. i1Fi E'_ .. TIFF. , u'UiOn . . :"1 C' ?"*ir -- 350, 0 . 30 'r-'io. r d !:'-JT0 vune r'e^o1'.JT i -T!* l 41 . 0 3 :1 , 30 `T1IO 03 S 3 . 33 35 : 0 3 5 3 ,3 3 5 3 . 350 , 3 . "i. VOL 130 iC:S T F iU E I T E j - , 3 0 {UT'I F nOHTRZD IOU ftBUMDfiNCES Fu i I Scale = 100 c . M. VOLTftGE ->3 t9 0H 234.00 Fu ll Scale = 50 DOW J 512713 MM SMI?m V . ' r .'3i3J*' i3i|ppi|r `5*.*iVj<S'iS$ii:ajWSi2-tSRsU -- . ........gjH iiiiB SM W M *-- .. i - . - J. -- : ' a 1i -; : r - i t " :> - . i !, V L ! HUE = L0U \ . '!H i lieb T .Tj"4T--. yT-ijr : rUr-1 ABUNDANCE 3 3 .3 5 i-: j t , uTuT -- 133,47 3 3 . 00" S3 . 0 404.13 144.14 UN i n h P L E T E , :.a' i t o i ' i d i n FUR - H il'- u E ID::."-,:' V r? Fh.sSES 3 4 . 00 1. i i : E 3 3 501. 3 1U ' { U E l i r / U - wO j -2:*" 4 . 0 0 viar ._ 13 c-. 0 0 35.00 142.47 19 0 . '50 . >; u1 tk7 .7 'i 7 U F r i do.y : -- . 00 3 3 . O S 3 . 0 15 0 . 0 01 3 5 0 . 0 0 3 5 .0 la . 3 S 4 0 4 . 1 2 1 4 4 .1 4 'I s ' O T R L Fu r: F I ME * 3 *" RnOiJi V i ;>JE CTED S' !M. M U - ' 3- . 3 J , :i - 7 3 . 0 l . 0 0' ' . i -. - 1 7 uj -2 3 2 . Ou ION =3 3 . 0 0 I 3u i 7 !- r 5 -- 3 FS - 4 0 4 FS = 14 31 ; . F ..... H --- i* i .: r ! : 1 4'i* di i ' b> ! r \ i i 7.: j i i i i M.um DOW 1512714 /-'f?tM.JWiril,!W:r < 1''- : z . .iwnsrossiw!raiimiswwi Mo *t- ~ " j.. j 3 r h .3 V M i/.ii oj' MM l|-|TO-r.=i.J S' H ' L' L. : i. Hi'i j aMi .s'I :[U; I 1" I aT-^ cv A f' / / V t - v -iny };' QC: '?t" "P. !:'Z -j o ' ;i f-'n ' i i !I*: -I fif *?' " li L-1 M K. d ccns V JO OJJ fMj: I! p 2 i- i :}ij! 'J5- V 1 f: M f ; itiS-jy j: ". i-.' V - r . v 7 3 . MINUTES CF STUhGE R V ftlL fiS L E EOF RUN# 'W V _ _ 4 CONTROL UR.IHB S P iK S P W;TH 2 ,4 # - T a - ^ -> r , J . i vfiS r J S f i N r L.E t ih V *\ w t i e- ;-iT r e m f y : r-m^ p .*!r-t i ; o : i i ; , i- i l S t . O c.ij v 1 0 . 6 - ' .'.rii ; itv.. RUN TME i 0_0 '"'fl. !: : i : r - i - i o p t r a i i n - a r ^ n d o . r d .u cd : . 0 8 2 3 6 . OO I ' - F . y O 2 3 2 . 0 6 NEL 'I NEC 3 3 0 . O 3 5 0 . 0 350.0 350.0 3-. . ;.. i; [Ml'OW 3 2 E = . 3 0 -fi . ' f i i O i u i ...t . 33 . Oil 2 6 3 . O 350.0 35.0 Pi'CU-iV O J E O T E j - 2 . 0 0 .,.vf ^ ! vn 1 3Ct SUM OF MONITOREO ION ABUNDANCES F -.i i 3 co. i fi- = 106 NiE3 H. ri, VOLTAGE -300 ^ P P |iS '' t'pl.. iWM ji! ft- Silp |S|g s; NE f: >' ___ I N nE 4t, 4 ION 2 3 4 . 9 0 F u l l S e a l fi r se ^ISaaasa-- - ------------- ^ ; to f ai l ____ m T o r * " * 3 2 . 0 0 L40.3 ; . 60 '33700' ,734.42 ;r ' 2 3 . t *7e* =jo f -.-n trlPLe.1 E > i.!a t-c. t.o i'fid i n RUN 3 ; - .i -- : . i-; . r vr J , 00 d a i fid " " '107 3 r r da y *;r. ..-r-r" 1*i.... . : - E : NSUNEr INCE 234 . t*b'j 350 ,0 0 316 .73 2. i 'Z- ,,00 5 5 0 , ti5 4 . 14 1 S .30 3 5 0 . t i 40.37 2 3 2 . 0 0 i.t- . 00 3 5 3 . O0 35w. 00 4 2 . 6 0 17 3 4 . 42 263,00 350.00 752.52 P:- : : : tTRL F UN TIME = '?. * FiNUMT I N J E C T E E s 2.0 FlG U p " JT RtTEN fiO N TIM ES O F PWENOXY He -Bi c,r s STANDARD CHROMA TDGrRAMS AND G C co n d itio n s. STANDARD* PH6MOXV HERflICIpeS AS METHYL ESreR S IMSfruheviT: Ycuritm 37^0 6m Cloryiim<L-b>jr?Y)k Opefolor.M<L..tAN&.H.P.Br.... Dais... 7.7.3.' 7 .................. Column N o .A I/ m .........Length...4.fh Dla...2rm..l.d.... Coaling. ............. Coacn.....-3.io................... Support. p a c t ........................Mesh.!9?./li-.Q.. TEMP: Col: Inlt..... .7 5 ? .............. C Final.................C Rale............. C/mln. Det.34l....0C ln|....iID.........C CARRIER G A S...hJiln}.gi.....Rate..... 3 0 .................ml./mln. Pressures: Inlet............................Outlet................................ Hydroge n ................. ml./mln. Air........................ ml./mln. d e t e c t o r ( T c ) N if:!....... T.C...................F.I.D.......................... Scavenger............................Rate.............................. ml./mln. Sens.Air. ifib t led.............Rec.Range......... I......................miv. SAMPLE... Ai..J.Jid.*/l.................................... Size.Afcliixfid.... Solvent..W.t Xta<.............. Concn........................................ 5 Oo: 'i f N S1' y o Z f a S - T (2 .1 3 p pm ) EFHYL ESTER. OF Z ^ S-T Cm ppm) STANPARP - 1,4,S-T AS E W Y L ESPER y j\ o -il * f aT' rni Si 4: 48 mmuieS - ) i 12 U __________I I III I1 o4 t minuTti --^ vz tv) 9 T i S T 9 l M O Q Cf5  - % t s - T - O -lS /rm ) Fieru/u 1 C'iR.OMfWDGrflAMS OF 2 ^ 5 - f A FHffc I6THYLA770M " Sm>kU,KIGr 'mAT ^ ESTER IS FORMEP DU|kj<t METTI YLATION ..... > '/ ) ?* v> i . . /I a aioH v t a a h * 2 5 ( c SrT)Nfflep i,? ppM ^ - T a P t r 'w tT ty J a f a n o tlo* < 7) 404*' '-V r\S r. y aHertuaiftui ' fr4*i) -U <r> C/ V . f*A L p : i ec J --- I ' 1i I o4 % rv>iruJLi25 --9 I IIii T2 O4 rmViuT <*S --? TZT IMOO 2418 A LONGEVITY SURVEY OF EMPLOYEES EXPOSED TO 2,4,5-TRICHL0R0PH5N0XYACETIC ACID or CD CJJ ro M. G. Ott, H.s. B. B . Holder, M.D. R. D. Olson, B.S. Medical Department The Dow Chemical Conpany Midland, Michigan RECEIV ED MAR 2 1 1973 REGISTRATION //A a - 1 6 8 .2 8 ABSTRACT A LONGEVITY SURVEY OF EMPLOYEES EXPOSED TO 2,4,5-TRICHLOROPKENOXYACETIC ACID Ott, M.G., Holder, B.B., Olson, R.D. cn O cCnO There have been few published reports regarding epidemiologic surveillance of individuals occupationally'exposed to 2,4,5trichlorophenoxyacetic acid (2,4,5-T). The present study examined the mortality experience of 204 persons exposed to 2,4,5-T during its manufacture. Exposure durations ranged from less than one year to a maximum of approximately 10 years over a period from 1950 to 1971. Within the scope of this mortality survey, no adverse effects were observed with respect to occupational exposure to 2,4,5-T. 1Q B2B p-si9Si> I MOO A LONGEVITY SURVEY OF EMPLOYEES EXPOSED TO 2,4,5-TEICHLOROPHENOXYACETIC ACID Introduction In 1976 Muranyi-Kovacs et al published results of a bioassav of 2,4,5-trichlorophenoxvacetic acid (2,4,5-T) for carcino genicity^. The 2,4,5-T, which contained less than .05 ppm of 2,3,7,8-tetrachlorodibenzo-p-d ioxin (TCDD), was found to produce a significant increase in non-incidental tumors (diagnosed during life or causing the death of the animal) in C3HF mice, but not in XVII/G mice. Both groups of mice had been fed 80 ppm 2,4,5-T on a daily basis until death. Previously, considerable variation had been demonstrated in 2 the kinetics of excretion on 2,4,5-T between species . An earlier screening bioassay study by Innes et al was not positive for tumorigenicity in two hybrid strains of mice 3 fed 60 ppm 2,4,5-T m their diet . The authors or the 1975 bioassay article, aware of the kinetic studies and paper by Innes, suggested that additional testing of 2,4,5-T was needed. A two year feeding study in rats is c urrently underway at The Dow Chemical Company Toxicological Laboratories in Midland, Michigan. Only limited epidemiological investigations of workmen exposed to 2,4,5-T have been c o n d u c t e d ^ '^ . In 1971, Poland et al 2,4,5-T Survey, Ott et al 456155 reported results of a health survey of 73 male employees in a 2,4,5-T and 2, 4-dichloropher.oxyacetic acid (2,4-D) manu- CD facturing plant'*. This survey was a followup of studies published by Bleibarg et al in 1964 on 29 employees in the same p l a n t ^ . An important finding in the follovnip was evidence of varying degrees of acne in 48 of the 73 employees The term "chloracne" was employed to describe the moderate to severe lesions observed for 13 (18%) of the individuals. Evidence of abnormal excretion of uroporphyrins was not found in the followup study in contrast to the original work. Also the authors in their summary stated that markedly less evidence of toxicity was found in other organ systems, such as the liver, than was reported in previous studies. It was noted, though not judged to be explanatory of differences in toxicity seen from the earlier work, that six months prior to the second survey, contamination of the process starting material, 2,4,5trichlorophenol (TCP) , with TCDD had been reduced from 10 to 25 p p m to 1 ppm. No detailed industrial hygiene measurements of 2,4,5-T or TCDD levels in the work environment were provided. The present study examines the mortality experience of a cohort of 204 employees engaged in the manufacture of 2,4,5-T. A review of health exam findings of phenoxv herbicide workers 7 in this plant was discussed in a paper by Johnson . The current survey compares mortality due to specific causes, with the corresponding U.S. white male population and with reference to other mortality studies conducted at this company location. 2,4,5-T Survey, Ott et al Historv o Process and Industrial liverione Measurements DOW ] 4 5 6 1 5 6 The commercial production of 2,4,5-T in the company began in March, 1950,- with the original process being operated con tinuously until May, 1971, when it was permanently shut down. In 1967, a second operation v/as developed that utilized different personnel and which has continued in production. Personnel from the second process were not included in the present study, because of the shorter latency period and because this more recent process produces esters of 2,4,5-T without isolation of the acid. The departmental unit under whi c h the original process v/as first organized also was responsible for manufacturing a variety of other products ranging from styrene butadiene latex to herbicides such as 2,4,5-trichlorophenoxy propionic acid and 2-methyl-4-chlorophenoxyacetic acid. Thus, many of the individuals included in the present study were potentially exposed to numerous other substances during their employment with this unit. The 2,4,5-T was manufactured by reacting sodium monochloracetate with the sodium salt of TCP, the salt being prepared by adding caustic to TCP. This v/as followed by conversion to the acid. A n additional step not considered part of the process, but taking place in the same building, was esterifi cation of 2,4,5-T with propylene glycol butyl ether or isooctyl alcohol. Continuing efforts were made to minimize TCD D con tamination in the 2,4,5-T plant by proper control of a separate 2,4,5-T Survey, Ott et al 3 OOW 1 4 5 6 1 5 7 plant which produced the TCP later used in the 2,4,5-T process. Wipe testing in 1970 failed to detect TCDD in the 2,4,5-T work area using a combined gas chromatography, mass spectrometry method sensitive to approximately 1 pg/sample depending upon interferences. The 2,4,5-T process was specifically run by a craw of four operators: a reactor operator, a salt wheel operator, an acid wheel operator, and a dryer operator. The reaction portion of the process in which the sodium salt of 2,4,5-T was produced was nearly a closed system. During the subsequent wheeling operations, the sodium salt v/as converted to the acid. The 2,4,5-T dust levels found in the plant were believed to have resulted primarily from finishing operations where the end product v/as dried and fed through a hammer mill. An industrial hygiene survey of the process was conducted in 1969 at which time 50 area and breathing zona samples were collected using a midget inpingsr containing isooctane at a flow rate of 2.2 liters per minute. The samples were subsequently analyzed by gas chromatography for TCP, 2,4,5-T, and 2,4-D. Concentrations of 2,4,5-T or its sodium salt ranged from <.l mgs/m 3 to 6.21 m g s / r n 3 . Estimated time-weightedaverage (TWA) concentrations for the three compounds by job classification are shown in Table 1. Concentrations of these substances were relatively similar for three of the job 2,4,5-T Survey, Ott et al .4 classified tiers reactor operator, dryer operator, and salt wheel operator. The acid wheel operator was exposed to lower 2,4,5-T levels and higher TCP co n c e n t r e t i o n s . The 2,4-D measurements are maximum levels. This product was dried occasionally in the building where 2,4,5-T was made. Often dust levels in the finishing area were high enough to cn Ob h-* cn oo be noticeably irritating. Sensory responses such as nasal irritation, sneezing, and a bitter taste were reported by unacclimatsd industrial hygienists to result from exposure levels of approximately .1 m g / m 2, 4 , 5-T and/or less than 4 mg/m^ of TCP. A review of medical visits from 1954 to 1970 revealed 19 episodes associated with acute exposure to 2,4,5-T or its esters among the 204 men in this study. All reported exposures involved eye o r skin contact, v/ith the mild to moderate responses apparently resulting from the irritating effects of the materials. Six of the exposure episodes occurred while the men were working as ester operators rather than directly on the 2,4,5-T process. The esters of 2,4,5-T are believed to exert similar toxicological effects as the acid after adjustments for the molecular weight of the ester itself. Method of Analvsis The employees included in the study wore determined by a two-stage procedure. In the first step all persons working 2n , ,1 , 5c - mi Survey, Ott et al DOW 1 4 5 6 1 5 9 in the department under which the process was organized were identified from annual census lists covering the period January, 1951, through January, 1971. The second step was a review of the complete work history for eachindividual to determine those who had experience on any of the four jobs of interest. These employees constituted the population of concern. This method of selecting the exposed population insured that all employees who worked continuously for at least one year with the 2,4,5-T work area were included, but could have missed some personnel who worked in the exposure area for shorter periods of time. A crew of 8 to 12 men operated the 2,4,5-T process on a daily basis. The flow of employees in and out of the department over the 21 year period resulted in 204 me n having worked for It months on at least one of the four jobs involved. The mortality experience was compared with the U.S. white male experience (5 year age intervals) for the years 1952, 1957, 1962, 1967 and 1971 by the indirect method. The vital status of former employees was initially traced through the Social Security Administration. Subsequently, verification of vital status has been obtained through contact of the individual or r elatives who could account for the former e m p l o y e e s 's vital, status. In this analysis exposure is expressed only in terms of length of emplovment on the four jobs of primary concern. Exposure 2,4,5-T Survey, Ott et al ie e a ? ) 6 DOW 1 4 5 6 1 6 0 durations co not take into account the unmeasured exposures to 2,4,5-T or esters of 2,4,5-T encountered on other jobs within the production department. One job did involve exposure to esters of 2,4,5-T and several other jobs may have required filling in on a day-to-day basis for the operators in the four classifications of interest, as well as other duties with minimal exposure. Since many of the employees in the 2,4,5-T study worked on a number of jobs wit h i n the d e p a r t m e n t , .the durations of exposure are c o n s e r vatively estimated. Sixty of these employees are also known to have worked in a styrene/butadiene latex plant organized within the production department. Thus, the persons included in the present study have been exposed during their employ ment to a variety of chemical compounds. Results The vital and employment status of the 204 workers exposed to 2,4,5-T and its sodium salts are shown in Table 2. Fifty-three of the 56 former employees have been traced through personal contact of the man himself or someone who currently knows him. For three persons vital status was verified at least through 1973, but not through 1976, by personal contact or social security c h e c k s . Two of the former employees had died as of followed through employment and retiree records. 2,4,5-T Survey, Ott et al .7 The distribution of employees by duration of exposure and date first exposed is shown in Table 3. More than 752 of th men had worked for less than 12 months in jobs involving defined exposure. None of the men were exposed to 2,4,5-T over a working lifetime. 456161 Medical records of employees were reviewed for evidence of chloracne or porphyria cutanea tarda, which might indicate exposure to TCDD. No case of chloracne or porphyria cutanea tarda was found. Tables 4 and 5 summarize mortality by duration of exposure and interval since first exposure. In Table 4 observed deaths were increased over expected only for the cause of death category "External Causes" (6 observed vs. 3.7 expected deaths). Three deaths in this category were due to separate automobile accidents, none of which took place while the individuals were employed on jobs involving 2,4,5-T exposure. One death was the result of a nonindustrial fire, and the .remaining two deaths were suicides among former employees that occurred more than 10 years after exposure had ceased. The single observed malignancy death in the cohort to date v/as a respiratory malignancy which was discovered in a 63 year old retiree who had been exposed to 2,4,5-T for 8 years and had a past history of cigarette smoking of up to two packs per day. 2,4,5-T Survey, Ott et al `3*S 1 DOW 1 4 5 6 1 6 2 exposure follows a pattern which we have observed in other g studies at this company location . The most favorable exposure followed by a relative increase compared to general population mortality. We have interpreted these findings to indicate a preselection effect due to initial employment or transfer of individuals in a state of good health which becomes less important both as the interval since employment increases and as the employees become older. Comment At the exposure levels experienced by the workmen in this study, no adverse mortality effects have been observed in association with the work environment. Within the scope of this limited survey, mortality has been favorable compared with the U.S. white male population and also compares well with the background mortality experience at this manufacturing g location . Because of questions raised by recent animal toxicological studies, mortality surveillance of this limited employee population will be continued. We recommend the initiation of mortality surveillance of other populations w h i c h have had past exposure to 2,*i,5-T. Ott et al 9 REF DREI:CjL.O 1 . Muranyi-Kovacs I, Rudali G, and Imbert J: Bioassay of 2,4,5-Trichlorophenoxyacetic Acid For Carcinogenicity in Mice. Er J Cancer 33:626-633, 1976. cn cn K* 2. Gehring PJ, Kramer CG, Schwets BA, Rose JO, and Rowe VIC: CD The Fate of 2,4,5-Trichlorophenoxyacetic Acid (2,4,5-T) CO Following Oral Admini s t r a t i o n to Man. Toxicol. Appl Pharmacol 26:352-361, 1973. 3. Innes JRM, Ulland BM, Valerio MG, Petrucelli L, Fishbein L, Hart ER, Pallotta AJ, Bates RR, Falk HL, Gart JJ, Kle i n M, Mitchell I, and Peters J, Bioassav of Pesticides and Industrial Chemicals for Tumorigenicitv in Mice; A Preliminarv Note. J Nat Cancer Inst., 42:1101-1114, 1969. 4. Aocelson 0, Sundell L: Herbicide Exposure, Mortality and Tumor Incidence. An epidemiological investigation on Swedish railroad workers. Work-Environ-Hlt 11:21-28, 1974 . 5. Poland AP, Smith D, Metier G, and Possick P: A Health Survey of Workers in a 2,4-D and 2,4,5-T Plant. Arch Environ Health, 22:316-327, 1971. 6. Bleibarg J, Wallen M, Brodkin R et al: Industrially Acquired Porphyria. Arch Derm, 89:739-797, 1964. 7. Johnson JE: The Public Health Implications of Widespread Use of the Phenoxy Herbicides and Picloram. Bio-Science 21:899-905, 1971. 8. Ott MG, Holder BB, Gordon HL: Determinants of Mortality in an Industrial Population. JOM 13:171-177, 1976. 0 D O w iv sk /ty J* CO o T a b l e 1. Time-Weighted-Average Exposure Estimates for 2,4,5-T Process Based on 50 Samples of Up To Five Minutes Duration and Time Studies for Each Job, 136". Job Reactor Operator ' Salt Wheel Operator TCP (mg/in3) 2.1 2.1 2,4,5-T1 2,4-D (mg/m3) (mg/m3)* <0.4 _ r-.VJ. 0.5-- <0.4 . Acid Wheel Operator 9.7 0.2 <0.4 Dryer Operator ' 1.6 0.5 <0.4 ^Highest possible values using levels of detection as real values. **Present in work environment as sodium salt. ^Product specifications for 2,4,5-T in 1966 called for a maximum of lppm T~DD, the sensitivity of the method of detection. In 1972, the maximum was lowered to .lppm TCDD. 1 Ii f `~ Tr'.rTi~ r ; ; ' ' ----------- ------------- <--------------------- ? -- > w . ... - v i- '* * - r .i ;* ^ J vV y , ' ....... :* ..vr.:c?vi'*vr';^r 'r,~y.v7-s-_Tv:u s r r .. M . . _ . ..................j p . , m 5ry jH h t* . 'C * ty jV W W 1*^5 .. Table 2. Vital and Employment Status of 204 Workers Exposed to 2,4,5-T as of 12/31/76. Vital and Employment Status Number of Workers Total Group Still Employed Retired Deceased (Company Records) Left Employment Other Than Through Retirement Deceased Known Alive Followup Through 1976 Incomplete 204 121 13 9 56 2 51 3 Table 3. Duration of Exposure by Date First Exposed Amo n g 204 2,4,5-T Exposed Employees. Date Exposure Began TOTAL 1950-1954 ` 1955-1959 1960-1964 1965-1969 19 70 + Total 204 50 45 51 35 15 Duration of Exposure* <1 Year 1-2 Years 3-4 Years 157 30 30 17 36 6 44 4 32 3 15 0 9 5 2 2 0 0 5+ Years 8 6 1" 1 0 0 16942 *Fifty-nine of the 204 employees worked as ester operators for from <1 up to 77 months (11 of these employees had worked for at least one year as ester o p e r a t o r s ) . The exposure durations as ester operators, or while employed in other capaciti.es within the production department, were not included in the table since exposure intensities had not been estimated. 99T92^ (wj m Tabic 4. Observed and Expected* Deaths Among 204 Employees Exposed to 2,4;5-Trichlorophenoxy 7vcctic Acid, by Cause and Duration of Exposure, 1950-1076. Cause of Death Category Duration of Exposure Total Exposed Group <1 Year Total Exposure 1+ Years Total Exposure Observed Expected Observed Expected Observed Expec ted All Causes Total Malignant Neoplasms Diseases of Cardiovascular Sys torn External Causes (Accidents and Suicides) All Other Causes 11 1 4 6 0 20.3 3.6 9.1 3.7 3.9 6 13.3 0 2.3 1 5.6 5 2.8 0 2.6 5 7.0 1 1.3 3 3.5 1 0.9 0 1.3 *Expccted numbers of deaths based on U. S. white male mortality rates. CT> to (J l MOO 9 I 9 S * Tabic 5. Observed and Expected* Deaths Among 204 Employees Exposed to 2,4,5-Trichlorophenoxy Acetic; Acid by Cause and Interval Since First Exposure, 1950-1976. *Expccted numbers of deaths based on U.S. white male mortality rates CTj CD MOO89T9f> I AGRICULTURAL PRODUCTS DEPARTMENT COPIES: 12/19/78 B. Schwetz, 1803 \ A. Morgan, 9008 \ R. Kodba. 1803 N L. E. Warren, Davis J. Davidson,9008 R. Johnson, 2040 B. Holder, 2030 2419 o o NJ sO DOW 1 3 6 2 5 6 8 from: J63O6H-4N82H6. DAVIDSON 695Z9CIW 0Q ASSESSMENT OF HAZARDS ASSOCIATED WITH USE OF 2,4,S-T, 2,4-D, AND SILVEX IN REFORESTATION PRACTICES In such a report as this it would be highly desirable to prepare a hazard analysis for each compartment or trophic level in the potentially affected ecosystem. This is at least very difficult and perhaps impossible to develop in a single document with the complexities of inter-level de pendence and ultimate dependence on many target plant species. There is an extensive literature on such effects, but in this report a decision has been made to concentrate on potential human impact. In that process, essential information on lower species appears to the extent necessary. There is an extensive literature on persistence, physical trans port, and degradation mechanisms of the phenoxy herbicides in the environ ment and their behavior is well established. These areas are discussed only in sufficient detail to establish essential facts. The section on TCDD is an exception and includes as complete a treatment as possible because of the unique character of the chemical. Furthermore, the author is not competent to critically analyze the entire literature on physical and chemical behavior. Problems Associated With Assessment of Human Health Hazard Associated With Use of Phenoxy Herbicides There are fundamental differences of opinion in philosophy of her bicide usage. A significant segment of the population consider insertion of any synthetic chemical into the environment as fundamentally wrong, regardless of benefits, however well documented. There are as well groups and individuals who are unable to accept any suggestion that some chemicals, as used successfully and with apparent impunity for decades, might constitute a hazard which is only now becoming evident. 116 DOW 1 3 6 2 5 7 0 This issue is no more clouded by those viewpoints than is any other debate over chemical usage, and we are best served by dealing with the problem without those extremes. Without question, the issue of phenoxy herbicides use has evolved to concerns about the contaminant TCDD in 2,4,5-T and silvex. Though 2,4-D has no such impurity, it has become tarred with the same brush, and it is not unrealistic to devote more space to the contaminant than any of the primary chemicals. Because of the extremely low environmental levels and enormous in trinsic toxicity of TCDD, the most critical technical question about that chemical centers on analytical methodology. There are few labora tories with the sensitivity to deal with concentrations on the order of 10 ppt or less, and there is real disagreement about reliability of detec tion or measurement at such low levels. When the data are considered, some samples in which TCDD was undetectable had high detection limits, some areas with no spray history were found to have measurable TCDD. Also, many samples of similar origin differed widely. Nonetheless, the data appear to be telling us clearly that some TCDD is present in some segments of the environment, that the amounts are uncertain, and that existing residue information must be augmented if we are to understand the behavior of TCDD. With any effort presently imaginable, however, it will probably not be possible to directly monitor the amount of TCDD in the physical environment. ' A proper analysis of hazard requires consideration of chemical be havior and ambient levels of the potential intoxicant, but in the case of TCDD we must rely on indirect assessment. The extent of uptake in 117 D0W13625 7 1 organisms that might concentrate TCDD, as compared with residues follow ing known laboratory exposures is of some value, but is still inadequate. There is a pervading argument over the problem of a specially sensi tive or idiosyncratic individual who responds to ouch lower doses than the surrounding population, or who responds in a highly exaggerated manner. Such cases are so rare that usually no field association with the causa tive event can be made. The effect is virtually impossible to find ex perimentally because it may have never been identified, and if it had, the genetic and species factors probably prevent any useful modeling. The argument about idiosyncracy follows every chemical in commerce, and society has not learned how to cope with it, or even whether it wants to try. In the context of excessive sensitivity there seems to be no reason to treat the present group of chemicals differently from any others. That is to say, every reasonable attempt must be made to locate or predict adverse effect, but it does not seem possible to anticipate the extremely rare response in areas not supported by research findings. A hazard analysis dealing with TCDD may or may not be strengthened by a position that EPA will apparently take; i.e., that 80-200 ppt TCDD in beef fat is an "effect level." The EPA document in question is as yet in draft form and will not be specifically attributed or referenced in this report. If the figures indicated are correct, any levels in beef thus far detected are within levels which will not do harm. The conclu sions were reached with the assumption that beef fat will constitute no more than 2.5% of the human diet. The concern in present forestry usage is primarily with deer which browse on treated foliage, and there is no clear indication of TCDD levels which might be expected in these ani mals. 118 DOW 1 3 6 2 5 7 2 The most difficult problem of the several that axe a part of the task of hazard assessment is, again, part of the decision pattern for any chemical, the risk-benefit analysis. Risk benefit analysis is an excellent basis for conversation but nearly useless in decision making. In the present case there seems to be a general conviction that herbicide appli cation is a highly useful tool in forest production. At the same time, estimates of differences in actual relative costs of tree production or retail materials, either near-term or long-term, axe difficult to find. Technically, economic benefit should be an accessible factor, but it seems elusive. Risk, on the other hand, is not quantifiable unless major and obvious effects occur; such situations make the decisions for us. If we are able to show any human illness resulting from environmental practices of chemi cals, almost certainly they will be disqualified. An exception may be in effects which axe certainly reversible. As a society we have yet to learn a usable method of determining whether, or how much, human injury can be considered acceptable. The assessments of hazard in this report axe therefore opiniors by one person about the potential for human harm resulting from distribution of the chemicals at levels that will achieve the forestry objec tive. This document should be taken as a working base enabling incor poration of other opinions, and it should be subject to periodic updating, based on new findings, existing papers inadvertently missed in review, and existing papers which may become more pertinent in the light of other new findings. 119 -4 Assessment of Human Hazard Resulting from TCDD as a Contaminant of Fhenoxy Herbicides Two arguments emerge frequently in discussion of TCDD. One is that the manifest injuries to workers and citizens in or near sites where trichlorophenol plants have had run-away reactions or explosions dictates a cessation of use. The several such accidents, some near catastrophic are certainly unique because of the enormous toxicity of TCDD. The argument has merit but the issue here is whether specified uses are hazar dous. There is little doubt that industrial safety often lags far behind existing capacity for safety, but specific industrial hygiene and health problems should be dealt with on the basis of their own weaknesses. In other words, solving the factory and community exposure problem by plant shut down may make sense, but solving it by stopping use of the agent does not. Another argument is that laboratory data is unrealistic and not useful if it doesn't duplicate potential human exposure. Nothing fills that criterion except accidental human exposure, which we do not need. Experience has given us considerable (albeit not perfect) confidence in our ability to estimate field consequences from laboratory findings. The concept of dose dependent response has been proven valid, although there are admittedly possible discrepancies at the very low dose range. In any case, without the expenditure of enormous amounts of time and money, we cannot have studies that precisely duplicate field exposure. It is possible to estimate a TCDD exposure rate that will not cause effect in the most sensitive parameters now known to be affected by TCDD. In rats, 0.001 yg/kg/day S days a week for 13 weeks, totalling 0.065 yg caused no detectable effect. Guinea pigs given .008 yg/kg/weekly for eight weeks also were not affected. Existing data from monkey 120 DOW 1 3 6 2 5 7 3 16 95( DOW 1 3 6 2 5 7 4 experiments has not produced -a "no observed effect" dose because the de tailed analyses available only through interim sacrifice have not been made in primates. The group of monkeys studied in Allen's laboratories first showed clinical symptoms after three months of exposure to about 0.01 yg TCDD/kg/day, or a total dose of somewhat less than 1 ug/kg, but there is no way of knowing whether pathologic examination would have detected changes at the more than 10-fold lower dose found ineffective in the rat and guinea pig. The existing literature also does not provide access to a useful single dose no observable effect level. There is no useful data that relates specifically to human effects. It therefore seems reasonable to accept 0.06 yg/kg as a subchronic total dose over a short term, say, one year below which no effect can be detected. From this point it follows that some attempt must be made to judge potential human exposure levels. It is clearly impossible to directly evaluate acquisition by surface contact with treated foliage. Direct analytical methods for TCDD are probably more sensitive than for any other organic compound, but measurement of foliar distribution can not be made at field application levels. In my opinion significant TCDD exposure by inhalation is highly im probable. An intake of 0.02 yg of TCDD would require inhalation of one g 2,4,5-T containing 0.02 ppm TCDD, along with 10 g of diluent at usual dilution rates. The volume of air in which the spray is distributed is very large. Such an intake for a 50 kg person would constitute 1/150 of the assumed no observable effect dose. The potential for inhalation of TCDD formed during combustion of 2,4,5-T is infinitely less, because of the enormous dilution in air. 121 Oral exposure in drinking water is also extremely unlikely because TCDD partitions from water to sediment very efficiently. With dilution in flowing water, TCDD at levels deposited during spraying disappears quickly. Furthexmore, TCDD deposited on soil and surfaces binds tightly, and while some material can wash off of leaves, once on soil it remains, neither leaching downward or migrating toward water courses. An acute spill of large amounts of undiluted spray formulation into a water course could present an isolated hazard but 2,4,S-T and its car riers are objectionable enough in taste and smell that such an accident provides its own alarm. However, a theoretical but remote possibility in such an accident is the selective extraction of TCDD onto sediment, fol lowed by very slow loss of TCDD from sediment to water over a sustained period. Probably the only way such an accident can occur is through a vehi cular accident resulting in loss of herbicide drums into a water course. Oral intake through consumption of meat or milk presents at least theoretical possibility that an individual might consume enough deer meat containing, say, 10 ppt TCDD to acquire a significant burden of the dioxin. The question then becomes one of the probability that such a circumstance can come to pass. TCDD in concentrations of this order have been found in cattle grazing on 2,4,S-T treated range land; we may assume that an occasional deer can accumulate similar amounts if forage is poor and the animals must eat forage that they have been observed to discriminate against. If uniformly distributed in all edible tissues the amount of TCDD in a pound of meat would be about 4.S ng. The no observed effect level in a SO kg human is assumed at 3.0 yg. To reach that amount would require nearly 666 meals of one pound of meat, or the meat from 5-10 deer, 122 D0W13 6 2 5 7 5 16952 and assumption of perfect retention of TCDD or its effect. In point of ' fact, the high TCDD concentrations are in liver and fat and such a hypo thetical whole animal concentration would not be approached. A slightly different approach by Dr. George Streisinger makes as sumptions about fat concentration and the percentage of fat in, as an example, ground meat. He has concluded that either 78 or 408 (depending on different no-effect assumptions) half-pound meals would exceed the danger barrier. Dr. Streisinger included a 100/1 safety factor, however, and the specified number of meals would bring a person to within l/100th of a possibly harmful intake. 2,4,5-T is applied on a given forest area only 1-3 times in a timber growth cycle. While it is possible for a deer to acquire significant residues in a single year, the likelihood of a long-term continuous ex posure of deer would require migration among sprayed plots, or repeated treatment of a single area, and is therefore remote. Even range land is not usually treated annually. The significance of TCDD in mothers milk is considerably greater than consumption in meat. The analyses by Dr. Meselson's group indicate the possibility that TCDD on the order of 1-2 ppt may be present in human milk. Dr. Meselson has been careful to state that while he has great confidence in the individual analyses, they are close to detection limits, and the data really asks rather than answers the question. For the sake of discussion, a sustained output of 1 ppt in human milk could provide an infant dose approaching the no observed effect level. Assuming a liter of milk consumed daily at 100 days, total intake would be 0.1 pg. If the average weight of the infant were 6 kg, the 100 day 123 DOW 1 3 6 2 5 7 6 IO? uq Uer <3 m dose would be 0.016 Ug/kg, or about 1/4 of the no observed effect level. Exposure for 200 days would produce a somewhat lower dose per unit weight because infant weight increases but milk output may not. It is appropriate to inquire how a human mother can acquire enough TCDD to excrete 1 ppt or 1 ng/L in milk. If a constant input by consump tion of one pound of meat daily is assumed, the individual will take in 4.5 ng daily. Almost all ingested TCDD is excreted in feces, with a minor component excreted in urine. Most chlorinated hydrocarbons emerge in milk to a limited extent, and it is not unexpected that TCDD should be found at low levels in milk. A pound of meat containing 10 ppt TCDD ingested daily would bring into the body 4.5 ng daily. As with any chemical, an equilib rium will eventually be reached where excretion and metabolism of the chemical will equal intake. In the case of TCDD, metabolism to other forms is minimal. There are not data on the fraction of TCDD excretion in milk, but it may be expected to be quite small. If we assume a high figure of 20%, however, an output of about 1 ppt is at least possible. The possibility of such sustained intake of TCDD is remote, however, re quiring consumption of 2-3 deer over a 6 month period. An alternative is a more massive exposure over a short period. We have no knowledge of the distribution into milk of, for example, 1 yg TCDD/kg as a single dose. We do know, however, that TCDD has a half-time of residence in the body of no more than 30 days, and probably closer to 20 days. Milk concentrations will decrease at the same rate as tissue residues, if not faster, and a 200 day nursing period covers more than 6 half-times. A one ppt concentration in milk arising from a single expo sure will dwindle to 0.5 ppt in 20-30 days, to 0.25 ppt in 40-60 days, and 124 DOW 1 3 6 2 5 7 7 10354 0.12 ppt at 60-90 days. Exposure of a nursing infant will therefore be minimal. It appears to me therefore that the potential for harmful exposure of infants through human milk should be negligible. This route is none theless the most probable of the several potential means of contact, and demands a thorough analysis of human milk in exposed populations. The data on TCDD carcinogenic potential suggest that it is not a carcinogen. It has been suggested that TCDD is a promoter of carcinogenic activity on the basis of a wide variety of tumor types developed over a long exposure period by the Wisconsin group. The recently completed Dow Qiemical Co. study indicates that tumor incidence changed only at doses that were lethal to many animals over the two-year test period. The data base exists for one and probably several human epidemiological studies irfiich could answer the question of influence on human cancer incidence. A recommendation is made later for such studies. Of the toxicological data evaluated, perhaps the most disturbing is that of Allen et al. (1977} suggesting that the lethal dose in monkeys is similar whether the agent is administered over a short period or over several months. Time independence of dosage has never been demonstrated for a chemical. If it truly exists for TCDD, there is implication that the compound leaves permanent damage, even though it has departed from the body. In this situation, continual low level impact would cause gradually accumulating injury until clinical illness would prevail. In that sense, the idea of a no-effect level would not be applicable, and no exposure would be permissible. As with radiation, however, a small intake is possible without endangering health over a lifetime. In the case of TCDD this amount is not known, but it is finite. In view of a 12S D0W13 6 2 5 7 8 QK DOW 1 3 6 2 5 7 9 long history of use without apparent injury and an apparently rapidly improving data base, it seems justifiable to allow use of 2,4,5-T and silvex under conditions that will permit virtually no inadvertent or unknowing exposure. It appears to be practical to diminish ambient contact to levels which will have no significance, accepting minor one time defects in the system which should also have no consequences, and to allow individuals the informed opinion of exposure. Such a stringent condition is not necessarily incompatible with use of a necessary herbicide. It seems possible to design application methods and associated policies that would prevent involuntary and inadvertent exposures of humans to TCDD. The present knowledge of dioxin effects and behavior is not suffi cient to make an unqualified statement of reasonable safety. Several areas of needed research, suggested in a later segment of this report, should improve our level of confidence. Nonetheless, it is my opinion that 2,4,5-T containing less than 0.02 ppm TCDD can be used safely in reforestation if certain protective practices listed later are instituted. In brief, these, involve absolute avoidance of spray intrusion across property lines, identification and protection of dwellings and water supplies reentry discipline and adequate public information programs. i 126 4 Hazard Assessment-- 2,4,5-T The acute toxicity of 2,4,5-T is quite low and in itself is not a factor in the environmental hazard potential of the herbicide. This seg ment is concerned only with 2,4,5-T; the implications of the dioxin con taminant have been considered earlier. A wide variety of specific toxic changes have been found in experiments with acute or short-term repeated administration of high doses of 2,4,5-T. 2,4,5-T is teratogenic, but again, only at high doses. The dose response to 2,4,5-T is such a large fraction of the maternal lethal dose is required to produce birth defects. There are substantial differences in effective teratogenic doses among strains of mice. The lowest effective dose is still substantial, however, and the kind of teratogenic response remains the same. The differences among the genetically very specific mouse strains do raise the possibility of high individual sensitivity in the heterogeneous human population. This question applies to any potential effect in humans by any chemical and really constitutes a common social question that we have not learned to handle. The excretion of 2,4,5-T by mammals is rapid, with relatively little conversion to other compounds. Initial residues after application are high enough to possibly cause some temporary slight tissue deposition of 2,4,5-T in tissues of grazing animals, if sustained for a period of more than two weeks, but environmental degradation of 2,4,5-T is rapid and the chemical does not migrate extensively, once deposited. For these reasons and because general toxic responses to the herbicide only occur at high doses, I do not consider that 2,4,5-T as used properly in forestry proce dures represents a general toxic or teratogenic hazard to the human popu lation. 127 DOW 1 3 6 2 5 Co o iC S '5 7 DOW 1 3 6 2 5 8 1 The bulk of evidence available at this time indicate that 2,4,5-T is not carcinogenic or mutagenic. It oust be emphasized that this evi dence really assures us only that the herbicide is not highly carcinogenic. An epidemiological study of humans occupationally exposed has also been negative, although other herbicides were found in the same study to be possibly associated with an increased incidence of tumors. Mutagenic assessment in a number of experimental systems has shown no evidence of such change, and epidemiological study of 2,4,5-T produc tion employees has shown no evidence of cytogenetic change. I do not believe the issue of carcinogenesis by 2,4,5-T can be arbi trarily closed yet, although at this time it appears that there is not a carcinogenic or mtagenic hazard at exposure levels countered following typical application. I have made recommendations relating to needed in vestigations which should establish a more specific level of confidence in that opinion, or possibly cause it to change. An industrial study of carcinogenic effect of a two-year treatment of rats with 2,4,5-T is almost complete and should also shed more light on the issue. I do not believe that 2,4,5-T per se as used in forestry constitutes a human health hazard. Hazard Assessment-- 2 f4-D The acute toxic dose of 2,4-D is quite high, but a number of indivi duals occupationally exposed to 2,4-D have suffered severe neuromuscular and gastrointestinal effects. These incidents have been the result of gross mishandling of the chemical and are not a part of the environmental health issue. 128 16958 DOW 1 3 6 2 5 8 2 The reproductive effects of 2,4-D do not\appear until doses approach* ing the lethal level axe reached, and there seems to be no reason for concern in this province. As a potential carcinogen, 2,4-D has had very little study. The only evaluation of which I am aware was negative, in one species, which indicates that the compound is not highly carcinogenic. This finding of course can give no confidence about low level carcinogenicity. Sev eral studies of mutagenic potential have been negative, adding some confidence. Perhaps the key information lies in the rapid excretion of intact 2,4-D in the urine. This process is rapid and relatively complete. In some species a portion of the compound is converted to other forms for excretion, but the process is rapid. Rapid excretion probably is the factor that prevents 2,4-D or its products from reaching the detectable margin in milk after field exposure. It is possible experimentally to overload an animal to the extent that the material will appear in milk. Because of its short persistence in the environment and the absence of toxic responses at any doses that might be found in the field, I be lieve the uses of 2,4-D in practices presently considered standard is not hazardous. There are, as with any chemical, some open questions, which are addressed in the section on recommendations. These relate primarily to epidemiological needs and clinical surveillance. Hazard Assessment-- Silvex The general considerations applicable to 2,4,5-T may also be applied to silvex. There are some minor differences between the compounds, but the ranges of toxicity, the manner of biological disposition, and the 129 environmental behavior are similar enough that similar standards should apply. In the absence of data on silvsx, findings from studies of 2,4,5-T should be considered applicable. As with 2,4,5-T, the issue of TCDD contamination overshadows the characteristics of silvex itself. The one mitigating circumstances is the more limited distribution of silvex and therefore less extensive distribution of TCDD. It is my opinion that present uses of silvex do not constitute a hazard, from silvex itself. The issue of the TCDD contaminant is sepa rately addressed. There is, however, further information needed to in crease confidence in that opinion, and recommenations have been made in the appropriate section. DOW 1 3 6 2 5 8 3 130 K ft 1?9939ClM0a RECOMMENDATIONS OF STEPS WHICH SHOULD BE CONSIDERED TO ASSURE THAT EXPOSURE TO TCDD IS MINIMIZED OR PREVENTED I have stated my opinion that 2,4,5-T can be used safely, with cer tain additional safeguards. I believe that opinion should be reviewed as new data emerges. A number of clinical questions now being asked have accessible answers, and these must be obtained. In addition, the toxic nature of TCDD and our inability to measure it satisfactorily in the environment dictates a very conservative attitude about its distribu tion. I see no inconsistency in accepting its presence in small quanti ties and recommending unique steps to prevent those quantities from reaching people. To assure public protection and a more compatible relation with the public, I suggest the following considerations in designing a spray pro gram. 1. With the consideration of health hazard, there is a political reality that needs more attention. Every treatment operation oust be designed to prevent intrusion of spray onto premises not under control of the agency or firm using the chemical, as a matter of principle. I would not be surprised if Forest Service policy includes that concept, but I would also be surprised if its application is somewhat leas than perfect. Personal rights are becoming more and more clearly defined, and it seems to be time to decide where such rights begin and end, and take a visible public position on the issue. 2. As a means of preventing any involuntary exposure, there should be assurances that every residence is identified, with any water sources that may be in the Forest. Non-legal residents should also be identified. 131 DOW!3 6 2 5 8 5 Questions of liability and informed consent and other relationships with the Forest Service ought to be clearly laid out. 3. Present buffer procedures should be examined in detail and pub licly shown to be adequate. If a 100-foot zone cannot be proven certainly safe, it should be expanded. 4. An intensive posting and advertising program should be used to notify the public where herbicide treatments are located. The informa tion should be directed toward special users of the area, such as hunters, as well as the adjacent population. 5. There is definite need for documented assurance that applied .herbicides arrive only at the intended target area. If this requires a spat monitoring program during and after application it should be insti tuted. Here again is an issue of public confidence; precision of appli cation may be very, high, but no one outside the industry knows about it, if it is so. RESEARCH NEEDS TO MORE CERTAINLY ESTABLISH THE SAFETY OF PRESENT USES OF PHENOXY HERBICIDES 1. During discussions of herbicide use issues we are confronted \ by innumerable allusions to people made ill by application of the agents. These incidents range from word of mouth descriptions of a neighbor's experience to an extensive series of carefully constructed interviews with Vietnamese who were subjected to herbicides as chemical warfare. As they appear in the context of our forestry practices, these anecdotal descriptions of illness cannot be documented and are of little value in assessing toxic hazard. They are of concern, nonetheless. A clinical surveillance team should be commissioned to evalua*immediately any alleged herbicide contact incidents. There is no doubt 132 DOW1 3 6 2 5 8 6 in my mind that people complaining of physical injury are in fact affected. I am skeptical that the application of herbicide causes these effects in more than a few incidents, but it is possible. Of more importance, there may be some other public health hazard operant in the area which causes the symptoms. It is even possible that other illness is brought to the attention of the victims by their immediate concern about improper her bicide intrusion on their private property. 2. The opinion of Van Miller et al. (1977) that TCDD is a promoter of carcinogenic effect by other compounds seems reasonable according to their evidence. If the forest application of 2,4,5-T containing TCDD is inserting effective levels of TCDD into the human environment, epidemio logical evaluation should disclose higher than normal incidence of various forms of cancer in 2,4,5-T use areas. Lane County, Oregon, has a very effective tumor registry program, with virtually all pathology of human cancer examined by a single consortium of specialists. These data should provide evidence of any existing difference in cancer patterns from other areas. A more definitive study should be possible in rangeland or rice growing areas where the herbicide is used annually. Epidemiological studies such as these may settle the persistent question of cancer latency, because on an area basis, the pattern of past use of herbicides should be reasonably accessible. 3. A thorough health surveillance should be made of all herbicide applicators and others with industrial or agricultural exposure to 2,4,5-T or silvex. Cytogenetic evaluation through several seasons of the year should be an integral part of the study. Design of the medical components of the survey should be by a nationally constituted panel. 133 4. Environmental degradation of TCDD is still inadequately under stood. Photodegradation by light reflected from or transmitted through foliage must be measured as must reaction in shade and under cloud cover. 5. With, present sensitivities of analysis, translocation of TCDD in plants should be restudied. 6. Affinity of TCDD to plant surfaces should be examined directly, to determine how efficiently the chemical can be removed by surface contact and by animal digestion of forage. 7. Augmentation of industrial efforts to eliminate TCDD from trichlorophenol derivatives seems to be a legitimate governmental concern, and should be encouraged. Elimination of the contaminant would obviously eliminate the issue. 8. A search should be made for chemical additives that would react with TCDD or accelerate its breakdown. 9. The human milk and fat biopsy program being developed by EPA should be encouraged. DOW1 3 6 2 5 3 7 DOW1 3 6 2 5 3 8 ASSESSMENT OF HAZARDS ASSOCIATED WITH USE OF 2,4,5-T, 2,4-D, AND SILVEX IN REFORESTATION PRACTICES In such a report as this it would be highly desirable to prepare a hazard analysis for each compartment or trophic level in the potentially affected ecosystem. This is at least very difficult and perhaps impossible to develop in a single document with the complexities of inter-level de pendence and ultimate dependence on many target plant species. There is an extensive literature on such effects, but in this report a decision has been made to concentrate on potential human impact. In that process, essential information on lower species appears to the extent necessary. There is an extensive literature on persistence, physical trans port, and degradation mechanisms of the phenoxy herbicides in Che environ ment and their behavior is well established. These areas are discussed only in sufficient detail to establish essential facts. The section on TCDD is an exception and includes as complete a treatment as possible because of the unique character of the chemical. Furthermore, the author is not competent to critically analyze the entire literature on physical and chemical behavior. Problems Associated With Assessment of Human Health Hazard Associated With Use of Phenoxy Herbicides There are fundamental differences of opinion in philosophy of her bicide usage. A significant segment of the population consider insertion of any synthetic chemical into the environment as fundamentally wrong, regardless of benefits, however well documented. There are as well groups and individuals who are unable to accept any suggestion that some chemicals, as used successfully a '*ith apparent impunity for decades, might constitute a hazard which is only now becoming evident. 116 ':V^/y `-J- AGDSEPJALRTTUMREANLTP-RO90D0U1CTS Midland, Ml 48640 COPIES TO: INDEX 13 B . SCHWETZ 1 8 0 3 -K. WATSON R. MOFFAT B- MOSS HONG KONG R COOK 1 8 0 3 w- CRCJMMETT 5 7 4 D. MORGAN B- MCCREDIE o Xi O 'O ro :- O -?s reon-vl h -* JS. H #r o ;s - -^-^%r^T-i'v-_ 1V.;,// '-r -- ., r- ' t - -J " rr. - _T r'.'F V u " a r * ^ . --i .......... -a V- / - ; - ~ T*f ~t from: i'.-L//*:".;.* JOHN DAVIDSON 517- 636-4826 16S8 -- ` -X- - -- ---'*'' -r . * -.ru -- v *La ^ > `* - * = 1 Environmental Health Perspective Voi. 36, pp. 21-240, 1930 / 271527 PLPooonllyygcc-hhTlleoorrrmiinnaaHtteeaddzaDDrdiibfsaeeonnfzzoodfuiorxainnss*and by J. E. HufV J. A. Moore,1 R. Saracci,* and L. Tornatisi During January 10-11, 1978 in Lyon, France, a joint National Institute of Environmental Health Sciences/International Agency for Research on Cancer ad hoc Working Group consid ered and discussed the feasibility of coordinating epidemiological studies on the long-term haz ards associated with the chlorinated dihenzo-p-dioxins and chlorinated dibenzofurans (PCDDs and PCDFs). Nineteen invited scientists from eight countries presented introductory working papers summarizing the most up-to-date and relevant information available from their individ ual programs. This report represents the collective views and scientific opinions of the Working Group. The greater part of this document comprises epidemiological studies related to episodes of human exposure. The review begins with a brief section concerning possible routes of human exposure, an overview of the pertinent chemical characteristics, and the salient toxicological properties of the structurally siimilar PCDDs/PCDFs. The Working Group report ends with recommendations for future activities. Introduction Human exposure in the workplace can occur when chlorinated dibenzo-p-dioxins (PCDDs) are formed during the production of certain com pounds such as the herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), the fungicide pentachlorophenol, and the germicide hexachlorophene (1). The dioxins, impurities/contaminants associated with these end-products, result most often from treatment of chlorinated benzenes at elevated temperature and pressure under alkaline conditions. Via the widespread use of these com mercial products (J, 2) the general population may also become exposed. In recent years, out-of-control chemical reac tions during the production of 2,4,5-trichlorophenol have proceeded to the explosive *This report was prepared by the NIEHS/1ARC Working Group and the full proceedings were printed in June 1978 as IARC Internal Technical Report 78/001. References cited in this report rellect in general those published prior to June 1978. Participants of the NIEHS/IARC Working Group: A. (J. Ar atila, University of JyvaskylS. Finland: 0. Axelson, Regional Hospital, Linloping, Sweden (Vice Chairman); H. Bartseh, IARC, Lyon, France; P. J. Baxter, Employment Medical Advi sory Service, London, England; F. Bercino, Instituto Nazionale per lo Studio e la Cura dei Tumori, Milano. Italy; L. Bisanti, Uffici Regione. Milano. Italy; R. Frentzel-Beyme, Deutsches Krehsforschungszentrum, Heidelberg, Federal Republic of Germany; A. Hay, University of Leeds, United Kingdom; J. . Huff, IARC, Lyon. France: L. Jirsek. Universit Karlova FVL, Prague, Czechoslovakia; T. Kuroki. IARC, Lyun, France; G. May, Derbyshire, United Kingdom; R. Montesano. IARC, Lyon, France: J. A. Moore, National Institute of Environmen tal Health Sciences, Research Triangle Park, N.C., U.S.A., (Chairman): J. Parizek, WHO, Geneva, Switzerland; G. F. November 1980 Peruzzo, Uffici Regione. Seveso. Milano, Italy; F. Pocchiari. Is tituto Superiore di Sanit, Rome. Italy; A. Poland. University of Wisconsin Medical School. Madison, Wise.. U.S.A.; C. Rappe, University of Ume. Ume, Sweden; V. Riihimki. institute of Occupational Health, Helsinki, Finland; R. Saracci, IARC, Lyon, France; I. J. Selikolf, Mount Sinai School of Medicine, New York, N. Y., U.S.A.; R. R. Suskind. Kettering Laboratory, University of Cincinnati Medicai Center. Cincinnati. Ohio U.S.A.; L. Tomatis, (ARC, Lyon, France; J. G. Vos. Rijks Instituut voor de Volksgesondheid, Bilthoven, The Netherlands: N. Wald. University of Oxford. Oxford. United Kingdom; J. Wilhourn, IARC. Lyon, France. Address reprint requests to J. E. Huff. National Toxicology Program, P.O. Box 122:t3, Research Triangle Park. NC 27709. f National Toxicology Program, P.O. Box 12223, Research Triangle Park. N.C.. 27709. *International Agency for Research on Cancer, 150 Cours Alhert-Thomas, 69372 Lyon, Cedex 2, France. 221 stage thereby exposing persons to toxic levels of PCDDs. From certain of these accidents, more over, not only did those occupationally involved receive dangerous exposure but also those in habiting the surrounding areas received uncom mon risk. The structurally-related chlorinated dibenzofurans (PCDFs) are contaminants found in some polychlorinated biphenyl compounds: Aroclor, Clophen, Phenoclor (3). These impurities are more toxic and represent a greater environmental hazard than the com pounds they contaminate (1, 3-9). For instance, 2,3,7,8-tetra-CDD has been recently found in beef fat from cattle grazed on 2,4,5-T-treated rangeland and in breast milk from women living in areas where 2,4,5-T is used on rangeland or in for est areas (10). Various investigators (11-14) have also discovered PCDDs and PCDFs in fly ash and flue gas from municipal incinerators, and in dust from fungicide-treated wood (15). Chemical Aspects The PCDDs and PCDFs are two series of tri cyclic aromatic compounds which exhibit similar chemical and physical properties (1, 3, 4). The basic two-dimensional structures (I, II) have eight possible points of chemical addition. From the monochloro to the octachloro derivatives, a va riety of positional isomers are possible: 75 PCDDs and 135 PCDFs (Table 1 ). The extreme toxic potency of some of these compounds, as well as the large number of poten tial isomers, warrant analytical methods exhib iting high sensitivity and specificity to monitor the environment. A desirable detection limit of one part per trillion (ppt, 1 picogram/gram sample) is being reached with current methodol ogy. Essential requirements included efficient clean-up, good separation and selectivity, ultra sensitive quantification, and validation (IS, 17). Toxicological Aspects Animals The prototype and most extensively studied iso mer of the PCDDs and PCDFs is the 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-tetra-CDD), perhaps the most potent man-made toxin pres ently known. The comparative oral lethal dose val ues for various PCDDs in mice and guinea pigs (Table 2) show dearly that the 2,3,7,8-tetra-CDD and the 1,2,3,7,8-penta-CDD isomers are the most toxic (IS). Toxic effects induced by PCDDs and PCDFs vary quantitatively and qualitatively among dif ferent species; however, within a single species the untoward consequences are markedly similar for all PCDDs and PCDFs that have been studied. For example, the toxic effects induced by 2,3,7,8- tetra-CDD which are most often observed in mice, guinea-pigs, and monkeys, are illustrated in Table 3 (20). In a brief report, daily oral intake (12-61 days) of < 1 pg/kg body weight 2,3,7,8-tetra-CDD was stated as being lethal to young male rhesus monkeys (21), whereas McConnell et al. (22) re- ^5 ; ported an LD*, in female rhesus monkeys as <70 pg/kg body weight. A preliminary report on 2,3,7,8-tetra-CDF con- - cerning the toxicity of PCDFs (23), and a report on PCDFs (24) have been published. ^ The toxic syndrome produced by PCDDs and PCDFs may be divided into seven categories: Chloracne. 2,3,7,8-Tetra-CDD and the tri- ^ PCDF and tetra-PCDF were found to be active^-* skin irritants and to induce acneform lesions in^O the skin of rabbit ears (25). Classical chloracne is a hallmark of PCDD ex posure in humans and an analogous hyper keratosis and the modulation of sebaceous struc tures to keratin cysts have been observed in monkeys, rabbits, and hairless mice. Chloracne or acneform dermatitis is a common occupational dermatitis characterized by com edones, keratin cysts, pustules, papules, and ab scesses. In 1957, Kimmig and Schulz (26) found that 2.3,7,8-tetru-CDD was the agent responsible for causing occupational chloracne in employees of chlorophenol-producing factories. Further, in 1971 PCDDs were implicated as causing chloracne in male workers in a plant producing 2,4-D and 2,4,5-T (27, 28). Chloracne may appear weeks or months after the initial exDosure to PCDDs and PCDFs. Heputoxicity. The degree of hepatic in volvement appears to be dose-dependent, and the severity of the changes produced varies between qpocies (29). Hepatic necrosis produced by 2,3,7,8- tetra-CDD is prohably a contributing cause of death in rats and rabbits, while hepatic necrosis and liver insufficiency are less extensive in mice and are minimal in comparison in guinea pigs and monkeys (22, 30-37). Hepatic porphyrin accumu lation has been observed in mice, rats, and chick ens. H ypoplasia of the Lym phoid T is sues. Particularly involved are the cortical cells of the thymus and this hypoplasia has been ob served in mice, rats, guinea-pigs, and monkeys. The most significant findings in both mice and Environmental Health Perspectives %o Cly I II DOW J2 7 1 5 2 9 guinea-pigs treated with sublethal doses of 2.3.7.8- tetra-CDD were in the lymphoid system, resulting in suppression of cell-mediated immu nity, particularly in young animals (36, 38). Low levels of 2,3,7,8-tetra-CDD that did not produce overt clinical or pathological changes still reduced host defences: 1 /tg/kg bw given orally once weekly for 4 weeks to mice before infection with Salmonella increased mortality and decreased the time from infection to death (39). The increased mortality may be caused by the endotoxin content of these gram negative bacteria, since 2,3,7,8tetra-CDD markedly increases the susceptibility of mice to endotoxin (lipopolysaccharide of Esche richia coii) (4 0 ). Treatment of female mice and rats with 2,3,7,8-tetra-CDD during the latter half of gestation and in the postnatal period resulted in a severe depletion of lymphocytes in the thymic cortex of the offspring (At). Cellular immunity was impaired. Hematological changes in mice, rats, and guinea pigs treated with 2,3,7,8-tetra-CDD in clude lymphopenia and thrombocytopenia (12, 43); manifest also is an increased susceptibility to infection concomitant with the suppression of cell-mediated immunity. For 9 months, female rhesus monkeys received a diet containing 500 ppt 2.3.7.8- tetra-CDD; within 6 months, the monkeys became anemic and after 9 months pancytopenic Table 1. Possible number of isomers for polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans. Chlorine atoms PCDD isomers'* PCDF isomers* l 2 3 4 5 6 7 8 Total 2 10 14 22 14 10 2 1 75 4 Id 28 38 23 16 4 I 135 ` Chlorinated dibenzo-dioxins: empirical formula C,2H7.U Cli.,0-; molecular weight ranges, 213--WO. h Chlorinated dibenzofurans: empirical formula. Cl2HT.0 CIi.hO; molecular weight ranges, 202-444. November 1980 (44) The marked thrombocytopenia was associ ated with widespread hemorrhage. Death oc curred in five of the eight monkeys between months 7 and 12 of the experiment at total ex posure levels of 2,3,7,8-tetra-CDD of 2-3 /tg/kg body weight. At autopsy, in addition to extensive hemorrhage, there was a distinct hypocellularity of the bone marrow and lymph nodes. Hyper trophy, hyperplasia, and metaplasia of the epithe lium in the bronchial tree, bile ducts, pancreatic ducts, salivary-gland ducts, and palpebral conjunctivae were observed. Squamous metaplasia and keratinization of the sebaceous glands and hair follicles were present in the skin. Death was attributed to complications from the severe pan cytopenia (44). General Debilitation and Wasting. Animals that receive a toxic or lethal dose of PCDDs or PCDFs exhibit a chronic and progressive weight loss with parallel mobilization of peripheral fat, increased serum triglyceride levels, and develop ment of a fatty liver. Death due to PCDDs or PCDFs intoxication is delayed, as exemplified by an elapsed time period of 6 to 8 weeks following administration of a lethal dose and eventual death (18, 22, 44). Embryotoxicity and Teratogenicity of 2,3,7,8- tetra-CDD. In repeated or single doses of 2,3,7,8-tetra-CDD to mice, as little as 1-10 /tg/kg cause increased frequencies of cleft palate and kidney abnormalities (43-43) (see Table 4). In rats, embryo-lethal effects occur under experi mental conditions (49, 50), and kidney anomalies (4-5), intestinal hemorrhages, and general edema can be produced in the fetuses (51). Few follow up studies of the effects of prenatal exposure on postnatal functions have been published. In mice, fetal kidney abnormalities caused by 2,3,7,8-tetraCDD may progress into a hydronephrosis during the postnatal period (52). Chick Edema Disease. Hydropericardium, as cites, subcutaneous edema, liver necrosis, and death were described in 1957 following the acci dental administration of toxic fats in the feed of broiler chickens (ascites have been observed also in mice) (l). The toxic material was later identi- WJ i; & s^. 3U- >5r1 =*: % 3 -i -5 '-4V . 7 i ? -M Table 2. Estimated single oral LD50-30 values of certain polychlorinated dibenzo-p-dioxin isomers.* Guinea pigs Mice Chlorine isomer 2,8 2,3.7 2,3,7,3 1,2,3.7,3 1Z4.7.8 1,2,3.4,7,8 U.3.6,7,3 1,2,3,7,3,9 1,2,3,4.6,7,8 l-NO-3,7,3 1-NHL3.7.8 l-NOo-2,3,7,8 l-NHj-2.3,7.8 Mg/kg >300,000 29,444 2 3.1 1,125 72.5 70-1006 60-100b >500 >30,000 >30,000 47.5 194.2 /imole/kg >1,180 120.41 0.006 0.009 3.15 0.185 0.178-0.255 0.153-0.255 >1.400 >90 >99 0.129 0.576 n/kg __ >3,000 283.7 337.5 >5,000 825 1,250 >1,440__ __ __ >2,000 >4,300 pmoie/kg >10 0.88 0.94 >14 2.11 3.19 >3_._67 __ __ >5.4 >14.2 * Data from McConnell et al. (IS). The LDw.jl0 was calculated by the Spearman-Karber method (19). b Estimated range due to variability in replicates. to fied in commercial oleic and stearic acids produced from inedible tallow recovered from animal hides; trichlorophenols and pentachlorophenols had been used in the curing of the hides. The edema causa tive was termed toxic fat and more specifically chick edema factor and was characterized by xray crystallography as 1,2,3,7,8,9-hexa-CDD (53). 2,3,7,8-Tetra-CDD, hexa-CDD, and octa-CDD have been also identified in several commercial fatty acids (5U). Daily doses of 10 or 100 /zg hexaCDD/kg bw, or of 1 or 10 /tg 2,3,7,8-tetra-CDD/kg bw, produced a positive response in the chick edema bioassay; 0.5% octa-CDD in the diet had no effect (35). Similar edematous effects were ob served in rats, pigs, dogs, and monkeys, but not in Table ;{. Summary of the toxin effects of 2,3,7,3tetr.ichlorodihenzn-p-dioxin.* Thymus involution Spleen reduction (white pulp) Bone marrow hypoplasia Liver megalocytosis/generation Bile duct hyperplasia Testicular degeneration Renal pelvis hyperplasia Urinarv bladder hyperplasia Adrenal cortical atrophy (zona t j L o m u r u l o a a ) Hemorrhage Intestinal Adrenal Ascites Cutaneous lesions Mice +++ + Guinea P'K* +++ + Monkeys (female) +++ + ++ +++ - ++ ++ + - ++ - ++ - ++ 4* +++ NA + -- -- ++ -- ++ -- - -- +++ * Data from Moore (0). guinea pigs (55). Decreased serum albumin m ay^o be associated with the edema; edema has b e e n ^ j also shown to occur in chicks dosed orally with 2.3.7.8- tetra-CDF (56). Other Effects. In one or more species of labo ratory animals, bone marrow hypoplasia, testicu lar degeneration, renal pelvis and urinary bladder hyperplasia, and hemorrhage in the intestines and adrenals have been observed. Enzym e Induction. 2,3,7,8-Tetra-CDD and other halogenated dibenzo-p-dioxins and dibenzofurans stimulate a number of enzyme activities, most notably in the liver (1). 2,3,7,8-Tetra-CDD is a potent inducer of hepatic and renal microsomal drug metabolizing enzymes (57-6*5). Intoxication with 2,3,7,8-tetra-CDD results in a marked in crease in the ceilular smooth endoplasmic reticu lum content of hepatic and renal cells (60,69). 2.3.7.8- Tetra-CDD can simultaneously activate and suppress certain microsome-associated for eign-compound and steroid-hormone-metabo lizing enzyme systems (63) as well as increase the activity of both renal and hepatic glutathione-S transferase (70). 2,3,7,8-Tetra-CDD is the most active of the PCDDs in inducing hepatic S-aminolevulinic acid (ALA) synthetase and aryl hydrocarbon hydroxy lase (AHH) in chick embryo liver preparations (71, 72). The PCDDs that induce ALA synthetase in chick embryo have two common properties: (1 ) halogen atoms occupy at least three of the four ring positions (2,3,7.8), and (2) at least one free, nonhalogenated carbon atom is unoccupied (72). The available toxicological data (35) indicate that those PCDDs that are lethal at low doses, terato genic, or produce acne also induce ALA synthe- 221 Environmental Health Perspectives 16b70 BOW] 271531 Table 4. Evaluation of reported embryotoxic and teratogenic effects induced by 2,3,7,8-tetrachlorodibenzo-p-dioxins in rats and mice* Dose, pg/kg Species Strain Embryotoxic/ teratogenic effect Lowest Tested0 ED*,5 Period of dosing, days Route Reference Rat Mouse CD CD-I DBA/2J C57BL/6J NMRI Intestinal hemorrhage Kidney abnormality Cleft palate Kidney abnormality Cleft palate Kidney abnormality Cleft palate Kidney abnormality Cleft palate 0.125 0.5 1? 3 1 3 3 3 3 3 9 15 5 0.5? >1 >3 1-3 >3 >3 >3 <3 6.5 <9 40 15 Oral (50) 6-15 S.C. (45) 6-15 S.C. (45) 6-15 S.C. (45) 6-15 S.C. (45) 6-15 S.C. (45) 6-15 S.C. (45) 6-15 S.C. (45) 6-15 Oral (45) 9-13 Oral (45) 13 Oral (47) 11 Oral (47) * Data from Neubert et al. (47). bThe lowest dose with which an embryotoxic or teratogenic effect detectable at birth has been produced is indicated. Since sometimes only one dose level was tested, this does not necessarily represent the lowest dose from which an effect could result. * EDjo-dose required to produce an embryotoxic effect in 50% of animals. tase; those PCDDs that are not toxic generally do of its relative potency (or rank order) to produce not induce ALA synthetase. The structure-activ other toxic manifestations. ity relation of PCDDs to induce AHH in chick em Hepatic Cytosol Binding Protein. A macro- bryos was identical to that in inducing ALA syn molecular binding species has been characterized thetase (71). in the hepatic cytosol fraction of mouse and rat Mixed-function oxidase enzyme systems of liver which has the in vitro binding properties mouse strains "non-responsive" to other aromatic predicted for the receptor for the induction of hydrocarbons were induced by single doses of AHH activity based on the in vivo biology (78): 2.3.7.8- tetra-CDD, as evidenced by increases in namely, (1) JH-2,3,7,S-tetra-CDD binds to this hepatic monooxygenase activities and in concen cytosol protein reversibly with a high affinity (K d trations of cytochrome P-448 (73-76). Genetic = 0.27 nM) comparable to the ED^ for hepatic resistance to induction of AHH by 3-methyl- AHH induction (EDWin mice = 1 nmole/kg); (2) cholanthrene in DBA/2J mice was overcome by the binding affinity of halogenated dibenzo-p-di- treatm ent with 2,3,7,8-tetra-CDD. This result con oxins and dibenzofurans for this protein in vitro flicts with the hypothesis that induction of AHH corresponds to their potency to induce hepatic activity is a consequence of the formation of cyto AHH activity in the chicken embryo; and (3) chrome P-448 (77). A component that has a high other compounds, such as the polycyclic aromatic binding affinity for 2,3,7,8-tetra-CDD was found hydrocarbons, which induce AHH activity and in mouse liver cytosol (73). cytochrome Pt-450 also compete for this cytosolic 2.3.7.8- Tetra-CDD induces AHH even in `poorly binding protein, but compounds which induce responsive' strains of mice (79), not only in liver other types of microsomal monooxygenase activi but also in lung, kidney, and colon. The DBA/2N ties (e.g., phenobarbital) and steroids fail to bind. strain, which responds only weakly to the sarco- Thus, this cytosolic binding protein may be the re matogenic action of 3-methylcholanthrene, be ceptor for the induction of AHH activity. comes highly susceptible after treatm ent with Structure-Activity Relations. The pathologic 2.3.7.8- tetra-CDD (74, SO). effects produced by the toxic PCDD and PCDF 2.3.7.8- Tetra-CDD is approxim ately 30,000 isomers are similar to those of 2,3,7,8-tetra-CDD times more potent than 3-methylcholanthrene in fo ra given species, differing only in the intensity inducing AHH activity in rat liver (SI). of the toxic etFect produced by a given isomer. McConnell et al. (IS) reported that the com The toxic PCDDs have chlorine atoms in at least parative toxicity of 13 PCDDs in mice and three of the four lateral ring positions (2,3,7, and guinea-pigs (see Table 2) supports the idea that 8) with at least one unsuhstituted ring position the relative potency (or rank order) of a congener (the octa-CDD is comparatively inactive). To the to produce one toxic response is a good indicator extent that the toxicity has been determined, a November l!).SO 6971 DOW / 2 7 1 5 3 2 similar structure-toxicity relation has been ob McCann (88) tested 2,3,7,8-tetra-CDD in S. typh served for the PCDFs. imurium, both with and without metabolic acti The structure-activity relation established for vation, using a spot-test and the standard' plate PCDDs and PCDFs for the induction of hepatic test with strains TA1532, TA1535, TA1537, and aryl hydrocarbon hydroxylase (AHH) activity TA1538; all these tests were negative. and for binding to the hepatic cytosol binding Octa-CDD was nonmutagenic in 5. typhimur species has been extended to other classes of ium strains G46, TA1530, and TA1531, and doubt chlorinated aromatic compounds. 3,4,3'4'-Tetra- ful results were obtained with strains TA1532 and chloroazoxybenzene (TCAOB) and 3,4,3',4'-tet- TA1534 (57). Metabolic activation system s were rachloroazobenzene (TCAB) are potent acnegens not included in any of these microbiological as formed as trace contaminants in the synthesis of says. 3,4-dichloroaniline or herbicides based on this Inhibition of mitosis and chromosomal abnor compound (82). At high doses in animals, TCAB malities (dicentric bridges and chromatin fusion is reported to produce thymic involution and liver with formation of multinuclei or a single large damage similar to 2,3,7,8-tetra-CDD (83). Both nucleus) were observed in endosperm cells of the TCAOB and TCAB are potent inducers of hepatic African blood lily (Haemanthus Kat h erina e AHH activity and bind to the hepatic cytosol Baker) treated with 2,3,7,8-tetra-CDD in the binding protein with a high affinity. Congeners presence or absence of 2,4,5-T (89). such as 3,5,3'5'-tetrachloroazoxybenzene and No chromosomal aberrations were observed in 3,5,3',5'-tetrachloroazobenzene fail to induce AHH bone marrow cells of male rats treated with 2,7- activity, fail to bind to the hepatic cytosol species, di-CDD, 2,3,7,8-tetra-CDD, or dibenzo-p-dioxin by and fail to produce chloracne. oral intubation, with 2,3,7,8-tetra-CDD by intra- Of 16 halogenated biphenyl compounds tested, peritoneal injection or orally (90). However, when only 3,4,3'4'-tetrachIoro-, 3,4,5,3'4'5'-hexachloro- Osborne Mendel rats of both sexes were treated and 3,4,5,3'4'5'-hexabrom obiphenyls induced twice weekly for 13 weeks with 2,3,7,8-tetra-CDD, hepatic AHH activity and bound to the hepatic a significant but weak increase in the number of cytosol binding species (84). The 3,4,3'4'-tetrach- chromosome aberrations in bone marrow cells was lorobiphenyl has been reported to produce chlor reported (91). acne. McKinney et al. (58) found that of five 2,3,7,8-Tetra-CDD did not induce dominant le h e x a c h lo ro b ip h en y ls te s te d in ch ick en s, thal mutations in Wistar rats after oral adminis 3,4,5,3'4'5'-hexachIorobiphenyl was by far the tration to males for 7 days (51). most toxic, and the only one that induced signifi Carcinogenicity. Two reports indicate that cant chick edema and involution of the thymus. chronic administration of low levels of 2,3,7,8- Pharmacokinetics. In the rat, following acute tetrarCDD to rats is associated with an increased or chronic administration, 2,3,7,8-tetra-CDD is ac incidence of neoplasia (1, 92, 93). cumulated primarily in the liver and to a lesser Groups of 10 male Sprague-Dawley rats were extent in the fat, and is largely eliminated unme fed a diet containing 2,3,7,8-tetra-CDD for 78 tabolized in the feces with a whole body half-life of weeks in the following amounts (figures in paren about 3 weeks. Some pharmacokinetic experi theses are approximate weekly doses): 0, 1 ppt ments suggest the formation of a polar metabo (0.0003 p g /k g body weight) 5 ppt (0.001 p g /k g ), lite appearing in the urine, but direct attempts to 50 ppt (0.01 p g /k g ), 500 ppt (0.1 p g/k g), 1 ppb demonstrate metabolism with hepatic microsomes (0.4 p g /k g ), 5 ppb (2.0 p g /k g ), 50 ppb (24 p g /k g ), in vitro have been negative (1). 500 ppb (240 p g /k g ), and 1000 ppb (500 p g/k g). Mutagenicity. Only four dioxin isomers have The three highest dose levels (50, 500, and 1000 been evaluated for mutagenicity: the 2,7-di-, ppb) were toxic and killed all animals by the 2,3,7,8-tetra, and octa-CDDs as well as the un fourth week. Of the six remaining test groups, S substituted dibenzo-p-dioxin (55). the overall incidence of neoplasms was 23/60 2,3,7,8-Tetra-CDD increased the reversion fre (38%); none occurred in the l ppt group. In the 5 quency to streptomycin independence in Esche ppt group, 5/10 animals had 6 neoplasms [ear- richia coli Sd-4. In Salmonella typhimurium. duct carcinoma, lymphocytic leukemia, adeno fram eshift mutations in strain TA1532, but not carcinoma, malignant histocytoma (with metas- .,1-- T<lU' base substitutions in strain TA1530, were induced tases), angiosarcoma, Leydig-cell adenoma); the by toxic concentrations of 2,3,7,8-tetra-CDD (86). following groups also showed neoplasms: 50 ppt, In plate assays, the response was positive with three observed in 3/10; 50<> ppt, four 4/10; 1 ppb, typhimurium TA1532. doubtful with TA1531 and five observed in 4/10; 5 ppb, ten observed in 7/10. TA1534, and negative with G46 and TA1530 (57). Neoplasms were not observed in the controls (52). 226 Environm ental Health Perspectives O V' & VC. j g ^ g s a S i g *Xt -- **'* f T - _ . i V . - . -- *~~t - r r > l Groups of 100 Sprague-Dawley rats (50 males and 50 females) received for two years diets con taining 0, 22, 210, and 22.000 D D t . equivalent to 0.0, 0.001, 0.01, and 0.1 pg 2,3,7,3-tetra-CDD/kg/ day. Continuous ingestion of 0.001 /ig/kg/d ay did not cause any chemically related changes in tumor incidence or toxicity; feeding with 0.01 p g/kg/day induced an increased incidence (p < 0.05) of he patocellular hyperplastic nodules (female: 18/50 versus 8/86 controls), of focal alveolar hyper plasia in the lungs, and of urinary excretion of porphyrins (fem ale). Dietary intake of 0.1 /ig /k g / day caused an increased incidence (p < 0.05) of hepatocellular carcinomas (female: 11/49 versus 1/86) and squamous-cell carcinomas of the lung (female: 7/49 versus 0/86), of the hard palate/ nasal turbinates (male: 4/50 versus 0/85; female: 4/49 versus 0/86), and of the tongue (male: 3/50 versus 0/85). Further increased were adenoma of the adrenal cortex (male) and hepatocellular hy perplastic nodules (female). At this dose, certain age-related lesions were reduced (males: acinar adenoma of the pancreas; females: granulosal cell neoplasm of the ovary, benign and malignant tu mors of the mammary gland, pituitary adenoma, and benign tumors of the uterus). Also, chronic administration of 2,3,7,8-tetra-CDD caused mul tiple toxicologic effects, including increased mor tality, decreased body weight gain, slight depres sion of certain hematologic parameters, increased urinary excretion of porphyrins and -amino levulinic acid, increased serum levels of alkaline phosphatase, glutamyl transferase and serum glu tamic pyruvic transaminase, and morphologic changes primarily of the hepatic, lymphoid, res piratory, and vascular tissues of the body (55). These two reports show that^ehronic adminis tration of 2,3,7,3-tetra ODD clu ses an increased incidence of neoplasms, but not whether 2,3,7,8tetra-CDD acts as an initiator or promoter. This consideration is particularly important because unequivocal evidence is lacking that 2,3,7,8-tetraCDD is a mutagen or is metabolized, and no evi dence ^available that 2,3,7,8-tetra-CDD and/or metabolite (s) bind covalently to macromoleculcs. As summarized in Table 5, at least 24 long-term carcinogenicity studies on mice and rats are in progress (94). Humans Toxic Effects in liumsms. Toxicity due to 2,3,7,8-tetra-CDD has been reported after occupa tional exposure during tfi|! industrial synthesis of 2,4,5-trichlorophenol (TCt?) and 2,4,5-T, after ex posure in factories and in the surrounding envi ronment due to accidents occurring during the November 1980 synthesis of TCP, and after exposure to herbi cides and other materials containing 2,3,7,8-tetraCDD. Exposed subjects have been found to de velop a wide variety of lesions and symptoms (Table 6). For instance, a typical exposure victim experiences a number and a variety of clinical signs and symptoms: early exposure symptoms may include a burning sensation of the eyes, nose, and throat followed by headache, dizziness, nau sea, and vomiting. Some days later, severe itch ing, redness, swelling of the face, more marked ^ over the eyelids, nose and lips, may develop. ^ Within the initial weeks after exposure, inflamed w g . nodules as well as pustules appear on the face, forearms, shoulders, neck, and trunk, leading then* to comedones and cysts. A fter a month or two, a c -j^ neform eruptions emerge and the skin becomes^ hyperpigmented. At about the same time, aching , muscles, mainly in the thighs and chest area, be-^-j come m anifest and aggravated on exertion. In-r n somnia, extreme irritability, and loss of libido alsq^j occur during this stage. Other than the consistently found clinical feature of acne, other findings in humans mayinclude: neuromuscular symptoms (weakness and pain with nerve conduction abnormalities), porphyria cutanea tarda, hepatic dysfunctions, hyperiipidemia, cutaneous hyperpigmentation and hirsutism, chronic eye irritation, emotional dis orders, and neuropsychiatric syndromes. Chloracne, one of the most constant and promi nent features of 2,3,7,S-tetra-CDD exposure, has been described as a refractory acne characterized by inclusion cysts, comedones and pustules, with eventual scarring of the skin, more frequently originating on the face and sometim es spreading to other parts of the body. Many patients also have blepharoconjunctivitis and irritation of other mucous membranes. Sometimes the chlor acne is preceded by erythematous and edematous skin lesions. The latent period between exposure and the appearance of clear signs of chloracne ranges from a few weeks to several months (106). An important and unique episode revolves around three scientists who were self-exposed to 2,3,7,8-tetra-CDD: one heated trichlorophenol in an alkaline solution, a second heated potassium trichlorophenate, and a third svorked in the same laboratory as the second and used a diluted solu tion of the synthesized dioxin (107). The first two scientists developed chloracne eight weeks after exposure, whereas the third showed no evidence of the characteristic acneform lesions; Delayed symptoms, probably due to 2,3,7,8-tetra-CDD, developed approximately two years later, and the second two scientists showed personality changes ' 1i [ '* i ? j ; ] ! ;; \ i j ! :: i ; j j i ! ; I I | j j .j ; .-r.v-T DOW F 1 Table 5. Ongoing long-term carcinogenicity testing of chlorinated dibenzo-p-dioxins.*-* Compound Number of studies Route Species Dibenzo-p-dioxin 2,7-Di-CDD 2,3,7-Tri-CDD 2,3,7,8-Tetra-CDDd , l,2,3,6,7,S-Hexa-CDDd l,2,3,7,8,9-Hexa-CDDd 1,2,3,4,6,7,8,9-Octa-CDD 4 Oral (diet) Mouse, rat Skin Mouse Mouse (with DMBA)' 4 Oral (diet) l Mouse, rat Skin Mouse Mouse (with DMBA)' 3 Oral (gavage) Mouse, rat Skin Mouse 5 Oral (diet) Rat Oral (gavage) Mouse Oral (gavage) Mouse, rat Skin Mouse 3 Oral (gavage) Mouse, rat Skin Mouse 2 Oral (gavage) Mouse Skin Mouse (with 1,2,3,6,7,8-hexa-CDD) 3 Oral (diet) Mouse, rat Skin Mouse *Data taken from Information Bulletin on the Survey of Chemicals Being- Tested for Carcinogenicity, No, 7 (H). Details of these studies as well as the authors/institutes are available in this source reference document. bAs of October 1979, carcinogenesis bioassay testing within the National Toxicology Program included unsubstituted dibenzo- p-dioxin (UDD: CAS 262-12-4; NCI Tech. Rept. No. 122), considered not carcinogenic to Osborne-Mendel rats and B6C3F1 mice when administered in feed at dose levels of 5 and 10 ppb, and 2,7-dichlorodibenzo-p-dioxin (DCDD; CAS 22857-26-0; NCI Tech. Rept. No. 122), considered not carcinogenic to Osborne-Mendel rats and female B6C3F1 mice but suggestive of a carcinogenic ef fect in male B6C3P1 male mice when fed concentrations of 5 and 10 ppb. Studies are in progress on 1,2,3,6,7,8-hexachlorodihenzop-dioxin (HCDD, CAS 57653-85-7) and 2,3,7,8-tetrachIorodibenzo-p-aioxin (TCDD: CAS 1746-01-6) by gavage to Osborne-Mendel rats and B6C3F1 mice ami by skin painting on Swiss mice. Testing on 2,3,7,8-tetrachlorodibenzofuran (TCDF; CAS 51207-31-9) is to begin in fiscal year 1980. For chemical disposition studies octachlorodibenzo-p-dioxin, 2,3,7,8-tetrachlorodlbenzofuran, and the stereochemically related 2,4,3',4'-tetrachIoroazobenzene are also proposed. ' DMBA = dlmethylbenzanthracene. d The National Toxicology Program has completed and reported the results for the long-term carcinogenesis hioassay studies on 2,3.7,3-tetrachlorodibenzo-p-dioxin and l,2,3.6,7,8-/l,2,3,7,8,9-hexachlorodibcnzo-p-dioxins, with the following results. 2,3,7,8-tetrachlorodihenzo-p-dioxin--gavage, carcinogenic for Osborne-Mendel rats (increased incidences of follicular-cell thy roid tumors in males and of liver tumors in females) and carcinogenic for B6C3F1 mice (liver tumors in both sexes and thyroid tumors in females); dermal, carcinogenic for female Swiss-Webster mice (fibrosarcoma in the integumentary system) and al though not shown carcinogenic for male Swiss-Webster mice, an increase in the same tumor type was observed. Mixture of hexachlorodibenzo-p-dioxins--gavage, carcinogenic for female Osborne-Mendel rats (hepatocellular carcinomas or neoplastic nod ules), carcinogenic for male and female B6C3F1 mice (hepatocellular carcinomas and adenomas), and not demonstrated as carcinogenic for male Osborne-Mendel rats; dermal--not considered carcinogenic for male and female Swiss-Webster mice. 07 GD (mainly loss of energy and drive); impairment of vision, taste, and muscular coordination; sleep dis turbances; gastrointestinal symptoms; and hir sutism. The first of the three experienced none of these adverse effects. All three exhibited hyper cholesterolemia (>300 mg/100 ml). Human Exposure to PCDDs and PCDFs Major sources of human exposure to PCDDs and PCDFs include: exposure in the workplace; exposure in factories and in the surrounding envi ronment from industrial accidents; exposure to contaminated materials, wastes, or food in the general environment; and exposure in Vietnam and other intensive herbicide spraying opera tions. (Prior and subsequent to use as a defoliant, 2,4,5-T was used in weed-killing and forest-thin- 223 ning operations in the United States of America and elsewhere). Occupational exposure may occur in manufac turing plants producing chlorinated phenols (tri-, tetra-, and pentachiorophenols), or phenoxy acid herbicides (2,4-D, 2,4,5-T), or PCBs; in factories utilizing these chemicals for the production of other substances (hexachlorophene from 2,4,5-trichlorophenol) ; in factories manufacturing or re pairing transformers and capacitors or having heat exchange or heat hydraulic system s contain ing PCBs; and in the use processes of these chem icals under various occupational conditions such as spraying of herbicides, using chlorinated phe nols for a variety of applications (especially wood preservative), sawing, or otherwise processing treated wood, and using hexachlorophene in sani tary occupations. Environm ental H ealth PersDeti>UiS Table 6. Toxic effects of 2.3.7,8-tetrachlorodibenzo-pdioxins in humans. Effects References Dermatological Chloracne Porphyria cutanea tarda Hyperpigmentation and hirsutism Internal Liver damage* Elevated serum hepatic enzyme levels Disorders of fat metabolism Disorders of carbohydrate metabolism Cardiovascular disorders Urinary tract disorders Respiratory disorders Pancreatic disorders Neurological Polyneuropathies (peripheral neuritis) Lower extremity weakness Sensory impairments (sight, hearing, smell, taste) Psychiatric Neurasthenic or depressive syndromes (25, 28. 95-108) (27, iOi, 105,109) (27, 28,107) ' (27, 95, 98, 101,102, 104106, 110) (27, 28. 96,104-106, 110) (28, 104, 107) (23, 101, 102, 104. 105) (101, 102, 104, 105) (97, 101, 102) (95, 101. 102) (101, 102) (101, 102, 104,105) (23, 95, 99, 101, 102, 104, 105,108) (28, lt, 102, 107, 110) (28, 95, 99, 101, 102, 104, 105, 107) * Mild fibrosis, fatty changes, hemofuscin deposition and pa renchymal-cell degeneration were observed in a few cases. The burning of materials impregnated with commercial 2,3,4,6-tetrachlorophenates yielded 150-1000/tg of mixed PC DDs/g chloropnenate. Al though only found as a minor constituent, 2,3,7,8tetra-CDD has been quantified at levels exceeding 10 /xg/g chlorophenate (111). Pyrolysis of a technical grade PCB mixture yielded many PCDF isomers; the total yield could be as high as 3-25%. One of the main constituents is 2,3,7,8-tetra-CDF, the most toxic PCDF-isomer. Consequently, uncontrolled burning of PCBs can be an important environmental source of the haz ardous PCDFs, and operations such as welding or soldering electrical equipment containing PCBs, or using casting waxes in foundries, may possibly entail a significant exposure (112). A PCB used in a heat exchange system for two years contained approximately 1.25 ppm of 2,3,7,8-tetra-CDF and a total of 15 ppm of PCDFs (113). Apart from accidents such as the one which oc curred in Seveso in 1976, general environmental exposure may originate from herbicide spraying and waste disposal. An outbreak of PCDDs poisoning in humans. November 1980 horses, and other animals occurred in Missouri in 1971 (97, 11U) following the spraying of contami nated oil for dust control in horse arenas. Another possible source of exposure to PCDDs and PCDFs pollution are waste oils, and possibly other waste, when burned both in industrial and municipal incinerators. Under simulated environ mental conditions, the combustion of a standard 2,4,5-T formulation led to formation of small amounts of PCDDs and PCDFs (115). Buser and Bosshardt (11) quantified the total amount of PCDDs and PCDFs in fly ash from an industrial incinerator heating facility as 0.2 and 0.1 ppm, and in the fly ash from an industrial heating facil ity in Switzerland as 0.6 and 0.3 ppm. More than 30 individual PCDDs can be identified in the fly ash, but the known highly toxic PCDD isomers are only minor constituents (12). The number of PCDF isomers was larger; but, in this case, the known highly toxic isomers are major constitu ents (13). An additional potential source of human ex posure has been revealed: beef fat taken from cattle grazed on 2,4,5-T-treated rangeland con tained 2,3,7,8-tetra-CDD; of the 11/14 positive samples, the four with the highest levels had 12, 20, 24, and 70 ppt (10). In another study, 3 of 24 samples of beef fat contained 3-4 ppt 2,3,7,8tetra-CDD (116). Moreover, in a preliminary re port of an ongoing enlarged study of women liv ing in areas where 2,4,5-T is used on rangeland, 4 / 18 breast milk samples each contained approxi mately 1 ppt (10). Workers in wood processing industries are ex posed to wood dust containing preservatives as well as accompanying impurities and degradation products. Wood dust from a saw-mill in which a 2,3,4,6-tetrachlorophenol formulation was used as a fungicide was found to contain 1-10 ppm PCDFs and <0.5 ppm PCDDs (15). In 1968, more than 1200 persons in South-west Japan were intoxicated by consuming a com mercial rice oil contam inated with 1000 ppm PCBs. Nagayama et al. (117) analyzed the rice oil (Yusho oil) and found 5 ppm PCDFs, the major constituents of which were tetra- and penta- CDFs. Buser et al. (113) recently showed that 2,3,7,8-tetra-CDF was the main PCDF in the Yusho oil (0.45 ppm). The high level of PCDFs was caused by leakage from heat exchangers con taining PCBs contaminated with PCDFs. Workers manufacturing 2,4,5-trichlorophenol (TCP) or 2.4,5-T during normal production opera tions, and/or following explosions taking place in these plants, may have been exposed to a variety of polychlorinated chemicals whose type and CH CO cn 16975 229 quantity depends on the particular chemical proc ing up to 30 m g/kg or more 2,3,7,8-tetra-CDD), esses in use and on the phase of the reaction in may be found in the literature (1,110,125-127).* which the accident took place. Apparently, for in stance, PCDFs are produced in the earlier stages when mainly tetrachlorobenzene is present and PCDDs are produced nearer the end of the reac tion when primarily trichlorophenol is extant. The Exposure Episodes Considered in Detail by the NIEHS/IARC ad hoc Working Group concentration of chlorophenols and chloroben zenes, for example, was probably higher in the 1963 episode in The Netherlands, where the acci dent took place at the beginning of the reaction, The text below is a condensed version of the discussions which took place during the two-day NIEHS/IARC ad hoc Working Group Meeting. then in the 1968 episode in the United Kingdom, or the 1976 accident in Italy, where the explosion Phenoxy Acids Exposure ^ took place at the end. Cohort studies on herbicide sprayers have been A thorough description of the reported indus trial accidents and other cases of intoxications ob conducted or are being planned in Scandinavian^countries. The more advanced of these concerns* _ served in exposed workers is given in the IARC Swedish railroad workers with exposure to a vari-T*"? Monograph (1). In this present report, only those ety of herbicides. These people exhibited a sign if-- r. episodes specifically discussed at length by the icantly increased tumor incidence (apparently^'' NIEHS/IARC ad hoc Working Group will be con dose-dependent) and tumor mortality (129). The^- sidered. (A sequential perspective of known acci excess of tumors was found particularly among dents is given in Table 7). workers w ith exposure to am itrole (amino- In 1949, the first reported cases of industrial triazole) , whereas those exposed to phenoxy acids poisoning due to the formation of 2,3,7,8-tetra- (2,4-D and 2,4,5-T) showed only a slightly in CDD in uncontrolled exotherm ic reactions oc creased excess of cancers. The study was small curred during the m anufacture o f 2,4,5-tri- sized, comprising 2978 person-years at observa chlorophenol at a 2,4,5-T-producing factory in Ni- tion in the total cohort and with 18 deaths versus tro, West Virginia; 288 persons were affected (99, 20.54 expected. The original conclusion from this 118). In November 1953, an accident occurred in study was that am itrole exposure may have Ludwigshafen, Federal Republic of Germany, caused an excess of tumors, whereas there was during the manufacture of TCP (101,102,119,120); probably no pertinent increase in tumor incidence 53 workers were affected by chloracne. associated with exposure to phenoxy, acids. The Five cases of chioracne were reported following study has been recently reanalysed using a case- an industrial accident in an Italian TCP-produc- control approach, and through stratification on ing factory (121). In 1963, an accident occurred at amitrole when considering the effect from phe the 2,4,5-T-producing factory in The Netherlands; noxy acids, and vice versa. The results show a p o s-' approximately 50 persons were affected by chlor sible and previously masked tumor-inducing e f acne (122, 123). In 1966, Dugois et al. (98) ob fect also from phenoxy acids. served 21 cases of chloracne after an accident in a Another retrospective cohort mortality study, French factory producing TCP in the Grenoble re conducted in Finland on workers of five com gion. In 1968, an accident occurred at the TCP- panies involved in spraying 2,4-D and 2,4,5-T on producing factory at Bolsover, Derbyshire, United Kingdom (103, 106). Within the next 7 brushwood, did not show any increase in mortal ity. During 1955-1971, in the younger group of months, 79 workers developed chloracne. In 1971, workers (under 45 years of age), however, four 2,3,7,8-tetra-CDD contaminated waste oil caused cancer deaths were observed versus less than two A an outbreak of poisoning in humans, horses, and expected (no statistically significant difference). l- --c other animals (97, 124). In July 1976, an accident A prospective follow-up study for the period 1972- at the TCP-producing factory in Meda, Italy (96) 1976 revealed fewer cancer-related deaths than resulted in the contamination of a large, densely expected in all age groups. Clinical and anamnes- populated area, including the towns of Seveso, Meda, Cesano Maderno, and Desio. Key information concerning the effects of hu man exposure to herbicides in Vietnam, especially to the so-called ``Agent Orange" (a 50:50 mixture " More than 2.000.000 gallons of Agent Orange remaining from military defoliant operations were destroyed by in cineration on Imard ship in the Pacific Ocean, 120 miles from Johnston Island. Temperatures not lower than I250C were of the n-butyl esters of 2,4-D and 2.1,5-T, contain used. The steel containers were melted ( /ti.V). Environmental Health Perspectives > 16978 tic investigations were also performed showing a , picture of acute complaints during and following the spraying operations: headache, transient diz ziness, fatigue, abdominal complaints, skin and mucous irritations, and a few cases of persistent papulae. Interestingly, some samples of 2,4,5-T used in Finland for spraying operations contained from 0.04 to 0.07 ppm 2,3,7,8-tetra-CDD. This may im ply that the 2,4,5-T produced before 1965 con tained lower levels of 2,3,7,8-tetra-CDD impur ities than has been observed subsequently from 2,4,5-T used elsewhere. However, the analytical methods used in the determ ination of 2,3,7,8tetra-CDD in the Finnish samples were anti quated in view of the rapid advancements made in analytical m ethodology and thus a con firmatory analysis of the samples using modern techniques was made by Rappe et al. (130). Five samples of 2,4,5-T ester dating from 1962 to 1967 were analysed for PCDDs and PCDFs; levels of 0.1-0.95 ppm 2,3,7,8-tetra-CDD and 0.1-0.15 ppm tetra-CDF were found. A second feasibility study was designed and conducted in Finland to determine whether one could obtain anamnestic, clinical, hematological, and im m unological inform ation on F innish railway and forestry workers who had been ex posed for several years to herbicides containing 2,3,7,8-tetra-CDD. The exposed group consisted of 30 men who were control-matched to persons of the same age coming from the same district with similar job backgrounds and living conditions. Of the tests made, including liver and immunofunction studies, no differences were observed be tween the exposed and control groups. Although the population study is too small to permit any general conclusions as to the potential adverse health effects from long-term exposure to phenoxy acids, the investigation shows that follow-up is possible on the health status of persons exposed for several years to 2,3,7,8-tetra-CDD-containing phenoxy acids, and then to compare the exposed group results to carefully matched controls. The study is in progress. Hexachlorophene Exposure An excess of malformations, some severe, has been reported among children whose mothers were employed as nurses in a hospital. The mothers were exposed to hexachlorophene soap during early pregnancy, and the hypothesis of a causal relation between such an exposure and the occurrence of the malformations has been ad- vanced (131); five severe and six slight malforma tions were observed in 65 children in the exposed group, whereas only one slight malform ation was observed in the 68 children of the unexposed group. This report has been followed by another study (to be published) of a similar group of chil dren of exposed mothers in comparison to chil dren of unexposed mothers. Again a high fre quency of malformations among the offspring of exposed mothers was reported (132). From these studies, however, it is not clear if exposure to other hazardous chemicals could be excluded. A retrospective-prospective study is being initiated among long-term workers of an United States' factory which used Seveso-produced 2,4.5-trichlorophenol in the manufacture of hexachlorophene. However, in the case of hexachlorophene, polychlorinated xanthenes have been also identi fied as contaminants at a higher level than 2,3,7,8tetra-CDD (133). Phenoxyacids and Chlorophenols Exposure in Forestry and in Wood Industry Workers At the Regional Hospital in Umea (Northern Sw eden), Hardell (134) observed that several pa tients suffering from mesenchymal tumors re ported occupational or other exposures to phen oxyacids. More specifically, 87 mesenchymal tumors were diagnosed during the years 1970 through 1976. Of these cases, 55 were men (more than expected) and 43 of these 55 men were known by profession: 19 were either forestry workers, farmers and forestry workers, or work ers in sawmills and papermills where exposure to chlorophenols is common. Based on the official sta tistics of Sweden, one can calculate approximatively the expected fraction of tumors within these trades, resulting in an expectancy of approxi mately 11 cases versus the 19 observed. The Mount Sinai School of Medicine in New York is currently planning a field survey on long term health effects on wood-preservative workers in Arkansas and Oklahoma in the United States of America. Exposure to 2,3,7,8-Tetra-CDD during Production of 2,4,5-T or Polychlorinated Phenols and Following Industrial Accidents The following cases, as well as others not con sidered at the meeting, have been described in 1ARC Monographs Volume 15 (1), and only some November 1980 169?^ _ -- _ i &? ft, Z-&: tes & iaK' 3 j 271538 of the previously available information will be All the 75 workers could be traced in a cohort , given here. The ongoing epidemiological studies on these cohorts are summarized in Table 7. As each individual cohort has a relatively small number of person-years, a study has been pro posed in which all the cohorts would be pooled and the mortality compared to that expected from the study 25 years later; mortality was compared both with the regional and national mortality and with a control group of workers from the same factory. In the exposed group, 17 deaths were observed (11 to 25 expected depending on the control popu lation); six from cancer (four or less expected), national statistics. five from cardiovascular diseases (as expected), The first reported cases of industrial poisoning two from suicides (0.2-0.6 expected), one from due to the formation of 2,3,7,8-tetra-CDD in un liver cirrhosis, one from a urogenital tract dis controlled exothermic reactions occurring during ease, and two from traffic accidents. the manufacture of TCP were seen in 1949 at a Of the six cancer deaths, three were from stom 2,4,5-T-producing factory in Nitro, West Virginia, ach cancer and occurred in the age group of 60-69, USA; 228 persons were affected. These individuals which is significantly more than expected. This were studied by Suskind and Ashe (135) and foi- effect was more pronounced when a minimum ob ^ lowed up for a period of four years. Symptoms in- servation period of 10 years was considered, and SJS eluded chloracne, nausea, vomiting, headaches, se- more so for stomach cancer after a 20-year obser "t* vere muscular aches and pain, fatigue, emotional vation period. (Use of a long observation period '' instability, and intolerance to cold. Laboratory permits a better estimation of the relation be findings showed raised total lipids and raised pro tween exposure and disease when long "latency" thrombin time. Among those affected were not periods are involved, as for cancers). only workmen, but also laboratory personnel, A similar accident occurred at the 2,4,5-T-pro- medical personnel, and even the Safety Director ducing factory in The Netherlands in 1963; 106 who visited the areas of exposure. Several wives men are likely to have been exposed to 2,3,7,8- who had never visited the plant also developed tetra-CDD (and possibly PCDFs) as they were in acne, usually at the same time as their employee the building where the accident occurred during hushands. the subsequent period, March-July 1963. These It is important to note that information on the workers may be divided into three groups: (A) toxicity as -well as on the stability (long per factory employees (exposed during all phases of sistence and slow degradability) of 2,3,7,8-tetra- the cleaning and reconstruction activities), 44 CDD was not available at the time the first re men; (B) clean-up crew (nonfactory personnel, ports of acute toxicity were observed, and no exposed during the months May-July), 18 men; measures were taken to decontaminate the facto and (C) plumbing, painting, and insulating per ries and control the residue levels of 2,3,7,8-tetra- sonnel (nonfactory workers, exposed during the CDD. In fact, the presence of 2,3,7,8-tetra-CDD or months May-July), 44 men. other PCDDs and PCDFs was not even suspected. During the explosion in Amsterdam, two oper Workers, therefore, were probably exposed for a ators were present in the building. With the ex considerable time to 2,3,7,8-tetra-CDD following ception of these men, who were probably exposed the first observations of acute toxic efFects. primarily by the inhalation route, all other work In November 1953, an accident occurred at a ers used safety masks and were probably exposed TCP factory in Ludwigshafen, Federal Republic by dermal contact. Chloracne was the most com of Germany; 75 workers were exposed to the reac mon and prominent lesion observed follow ing tion products during the accident and the sub 2,3,7,8-tetra-CDD exposure (26/44 examined in sequent cleaning work; most were affected by group A, 10/16 in group B, and 8/16 in the group chloracne, 42 severely: 21 of the 42 suffered con C). Liver function tests (thymol turbidity and sequent damage to internal organs or distur- serum glutamic pyruvic transaminase and serum r bances of the nervous system. The most relevant glutamic oxaloacetic transaminase) did not in features were polyneuritis, sensorial impair- dicate liver damage. A few men complained of fa ~ . ments, and liver damage. The son of one of the tigue. The latent period between exposure and workers developed chloracne following contact the appearance of chloracne, characterized by " with his father's work clothes. An additional case comedones, pustules, and cysts on the face and j of poisoning occurred 5 years later in a worker sometimes on other parts of the body, was ap j who was involved in repair work (welding one of proximately 4-6 weeks. Som etimes, erythematous j the auto-claves) at the contaminated site; sub- and edematous skin lesions, possibly due to phe j sequently this worker died with necrotic pan- nolic compounds, were noted one day after ex i creatitis. posure. No skin iesions (chloracne) were reported Environmental Health Perspectives 16978 -'liy f ^riy~ in family members of the employees. Of group A, 3/44 workers died, one of pancreas carcinoma in 1964, one of myocardial infarction at the age of 69, and one of a traffic accident. Of the 17/18 traced individuals in the B group, four have died (three from sudden death, probably of myocardial infarction, at ages, 41, 53, and 65, and one of illdefined pulmonary or cardiac cause at age 44). Only 32/44 of the C group were traced, and one of them died of sudden death, probably myocardial infarction, at age 50. Jirsek et al. (104, 105, 109) studied 55 subjects from a cohort of 78 workers from a factory in Czechoslovakia producing 2,4,5-T and pentachlorophenol, who were affected by chloracne. The workers were probably exposed during the years 1965-1968 to unknown levels of 2,3,7,8-tetraCDD. A significant symptom was the disturbance in porphyrins metabolism with signs of porphyria cutanea tarda. Many workers also suffered severe hepatic and neurological damage and had raised blood levels of cholesterol and total lipids. In the first years of follow-up, five deaths were observed, two from bronchogenic carcinoma at age 47 and 59 (only 0.12 lung cancer deaths were expected from national mortality statistics), one from atypical atherosclerosis at age 57, and one from the acute occupational intoxication. One further death, probably from iiver cirrhosis, has recently been observed and 50 workers are still being fol lowed. Many workers continue to show lipemia and hypercholesterolemia and have developed prediabetic changes and hypertension. The work ers lost to follow-up are mostly foreigners who re turned to their country of origin. In July 1976, an accident in a TCP-producing factory in M eda, Italy resulted in the con tamination of the towns of Seveso, Meda, Cesano Maderno, Desio, Nova Milanese, and possibly oth ers of a large, densely populated area called the Brianza di Seveso with a total population of about 220,000 inhabitants. A retrospective health survey conducted on the workers of the CMESA factory revealed that two workers among those directly involved in the production of 2 ,1,5-trichlorophenol suffered from skin lesions previous to July 1976. These facts may be indicative of a previous 2,3,7,8-tetra-CDD exposure. A large and intensive follow-up program is in progress in the Seveso area; data were presented about the first dermatological, neurological, clini cal, and laboratory findings, as well as about fetal damage. Dermatological examinations, including' the. screening of 32,000 children, resulted in the finding of hundreds of children with skin lesions, 135 of which were eventually identified as chlor- November 1980 acne; 59 cases were from the more contaminated area (Zone A). However, precise description of diagnostic criteria and accurate anamnestic infor mation, including, among others, data on places of residence, were not included. This information is needed before evaluating the m eaning of the chloracne incidence data by territorial areas and efforts should be made obtain it. Chloracne cases were not systematically searched for in adults. Neurolog'cal examinations showed both signs of subclinical neurological damage and cases of clini cally detectable polyneuropathy in adults (34/338 persons from zone A and 8/185 from the sur rounding areas). In about 30% of 1654 adults from both A zone and nearby zones, hepatomegaly was reported to be present on clinical investigation. No informa tion, however, is given on the criteria by which the hepatomegaly was evaluated. The same per centage of abnormalities was observed in one or more liver tests (mainly glutamyl transferase and serum glutamic pyruvic transaminase and serum glutamic oxaloacetic transaminase). Ex tensive monitoring of various hematological pa rameters from 25,000 persons is now in progress and the data are expected to become available during 1978. Results of this investigation should allow a better understanding as to whether or not these alterations are caused by exposure to 2,3,7,8-tetra-CDD and PCDDs. So far, immunological investigations, cyto genetic research, and embryomorphology analy ses on cases of therapeutical abortions have not given abnormal results. However, the study of the frequency of congenital malformations and spon taneous abortions seems to be very difficult to ac complish. The importance of a system atic study on this subject has been stressed by the Working Group, because the questions on the teratogeni city of 2,3,7,8-tetra-CDD in humans cannot be solved by any other study. A preliminary mortality study has been pos sible in 2 of the 11 towns of the Seveso area. The 1975-1977 mortality rates from liver cirrhosis and leukemia in these two limited zones of the Seveso area were compared to that of a nearby area (province of Varese). Within an overall mortality which did not appear different, an increase of deaths from liver cirrhosis and from leukemia was noted. The validity and significance of these observations should be carefully evaluated. Recommendations A chemical analytical program should he en couraged to identify and standardize analytical 233 16979 u g i: i !-iV-.* M/.vC ' I* WIv Table 7. Epidemiological studies on 2,3,7,8-tetrachiorodibenzo-p-dioxin; human exposure episodes caused by accidental or occupational exposure occurring in factories producing2,1,5-trichloroplienol and/or 2,-1,5-lrichfornphcnoxyucetic acid. Town and country Number Year of of exposed exposure persons Clinical follow-up and cohort studies Observations to date Proposed actions Comments and recommendations of theNIEHS/IARC Working Group Accidental exposures Nitro, West Virginia, (U.S.A.) 19-19 I.udwigshafen/Rhein, Federal Republic of Germany 1953 Amsterdam, The Netherlands 1963 n 3< 3 3it 3 *3 Uolsover, Derby shire, United Kingdom 1963 228 Only 36 individuals were No significant long-term Mortality cohort followed, for a period of observations arc yet avail study being planned I years able (some fulfowed-up individuals had symptoms of severe intercostal neuritis 75 A mortality cohort study has 6 Cancer deaths were ob Follow-up to be conducted 24 yr after the served: 3 of stomach cancer continued accident; all exposed workers in the age group 60-69 were traced for a total of (significantly higher than 1525 person-years of ob expected), 2 of oat-cell servation carcinoma of the lung, and 1 of colonic adenocarcinoma 106 Preliminary observations Of 8 deaths, 5 or 6 were from Full report planned on mortality are available; cardiovascular diseases, 5 for 1978 93 exposed workers have probably from myocardial been traced up to 1977 infarctions; the myocardial infarction death rate seems higher in the most heavily exposed workers all'ected by cbloracrie. One worker, who did not develop chloracne, died from puncreatic car cinoma 14 months after the accident; however, he com plained of abdominal pain prior to the accident 90 Of the workers belonging One worker is known to Epidemiological cohort to the original cohort, 50% have ilied from coronary study to be planned are still employed and thrombosis when the results of routinely undergo clinical the present clinical and laboratory investiga follow-up investiga tions tion become available Efforts should be made to trace the individuals who were exposed, possibly through the employment compensation files. The results of the continuing follow-up study should periodically be made avail able. Efforts should be made to trace all the wurkers who were exposed. Efforts should be made to trace all the workers who were exposed. H4 ~ 05 =r co? 00 2 Oa tns>. Q i S U Z I f la g V. November 19f<0 Mcda, Urianza ili Sovcso,Italy Occupational exposure Czechoslovakia 1376 19651969 A clinical follow-up of the inhabitants from the more contaminated areas is being carried out. At the time of the accident, living in Zone A was a population of 760 people, with 200 of those being between 0 -1-1 years of age. Of these 730 persons, 623 (125 between 0-14 years of age) were followed-up. Zone II con tained a population of 4732 inhabitants with 1203 between the ages 0-14 years. An accurate count of those followed in Zone B is nut available, but 943 young sters between 0-14 years of age are included in the follow-up Initial clinical observations showed a high incidence of 2,3,7,8-tetra-CI)IJdependenl skin lesions among children living in the more contaminated area. Also, a number of persons residing in the zone sur rounding the more con taminated areas hud skin lesions, hut with poorly de fined, clinical features; these lesions may be the result of 2,3,7,8-telra-CDD ex posure. Moreover, both clinical and laboratory find ing's suggest an increased incidence of hepatic suifercnce among adults living in the highly contaminated areas. A preliminary mortal ity study suggests that al though the overall rates from 2 Seveso`lowns are not different from a nearby area, an increase of deaths from liver cirrhosis and leukemia was noted Among other ongoing investigations, a long-term morbidity study has been Initiated 80 A follow-up has been made regularly on 55 workers of the original cohort. Thu workers lost to follow-up are mainly foreigners who left the country Five patients died during the first 5 year-follow-up period: 2 died from bron chogenic carcinoma and 1 from a rapidly developing atypical atherosclerosis. One further death, probably from liver cirrhosis, has recently occurred. Many of the workers are now suffer ing from hypertension and show signs of hyperlipi demia and hypercholeste rolemia us well as predia- lictic symptoms and signs Follow-up to he continucd.A 10-year report will be prepared during 1978 Possible teratugenic and other adverse reproductive and developmental effects from 2,3,7,8-tetra-CDI) exposure shuuld be investigated. A mortality register and pop ulation tiles, suitable fur adequate descriptions of morliidity data, should be established. Further, the cancer registry that already covers a nearby province, should be extended to in clude the Seveso urea. The results of the continuing follow-up study should periodically be made available. ` No reliable information was availatde to the Working Group about the actual number of exposed persons; the entire area has a population of approximately 200,000 people. 3J d 9 8 X 235 ifsiLz I MOlf methods used, to catalogue products contami nated with PCDDs and PCDFs, and to establish a register of known PCDD and PCDF standard samples. The Working Group unanimously recommended that a system be developed for an international exchange of information and research coordina tion on the health effects of chlorinated dibenzo-pdioxins/chlorinated dibenzofurans. Further, and in particular, the following three areas were in dicated as deserving special attention: 1. Development of sensitive and reliable mea surements of body burden; improved, more sensi tive, and less expensive analytical technology should be generated. Standardized sampling (air, water, soil, tissues and body fluids, environmen tal), preparation, clean-up, and analysis should be promoted; 2. Development of common protocols for clini cal examinations (including reproductive experi ence) and, in particular, design of a protocol for basic core information; 3. Development of an international registry of exposed persons to serve as a basis for long-term follow-up: this was considered especially impor tant because the relatively small size of popu lations involved in individual exposure episodes are an obstacle to risk assessm ent and thus pool ing of data is almost a necessity. The Working Group recommended that IARC explore the technical and financial feasibility, pos sibly in cooperation with other national and/or in ternational organizations, of setting-up such a permanent mechanism which could include as a minimum starting program: (a) a periodical, per haps biennial, meeting to up-date the progress of ongoing studies, and to identify needed develop ments; (b) an exchange of relevant information accruing during the interval between meetings; and (c) a register of chloracne cases, containing simple, essential information in a standardized form. This PCDDs/PCDFs exposure-related sign may help to better define an exposed cohort popu lation suitable for long-term follow-up. This report represents the views ami opinions of the U.S. NIEHS/fARC (National Institute of Environmental Health Scienres/internationnl Agency for Research on Cancer mi hitr Working Group which met January 10-11, 1973 in I.von France to review the history of human exposure to these chemicals, to collate current information, anti to plan anil fore cast neetleil new ilirections. The meeting was funded jointly by NIEH.S and IARC. REFERENCES l. International Agency for Reserach on Cancer. IARC Monographs on the Evaluation of the Careinoifenic Risk of Chemicals to Man Vol la. Some Fumigants. the Herbi cides 2.I-D and 2,4.5-T. Chlorinated Dilienzoilioxins and 23H Miscellaneous Industrial Chemicals, IARC, Lyon, August 1977. 2. Gosselin. R. E., Hodge, H. C.. Smith, R. P., and Gleason, M. N. Clinical Toxicology of Commercial Products, -4th ed,, Williams & Wilkins Co., Baltimore, 1976. 3. 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Ge netic expression of aryl hydrocarbon hydroxylase activ ity in the mouse. Arch. Biochem. Biophys. 166: 559 (1975) . 80. Kouri, R. E. Relationship between levels of aryl hydro carbon hydroxylase activity and susceptibility to 3methvlcholanthrene and benzo(a)pyrene induced cancers in inbred strains of mice. In: Polynuclear Aromatic Hy drocarbons: Chemistry, Metabolism and Carcinogenesis. Vol. 1, R. I. Freudenthai. and P. W. Jones, Raven Press, New York, 1976, pp. 139-151. 81. Poland, A., and Glover, E. Comparison of 2,3,7,3-tetrachlorodihenzo-p-dioxin, a potent inducer of aryl hydro carbon hvdroxvlase, with 3-methvlcholanthrene. Mol. Pharmaco'l. 10: 349 (1974). 32. Poland. A., Glover. E.. Kende. A. S., DeCamp, M.. and Granasmenico, G. M. 3,4,3'4'-Tetrachloro azoxybenzene and axobenzone: potent inducers of aryl hydrocarbon hy droxylase. Science 194: 627 (1976). S3. Du Punt inc. Personal Communication to A. Poland. 1973. 84. Poland, A., and Glover. E. Chlorinated biphenyl induction of aryl hydrocarbon hydroxylase activity: a study of the structure-activity relationship. Mol. Pharmacol. 13: 924 (1977). 35. Wassom, J. S.. Huff, J. E., and Loprieno, N. A review of the genetic toxicology of chlorinated dihenzo-p-dioxins. Mutat. Res. 47: 141 (1977/1978). 86. Hussain, S,, Ehrenberg, L., Ldfroth. G., and Gejvall. T. Mutagenic effects of TCDD on bacterial systems. Ambio 1: 32 (1972). 87. Seiler. J. P. A survey on the mutagenicity of various pes ticides. Experientia 29: 622 (1973). 88. McCann, J. Unpublished data (1978). 89. Jackson, W. T. Regulation of mitosis. III. Cytological ef fects of 2,4,5-trichloniphenoxyacetic acid and of dioxin contaminants in 2,4,5-T formulations. J. Cell. Sci. 10: 15 (1972). 90. Green. S., and Moreland. F. S. Cytogenetic evaluation of several dioxins in the rat (abstr. 99). Toxicol. Appl. Phar macol.. 33: 161 (1975). 91. Green. S.. Moreland, F.. and Sheu. C. Cytogenetic effect of 2,3,7,3-tetrachlorodihenzo-p-dioxin on rat bone mar row cells. FDA Bv-Lines, No. 6: 292 (1977). 92. Van Miller. J. P., Lalich. J. J., and Allen. J. R. Increased incidence of neoplasms in rats exposed to low levels of 2.3.7.5-lei.rachlorodihenzo-p-dioxin. Chemosphere 6: 537 (1977) Environmental Health Perspectives SOWj 271544 93. Kociba. R. J., Keyes, D. G., Beyer, J. E., Carreen. R. M., Wade. C. E.. Dittenber. D. A.. Kalnins, R. P-, Franson, L. E., Park, C. N',, Barnard, 5. D, Hummel, R. A., and Humiston, C. G. Results of a two-year chronic toxicity and ongocenioity study of 2,3,7,8-tetrachiorodibenzo-p-dioxin in rats. Toxicol. Appl. Pharmacol. <16: 279 (1978). 94. Ghcss. VI. J., Bartsch. H., Huif, J. E., and Tomatis, L., (ARC Information Bulletin on the Survey of Chemicals Being Tested for Carcinogenicity, No. 7, Lyon, January 1978. 95. Bauer, H,, Schulz, K. H., and Spiegeiberg, U. Berufliche Vergiftungen bei der Herstellung von Chlorphenol-Verbindungen. Arch. Gewerbepathol. Gewerbehyg., 18, 538555 (1961). 96. Bert, G,, Manacorda, P. M,, and Terracinin, B. I controlli sanitari: la sanit incontrollata. Sapere, 796: (1976). 97. Carter, C. D,, Kimbrough, R. D., Liddle, J. A., Cline, R. E., Zack, M. M., Jr,, Barthel. W. F,, Koehler, R. E,, and Phil lips, P. E. Tetrachlorodibenzodioxin: an accidental poi soning episode in horse arenas. Science 188: 738 (1975). 98. Dugois; P., Amblard, P,, Aimard, M., and Deshors, G. Acn chlorique collective et accidentelle d'un type nouveau. Bull. Soc. Franc. Derm. Syph. 75: 260 (1968) 99. Firestone, D. The 2,3,7,8-tetrachlorodibenzo-para-dioxin problem: a review. In: Chlorinated Phenoxy Acids and their Dioxins: Mode of Action, Health Risks and Environ mental Effects. Ecol. Bull. pp. 39-52. Vol. 27, C. Ramel, Ed., Stockholm, 1978. 100. Gianotti, F. Chloracne au ttrachloro-2,3.7,8-dibenzo-pdioxine chez les enfants. Ann. Dermatol. Venereol. 104: 325(1977). 101. Goldmann, P. J. Schwerste akute Chlorakne durch Trichlorphenol-Zersetzungsprodukte. Arbeitsm ed. Sozialmed. Arbeitshyg. 7: 12 (1972) . 102. Goldmann, P. J. Schwerste akute Chloracne, eine Masse nintoxikation durch 2,3,6,7-TetrachIoridbenzodioxin. Hautarzt 24: 149 (1973). 103. Jensen, N. E., and Walker, A. E. Chloracne: three cases. Proc. Roy. Soc. Med. 65:.687 (1972). 104. Jirasek, L-, Kalensky, J.. and Kubeck, K. Acne chlorina and porphyria cutanea tarda during the manufacture of herbicides. Cs. Dermatol., 48: 306 (1973). 105. Jirsek, L,, Kalensky, J., Kuheck, K., Pazderov, J., and Luks, E. Acne Chlurina, porphyria cutanea tarda and other manifestations or general intoxication during the manufacture of herbicides. II. Cs. Dermatol. 49: 145 (1974) . 106. May, G. Chloracne from the accident production of tet rachlorodibenzodioxin. Brit. J. Ind. Med. 30: 276 (1973). 107. Oliver, R. M. Toxic effects of 2,3,7,8-tetrachlorodibenzo 1,4-dioxin in laboratory workers. Brit. J. Ind. Med. 32: 49 (1975) . 108. Suskind, R. R. The chemistry of the human sehaceous gland. I. Histochemical observations. J. Invest. Dermatol. 17: 37 (1951). 109. Jirasek, L., Kalensky. J., Kubeck, K., Pazderov, J., and Luks, E. Chlorakne, p o r p h y r i a c u t a n e a t a r d a unde an dere Intoxikationen durch Herhizid. Hautarzt 27: 328 (1976) . 110. Ton That, T. Pathologie humain;: et animale de la diox- ine. Rev. Med. (Paris): 18: 653 (1977). 111. Rappe, C., Marklund, 3.. Bser, H. R.. and Bosshardt. H.- P. Formation of polychlorinated dihenzo-p-dioxina (PCDDs) and dibenzofurans (PCDFs) hv hunting or heating chlorophenates. Chcmosphere 3: 269 (1978). 112. Buser. 11. R,, Bosshar.it. H.-P, and Kappe. C. Formation of polychlorinated dibenzofurans (PCDFs) from the pyrolysis of PCBs. Chcmosphere 7: 109 (1973). November 19S0 113. Buser, H. R., Rappe, C., and Cara, A. Polychlorinated di benzofurans (PCDFs! found in Yusho oil and in used Japanese PC8. Chemosphere 7: 439 (1978). 114. Beale, M. G., Shearer, W. T., Karl, M. M., and Robson. A. M. Long-term effects of dioxin exposure. Lancet i: 748 (1977). 115. Ahling, B., Lindskog, A., Jansson, 8., and Sundstrom, G. Formation of polychlorinated dibenzop-dioxins and di benzofurans during combustion of a 2,4,5-T formulation. Chemosphere 8: 461, (1977). 116. Kocher. C. W., Mahle, N. H-, Hummel, R. A., Shadoff, L. A., and Getzendaner, M. E. A search for the presence of 2,3,7,8 tetrachlorodibenzo-p-dioxin in beef fat. Bull. Envi ron. Contam. Toxicol. 19: 229 (1978). 117. Nagayama, J., Kuratsune, M., and Masuda, Y. Determi nation of chlorinated dibenzofurans in Kanechlors and "Yusho oil". Bull. Environ. Contam. Toxicol. 15:9 (1976). 118. Suskind. R. R. Personal communication, 1978. 119. Hofmann. H. T. Neuere Erfahrungen mit hoch-toxischen Chlorkohlen-wasserstorfen. Arch. Exptl Pathol. Pharmakol., 232: 223 <1957). 120. Thiess. A. M,, and Goldmann, P. Ober das TrichlorphenolDioxin-Unfall-geschehen in der BASF AG vom. 13. No vember 1953. In: Vortrag auf dem IV. Medichem-Kongress, Haifa, 1976, in press. 121. Hofmann, M. F., and Meneghini, C. L. A proposito delle follicolosi da idrocarburi clorosostituiti (acne ciorica). G. Ital. Dermatol. 103: 427 (1962). 122. Dalderup, L. M. Safety measures for taking down build ings contaminated with toxic material. II. T. Soc. Geneeskd. 52: 616 (1974). 123. Hay, A. Toxic cloud over Seveso (Editorial). Nature 262: 636 (1976). 124. Kimbrough, R. D,, Carter, C. D., Liddle. J. A.. Cline. R. E., and Phillips. P. E. Epdemiology and pathology of a tet rachlorodibenzodioxin poisoning episode. Arch. Environ. Health 32: 77 (1977). 125. Committee on the Effects of Herbicides in Vietnam. The Effects of Herbicides in South Vietnam, Part A. Sum mary and Conclusions, National Academy of Sciences, Washington, D.C. 1974. 126. Westing, A. H. Ecological considerations regarding massive environmental contamination with 2,3,7.8tetrachlorodibenzo-parn-dioxin. In: Chlorinated Phenoxy Acids and their Dioxins: Mode of Action, Health Risks and Environmental Effects. Ecol. Bull. Vol. 27, Stock holm, 1978, pp. 285-294. 127. Meselson, M. S., Westing, A. H., and Constable, J. D. Background material relevant to presentations at the 1970 Annual Meeting of the AAAS. American Associa tion for the Advancement of Science, Herbicide Assess ment Commission, 92nd Congress. 2nd Session, US Con gressional Record 118: S3227-S3233 128. Walsh. J. Odvssev of Agent Orange ends in the Pacific. Science 197: 966 (1977). 129. Axels.m, 0., and Sundell, L. Herbicide exposure, mortal ity and tumor incidence. An epidemiological investiga tion on Swedish railroad workers. Work-Environ. Health 11:21 (1974). 130. Rappe, C., Buser. II. R.. and Bosshardt. H.-P. Identifica tion and quantification of polychlorinated dioenzo-p-dioxins (PCDDs) and dibenzofurans. (PCDFs) in 2.4.5-Tester formulations and herbicide orange. Chemosphere 7: 431 (1978). 131. Hailing, H. M isstankt sam hand mellan hexaklorofenexposition ix-h mts.shildningsbord (Suspected link be tween exposure to hexachlorophene and birth of mal formed infants). Lakartidningen 74: .5-42 (1977). . 1 6 9 8 5 2TJ 132. Hailing H. Personal communication to 0. Axelson (1977). 133. Baughman, R. \V. Tetrachlorodibenzo-p-dioxins in the en vironment. High resolution mass spectrometry at the picgoram level. Thesis Harvard University, Cambridge, Mass. 1974. 134. Hardell, L. Maligna mesekymala tumorer och exposition for fencxisyror--en Klinisk observation (Malignant mesenchymal tumors and exposure to phenoxy acids--a clinical observation). Lkartidningen 74: 2753 (1977), 135. Buskind, R. R., and Ashe, W. F. Unpublished reports and personal communication (1979). DOW 1 2 7 1 5 4 6 * ? 3 1 1 1 240 i I I II i I1 I Environmental Health Perspectives 163B8 *:f.;r=rc~NFaartmioenrasl Union 24 M r*J RESOLUTION on The Consolidated Hearings on Cancellation ot: the E.P.A. Registration of 2,4,5-T and Silvex Herbicides. FIFRA Docket #415 et al To: Douglas Castle, Director Environmental Protection Agency flQYJ I 0 8 3 9 2 8 WHEREAS, The National Farmers Union, a national farm organization which represents over two million stockmen and farmers throughout the United States, together with one thousand three hundred local cooperatives who serve them-, and WHEREAS, the action by the Environmental Protection Agency has been started to cancel the registration of the herbicides 2,4,5-T and Silvex because eight women in Alsea, Oregon reported a coincidence of abortion and spraying the forest. Activist groups who are opposed to spraying pesticides in the U.S. forests have forced EPA to hold this public hearing, and WHEREAS, reputable physicians and scientists haw? now refuted the Alsea conclusions and have reposted on the long time study of mother's mil!: r m n the area; f".n milk does not contain TCDD, the dio:;-.r of 2, ,5-' ' herbicide, and esoeso^M OO 2-National Farmers Union Resolution FIFRA Docket #415 et al WHEREAS, currently, EPA registers the labelled 2 , 4 , 5 - ' : ' a nd Silvex uses as safe and eff icacious. Cri this basis, the herbicides and their use are highly beneficial to the stockmen, ranchers, foresters, rights-of-way users, rice growers and others, and WHEREAS, further benefits include the future of the timber industry, which depends on vegetation management, and a reduction in the losses of livestock to poison weeds. As much as 5% of some herds die a violent death, and as much as 8 `i of some herds have early abortions and deformed fetus ' caused by eating poison weeds. The poison weeds have been kept under control by using 2,4,5-T and Silvex. Their use is not toxic to the livestock or wild animals, and THEREFORE, BE IT RESOLVED, that the National Farmers Union join the ocher national farm organizations in requesting the U.S. Environmental Protection Agency to step pursuit of its hearings with intent to cancel the register?'.] uses of 2,4,5-T and Silvex, for the management of vegetation in forests, range forage improvement, rights-of-way, poison weed control, ricr. production and other prudent uses. 16988 3-National Farmers Union Resolution FIRFA Docket #415 et al This request is based on findings from data available from universities, research institution:;, industry, and the fact that there is no documented report of damage to applicators, the users of 2,4,5-T, throughtout the area. ** ********** DOW 1 0 8 3 9 3 0 me ^ 2423 ! 2421 A Mortality Analysis of Employees Engaged in the Manufacture of 2,4,5-Trichlorophenoxyacetic Acid M. C. Ott, MS.; B. B. Holder, M.D.; and R. D. Olson, 8.S. e r+ ~ lr - zz. o O' Jr* v*l CD *Vl C* O cn There have been fewpublished reports regardingsurveil lance of individuals occupationally exposed to 2,4,5-trichlorophenoxyacetic acid (2.4S-T). The present study ex amined the mortality experience of 204 persons exposed to 2,4,5-T during its manufacture from 1950 to 1971. Length of employment in job assignments within the 2,4,5-T pro cess area ranged from less than one year to a maximum of approximately ten years. Efforts to minimize 2J,7,8-tetrachlorodibenzo-p-dioxin (TCDD) contamination of the product resulted in nondetectable concentrations using a method of detection developed in 1966 that was sensitive to 1 part per million. Within the scope of this mortality survey, no adverse effects were observed with respect to occupational exposure to 2,4,5-T or its feedstock, 2,4,5-tri- chlorophenol. osop1aoeafmp7fiinnoo'trb39rnmblcuogeall7setnOlldy4moaohpvr2e1toke8yinei9lnww,rocaore.evmlulPy--eyfodseeasuuoAsemoalfydcypplldeelsllsliaspoidtfxtmmohtsenoollewpueot,(temdpfxroisoud2y-tlcseus,isdseio1ee4n7r,et3dydeypestu-3ed,eDes.tsd(avtwies1ihou)eieAnliietc*dsan8ecnmomplsrsecht%iriiihrtbpaedonnho2peo)elnpecna,eosfuva4usoeuotmuyibr,dsgutffr52eamlhatiateiorho-,heestseo4cmTmnhflsthedo,tpnce5.ueetatgmhoeoor-orldrTiTeaiirpitnyvconxpothsvldeabhjidaghaufeuecitrleyneyvlndhv,itptbdrrsiagetyftdBiialetiennarnehuA2otlryevseewddnaama,fineni4ninuabtlnawss-tgttseiTogdothc.mtawirhcghsdioogNscfbhepaieaornsshoosesalogteuefdolifsoorlortvntueereturshurtneaadaechxveotrnrsacnvpitpsleespd7edenttoluiheeanoodiyoerrfnlednnreti.fvif"nnew5inoceasga1ddoeatitywt*ie9cohhntoixsnhn6mnaooeaarIyinegn4eysasrfrt-l) I. Nj t u Y.CO mo 10A r0bbcccXt2M2acg2tmphiwr.aa,lii.e.b-V0eoo4e4g4eiedusrolc5I.a,aaI.e.cn5ti5sI5he-noskess/ai?ytpi--Gnvisensid-xwTgnneara1oaagieanearai9yrygmtiontlinhtrrst7aacTeTnihe(oic(af6ntTctnspeeKeisfiiteooanCotpieetdMcuo2d.nnfeoDardyidtdc.et-ruh4BtdftmiyDiaybinuhabnre,.doekiei)amg5etinacli,ilhtiyrxtnbt-lTlhiwoiiostdkcwdeooytyhrobrtwgireeiitginuanensceef-arenroa.KsdaehtaItsto(nsnitlh2yllitoopma4uso.inhf,)ecnvpos.l4ptirTeyneaupoCm,ustashb5sposeucnpnronetr-)etocfasmuhtTiidnieodinritmadflee,2scotgefiusdtn,mdeesarwo4tw2tsaotesnalhoh,ri,)haa5yxcaat3oalpf(ralsii1-yedti*,ncradrnThn7das2iohctasw..pd.hCii,bc1dood8o4guaaeeP3oucnA-n,pnfsbd5eMttorfcdsaoeinnt-lencheniFuTsptombsvonreteecdeaehtiaafmoaoiwatderecce1cietuiunriienman9dhbscddldspeis7dliyeepluoogffdy(6ritue,ero2nrenrn,noIioddcnbsb.^snss.iel4cf3edneiMuiuctgieto,o68rsc0eii5r^ltavdbtasin00eass-odlmenteesiTse,^neflyppdsoatnei)nogtsdhd<ap.pntziufff'aenfiyoooommodngiirAngrnnarrrfe,-a artti- odT2ppUpa2ttTya..haepfCC4c4lSpeTmtido..DDta.d55enyhuhwiDDi--roelfeeotfshoxebrdpiTtlyrittyurect.rio1eeceodovhiJnhnesinfApseemoceldlt2pospsrheanuab0ermnsmtrsolii4ccnecesstopiiiroevfsntdipinhitnuinamciheaexoded.lewt'ppucwnyitmooTlhaucwoooenyouhxtly!roaeoxgseinkec(adtfreiTtoeieekihcmostCrfnsyaushnsiPeewntree,t)nrbiehsn,naietatmveheseghhlnntiteifrhsaheatdotnohitgpadrsshnwceeersueaoombfpudimrrxtcetmtolvrhheaaeeieeoomnenpnmmsnryrfatestttseiharc-nstnwwteehsneohulyaaicedetttmleasmttosyruilsreoocnpctdaeoeionocdaenipnxsaafrfrdgprruecsrtooefi2eluufsfoiitasvnrem,rsrhn4oipivmcdsrede,.ameotei5neunrotwynd-cedgrTmr.d1eeort.siaNi0inroanoook-lorgli2a^rf,f.o5f' odbdHepoeisgevwTtaerhonanlerotyepicnidneoodfmMMcPmoawranoeyrhctcrieicnh1csiu9haso71l 1au9pe.n5srm0dloyI,ndpInulwuo1dcniy9tutehit6osidl7tnr,tihiaotdaelfifwH2fsoea,yer4rsigcge.5oiienn-npTntadeelirnpmoMpeptarerhoesnaecoreseancnustnoitrsoleemynlmbpeseawahninnnautgdysst From the M e d ica l Department. D o w C hem ical U S A.. Midland. M l 44640. which has continued in production. Personnel from the Journal of Occupational Medicine/Vol. 22, No. 1/January 1980 16999' 0W 3 jjMw2mtswdsspslsitswlcsprotrui2cieImsDebl2bmuirneonmooanenh^.aaoeyoaauropeeyiEax-e.e4mnghgvingiwpo4dammssmoocdAmtcpdlmnsrcTeait.dTce/ii!iegM1rnst5.wehihiccrntpiomotoeisiednara5hvtppleuhees9eenug-sdateyaheonslninemedwuieu-llpoBremtotod7Jddeeemrretlehsecdsif.anshyrroifa0ioe23yppn.ssbTufSedlboehyTcleingoidyyfErs,cmrrarf2rndsnus1asodc!y4Duclp,tw.oeeeiwdolreoto-.uatsu^wafyilpaow.ter4pesn4dTfiplasr1draurte5rscrtvcdioaTlcasolmenoo,snfepipgtt-na9adcCnuirt-ormwh5ecitoinciatnrerwhpiTmptr/etne6etaorrctndchwn-etnssDaleildhiebh,ahegToiyo9sgaaecaceewpfTsanngvotacpbldlDistets.nasanoii,oltfrrslerdcCemfuee2sfotunusiailusoteeohinwsraatrtthts2rmsd,cPhilddstubhh,ctghopwittw4sddmliriopt1cnneta,mayeaphbshy.ereebeyelipi,4etiaiow.etnaeeoysft5lhgcuheltoslsoidseitahff2rt^lehswlmn,gerhcn-ypesbhtoairialesmhoCrret-e.ednTeoeisTodtvt,tcrrhi4msuteiltylrduiqfreeniootaneaghanrcdetCwrioeomoeo,eohbswoudsoiufnur5-snuethaenulop2cs,rrmopPnrmottwtsispi-enaoatiohngoc,lfrnhttrxgunprTeerettipa4mteoessnpolewntasloehhnegehyouiltrswia.ndqie,tbommoturrnrttoopgtieent5ttaeihahfraylpigriedutpnrhreayrrfyaafacncuoe-aetcnrayettinrvewitohreirTgrnrneeacsaoheacldonenrnoofreeeatceeuaptnhtsdmaoiiirtc5eeuaurgndgepdaotcwshyyftmtulufth.cstaitiid0thsnaceesrbddcechuoosnehieruo2ommeo2owmsooititpoadce-re.eneucnsnza-eitbepmifb,ucbnreacpan2hetsldhdf4etalimmsArektydepuobiudywfucwotvereooare-abesdrnhzsrlonrsttinDiigtexTeatoraiohcTododnvotochjieiaoeubstetaonlsnureyorre.wmaiCneecditc.eflidaddaffydaeatasenibgdtopwtanretfjrn,dTmoahTDigC.dano.yeslktedetyrfcpcs2ittaCg<resaehhecaf.mddlohnbDribonTie,tsTrto,nswtaprleoPuleon4oueiaspTglyhnnsavef2hhotpfub.g0eaase.cd.ccfeiisrTalsfihaeec,st5eeop.ciiore,iphrnrlc4erioens1rneerTWeaTvgesa-rleeondpererabt,ssamTmirogp2eadnsiCh5i.eareonrhacli2usnamfnvettiAslp.ataseapsiwi-etcestayPt4chifase,colgtccdrruTohnyewri4ctr)eogopxiwa'enf,ahraiiaml,sbnraieauiodrce,.5ocnp/wprnatctocsgyi5tuiattasmgatssceiethtnc-Ceioemtirtao,orghradheo-atsfsTtntopoiosihonowrstapToendJtnnfneonesmo.nsooaapiuczdpa,ndt,rfrottdhsccnittismpseTotashtpthlrilizacasueuoatnteotfnheuuitaottlotesh:epernhheioheherhenaidornlcasnnoemnsoegnoxonsldei6deeesnrdeedeildaylsy:ttftlr.-ftrtt.a2l torTable 1. -- Tme-Wetgbted Avarags Exposure Estimates 2,4.5-T Process Based on 50 Samples of Up to .wpTfmth1eefstaoTmrleereoieso9piyohpsfhoiocveotatg7itsnepDeemstheenTnlciu0se.rroerbluCatestsorstacdnososese.lsPhtxlacuehnaiiptrytAase.mieiemseelmnedlotrareolspnieedmsilrnporalaviraiozawersernoesmhtiwtirterbtoxlenorhgsiildhfitscappdgoteaglroea2eoyesteohoti,xitce,toghntoa4ssieir0ihbtalrnmrah.thu,b.ar,eetun51ogmttohoArluteTdddi-yechslepoTmodCdmrec2eerseyrfadifufP0eerangewfieroiene4tlrvrprabnt/gehrcrrfriemhicietostsviiaeeoothtoattwmohedrba*thtswnprnteerelietheecseanyeoirwosnwleod.denrgcrifatreeftgahrenfiauTeacrie2sav.tnirstttsehsmiilop.rherednevp4itaec2iorseedt,eeoo,,Uat,sten5t4ilaxndlhtpeoyaxstmf-vnho,posrfiTerel5pnnectfoiaoeofoase.s-odstademcmssTnoedtr.slexecasrnueuesasTetwrldvpahieycritulndhrwmiaeuaeplseettxctjesltsudiweapstahwtowsot2ossyr2r.ooetmae,erhatex,t4sSrmlf4shsenisode2aurr.hci-5aeokxete.wdrndDoil4w-neigvmylnenaTrleo,ehioio5to.msnerl4rsfcapeg-erapd1edToekrlvtifl2smee9nuochoaineu,norid5ocoas4ersgrtlalcg4seratru.tlu/ttri5icesmtochgne1iriotaa-aaxtsetroheg9TfssJ,f..l wbchwcabodvcMJptiehtmtfsttnehhohaotaaoeanexayultahasreeeeeecrnnptdurvTAeptslutointiaetatuouocisnefahtcfhrnUiaohwoseceastnwcetrcdwtogh..swreSrutudrwra,SouagmaiefadnyotertrwoToto.roiiadheswy.iftdmolfkechorry1ho-joernwToenkisneocf9anahapaorthiftohbtzedbhhohs5ktrmlraaltahfiseAreooasee1sieemdomgtvyiaaesidyfnesdnmevieei1pieinif.eStsavtealegneofoa9haf.emvmmlToeitrnpexheodyrrt5rrhrrsoTathmyrpnrcosmitei2pareehstiovlhelieunuhvut.idlslmssofoepincooeesreraodedgh,es1ndreilicyttpeodtlurheeod9ah1bfeedylp2lelonuy.ac5pro2teeyoeusoc1utmecodJof7lyaaTewoser-mpsetea2ne,rseeycrhrphAnmou.nsteddhehee.me1l4escmorpodoluelasnau9a,Toewefnsim5oyimawseinrs6ntpcnhtnr-eeorwhrien2idTboitieeeoypasodmeptnitop,atneihhnlrtnerdi'veiiwmiss1fsrstpges1euwtywrsiiearou9trdi(l9tnroansoooavsttrcfle7nostouo6rhiriatdendtyisttov1atlnerkt7afyfaeuteetdkcaes,bmcedihaltrdoroeettalet-eitelaesieovhatyemynsrvdttrxdwwxnosspeehhfeeeiteop.pndtuwheashiheecvaardnonaiewelo.fiiniooettrnesc1eolw2ruwedadlapaSrinieh9gtww,steudaese,en4hotitpud7t.angriorh,drwnopletod1bt5ieeecmtlphhnrrljhr.uu.es-fieokyoaoesocetTieieoltiThtebsnnu2ouanoephoqutthpsp0idncegttthruudefuteisperro4mlshohroullooeitoerlatndeoncyhanvhdccfminvwcnfetrunooaeeetietiiotttfoaegoehmthhsilsilssoooodansfnycnnddheoeesesirff,f),l Five Minutes Duration and Time Studies lor Each Job, 1969. Tabla 2. - Vital and Employment Status of 204 Workers TCP 2,4.5-T* 2.4-0 Exposed to 2,4,5-T as of December 31, 1976. Job (mg/rn1) (mg/nr*) (m g/nrit Vital and Employment Statu No. ot Worker* Reactor ooerator Sait wneet ooerator a eia wneet ooerator Dryer ooerator 2.1 . 2.1 9.7 . 1.6 o.st 0.5$ 0.20.5 <0.4 <0.4 <0.4 <0.4 Total group Still employed Retired Oeceased (company records) 204 121 18 9 *Proauci soeciticaiions tor 2.4.5-T in 1966 called tor a maximum <rt 1Dorn rCDO. me sensmviry at me method at selection, in 1972. me maximum was lowered to O.t aDm TCDD 7Highest oossicie values using levels of detection as real values ; Present m work environment as sodium sad Lett employment otner man ttirougn retirement Oeceased Known alive Follow-uo tnrougn 1975 incomplete 56 2 51 3 48 Mortality Analysis of Emoloyees Engaged in the Manufacture of 2.4,5-T/Ott. Holder, and Olson Table 3. -- Duration oi Exposure by Oate First Exposed Among 204 Employees Exposed to 2,4,5-T. Oita Exposure B a g Total 1950-54 1955*59 1960-64 1965-69 1970+ - Duration ol Exposure* Total <1 Year 1-2 Years 3-4 Years 5+ Years 8204 157 5 1SB 30 V45 ' 36 30 17 6 9 2 * 51 44 4 2 .1 35 32 3 0 0 15 15 0 0 0 *Filty-nine ol the 204 employees worked as ester operators tor from <1 up lo 77 months ( 11 of these employees had worked for at least one year as ester operators). The exposure durations as ester operators, or while employed in other capacities within the production department, were not included in the table since exposure intensities had not been estimated .dcwosdpdpamtculceiotooorneuaunfoyneemnsdmurmycItrrgsanhunsek-nte.pteittseretnhotioentooaoeeshdEenO-.tsunrevfodi-xessuSesnbnoafipdedtnrriduenuaynoeaoemetstndcsldeaopfmjabpeauyoroddnaeeaellrpbynoitumhexrxsehslstyuopripaonmstediaiedmostonvyehirnaeu,sedfesgmbsoeyujsurneolbaeraerrirtwxotbneheaetrtnpitejsfsveereoohTtooeaxonltnibethlmsrhfroolsseauvuepeanejoasleo2rxslscmedwp,ayeb,poto4eoeohnmsoiptin,htsxthrekt5shlhapsawpnoen-eeioeeltvTonfooydooixorertrsypmtghwropvutusdeetraaoirrhntreenrureeantetseisinatonsqjkvitoiostzetouetehvnebpeieotsnileahsdssrrdyhieotreewntaediohodeideswtnvriefnoesftstuteocehfiyptltciilypo2ruhlmauawsolt-,mrfiriidc4irnionafonm2ot,cecignmt5crn,feoldk4tat-haiehdTeum2e,irdes5nre.y,nnidemssmn4-atStToipt,clfps5iuiiinnatctotecxre-hdhhaoTronatnxeeyeytaal,f- vc1eewtsfta7jpcRFohhoh9oxhinvo5ihebtrrlfpe7imadlsTT%Mlootsdisooyo6ccelhhuuueerwbe-khsdeaeliggtnostoasenydheschhtctn.dnvdvfiraomnddceeediiTotetts1aatueh2iaplwotg9tvlotswnh,ereloe74hooiiifrnrba2hrn6.torwsfm5fg.nuefeo,oioc4uoa-rtdcetiThhn,sgfnbsdir5dooncmeatlhedyeop-earnulTvdemifronaeh5ceripeasxndtraor6racopmehprcepedftoivelrsoinffehnodotpsoienmesseewytyoflrwrltmeodreypemsmanoideayoxaoxlpaceroeermpakprdkltlmiewyoscnrnooetieeucyouptoswosdesoleemnotusefulwrmhabiosektnttrarfoashnsyeeoisppstsanwhteea.earolutnogabrheacnlttrNsvdtlydhyotipestsmheleooitesihnaorfddardesn.eefTyowrrruiseTedtrtetiuCtaiFirnehihbdrmaaaaghmDsoerdoeaybehtaheeriafDiwonlv2ocvoes.snia.0t1uetnrwdorh1hoges439etuce2anNbroc.7fvewiafneioaM3foiontmimeelneehro,ludedwonearoesxncTisobpkrvnenape.deeeearutitdtrsdoc.rrnbhatawesstuswudlsrhcoeuendraefeianioootrraoitl2xhdnensesyfr,f.t ptpeoaoetmr6eofptistpvitinoneaohwensualxbm3irtfofaggtnaehtves.dpirose-seTTgcichsepopletyuno3euri2ceyirhoaeegtdledrivrp.sisraro,reed7aotbpfnv4aeeaaytuawiuyiaaldbraer,aeslertrtscetiets5rsoh-olealhrradassnktexeohe-aetourielnersTcplleystnsas4defofsdedgdemmyeoaidioefefxeenfefcbaattillorpoprlfxhenatcbdmdatsenfnoeehoerpoileeertryeeuncodcdwtmh,,dtfaosriiaaaeotdrysagwiXalusosidwene5ittxmlimnaglautrhhinmeehderptwehtsnTrnryageeaemiipoee,ceouocvedahtiwstrnsotnha.mhihmrvfebopprntduotehiheeptsOtaxslialceupormbdltoaloestoupelelhtyhgnalwoeeidytorlneiaeeedaopeslcnhcrwmhysicrart.retiareotoadiriwanerhnieyecdzawceaoremmdirdcecpncehdeoentn"anedershwiaaecpeiamshbdectscramsebsstaxfteheeeewsofhemyehatyitnapeidnolirr.oehcereniihtassoynenntrwacrhsmisoeittowcccrnisscttpan,atdefhrotvhraptauaewrlegsleoi.xioeienmtlilsxsrlatnopoeolriTcsrdysopcattysdoyhcpycaheaatnoteeiwbsehiicedia.oetnolutsnevvsxeieeuyaditoruostifespeWrcdstdevrternoeacdeorgstihueewrniiseo.seafnvmunocntoed.a*g"aoduvnattcnrroewlesojl(aelsyIdrlheeob6btan2mdeTkehrtaabsostwoieid,aoihohfoin4nivsoreTtcfondufsbebelshna,eegryrha5ecniesasresavncee-abeeoleuyiTytvcmwsitsnnltrrtnedfopehddootfvovteoaiattoffoeaeereuumlhhoortvtrniss4xknrddoeneeeseaaerr,-tt' c d Comment \ (19A66t tphreodeuxpcot ssupreeccifoicnacteionntractaiollnesd ofof rT<C1P panpdmoTfC2D.4O,5-iTn wsaopmthtasfiueatsrhdtenohydfuciis,nifatatnaohlticolimeottuhanpitrdareibwonvtdaedgoitcruhsfskcueUglttroh)rvmcSoeeea.uoyxwwtn,ripotdohmaenrirltk.oiei*temyrentmaneocTalefvrihflttdieeeyarsoclih,btntsaymyamsnhoetdabhrenveteaxaetepllsnWiwbetoyerofiiceaetrhonkvncimmocnooerpmbeatahsnbpreelaaeeritsrvsnicecswooodtthhepnmiiielsnssl Table 4. -- Observed and Expected* Deaths Among 204 Employees Exposed to 2,4,5-T, by Cause and Duration of Exposure, 1950-1976. Causa of Death Category All causes Total malignant neoplasms Diseases of cardiovascular system External causes (accidents ana suicides) All other causes Total Exposed Group Observed Expected 11 20.3 1 3.6 4 9.1 6 3.7 0 39 *Expected numoers of deaths Qasea on U.5. white male mortality rates Journal of Occupational Medicine/Vol. 22. No. 1/January 1980 Duration of Exposure <1 Year Total Exposuro Observed Expected 6 13.3 0 2.3 1 5.6 5 2.8 0 2.5 1 + Years Total Exposure Observed Expected 5 7.0 1 1.3 3 3.5 1 0.9 0 1.3 * 49  Table 5- -- Observed and Expected* Qeattis Among 204 Employees Exposed to 2,4,5-T, by Causa and Interval Since First Exposure, 1950-1976. j L1 Causa of Outft Category au causas Total naiignani neoplasms Diseases ol cardiovascular system External causes (accidents and suicides) AU other causes OQreire Observed Expected 3 6.6 0 1.0 0 2.3 3 2.0 0 1.3 Interval Sines first Exposure 10-14 Years 16-19 Years Observed Expected Obsarvad Expected 5Q 4.7 A 4.6 0.9 0 0.8 0 2.2 3 2.3 0 0.8 1 0.5 0 - 0.8 0 1.0 20+ Ytar* Observed Expected 4 4.4 1 0.9 1 2.3 2 0.4 0 0.8 DOW 1 0 7 9 4 0 8 Expected numbers of dealns based on U.S. whits mats mortality rates (Amwtpdtfarlcitpsoineohaimsaunaurlonaeuntlekcsilieetmueciltrtshhttiyr,pguele,ientdasewarolndntaasdloxhciatttuttpotaestbbeewthienooruomdbeamvltxonsnaylpbteeain.ouph,is0lcrniilslerloltly.leoitileo0somahtbdslaTy1yopoenoaaitnaaa.ergolbcbomabdebbyleiseasBcfslioc2peelerbpmateit.oguorlatsr4leecolvyybevtsbfJaespas4sscu1u-1toroduettuiaTel5z5is)taaforSldrh,eefav%nrtolniMoe.iieiietwdoejnsir.borCoscRndghmrs,tfn5mIopeseefmolooinconeqmwraaorrutovfs,puoryheiifpsirdmetluenrieelrynettsblugtemahlapebhnatestcieltoeafraoceitiiliautnieorsiennsvnyncsPsgencitesdoostasoisattnetnwntruirhefsertedtittwtrasehseoshidei.vlnnkitaraohe.siervdudmnnteitftiaicFeaehlivhtdlardlhraaotdaetesutawianrte.ttsbhehencrsoteTepiysiarssdesxxhrirvatbkodedpcaeiorpemnuoveeolumfawodmtinacsaedhittpw,eouestihtaeovhleitrnraneeisdoedrsesess.t,r Reference^ 1. Muranyi.Kovaa I. Rudali C. and Imbe J: Btoassay of 2.4.5- tnchlorophenoxyacetic acid for carcinogenicity in mice. 8 f I Cancer 33:626-633,1976. 2. Cehrmg PI, Kramer CC. Schwetz BA, et al: The fate of 2.4.5tion to tmriacnh:loTroopxihceonloAxpypacl ePthicaramcaidco(2l .246,5:3-T52) -f3o6l1lo.w19in7g3.oral administra 3. Innes IRM. inland 8M, Valerio MC. et al: Bioassay of pesticides nano4dte..iKnI doNucaisbttraliCaRla|n,cchKeeremyIniecssatlOs4C2f:,o1rL10its1uo-mw11eo1rRi4gW.e1n9, i6ec9itt.yaLinRmesiuclets: A of preliminary a two-year chronic toxicity and oncogenic study of rats ingesting diets containing 2.4.5- trichlorophenoxyacetic acid (2.4,5-11 fo o d Cosmet Toxicol 17:205-221,1979. 5. Axeison O and Sundeil L Herbicide exposure, mortality and tumor incidence: An railroad workers. Work Eenpvidireomn iHoleoaglithcal11:i2n1v-e2s8t.ig1a9t7io4.n on Swedish 6. Poland workers in a AP, Smith 2.4-0 and 0 . Metier C. 2.S.5-T p lan tarA.drcPhoEssnivckiroPn: HAehaeltahlth22s:u3r1v6e-y32o7f. 1971. phy7.riaB.leAibrcehrgDI.eWrmaalltoenl M. Brodkin 89:739-797, R. et 1964. al: Industrially acquired por 8. Johnson IE: The public the phencxy herbicides and hpeidaoltrhamim. pBliioca-Sticoinesncoef widespread use of 21:899-905.1971. in 9a.nOinttduMstCri.aHl polodpeurlaBtBio.na.n/dOCcocrudponMHedI: Determinants of 18:171-177. 1976. mortality ' \ Skills Productive Capital wmtnmtPhieoeraeesinTTSnlksnf.hfhacectoeSeechrriehrtnucmoasa1hloetntte9zoiofco7tdoUhonfnr9uleneaantchdvbtilrabviieeuovatemecitnenoprhisadspadnraioiil,atnseviyednonnti,ofruitdtfdaersaicIceirn'ninoteniaiodedivfsdnifneaatpgiTvtnst,eishinhsduokerevouseipholicelalslusldNieaealmosogooatoerferbafiesfcdrtenhhshdaWluw,eclealmPc.iatntrkeahrpeaSdiirnznsinmcteSodaehbsbuisclxnu.ee,rhpelcfiHtunenoeezdriogersxtizeobstpee,nayfloiacmcnswnttoiedhhnphtln.yheeehioicendagaUmhfsrmiooanniihczrndisoamvesiususedtaathnraebtsttetreinehieootsceeyanefnWos,oecstfahx.afbucttepahmCeAqysienthurpeattihitdhcHrliateoauotaovhdngrreneovw.btLy.aohhyerbhaidwcisatnhiesBvvt,rheeutvehssoaitneyif -- from "Nobel Winner Dealt Weh People. Not TbeaV by Herpen Stew, n The Pmourgh Pens. October 28.1979. 50 Mortality Analysis ol Employees Engaged in tha Manufacture o< 2.4,5-T/0tt. Holder, and Olson 16993 r?, 2 ' / } 3 . / , /?7J /- Dow Redefines Word It Doesn't Like Teratogenicity is an unpopular word at the Dow Chemical Company. Ever since the thalidomide tragedy, the public has reserved a particular horror for any chemical suspected of causing congenital malformations. Recently Dow lir.s kiici (he misfortune to hewe one of its*best selling herb!* cides, 2,4,5-T, found teratogenic by scientists working under contract to the federal government. The discovery eventually led to the cancellation of certain uses of 2,4,5-T by the Environmental Protection Agency. Suspicion of teratogenicity was also cast on a related herbicide, 2,4-D. The original study indicated that 2,4-D is teratogenic in mice and a more recent experiment, by K. S. Khcra and W. P. McKinley, indicates that it also causes fetal abnormalities in rats. Dow scientists decided to repeat the Khcra-McKinlcy experiment, but, unfortunately for Dow and 2,4-D, got similar results. So they published a paper saying that 2,4-D is not teratogenic. How can a teratogenic substance not be teratogenic? Easy-- you redefine tcratogencsis. Teratogenic means the property of causing any kind of congenital malformation in the fetus. Naturally there arc differences of opinion as to what constitutes an abnormality and what is within the limits of normal variation. But that apart, there is broad general agreement as to what the word means. The Dow chemists-- B. A. Schwctz, G. L. Sparschu, and P. J. Gehring-- have redefined teratogenicity as "that degree of embryotoxicily which seriously interferes with normal development or survival of the offspring" lF o o d a n d C o sm e tic s T o x ic o lo g y 9, 801 (1971)]. This means that none of the minor deformities caused by 2,4-D in rat fetuses--such as under weight, subcutaneous swelling, delayed formation of bone, and the growth of ribs in the lumbar region--count as terata, and therefore Dow's fast selling weed-killer is not teratogenic, according to Dow's definition. Even a chemical that caused a highly disfiguring deformity would not be con sidered teratogenic by the Dow chemists unless it "seriously interfered with" development or survival. Although there might be a scientific ease to be made for tightening up the definition of tcratogencsis, this is not the reason for the Dow scien tists' attempt to refashion the English language. Public relations is the motive. B. A. Schwctz, leader of the Dow team, explained to S cien ce, "if you tell congressmen or laymen or housewives that a compound is teratogenic they would think that here is something very serious that we should not be exposed to. Every compound labeled teratogenic, they as sume, must be as bad as thalidomide." The Dow redefinition, Schwctz said, is intended to remedy this unfortunate reaction or, as he put it, "Out of this will come an attempt to inform the general public that terato genicity is not teratogenicity, if you see what I mean. There are degrees of teratogenicity." In fairness to the Dew chemists, several of the specific deformities caused by their herbicide might not be considered evidence of leratogenesis, even under the usual definition. Delayed ossification, for ex ample, is not abnormal if it is only dei.iyed. But lumbar ribs, also caused by 2,4-D, is a teratogenic effect. Two leading authorities consulted by S cien c e, J. Warkany of the. Cincinnati Children's Hospital and Clarke Fraser of the McGill Department of Genetics, Montreal, said they dis agreed with the proposed new definition. "There's no need to redefine the word--why mess around?" said Fraser. Redefining words to suit the convenience of a special interest group can have untoward consequences-- indeed George Orwell wrote a book about them. But perhaps there is something to what the Dow chemists propose. If tcratogencsis is to be sanitized anil pul out of common use by reserving the word only for thalidomide-type disasters, then perhaps the same might be done for Dow, a word which, in many people's minds, is associated with the manufacture of napalm.--N.W. 2 C2 24, u As it turns out, ''government contact work" is not entirely new to the AGS. During the past year or so, several society officials have been quietly plug ging for federal support of internships in government and private laboratories as a stop-gap means of alleviating scien tific unemployment, in March 1971, last year's ACS president, Nobclist Melvin Calvin, suggested two such pro grams to the President's science ad viser, Edward E. David, Jr. In Septem ber, the White House announced the initiation of a $3 million internship project to provide jobs in federal labs for 4C0 to 500 unemployed scientists and engineers. This year, the ACS is asking the Labor Department, the National Sci ence Foundation, and science adviser David to establish a special intern pro gram for up to 1500 jobless chemists and chemical engineers. The ACS plan would have the government paying part of the salaries of the interns, who would work in industrial labs. According to a proposal it made last month, the ACS would administer this program. A similar concept is embodied in a bill called the Scientific Manpower Act of 1972 (H.R. 14298), introduced on 11 April by Representative Ronald V. Dcllums (D-Calif.). Modeled after a bill introduced in the California Assem bly last year at the behest of American Chemical Society's California sections, the Dcllums measure would set up an Office of Scientific Manpower in the Labor Department to administer sti pends of up to $700 a month for un employed scientists, who would work in -excess federal laboratory space. By no coincidence, Dcllums comes from Alan Nixon's hometown of Berkeley. One might reasonably ask at this point why ail organization with a $30.3 million annual operating budget finds it necessary to buttonhole its members for an extra few hundred thousand dol lars to pay for an emergency job pro gram. The answer seems to be that the ACS has already trimmed away all the budgetary fat it could find, and even then it rang up a $707,000 deficit last year. (Reserves from a recent dues hike apparently more than olTsct the loss.) Insofar as its finances are concerned, the ACS is first and foremost a publish ing house. It produces 17 journals, plus C h e m ic a l A b stra c ts, a series of mono graphs, three series of books, educa tional aids, films, and a radio program. I.iktf the rest of the publishing indus try! c;il,;;bl in a light squee/e SCIILNCI., VOI. I'h DOW CHEM ICAL U.S.A. 24`- November 9, 1977 MIDLAND, MICHIGAN 48640 P.0. Box 1706 Mr. R. F . Mountfort (PM-23) Registration Division (Wll-567) Office of Pesticide Programs bcc: M. L. Long c Environmental Protection Agency Action File (Siivex) C Waterside Mall, East Tower Washington, D.C. 20460 O' o Dear Mr. Mountfort: c/ SUBJECT: IR-4 Petition 4E147b Regarding the Use of Siivex on Citrus V Enclosed are copies of two toxicological reports on TCDD in rats: 1) An Ultrastructural Evaluation of Liver Cells From Female R.ats Maintained for Two Years on Diets Containing 2,3,7,8Tetrachlorodibenzo-p-Dioxin (TCDD). 2) Results of a Two Year Chronic Toxicity and Oncogenicity Study of 2,3,7,8-Tetracnlorodibeuzo-p-Dioxin (TCDD) in Rats. These I trust will enable you to now procede with your evaluation of the above petition. These have previously been submitted to Mr. H. L. Warnick but for your convenience copies are included for your files. Sincerely, W. R. Mullison Registration Specialist Government Registration Health and Environmental Research Enclosures jan cc: G. M. Markle Cook College Office of IR-4 P.0. Box 231 New Brunswick, N.J. 08903J C C (^, H ' /I/. D . 7T T . A 0. r t t , C y t/U cz. ^ .7 /. /. A N OPERATING UNIT OF THE D O W CHEMICAL C O M P A N Y "Vole CANADIAN LITIGATION DOW MOYER V DOW 1. 2i W. F. B. B. Fox Jones '--Far. 3. D. !. Ego 4. Safety of Pesticides 17th M arch, 1970. Dr. J . Antognini, M anager, pield Research and Development, Stauffer Chemical Company, P. O . Box 760, MOUNTAIN VIEW, C aliforn ia, 94040, U .S.A . Dear Joet 2,4-D and 2,4,5-T In view o f the present controversy opposite the continued use safety of 2 ,4 -D and 2 ,4 ,5 -T , one of our large industrial accounts has asked us for all possible up-to-date data which we can forward to them on toxicology, longevity and the possible effect on ecology of the hormone herbicides, particularly 2 ,4 -D and 2 ,4 ,5-T . This is quite an assignment and since this customer is p articularly valuable to Chipman, we are trying to gather together ail information we can on this rather timely subject. W e, of course, have a great deal o f data which dates back some ten or twelve years, but this information does not seem to be too valid in consideration of the present controversy. When we met with you in M ontreal, J o e , you mentioned you had read some very interesting data recently accum ulated on both 2 ,4 -D and 2 , 4 , 5 -T , and that some of the evidence against 2,4-D was even worse than the original information opposite 2,4,5-T . i should more than appreciate it if you could send me photocopies of any authentic reports, documents, e t c . , in connection with the toxicology, longevity, effects on the ecology, etc. of 2,4-D and 2 ,4 ,5 -T , as has been developed within the past year or so. Your co-operation In this will be more than appreciated. Very sincerely yours, CHIPMAN CH LIMITED c .c . C . G . Hal Iiday L. M . WWMUO^, Technical M anager. 16998 w L m rcn, ' ukumbie. a uw. o - < ju -a > o uu.aiu . P ^ 3 'VkJ' 4 U 1 U U kj t .L i i t r tJ t HANS-JOACHIM DO HM EIER RECHTSANW ALT RA Ooriineiur. L udw igatraSe 49. 6 7 0 0 L udw iQ snafen An Clark, Drummie & Company z. H. William B, Richards P.O. BOX 6850 Station "A" Saint John, N.B. Canada E2 L 4S3 i_ Luriui.igstraJ3 4 0 8 7 0 0 l.UW IGSHAFEN Tuterfon (0 6 31) 5 1 2 2 5-1 K*1ton: Pcfitproannt LLjrwuuchaian (BLZ 5 4 5 1 0 0 6 7 ) Kto.-Nr. 2 9 3 7 5 6 7 0 D r e s d n e r S A iik L'jdwigal-w(er< (BLZ 5 4 5 8 0 0 2 0 ) W.-Nf. 1009485 00 StadtsutukasBB LuiieriQShafen IQLZ 545500101 Kta.-Ni. 282 33.) Sprechzeiten: rftw iiremoan^; 22. Februar 1990 Sehr geehrter Herr Kollege Richards, bitte entschuldigen Sie die Versptete Antwort auf Ihr Schreiben vom 26. Januar 1990. Ihre Frage darf ich kurz wie folgt beantworten: Es ist mir bisher einmal gelungen, ein Gericht davon zu berzeugen, da der Magen krebstod eines Arbeiters auf eine berufliche Dioxinintoxikation zurckgefhrt werden mu. Das Urteil des Sozialgerichts Hamburg ist allerdings noch nicht rechts krftig. Die Berufsgenossenschaft der chemischen Industrie, bei der die Arbeiter der Firma Boehringer/Ingelheim versichert sind, hat es mit dem Rechtsmittel der Berufung angefochten. Ebenfalls einmal ist es mir gelungen, die Berufsgenossenschaft der chemischen Industrie davon zu berzeugen, da die akute myeloische .Leukmie eines Arbeiters der Firma BASF AG, die schlielich zu seinem Tod fhrte, auf eine einmalige, hohe Dioxineinwirkung zrckzufhren ist. Die Berufsgenossenschaft hat diesen Zusammen hang auergerichtlich durch einen entsprechenden Bescheid anerkannt. Mir sind ferner zwei Flle aus frherer Zeit bekannt, in dem die fr die chemische Industrie nach deutschem Recht zustndige Berufsgenossenschaft einen solchen Zusammenhang bejaht hatte. Der eine Fall liegt schon sehr weit zurck. Damals ist aufgrund eines Gutachtens des frheren Toxikologen der Firma BASF AG, Prof. Dr. Heinz Oettel, der Lungenkrebstod eines Arbeiters der Firma Boehringer Ingelheim als durch "Trich1orpheno1-ZerSetzungsprodukte1' anerkannt worden. In jngerer Zeit ist mir ein Fall bekannt, in dem die Berufsgenossenschaft der chemischen Industrie sich mit einem weiteren Arbeiter der Firma Boehringer, der chronisch d l D X inexponiert gewesen ist^ihm Entschdigungsleistungen zu gewhren. .ih ,* 17000 C L JH 1 U l - U U A l \ 1 \ , im UlW IM IL , cc v ^ u . u UU U. -2 - Ich vertrete weitere fnf ehemals dioxinexpanierte Arbeiter anwaltlich, die an Krebs erkrankt sind, bei denen bisher jedoch noch keine Entscheidung ber die Entschdigung,- sei es auergerichtlich oder gerichtlich, gefallen ist. Mglicherweise knnen Ihnen auch die diesem Schreiben beigefgten Fotokopien weiterhelfen, aus denen hervorgeht, da die Firma Boebringer bereits 1957 verschiedene amerikanische Firmen vor dem unerwnschten Nebenprodukt Dioxin gewarnt hat. Mit freundlichen Gren {Dohmeier), Rechtsanwalt 17001 Cjcj\ i q i ;u_A K t\, UKLMMlt. & LU. ; 3 -3 1 1 -3 2 ; 3:UZ4M 5Ut5 459 720;# 7/ 9 kk L , 3 An dl DOW Ch< m lo a l Company 1714 s etman Bd. Midland, Mioh. / PSA i 1 -' l i 1 ?> Dr. ffy/B 11. 2. 1957 Chlorakne. parBtellung von flrlohlorphenol :vf Sehr geehrte Harren | Vir beziehen une auf don Schriftwechsel ln der oben ange fhrten Angelegenheit, den wir mit Ihnen im Jahre 1955 ftthrten. Sie waren damals so freundlich, une Ihre Erfahrun gen mltsuteilen. Da unere eigenen Arbeiten Uber die Vermeidung der Bildung des Chlorakne--Erregers ni einem gewissen Abschluss gekommen sind, mchten wir Ihnen diese Erfahrungen sugnglg maahen und. tun das durch Beifgung dar kleinen Abhandlung sie Anlage Wir hoffen, Ihnen mit unseren Ausfhrungen e i n e n B e i t r a g *ur Sicherung der Synthese der grichlorphanonaasigatture gegeben zu haben und nehmen an, dafl der Beitrag auch fr Sie ton Interesse Ist. Vir gren mit Yorstlglioher Hochachtung C .H . BOEHRIBGER SQHN ppa. : 7 * Anlage 17002 ouu ui m uiB um : `tfi \-,\K " * 'mi> 30 ^T ''^TJuHd ^ v Jf.lU<*hrn>rjt!< cIm1- o*n Rh<ur -0/ a D a rste llu n g ron T rio k lo rp ^ n o rya a B ig a u rQ unter V e rse ilu n g d a r B ild u n g von C hlorakne - E rre g e rn , U n se re S y n t h e s e d e r 2,^,5 T r io h lo r p h e n o x y e s a ig a u r e l u f t l n folgenden Stu fe n i c i2 1 ) f r l c h l o r b e n s o l --- --- > t o t r a o h l o r b e n z o l *---- --- ' ' V a DTT 2) T e trao h lorb o n aoL-/* -- j J ric h lo rp h e n o lflA triu s )' A iu' t o k l a r et1n - R e a k t i o n b ) A b d a m p fa n d e s Off^QH 1 e) fiT e a a e rd a m p fd e a tllla tlo n dea A n ls o ls 4) Is o lie r u n g dea T rio h lo rp h e n o la durch Aneuera und a n sc h lie sse n d e D e s t illa t io n 3 ) m o h l o r p h e n o l - 5 i 5 t -- S 2 ^ ^ .?-? a > 2 , 4 , 5 - ^ r l o h l o r p h e n o i oigeauree H a triu a 4) W e ite rrsra rb e ltu n g ca re in e r k r is t . 2,4,5 T-3aure la a h u n se re n ir fa h r u n g e n l a t d ie ahlorakn .e-euolaeade W irkung a u f V e ru n re in ig u n g e n durch. N eb en p rod u kte a u rlic k z u f U hren, d l b e i dom k o a x e n t lo n e lla n P ro z e n u r d a n n e n t s t e h e n k n n e n , wenn T rlo h lo rp h a zw lzm trlu a bzw. and ers A lk a lia a lz e ro n T rlo h lo rp h e n o l h e rg e o te llt, g e r e in ig t und w e ite rre ra rb e ite t werden und a io h \ dabei R e a k tio n sb e d in g u n g e n e rge b e n , d l denen e in e r Salzoahm elsi. nah'- o d e r g le io h k o s u a e n * U nter diesem G e sic h tsp u n k t e r g ib t ic h a l t Bezug a u f d ie E n t stehung dea d h lo ra h n e -B rre ge ra f r d ie e in ze ln e n V e rfa h re n satufan fo lge n d e s i ZU 1 u n d 4 ) Diese S t u f e n sin d , rlllg ungefhrlich Z u 2) B ai d ie s e r Stu fe kann d e r C hloralcne-i& rreger e n tste h e n . Zu 2 a) Ubt die bei der Autoklaren-Reaktlon au rer-- -- hindern. i s t e in s b e r h it z u n g d e s A u t o k la r e n - m iin lt s ou r e r a o ld e n (Hchsttemperatur 150 0). und W a lte r d a ra u f au nahten, da ln mglichst g r o s s e r Verdnnung a l t k e th a n o l gearbeitet w ir 170 0 ^ ^ Hans-Joachim Dohmeier Lawyer To Clark, Drummie & Company attn. William B. Richards P.0. Box 6850 Station "A" Saint John, N.B. Canada E2L 4S3 Day: 22.February 1990 Dear colleague Mr. Richards, please excuse the delayed response to your letter of January 26,1990. I would like to answer your question briefly in the following: I have managed once to convince the court that the death of a worker who died of stomach cancer was caused by a work related dioxin intoxication. The verdict of the court in Hamburg (social tribunal) has however not yet been finalized. The trade association (workman compensation board) of the chemical industry, through which the workers of the company Boehringer Ingelheim are insured, has appealed the verdict. Also once have I managed to convince the trade association of the chemical industry that the acute myeloic leukaemia of a worker of the company BASF AG that finally led to his death was caused by a one time high influence of dioxin. The trade association has acknowledged this correlation by excepting an out of court settlement. Further I know of two cases some time ago, in which the trade association which according to german law is responsible for the chemical industry, has affirmed such a connection. The one case is from quite a while ago. Back then, on the basis of a report of the former toxicologist, Dr.Heinz Oettel, from the company BASF AG the lung cancer death of a worker of the company Boehringer Ingelheim was accepted as caused by trichlorpherol - disintegration product. Lately I know of one case in which the trade association agreed to pay compensation to another worker of the company Boehringer, who was chronically exposed to dioxin. I legally represent five more workers who were exposed to dioxin, and who suffer from cancer, whose cases however have not yet been settled, be it in court or out of court. The photocopies attached to this letter may possibly help you out further, as they go to show, that the company Boehringer has warned different american companies of the undesired by-product dioxin as early as 1957. Best regards, (Dohmeier) Lawyer 17003 To the Dow Chemical Company 11 /n 1i 4M nnci_t_b_ui_i_u_d_iin Jnu. Midland. Mich. / USA Dr. Wey/B 11.2.1957 Re: Chlorine acne. Illustration of Trichlorohenol Dear Sirs! We are writing in regard to the correspondence we had with you in 1955 concerning the above mentioned matter. Back then you were kind enough to share your experiences with u s . Because our own research about discouraging the forming of the chlorine acne causing agent has come to a certain end, we would like to share our findings in turn with you, and would like to do so by means of the little report attached. We hope to have helped you secure the synthesis of the trichlorphenoxy acetic acid, with this report, and assume that you would find this of interest. Yours truly C.H. Boehringer Sohn attachments 17004 Illustration of trichlorphenoxy acetic acid avoiding the forming of c h l o r i n e a c n e c a u s i n g a g e n t s . _____________________________________ ________ Our synthesis of the 2,4,5 trichlorphenoxy acetic acid takes the following steps: 1) Trichlorobenzene -C12- Tetrachlorobenzene 2) Tetrachlorobenzene -NaOH- Trichlorphenolsodium a) autoclave reaction b) evaporation of 0H3 Oh c) water vapour distillation of the anisole d) isolation of the trichlorphenols through acidification and following distillation 3) Trichlorphenol -NaOH CH2 CICOONa- 2,4,5-Trichlorphenox acetic acidic sodium 4) further processing to pure crist. 2,4,5 T-acid According to our experience the chlorine acne causing effects are stemming from pollution through by-products, which during the conventional process can only occur, if trichlorphenolsodium or other alkaline salts from trichlorphenol are produced, cleaned and processed and throughout this reaction conditions are given, that are similar or the same to that of a salt-melt. From this perspective then the following picture for the individual processing steps emerges in regard to the development of the chlorine acne causing agent: concerning H and 4) : these steps are completely safe concerning 2 ) : at this step the chlorine acne causing agent may be developing concerning 2 a) : to avoid this during the autoclave reaction, an overheating of the autoclave contend is to be avoided (max temp. 150*C) and further attention should be given, that the methanol is worked with as diluted as possible. 17005 concerning 2 concerning 2 c) concerning 2 d^ concerning 3) during the methanol distillation the yellow water in the distillation bubble should be held back, so that the dangerous dry heating of trichlorphanolsodium is avoided. The mud temperature should not be higher than 100*C. the water vapour distillation ...... of the trichloranisols must be done in such a way, that no change should occur in the concentration of the trichlorphenolsodiumsolution....... water added. during the distillation of the unprocessed phenol it has to be watched, that no trichlorphenolsodium and no table salt is brought into the distillation bubble and heated together with the phenol. at this step chlorine acne causing agents may also develop. To avoid this the condensation of trichlorphenolsodium with chlore acidic sodium may not be done in a water free medium. A concentration of more than 40% is to be avoided in any case. About the qualities of the chlorine acne causing agent can in short be said the following: As a neutral body it is water vapour volatile, so that it can accumulate in step 2 c) in the distilling trichloranisole. It is therefore practical to forget about using trichloranisole and to destroy it through burning. Since the chlorine acne causing agent shows signs of sublimation already at temperatures of 100*C (even though it has a high melting point), the reaction-product of step 2) and 3) should be processed in completely closed apparatuses and the lab should be well aired. 17006 Re: Chloracne. Illustration of Trichlorphenol Dear sirs i We are writing in regard to the correspondence we had with you in 1955 concerning the above mentioned matter. Back then you were kind enough to share your experiences with us. Because our own research about discouraging the forming of the chloracne causing agent has come to a certain end, we would like to share our findings in turn with you, and would like to do so by means of the little report attached. We hope to have helped you secure the synthesis of the trichlorphenoxy acetic acid, with this report, and assume that you would find this of interest. Yours truly 17007 Dear Mr. Richards, please excuse the delayed response to your letter of January 26,1990. I would like to answer your question briefly in the following: I have managed once to convince the court that the death of a worker who died of stomach cancer was caused by a work related dioxin intoxication. The verdict of the court in Hamburg (social tribunal) has however not yet been finalized. The trade association (workman compensation board) of the chemical industry, through which the workers of the company Boehringer Ingelheim are insured, has appealed the verdict. Also once have I managed to convince the trade association of the chemical industry that the acute myeloische leukaemia of a worker of the company BASF AG that finally led to his death was caused by a one time high influence of dioxin. The trade association has acknowledged this correlation by excepting an out of court settlement. Further I know of two cases some time ago, in which the trade association which according to german law is responsible for the chemical industry, has affirmed such a connection. The one case is from quite a while ago. Back then, on the basis of a report of the former toxicologist, Dr.Heinz Oettel, from the company BASF AG the lung cancer death of a worker of the company Boehringer Ingelheim was accepted as caused by trichlorpherol - disintegration product. Lately I know of one case in which the trade association agreed to pay compensation to another worker of the company Boehringer, who was chronically exposed to dioxin. I legally represent five more workers who were exposed to dioxin, and who suffer from cancer, whose cases however have not yet been settled, be it in court or out of court. The photocopies attached to this letter may possibly help you out further, as they go to show, that the company Boehringer has warned different american companies of the undesired by-product dioxin as early as 1957. Best regards, (Dohmeier) Lawyer 17008 Illustration of trichlorphenoxy acetic acid avoiding the forming of Chloracne causing agents. Our synthesis of the 2,4,5 trichlorphenoxy acetic acid takes the following steps: 1) Trichlorbenzol -C12- Tetrachlorbenzol 2) Tetrachlorbenzol -NaOH- Trichlorphenolnatrium a) autoclave reaction b) evaporation of 0H3 Oh c) water vapour distillation of the anisole d) isolation of the trichlorphenols through acidifying and following distillation 3) Trichlorphenol -NaOH CH2 CICOONa- 2,4,5-Trichlorphenox acetic acidic Natrium 4) further processing to pure crist. 2,4,5 T-acid According to our experience the chloracne causing effects are stemming from pollution through by-products, which during the conventional process can only occur, if trichlorphenolnatrium or other alkali salts from trichlorphenol are produced, cleaned and processed and throughout this reaction conditions are given, that are similar to that of a salt-melt. From this perspective then the following picture for the individual process steps emerges in regard to the development of the chloracne causing agent: concerning 1) and 4) : these steps are completely safe concerning 2 ) : at this step the chloracne causing agent may be developing concerning 2 a) to avoid this during the autoclave reaction, an overheating of the autoclave contend is to be avoided (max temp. 150*C) and further attention should be given, that the methanol is worked with as diluted as possible. concerning 2 b) during the methanol distillation the yellow water in the distillation pocket should be held back, so that the dangerous dry heating of trichlorphanolnatrium is avoided. The mud temperature should not be higher than 100*C. concerning 2 c) the water vapour distillation ...... of the trichloranisols must be done in such a way, that no change should occur in the concentration of the trichlorphenclnatriumsolution........water added. concerning 2 d) during the distillation of the unprocessed 17009 concerning 3) phenol it has to be watched, that no trichlorphenolnatrium and no table salt is brought into the distillation pocket and heat together with the phenol. : at this step chloracne causing agents may also develop. To avoid this the condensation of trichlorphenolnatrium with chlore acidic natrium may not be done in a water free medium. A concentration of more than 40% is to be avoided in any case. About the qualities of the chloracne causing agent can in short be said the following: As a neutral body it is water vapour volatile, so that it can accumulate in step 2 c) in the distilling trichloranisol. It is therefore practical to forget about using trichloranisol and to destroy it through burning. Since the chloracne causing agent shows signs of sublimation already at temperatures of 100*C (even though it has a high melting point), the reaction-product of step 2) and 3) should be processed in completely closed apparatuses and the lab should be well aired. 17010 17011 ?' ,* SYMPTOM SILVEX causes may cause 45. BUTTOCK PAIN 46 . CALCIUM DEPOSITS: IN ARM KELOID LUNGS 47. CENTRAL NERVOUS SYSTEM DAMAGE 48. CERVICAL GLANDS ENLARGED 49. CHEMICAL SENSITIVITY 50. CHEST PAIN 51. CHEST "RATTLE" 52. CHOKING SENSATION 53. CHOLESTEROL HIGH 54 . CHOLESTEROLOSIS (GALLO EjADDER) 55. CIRCULATION IN HEART POOR 56 . CIRCULATORY PROBLEMS 57. CLAMMY COLDNESS 58. COLD SORES 59 . CONCENTRATION IMPAIRED 50 . CONJUNCTIVITIS 51. .CONSTIPATION 52 CONVULSIONS 53. COUGHING (with breathing - difficulty, congestion, burning in nasal passages and lungs) >4 . 5RAMPS 5 . "CRIPPLED-UP" (unable to move due to general pain) .6 . CROUP X x TCDD GH C' en 03 cannot causes may cause cause X. X XX can X }( X > > X X x X > X ) < X X X X X X *XX X X X X X XX X\y X X X X x v X XX X /;\ -.7012 X /X 1 COMMENTS ON SILVICX A N D T CDD SYMPTOMS The category cannot cause has been interpreted as u su a l l y will not cause, since it is impossible to say that s o m e t h i n g will never happen. Scientifically one cannot prove the negative. Some of the general terms such as energy loss and anxiety are so non specific as to be associated with almost any illness. Unless these are characteristic of Silvex, they have been listed under cannot cause. TCDD has been treated in a similar manner. vj c c c c c c b Only symptoms known to occur in humans have been listed under causes . Under may c a u s e , most of the symptoms are those seen in animals or might be expected to occur based on our know-, ledge of the toxicity of the compound in h u m a n s . Naturally symptoms must be interpreted in relation to the time of alleged exposure and amount of exposure. For example, a dermatits that occurs months after exposure could hardly be caused by the chemical (contact dermatitis). On ther other hand, chloracne has been known to occur several months after e x p o s u r e . 17013 K> 0*0 e ' SYMPTOM 1 . ABDOMINAL ADHESIONS 2 . ABDOMINAL CRAMP 3. A BDOMINAL PAIN 4 . ABDOMINAL SWELLING 5. A CERUMENOSIS 6 . ACNE 7. A CNE I F O R M LESIONS 8 . ALCOHOL INTOLERANCE 9 . ALLERGIC REACTION (pain killers/tranquilizers) 1 0 . ALLERGY (new) 1 ALLERGY (reemergence) 12 . ANAL PRURITUS 13. ANCIILORHYDRIA 14 . A NEM I A 15. ANGINA 16. A NGIO-EDEMA 17. ANOREXIA ANXIETY .i 19. APPETITE LOSS 2 0 . APPETITE ERRATIC 2 1 . ARM PAINFUL 2 2 . ARM STIFF 23 A R T H R I T I S ; LOWER BACK (new) 24. ARTHRITIS; RHEUMATOID (aggravated) SILVEX causes may cause X X 24<j TCDD a G C'j canno t causer. mny cause c a u C2 cr c:,_ X X X XX X XX XX X x \ X V X X> X> X> X XX X X V / X. X X X XN X 17014 ' ' SYMPTOM 25 . "ATTACKS" (simultaneous chest pain, breathing difficulty, numbness in arms/hands, dizziness, paralysis arms/legs, difficulty sleeping) 2 6 . AUDITIVE DISCRIMINATION (decreased) 2 7 . BACKACIJE/PAIN 2 8 . BED WETTING 2 9 . BLADDER INFECTION 30. BLADDER ULCERS 31. BLEEDING NOSE/EARS 3 2 . BLISTERS: FACE FEET CilEST LEGS 3 3 . BLOOD SPOTS IN EYES 34 . BLOOD SUGAR LOW 35 . BLOODY PATCHES: FACE HAIR MOUTH 16 . ELURRY VISION !7. BLURRY VISION WITH LOSS OF COLOR PERCEPTION 8 / BOWEL MOVEMENT DIFFICULT 9. BREAST CYSTS 0 . BREAST DISCHARGE ("milky") 1. BREAST TENDERNESS 2. BREATHING DIFFICULTY 3. BRONCHITIS 1. BURNING SENSATION: LEGS o SI I,VEX caur.es may cau3o Tcnu cannot causes causo X may c a u:iQ Crl; Cill V X. / X X\ / X> X XX XV X> X> X> X> Xx X X X X X X X' x X XX XX XX X> xX X. 1701E- > XX S 11.VJJX TCDD CO l cc - CO SYMPTOM causes may cause 180. MEMORY LOSS 181. 182. MEMORY SLOWED i MENSTRUAL DISTURBANCES: HEAVY PLOW HEMORRHAGING IRREGULARITY SKIPPING 183. MENTAL EXHAUSTION L84 . M E NTAL SYSTEMS DETERIORATING 185. MUMPS 1.86 . MUS C L E CRAMPS 8 7 . MUSCLE PAIN: ARMS BACK CHEST NECK . LEGS 88. MUSCLE SPASM: ARMS BACK CHEST EYES NECK LEGS 89. MUSCLE SPASM CAUSING BACK DISLOCATION 90. MUSCLE WEAKNESS )1 . NAUSEA >2 . NEARSIGHTEDNESS i 3. NECK PAIN (with pain left side of body) 4 . NECK AND SHOULDER PAIN 5 . 7ERVE DAMAGE: AREA OF SCAPULA CENTRAL NERVOUS SYSTEM RIGHT LEG * X, X cannot causes may cause cause X X X X X X X x' x car car >< \ / > X X X X x X > X X X X X X V x X X X X ? ? >  SYMPTOM 67. 68. CYSTS: ARM BREAST EYELIDS KNEE 1 DENTAL CONDITION POOR 69. DEPRESSION 70. DIAPHRAGM AREA PAIN 71. DIARRHEA 72. DIFFICULTY FOCUSING EYES 73. DIZZINESS WITH LIGHTHEADEDNESS 74 . DIZZINESS WITH LOSS OF EQUILIBRIUM 75. EARACHE 76 . EAR BLEEDING '7. EAR CONGESTION 8 . EAR INFECTION 9 . EAR PAIN 0 . EAR SHEDDING SKIN 1 . ECZEMATOID 2 . EMOTIONAL DISTRESS 3. ENDOMETRIOSIS 4. ENERGY LOSS 5. ENZYME SYSTEM DAMAGE 5- EYE A-V NICKING 7. 'YE IRRITATION (burning, dwelling, durulent itching) SILVEX acz: Tcnn CO cauno:; may cause <7anno L causes cause X X XX X X X X -A X may cause X cam O.iU: ~ Xx X X X 1 X > * vy X XX X A X X X X X X X X X A > >< X X X X x X X X X X xX 17017 2 SYMPTOM 8 8 - EYE SCARRING 89. EYE SORENESS (with con- genstion burning) 90. EYE SPASM 91. EYELID ITCHING 92. EYELID SHAKING 93. EYES TURN IN SOCKET (when in pain, shows white only) 94 . FACIAL BLEMISHES 95. FACIAL GROWTHS 96. FACIAL SCALES FATIGUE 98. FATIGUE (with loss of strength in limbs) 99. FEVER 1 0 0 . FINGERNAIL COLORATION (darker under nails) 1 0 1 . FINGERNAIL SPLITTING 1 0 2 . FOOT CRAMPS 103 . FOOT ITCHING 104 . FOOT PAIN 105. FLAKING SKIN; HANDS/EARS 106 . FLU & COLDS 10 7 . FOOD SENSITIVITY 1 0 ' GALLBLADDER DISEASE 109. GAMMA (GLOBULIN) LOW 1 1 1 0 . GASTROENTERITIS SILVLX causes may cause TCDD O Cc C cannot causes CelUSO mny C Si u:jG C-~ C x- X v A A X X X - < / A x X X A X. ' X X. X X X X X X X X X ' X V / V / \ \ y \ V X \ / V 1 7018 * ' SYMPTOM L58 - JOINT PAIN .159. KIDNEY, BLADDER, URINARY TRACT INFECTION 160. LACK OF MOTIVATION 161. LEAKY VEINS WITH SUFFUSION 162. LEG PAIN 163. LEG SWELLING 164. LEG WEAKNESS 165. LIBIDO INCREASED L6 6 . LIGHT SENSITIVITY L67 - LIPS SWOLLEN L 6 8 . LOSS OF AMBITION .69. LOW BLOOD SUGAR 70. LUMP IN TIIROAT 71. LUMPS: ANKLES ARMS HANDS KNEES 72. LYMPH NODE SWOLLEN 73. LYMPHOCYTOSIN ? 74. MALAISE 75. M A NU A L DEXTERITY DECREASE (due to numbness in hands) 76. MASCULAR LESIONS ? 77. MASS, LEFT BREAST 78. MEASLES 79 . M E M O R Y LAPSES ... ...... i )OW SILVI DC TCDD CO cn V-' 4 nr causes may .cause cannot causes cause X X may C U Ijc car *'-a u ~x > X X X X X X X X. X X X, & X X Xs X > > X > > X X X X X X X -X X X* XX 1 XX -- -- X> X> X 17019 >< SYMPTOM 111. GINGIVITIS 112 . GROWTHS 113. HAIR ABNORMALITY 114 . HAIR LOSS 115. HAIR WON'T G|<()W 116 . HALLUCINATIONS ("feels that one is being oaten from inside o u t , l,Y w o r m s ) 117. HAND COLDNESS 118 . HAND CRAMPS 119. HANDS CRACK 12 HANDS SHAKE 1 2 1 . HAY FEVER 1 2 2 . HEIiDACHE (sovt'fg^ some last for weeks) 123. 124. HEARING DIFF 1('(JLTY/LOSS HEART FLUTTER 125. HEART PAIN 126 . HEART SOUND (3 ^) 127. 128. HEAT SENSITIVITY HEELS CRACK 129. HIATAL IIERN.1A 130. HIPS PAINFUL 131. 132. HOARSENESS HYPERACTIVE 133. HYPZRINSULINISM oO CE . SYMPTOM S 11.VEX causes nay cause L34 . HYPERTENSION L35. HYPOCHROMIA 136. HYPOGAMMAGLOBULINEMA L37. HYPOGLYCEMIA L38. HYPOTHSIA 139. HYPOVITAMINOSIS 140. ILEITIS L4 1. ILEOCOLITIS L4 2. ILLNESSES EXACERBATED L 43 . INABILITY TO FOCUS EYES .44 - INCOORD T.NATIOH/EQUILIBRJ.UM LOSS .45. INABILITY TO ACHIEVE ERECTION X K .46. INABILITY TO CONCENTRATE .47. INFERTILITY X 48 . INFLUENZA ,49. INSOMNIA 50. INTESTINAL KINK t .51. INTESTINAL SPASM .52. } .53. INTERTRIGO IRRITABILITY 54. ITCHING .55. JAW INFECTION s .56 JAW PAIN .57. JOINT DIFFICULTIES o O TCDD cannot causes cause X X X X X nay enutif; _ C7 cn CO w ^can: cam X X X X X XX X> X > X> Xv X X > X X. X X X X X X X X, X .L7021 X X y X X X >< \ / X X >1 1 X /  S ILVEX Tenu SYMPTOM 1 96. NERVOUSNESS 197. NEURITIC PAIN 198 . NOSEBLEEDS causes may cause cannot causes cause X X X may cause X 199 . NUMBNESS: ARMS ARMS & HANDS FEET FINGERS & WRISTS LIPS S. TONGUE (with wheezing and epigastric distress) 200 . NUMBNESS & PARALYSIS: HANDS & LEGS 2 0 ' OTITIS MEDIA X ? Y X X * 2 0 2 . OVARIAN CYSTS 203- OVARY IRRITATION 204 . OVARY PAIN 205. PAIN, BACK OF HEAD & AROUND EYES 206. PALPITATION 207. PANCREAS AREA PAIN 208 . PARAPHIMOSIS 209 . PARALYSIS OF HANDS (partial) 2 1 0 . .PARALYSIS OF LEGS (partial) 2 1 1 . PARESTHESIA 2 1 2 . PELVIC INFLAMMATORY DISEASE 21. 214. PELVIC TENDERNESS/PAIN 9 PERIDONTOCLASIA ' 215. PHYSICAL EXHAUSTION X X X X X ,X X * X. X X X -- X - L7022 r~ SYMPTOM 216 . PHYSICAL SYSTEMS DETERIORATING 217. PNEUMONIA 2 1 8 . POLYPS 219. PROSTATE ENLARGEMENT/PAIN 220. PURPURA 2 2 1 . RAPID HEART BEAT 222. RASH: ARMS FEET HANDS LEGS 223. RHINITIS 224 SCALING IN EARS WITH BLOODY PATCHES 225. SCALP BLOODY 226 . SENSITIVITY TO LIGHT 121. SENSITIVITY TO NOISE !28. SHORTENING OF LIFE EXPENTANCY 2 9 . SHORTNESS OF BREATH 30. SHOULDER PAIN 3 1 . SHRUNK ONE INCH SINCE SPRAY 3 2 . SIDEACIIES 33. SINUSITIS 3 4 . SKIM IRRITATION (burning, i telling) 35. SKIN LESIONS: HANDS 36. SLEEP COMPLAINTS SILVliX causer; may C iU U iO ~' c tcdu canno t 'causes CJi IJ : | n ma y C (U | n e:a n> X >< X* X> XV / X> X> X XX XX XX XX XX XX XX XX XX XX X 117023 \ / 1 SYMPTOM 237. SNEEZING 238. S O R E THROAT-i 239 . SPINAL MUSCLE STASMS 240. SPINAL PAIN 241. STOMACH CRAMPS 242. STOMACH PAIN 243. STREP THROAT 244 . SUDSTERNAL PAIN 245. SUSCEPTIBILITY TO INFECTION & DISEASE INCREASED 2 ` SWALLOWING DIFFICULTY 247. SWAY BACK 248 . 249. SWELLING: ABDOMEN ANKLES FEET HANDS LEGS LIPS BLOATING TACHYCARDIA 250. TANTRUMS 251. * 252. TEMPORAL PAIN TENSION 253. THIGH PAIN 254. THROAT INFECTION 25' T H R O A T R A W 256. TH Y R O I D PROBLEMS <= c SILVEX cr: TCDD cnusnfi mny cnnnrjt cjau.'ifif. mny f'X cause cause cause c: X' x X * XV X X /\ /V. X i V X X/ X\ - X V X XX * _A _ XX V X. X ......... 'X X -- ...... VX -- X XX X X X X X " r?024 4 ' - SYMPTOM :il v . ....... causes may cause :.. e.lliir'l cause ..... . causes `W l 1 ray | un cause | . >.51. TINGLING SENSATION : FEET & HANDS FINGERS & TOES '58. TIRES EASILY 25$ . TONS] i.rn S 260. TUBALIC INFECTION 261. TUMORS & GROWTHS 262. ULCERS : BLADDER BLEEDING DUODENAL 263 . UPPER RESPIRATORY INFECTION 26 4 UPSET EASILY 26 5 . UPSET STOMACH 266 . URINATION FREQUENT !67. URINARY TRACT INFECTION 00 VO VAGINAL DISCHARGE 69. VAGINAL IRRITATION (may be followed by bladder infection) 70. VAGINAL ITCHING 71. VAGINAL LUMPS 4 72. VOMITING 73. WARTS 74. WEAKNESS 75. WEIGHT GAIN 76. WEIGHT LOSS 77. WHITE BLOOD CELL LOSS - X v A X X y y y y V y y v y X x y y y * y y >< y ,> X :> \ j V/ X \ / > \ / \ 4 \ / \ y X X y X * X 17 325 > % / X X > DOW 1 s ynrTon S i l v i :;-: causo: may cause reni) c a n n o t causes may causo cause c s 27 8 . WITHDRAWN EMOTIONALLY 279. WORD TRANSPOSITION : SPOKEN TYPED WRITTEN 2 8 0 . WORKING CAPACITY IMPAIRED 2 8 1 . WOUNDS HEAL SLOWLY 282. WRITING DIFFICULTY: HANDS NUMB LACKS CONCENTRATION WORD TRANSPOSITION 283 . WRIST ACHE y VC. V V V < 17Q2S 23T0NH > s m i i M oom S***- ot0 0 4 4 CO / /fo ; t r # e e > JN 00 w rl (LIMEAD) (1962) TRANS. MID. NO. 12182 NTC. NO. LILLE MEDICAL. LILLE. V . 7(10)104 Ser.3 (1962) Polyneuritis after usins a weed killer? containing acid 2 f4-D. AUTHOR? Foissac-Gedoux* Phil TRANSLATOR? Farinas DATE? November 1980 REQUESTED BY? U. Mullison* 9001 TRANSLATION NO.? 80-11-34 17027 12182 DOW 1 7 1 4 1 5 Trans. &>- l l ~ 2 Record _ /o > r? MID. * * * > /g A ' CODEN ci Lille Medical v. 7 (io) *1 0 1 9 - 5 1 (1 9 6 2 ) Clinical Facts POLYNEURITIS AFTER USING A WEED KILLER: CONTAINING ACID 2-*l-D. By Philippe Foissac - Gegoux, Annie Lelievre, Bernard Basin and Pierre Warot. - `' By 1958, one of us (*) had already drawn attention on the risks involved with the more and the more frequent use of chemi cal products In agriculture: two observations were considered at the beginning of this work which concerned the dangers de rived from handling organics derived from phosphorus, powerful Insecticides; one of these observations.concerned an agricul tural worker who handled, many months before the installation of a polyradiculorephritis syndrome weed killers, sodium and 17G28 00W 1 714156 2 potassium salt3 of 2 - methyl -4- chlorophenoxyacetic acid; for several reasons, we had eliminated in this case the toxic origin of the neurological troubles..., but we ignored at that time that these products could have a toxic effect. In truth, the cases of intoxication due to weed killers are rare and are especially known by toxicologists and doctors; but it is feared that they may multiply: for almost all. the substances destined to stop the development of weeds are dan gerous to man. Mineral compounds were being used such as chlo rates and sulphuric acid: these were three times more incon venient with an action often little selective, hence a global destruction of grasses and cereals, of a delicate use (risks of explosion and fire) and of a sure toxicity (burns-methemoglobinemy). The "vegetable hormones", the last commers, make up an undisputed progress. This name is given to chemical bodies whose action is comparable to that of phytohormones elaborated by the-plant itself. In small doses, they in fact stimulate the growth, of young vegetable cells; but in the large doses that they are used they cause "a crazy exaltation of the ma n i festations of growth, a disorderly activity which drives the most deverse monstruosities, the intense consumption of reserves and finally the death of the grass". These "hormones" are oxyacetic derivations of the benzine nucleus and of the naphtalene nucleus of the phenyl, naphtyl and indolacetic, propionic and butylic acids as well as some of their derivatives. One of the most widely used is 2-^dichlorophenoxyacetic acid (Ac. 2-*l-D.) whose action powerful and 17029 DOW 1 7 1 4 1 5 7 3 selective, is not, hoviever, without inconvenience as the following observation proves. Observation: G... Gerard, 52 years old, farmer, was referred to the Neurology Clinic on July 30, 1962 by Doctor Chuffart for sen sory and motor problems of the lower limbs. This man, without any previous pathological problem, who is not an alcoholic, dates the beginning of his troubles precisely on June 2, 1962. On that date he felt, suddenly, an acute pain throughout the entire right orbital and periorbital region becoming weaker the next day making room for (burning sensation) paresthesra and rd anumbness in the same area. Also on June 3 , he noticed (decreased sensitivity) hypoesthesia in the right leg. On June 16 , two weeks.later, the right leg recovered a / normal sensitivity but the numbness was now felt on the left leg; besides, the lower left limb is now "weaker" and cannot move except with the aid of a cane. The problems remained about the same untill July 30 when 'T he entered the service. He now felt a persistant hypoesthesia in the right eye area, with hypoethesia of the cornea, the patient now felt some pain in the same area. The subject is uncertain of his lower left limb where a slight reduction -global- of the segmentary force is noticed. There is no other trophic vaso-motor trouble. The knee reflexes are rather sharp while the ankle reflexes are suppressed. The lower left limb suffers from a global 17030. DOW 1 7 1 4 1 5 8 4 hypoethesia only deep sensitivity was maintained. The neurological examination of the upper limbs is strictly negative. Besides the general condition is excellent. There is no albuminuria. The blood formula reveals an eosinophilia (8# on Aug 2 and 9# Aug 30). Two electrophoretic blood tests, several week3 apart show a slight decrease in albumina (43 then 46 grams) and an increase of alpha -2 - globulines (13 then 15 grams per liter). The renal biological exam, the galactosuria provoked, the reactions of floculation do not show any abnormalities. The electrocardiogram is normal. So is the backside of the eye and the E.E.G. The electrodiagnosis shows the following results: ----- proof of stimulation of Aug 2, 1962: integrity of the upper limbs; in. the lower limbs there.is no evident weakness but slight problems of excitability (galvanic hyperexcitability galvanic and faradic hypoexcitability of the extensor of the left big toe ---- high chronaxies of the extensors of the left big toe) witness however a slight neurogenic seizure (Doctor Spy); ------- electromyography of the two frontal tibia on August 4, 19 6 2 (Doctor Ramez): trace of neurogenic seizure of the two muscles examined. The patient leaves the clinic on September 8 , 1962: during hospitalization he was submitted to a daily injection of 200mg of vitamin B1 and 250mg. of vitamin B6 ; besides 5,000 gammes of hydrocobalamine were administered every three days. The facial aches practically disappeared; the deficiency of sensitivity in 17031 DOW 1 7 1 4 1 5 9 5 the face and the lower left limb was notably Improved; the motor deficiency disappeared and the patient was able to walk normally; the areflexia achilleine persists, there is no visi ble atrophy. There are still electromyographic signs of neurogenic seizure of the right frontal tibia (the left side was not examined). On the contrary the electrodiagnostic of stimula t i o n : ^ August 28 are absolutely normal. The aetiology of this polyneuritis of the lower, limbs with irritative and deficient right trigeminus was suggested to us by the patient himself who was able to relate the begin ning of his trouble while killing grass. Made June 1st and the last days of May 1 9 6 2 . Ihis operation consisted of a spraying of two different solutions but both having a base of acid 2-^-D, containing 235 and *110 grams per liters. It was carried out with a tractor which tows the spraying device and which is in a cabin, open in the back; it was very windy when the operations took place and the wind beat the toxic substance in the cabin. These exceptional circumstances, the long exposure to the toxic substance, we had to admit that it was a polyneuritis due to 2-*J-D a c i d . Besides, this observation is not alone in the litterature that includes a certain number of facts of intoxication by these substances, notably In the case of farmers: some hours after inhalation of the toxic substance there Is generally vomiting, DOW 1 7 1 4 1 6 0 then subjective sensitive troubles of the type of paresthesis or even pain, then motor troubles, the paralysis of the four limbs or the lower limbs. This sensitive - motor polyneuritis inconstantly associated with an albuminuria and an interocolite board picture chart description ----- is usually irre versible or very slowly and very partially reversible. The toxicity of these substances is equally proven in the case of intoxication of workers at a vegetable hormone factory: The penetration of the toxic substance through inhalation, but also through the skin; the workers often complained of somnolence, of the lower limbs feeling heavy, gastralgia, loss of appetite, hypersialosis, as well as hypersensitivity of hearing: all of these troubles are, generally, transient. Finally, experimen tally, 2-^-D acid administered intravenously or even orally can be fatal: this happens suddenly, either in a neurological stage in the form of a coma with hypertonic of the limbs, or ventricular fibrillation with relatively large doses, but varying according to the animal tested (about 300mg to one gram). To our knowledge, there was no acute intoxication. Bibliography - Assouly M.- Selective weed killers and growth substances. Tecnical survey. Pathological effect on man during the manu facture of the ester of 2-^-D. Arch. Mai. Prof., 1951 1, 26. Golstein N. P . Jones P.H. and Brown J.R. --- Polyneuritis after exposure to an ester of 2-^-D acid. 17033 DOW 1 7 1 4 1 6 1 7 Hill E.V. and Carlisle A. ----- Toxicity of 2-4-D. for experimental animals. Jour. Indust Hyg. and Toxic, 1974, 29, 2 , 85-95. Lhoste I. - Chemical weed killers. O.R.S T.O.M., Paris, 1958. Footnote p. 1 (*) P. Nayrac, M. Fontan, P. Warot, J. Lescut and J. Delahousse: Lille Medical, 1958 3, 3, 161-164. 17034  - n - iX - \ FAITS curii2 U L l M d i c a l v < i( t o ) io w -n [ i l ' ) l'DLYSE\ ItlT E A M E S (SAGE DA S DES HEUHAST : L'A U D E A-.YD. par Philippe Fui^AC-t.'KiMirx. Annie* Lmukyuk. l!<-rn;ii-<l li\six i*t I'icm* \Y\itt>r. j DOW 1 7 1 4 1 6 2 Dj en liifiS. l'im d'entre nous (.*) avait attir l'attention sur 1rs risques que ('importait l'u tili sation lr plus rn plus fivqurtito en agriculture de produits chimiques : deux observations taient l'origine le ce travail dans lequel l 'aeccnt avait t mis sur 1rs dangers de la manipulation des drivs organiques du ph.sphore, insecticides puis sants ; l'utir le r*s observations concernait un ouvrier agricole ayant manipul, plusieurs mois avant l'installation d'un syndrome de polyradiculonvrite. des dsherbants. s*Is sodique et potassique de l'ae'ulo 2-mtbyl-4-ebloropbn)xyactiquc ; pour plusieurs raisons, nous avions limin dans ce cas l'origine toxique des troubles neurologiques..., mais nous ignorions I poque que ces produits pou vaient aviir une action toxique. A vrai dire, les cas d'intoxication par des dsherbants sont rares et sont surtout connus des toxicologues et d*s mi'ilecins du travail ; mais il est rmindre pi'ils m* se multiplient : car presque toute les substances destines entraver 1; dve loppement des mauvaises herbes sont dangereuses pour l'homme. On utilisait nagure des composs' minraux parmi lesquels les chlorates et l'acide suli'nrique : ceux-ci avaient le triple inconvnient d'une action souvent peu slective, *r) une des truction globale les herbes et des crales, d'un emploi l!irat trispies l'explosion *t d'incendie) t d'une toxicit certaine (brlures - mthmoglobi nmie). Les < hormones vgtales , dernires venues, constituent un progrs indiscutable. On donne ce nom des corps chimiques dont Tact ion est comparable c*lle d*s phytohornnuH's labores par la plante rlli-mmc. A doses taibh's, *Ues stimu lent en cct la roissance les cellules vgtales .jeunes ; mais aux loses fortes auxquelles on les emploi*, elles provoiucnt une exaltation folle des manifestations le croissait-*, une activit lsorIo iiik V pii entrain* l'apparition de monstruosits les plus livers*s, la *unsommation intense des rserves et finalement la mort au stade herbac . ( ) P. N a v ra -. M . F u s t o .'. P . W a r o t , J . Lus u t et J . Di i-.wiocssi-: : IJ il r Mcilical. 1958. :l. 3. 161-161. ( 's hormones sont les drivs oxyacthpics du noyau benzne et du noyau naphtah'-iie dits acides phiiyl, naphtyl *t iiulolactiipn-, propionique et butylique. ainsi que de ci-rtains h* leurs drivs. I/iiu les plus employs est l'acid. '2-4lichhirophnoxysctiquc fAc. 2-4-1).j dont l'action, puissant* et slectiv*, n '*st c*penlant pas lniie le tout inconvnient ainsi pte I* prouve l'observa tion suivante. O SK ltV A TlO N : Ci... ( it u a iil. 53 ana. a g ric u lte u r, est adress la C lin iq u e Neinologi;. le 30 Ju illi-t 1962, |ia r le D octeur C u i rru - .r pour l-s trn u lili-s s e n s itifs s m oteurs l-s meml:r-s iin r ie m s . O l hom m e, sa n s antecdem s |>:fliolo g iqucs no tables. q u i n'est [>as th y liq u e , s iin e trs prcism ent le dbut de s-s troubli-s au 2 ju in 1962. I l iT S se u tit ce jo u r-l . brusquenn-nt. un.- douleur v iv e dans toute la rgion o rb ita ire et p rio rh ita ire droite, s'attnuant ds le lendem ain pour fa ire place des p a re s ilu;.si*s et une a n e s ili s ic cupuiil le nu'n<- i -rrilo i re. L e 3 ju in g ale m e nt. il note i'^ p p ariiio n l'une li>poesihsie de la jam be droite. L e 16 ju in , so it liu x si-m aim -s ap rs le dbin. la jam b e d ro ite a r cu p r une s e n s ib ilit n o i: .le n ia is l'an e sth sie , lui p e rsiste lu face , a gagn la jam be gauche ; d'au tre p a rt. 1; nn-mlir* in f rii- ilr gauche *sl s plus fa illie .> et la m a rch e n'est possible qu'avec l'aid e l' une canne. L e s troubles restent sensiblem ent iilr iit iip c s jusiu'au 3i) ju itle r. late de l'e n tr e lans le servie'. On constate alo rs la persistance d'une iiypoest hsie lans le te rr.to ire de l'opluaIm iqne d ro it, avec liypoesrhsie corn-unt* ; le m alade accuse enco-e d an s ce mme t e rr iio ir e quolques pi.MJth-s lo uliiuri-ux tr'*s passug.-rs i-t l'iiit. u s it ' modre. L e su je t s* lit in c e rta in do sou im n il.re in f rie u r gaueli. an iiiv<-an iliu p iil on coust.-u- un. h-g- liminui ion -- globale -- 1p la fo rte seg m en taire. i i n 'e xiste aucun trouble tro p hiq ue, aucun trouble v.isu-umiui-. L e s rlln xcs lo iu lie u s sont plutt v ifs tan dis que les acblllens sont abolis. Le membre in f rie u r gauche'est le sigi d' une hypo<-sthsie glo b ale, .seule la s lisib ilit profonde tant conserve. L ille M d ical. 3' S rie . A nne 1962. T o m e V U , N 1) le 19 17035 DOW 1 7 1 4 1 6 3 LY xa m e n ncui ologiqiip d is m em bres sup rieu rs se lvio strictem ent ngatif. D'autre part, l'iat gnrai est excellent. II n'y a pas d'album inurie. I.a form ule sanguine r v le un* o sin o p h ilie ( S ' , le 2 aot .t ' J' , le 30 a o t). Deux exa m en s lectro p ho rtiq u es sa n g u in s. A plusieurs sem aines d 'in terva lle . montrent une baisse lgre de ralbum in* (13 p u is -10 gram m es j et une aug m entatio n d is :il|d ia-2 -g Io h u lin fs (13 p u is 15 gram m es par litre). Le b ilan biologique r n a l, la g a lu rto siirie piiivn<|ue, les rnciions de lloeulatinu ne m ontrent pas d'anom alies. L 'lectro carriio g ram m e est n o rm al. 11 en est de mme 'lu fond d'flcil et de l' E .E .G . L' le c tro d in g n o stic donne les renseignem ents su iva n ts : -- preuve de .stim u la tio n du 2 aot 1962 : in t g rit des membres suprieurs ; aux membres in frieurs, il n'y a pas de ractio n de ralentissem ent vidente m ais les lgers troubles de l'e xe ita b ilit (h y p e re xcita b ilit g a lv an iq u e h y p o e x c ita h ilit g a lv an iq u e et fara d iq u e de l'e x te n se u r propre du g ro s o rte il gauche rh m n a x ie s leves les extenseurs il il gros o rteil gauche) tmoignent cependant d'une lgre attein te neurogne (D octeur jrx ) : -- lectrontyngraphie des deux jantbiers an trieu rs du 1 aot 1962 (D o c te u r H .i J Ii /.) : trac d 'atte in te neuro gne des deux m uscles explors. L e m alade q u itte la c lin iq u e le 6 septem bre 1962 : d u ra n t l'h o s p ita lis a tio n il a t so u m is . une in je ctio n quotidienne de 2uo nig. le v ita m in e B t et 2 m g.. de vitam in e B 6 ; en outre, l'hydrocobalaniine lui a t a d m in istr e la dose le 5.uuo gam m as tous les* tro is jours. L e s algies faciales ont pratiquem ent disparu ; les troubles se n sitifs d ficitaires de la face et du membre in f rie u r gauche se sont notablem ent attnus : le dficit m oteur a d isp a ru et la m a rch e est redevenue n o rm a le ; l'arflexie achillenne persiste ; aucune atrophie ne s'est dessine. Il persiste des signes lecirom yographiques d'atteinte neurogne du ja m h ie r a n t rie u r droit (l'exam en n'a pas t pratiqu du cftt g a u ch e ). P a r co n tre, les rponses l ' le ctro d iag n o stic de s tim u la tio n , en date du 28 ao t, sont absolum ent norm ales. L 'tiolo gie de cette p o ly n v rite des m em bres in f rie u rs avec a tte in te ir r it a t iv e Pt d fic ita ire trig m e lla ire d ro ite nous a t suggre p a r le m alad e lui-m m e qu i n 'a pas manqu defa ire le rap p ro ch em en t e n tre le dbut de ses troublps et une o pration de dsherbage effectue le 1 " Ju in etles d e rn ie rs jo u rs de m ai 1962. Celle-ci a consist en une p u lv risatio n le deux solutions d iff rentes m a is toutes d eu x base d 'acide 2-4-D. et en contenant 235 et 110 g ram m es par litre . E lle s'est effec tue grce un tracte u r qui rem orque le p u lv risateu r et qui est surm ont d'une cabine, ouverte A l'a rri re ; or. les oprations se sont droules par vent violent et celui-ci rab attait dans la cabine le nuage de substance toxiqup. Ces circonstances exceptionnelles, la longue dure d'exposition au toxique, nous ont fait adm ettre qu'il s 'a g issa it vraisem blablem ent d' une p o ly n vrite dite h l'arid e 2-l-D. Ad l'estt. celle observation nY-d pas isole dans la littrature t|iii comporte un certain nomlire de faits d'intoxication par ees substances, iiotainmcnt fiiez des agriculteurs: quelques heures aprs l 'in halation du toxiipii- surviennent hnhitur!h-im-nt tics vomissements, puis des troubles sensitifs subjectifs type de paresthsies ou mme de douleurs, puis les troubles moteurs, l'atteinte paralytique pou vant intresser les quatre membres ou les membres infrieurs. Cette polynvrite sensitivo-motriee -- incuusfammcut associe une albuminurie et un tableau d'entrocolite -- se rvle habituellement irrversible ou trs lentement et trs partiellement rversible. La toxicit de ees .substances est galement prouve par !-s cas d iutoxieatiou chez les ouvriers travaillant la fabrication les hormones vgtales: la pntration tin toxique s<- ferait par inhalation, mais aussi par voie cutane : les ouvriers se plai gnent souvent de somnolence, de sensations le lour deur des membres infrieurs, de trustrallies, (l'ano rexie et d'Iiypcrsialorrlie. ainsi que d'une hyper sensibilit de l 'oue: tous ees troubles sont, dans la renie, fucaci's. Knfiii. exprimentalement, l'acide '2-4-I\. administr par voie intraveineuse ou mme par voie orale, petit entraner la mort : celle-ci survient, soit dans un tableau ncuroh trique sous forme de coma avec hypertonie des extrmits, soit par fibrillation ventriculaire, et ce pour des doses relativement leves, mais videmment varia bles suivant l'animal en exprience (de l'ordre de 300 mg. un rrantmo en une prise). A notre con naissance. il n'a pas t effectu 'l'intoxication subaiiru. a' B IB LIO G R A P H IE A s s o c i a M. -- D sherbants, s le c tifs et su b sta nces d croissance. Aperu technique. E ffe t pathologique sur l'h o m m e au co u rs de la fa b ric a tio n de l 'ester du 2-l-D. Arrh. M"l. Prof.. 1951. 1. 26. Giu .s i k i x N .P ., J o skn P .H . and n iio n s J . R . -- P o ly n v rite aprs exposition un e ster de l'acide 2-l-D. In Arcli. Mal. prof.. 1969. p. 381 (a n a ly s e ). H i l .i . E V . and Caki.isi.k A . -- T o x ic it y of 2-l-D. for e x p e rim e n ta l a n im a is . Jour, huluxt. lluo. oU Torir. 1947. *2il. 2. 85-95. L iiostk I. -- /.** ilrxh,,rlnintx rlihiii'iti' i. O .ll.S T .O .S L P a ris , 1958. 1050 . L i l l e M d ical. 3' S rie . A nne 1982. Tom e V I I . N 10 17038 . Mq.viKc.x G ' e l D i V i t o G. -- S u r l'in to x ic a tio n al cue "p a r` un dsherbant. l'acide 2-l-D. C ontribution Cli nique. f - l i - i J/ e d ic t. 1161. H . C. S O -IS . T u t .t M .S. -- A t: suj'-t des d sh e rb an ts rc lt- c iiis . . \ n h. 1 1951. J. 2C-3n el lu. . I.'i. un M .K . a n il N o i:m i.\ I l . T . -- E ffe c ts of 2-1 d lc h V >. I)!it n o \ y a c " t ic nci<l on c h ic k s S c n in:'. I l l s . z `. \ 79-13'). Le s em plois en u c ric u liu iv des dsherbants s h c iits I ih s rc K iilttris a te u is i!*1 vg tation. Ayriculturr F n n i \ 't i \ r , 1956. 111. 17'i. 45-5-t. BOW 1 7 1 4 1 6 4 M H S ! S U I T E .1 U s T i : V I . \ c i Dinsox MOXOCYTOCllX :s D D L \ \ D I L T 11. I X ( 'A S DU Pierre W a k o t , .JjwM|iit"s D e -u x . Ren L i-h a o k et lliehel 1)tjuctii Longtemps considre comme l'apanage presque exclusif tle 1'animal, / 'infection listrienne semble .se manifester chez ("homme avee une frquence accrue : il'aprs Bi_s\\fci^r et StmiEit, 70 cas seule ment le listriose luimaVne avaient t rapports avant 1!>."il. taudis que '!!<') nouveaux cas l'taient ,1e lil.",!I i:>.',7. \ Sans doute le <iiniriiosti;*\I>it*ti*rit>l,jrit|Ue est-il fait plus souvent qu'aul rcl'oisV: un passe souvent ct du diagnostic bnclriologispic parce t|ue l'un carte trop vite, sous l 'appcllatiutv.le facilite de cuutumiiiants diplitriniorphcs tlesHuieilIcs (7ram sitif isols d'hmocultures, de liqtiiHe cphalo- . -.eliitlieti ou tle tout autre pruduit e t \|ti i sont il 'authentiques listiia il..u,i:\'ONXtE). \ l a i s il est Mrs vraisemblable aussi que la diffusion, \ceon- nue, de riofei-tiuu dans le rsilie animal eut ruine In niulliplieatiou les transmissions accidentelles^ l'homme. \ Il est rare que le clinicien fasse le diagnostic tle listriose tri en demande continuation au hiolutristc : rien d'tounaut cela si l'on considre qu'il s'agit d'une infection de connaissance rcente et dont la frquence est d 'ailleurs toute relative : lu littrature franaise ne comportait en effet, en 10."'). que "i observations. D 'autre part, les list rioses se prsentent sous des aspects cliniques extrmement divers : l'im portante statistique de S i:i.ix<:i:k. portant sur les .'44 cas publis dans le monde eu lJti, relve KiO tals septicopyobmiques du nouveau-n. 100 mningites purulentes avec ou sans eiicplialite, 4] formes sanguines type de mononuclose infectieuse. 10 conjonctivites gratinloinateiises. les autres cas coucernaut les locali sations viscrales diverses : endocardites, myocar dites. mll'ites. etc... Tout au plus peut-on parfois souponner l 'ori gine listrienne d 'un tat septicopyohmiquc du nouveau-n,' ou d'une mningite purulente de l 'enfant ou de l 'adulte, parce q u 'il s'agit l des manifestations les plus frequentes de l 'infection. .Mais, le plus souvent, le mrite du diagnostic revient au seul bactriologiste... et ce n'est qu'a posteriori, lorsque le germe est identifi, que le clinicien mettra l'accent sur quelques nuances smiologiques qui auraient d faire voquer la listriose, mais dont 1a signification lui avait chapp. ("est ainsi que les choses se sont passes dans l 'observation que nous rapportons d'une mnin gite purulente de l'adulte, inquitante d'emble <le par l'intensit des troubles de la conscience et du drglement neuro-vgtatif : ce fut une sur prise d'apprendre que le germe responsable en tait listria moiiocytogne. spnsERVATION. .V tv L o n . 6<> a n s, m can icien, sa n s an tcd en t patholo g iqucN otiiuhle. prsente, le 17-3-1962. tr s b ru talem e n t, v e rs 12 h e u re s. un tat in fe ctie u x d 'a llu re g rip p a le , avec fivre 3yV co urbures, m alaise gn ral, qui l'oblige s'a lite r. C t \ troubles s'IntensiAent les jo u rs su ivan ts tan d is qu'appaiNilssent cphales de plus en plus intenses c i vom issem entA L e 22 m a rs est constate une ra id e u r m ninge et le ma Inde est ad tv.-^ la C liniq u e N eurologique. I l est adm is au dbut de Ism -fs-m idi. L'u n d'en tre nous cons tate a lo rs un syn d ro m X mning fra n c , un tat d'obnu b ila tio n in te lle c tu e lle ;Na-c lgre a g ita tio n psycho m otrice : la tem prature cm 39-5 ; le m alade a un hoquet perm anent ; l'examcW neurologique ne rvle aucun sicn e p a rticu lie r. Le liquide rachidien se rvle L ill e M dical. 3' S rie . A im e 19>2. T o m e V I I . N " 1" 10? I 4 '; r w 'J 1703? mm^v Sr' .\'v'  CCW06 I5 5 8 4 .I 1 -i JO^N o. CONNER S ellers, Conner & Cuneo ATTORNEYS ANO COUNSELORS IS 7 5 CYE STREET. NORTHWEST W A S H I N G T O N , O. C. 2 0 0 0 5 WILSIC M. AO*HS. j R ROeCO A. ANTHONY JTCvCN L. BHiCCCBman WILLIAM M. auTTCBflClO SOh Qan Oa n t l ' w C. STANkCY DECS HERBERT L. fEn STER RiCharo a. FLYC jamCS j . Ca u a Gmcr ROtCBT A. MAN&Ruh CharlCS a. O'CONNOR. ZD JOHN S. PACHTER THOMAS L. RATTEN RatmONO s . c. rusmxar ncii. h. ruttcn scr c marvCT o. SHCRZCR RICmarO c. SOIISARHC' WILLIAM j, SBBIGGS COWARO L. wCIOCNFELO BUEL WHITE ChaRlCS C. YOnhCRS October 29, 1980 JEFFREY P. ALTMAN JCO L. |A | IN JULIC FOX BlaCkSmaw JEFFREY A. BOCCACR JANlS A. CHERRY JOHN C. CONNER. JR. JOHN a. COuR* mauREEn OuiGnan LAWRENCE S. CBNER Lawrence m. Farrell O. MICHAEL FITZHUGH alien a. gre en ROBERT c. GREGG C. SANOERSON HOC JOE G. HOLLINGSWORTH "NOT AOMITTCC In CXC. THOHAS w. HUSSEY MICHAEL T. JANIK MICHAEL T. KAVANAUGH" STEPHEN O. ANIGHT FREOERIC M. LEVY ROBERT M. L'NDOUIST LOUiSC WISE LUCAS LANE MCVEY MARILYN LYNG O'CONNELL THOMAS C. PAPSON MITCHELL H. SEGAL DEL STILTNER CHRISTIAN VOLZ KENNCTH w. WEINSTEIN BARBARA G. WCRTHCR BY HAND 0 0 .1 1 0 0 ASHLEY SELLERS (19 0 2-19771 GILBERT A. CUNEO (1913-1876) MAX GOLOCN" ALBERT L. RE CVES j OCL p. S he do OF COUNSCL TELEPHONE (202) 7 6 8 - 7SOO TWX 710-622-01*8 CABLE: S CLCOnCu TELECOPIER (202) 768-7S6* WRITERS DIRECT OlAL NUMBER (202) 768- Director, Special Pesticide Review Division Office of Pesticide Programs U.S. Environmental Protection Agency 401 M Street, S.W. Washington, D.C. 20460 (TS-791) Attn: Ms. P a t r i c i a Cohn R e : Formation of 2,4-D Task Force Research Data Dear Ms. Cohn: . This letter is to advise you of the formation of the "Task Force on 2,4-D Research Data." The purpose of the Task Force is to develop jointly, p ursuant to the provisions of 3(c)(2) (B) of FIFRA, the a d d i t i o n a l data i d e n t i f i e d by E P A in its Ord er and Notice of August 29, 1980 to registrants of products con t a i n i n g 2 , 4-D. The C h a i r m a n of the T a s k Force, J o h n E. Davie s, n o t i f i e d all registrants with manufacturing-use products of the Task F o r c e ' s formation (as i d e n t i f i e d in A p p e n d i x E to EPA' s Order and Notice of Au g u s t 29, 1980) and invited such r e g i s t r a n t s to participate in the Task Force and attend the Task Force's o rgani z a t ional meeting h e l d on October 21, 1980. P a r t i c i p a t i o n on the T a s k Force is op en to all r e g i s t r a n t s w i t h m a n u f a c t u r i n g - u s e products. At the Task Force's organizational meeting the following companies indicated their desire to participate on the Task Fo-rce : CCW06 15585 Director, Special Pesticide Review Division (TS-791) Page 2 'October 27, 1980 BASF Wyandotte Corporation Diamond Shamrock Corporation The Dow Chemical Company PBI-Gordon Corporation R h o n e - P o u l e n c , Inc. Vertac Chemical Corporation The Task Force would appreciate EPA advising it of any c o m panies that should be advised of the formation of and invited to participate on the Task Force, in addition to those companies "listed on A p p e n d i x E to the Agency's O r d e r and N o t i c e of A ugust 29, 1980. The Task Force looks forward to working with EPA in r e s p o n d ing to its Order and Notice of August 29, 1980. Should you have any questions or comments, please feel free to contact me or Joh n Conner, Jr. T h a n k y o u for assistance in this matter. Very truly ypurs, /das J o h n D. Con ne r ..Counsel for T a s k Force cc: John E. D a v i e s R h o n e - P o u l e n c C he m i c a l Co. 17039 a d .c^iiiv^Xyybuiwii? thn.' tru^fitiarjs (ll c -ao I n f a s m a t l o s . -f-.-ifi.-- -' yJ : > ? K '- v+'i* I*-&.*'.*}.vy^, ^` ^ t,ot^kfC copy of theto.vicoio^icai i n f o z n & t X ^ & t '3' ^ """ ` -Jt4 l| copy o f a recant reloaao from, fcha:ffotlc arir*-t i? 4 An-' 1 1\' n tirm i1 'im i:s>iv <!> ' J t ; ...! v v ,0 tr.a a ''aa iii u ui. it1 Ua unsiiiiigoiw axt'jnalv* field tasting -rod tha ` by .many poodle and fig^ncid3 , and If fFi"-','<K*1 ito rbcognijwd and sat forth on , .. I a .i;j tuis 'Ijtt'-r la 1 twwoc' ui n *': tae .m:oration hich I iiivo &ivoa you iu tne :;rat. L n.;w C.r't in tne norr fnture, favwiiVbo-fSbisi So .f-avidj you ,i.ca nr..vra to your q u ^ a ^ i^ U , ShorClyyr<i w i l l omt you a m?w sat ot labaig v*ni.cn will, cover Uitat cut rout registered mul, thareiore, prcductijlvolvd# l us* a i.jr tin /J y, W. Glbucil ( m * -' Ait*lcultu:iral C i i z n i c a l ttevtslo.io&ut -nc. Toxicological Information on HarblcUioa *' .*_*'' ,*' "V -1 17040 t f -I l \ u t1o n a l L-/ea rin\|//o use POOR QUALITY t^ iJ rr 'Poison Control Centers , --- r*' K u!1efin i o ' - i )'tv ' h L>J. \ `A^ . ' .y U b. Df. PAR (MINT \ } [ h i A l i : 1 t ijijCA C1 N A.`n i e t Li A it PrClli.' h':.*ii: b r r . ' X *. . '. :- * . ``f r : i i : S rV-i ti if! te Oil D.O ' j l ' j l A Tl i ' R O i - . l C t i L O R I.' f A d-D ; ; M ii >. O X V A r . X T I C A C I D S 8- i\i C i-V } o 'd vj c i vm kiv;. o CJV 00 O O to 1 ;1>t r. o . s i \\ i d o l ' / l i e r IjL'.' i d e S a m d , i - i ), <>-l .1*) ^' _ T ; 'nfi r e l a t e d c o m - *...., 1Vi s . A 1`. u t h e r t. ~ n o t tlu-s. j f i ; a v . L u a i l y t o : '111 f'l m a t t e r o i t u : ; t r o - : - i i . '- - K . <u h*: l Ci.: r t o r . * i"; . . ;, . *| ; ; o ^ ) n o t b e < i; i; t P j , > r Hy w i l l ; ' 11ik : n : ' i **r n i v a l - . a r i.* u s t . < l as. <!: r e v t e d ' h - O ; :: ' ; u l o o r i n .eg r o. u i Lli I'e , le.;', t n e M i ( :. i _p.n t. j . r i: e r v. iio d e - V . i t.'t i i*. 11 i b . ' u r o i j (i .jy i \.j >i r do*.b-. . ft,.,-;- n r -p ,; li-i'. i y u . -,(>! ni.-; h c i i ' e 1,-. : i .-,,. t r r ;i 11 ' r *L*r\`.' f . : !'. : i : f>L; i ' - p : i*.* 1! . i . ' h t i ! l S p a t e if: i s . --t ' i *" i i'< l 1- : j ; ii 1G J' y-; -Vvj !; . p o i v--A op.. . 1: :%' i 11!.. - O i La o ^ 1-*l'J r : ole. y* : .** ; .. r - t i. i r s i u a y a r d v. n : ;i ..*.<: b p r y : ne e . i ly .. : r t l . : r . e hi- f o r - , T U i i . x X h ' i y n o t h i i*I^ i . t: g * - u e r n l i e d e r y t h e m a o t sit:: , ,ii ed> :i : t m . s .v e i l i n g (Ji l...- r ...i .. te i n a L n i u i . e u s . n . L r . u . c - - , l i g h t s . v . c l l i n g o f l i p s a n d ..</:l i d s , i n f l a m m a t i o n o i t h e i n ' m t h , < i . .i ..tuii o i i - a r i i t . ' tjc. j 'i - >:e : :j l o.' a. f a t a l e a s e i . i s t o r y d u e t o s a i o i d o i n a - 1 8 -, c a r - o l d C o n n e c t i c u t e . , a Ti / ' i. / . v wl t i l e C i :a r l n g :j( *u s I.*1s rL*[j`; f Ln v. n s m a d e . Iii Lin.* p a s t t h r e e ~ - i , tin.- C i a a r i r. g h o u u ! : a s r e c e i v e d se*. e r a l r e p o r t s o ! p e r i p h u r a l n e u r i t i s nd Utn rT-i: f o l l o w i n g e x p o -.ure to t h e e p r o m u . i ,, in a d d i t i o n to t h o s e ! in- -ni v uitud . f~-.,:., ' m p t o r r t r o t w e r a s 3 o< i i t c i v. i t : If.* . ! . l o r m e t e : : p i i i . ' i . o x y i . u r t u W I t i V ' - s : r v : ' . V : o k : o f !. : -l : . A l 1-:- 1 -.Oi i t>*ci W ith p i:': Il iO1:1'I : f ; r i a : l e t : . r g y w i t h p n . . r n - i 1- ` . ii .' -; \ \ j r o 1 1h r s w i t h a t a x i a , i d i . r i r v ! : m ... v ; :.;i i:.,ii',;v, i;. r i or '1 r>< : *. . . -, : a ft . . l ; . : L. t . I : i d : : :, t, - i' i1 . I. .!: . . . 1 ! 1 17041 2 ,-l-D and its de r:v a tiv Serve ns a ban.: m i l r r : 1 tint. > I.ll I - . I- i '. l - c s u r i and s a lts an." p ro d u c e d . T he LD5U oi ! p r . - d m t- : - nu- i n 300 to 700 m i l l i g r a m s p e r k il o g r a m o r a l l y . m a y p r o d u c t ; d e a t h . F o u r o a s e s h a v e b e e n ue.-c b.-u the l i t e m a p p r o x i m a t e l y 20.% 2 , 4 - D a n d -10% 2 , 4 , 5 - T , Witi:in an h o u r , lie b e i n m e nauseated and began to vom it. A p p ro x im ately one hour n iter die ingestion lie w a s fo und in a c h a i r c o n s c i o u s b u t in a d a / . e d c o n d i t i o n , lit.- w a s . . d m i t l e n to the h o s p i t a l an h o u r ancl a h a l f l a t e r , s ti l l c o n s c i o u s , b ut d i s o r i e n t e d . On his second hospital day he w as on the hospital critical list because his g e n e r a l condition w as getting w o r s e . His te m p e r a tu r e was 104 F . , his blood p ressu re 70/50, and although his u rin ary output was described as good, h i s B U N h a d r i s e n f r o m 16 m i l l i g r a m s p e r c e n t to 4 8 . He w a s h y p e r v e n t i l a t i n g and had basalar rale s, L ate in the second day of h o sp ita liz a tio n the p a tie n t's blood p r e s s u r e .vas v e ry low d esp ite la rg e d o se s of A ra m in e and a tr ia l on L evophed. He had sin u s t a c h y c a r d ia (150), a c e n t r a l v en o u s p r e s s u r e of m in u s 3, t e m p e r a t u r e of 104 F , h y p e r v e n t i l a t i o n , b lo o d P H of 7 . 4 3, and .a n u r ia . H e a l s o h ad a generalized erythem a. The p atien t developed s c a tte re d c r e p ita n t r a le s in the rig h t lung and died of card ia c stan d still (no v e n tric u la r a r r h y th m ia s w ere noticed) e a rly in the m o rn in g of his third h o sp ita l day, a p p ro x im a te ly 46 h o u rs a fte r the ingestion. This case had s e v e r a l s im ila r itie s to the c a se re p o r t of poisoning by M C P A (2 m e th y l- 4 - c h l o r o - p h e n o x y a c e t ic a c id ). V om iting o c c u r r i n g shortly after ingestion and u n co n sc io u sn e ss ap p earin g in a few h o u rs . Both had low ered blood p r e s s u r e but in the M C PA case it could be m a in tained with in e ta ra m in a l. H owever, none of the neurological sym ptom s (facial twitching, constricted pupils, d ecreased tendon reflexes, clonic s p a s m of lim b s) w e re m entioned in the p r e s e n t c a s e . E a rly d eath s in a n im a ls by la rg e d o s e s of c h lo rin a te d p h en o x y n cetic acid d e r iv a tiv e s w e re a ttrib u te d to v e n t r i c u la r fib rilla tio n . In d ela y e d d e a th s , th e re w as a d isin c lin a tio n to m o v e , p r o g r e s s in g to rig id ity of s k e le ta l m u scles (myotonia) and ataxia. The severe c a se s had progressive- apathy, m u scu lar w eakness of the hind lim bs, p a ra ly sis, clonic sp asm s and finally corn a. 17C42 Ingestions of the so herbicide- ..a s y m p to m a tic and su p p o rtiv e t ' ap\ Cl: P r o d u c t s r e c o m m e n d s Q u i n i u . S>.:f; ev.-ry two h o u rs for the f ir s t j ~ , and to s u p p r e s s , v e n t r i c u l a r c u cardiac m onitoring with d elib ru i-Y-vcr s h o u l d be t r e a t e d u s i n g phy s p o n g e s ) s i n c e a n t i p y r e t i c s m a y be in.- . < u r r t u i g a s t r i c iav.ig i- ut.d . it'i - lo g y ot C o n m e r r i a l 1 g ra m s o r-'liy i lyo to n ia, if p re se n t, .a .x a s e s m a y req u j re i d to th e c h e s t . ' . cks and alco ho l ndii ' ted . P ark e - Davis PARCODE P a r k e - D a v i s h a s r e c e n t l y i n i t i a t e d a n u m e r i c a l p r o d u c t i. . cion system known as PARCODE. The special num ber design ntifies each cap su le , K ap seal, tab let and E m p le t. The initials P - ^ identifies the product as a P a rk e -D a v is p rep aratio n and the im printed num ber identifies the p a rtic u la r p ro d u ct. Although the c o m p a n y 's m a n u fa c tu re d p ro d u cts will h e n c e fo rth c a r r y a P A R C O D E identific ation sy m b o l, th e re m a y be co nsiderable tim e req u ire d for utilization of the non-coded products currently in stock. Coding or identification, have already been established by Eli Lilly and Company and the N orwich P h a rm a c a l Com pany. The poison control centers have been sent a copy of the P a rk e -D a v is recognition code and will be in form ed if any other p h arm a ceu tical com panies adopt sim ilar sy ste m s. ACUTE OVERDOSAGE OF DORIDEN The CIBA P h a rm a c e u tic a l Com pany has recently published a booklet on acute o v e rd o sa g e of D o rid en (G lutethim ide). It in clu d es the re c o m m e n d e d supportive care, the indications for d ialy sis, collection of sp ecim en s for laboratory exam ination, a com m entary on acute overdosage as w ell as b ib lio g rap h ies. A copy of this booklet m ay be obtained by w riting to the M edical Com m unications Section, CIBA P h a rm a c e u tic a l Company, Summit, New J e r s e y Q7901. 17043 D E F ER O X A M IN E F o r s <_v e r e i y r ;i r ^ Liic C i b a C o r p o r a t i o n i *-1 - b e e t . i <_>i .' i 11 ti r e . - e .-r on u s e o f d e I*.; r o . ' : ; i :' Luo- ( D e s t e r a l ) , o l d e r i . a n v i a- s ! r r . r i' --=L1111-111 o i i r o n p o i s o n i n g . B e c a u s e 11i r i'.a\- n e i - u . - i - v e r - .. - p u b l i s h e d Li: tin- m e d i c a l l i t e r a t u r e o n it.^ e t f e . l : v . i n - - r-, : i * si- r ies s o i r e o n e s f o r t h i s 'm e d i c a t i o n w l u u . p o i . - o i . i : ; e - In* 11 r r ; d . S i n c e t h i s d r u g w in : u m l i i r i n v e s t i g a t i o n , i t \ v a s o n l y a v a i l a b i e t r.- a n ih o r in e d i n v e s t i g a t o r s . T h e l i s t of i m v li ^a to r , w a ll in a to . a r e f e r r a l s o f i r o n i n t o x i c a t i o n s , c o u l d n o t In* p u b l i - i n . - d . T i n - n - : o r - - , t ne N a t i o n a l C l e a r i n g h o u s e i n i t i a t e d a s e r v i c e to tin- 1'o i s o n C o n t r o l C o n t e rt* to p r o v i d e t h e n e a r e s t i n v e s t i g a t o r ' s n a n r.r a n d to- l e p h o n e n u m b e r v . r . e n a n i n q u i r y w a s m a d e f o r 'the i m m e d i a t e t r e a t m e n t o f an i n d i e id u a . c a m . : . V/e fe lt t h is m i g h t be o f b e n e f i t to a s e r i o u s l y i l l p a t i e n t , a s w e l l to the i n v e s t i g a t o r , by p r o v id in g h im a l a r g e r n u m b e r of o o se rv n tio n s t r o m w h ic h to ju d g e the u s e f u l n e s s of t h is m e d i c a t i o n . T h i s d r u g h a s b e e n r e l e a s e d f o r g e n e ra l m e d ic a l u s e , and u n til the M a n u fa c tu re r can i om pleto its d is t r i- bution this s e r v ic e w ill be co n tin u e d . D e i t -r ox<t.n i n e , a c h e l a t i n g a g e n t , c o m p l e x e s v. i l l : i r . to l u r m f e r r i o x a m i ne w h ich p re v e n ts tne iro n fro m ente r in .'. into fu r th e r i Lem h. .d r e a v tiot.r . I lu c h e l a t e i s s o l u b l e i n w a t e r , i s e x c r e t e d h v tin- k i d n e y , and, p r o d u c e - a c h a r a c t e r i s t i c r e d d is h c o l o r to the u r i n e . T h e n r e ti >a lly , d e f e r o x a m i n e w lil b i n d H . 5 u/o o f i t s - w e i g h t o f f e r r i c i r o n . T h u s , t h e i n i t i a l r e c o m m e n d e d d o s e of 1 g r a m w ould bind 85 m i l l i g r a m s o f f e r r i c ir o n and the m a x i m a l i t - hour d o s a g e o f 6 g r a m s w o u l d b in d o v e r o n e - h a l t u r a i n o f i r o n , th.e e q u i v a l e n t o f 2 1/2 g r a m s of F e S O ^ . T P ^ O . T h e m a n u f a c t u r e r h a s o f f e r e d to s u p p l y f o r d i s t r i b u t i o n pa< k a g o i n s e r t i on its u s e and c a u t i o n s to a l l o f the p o is o n c o n t r o l c e n t e r s . <1 Cl * Cl 0 01 H e n r y 1. . Y e r h o i ~t . D i r e - l . , . r Jo h n J . Cr-.tly , . M . D . , ih r r . t.a M ..., - >/ >w : THE DOW c h e m i c a V c o m p a n y 0 0 4 4 S5 MIDLAND. -7. ,. M a r c h '20, 1959 A-.. J Mrk Wolf . Btbchera Research Lab .634 Building V ' ": . ; i&>.*-r MAR 2 3 1953 k :i' ' M r Biochem, Res. Lab. Dear-Mark , ; i.-i . ;. By review of our conversation this morning (March 18) regarding the relative toxicity, of 1. l/2 to 2 gallons of Forron 245 in 100 gallons of water or Forron Brushkiller at t h e 'same concentration in water, as compared with Esteron Brushkiller O.S. in an oil-water emulsion, we would like, to outline the field situation and our needs as we see it. ,. or CJl CDh - ^ JO <1 o Vai CrDo o It is a :common practice on the utility right-of-ways to ; use 1 gallon of Esteron Brushkiller O.S. or Esteron 245 O.S. plus 10 galons of oil-; this oil could be either ' No. 1 or 2 fuel oil or kerosene in 89 gallons of water 7 for a total of ICO gallons of mix. This mixture is used because it gives quick, uniform knockdown, does a little better Job on conifers and actually has been promoted by some companies because it Is dramatic enough that It is easy to sell. .^Nonetheless it is being .used very commonly and our products are used In this manner when the customers decide they want to use oil. The ,use of this oil has a number of problems; in the first . place it costs money, it is difficult to mix with Esteron O.S. and water, it is messy to handle, it is hard to obtain, and It requires additional trucking facilities to handle the large volume of. raw material to be imported. We have been shooting at a formulation which would essen tially give the early uniform brown-out and kill of the oll-Esteron Brushkiller mix without having all of the disadvantages and handling problems of oil. These formula tions which Chem Engineering Lab has come up with are Forron Brushkiller and Forron 245. You have indicated to us that Forron formulations used In this manner are, somewhat more toxic to the handler than., the Esteron 245 or Erteron Brushkiller formulations and .17045 the question naturally comes up a3 to w h a t .is the relative .* * 1_ l 1. a a .m ' i i . . . . n ^ i . j U 4- U -- - . 4 *i . i- L ..J.; . . ^ r v . v . v f *. At*>c Mr. Mark Wolf March .20, 1959 Page v ;" .'/ A comblnatiun- --a o p c u u/ 4i g a nI tj* * #n..*c% w y u i ui4 1x 4i h1ca 4* ~ xjkj i..u...i..u...v. .n.........n...i.Vli>dn u the relative handling hazards are -of 1 1 / 2 or 2 gallons of Forron 245 or Porron Z^shkiller.-per 10 0 gallons of water or as compared with 1 gallon;; Esteron Brushkiller O.S. or Esteron 245 0,S. plus 10 gallons, of one of the above oils, ..plus 89 gallons of water. This should, of course, include skin irritation, eye irritation, possibly inhala tion and any other tests which you .think might be pertinent. : r ..... ' V'I-. : . it ' This information can be important|to us in furthering our Forron program and in counseling our customers proper t y -iii the use of oil-water mixtures with our present brush- 'killer formulations. We would appreciate your checking this out for us. Yours very truly, L. L. Coulter . : Agricultural Chemicals Development ; ; wb ' '<* " CJ1 cn u.. cn to 00 V- :TI; . if. & / ? . & # , -.-I: ; V '.; y 17046 W Vi - I'l.-* {I A ? - \! *C - ..II. L. OlaoiC/H-i.itw! D. B. M o C a s key \! .R .!!. Fi le ' /. 1 '' 0044S D O W C M G M I C A L BMTEEa-AlM C H I C A N L I M I T E D CABLE: DOWPANAM 1714 E A S T M A N R O A D M ID L A N D . M IC H IG A N O.3.A. April 21, 1953 (Diet. 4-16-53) Ccm:anhia Swift Do Brasil S.A. Rua Formosa 367 Sao Paulo, Brasil Attention: Mr. M. V/. Irwin Gentlemen: Your letter of April 10, 1953 about our E3teron Brush Killer causing nau3ea among the men applying it when it was used as a spray was very interesting to us. Our Esteron Brush Killer lias been used widely in thi3 country for the past few years, and this is the first instance of this sort that has coma to my attention. It has been used widely as a spray as you are using it, and with no adverse results reported in this connection until now. I am at a complete I030 to explain this, particularly so since the product used in the DuFont formulation Is.chemi cally identical with .that usod In our own. Thi3 makes me wonder if this.may.not be ono of those cases when soma other factor has brought thia about, and by chance it concured with the m e n 's u3eagQ of this product. I would therefore, suggest that this material be used again a3 a spray since since i t 's so much more econoraical and that a close check be maintained for other factors that might bring about this result. Very truly yours. Cl Cl rf*. 00 W . R , Mull Ison Assistant Technical Director THE D (pW CHEMICAL COMPANY 30 ROCKE. FELLER PLAZA NEW YORK SO NSW YORK \ Biochemical Research Department Licland, Michigan cci J o h n A. Gird, Ilion, he?. York or cn 00 O MN07 328o S u b j e c t ne r s o n iraa e m p l o y e d by John A . Gird, c u s t o m cornyer, R. D. f * 2 , I] Ion, Hen York, w h o n n rayed crush this cast summer w i t h Don E s t e r o n brush k i ller. I u n d e r s t a n d that Dr. ' I . C. Hutchins in Albany, N.Y. has tried to determine the cause of ?/r. S t e r l i n g 's illn e s s and th i n k s nerhnos that part of it may have been caused by the chemicals in the brush killer. P l e a s e k eeo thi3 le t t e r on file in case either I/.r. Gird or J/r. S t e r l i n g or Dr. H u t c h i n s w rite to you c o n c e r n i n g the m a t t e r s i n c e we have i n f ormed t h e m that any ir.fuSriea r e g a r d i n g the n a t u r e of the t o x i c i t y of Don Esteror. Brush K i l l e r should be d irected to your attention-. Very truly yours, flLC iacr . L. C o r b i n Agricultural Chemical Sal e > 0 0 4 4 b'3 TAL I ON 5 ft <_n A :> . ro Va I --o cn or 00 ( c i i t 369 LD C 0 HILLARD SMITH AG CHEM SALES M RECVD A LETTER FROM HY BRYAN, WESTERN MERCANTILE, ADVISING ONE OF THE MUN TELEPHONE COMPANIES HAS A SUIT PENDING FOR THE DEATH OF TOO COWS. PLAINTIFF CHANGES THAT THE DOWS DIED FROM CONSUMING OUR ESTERON BRUSH AL KILLER. THE DEFENSE ATTORNEY HAS ASKED THAT HY FURNISH HIM WITH THE T 1 CHEMICAL FORMULATION SHOWING ALL THE INGREDIENTS OF ESTERON BRUSH O Nf KILLER. PLS FORUARD THIS INFO DIRECT TO H Y IMMEDIATELY. THANKS. > R A CRANDALL AMS c Mo MU Nr H f ; , ..j ^ ir ' fi f.-4' u ' ) b c C; v :..V. 17049 c / 'i i c > c <e c 0 M M U "N CI TA I O NS ooa c h b m c o UNANCH S A L IS O FF IC E S N r V Y O I 1 K C i* * t>*N F H fiC I5 .C O PH ILA D ELPH IA LOS ANGELE9 W A S H IN G T O N SA IN T LO U IS C lVELANO HOUSTON C H ICA G O ATLANTA SE A T T L E BOSTON T u ie I ) ^ H C L iiC A L C o w l a u y M IDLAND M ICHIGAN July 27> 1951 0 .0 -1 'IO L DOW A. E, V/cil Ol en Acriculturai Chemical- Division St. Louia Office ce: VJ. U. Allen II. L. Smith en- CO G. J. Williams Ben Branch Larry Southwick SUBJECT: Esteron Brush Killer: Sprayed Area Reported to have Caused Polaoninc of Cattle near Carthago, Illinois 1. I wish to compliment you on your letter of July 9 in which you give a detailed account of your investigation of the subject case. It is one of the best reports from the field I have ever seen. 2. After looking, this report over, I could come only to the conclusion that the brush killer was not responsible for the death of these cattle. It does not seem likely to me that spraying on Juno 6 would havo any effect on cattle in open paoturo on June 26 . We have evidence, as you know, that the sprays them selves are not poisonous and insofar as wo know, the vegetation which you list in your letter as being found on the sprayed rightof-way aro not known to have caused poisoning ir cattle. Hee d less to say, we wish va had an explanation for this Incident, but at the present time I am afraid we have no explanation for tho death of these-cattle. 5. X rocoivod tho samplo of M o o r m a n 's Hog Minerals and have sent it in to the Main Lab. for analyses, A chock for fluoride did not reveal any. Analysis or mefc/ila did not reveal anything suspicious. Sincerely yours, . 1 17050 V, K. Rowe be Biochemical Research Department r 2 .3 0 -1 3 -2 0 004480 THO E>rj CHEMISAI. C O M P A W Y Iu j ;c o ? 1 0 rJ 2 M ID LA N D MN073280 ORIGINAL en en o"> Hr, Dan Sanford Ar^L<n.iltural Choraie-fil Salc3 1 -^ 7 a.CCt J w m i a u 3 , . l \ C. Poteraon, J, V/, Brittou Bnbjnctt Doatsi o f Ghaop etnd Cnttlo Allcecdly Duo to Ci*uh Killor ho nftornoQn of i'uoaday Jtmo 2'f, 19^2, Hr, Dau Sanford callcd and aakod rao-.to call a fcy Brandon, Cnrolina iroo Bervioo, Kiolby/Horth Carolina ,, uifch x*aard to nn allafad cas of livo'jtool poioonini? ac a ronn.lt of.tho opraylnj , of on A' and iU^Ut of Uay nuar Frru'&i'urt* llontucky, X calloc Hr*'jendoitt. and-ha"ln S o n so d mo that ha.had aprr-.ycd tho Hifd'it of Uay, Ono farwor olon," tho Vd;:ht of Wiiy had thrao oheop: dl: and nnothar farmor olone tho aient of Way had ono JTOOlb* bull dio and thoy uoro clalln^ that thcoo death.a traro duo' to ti-o dprayinf;, Hr, Brandon vantod to kaov iihcit uo covlLB do nhout unch a situation, I infoiiod iila that thoji'ij vas no anoatlon in our iand that tho shoup cvnd tho bull did not dio as a rooult- of Ineootion of Dot/ 'atoron Bruah KlUor, Ho ^uoried n wtth rocard to tho afi'oota tVmt ni "ht oceur from tho conarmptlon of aprayod foliano, v/h.loli ni e!it nb h ofchorwiao bo eaton and which nieUt bo polsonoua, I told hln I clid nofc hnvo an unowor to that #iuonfcionj that. it i/as a p vQ b lm vhloh m a .'haine invoatif'atod, I w | 551477 Juo 2 -;0 19U2 j o* tirita Icnd fron partinlly cnpty p-.'dnt n::22 i-.2:!fclian Einish- K I H oj?-aa toa aUo^od. ' I snceostod tlia I`j vZC\\* c -3 1 Dr* I^rfcig Gt Corsioll.UnivoroiXy tntion for hia cor^ants, curia aleo Dsv Grinsby ct 'I;o -inquired as- fco thafc lio bould do in caso o* vJuro acidonta in i;hich au topaico can bo porfoznod (t$ic ceduela taro ta!vO?i auay tilia ti;2o* bofc?o ar.y iutopoy conld be Jiavdo)*. I saecoatc-d tluj.t ha cat a record, of fcheir : aynpteas, esonsino -fbr.. tarduaro study t.o contenta o tholr stccacii i'os* proaanco o* poiconous vogotatlon or othoi* orelgn netorial, cot Daiijiloa for chorilcal anal yole, and aurvey too pasture arca fer poiaonov.a uaeda. Ho aacnoti cuito natioi'Icd vith tho -anssiwp and cercad'to !-:oop tic iniToi-tod i3 to tha outeono o 'tais caso. . r.ir.corcfly yourg*. <n/-. V. K, itot ; ; 17052 t-, Ito il L i i ?WSS Iv a * ; L>i. '...r<i&VVfi?c'gXif i "H ^ ^ r p e r $ c i^ r ^ ^ ' j^ ^ ? j:p jt ru a n . w l x i o t ^ o c ^ w ir o e i b u o * m 1t 6 c d a y s ^^Q iiAt h e ^ t li r < t d a y - oeaed .'to>,Iw cJlowed oaewhatndth anlna l:.gay 'th > ......... .... - f^-iifegoeK^S >. r-r V^-^r g e n e r a l appearsn BQHe u.eproBBioii ^T ne ttJi*' * "^ v . a j* " ' " r <(v r * * . --f vt ^ ,v^ **^i- y r y y ! 74. * ,/ ' w v r___ o o w in g t h e. > ;V-j ^ f H h l r d do a t h e a n l a l a a n o t a b ly o f f - f e d r ;g e n e r a l la s s lt u d o n ted 3id .;ru ^ B atloa:h ap 06a8ed ^ .S eiB p eratitre a s ;B t i l l ^ ^ ^ * d ,s eeon d vd ay t ^ ew ln g j t h e ;j!Iast-;d o s e -In e o o r d ln a ti n " l^ r a ^ n o te d ^ e r * / wi b;-g ligh tl^ i**TM rer th a a 'aoraal'^ l& iw e^ nas^ ira and; g e n e r a l *-;h_. -sr(fiavJ la B S ltu d e :To f *t h e "iiln&l^^TheV'heart^TBeat.: s e e a e d t o b e * , l i t t l e % . -tf'gr^^B low ed /and? iioew liit^ ircU cid^ ^ SB plratlon :;as';'aeBdrh& t; labor^T $ ^ jil^ ^ B d ^ fiaa n tioaD t. had::.9 e a a e d ^ ^ a ^ tta lr d > ;d a j:fo lle w ln g ^ th e . ' ; ^ ^ ^ t ^ V o . < ? B t e r c n - . - 1 i e i t e e ^ ^ p t m b e d v l n ' a ; . r e r j - / q i i l e t #:' 'g n t le ;::0 ^ 5 Ig n '.o ^ -p a ln -e r /a tr u g g lln g r ,t h e W m * n \ * a l JnBt: ieneC rt'^ getV pcrb greB B lT elx-'nore d e p r e s s e d , r e s-^ T ? * 4^ '^ ir a t lo n iaaB n Q tlo iea to ly :elo w er* ;h earh r a ta ; a s n sld era b ly . slow ed and weak o o n tln u e d vto d e e lln e .frea th er / A & i& c ^ d a j L a h tllid e a th ; raedor 07 o isp e a r eVs lsl rere* ro n a e e l MM :B e e ra -'ire ' 'hraxticenv rxoepiion->i fe fv g e n e ra lg ^F>5ra s 1 :darle; v p :Witv'ia tesearch^ efe m $> * m Ssyffi - a rS;;. .V .1/ ; .-lS' fT -O H . i . d*.w-.'i.l JS*j1\! ;**i-. M 4945 ' *. l'.V.*>V jJJi . -4<. '*'>.'.i--1r-.-.* -X 0 T2.30-Xj To: V. K. Rowe, BRD Subject: HISTOPATHOLOGIC IMPRESSIONS OP STEER FED DOW ESTERON BRUSH KILLER 4g44 z o voO "Ni <v*OG O O Lung: Heart: Liver: Kidney: Normal Normal Moderate pathology characterized by areas of focal hemorrhagic necrosis surrounded by areas of moderate fatty degeneration. <1 cn ^1x3 , Very slight interstitial edema and congestion _1__ In the medulla and cortical medullary region. Spleen: Adrenals: Pancreas: Testes : Thyroid: Lymph Node: Thymus Gland: Bladder: Normal Normal Normal Degenerated and non-spermatogenic . Normal Normal Normal Normal US**** yA) J * * Rumen, Reticulum, Omasum, and Abomasum: Conclusions: Mucosa, submucosa, and muscle layers appeared normal with no evidence of congestion, hyperemia, nor edema. The lesions in the liver are characteristic of toxic necrosis. F. Oyen 2-18-54 Jew 17056 CAG . MARK. BIRTH DATE: AGE IN DAYS? STARVED? ------ animal NO, MATERIAL? X /CSLIDES FILED. J o + BLOOD COUNTS ( ) BONE MARROW COUNTS ( j c BIOCHEMICAL RESEARCH DEPARTMENT , TISSUE EXAMINATION - -y * a FILENO. T 3 , EXPT.NO. RUN NO. DAYS & J a - J3 DIED ( KILLED ( ' ) GROSS EXAMINATION MICROSCOPIC EXAMINATION? DATE? / / - 7 S 3 CONDITION? BODY W T,_ KILLED BY DECAPITATION ( O R' EXAMINATION OP ORGANS?. APPEARANCE OF VISCERA? GRAMS r'J FORMALIN! A O O R._______ _ Da t e rem oved from f ix a t iv e . EMBEDDED? PARaFF1N( f ^ o R . / -- j ~ sr? TTT T=r SECTIONED BY ____________ STAINS? HEMATOXYLIN AND EOSIN ( O OR _____________________ 'i . (7 y ~ " r EXAMINATION OF SECTIONS? 752108 WT. -'.*.*.v.w. :.~*r -. , jU-?Oui V < : mi 2 LUNG..N Ul Ul oc . :ouo i o < u i. ouo.. ... 7 ' VENTRAL ` <D=O>RSAL UI a . "S an 3* ` OaUl ou*. rv- .V ' . \\i' - -V~rv Slf.'v :Xl%: ' * `-y LUimNGa. *. : JrT*'. : HEART ; .1; ".s' V.-.'' 'i.;>-;j;- Y irY> 'v '^ 'r i: Y LIVER? **'*".5* * V**.p.'-fl-.-C*.S' . fvf - , r o"i u,'.^ T 1 * '1 ' . i ' v ,:y.v< klDHEVSt; . t *1 y ADRE.N ALS?r_ < ` 7-*. i\ " ' . v .`jCr- // - " ;'!y: j f: ,L . "I )j . heart. *1 ^ j A' ~'^-f+.SiTESTE VAy; BOREMAHROB?'' ? * .!*<; . . - 5; S ? r ' 1V'*'V-7*5 '. 7v'`I',* pancreas? -1.. f - ' `A - .- .? ?' 0 : vr' ?v vV .r'-; . ,;v- -C `' : . 1 r. r^ '-* ' . .7-.. V > y c DATED . . til*-*- n in a 11 a l l ..... SIGNED' ' . . - . fafa'rt* ?.11 . 1 ]^' DATED SIGNED . BC T2.30-66 / /? 4947 - ( 0 \^ s '] / /; Biochemical Research Department M N O 69799 The Dow Chemical ComDanv RESULTS OP RANGE FUNDING TOXICO LOGICAL TESTS ON M-6 97 (ESTERON BRUSH KILLER-TYPE FORMULATION) File T 2 .30-66"/ Sample N o . 1 Chg. 1219-2 Rept. By T. R. Torkeison Signed -Checked Date ------------ Date PROBLEM 'y*H~ 3 . / THIS REPORT IS THE PROPERTY OF t h e DOW CHEMICAL COMPANY C c This material is a proposed formulation for use as a brush killer. What is its toxicity and what handling precautions will be necessary? How does' it compare with E 3 teron 2^5T and 24D brush killer? CONCLUSIONS This material has a low acute oral toxicity. There is no problem from ingestlcvi incidental to the handling and use of this substance. The undiluted material and a 5$ solution of kerosene may be expected to cause a moderate response on the skin. Precautions should be taken to avoid prolonged or repeated skin contact. Protective clothing may be required. A 10 and 1$ emulsion in water caused only a slight response upon the skin. Precautions should be taken to avoid repeated and prolonged contact with such dilutions. The material7its emulsion (10$ and 1$) in water and a 5$ solution in kerosene cause only a slight transitory effect (Continued) DOW 752078 i. t Biochemical Research Department T2.30-66 Page 2 (CONCHJSIONS CONTINUED) upon the eye. Safety glasses should probably be worn to avoid the pain and discomfort that results from contact. M -6 9 7 is very similar in toxicity to the brush killer formulation reported in T25.14-86-1. They both have a low acute oral toxicity and cause slight skin and eye Irritation. For practical purposes the two materials should be handled the same. These conclusions are based upon range finding toxico logical tests and are limited to precautions for industrial handling of the material and its use as a brush killer. D e velopment of this or other uses may require consideration of the ' health problems presented and of the need for further toxicolog ical studies. HAZARDS, TRECATJTTONS' TOR SAFE HANDLING, AND "FIRST ATP MEASURES Ingestion The material has a low acute oral toxicity. There is no problem from ingestion incidental to the handling and use of this substance. If large quantities are swallowed, accidentally or willfully, some injury may result; the likelihood of serious injury Is remote. Containers of the material should be labeled so that accidental swallowing due to mistaken identity cannot occur. 17059 DOW 752070 Biochemical Research Department T2.30-66 Page 3 Eye Contact The undiluted material causes a slight effect upon-'the eye. Pain and conjunctival irritation persists for several days. Precautions should be taken to prevent contact with the eyes. Safety glasses should provide satisfactory protection. If the eyes are contaminated, they should be flushed immediately with copious amounts of flowing water for at least 15 m i n u t e s . M e d ical attention should then be obtained. Emulsions (10$ and 1$ in water) and a ,5$ solution in kerosene have a very slight effect upon the eye. Contact is but very slightly painful and irritating and may cause transient irritation to the conjunctival membranes. It seems advisable to prevent contamination of the eyes simply to avoid the discomfort which may result. Minimal eye protection should be satisfactory. If the eyes are contaminated, they should be flushed with copious amounts of flowing water. Skin Contact - Irritation The undiluted material has a slight effect upon intact skin. Several exposures are needed before definite response occurs. The undiluted material is not likely to cause appreciable irritation unless exposures are quite severe. Good care and cleanliness should be exercised. Protective clothing may be helpful in preventing contact. Any injuries or irritations which may develop should receive medical attention. A 10 and 1$ 17060 Biochemical Research Department T2.30-66 Page 4 emulsion in water cause even less irritation upon the skin than does the 100$ material. Reasonable care and cleanliness should a o avert irritation. Any injuries or irritations which may develop should receive medical attention. The 5$> solution in kerosene, however, causes a moderate vj Vi response upon skin. A single exposure for 24 hours to a 5$ solution in kerosene is capable of causing slight irritation. 0 Q Repeated prolonged contact over a period of several days may result in blistering and a superficial burn. The material also causes a slight folliculitis. Precautions should be taken to prevent skin contact. Protective clothing, impermeable to the material, should be worn as required by circumstance. Contam inated skin should be washed with soap and plenty of water. Contaminated clothing and shoes should be removed and not re-used until thoroughly cleaned. 17061 752081 Biochemical Research Department T2.30 -66 Page 5 SAMP IE INFORMATION C.R.I. Name: M -697 Common Name: M -6 97 (Esteron type formulation brush killer) Source: George Scoles R e f .: WS B6P53 M.P. : Below 0F. Sample N o .: 1 Date Request Received: 11-29-55 Date Sample Received: 11-29-55 Physical State: Light amber solution Sol.: Kerosene, xylene, Emulsifiable with water Composition: 35.1# Dowanol 97B ester of 2,4,-D 32.5# Dowanol 97B ester of 2,4,5-T 2.5# Dow Polyglycol 59-1 2.5# Caryly base 137B 27.4^ Penla heavy aromatic naphol 17062 Biochemical Research Department T2.30-66 . Page 6 SUMMARY OF RANGE FINDING TOXICOLOGICAL DATA Acute Oral Toxicity Animal Preparation Dose Fed (g./kg.) Male Rat 20# emulsion in water 3.0 No. Died No. Fed. 2/2 Response-Remarks -- Male Rat 20# emulsion in water Male Rat 20# emulsion in water Male Rat 20# emulsion in water 2.0 1.0 0.5 1/2 Slight cloudy swelling in the kidneys. 0/2 Slight cloudy swelling in the kidneys. 0/2 Essentially no effect. Male Rat 20# solution in kerosene 2.0 2/2 -- Male Rat 20# solution in kerosene 1.0 0/2 Pathology essentially negative. Eye Contact - Rabbit Material Treatment Response-Remarks 100# Unwashed and washed Slight pain, moderate conjunct with water. ival irritation, very slight iritis which healed In 2 days 10# emulsion in water. Unwashed and washed Very slight pain, slight con- with water. junctival irritation which healed within 2 days. 1# emulsion in water. Unwashed and washed Very slight pain, slight con- with water junctival irritation which healed within 2 days. 5# solution in kerosene Unwashed and washed Very slight pain, slight con- in water. Junctival irritation'which healed within 2 days. 17063 Biochemical Research Department T2.30-66 Page 7 Skin Contact - Rabbit Material Condition No. of of Skin Appi. 100# Intact 10 100# Intact 10 100# Abraded 10# emulsion in water. 10# emulsion in w a t e r . 10# emulsion in water. 1# emulsion in water. 1# emulsion in water Intact Intact Abraded Intact Intact 1# emulsion in water 5# solution in kerosene Abraded Intact 5# solution in kerosene Intact 3 10 10 3 10 10 3 10 3 o Site Response - Remarks <J Ear Slight hyperemia, slight c, necrosis and .slight ex- t\ foliation. Slight cr folliculitis after 10 Oc applications. ^ Belly Slight hperemia, sligit edema, very slight necrosis, and moderate exfoliation. Belly Moderate hyperemia, slight edema, very slight necrosis. Ear No response. Belly Very slight hyperemia, slight exfoliation. Belly Slight hyperemia, very slight edema and necrosis. Ear No response. Belly Very slight hyperemia, slight exfoliation after 5 exposures. Belly Slight hyperemia and slight exfoliation. Ear Slight exfoliation and slight hardening and folliculitis of the ear. Belly Moderate hyperemia, slight edema and moderate necrosis, moderate exfoliation with scab and scar formation. DOW 752034 Biochemical Research Department T2.30 -66 Page 8 Skin Absorption There is no indication from the skin irritation tests conducted, that this material is absorbed through the skin in toxic amounts. d I 17065 Biochemical Research Department T2.30 -66 Page 9 -UNIT INDEX CD CD Effects resulting from ingestion, eye contact and skin contact are given. Hazards precautions for safe handling, and first aid measures are discussed. INDEX HEADINGS 4 "<1 <U1 VO o00 cn C.R.I. Name: M-697 (Esteron type formulation brush killer', Esteron 245T Esteron 24D Brush Killer DISTRIBUTION "Director of Research - R. H. Boundy Central Research Index Western Central 'Research Pile Texas Central Research Index Medical Department - Dr. H. H. Gay Texas Medical Department - Dr. D. J. Kilian Safety Department - S. M. MacCutcheon Texas Division Safety Department - R. L. Allinson Western Division Safety Department - D. Elshere Legal Department - W. W. Sunderland E. C. Britton Research Laboratory - E. C. Britton Technical Service and Development - A. Hart East Main laboratory - E..N. Luce West Main Laboratory - L. M. Greene Special Services Laboratory - A. W. Beshgetoor Spectroscopy Laboratory - N. Wright Agricultural Research Laboratory - D. Martin, Seal Beach Chemical Engineering laboratory - G. Scoles Agricultural Chemical Development - L. L. Coulter & September I S , 3557 /f i . C. Suttar-C lsveland Or l a i s s u s o f B oehringar was h e re l a s t week to d is c u s s th e a c q u is itio n from Diamond of our know-how f o r th e p ro d u c tio n o f pent a-- chlorophenol He asked s p e c i f i c a l l y i f we bad observed any in d ic a tio n s . of chlorscnegene in o u r product I t o l d him t h a t in th e work -th a t A1 S irs c h and Irv in g Rosea had done s e v e ra l y e a rs ago and th e nor e re c e n t work dona by Jack Jenney in th e la b o ra to ry and by i l Lewis in th e p i l o t p la n t we had n o t been s c ru p u lo u sly c a r e f u l t o av o id c o n ta c t, b u t a t th e same tin e had had no in d ic a tio n s of c h lo ra c se tro u b le * H th e n asked i f we had re c e iv e d his r e p o r t on th e s o lu tio n to the chloracse problem which a t ona t l s a had fo rce d the shutdown o f th e B cehringer trlc h lo ro p h e n o l p la n t I t o l d him I d i d n 't th in k we had seen it He p ro a ia ed to send over a copy I n th e meantime he p o in te d o u t th a t a compound \ .Cl *3EP 19 IS. id e n tif ie d as an ex trem ely to x ic m a te ria l and p ro b a b ly th e cause o f some of the chloracne d if f ic u l tie s . This m a te ria l i s not formed i f the t r i chlorophenol a n i o d i v e te n p e r s tu r e la k e p t below ,l;5*C and I f th e d rie d TCP-caustic crude mixture i s not allowed to exceed 120* C. In view o f our problems with, ohloracna in our tric h lo ro p h e n o l p la n t, i t would c e r ta in ly seea in order to check these observa t io n s , i f p o ssib le , in t r i a l plant runs. I t i s q u ite l i k e l y t h a t by dro pp in g o u r r e a c tio n t e mpe r a t u r e 15* o r more from what I u n derstand is o u r c u r r e n t l e v e l o f o p e ra tio n of about 170* C , we may s u f f e r a s ig n i f i c a n t d e c re a se in r e a c tio n r a t e and p ro lo n g a tio n of our r e a c tio n cy cle tim e , I b e lie v e Hay G oidi has had a good b it o f experience in continuous e a u s tlo chlorobenzene re a c tio n s and I would guess t h a t we might be a b le to conver t o ur e x i s t i n g a u to ca lv e to a continuous u n it by pro v iding a slu rry charge pump, a re flu x condenser, and a B32nr.'of c o n tr o l valv e S in es com plete c o n v ersio n would n o t be e s s e n tia l, lb should be possible to operate such a u n it a t the point an th e autoclave curve a t which th e ra ta o f re a c tio n should be f a i r l y g re a t and we might be a b le to a f f e c t an a c tu a l in c re a s e I n o ur p ro d u c tio n c a p a c ity and a t th e same tim e e lim in a te chloracne p ro h lsas.. D JP jsja DS 000174-15 D J . Partor a . -u n io n -- a e w r i -JL >' ~ - X . i l . 'O-' 7~3T'.Lakea /H . C. Suttar-C leveland September I S , 1557 B. J . P o rte r - Faine a v ilie Dr Kodszus o f B ceh riu g er wan. h e re l a s t week to dLscnss th e a c q u is itio n from Diamond o f our know-how f o r th e p ro d u c tio n o f penta*c h lo ro p h e n o i. He asked s p e c i f i c a l l y i f we had observed any in d ic a tio n s of- chloracnegene in o u r p ro d u c t. I t o l d h-im t h a t in th e work t h a t A1 a i r sen and I r v in g Sosen had dene s e v e r a l y e a rs ago and th e more re c e n t work dons by Jac k Jenney in th e la b o r a to r y and by -1 lew is in th e p i l o t p la n t we had n o t been s c ru p u lo u sly c a r e f u l t o av o id c o n ta c t, b u t a t th e sane tim e had haH no l-nrH/a-fclnTT. o f c h lo ra cn e tr o u b l e . He th e n asked i f we had re c a iv e d h is r e p o r t on th e s o lu tio n to the chloracne problem which a t one tim e had forced the shutdown of th e B oehrlnger tric h lo r o p h e n o l p l a n t . I t o l d hlm I d id n 't th in k we had seen i t . He promised to send o v er a copy. 'ScP 1 9 : <r> id e n tif ie d a s an ex trem ely tm H e m a te r ia l and p ro b ab ly tilS C3.USS u i SCutt o f tha chloracne d if f ic u ltie s . T his m aterial is not farmed i f the t r i c h laro p h en a l a u t o d i r e te n p e ra tu re i s k e p t below 255 *C and i f th e d rie d TCP-caustic crude m ixture i s not allow ed to exceed 120" C. In view o f our problems w ith xLaracna in our tric h lo ro p h e n o l p la n t, i t would c er t a i n l y seem In o rd e r t o check th s s obs e r va t io n s , i f p o s s ib le , in t r i a l plant m s , I t la q u ite lik e ly th a t by dropping our re a ctio n tem perature 15" o r more from what I u n d erstan d l a o u r c u rre n t l e v e l o f o p e ra tio n of about 170* C , we may s u f f e r a s i g n i f i c a n t d ecrease i n re a c tio n r a t e and p ro lo n g a tio n o f our re a c tio n c y cle tim e . I b e lie v e Hay G uidi has had a good b it o f experience in continuous e au a tlo chlorobenzene re a c tio n s and I would guess t h a t we might be a b le to conve r t our e x i s t i n g autoc&lve t o a continuous u n it by p ro v id in g a s l u r r y charge pump, a r e f lu x co n d en ser, and a TSKartoff c o n tr o l v a lv e . S in ce com plete conver s io n would n o t be a sse n t i n i , i t should be p o s sib le t o operat e such a u n it a t th e p o in t on th e autoclave curve a t which th e r a te o f re a c tio n should be f a i r l y g re a t and we s i g h t be a b le to a f f e c t an a c tu a l In c re a s e i n our p ro d u c tio n c a p a c ity and a t th e same t i n e e lim in a te ch lo racn e p ro b lem s. D J2 ;s.ja DS 000L74L5 . D. J . P o r te r C. H. BO E H RI N G E R S O H N C H E M I S C H E FABRIK. N itu n k ilh i is litlili fwG 13 1- u . . o.c w. L * m. t. w . S - A. I. ftu ! otrrwoT Mr. J.A. Borroy c/o DIAMOND ALKALI COMPANY Union Commerce' Building-- Cleveland 14. Ohio / USA knZckWa kttrifc k n WMtk J (httn NwfirVfa J TfT Mn m Al* C<xik GAmci CmcMHkriA Dm o , Hntwrf 1 DlA B it A. Bfah IM . [nll b > M 0 ia I k h H i.lM iTiuUm (M^i| KrJIU om, zdd ' Dr .Mz/Fc GC/Sg . - @ Ingelheim am Rhein August 10, i960 Dear Mr. Borroy: Recently we received a letter from Mr. J. Burton, dated June 22, i960, addressed to Mr. Doll, Managing Director of CELA G.m.b.H. Mr. Burton requested to .have the answer addressed-to.you. Unfor tunately his letter was sent by surface mail which meant a several weeks1 delay. We therefore hasten to let you have an answer and the desired .information. We thank you, also in the name of CELA, for the information * regarding your process for the production of 2,A,5-Trichlorophenol from 1,2,4,5-Tetraeklorobenzne, as well as for the description of the explosion which occurred in your Factory. It was very interesting for us to read that in your laboratories you are presently working on a modified method according to which the autoclave is at first loaded with the full quantity of Tetrachlorobenzene adding slowly the solution of caustic soda. We have had good experiences over long years with a principally equal process which in our opinion offers a great operating safety if working below certain temperatures.- Here below we are outlining our standard process r _e re loading the autoclave of 7^00 Litres with 1^00 Kg 6,5 K g Mol; cold symmetrical Tetrachlorobenzene, suspended .ihrlOOO. Litres- Methariol, and dilute therein with.another _2500 Litres Methanol. This amount o f Methanol is regenerated .from former batches- and. has. a content, of 95$- - w . 2J-; DS 00022020 ttr ~ 2. Boefvinger Soiin - 2- Mr* J.A. Borroy, Diamond Alkali Co. USA 10 -8 -19 6 0 .The autoclave la then locked and heated to an internal temperature of 1 3 0 - 1 3 5 # the pressure thus reaching 9 attl. The steam is shut off and over a period of 5 hours 730 Kg of aqueous caustic soda solution min'iimim 49$ are injected .( 18,24 Kg Mol 100#)* The heat thus developped brings the contents of the. autoclave, to a temperature of 15 0 -1 5 3 within one hour* Generally a 'further increase, in temperature in the course, of reaction of 12 hours will not take place* By the end of reaction it is necessary to add some heat in order to maintain temperature at 150. 8 hours after having finished the injectionof caustic soda solution a pressure of 20 attL is reached, which rests constant until the end of r e action* ... How the contents o f the autoclave is cooled down to 105 - and filled in a distilling apparatus of 7000 Litres in order-to distill off the Methanol. Following the evaporation 'of the Methanol during which the temperature must not exceed 115, and after adding 300 Litres of water by blow ing in steam (3 * 5 attl), the formed.Trichioroanisol is distilled off. It remains a solution of about 3656 2,4,5TrichlorophenoL. in surplus caustic soda solution, for onward processing into Phenol* He consider it especially important that whilst evaporating methanolic or aqueous solutions of Trichlorophenolate solutions a concentration of 4o is. not exceeded because i otherwise there exists the danger of a sudden exothermic formation of chloride acne-active substances which, as you know, has led to a severe damage to the staff of an important European Factory* In a letter dated September 20, 1957* addressed to your Research-Center, Painesville, Ohio, we described oxtr own experiences in.this connection. ' He- should be pleased if you - in supplement of your- letter, dated June 26, i9 6 0 -- would tell us how you elaborate the /-"Vreaction:.product- of the autoclave to Triohlorophenolate. ' . -:The information regaining yoiir process-will, of course,-- be; treated strictly confidential and we sincerely ask you '--'v.'Vto.-'act-.accordingly with regard to our indications*. /\ The acne cure announced by Eoshringer in Cher,> VJsek for June 20, 1959 is confirmed as inactive for chicracne. Boehringer has had no new cases of chloracne in 3-5 years. They did this by discovering the compound which is the bad actor and eliminating it as a by-product. After they accom plished thi3 processwise, they then cleaned up their factory in a major fashion before-reopening - it was closed a year. Dave Porters memo of September 18, 1957 to you and -yours to me of July 28, 1959 set "forth substantially the require ments. As Dave points out, the bad actor is a tetrachlcrcosnaodioxime. As you pointed out, certain conditions of temperature in the nrocess can cause the trouble. In addition, even though Boehringer is sure it has no more dioxins in Its process, it ventilates its plant with great care, issues clean work clothes every day and continuously checks its triclilorphenol on rabbit ears per the test described in tho Dermatologies.paper (Derm. 115, 5k0, 1957) copy of which you 3ent me. Kudssus has reneged on sending out the report he pro mised Dave - says the dioxime is so active as to be a chemical warfare chemical. But we have all dope orally. Do you distill TCP? This i3 said to be a most danger ous step. In distillation, if any alkali or salts are present, oxime forms very rapidly. Recommend that alkali and salt be washed from crude TCP before distillation. Referring to your points 1, 2 and 3 in your memo to me of July 28, 1957 (H. S. V/einer has a copy): DS 00017413 17071 j . 3 -r ton .~:e: Scshringor - Chlcracna Prcfcl 502- S e p te m b e r , 1 9 5 9 1. After dilution wit h methanol, the reaction mass ie only dangercua over 170 C. 2. Distill out m a j o r portion of methanol under 110, then strip out remainder of methanol with 3taam prefe r a b l y at 100 (120 C., cited b y you 3aia to be dangerous). ad" is 3 Boahringer offers to evlev your process conditions and O'l >-J7J--*-.i r->- { - ?r" keee ideas don <: do the job. Pinally, after Boeliringer did all the above, they tore out piastar walls, floors and similar parts of buildings until no remaining structure gave positive rabbit eer test. This done by c a r e f u l l y protected x:orkmon. Cnca clean and following above p r o cess steps, they have enjoyed good experience. Bettor try a few rabbit ears cn your joint if y o u are still having trouble. Oil, yes, Bcehringer liver damage cases are still on compensation after more than five years i W E :s jm 10/5/59 T h o rnton P. Hoid-sr DS 00017414 17072' THE D O W C H E M IC A L COM PA N Y MIDLAND, 'Michigan March 2S, 19^5 / Mr. K. Rowe ~ Biochemical Research Laboratory 1701-Building &f] , cc: P- H. R i l e y R. N- Smiley L. B- Grant C. 0- Hutchenreuther P. C- Amstutz W- P. Palsey G. E- L y n n ' W. M. Gill M. G. Wiltse D. E- Fletcher W. L- Corbin D- D- Irish J. E- Peterson J. C- Tucker J. W. Harris H. W. Feinauer E. C- Staehling C. E. Otis K- Y. .Hansen R. C. Hoff W. J- McCoy J. D. Doe d e n s K. C- Barrons H. R. Hoyle B. B. Holder, .M-D. S. E. Sadek REPORT ON THE CHLCEACNE PROBLEM MEETING ON 3 / 2 k/65 Present: Dr. J. Wilkenfeld and Mr. Raymond Verhoeze/ Hooker .Chemical Corporation Mr. Francis Kennedy and Dr. Ed Chandler, Diamond Alkali Company Mr. C. L- Dunn and Dr. John p. Frawley, Hercules P o w d e r C o m p a n y V. K- recapped the Dow situation in terms or the p r o b l e m and the Initial studies by Toxicology and Environmental Research Laboratory regarding the in-plant situation. He expanded this in general terms to the study of end products, ours ana other peoples. He made reference to symmetrical tetrachloro-p-dibenzodioxin. He referred to the evidence for unknown acnegen3. There were some questions from the group about the unknowns. We (Dow) were not able to a n s w e r these questions except to review the evidence Tor their existence in the process samples and end product's - ,! . r\\3JCT TO iNjb'NCnC' CONMF'.USm k .v- w_/PA D.C. EXHIBIT 18 . 17073 Dr. Holder reviewed the medical side of the Dov; experience; he said that we now have approximately 60 to 7 0 cases o f individuals with chloracne ranging from two severe cases to some very mild cases that were difficult to diagnose. H e showed slides of the more dramatic cases. The slides were exclusively views of the faces of the individuals afflicted. He described in fair detail the appearance of the Indivi duals mentioning the blackheads specifically- He then reviewed the clinical studies that are being made on these - people with emphasis on the liver function tests- He m e n tioned the single liver biopsy that has been taken and studied in which the liver was normal although the man had a rther pronounced case of chloracne. Dr. Holder also mentioned the incidence of fatigue among the arrxicted ~g^ople as" being the only ocher significant b i n d i n g in these folks. He touched briefly on treatment indicating that various topical treatments were not particularly effective. He descriDea the cycling or this disorder in individuals w h o had been completely removed from exposure. He mentioned that some fellows are approaching the end of their trouble two or two and one-half years after onset of the skin d i s order. He also described "acute chloracne11 w h i c h is a n a c u t e inflammatory condition that appears considerably sooner than, the normal chloracne in individuals and appear? after pro nounced single exposure. The acute chloracne shows up within a few days of exposure. Dr. Holder mentioned five to eight days specifically.. There w a s 'considerable discussion b y t h e group on the skin d is order Itself. The Hooker repr e sentatives related experience of skin condition thirty years after expo- ^sureT T h eir, cases were more similar to the Dowicide bumps which Dow ha3 experienced in that there were large boils or . large Dumos rather than m e multitude of small blackheads and eruptiohS Willch~I)ow is seeing m the "current cases- " Dr. Sadek showed slides of ears and livers of rabbits th a t h a d, been ex p o s e d " ^ ' tne symmetrical tezrachloro-p-dibenzodioxi He "discussed the pathology in detail w h i c h X w i l l not a t t e m p t to summarize.. -- -- V. K. mentioned the studies in wh i c h the rabbit ears h a v e been treated with TC3D in benzene or corn oil and then washed w i t h soap .and water at various time intervals later. If exposure occurs for very long, washing does little gaod. He also briefly mentioned the oral studies but without detail. Silverstein described the plant study on washing of contamination from tools and surfaces. This study indicated that benzene, acetone and Chlorothene NU were effective in removing the contaminant from tools and also that detergent and water with scrubbing action.could clean up tools and equipment. Some discussion ensued on the use 17074 V. K.. o w e - 3- March 29, I955 of detergent -and water and the point was made a g a i n tha.t strong scrubbing action was necessary Tor this approach to be successful. . .* Harold Gill then discussed the analysis for tetrachloro-p-- . dibenzodioxin by vapor phase chromatography. He listed the limit of-sensitivity on various process materials. H e mentioned the oil which he defined as a non-- saponifiable mixture of chloro anisoles, tetrachlorobenzene and tri chlorobenzene; the limit of sensitivity for TCBD in this material.is 10 ppm. The limit is 1 ppm for 2,A-,5-trIehlorophenol, and for 2,4,5-T Acid, either acetic or propionic. Gill then defined 1 p p m as a very discernible, peak.- ' H e m e n tioned that he-might estimate 0.5 ppm in 3one instances but -to be conservative the analyst reports <1 p p m i f the p e a k does hot measure up to the quite identifiable level of 1 ppm. The analytical problem has not yet been solved f o r the .T-Acid esters. The general procedure used f o r the T - A c i d s is to extract the sample (arbitrarily about 20 grams) w i t h chloroform (about kO milliliters), filter the'-chloroform to remove solids and wash with an equal volume of N /lO caustic to remove any acidic materials* The chloroform, extract then is concentrated by evaporation to"'one-tenth the original volume; thus, 'the concentration, of the d i o x i n in the chloroform will be ten times higher than in the original sample- When the analysis is conducted on tr i -- . chlorophenol, the material is dissolved in N/l caustic t o the extent of 10$, and this solution is then extracted with the chloroform and handled as indicated above. A question was asked about the utilization of detectors other than the flame ionization which is specified in the Analytical Laboratory write-up for this analysis. Gill has .'not tried the micro coulometric detector bec a u s e h e is not set up to do so, but he has experimented w i t h electron capture. He stated that theoretically this unit should not. .provide any greater increase in sensitivi t y . In actuality he found a slight increase in sensitivity but there are usually too many chlorinated species present which may saturate the electron capture cell whose recovery is too slaw to be of practical use. He summarized b y s a y ing that the slight -increase in sensitivity' is not w o r t h the effort -to switch f r o m flame ionization to e l e c t r o n capture. A question was asked about how' the e x t r a c t i o n 3 performed. Gill stated that it i3 performed in a w i d e mouth bottle on a shaker for one hour. (It wa s m o t m e n tioned, but it is the case that this is done at room temperature.) He mentioned that spiked samples have been 17075 v - uawe 4 M a r c h 29,, I965 run this w a y and the recovery ranged from 9 0 to 100 p e r cent- The ratio of solvent to the material being extracted on this step is not critical according to Gill. -Their , standard .procedure is 20 grams of sample'and 40 milliliters of chloroform. On trichlorophenol samples specifically, 20 grams of phenol is converted to phenate -- about 10 p e r cent concentration in water. The phenate solution is extracted with 20 milliliters of chloroform in a single extraction. The chloroform is then concentrated so that the concentration of the dioxin will be ten times that in the origina l s ample. The question of volatility of dioxin came up and Harold Gill .stated that he-found he can distill o-dichlorobenzene av/ay from tetrachlorobenmodioxinJ 'He said that i n his o p i n i o n the secret-was to avoid distilling to dryness. A member of the group asked if samples of standard TCBD were available. ' The answer was yes and 100 mg samples were pro vided to one of the representatives from each company- (a sample had previously been given to Dr. Kelly of Monsanto.) A question of laboratory safety in the analytical work came up and the basic precaution of v/earing vinyl gloves w a s mentioned. Information relative to the gloves_we used was provided to the group. Disposal of contaminated laboratory materials and plant materials was discussed. V/e mentioned that D o w b u m s some small amounts of x*aste. Harold Gill stated that his l a b oratory study of- combustion showed that 9 9 -9o per- cent of *' .the dioxin sample was burned at 800C. V/e described w h y we felt that our practice of burning small amounts of dioxin was a. safe one. V. K. then outlined the project in which plant samples and products (not mentioned by name) were spiked w i t h known, amounts of the TCBD- The spiked samples were split f o r the purpose of checking our analytical procedures for recovery and correlating these results with the bio-assay method. The question of specification, quality control specification that is, was raised and w e were asked if w e could g i v e l e v e l s of dioxin contamination which were permissible limits. V. K. mentioned that at present v/e a r e using zero w i t h a confidence of 1 ppm in process samples. There was some discussion on the* problem of customers using finished p r o ducts under far less desirable conditions of health control than we can provide our workmen in our own plant- There seemed to be agreement among the group that w e could n o t afford to sell contaminated products. 17078 V . K. Rowe - 5- fla rch 29, 1965 Jack: Peterson, then discussed the data from animal e x p e r i ments using pure symmetrical tetrachlorobenzodiaxin-' Doses ranging Tram 2 parts per billion to 1000 parts p e r million or tetrachlorobenzodioxin in benzene had ,been administered to the rabbit ear. Dosage in most cases was 0.1. m l p e r day. Both single and multiple exposures have been studied and multiple exposures administered on a rive days per week basis'. The significant factors in the study are dose, t h e number of applications and- the days on exposure of the animals. The r e s p o n s e which is reported in the gross ob servation of the condition of the rabbit rs ear b y the toxicologists- This does not include pathological findings there is not enough .data in this area to discuss. The .level. -- response ranges from none through v e ry slight, slight, slight to moderate, moderate," moderate to-severe, severe, and extremely severe. Jack indicated *to the group that there is not a sharp definition between these categories of response and indicated also that there is some difficulty in graphing this type of response. He.described the response from single applications to the rabbit ear first r at 100 parts per million there was a severe response in eight days; at 40 parts per million there was a slight response in eleven days; a t '20, 10, J and 4 parts per million there w a s no response. These tests were run on s i n g l e .rabbits and without w a s h i n g the material off. J a c k then discussed the .multiple application data which he took from his major graph of this data. The important points that he made from this data were first that at the limit of.VPC sensitivity a severe response m a y be produced. I n other words, e v e n if. the VPC does not detect TCBD, an a n i m a l .response m a y s-till occur. His. second important point was that the I n d u c t i o n period for response averaged about ten days on the animals in the studies. There was a brief discussion then about the air samples''t h a t were taken in the plant- Silverstein mentioned that some air samples have shown activity on the animals. The degree of response Is slight and the number of samples that show activity is small out of the total number taken and the amount of air that must be sampled is very much larger than the amount a man. normally breathes In a n eight h o u r day. The meeting was 'ad Journed- The group then proceeded to t h e Toxicology Laboratory to view some of the test animals. T h e y were shewn responses of varying intensity and these were described. This demonstration appeared to have cansldej/able Biochemical Research Laboratory 1701 Building 1LG7S0c7s7Jl V iV. * w * v. -o Postscript All participants seemed to appreciate w e l l the p r o b l e m a n d all indicated that they would return home and attempt to convince their management to institute safety specifications (really quality control) for their various products in this a r e a - ~All agreed that the industry should meet its own responsibility. All were very appreciative of Dow's effort to steer them away from a danger area. Time will tell whether-we accomplished our mission, but as of now I feel satisfied with our effort and the reception it received. . VKH. % 17078  r*i' July 30, 1964 THE DOW CHEMICAL CO M PANY ' MIDLAND MICNIOAH 4M A O Mr. H. R. Hoyle _ Environmental Research 1701 Bldg. _ Z0 ^ Subject: M ANUFACTURE OF T R I C H L O R P H E N O L A T 199 B L D G / -' *. y m ,, We started making 2,4,5-TrichlorphBndl-in 199 In mid 1946.. We dissolved flake (anhydrous) caustic in si/ne/ N L ^ Q a n d u s e d e n o u g h of this solution to supply, of caustic per mole of t e t r a c h l o r - benzene. This reaction was run in batch (tumbler) reactors until late 1 9 5 2 . I n late 1952 we started t o r u n this same r e a c t i o n i n a c o n t i n u o u s co: reactor. We used the same chemicals and the same mole ratios. Reac ' ticn time and temperatures were similar to those of the batch reacto: In April of 19 6 2 we started adding water to the caustic-. ' solution. We added enough Huron water to be equivalent to 7 3 ^ c ' caustic which we hoped to eventually substitute for the flake caustic We used the same amount of \ and tetrachlorbenzene as w i t h the - aqueous caustic and ma d e a l o n g t e r m p l a n t r u n to stu d y the e f f e c t of :y w a t e r on this reaction. Th e t e m p e r a t u r e wa s a d j u s t e d u p w a r d t o gi v e the same conversion. Yield and quality were as good or better than w h e n v/e used anhydrous caustic, bu t we sti l l h a d a ll of the mechanica. operating troubles caused by the Insoluble sodium chloride formed in . the r e a c t i o n - We o p e r a t e d this w a y u n t i l J u l y 1, I 9 6 3 , e x c e p t f o r a short pilot plant run made in September 1 9 6 2 . I n Sept e m b e r 1 9 6 2 we m a d e a t w o iveek p i l o t p l a n t r u n u s i n g p i p e line caustic (app. 32J$ NaOH) d i l u t e d w i t h H u r o n w a t e r t o app. caustic. The same amount of j and tetrachlorbenzene were again used. The temperature was raised to give app. the same conversion, t h e yield and quality were good. In fact there was a slight drop In the Impuri ties which the Infrared Lab had long referred to as A and B. The caustic insoluble oil made during this run was studied by the Biochem Lab, R e p o r t No.. T 2 - 1 1 3 - 1 d a t e d 12-20-62. T h e s o d i u m c h l o r i d e f o r m e d in the hydrolysis was soluble in this reaction mixture so the coil plugging from salt has been eliminated. With the old process, most of the. f^me we had b e e n able to w a s h the coi l s b e f o r e they p l u g g e d , but often they did plug.and this unplugging operation was always a serious safety hazard. -fcQEMIiAiate September 1 9 6 2 and July 1, 1 9 6 3 we designed and built equipment to increase our capacity to hydrolyze tetrachlorbenzene .re caustic method. During this time we ran the plant again j-t Oron. f-lgke caustic diluted to 73? caustic equivalent. The plant was _ 17079." PreShntiatiibtjm 7-1-63 for Installation of the'new equipment. MDL N? f el .. <u^ uuuo -2- : K :- . * [ " ' The plant was started up In late July 19^3* We had some s t a r t u p difficulties but not serious, and because of.a tetrachlorbenz.ene* shortage we 'were net p u s h e d . Most of ou r t r o u b l e was caused b y a small amount of paradichlorbenzene in the tctrachlorbenzcnc receiv from 466 Bldg.-- 466 Bldg, started making all of their tetrachlorbe zene f r o m p a r a d i c h l o r b e n z e n e app. J u l y 1, 1 9 6 3 , b e f o r e -this t i m e t used rconochlorbenzene or orthodichlorbenzene. Part of this paradi distilled over with our recovered \ and we could not keep i back. This paradi chi or then separated out in the caustic-\ solution and caused plugging of lines because of freezing. We got extra exposure because of this plugging. Eventually we got all-11 traced and covered but this had neve3 been a problem before. In November and December 1963 and January and February 1964 we wer running at the limit of our hydrolyzing capacity. The caustic ins uble oils were r u n n i n g h i g h e r t h a n n o r m a l a n d b e c a u s e our. d e c a n t e r small v;e were d r a w i n g off oil (which goe s to t h e bur n e r ) e v e r y da y we have done for years.^ Because.we were pushing the equipment and having trouble with the*presence of paradichlorbenzene we had more exposure than normal. About Feb r u a r y 1, 1964 we n o t i c e d th e f i r s t t r o u b l e w i t h c h l o r a c n e Two supervisors, three trichlorphenol operators and one laboratory e m ployee started to ha v e a r a s h on t h e i r f a c e s . We call e d the. Environmental Research group almost Immediately. Also we Installecapacitance probe (app. 2-10-64) in the oil draw-off line so that - 6 operators do not have to be exposed to vapors while they watch the separation. The operators started 'wearing an air hood when they lowered the oil drain pipe into the dempster box, or took raeasureme etc. We thought the most exposure came from around this oil draw-c and v/e kn e w this oil ha s always b e e n bad. I -Starting in the middle of February 1964 Phoenix contractors moved 1 199 Bldg, to install a 10" steam line, an additional reactor coil, larger oil decanter and revised water lines to the\ . column condensers. Their work was all in the area of the trichlorphenol p from the roof level to the floor. They did not make any tie-in to caustic i n s o l u b l e oil lines. V/e s t a r t e d to u s e the r e a c t o r c o l l ar. new oil decanter in early April and the contractors .were f i n i s h e d b 4-15-64 when they left this area. 17080 The reaction product from our reactor goes directly to the recover?/ column. (See a t t a c h e d f l o w sheet- a n d e q u i p m e n t l a y o u t ) I\ cwomwes *off^ the top of thwe - rwewc-ov e r^y --c--o--l u m n --a n a t he phenate and caustic insoluble oils off the bottom. The bottoms go through an oil decanter and then to the top of the steam stripper t ------ *^he last traces of caustic i n s o l u b l e m a t e r i a l . The s t e a m a n v*oVl'atiilc-nUiautWcWrl l a l s *htuaVvWe a l w a yWs g o n e twow the ai r .w W" ew n e v e r h a d a n y trouble w i t h this ve n t u n t i l a b o u t N o v e m b e r 1, 1964, then, a t incre rilst star t e d f a l l i n g out a r o u n d the p h e n o l t r e a t i n g S e " Pr^feiSiinPt c " A demister installed in December 1963 stopped the caus gTtion, but then paradichlorbenzene started falling out as wet sno w h i c h c o l l e c t e d on roof and on above" r o o f s t r u c t u r e 'pv.i - J probably a bad source of contamination. * The Phoenix crew worked in this area part time for a few d a y s . On . 5-12-64 we installed a line taking the tops^ (vent) f r o m the strippi column and. put it in the b o t t o m of the / " column This volat material should~now Join the stream of oil removed by the oil decanwhich gees -to the burner. S i n c e e a r l y Apr i l 1 9 6 5 we have h a d the larger oil decanter and have only drawn off oil twice a week instea of daily as we had done for several years. Summary ---------------------- - 1. Started m a k i n g t r i c h l o r p h e n o l in 1 9 9 Bldg, in 1946, u s i n g anhyd caustic and batch reactors. 2. Started u s i n g a c o n t i n u o u s coil r e a c t o r in. 1952, w i t h s a m e c h e m and rates. Used T5% caustic April 19 6 2 to July 1 , 19 6 3 . 4. Pilot pla n t run, of tv/o w e e k s duration, in S e p t e m b e r 1 9 6 2 , usin pipe line caustic diluted to 22% NaOH. 5 . Plant started on 2 2 % caustic 8 -I-6 5 . - 6 . November- 19 6 5 pushing existing plant to limit. 7- D e c e m b e r 1 9 6 5 d e m i s t e r i n s t a l l e d . 8. F e b r u a r y 1, 1964, s i x c a s e s of c h l o r a c n e t r o u b l e r e c o g n i s e d . 9. F e b r u a r y 10, 1964, i n s t a l l e d oil d r a w - o f f probe. 10. Early April 1964, new coil and large decanter Installed. 11. May 12, 1964, vent f r o m top of stripping column to b o t t o m of [ ___ column. A&G000087 Ray Holmes 199 Bldg. PS CONFIDENTIAL Disclosure Restricted Pursuant To Court Order. "Agent Orange" Product Liability 1 7 0 8 1 L*t'eaiion'MDL No'3S1> Mr. J. 0. King Dow Chemical Co April 6, 1566 Mr. J. C. Kelly On March 21, we directed a sample of our Technical 2,li,5-T Acid to subject account. 2h talking with Ken Hanson cm April U, he advised that they would not be in a market for our material. Apparently, they feel that our material could conceivably re create a chlor-acne problem at Midland and, as such, would not entertain the purchase nf our present pro duction. j/ * JCK/ia cc. Mr. F. E. Kennedy - Kevark Jfr. R. A. thiidi / /. /' /./ H / /' / 17082 f Diamond Sham rock Chemical Company FineChemicals Division / 60 Park Place / Newark. New Jersey 0 7 1 0 2 / Telephone (201 ) 484-8400 September 2A, 1973 Chemicaland Corporation c/o Cloray, N. J. Corp. 80 L is t e r Avenue Newark, New Jersey 07105 A tt.: Hr. William Mitchell Dear Mr. M itc h e ll: I t was a pleasure to meet you on my v i s i t to your place on September 11, 1973- As I sa id at that time I w ill do what I can in the time a v a ila b le to a s s i s t you and your personnel in the sta rt-u p o f 2, A - D operations. Per John Brennan's request I delivered two copies each o f the fo llo w in g on my v i s i t : MCA operating in stru c tio n s, W. Tobin 7/15/63 DCP opera 11rig In s tr u c tio n s , V. Tobin 7/15/63 MCA process flowsheet, drawing no. MF-200-3 DCP process flowsheet, drawing no. NF-200-A Enclosed are two copies each o f the follow in g items that you requested: 1. Product s p e c if ic a t io n s for 2, A - D acid Muriatic acid 2, A - DCP k ? Dimethyl amine - D 6 Dimethylamine - D 2 . t 2, A - D operating in stru ctio n s 2, A - D Condensation Reaction, W.A.Goodloe/J.Mattts, Jr. 12/19/69 New "D " Melt Unit, F.G.Steward 10/27/67 Prep o f DCP S o l 'n for 0 Reactor Revised 2, A - D A c i d i f i c a t io n Procedure, V/.A.Goodloe 1/16/69 *T- 3. Monthly Operating Data August 1968 - July 1969 DSOOOIH b5 3 A Unit of Diamond Shamrock Corporation 17083' Chemiealand Corporation September 24, 1973 Page =2 4. Chloracne Inform ation 2 menos r e p o r t i n g a meeting w it h r e o r e s e n t a t i v e s o f Dow, H o o k e r , H e r c u l e s a nd Di amond r e g a r d i n g chloracne. The requ ested data on lab t e s t s run on the p r o d u c ts and n e c e s s a r y lab equipment is no t y e t a v a i l a b l e . I t w i l l be forw a rd e d a s soon as 1 can get i t together. Very truly yours, DIAMOND SHAMROCK'CHEMICAL COMPANY FGS: bk 7, cf F. Gordon Stew ard, Production Manager Nopco Chemical D iv is io n c c : Mr. F. R. Kennedy Mr. M. C. H e i s e l e jjsOOO UbSH 17084 ~ JOHN GOHT, JR. S, L. CHAHDLM1 CKLOROACHB - DOW MSKTIMO * /' cc t. R* JCcnaody - Hgr,, Newark plant x' J T 0. Kins M. F. Wilkerson p 3/25/65 On March 2U, KikB !C*nnscy and I nyt w ith two p e o p le f r o a iiooker Q is a io a l C o ., two f r o a H arcu lo * , and w ith th e Dow group t o d is c u s s th e to x ic o lo g ic a l im p u r itie s fi) a s s o c ia te d w ith 2 ,U ,5 triC h lo ro p fa e a o l .and r e l a t e d a t e r a i s . % Dr. Roce of Dow C h s a lc a l opened th e mealing by s t a t i n g t h a t th e y had o p e ra te d for 25 year* w ith o u t t r o u b l e ; b u t , in th o l a s t y e a r , th e y hod 60 to 70 o a s e s of h ohlcreasie. Ton of th o s e were m o d e ra te , and f i v e t o ton were e x tre m a ly s e v e r e . Thair approach vas a q u a l i t a t i v e one a t f i r s t . They wanted to f in d th o c a u s a tiv o caterial, l e a r n how t o i d e n t i f y i t , and t r y t o av o id c o n tin u a l tr o u b le v i t h the ifi) unkneun. They t e s t e d v a rio u s m a ta r a is from t a r f r a c t i o n s and f r o , as th e y pet it, "gunk", e t c . Ttiay found t h a t t h e r e a r e a number o f suspect m a t e r i a l s , prcbcbly 26 or 27; but th e major "b a d a c to r " t h a t th e y i d e n t i f i e d and which stsy tsd to consistently cau se th e problem was 2 ,3 ,T ,B -T e tra c h lo ro d ib e n z o p-Dioxia ( o y c s a t r i c a l ) . ,A -p A\ i 0A r. . \\ \ I ~f ^ j 7, f ~f~&T~fi.fi C H u C f l O 0 l i 8 p - Dio*-/*' r C S y 'lfiieT fi/c./*'-) This incidentally waii previously listod as a suspect material by'Cy PerldjS3 of otar oesrpeny. A similar material ia the unsytsmotrloal l,37,8-TCUUDf also nocartirtas listed as 2,3*7,?-"CE33. \ The Dow people used the white glove approach and found this contaminant cn tool hnsdlcs, benches, Instruartnta, end other fora.ites. In test animals, they could consistently cause the oyraptexs to appear. Dr. Holder of Dow, orus of thoir radical doctors, fcnd excellent color 3lidcs of the various 7>attents, The difficulty sioris with cultiple blockheads resulting in closed cystic structures which make the patient look like hs needs to wash his face. Trio disease develops slowly, not appearing until six weeks to two months after did exposure but appearing in five to oovea days vith very heavy exposure. Ooo bench chealst has bean under trostennt for two years and hio face is starting to show signs of elecring. Dr. Holder says that he believes this inn's problems will be solved in another six rrmt-hs. Cr. *dok, who does their d c r o eooplo work in connection vith their caical lebcrsfcor/, showed photc micrographs of the cysts as thay form3d in the ccrc of rtbbits. Tho cysts coirelattd with those found on the faces of the n=m. JJSOOO I H 5 5 17085 ChJaroaone - Ba Meeting ' ) -2 ftarch 25, h$65 Basically, thare i* ~ntlfiold deposit In th hair follicles end oil drrrts In the fees, Tbcao eventually go iron the blockhead eta^o to fera a closed, heavy oar* deposit. Too onctrLcol cannot bo round In the facial tissues or in th cores, but the problea still persists after scpceure. Tha best description of the acuta stag la, that tha facial tissues reaczzble tho exaggerated aurfaae torture of cn orec^o^ rather glased and warbly with the m*Io2sd bard core deposits. A secondary oyepbon, vhich does not correlate directly with tho eacruzrt of facial damntitia, la a fatigue reaction whore the criplaycs Is ccnplotoly listless, tired out, cr.d crt-sly isc^.eacitsiei. A ccnplote biopsy of liver, kidney, etc., ebsrs no daecnsrctica of cajor erg a. A ccsplste clinical examination of tho patients shoved no jesasuruble affect on hoart, blood pressure, respiration rate, blcod ov.^^r, etc. The fatigued patients aotuwd to bo helped by heavy doses of vitaaiiu, perhaps related in ecae way to the carotene uztabolisu of tho body (involving vitcrln A, etc,) y An oral dose of 17 teicrograus ijossdiately killed the test animals. Tho Osar people did not lower this dosage to obtain an but decided that, when thoy can detect this cofjpoiBTd, it should rot be in the product. They found that, after fsrpesure to the material, washing within 15 minutes did not help a groat deal, but did clow down tho speed at which tho syrpicnj appeared. Meshing after css he;? was of absolutely no help whatsoever in reducing total derantitls or speed of appearance cf the reaction, Moderate scrubbing vith detergent does not recove this material. . Csircsnly hard scrubbing can acconplish the task or tho use of solvents, ouch es l,l,l-trlchlaroflthii3. "ZT\ Dev has developed a nev a n a l y t i c a l i:*rfchod i n w hich th e y have o c a fid s n s o in M I t h e i r s e n s i t i v i t y t o 1 ppm. They can o n ly tit a te in le v e ls below t h i s th a t c cn s cay *-- y bo p r e s e n t below th o 1 ppx. Thoy s t a t e d t h a t th o y hav e n e t used n ic r o - c o lc r ir c r f c r la c s th o d s , and th e e le c tro n c ap tu re te c ta th a t th e y ra n node only a v ery s lig h t., le proveagnt In s e n s itiv ity w ith th is cexpound. T heir a n a ly tic a l ch caist s ta te d th a t J th e e lec tro n c e ll sa tu ra te s because o f th o presence o f other m aterials in high c o n c e n tr a tio n ooap&reo t o th e dioxin. Thia Eatcrlal has sooa otrango properties. It has a fairly high vapor pressure but nevertheless Is quite persistent ss a contaminant. It con be separated iron benzene by boiling if it is not carried down to dryness. The Dow poopio cro extremely careful in all of their work with this cocpound. They toe PVC thrcw-ocry glares, end all ecrplca aro burned in a special furonce which operatea eij QGCPj?. These saxplua are sealed before going to the burner. They use bioassey nsthods on rabbits far qualitative checking only. The Sow people stato that they intend to set a limit of soro with sensitivity of plus or sinus 1 ppa on this notarial. They hove analyzed materials from other oospraies. Including our cccpaoy, end have found eaounta as high as 10 ppa in 2,U,5-T o d d end 20 to 30 ppa 1a phaaatea. They have m d p a single application to the oars of teat rabbits and found that 20 ppa will not givo folliculitis.. Forty ppa doec give a slight effect, end 100 ppa la severe. They have node repeat applications of iron 10 to 100 prb, end 25 of these trcatrrsrto do cot cause a reopenso; hewovor, 1000 ppb (l ppp) gives a slight response with nine applications cad a oarere rocsticn with 11 applications. They conclude, therefore, that 1 ppn with repent exposure oen create a prtblca. Bow's people eutllnsd a rothad fer ccxtracting end running ccrcplcs cn 2,U,5-?j 2,h&+?i ctd phenols. It involves a ehlcrofora entreaticn, follcsred by j>S0 0 0 11>b 5 b HHSXEG HELD GF H E EESEIT KCElOEDu, i&ftCH S k } ly b 5 A5 Dia3 ?X^-Cn^S?g.\ gE3S&aCH LfU5gaaTCfiC3 HSSLftJTP* I Z C& Otirsr Ylcitas3 to tha esotins lnclrdLsd lr. Dca, vho cecccptaiad Dr. Prcrlcy frca Earcules Fardo?. Dr. Rally fren nemunto id cet attend, but and vieited vith Der? ths gfgvicua voek. Tha Dsv psapla ai iha coot- I25 ^cre Q3 falloua: Y. R. Eevo, Assistant Dimeter - BisChemical Et-' casrch Lnbj Dr. Holder, M.D., Phyniaina roaponsibl for troatsoct of patiente) Dr. Sedoh, Pathalogiat;-K. Silveratein, Chault; J. Potercca, CbgfflAcal EaglTiggg handling stetistles, end Eevard (?), Chenist racpon3ible fctr tha dsvalcpcant of tbe gus chracatograoh eethcd of euulynlo. Dr* Solder epsaod tha oeeetlrig vith colorad alias of Dow patienta taies treata as a recuit of ccocurs in I5S3 . The picturoa ebered a typicrl bleskhccd fGreaticn agoued ths cyce and forehasA. The ruptions picturad esra cash cera jateaos than onything I paroccally hve eean at aur FlnnS* V . "K. Rena be-d eaid thsy had > to 10 crees, but this statsrazrt -sa3 cpalekliz carrested by Dr. Haider, to 70 te75 casco. Dring a question and entrer r guried, Dr. Solder eccrlbod tha preseros cf couedocae end ccrbunclaci ccrcc. tha chculer bledos, bcak crd butteehn areas. U? vintil thia point, 2 vrcu> dored if thoro mro tuo ccparcto typas of chiurecna va verc dicouaeinig. Eo claiaa tkat 21/2 peurs out of tha centast arco is ci21cieat to clcar patient of eynytona. Thia dosa rot cesa possibla, eines 2-1/2 yuur3 haro E3t elnpred. Ho claies to bave cortad fatigua as a crzryicn also. Fyo cf tinIr care sovero caso3 rrere cubaitted to crtecnive tcatirg, mich imludad epen (7) livor hispa7 ;pcrphyrirs; standard dtabolic testa; kicrny thyroid, lurg erd. harrt funotienn. la all caces, all cf tiesa tasto ohcrrd n r ral frmrticairg of .tha cerrera irval" d, Slia bicarias trinen id r.tt ~'_~v r.h2rr.s-ccrlG tic iro rca o a -'. <-- - - ?N O *s ^ :i U C o h a v e n o t e s js rb a s c e r t a in e d 't d n t k r r e a p c s u r c la th ro u g h tv ~ ~ ia a ? la s y s - b a sic . T h e y e r e r o a e o s n b ly p o s it iv e t h a t i t la c o t c a u s e d b y d i r e c t c a n - t a c t ,, c a e v e ry c a s e la b i - l a t s r e l . Conteory to sacs of our feelings, they put little stock la natural lonunity c a d a r jp a r ic n c e e o d i f f e r e n c e l a G k ln t y p e s . D r . H o ld e r c a e c a t o 02 p a r - i dialing tha trestnani vork decs by Dr. Bielcar3, that cf treating tho eycptoiss by blackhead oca ccuedons renovd and tbs edalalstratlcn cl vitaains, particularly vitoain A. T h a e n t ir e Dew g ro u p a r e c c u g le t e ly c o n v in c e d t h a t th e c h lc r a s r a g e a 2 , 3, 6 ,& - d ic h l o T o - q ib - n c o ^ p - d io n ria . T h is I s th e cc^ p o u n d s u g g e s te d b y C y P e r k in s in a r e p o r t t o J n s k h o r r o r o n J u n e 7 , 19 6 0 . T h e r e I s a n \ a 1270n n t r i c a i i s a r o r 1 , 3 / 7 /^' " t h i s h a s &CSES a c t i v i t y , b u t d o e s n o t a p p r o a c h t i f i t o f t h e s p v :- c e t r i e d . In t h e ir s t u d ie s , th e y lo o k e d f o r th e d ib e n z e a e - ft ir e c i, a k n a v n e e n o ^ n in c a p th d e n e p ro d u c tio n . T h e y d id c o t f in d t h is c c a p o u rd , b u t hod n o t e l i d ra te d it s p o s s ib ilit y . The d ic s in e o lu b ilit y is le s s th a n 10 ra n in e th a n o l end a b o u t hCO p p n in c a m a n o . B a n n e rs v a n u se d to e n t r a n t v ip e c a n p lc s in th e P la n t an d a s a c a r r ie r f a r t h e ir r a b b it t e s t s . Con i n t e r e s t i n g .c o t e = t h e s i g n i f i c a n t l y s h o r t t i n e o f c o n t a c t n e c e s s a r y t h a t t r i l l z n o 3 c h lc r c s n e . In o n e c a s e , th e y v a n n e d o f f v it h d l rc - in 15 c la a la s a f t e r a p p lic a t io n . T b a r a b b it ' 0 e a r b c c a c e a ffe c t e d in s p it e o f c o n tia a u s vaab J-n g s e v e ry c u e - h a lf, up to k h o u rs . Dr. Croak ohevad d i d o s of call stnructurc vbiei: is in the skin cf rabbit ears, vith d i d had covers cases cf chlcracac. Moot of ids prccontaticn a bssyond ny coupmbension. Tbo rabbit suntr.lmd liver snags in d a c s b ell cases. This dosage (necrosis?) occurred very close to the bilo dost. DrS o l ok s t a t e d t h a t i n c a t t l e , 1" ~r-t\r: 7t o 3in e r r m ln h r .i v a t t ,---- ,1 -- --1-U T) s n f: n i .i ^ - " 3- vi+-.>-** * r~ ria w-uJ-uL'^v? of Yitaoic A in tri b l c d ctrcrsi la a c vcry sic? prcccs:!. Tri eccunt ci vcrd corsa by tri Eio-Crirriccri Ss-riicn vaa thcjciigh soci crrinaaiva. Tenta ci o errali dece ci 20 ree shered cc ro- cpcnco. kO ppa dcrclo^cd a aligeri folliauiitia le 11 dopo. A CI3 3 I0 eco ci ICO jrrn coarod a severe ree-- ico le S ars. Dee ucas a -ceri cecia ci S tersa, vcorilcg iroc ^ .'0 r-cccccce!' to **7cr7 Savore1', gc tnt iriorprotir tcn ci reculto la conicaie^. Ca a multiple appileceIca oi 1 ppn, a ecd arata resecare vas Lstcctod aitar > applicatieoe, ari. a cover recrocce aitar 11 esplicatisi;. 2j applicatlcr.a caca oi 10, 20 ari. 100 ppb alicrcd co oiieet, Aa pcrt ci triir procrea, t-riv ocsted catrplea fresi all carpareitera eri vere U r i ensugh ta soni ero result ci tri ir firiioga psrscriLiy to co ri tri Pieri. Trias ai cur T=acid aarpris producati la Septaobar ai 1961 abtvcd allght raoprare aitar 13 aro ca tee rabbts, ari 2 of tri sanraLeo ehrrrvd 5 cri 16 po ccalTticaily. Ci rio acenriu ai trlchlcrrorrirete, erta ddcved a oliglit to eriarcri reeversa ri dayo, ornila tri otrir orivcd ri re Gprrse ri 25 triyo. leitri? of trino cc_rplc3 vere arlyted by ericca risieri, t tdia tiri, tri crriupri ci tri orisric csvriloa ria eri tesa ririrvirri. Udita rata aro cct oced far tiri 'rp: ci alia test becauaa triy do rat io epuri prcparly ( 7) ; do tot <rivc i a t o e a l a r a c c a ( ? ) . M rine as ppc,, ..5 * j - / . tire c..t 20 arra vare ferri ori T--ioli at t cue o ri egrse vitir t ir i a r lT tic a l io calta ai la seri te ri. tri:i ; ri.;: imperieselag triir jrioblcri ri tic Plori, tri7 drivetei 20 pur. ri tri vrirri.ee. K. Silverstari speri ai eleanlag, up triIr plori crea, t -n, rrlth varlcu o o c lv c r r i. A lv a t" _b 1 1.. -* -- -ri- n . . J ' - -- - - - -- * -, " ticori feo* plori usa io fw.v:-.*. riotri thrvt l,l,lrirxblcrc*c-tririi vcvirri I - - 4 - *" aa `roll. Sprang datergnats arc not affective vitnout intense scrubbing and herd trori. Proa his cerriez:ta, I inasiaa a ceccaT^nsizrstinn prenons ras parfcrsxd. in their unit. Free: their tecta> it vaa dottrrized that the dloxin dsccupcsss at C<X)C. Sven s^-cugh I>cv has a very Inrya Industrial vaste burner vith Arrears tei.<?orature6 of over 1200*C, they continua to bury tbair vastes. They vare hesitant to continue discussions ohcry; thaoo lines. laboratory vastc3, including slaves required in handling this micrial, era incinerated. Hcvurd (?) stated that the c h r o m tographic EShhcd of mnlycis etna detect 10 ppn in an anisole sarnie and 1 ppr in TCP end T-caid. An cf yet, they hove no esthod for 33tors cr fcrnulatiaoa. TCP casipla prepara* ticn for analysis is os follovs: 20 grans of TCP vers converted to the eediun salt end extracted with 2G cc of cbleroforu. The clilorofcra eztract la concentrated 10 to 1 and injected into the snehine. Phenate seint-iera cre reduced- to a 10 phenate ccm&ntraticn extracted with chlcrcfcm csa handled as above. T-ocia ecnplea sre prepared by extracting 20 g r a m cf the Tctid Trith HO cc cf chlcroicru. The chlerofom is filtsrod end ccmtc<*taxhcd vith cro^barrti. cstrual caustic and the chlorofcrt: comnn tested es above. Plant wipe eaxplac rare extracted n t h 2 cc of chlcrcfom and used as cunh. lia \rill have to develop cur cvn retried of doteruir.ing circmsc-graph re spouse in t e r m of per.. Throve entire tecsim O i'i to be presented. Far everyone1s protection, everyor.s should clean up :d.3 final product and certainly on the local level, this is very necoscc-ry. r Rove stated m a y tires that each coganinaticn could linndle tin problcn in can v T r e e , lifl presentation, I ratliarre teat detect ion vus ths primary s m i l e tied that steps to eiiniuate its cerry-over into th-e final product vas veil vithla thii capabilities of al 1 people involved, A srnll sarnie cf the dicurln van i^ves to each ccsqiaay attending tlvs .testing. DS0 0 0 I 4 bfa2 17091' [1 April 1991] Long-Term Chemical Carcinogenesis Experiments For Identifying Potential Human Cancer Hazards. Collective Data Base of the National Cancer Institute & National Toxicology Program (1976 - 1991) by James Huff & Joseph Haseman National Institute of Environmental Health Sciences Research Triangle Park, North Carolina USA [Presented at the Conference on Data Bases of Genotoxicity and Carcinogenicity and Their Usefulness for Hazard Evaluations. Castello Simon Boccanegra in Genova, Italy, 16 - 18 January 1991] N ote: Pans of this overview paper come from our previously reponed and published analyses and interpretations. Thus for those wishing more details and perhaps larger bibliographies please consult the references given at the end of this paper. Most of the papers authored by us or the individual printed Technical Reports on the chemical carcinogenesis studies are. available upon written request. 17092 Chemical Carcinogenesis Data Base J. E. Huff & J. K- Haseman Abstract The carcinogenicity data base used for this paper originated in the late 1960s by the National Cancer Institute (NCI) and since 1978 has been continued and made ,more comprehensive by the National Toxicology Program (NTP). The extensive files contain among other sets of informa tion detailed pathology data on more than 400 long-term (most often 24 month) chemical carcinogenesis studies, comprised of nearly 1600 indi vidual experiments having at least ten million tissue sections that have been evaluated for toxicity and carcinogenicity. Using this data set we have 1) determined the concordance in carcinogenic responses between rats and mice to be 74%, and between sexes to be 85% (rats) to 87% (mice); 2) discovered that using male rats and female mice would have identified correctly 96% of the positive or no evidence chemical carcino genicity results obtained using the more extensive protocol; 3) estab lished an historical control file of tumor incidence data; 4) evaluated the false positive rate in the interpretation of carcinogenesis studies, conclud ing that this rate is probably no more than 7-8%; 5) compiled listings of chemicals having like carcinogenic target sites for each of the 37 organs or systems for which histopathology diagnoses have been recorded routinely; 6) demonstrated that evaluation of site-specific carcinogenic effects are preferable to doing analyses based on overall (all sites combined) tumor rates; 7) learned that few chemicals cause only benign tumors or only liver tumors, the most common target site for chemically induced cancers; 8) identified key sources of variability in tumor rates in long-term car cinogenesis studies; 9) ascertained that com oil gavage or gavage per se exhibits little if any adverse impact on long-term studies; 10) showed that the Salmonella multi-strain assay was as good as a battery of four short-term in vitro tests for predicting in vivo carcinogenicity, yet was only 66% concordant with an 89% positive predictivity and a 55% negative predictivity. 11) investigated the relationship between chemically induced toxicity and chemically associated carcinogenicity, finding that very few chemicals cause tumors only at the highest exposure concen tration (EMTD). These (and other) derived compilations are most useful for maintaining an historic and objective perspective when evaluating the carcinogenicity of contemporary experiments. 17093" 4/2/91 page 2 Environ Health Perspect Chemical Carcinogenesis Data Base J. E. Huff & J. K. Haseman Introduction Since the introduction of exposing animals to chemicals in 1918 by Yamagiwa & Ichikawa for detecting chemical carcinogens (1, 2), much has been learned about the relevance of these findings for possible effects in humans. Likewise an enormous amount of knowledge has been gained over the years on how to design, conduct, monitor, evaluate, and interpret the data collected from these carcinogenesis studies (3-7). Evaluating chemicals in laboratory rodents as surrogates for potential human health hazards remains as the cornerstone for identifying those chemicals most likely to cause cancer in humans (8-14). Besides human experience and epidemiological investigations, long term studies in laboratory animals are the only validated and universally accepted means to determine carcinogenic hazards to the public health and to the environment (as examples 5, 6, 8-21). The major public health attribute of these long-term chemical carcinogenesis experiments is to allow better risk assessment (22) and risk management decisions (23, 24) to be made for reducing, preventing, or eliminating exposures to those chemicals identified as constituting real risks to humans (25-27). The findings from these long-term studies assume a major role in the key first step in the risk assessment-risk management process, and a contributory part in the second step of the process (Table 1). As illustrative and important examples of preventative medicine, the International Agency for Research on Cancer (25, 28, 29) periodically re-evaluates all those chemicals or agents having available human data, 17094 4/2/91 page 3 Environ Health Perspect Chemical Carcinogenesis Data Base J. E. Huff & J. K. Haseman that contain groupings of chemicals and agents considered to be carcinogenic, probably carcinogenic, or possibly carcinogenic to humans; and those not classifiable or probably not carcinogenic to humans (25). Similarly, and as mandated by the U.S. Congress, the Department of Health and Human Services via the U.S. National Toxicology Program (NTP) evaluates the available data and places chemicals into one of two categories: known human carcinogens and those reasonably anticipated to be human carcinogens (27). Once these are identified by either of these organizations, other state, national, and international agencies as well as public and private interest groups assess the possible adverse health impact these agents may have on their particular constituents. Various actions may be taken to reduce or eliminate exposures to the identified hazard, to locate and study relevant human cohorts for possible carcinogenicity, and to attempt further studies to better characterize the identified potential risk to humans (8, 10, 12, 13). In the middle 1960s and early 1970s, the National Cancer Institute (NCI) initiated an extensive carcinogenesis bioassay screening program, and published in 1976 the first of 200 Technical Reports (30, 31). The National Toxicology Program (NTP) continues these efforts, and about 200 more Technical Reports have been issued or are in press (11, 32). These data and various sub-combinations form the bases for this overview paper. The overriding aim for doing these individual and collective analyses comes from the never-ending need to more completely understand the fundamental biological principle that extrapolation of experimental and epidemiological findings among the mammalian kingdom is sound science. 17085 4/2/91 page 4 Environ Health Perspect Chemical Carcinogenesis Data Base J. E. Huff & J. K. Haseman The ultimate value of these data and resultant interpretations will continue to allow more knowledgeable public, occupational, and environmental health decisions. Materials & Methods The chemical carcinogenesis data given in this paper come from the NCI & NTP Technical Reports series which describe the results of long-term studies in rodents (11, 32). Compared to others who compile information about carcinogenicity of chemicals, our Program is unique in that we design, conduct, and evaluate our own experiments, whereas others typically record the results and conclusions made by the various investigators reporting their data in the literature. Further; and most importantly, our data and interpretations are peer reviewed in public sessions before the Technical Reports are finalized and made ready for printing and distribution. In total, the data base used for this paper comprises 379 long-term chemical carcinogenesis studies involving 1394 individual experiments: male rats, female rats, male mice, & female mice ( 10). These toxicology studies are typically carried out using both sexes of two species of rodents divided randomly into sets of 50 - 60 animals per group; a control group and two or three exposure concentrations are graduated down from a carefully selected top level (3, 5, 6, 11, 19, 33-35). The species most often used by the NTP are the inbred Fischer 344 rat and the hybrid B6C3F1 (C3H x C57B16) mouse. Duration of exposure is generally two years (or about 2/3 the life span of these rodent species). 17096 4/2/91 page 5 Environ Health Perspect Chemical Carcinogenesis Data Base J. E. Huff & J. K. Haseman The data, results, evaluations, and interpretations are peer-reviewed in public meetings, and this chemical-specific information is made available in the NTP Technical Report Series (11). Results and Interpretative Observations Long-term chemical carcinogenesis studies. A continuing evaluation of the NCI/NTP database of long-term chemical carcinogenesis studies has resulted in a number of useful scientific findings, several of which are summarized in this section. Nearly 400 chemical-specific studies have been reported, most often involving groups of male and female rats and mice exposed to a chemical for two years (11, 30-32, 36, 37). The collated findings are evaluated, interpreted, and presented in public meetings to a non-government peer review panel of experts in chemical carcinogenesis. Each sex-species experimental grouping is given an overall level of evidence of carcinogenicity selected from 5 categories: two positive levels (clear evidence and some evidence), one uncertain (equivocal evidence), one for no observed response (no evidence), and one for seriously flawed experi-ments (inadequate experiment) (38-41). Roughly one-half of the chemicals induced a positive carcinogenic response in at least one of the several experiments (Table 2). Only 43 of the 313 chemicals (13.7%) studied adequately in male & female rats and in male & female mice caused cancer in all four experimental groups; and 25 (8.0%) produced cancer in one or more sites in three of the four experiments (Table 3). These findings will generally cause a chemical to 4/2/91 page 6 17097 Environ Health Perspect Chemical Carcinogenesis Data Base J. E. Huff & J- K. Haseman be placed into the s u f f i c i e n t e v i d e n c e o f c a r c i n o g e n i c i t y category (25, 26) and into the group of s u b s t a n c e s r e a s o n a b l y a n t i c i p a t e d t o b e c a r c i n o g e n s (27). A prime value of these results permits identification of those chemicals considered most likely to be potentially carcinogenic to humans, and thus epidemiological investigations having adequate cohorts could be initiated. As an example, the carcinogenicity of 1,3-butadiene was first determined in animals, and a subsequent epidemiological investigation revealed a positive association between exposure and cancers (8). Species correlations. In these studies similar results are observed in both species 74% of the time, and the concordance between sexes within a specie ranges from 85% (rats) to 87% (mice) (Table 4) (42). To maintain the important contribution of hormonal influence on the carcinogenesis process, we conducted a retrospective evaluation on this question: for how many of the outcomes would we have found the same (a simple qualitative 'yes' M or 'no' H) result if we had used a reduced protocol of only one-half the experimental groups? Using male rats and female mice, the answer was that 96% of the chemicals would have been correctly matched to the + or - result of the more extended experimental protocol (10). Importantly however, 12 chemicals causing single sex-species positives in either female rats (four) or in male mice (eight) would have been missed as would 2 chemicals causing carcinogenic effects in both female rats and in male mice (Table 3). For all 14 chemically associated responses there were only single target organs per sex-species (not considering here equivocal responses), and for only one chemical was the target site sex-specific (uterus). 4/2/91 page 7 17CS8 Environ Health Perspect Chemical Carcinogenesis Data Base J. E. Huff & J. K- Haseman The major questions that arise from this retrospective evaluation centers on whether using this modified protocol in the future on the next group of 400 equally diverse chemicals would 1) permit the same percentage of 'correct' responses and 2) allow us not to miss any potential carcinogenic hazards to humans? While we contemplate answers to these questions, perhaps one could consider using a modified protocol for certain structural certainties: that is if an organization had to study a certain nitrosamine, a benzidine or anthraquinone dye, or an aniline compound, as example, then a modified protocol could be possible. For 'unknown* chemicals one would be wise to remain with the historically and currently acceptable paradigm of both sexes of two rodent species. Historical control tumor data. Although when evaluating long-term chemical carcinogenesis experiments the most appropriate control group for comparative and interpretative purposes is always the concurrent control, there are instances in which the use of historical control information can aid an investigator in the overall evaluation of tumor incidence data. One example is for rare (or uncommonly occurring) tumors; another is for a tumor type that shows a marginally significant chemically related increase relative to concurrent controls. The NTP historical control tumor data file is a "moving window" of studies conducted within approximately a 4-5 year time period, and is updated approximately twice a year. Thus as new data are entered, the oldest data are removed (but of course not discarded). Periodically, control tumor rates are published for informational purposes (43-45). 17099 4/2/91 page 8 Environ Health Perspect Chemical Carcinogenesis Data Base J. E. Huff & J. K. Haseman The extensive NTP database is an important and frequently used source of information on historical control tumors, and in some respects differs from others in that 1) typically the tumor diagnoses and therefore incidence data have been verified by comprehensive quality assurance and pathology review procedures, 2) tumor diagnostic nomenclature and criteria across experiments and laboratories are consistent, and 3) these data come from one source (albeit several laboratories conduct the studies & record the initial tumor diagnoses) whereas other available tumor data bases often come from myriad locations. In each NTP Technical Report the relevant historical control tumor incidence data are given for all tumors showing possible chemically related effects. Most important are relatively recent studies carried out at the particular study laboratory. Investigators from industry and other governmental agencies also frequently request use of the historical control database so that they can better interpret and compare the background tumor data of their own studies. False positive and false negative rates. In long-term chemical carcinogenesis studies approximately 30-40 different tissue or organs are examined for possible carcinogenic effects in male and female rats and mice. Under these conditions it is not unusual to find "statistically significant" changes in tumor incidence that merely reflect random variability. Our data base provides a unique opportunity to examine the pattern and frequency of site-specific tumor incidences, and to estimate the likelihood of finding statistical differences by chance alone. For example, Haseman (46) examined the false positive rate in NTP studies by deriving a statistical decision rule that closely approximated, the 4/2/91 page 9 17100 Environ Health Perspect Chemical Carcinogenesis Data Base J. E. Huff Sc J. K. Haseman complex scientific judgement process used in the evaluation of these studies. This "rule'' (useful as a guideline, but should not be applied rigidly) is to declare an increase in the incidence in a commonly-occurring tumor to be biologically significant if the uppermost exposure level incidence compared to controls is significantly different at the p<0.01 level. For an uncommonly occurring tumor (background rate less than 1 or 2%), a p<0.05 increase is typically required. From this evaluation, the false positive rate associated with this decision rule was demonstrated to be no more than 7-8%, implying that the false positive rate in NTP studies is reasonably well controlled. Coupled with biological significance, possible mechanistic relevance, an overall historical perspective, and public peer review, we believe that false positives. results have been minimized in our program. A more difficult public health issue that has rarely been considered is the false negative rate within these relatively insensitive assays. Perhaps this will receive more attention in the future. The NTP database is also quite valuable for the study of statistical decision rules, particularly those that require knowledge of the incidence and variability of historical control data. Although such rules should not be rigidly applied, as noted above, these statistical methods may be useful in that they employ a formal multiple comparisons adjustment to limit the overall false positive rate. For a discussion of statistical decision rules that might be used in the evaluation of laboratory animal carcinogenicity studies, see Haseman (47). While attention is often focused primarily on controlling false positive rates, one must remember that rodent carcinogenicity studies 4/2/91 page 10 17101 Environ Health Perspect Chemical Carcinogenesis Data Base J. E. Huff & J. K. Haseman with only 50-60 animals per group are relatively insensitive for detecting weak to moderate carcinogenic responses. Thus, this insensitivity must also be considered when deciding upon how to guard against false positive outcomes. For example, as mentioned below, we demonstrated that analyses based on overall (all-sites combined) rather than site-specific tumor rates would have resulted in a marked increase in the false negative rate. That is, several chemicals showing positive results evaluated using site-specific comparisons would not have been identified using total numbers of tumor-bearing animals (48). Thus, the interpretative emphasis should continue to be on site-specific effects. Site - specific neoplasia. Using this data set we have compiled listings of chemicals having like carcinogenic target sites for each of the 34 organs or systems for which histopathology diagnoses have been recorded routinely (49). The most common tumor site is the liver (15% of all experiments; 50), followed in rank order by lung; hematopoietic system & kidneys; mammary glands; forestomach; thyroid glands; Zymbal glands; urinary bladder; and skin & uterus (Table 5)(49). These compilations are most useful for maintaining an historic perspective when evaluating the carcinogenicity of contemporary experiments. Equally important, the chemical-tumor-organ connection permits an evaluation of how well chemically induced cancers in a particular organ in one sex or species will predict or correlate with the other sex or species. Using liver cancers as an example, the overall inter-species concordance is 80%. Likewise target site predictions can be made for chemicals selected for study that may be similar to those already evaluated, thereby experimental protocols could be adjusted to allow for example more extensive pathology on preselected 17102 4/2/91 page 11 Environ Health Perspect Chemical Carcinogenesis Data Base J. E. Huff & J. K. Haseman target organs (i.e., serial sections of the kidney). Further from these observations, one could decide to use two strains of mice to evaluate a short-chain chlorinated aliphatic compound or to study a human carcinogen in a sex-species known to develop chemically induced tumors in the same site observed in humans. Structural classes of chemicals having a propensity for certain organs can be easily identified from these data. Sex-species responders to particular chemically induced cancers, such as the kidney in male rats, can be recognized at a glance. Like humans, the top ten sites of cancer are somewhat different between the sexes of rodents. Yet when compared among the mammalian species in general (including humans) the sites and rankings are remarkably similar (10, 12, 20, 49). Site specific versus total tumors. Using a sub-set of 81 carcinogeni city studies, we evaluated the issue of interpreting the tumor incidence results based on the proportion of animals with primary tumors (all sites) or the proportion of animals with malignant neoplasms (all sites) compared to analyses of site-specific carcinogenic effects (48). Less than half of the 45 chemicals considered to have induced a carcinogenic response in at least one site in one sex-species experiment showed a significant increase in the incidence of primary tumors combined (22 chemicals) or malignant tumors combined (21 chemicals). Among the 29 chemicals interpreted as not carcinogenic based on site-specific effects, two showed significant increases in overall tumor incidence. Thus, consideration of overall tumors rates seemingly masked several important site-specific effects, while identifying only two additional chemicals apparently "missed".* ha 4/2/91 page 12 Environ Health Perspect Chemical Carcinogenesis Data Base J. E. Huff & J. K. Haseman using site-specific analyses. These latter two "carcinogenic responses" were not considered to be biological relevant (48). In our opinion, at least two major problems are associated with an evaluation based on overall (all sites) tumor rates: 1) combining tumor types of varying morphologies and topographies is biologically unsound and scientifically questionable, and 2) pooling various tumor types reduces study sensitivity for detecting chemically related increases in sitespecific tumor incidences. Further most national and international guidelines for studying chemicals for carcinogenicity in rodents (or in humans) emphasize site-specific effects (6). Thus, despite purported advantages of analyses based on overall tumor rates (e.g., simplicity; reducing occurrence of false positive and perhaps false negative results), primary emphasis should continue to be placed on site-specific analyses. Benign tumors. The importance and relevance of benign neoplasia in evaluating the carcinogenic potential of a particular chemical remains a area of active discussion, even though few if any chemicals only cause benign neoplasia. To explore this issue we evaluated the long-term carcinogenesis results for the 143 chemicals reported by the NTP: 81 of these showed neoplastic responses in one or more of the S24 species- gender experiments (31): Of these 81 positive studies, 60 (74%) were considered positive based on malignant neoplasia; 16 (20%) were positive due primarily to benign neoplasia, but had supporting evidence of malignant neoplasia in the same organ/tissue; and 3 (6%) were positive based on benign neoplasia alone. 17104 4/2/91 page 13 Environ Health Perspect Chemical Carcinogenesis Data Base J. E. Huff & J. K. Haseman Thus, only 5 of the 143 chemicals evaluated induced benign neoplasia alone (3.5%), and those observed benign neoplasms are known to progress to malignancy (51, 52). Accordingly, we consider chemically induced benign neoplasia to be an important indicator of a chemical's carcinogenic potential in rodents, and believe these should continue to be made an integral part of the overall weight-of-the-evidence evaluation process for identifying potential human health hazards. Sources of variability. A major advantage of an extensive historical control database is that it allows an examination of trends in tumor incidence, (and other potentially changeable biological parameters) over time and within & between laboratories, thereby permitting the identification of important sources of variability. This information is useful in the design of long-term chemical carcinogenesis studies, and may allow the investigator to address what would otherwise be confounding factors in the evaluation and interpretation of the data. Potential sources of variability include the animal room environment, longevity and survival patterns of animals, dietary factors, and differences related to pathology (4, 53). For example, we learned that the Fischer 344 rats used in our program have shown a steady increase in the background rate of certain commonly occurring neoplasms (e.g., leukemia, and for certain glandular organs such as pituitary, mammary, thyroid, and adrenal glands), together with a decreased survival and an increased body weight (54). A review of slides from early and relatively recent studies identified possible reasons for these shifts, [note: every slide from every study is a 4/2/91 page 14 Environ Health Perspect Chemical Carcinogenesis Data Base J. E. Huff & J. K. Haseman security archives that allows these historical comparisons, and also permits others to view slides to verify our diagnoses; further for at least ten years after a study is reported, the tissues and remaining organs from each animal are retained in case new slides are needed]. The possibilities include 1) changes in histopathology diagnostic criteria over time, (2) changes in the amount of tissue examined, (3) intra- and inter-laboratory variability, and (4) dietary factors; i.e., the incidence of certain neoplasms (particularly endocrine system and mammary gland tumors) are known to be positively correlated with body weight; differences in protein content influence kidney lesions in the rat. A similar investigation in B6C3F1 mice (55) did not reveal the same striking time-related changes as seen in rats. The only notable change was an increased incidence of pituitary gland neoplasms in female mice in the more recent studies, which may have been associated with increases in the amount of pituitary gland tissue examined. Additional investigation revealed that liver tumor incidence in mice (particularly in females) was highly correlated with body weight (53). Another factor that might have influenced body weight (thereby perhaps indirectly affecting liver tumor incidence) was a program change in protocol made in 1984 that resulted in mice being housed individually rather than in groups (56). Our investigation of sources of variability will likely lead to certain other suggested changes in experimental protocol or design. For example, an alternative diet containing (among other modifications) less protein and more fiber is being studied and will probably be adopted in the near future. This should improve survival and reduce tumor rates by limiting i h i n. o 4/2/91 page 15 _Environ THTealth Perspect Chemical Carcinogenesis Data Base J. E. Huff & J. K. Haseman the weight gain of the animals, as well as reducing the amount and severity of protein-associated lesions in the rodent kidney. We have also gained a better understanding of the value and limitations of historical control data in the overall assessment of tumor incidence (mentioned earlier). Routes of exposure. The optimum route of exposure for chemical carcinogenicity experiments should be one that most closely mimics the major human exposure route; this is not always possible, but the attempt should be made. Historically, chemicals have been administered by a single route of exposure: usually in the feed (60 % of the time for the data base of the nearly 400 studies we evaluated), but also by oral intubation (27 %), by inhalation (5 %), by application to the skin (3 %), by intraperitoneal injection (3 %), or in drinking water (2 %) (10). Intubation is generally used for administering unstable, volatile, or reactive chemicals. Microencapsulation is a newly developed technique for administering these agents in feed, and will generally be used to replace the gavage technique (57, 58). This data base permits an evaluation of the possible effects of route of administration on carcinogenic response. Since oral gavage frequently employs com oil as the vehicle, a question of particular interest was whether or not com oil affects tumor incidence. To answer the question, a comparison was made of tumor rates in untreated (or basal diet) controls and com oil gavage controls, taking into account any inter-laboratory variability and time-related trends. Haseman et al., (44) found that com oil has no apparent effect on tumor incidence in male and female B6C3F1 mice or in female F344 rats. In male 1 7 1 0 7 4/2/91 page 16 Environ Health Perspect Chemical Carcinogenesis Data Base J. E. Huff & J. K. Haseman F344 rats, however, com oil was associated with a decreased incidence of mononuclear ceii leukemia from approximately 27% to 14% and an increased incidence of acinar cell tumors of the pancreas from approximately 0.2% to 4.4%. These changes appeared related to corn oil rather than to the gavage technique itself, since controls from gavage studies using water as the vehicle showed a tumor response for leukemia and pancreatic acinar cell tumors similar to that observed for untreated basal diet controls. Interestingly, acinar call tumors of the pancreas were not affected uniformly, since contemporary controls administered com oil from the identical batch did not show similar increases. Further, if the two control groups with the largest average body weights are removed from the analysis the difference for pancreatic tumors between basal and com oil controls is no longer statistically significant. A long-term study was designed to evaluate the influence of various levels of com oil and of select other oils (sesame seed, sunflower seed, and tricaprylin) on the carcinogenic potential in F344 rats. Preliminary results strongly confirm both of the effects noted above. Our increased understanding of the impact (or in most cases, the lack of impact) of com oil gavage on tumor incidence increases our confidence in the interpretation of studies using com oil as the vehicle (and gavage as the route of administration). These results may also have implications concerning possible dietary changes to increase the survival of F344 rats (leukemia is the leading cause of death in these animals). Predicting carcinogenicity with genetic toxicity assays. Four widely used in vitro genetic toxicity assays were evaluated to determine their 4/2/91 page 17 17108 Environ Health Perspect Chemical Carcinogenesis Data Base J. E. Huff & J- K. Haseman individual & collective concordance with the carcinogenicity of a number of chemicals. The end-points and short term assays were mutagenesis in Salmonella typhimurium and in mouse lymphoma cells and chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells. The original investigation with 73 chemicals (59) has been followed up with an additional 41 chemicals (60-63). Results from both studies were similar, and are summarized in Table 6 for the combined 114 chemicals. Salmonella performed best among the four short term tests, achieving a 66% (75/114) concordance, an 89% (32/36) positive predictivity, and a 55% (43/78) negative predictivity of carcinogenicity. Chromosome aberrations also showed a significant association with rodent carcinogenicity, but none was observed for the sister chromatid exchange or mouse lymphoma assays. Although the performance of individual short term tests was of interest, the primary focus of the investigation was whether the performance of individual short term tests for predicting carcinogenicity could be improved by utilizing a battery of two or more tests. Importantly, these data demonstrate, at least for these assays and for this particular 114 chemical data set, that there was no evidence of complementarity among the four short-term tests, and no combination constructed from these assays improved substantially the performance over the Salmonella multi-strain assay alone. These results led our program to adopt Salmonella as the primary in vitro short term assay now used to identify mutagens. Use of the three iiios 4/2/91 page 18 Environ Health Perspect Chemical Carcinogenesis Data Base J. E. Huff & J. K. Haseman other short term tests noted above has been curtailed. The NTP is now evaluating in vivo tests for chromosome aberrations and micronuclei as a possible means of predicting or confirming in vitro mutagenicity and in vivo carcinogenicity. Chemical toxicity and carcinogenicity. The possible interrelationships between toxicity (histopathological observations), genotoxicity (i.e., Salmonella), and chemical carcinogenicity in laboratory rodents was investigated using information obtained and reported from two-year studies involving 99 chemicals (64). Although target organ toxicity and carcinogenicity occurred together in some studies (particularly for the nasal cavity and kidney), many chemicals produced carcinogenic effects in organs showing no evidence of toxicity, and conversely, toxicity was frequently observed in organs showing no chemically related carcinogenic effects. The data suggested that only seven of the 53 chemicals causing cancer in at least one organ of one sex of one species exhibited the types of target organ toxicity that might have been the cause of the observed carcinogenic effect. Of the 127 positive sex-species experiments that utilized multiple doses, 54 (43%) produced statistically significant (p<0.05) increases in tumor incidence only at the top dose. However, in 78% (42/54) of these experiments the incidences of site-specific tumors in the lower-dose groups were also numerically elevated relative to controls, and were considered to be biologically relevant. Thus, only 9% (12/127) of the carcinogenic effects appeared to reflect a "high dose only" response. Moreover, no apparent difference in mutagenicity as measured by the 4/2/91 page 19 Environ Health Chemical Carcinogenesis Data Base J. E. Huff & J. K. Haseman Salmonella assay was observed between "high dose only" carcinogens and the entire set of chemical carcinogens. In a subsequent correlational analyses of an additional 31 chemicals, the results substantiate those summarized above (65). Although cell proliferation and its possible impact on carcinogenic response were not assessed directly, these results nevertheless suggest that only a relatively small percentage of chemical carcinogens can be identified as possibly acting through an indirect or secondary mechanism. Thus, any attempt to develop generic regulatory policy for chemical carcinogens based solely on the use of two-year rodent studies to differentiate between "primary" and "secondary" carcinogens will likely be ineffective and/or inaccurate unless specifically backed by relevant mechanistic studies (64). Melnick (66) evaluated the available information on the influence of cell proliferation (or mitogenesis) on the carcinogenic process in rodents. Although cell proliferation has long been known to have a role in chemically induced tumor development, Melnick (66) concluded that a correspondence between sustained cellular proliferation and carcinogenic response has not been demonstrated adequately to support the hypothesis that chemically induced cell proliferation causes liver cancer. Further, the proliferative response resulting from exposure to many "non-genotoxic* carcinogens is not at all well sustained, yet the elicitation of a carcinogenic response by these chemicals often requires a prolonged exposure duration. Thus, much more research needs to be accomplished before any basic axioms about this important issue can be established (67). y 17111 4/2/91 page 20 Environ Health Perspect Chemical Carcinogenesis Data Base J. E. Huff & J- K. Haseman Deductive Conclusions Long-term chemical carcinogenesis studies must be properly designed adequately conducted and monitored, subjected to multi-tier pathology diagnoses review, and objectively evaluated and interpreted. In addition to having these essential scientific characteristics, NTP studies undergo a unique peer review process that is conducted in open and public sessions. In our view, this makes the findings and results from these long-term chemical carcinogenesis experiments even more useful and valuable for identifying potential carcinogenic hazards to public health. In addition to alerting us to possibly new chemical concerns and substantiating epidemiological observations, the collective data are. valuable and useful for a myriad of other scientific purposes. Some have been given in this paper. Others used or developed by us have been published or are at various stages of being published . In one manner or another most if not all allow us to bring further knowledge to and support for increasing confidence in extrapolating results from animals to humans. The knowledge extends from the clear awareness that all of the chemicals known to induce cancer in humans also cause cancer in adequate long term animal studies (8, 10, 12) to the increasing awareness that oncogene activation patterns in human and animal tumors are strikingly similar and represent evolutionary conservation (e.g., 68-70). In our opinion, the data from these studies together with our experience over the years permit us to make the following conclusions (not given in any particular rank order): 17112 4/2/91 page 21 Environ Health Perspect Chemical Carcinogenesis Data Base J. E. Huff & J- K. Haseman 1. Carcinogenicity findings from experiments in laboratory animals are logical and scientifically reasonable for identifying and predicting potential carcinogenic effects to humans. 2. Most chemicals are not carcinogenic. 3. Chemicals considered to be carcinogens may differ significantly with regard to the strength of the induced carcinogenic response, and for practical purposes can be divided into qualitative groups based on these empirical indicators of "potency": i.e., exposure concentrations, number of positive experiments, multiplicity of tumor sites, numbers of tumors per site, common versus uncommon tumors, site correspondence across sexes and species, magnitude of incidence rates, dose response patterns, latency, mtastass, preneoplastic lesions (see Table 3 for example). 4. Malignant and benign tumors of the same site and/or type should be combined for interpretation. However, combining biologically unrelated tumors for statistical evaluation should be avoided. 5. Benign tumors induced by chemicals are relevant for judging carcinogenicity; few chemicals produce only benign tumors. 6. Site-specific tumor analyses should be used for determining carcinogenic effects. 7. Liver tumors are appropriate and valid for identifying chemical carcinogens and for determining potential cancer hazards to humans. 8. Cellular toxicity and resultant sequelae are not uniformly associated with chemically induced carcinogenicity. Many chemicals produce carcinogenic responses in organs showing no evidence of toxicity, and conversely toxicity frequently occurs in organs exhibiting no chemically related carcinogenic effects. . 1 7 1^3 4/2/91 page 22 Environ Health Perspect Chemical Carcinogenesis Data Base J. E. Huff & J. K. Haseman 9. Most chemical carcinogens do not cause cancer only at the highest exposure used. 10. Mechanisms of action are not yet considered to be understood well enough to become significant factors in the evaluations of chemically induced carcinogenesis, but certainly all relevant biologic information (oncogene activation and tumor suppressor genes, pharmacology and pharmacokinetics, hormonal influences, DNA damage and repair, among others) should be considered when deciding a single level of evidence of carcinogenicity. ' l l . Cell replication (proliferation, mitogenesis) is an important factor in chemical carcinogenesis, yet scientific data do not sustain the hypothesis that enhanced cellular proliferation in a particular organ associates consistently with an increased induction of neoplasia. 12. The route of exposure has little or no effect on the inherent carcinogenicity of a chemical, although the specific sites of carcinogenicity may vary with the route of administration used. 13. Com oil has little or no influence on whether or not a chemical is or is not a carcinogen. 14. Inter-species concordance in carcinogenic response is good, yet at least two species should in most cases continue to be used for identifying chemical carcinogens. 15. Salmonella mutagenicity has a relatively low concordance with rodent carcinogenicity. 16. Cage location and related factors have no important impact on chemical carcinogenicity. 17. Chemical structure in general does not allow for cancer prediction in rodents or humans. 17114 4/2/91 page 23 Environ Health Perspect Chemical Carcinogenesis Data Base J. E. Huff & J. K. Haseman 18. False positive rates associated with evaluating chemically induced carcinogenic effects in rodents are quite low. Unfortunately, little .' is known about the more public health important false negative rate. In conclusion, much has been learned from these largely 'observational' studies that permits us to make the above statements, all of which are based on the data and facts garnered from the extensive chemical carcinogenesis data base developed in sequence by the National Cancer Institute and by the National Toxicology Program. This data base is unique in the sense that not only is it the single largest available collection of program-generated chemical carcinogenesis facts and figures, but it is perhaps the only system containing carcinogenesis (and other) data obtained from experiments that have been conducted and evaluated using a reasonably consistent core of design protocols, histopathological diagnostic criteria, and interpretational guidelines (all of which have been established and honed by us over the years to keep reasonable pace with new and relevant scientific advancements). Another unique character of our data collection and complementary pathology archives of tissue specimens and histopathology slides is that we make the original data & slides available to others to use in any way they wish. Not only that but we invite individuals and organizations to study and scrutinize the 'raw' data and tissue specimens & sections that represent the actual experimentally generated information sources of the data base. 4/2/91 page 24 Environ Health Perspect Chemical Carcinogenesis Data Base J. E. Huff & J. K. Haseman Staff consistency and balanced scientific standards together with a public peer review process and a keen awareness of the public health ethos must also be considered unique, desirable, and supportive of the value of this particular data collection. Acknowledgements We thank and dedicate this paper to Dr. David Rail, who has recently retired from the U.S. Public Health Service after a exemplary career as a physician and scientist, for his leadership, his public health and environmentally oriented conscience, and for his belief and practice that good research comes from good scientists who not only must be supported but who must also be allowed to pursue their research efforts unencumbered and with resolute freedom. We thank Dr. Jef French and Dr. Chris Portier for reviewing this manuscript and for offering valuable suggestions. Ms. Donna Mayer was most helpful throughout the preparation of this paper. 4/2/91 page 25 Environ Health Perspect T* aMh l A1. RISK ASSESSMENT -- Comparative Definitions National Research Council Task Force on Health Risk National Academy of Sciences 1983 Assessment 1985 1) Hazard identification: The determination of whether a particular chemical is or is not causally linked to particular [adverse] health effects. 1) H azard identification: The qualitative indication that a substance/condition may adversely affect human health. 2) Dose-response assessment: The determination of the relation between the magnitude of exposure and the probability of occurrence of the [adverse] health effects in question. 2) H azard characterization: The qualitative and quantitative evaluation of the nature of the adverse effects, including their expression as functions of the amount of exposure (dose). 3) Exposure assessm ent: The determination of the extent of human exposure before or after application of regulatory controls. 3) Exposure ch aracterizatio n : The qualitative and quantitative evaluation of the degree of human exposure likely to occur. 4) Risk characterization. The description of the nature and often the magnitude of human risk, including attendant uncertainty 4) Risk determ ination: The integration of these steps into a scientific determination of the level of risk as a basis for policy consideration 17117 Table 2 Summary results from 379 carcinogenicity studies in rodents Study Result By Experiment Male Female Male Female Total Rats Rats Mice Mice By Chemical Rats Mice Overall Positive Equivocal No evidence 127 107 41 36 183 211 102 123 35 20 204 205 459 146 137 198 132 48 35 53 803 162 178 128 Totals 351 354 341 348 1394 356 350 379 Taken from reference 49. r fv ^^ ra\ i w aniAv rgrvAiiiiii vaiikf tyj Table 3 iI*VA^r Ou Ul Ut eO IKJl *211 JU ^u ^^ ,, i U 1U 1U 141 iiuui^om ^ ^ 4 A i* m l* /N A M . 1U U U I 1 Proportion of Male Female Male Female Number of Studies % Positive Studies Rats Rats Mice Mice With These Results 4/4 ++ ++ 43 Subtotals 43 13.7 3/4 ++ + 1 ++ -+ 11 +- ++ 7 -+ ++ 6 Subtotals 25 8.0 2/4 + + 19 +- +- 2 +- -+ 7 -+ +- 2 -+ -+ 3 -- ++ 23 Subtotals 56 17.9 1/4 + 17 4- - - -- +- 9 -- -+ 8 Subtotals 38 12.1 0/4 - 151 Subtotals 151 48.2 Totals 313 100 Includes only those long-term studies considered adequate in all four sex-species experiments. Note: Equivocal evidence (or marginal) results are considered to be between a positive response and no evidence of a response; these results were placed into the no evidence category. Taken from reference 49. 17119 Table 4 Intra- and inter-species concordance in carcinogenic responses in 379 chemical carcinogenicity studies in rodents Comparison Observed Response +f +- -+ - - % Concordant (++ or --) Responses Male rats vs female rats 8 8 38 16 207 Male rats vs male mice 54 54 40 169 Male rats vs female mice 70 41 41 169 Female rats vs male mice 53 38 42 185 Female rats vs female mice 65 28 47 183 Male mice vs female mice 88 14 3 1 206 84.5 (295/349) 70.3 (223/317) 74.5 (239/321) 74.8 (239/318) 76.8 (248/323) 86.7 (294/339) Rats vs. mice 82 40 40 151 74.4 (233/313) Note: Equivocal evidence (or marginal) results are considered to be between a positive response and no evidence of a response; these results were placed into the no evidence category. Taken from reference 49. 17120 Table 5. Organs/syslems most frequently observed in RATS & MICE with chemically induced site-specific carcinogenic effects from 379 long-term chemical carcinogenesis studies. Rats Site No. Positive Studies 1. Liver 44 2. Kidney 28 3. Mammary Glands 22 4. Zymbal Glands 18 5. Thyroid Glands 17 6. Hematopoietic System 17 7. Forestomach 15 8. Skin 15 9. Urinary Bladder 14 10. Clitoral glands 10 Mice Site No. Positive Studies Liver 86 Lung 23 Forestomach 17 Hematopoietic System 15 Circulatory System 1 1 Thyroid Glands 9 Mammary Glands 9 Ovary 8 Harderian Glands 7 Uterus 7 Rats and Mice Site No. Positive Studies Liver 104 Lung 30 Hematopoietic System 29 Kidney 29 Mammary Glands 27 Forestomach 23 Thyroid Glands 19 Zymbal Glands 18 Urinary Bladder 16 Uterus & Skin (@) 15 note: Table taken & updated from reference 10. Table 6. Pattern of short term in vitro test results and long-term in vivo carcinogenesis results for 114 chemicals Short term in vitro test and results Rodent carcinogenicity results SAL ABS SCE MLA Pos Neg 4/4 + + + + * 3/4 + + + ++ - + + - ++ - +++ 2/4 + + - + -+ + - -+ - ++ -+ -+ - - ++ 1/4 + - - - +- - - +- - - +- - - 0 /4 - - - - Totals 22 Subtotals 0 24 8 Subtotals 0 0 2 2 0 7 Subtotals 2 1 3 3 Subtotals 11 Subtotals 22 14 11 9 11 67 3 0 0 1 6 0 0 0 3 0 12 0 1 1 6 14 SAL: Salmonella typhimurium; ABS: Chromosome aberrations (CHO cells); SCE: Sister chromatid exchanges (CHO cells); MLA: Mouse lymphoma 17122 Chemical Carcinogenesis Data Base &J. E. Huff J. K. Haseman References 1. Yamagiwa, K., and Ichikawa, K. (1918). Experimental study of the pathogenesis of carcinoma. J. Cancer Res. 3: 1-29. 2. Shimkin, M. B. (1980). Some Classics of Experimental Oncology: 50 Selections 1775-1965. NIH Pub. NO. 80-2150. Washington, DC: US Dept. Health and Human Serv. 739 pp. 3. Chhabra, R.S., Huff, J. E., Schwetz, B. S., & Selkirk, J. (1990). An overview of pre-chronic and chronic toxicity/carcinogenicity experimental study designs and criteria used by the National Toxicology Program. Environ. Health Perspect. 86: 313-321. 4. Haseman, J.K., Huff, J.E., Rao, G.N. & Eustis, S.L. (1989). Sources of variability in rodent carcinogenicity studies. Fund. Appl. Toxicol. 12: 793804. 5. Huff, J. E. (1991, in press). Long-Term Chemical Carcinogenesis Studies: Strategy, Results, and Relevance to Public Health. Scand. J. Work Environ. Health. 6. Montesano, R., Bartsch, H., Vaino., H., Wilboura, J., & Yamasaki,H. (1986). Long-term and Short-term Assays for Carcinogens. A Critical Appraisal. IARC Scientific Publications No. 83. International Agency for Research on Cancer. Lyon. 564 pp. 4 /2 /9 1 page 1 17123 EHP References Chemical Carcinogenesis Data Base 3.J. E. Huff & K. Haseman 7. Rao. G.N., & Huff J.E. (1990). Refinement of long-term toxicity and carcinogenesis studies. Fund.. Appl. Toxicol. 15: 33-43. 8. Huff, J.E., & Rail, D.P. (1991 in press). Relevance to humans of carcinogenesis results from laboratory animal toxicology studies. In: Last, J.M. (ed), Maxcy-Rosenau's Public Health and Preventive Medicine. Thirteenth Edition. Appleton-Century-Crofts, Norwalk, CT. 9. Huff, J. E. & Hoel, D. G. (1991). Hazard identification. Perspective & overview on the concepts & value of the initial pase in the risk assessment process of cancer & human health. 10. Huff, J. E., Haseman, J. K., & Rail, D. P. (1991). Scientific concepts, value, and significance of chemical carcinogenesis studies. Ann. Rev. Pharmacol. Toxicol. 31: 621-652. 11. 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. (1988). Carcinogenesis studies: Results from 398 experiments on 104 chemicals from the U.S. National Toxicology Program. Ann. N.Y. Acad. Sci. 534: 1-30. 12. Tomatis, L., Aitio, A., Wilbourn, J., & Shuker, L. 1989. Human carcinogens so far identified. Jpn. J. Cancer Res. 80:795-807. 13. Tomatis, L., Aitio, A., Day, N.E., Heseltine, E., Kaldor, J., Miller, A.B., Parkin, D.M., & Riboli, E. (1990). Cancer Causes, Occurrence and Control. 4 /2 /9 1 page 2 17124 EHP References Chemical Carcinogenesis Data Base J. E. Huff & J. K. Haseman *F4 ABf PnhWliA/V'aM rinn *MrVi Cancer, Lyon. 352 pp. 14. OSTP (Office of Science and Technology). (1985). Chemical Carcinogens: A Review of the Science and its Associated Principles. Interagency Staff Group on Chemical Carcinogenesis. OSTP, Executive Office of the President, Fed. Reg. 50: 10371-10442. Also published in: Environ. Health Perspect. 67: 201-282 (1986). 15. NRC/NAS (National Research Council/National Academy of Sciences). (1977). Chemical contaminants: Safety and risk assessment. Chapter II: 1962. Drinking Water and Health. National Academy of Sciences, Washington DC. 939 pp. 16. OSHA (Occupational Safety & Health Administration). (1980). Identification, classi-fication & regulation of potential occupational carcinogens. Fed. Regist. 45: 5001-5296 17. OTA (Office of Technology Assessment, Congress of the United States). (1981). Assessment of technologies for determining cancer risks from the environment. Washington DC. 240 pp. 18. OTA (Office of Technology Assessment, Congress of the United States). (1987). Identifying and regulating carcinogens. Washington, DC. 215 pp. 4 /2 /9 1 page 3 EHP References 17125 Chemical Carcinogenesis Data Base J. E. Huff & J. K. Haseman 19. NTP Ad Hoc Panel. (1984). Report of an ad hoc panel on chemical carcinogenesis testing and evaluation. Presented to the NTP's Board of Scientific Counselors, National Toxicology Program, Research Triangle Park, NC. 280 pp 20. Muir, C. (1990). Epidemiology, basic science, and the prevention of cancer: Implications for the future. Cancer Res. 50: 6441-6448. 21. Hakama, M., Beral, V., Cullen, J. W., & Parkin, D. M. (Eds). (1990). Evaluating Effectiveness of Primary Prevention of Cancer. IARC Scientific Publications No. 103. International Agency for Research on Cancer, Lyon. 206 pp. 22. Huff, J. E. (1991b, in press). Merit and Value of Using Experimental Findings in the Risk Assessment Process. Scand. J. Work Environ. Health. 23. NRC/NAS (National Research Council/National Academy of Sciences). (1983). Risk assessment in the Federal Government: Managing the Process. National Academy Press, Washington, DC. 189 pp. 24. DHHS Task Force on Health Risk Assessment, Department of Health and Human Services. (1986). Determining Risks to Health. Federal Policy and Practice. Auburn House Pub. Co, Dover, MS. 410 pp. 25. IARC (1987). Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1 to 42. Supplement 7. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, International Agency for Research on Cancer, Lyon. 440 pp. 4 /2 /9 1 page 4 EHP References Chemical Carcinogenesis Data Base J. E. Huff <& J. K. Haseman 26. IARC. (1990). Preamble. In: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Pharmaceutical Drugs, 50: 11-31, Inter national Agency for Research on Cancer, Lyon. 415 pp. 27. DHHS/NTP (1989). Fifth Annual Report on Carcinogens. National Toxicology Program, Research Triangle Park, NC. 745 pp. 28. Vainio, H. (1991, in press). Classification of Chemical Carcinogens: Categories of Evidence of Carcinogenicity Developed and Used by the International Agency for Research on Cancer 1972 - 1991. Scand. J. Work Environ. Health. 29. Vainio, H., Coleman, M., & Wilboum, J. (1991, in press). Carcinogenicity evaluations and on-going studies: The IARC Databases, Environ. Health Perspect. 30. Chu, K.C., Cueto. C., & Ward, J. (1981). Factors in the evaluation of 200 National Cancer Institute carcinogen bioassays. J. Toxicol. Environ, Health 8: 251-280. 31. Griesemer, R.A. & Cueto, C. (1980). Toward a classification scheme for degrees of experimental evidence for the carcinogenicity of chemicals for animals. 27: 259-281. In: Molecular and Cellular Aspects of Carcinogen Screening Tests. Montesano, R., Bartsch, H., and Tomatis, L.(eds). IARC Scientific Publications. No. 27. International Agency for Research on Cancer, Lyon. 440 pp. 17127 4 /2 /9 1 page 5 EHP References Chemical Carcinogenesis Data Base J. E. Huff & J. K. Haseman 32. Haseman, J.K., Huff, J.E., Zeiger, E,. & McConnell. E.E. (1987). Comparative results of 317 chemical carcinogenesis studies conducted by the National Cancer Institute and the National Toxicology Program. Environ. Health Perspect. 74: 229-235. 33. Gart, J.J., Krewski, D., Lee, P.N., Tarone, R.E., & Wahrendorf, J. (1986). Statistical Methods in Career Research. Volume III - The design and analysis of long-term animal experiments. IARC Scientific Publications No. 79. International Agency for Research on Cancer, Lyon. 219 pp. 34. Grice, H.C., Arnold, D.L., Blumenthal, H., Emmerson, JX., & Krewski, D. (1984). The selection of doses in chronic toxicity/carcinogenicity studies. 1-49. In: Current Issues in Toxicology. Grice, H.C. (ed). Springer-Verlag, New York, 114 pp. 35. McConnell, E.E. (1989). The maximum tolerated dose: the debate. J. Amer. Coll. Toxicol. 8: 1115-1120. 36. NCI (National Cancer Institute) (1976-1980). NCI Bioassay of "Chemical" for Possible Carcinogenicity. Carcinogenesis Technical Report Series No's 2-100, 202-205. National Cancer Institute, Bethesda, MD. 37. NTP (National Toxicology Program) (1980-1991). NTP Toxicology and Carcinogenesis Studies of "Chemical" (CAS No.) in F344/N Rats & B6C3F1 Mice ("Exposure Route). Technocal Report Series No's 201, 206-411. National Toxicology Program, 4 /2 /9 1 Reserarch Triangle Park, NC. page 6 EHP 1.t l C References Chemical Carcinogenesis Data Base J. E. Huff & J. K. Haseman 38. Huff, J. E. & Moore, J. A. (1984). Carcinogenesis Studies and Experimental Data Interpretation/Evaluation at the National Toxicology Program, 43 - 64. In: Jarvisalo, J., Pfaffl, P., & Vainio, H., (eds). Industrial Hazards of Plastics and Synthetic Elastomers. Alan R. Liss, New York.441 pp. 39. Huff, J.E. (1991a, in press). Classification of chemical carcinogens: Levels of evidence of carcinogenicity developed and used by the National Toxicology Program (1983 - 1990). Scand. J. Work Environ. Health. 40. Rail, D. P. (1986). National Toxicology Program (NTP). Levels of Evidence of Carcinogenicity Used to Describe Evaluative Conclusions for NTP Long-Term Toxi-cology & Carcinogenesis Studies; Request for Comments. Fed. Regist. 51: 2579-2582. 41. Rail, D. P. (1986a). National Toxicology Program (NTP). Notice of Modifications in the Levels of Evidence of Carcinogenicity Used to Describe Evaluative Conclusions for NTP Long-Term Toxicology and Carcinogenesis Studies. Fed. Regist 51: 11843 - 11844. 42. Haseman, J.K., & Huff, J.E. (1987). Species correlation in long-term carcinogenicity studies. Cancer Lett. 37: 125-132. 43. Haseman, J.K., Huff, J.E., & Boorman, G.A. (1984). Use of historical . control data in carcinogenicity studies in rodents. Toxicol. Pathol. 12: 126135. 17129 4 /2 /9 1 page 7 EHP References Chemical Carcinogenesis Data Base J. E. Huff & J. K. Haseman 44. Haseman, J.K., Huff, J.E., Rao, G.N., Arnold, J.E., Boorman, G.A., & McConnell, E.E. (1985). Neoplasms observed in untreated and com oil gavage control groups of F344N rats and (C57BL/6N x C3H/HeN)Fl (B6C3F1) mice. J. Nat. Cancer Inst. 75: 975-984. 45. Haseman, J.K., Arnold, J., & Eustis, S.L. (1990). Tumor incidences in Fischer 344 rats: NTP historical data. 557-564. In: Pathology of the Fischer Rat, G.A. Boorman, S.L. Eustis, M.R. Elwell, C.A. Montgomery, Jr. & W.F. MacKenzie (eds). Academic Press, Inc., San Diego, 580 pp. 46. Haseman, J.K. (1983). A re-examination of false-positive rates for carcinogenicity studies. Fund. Appl. Toxicol. 3: 334-339. 47. Haseman, J.K. (1990). Use of statistical decision rules for evaluating laboratory animal carcinogenicity studies. Fund. Appl. Toxicol. 14: 637-648. 48. Haseman, J.K., Tharrington, E.C., Huff, J.E., & McConnell, E.E. (1986). Comparison of site-specific and overall tumor incidence analyses for 81 recent National Toxicology Program carcinogenicity studies. Reg. Toxicol. Pharmacol. 6: 155-170. 49. Huff, JJS., Cirvello* J,, Haseman, J.K., & Bucher, J.R. (1991, in press). Chemicals associated with site-specific neoplasia in 1394 long-term carcinogenesis experiments in laboratory rodents. Environ. Health Perspect. 4 /2 /9 1 page 8 171 EHP References Chemical Carcinogenesis Data Base &J. E. Huff J- K. Haseman 50. Maronpot, R.R., Haseman, J.K., Boonnan, G.A., Eustis, S.L., Rao, G.N., & Huff, J.E. (1987). Liver lesions in B6C3FI mice: The National Toxicology Program experience and position. Arch. Toxicol. Suppl. 10: 10-26. 51. Huff, J.E., Eustis, S.L., & HasemanJ.K. (1989). Occurrence and relevance of chemically induced benign neoplasms in long-term carcinogenicity studies. Cancer Metast. Rev. 8: 1-21. 52. Eustis, S.L. (1989). The sequential developoment of cancer: a morphological perspective. Toxicol. Lett. 49: 267-281. 53. Haseman, J.K. (1990a, in press). Controlling sources of variability and use of statistical decision rules in rodent carcinogenicity studies. Proceed. Biopharmaceut. Sect. Amer. Statist Assoc. 54. Rao, G.N., Haseman, J.K., Grumbein, S., Crawford, D.D., & Eustis, SX. (1990). Growth, body weight survival and tumor trends in F344/N rats during an eleven-year period. Toxicol. Pathol. 18: 61-70. 55. Rao, G.N., Haseman, J.K., Grumbein, S., Crawford, D.D., & Eustis, S.L. (1990a). Growth, body weight, survival and tumor trends in (C57BL/6 x C3H/HeN)Fl (B6C3F1) mice during a nine-year period. Toxicol. Pathol. 18: 71-77. 56. NTP (1987). NTP General Statement of Work for the Conduct of Toxicity and Carcinogenicity Studies in Laboratory Animals, National 17131 4 /2 /9 1 page 9 EHP References Chemical Carcinogenesis Data Base J. E. Huff & J. K. Haseman Toxicology Program, Research Triangle Park, NC. 175 pp (plus appendixes & 1989 modifications). 57. Melnick, R.L., Jameson, C.W., Goehl, T.J., & Kuhn, G.O. (1987). Application of microencapsulation for toxicology studies. I. Principles and stabilization of trichloroethylene in gelatin-sorbitol microcapsules. Fund. Appl. Toxicol. 8: 425-431. 58. Yuan, J., Jameson, C.W., Goehl, TJ., & Collins, BJ. (1991, submitted). Application of molecular encapsulation for toxicology studies. 1. Molecular encapsulation of p-chloro-a,a,a-triflorotoluene with a-cyclodextrin. 59. Tennant, R., Margolin, B., Shelby, M., Zeiger, E., Haseman, J., Spalding, J., Caspary, W., Resnick, M., Stasiewicz, S., Anderson, B., & Minor, R.(1987). Prediction of chemical carcinogenicity in rodents from in vitro genetic toxicity assays. Science 236: 933-941. 60. Haseman, J.K., Zeiger, E., Shelby, M.D., Margolin, B.H., & Tennant, R.W. (1990a). Predicting rodent carcinogenicity from four in vitro genetic toxicity assays: An evaluation of 114 chemicals studied by the National Toxicology Program. J. Amer. Statist Assoc. 85: 962-971. 61. Zeiger, E., Haseman, J.K., Shelby, M.D., Margolin, B.H., & Tennant R.W. (1990). Evaluation of four in vitro genetic toxicity tests for predicting rodent carcinogenicity: Confirmation of earlier results with 41 additional chemicals. Environ. Molecul. Mutagen. 16: Supple. 18: 1-14. 4 /2 /9 1 page 10 - 1713 EHP References Chemical Carcinogenesis Data Base J. E. Huff & J- K. Haseman 6 2 . Hasem an, J. K. & Clark, A-M . (1990). C arcinogenicity results for 114 laboratory anim als studies used to assess the predictivity o f four in vitro genetic toxicity assays for rodent carcinogenicity. Environ. M olecul. M utagen. 16: Supple. 18: 15-31. 6 3 . T ennant, R.W . (1991, in press). The genotoxicity d ata base o f the N ational T oxicol. Program : Evaluation of the relationships betw een genotoxicity & carcinogenicity. Environ. H ealth Perspect. 6 4 . Hoel, D.G., Hasem an, J.K ., H ogan, M .D., H uff, J., & M cC onnell, E . (1988). The im pact of toxicity on carcinogenicity studies: Im plications for risk assessm ent. C arcinogenesis 9: 2045-2052. 6 5 . Tennant, R. W ., Elw ell, M . R., M aronpot, R. R., Spalding, J. W ., & G riesem er, R. A. (1991, Subm itted). Proliferative responses to toxic injury are not sufficient for induction o f chem ical carcinogenesis. 6 6 . M elnick, R .L. (1991, Subm itted). D oes chem ically induced cell proliferation predict liver carcinogenesis? 6 7 . W einstein, I. B. (1991, in press). M itogenesis is only one factor in carcinogenesis. Science. 6 8 . W einberg, R .A . (1989). O ncogenes, antioncogenes, and the m olecular bases of m ultistep carcinogenesis. C ancer R es. 49:3713-3721. 4 /2 /9 1 page 11 EHP References Chemical Carcinogenesis Data Base J. E. Huff & J* K. Haseman 6 9 . Y ou, M., C an d rian , U ., M aro n p o t, R .R ., S to n er, G .D ., & A n d erso n , M .W . -\(--i1-7-n--0-O--7-n-;-\ . n--Aw/i#--1i--1r-1-a-4-u#-4-u-A-i-M-i u i u--U-i--ga- iv I--i _' #i fa--t aA M^...lM.U.A..*l..Ua..m.U..m.U.MC.A..UA..A.^..u...gA. m fa..Mp...Av..uM. tfanun wA Av uI l ~co&l ji r"r .uA..wA..LA..U.k.i.m.i...u.m.i..ga. and chem ically induced lung tum ors of the strain A m ouse. Proc. Natl. A cad. Sci. USA 86: 3070-3074. 7 0 . B arbacid, M . 1987. ras genes. A nn. Rev. B iochem . 56: 779-827. 4 /2 /9 1 page 12 EHP References , '\ Biochemical Research Laboratory THE D O W CHEMICAL COMPANY Subject TOXICITY OF 2,4,5-TRICHLOEOPKEJOXY ACETIC ACID, ^' ` y $ , CONFIDENTIAL. S'<->--T a c .e d .*. ENT 9-79 O& rO-j i>'j'"i13 269 me wc Fa. T23.14-23-1 < ch,. 121QA ^ R.c'd 3-15-45 J*? Fin'd 8-8-45 Worb By C. G eisel y--k au To Tech. Service & Developcheck W . W . Allen W. R. Veazey ^ Rpt. Br ^ ./C. Problem What are the handling hazards to be associated with 2,4,5-trichlorophenoxy acetic acid? Material - Name - 2,4,5-trichlorophenoxy aoetic acid - K4568-2 Formula - Cl 0 Structural - Cl < O - 0 - < ? - C - 0 - H Cl ! Empirical - CgHgOgClg Source - Organic Research Lab. - L. Begin Ref. - #410-5-258 Experimental Results Acute Oral - Weighed doses of the acid were emulsified in 5-10$ gum arable solution and fed to cavies in single oral doses by means of a stomach tube. The material as the sodium salt, ad justed to pH = 10,was also fed. The results are given in Table I ' Table I The-Acute Oral Toxicity of 2,4,5-Triohloro-phenoxy Acetic acid and its Sodium Salt for Cavies. \ Material Acid 100$ Survival Dose sAs. 0.3 100$ . Lethal Dose sAg. 1.0 Salt - pH 3 10 0.3 0.5 / THiS REFORT 13 THE PROPERTY OF \ 1219 25 25C 1144 17135 032715 rage 2 w *? v O )^ Thee figures indicate that the subject material is moderately toxic when given in single oral doses. No information upon the effect of repeated administrations was obtained. It was noted in this acute oral work that the animals did not exhibit the nervous symptoms caused by 2 ,4-dichlorophenoxy acetic acid, sodium salt. The animals fed large doses of this latter material exhibited paralysis of the posterior portion of their bodies. Skin Irritation - The acid as a 1 C solution in butyl carbitol acetate v/as applied 10 times in 11 days to the ear and shaven belly of a rabbit. A very slight irritation developed on the ear and a slight to moderate irritation appeared on the belly. A 1ia aqueous solution of the sodium salt failed to pro duce any significant irritation on the ear even after 20 exposures in 27 days; similar exposure on the belly resulted in a very slight simple irritation. Conclusions 2,4,5-Trichlorophenoxy acetic acid has a moderate acute oral toxicity and is slightly irritating to the skin of rabbits. We conclude that excessive exposure to th dust of either the free acid or the salt would be likely to cause skin irritation as would exposure to concentrated solutions for prolonged periods of time. Exposure to dilute solutions such as those used in practical application would not be expected to cause trouble except among those who persist in spraying themselves or who do not take the necessary precautions to prevent prolonged contact with the -material. Reasonable handling precautions which will prevent In gestion and prolonged skin contact with the material will suffice to prevent serious trouble. jf-5 copies. 17136 BIOCHEMICAL RESEARCH LABORATORY Test on r 2 = - . ----- Acute oral toxicity, E*t, Cavy '-/ Prob, T 2 . S . S * / Q- V. g -r-zS J l Date 3 > - 2 h t/ S ' Animal # 2 > 3 * 7 Weight kg. T7^ Dose gm/kg o ./ Dose gnu .o S ~ 7 Dose cc. u jtr wt; 3/xz ^ipljemarks 2.7 M l \ 2 . o 7 /7* 0. / . o<7 411 h s ./ H i L U J \ s * 3 0 ~ f P /& 7 c r j S"% * ?. 3 . / / / 7 7 * 1 . ,70 0-3 .3-*/ . .S'*/ / * .5"2>/ ! J T 2 <7 /. a . / * ! ? < + ..rs'S"' 3 . o /. < r & SL J ....... J & J U 7 U L 3-^*1- -- 'A tT ' 3 ^ a J ? -3 - *3-X - ' <T ' A o ^ - z ^ r 9 3 - X / - .<"'* i& t* < 3 O / e r f . 3 7 t 3. * /. <?*/ / 7 / */* * > 7 /< A O . 7 o- ccI L l . f J L * * ^ * 3 - z t V .*' S " 7 7 Jo. O r .y ? sts+ L & iL ' i c M 1 - "W - V . r e d * - ( ," "''' lV J t+ tin S . 3 - 2 . - ( - 1219-t3-5c-xo-B . 17137 BIOCHEMICAL RESEARCH LABORATORY 't r so C O Test on / t v .* v - z ' <7 g ^ ) "\t< jU 'u a ? a CO Acute oral toxicity. Rat. Cavy <7'/? Prob. T J 3 . / Y - 2 3 -/ ro 1219--43--5C--642 8I^^G (M on BIOCHEMICAL RESEARCH LABORATORY Test on /r'YS" 6 ? ' 2- 'J ) _________ Acute oral toxicity, itjcfe. Cavy Prob. T / Date AniTJTXmal Weight kg. JL 0 ~? l) 6 h Lr> 3 5 7 ( /&. <i ^ a . o / ^ Dose gm/kg 0.3 Dose `gm. -2 yj-f. ?t !1 . I :` Remarks **'?f"7 __ lii -4-r-,u Hi <43 J %. 0 V 33 w 1 ~7/-u J.3 .1 0 7 / I > H ** S.7 f i f 2- i f / \ n. JL/a - 3 3 0 0 .3 .0<tf -< r.? o H i ___-- s\ 7 flrfT ^ A * 3 -z- . I g l I f . / \r*.oo 9 .io 3/? 2 L7 1 . U S ' 17.S ' I* - * * *7.So _________ \ .... \ io l A1 ,-3?f O .l" 1^ ^ .nwti / 1 /i.fii i. i.ii M l ? J 4 -i X> -u -^ r C JS L - J ... '!X?'j - . ...,. ' : -.' . -; (; . ...*t.' 1219--43--5C--642 1 1 ! 1 .... a I e i 1. O o Q c> Test on BIOCHEMICAL RESEARCH LABORATORY /f $0 7^ ^ & .C .C L . it ZcL--^/} ' r A A O n Skin Irritation No. of Applications X-''? Quaj^tUrte-trtv* 7* * ~> Ht; Ear A /^ C^A-A-LstC Afeetoaao-- Rabbit ft f-/ 72. J-y Cage Prob. T S.sy'- 3 - / L. r 07/ 'Test on BIOCHEMICAL RESEARCH LABORATORY /f S~Za ~ _____________________ ' *7o Skin Irritation Qaa~:it-j.ta<fc.-irve No. of Applications (/ -Ssa Abdomen /O Rabbit ft u / 72- ^7 Date D.aXTLy Q *3 -2-4--*7,5 " ( 3 - 2- 3 - A 2 2 - 7 X J3 Sxp. TXT f 42_ / y^ - 2.3 **fS" <T X 7 3-a- --*/JT' r 7 ? 5T Cage ft /. 7 7 A V Prob. 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Z ltJ j L . . . u . * // j- 3 - S s - s~ y it /o h d - r~ -< /~ 7 & 7 fi // -- * /- / / <T s " tf- f - Y s ^ /2-- ) 7i =3 Y O i/ - ~ *s~ r r J/--r / / it ^ / S ~ " a -- -- D a tt * ..... . r A.y.. -- .i~ f S ' r/--f*-- /3 TiT ^ 2f'.,./ --- -- / c7 _______ 1M * * 2-2- ^ 7 --7 7 < r JL ~ 1 ,3 > -~ u d _ .. . ... Y - x < - */-d~ 7 ^ /? J2. > < R i (7. _. " (/ i - --. -. i/ -. 6 ... C 1 2 1 9 - 2 C -- 1M-1+5 iri -;t U 0 L, i : nJ 'T 2 St *On BIOCHEMICAL RESEARCH LABORATORY / f C jT S f'a 9 - Skin Irritation Mo. of Applications C/>->3 ILt\ ~~2v-*- Ear S 7Z~L X_ **--> Abdomen Rabbit ? - / f O--h Cage 2Prob. T Date Day Exp. 2 -- Reaction ./, J^ _______Z^-.x.) > 3 0- ^ r / Si 3 2.33 //& / . d 2 - ~ ~ ~ --- - / 6 - X ) -/ <J~^--<r y ~ y -- </ y - y 3 j T y y - y y -7 << S*SAb-~~._____ /--/-S' 7- y- // y /3> - /-r" / a - 7 <? *2,"? /<A- /,/. o f s?.^^.?.. S 1 y- //- y y ty*wt> - y. _y yC_/5^/ /3 /y /_r /5 // /3- i ---- Z / 1' ^ - r y -'/S ' / f y y r JW // /S~ ,1. / / > *'+/-*'+X>-*/ _ 'S /7 sT" f t V- ^ / L </<" si .*1^ --. // <5.y y $fL& 7A.-X-/ y /-V^A -- X J* > _ A 7 , cvo *.. y > 3 3.0 V ^ fi (f ? r Z a -- - ... ...*/-y----Z-.--6----yh-i....- - -- # \ -.: ' . . . . ' . . 1213-2C-1M-14-5 BIOCHEMICAL RESEARCH LABORATORY . T 8 3 t 'o n / ir X 6 9 - z . Skin Irritation I Mj r ? s , 2 Z ? ^ J .) TV Mo. of Applications & L^o U&4-^3^irV e Eh t Abdomen a -i U Rabbit $ ? ~ / f Q~h Cage L 3f Prob. T 2 3.Sy - 3 - / Date >3o-^ V- a-- Day Exp. ## e> / > 3 " m. /t*& ^ Reaction ./ .0 A-- --- .f ^ t ) /.2. ---- -- 2-X) C c r br- </- i'-y'r 3"" </ y- ^ 3 " -7 /- -*/s~ ir J-9- // y1-/3- /-r" /=- y- /y- y s " 7 ... ' . $ /^. J*o. 7 t f \ .aA^^c-T7-"-i-- - </ --ft. /> > 3 T . / _ y--Ly /-/ // y - / s - y y /jT J d ^ /4 -< i< r /-r /* 'f-' V ' / f / / XLs^JZ---*' ^ V / & - */~ JW aT d* 'f - 4 f .1./ *'**5*9 *y s 2.-2-. / 7 y- 3 S -^5" i- f t V. z.//, </<" >*0 / i y-xsr^yV'''' >o 3.n y " --v n . f S ? ' ^ --- - Vi/ -Z. a -y y .. -- '-->-^-3 /// . r . ,. ^ T T . . \ * ' ... - - ' " ' -`- .1 :: fl U. THE LANCET Vol 338 Saturday 26 October 1991 No 8774 Cancer mortality in workers exposed to chlorophenoxy herbicides and chlorophenols Rodolfo Saracci Manolis Kogevinas Pier-Alberto Bertazzi Bas H. Bueno de Mesquita D avid Coggon Lois M. Green T imo Kauppinen Kristan a . L 'AbbE Margareta L it t o r in Elsebeth L ynge John D. Mathews Manfred N euberger John Osman Neil Pearce Regina Winkelmann Epidemiological studies have revealed an increased risk of cancer, notably soft-tissue sarcomas and non-Hodgkin's lymphomas, in people occupationally exposed to chlorophenoxy herbicides, including those contaminated by 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (T C D D ). W e report here a historical cohort study of mortality in an international register of 18 910 production workers or sprayers from ten countries. Exposure was reconstructed through questionnaires, factory or spraying records, and job histories. Cause-specific national death rates were used as reference. N o excess w as observed in all-cause mortality, for all neoplasms, for the most common epithelial cancers, or for lymphomas. A statistically non-significant two-fold excess risk, based on 4 observed deaths, w as noted for softtissue sarcoma with a standardised mortality ratio ( S M R ) of 196 and 95% confidence interval (Cl) 53-502; this was concentrated as a six-fold statistically significant excess, occurring 10-19 years from first exposure in the cohort as a whole ( S M R = 606 [165-1552]) and, for the same time period, as a nine-fold excess among sprayers ( S M R = 882 [182-2579]). Risks appeared to be increased for cancers of the testicle, thyroid, other endocrine glands, and nose and nasal cavity, based on small numbers of deaths. The excess of soft-tissue sarcomas among sprayers is compatible awith a causal role of chlorophenoxy herbicides' but the excess does not seem to be specifically associated with those herbicides probably contaminated by T C D D . Lancet 1991; 338:1027-32. Introduction Chlorophenoxy herbicides have been used extensively since the mid-1950s for control of weeds and for removing unwanted brush on non-crop land.1In the 1960s an equal mixture of 2,4-dichloro and 2,4,5-trichloro phenoxyacetic adds (agent orange) was heavilyused in South Vietnamand Cambodia for defoliation by the US armed forces. Since 1969 in several industrialised countries, production and use of some compounds, and especially of 2,4,5trichlorophenoxyacetic add (2,4,5-T) and its derivatives have been reduced or banned. Chlorinated phenols are ADDRESSES: U nit o f A nalytical E pidem iology, In te rn a tio n a l A gency f o r R e search on C a n cer, Lyon. F ran ca (R. Saracci, MO, M. Kogevinas. PhO, R Winkelmann. M A ); U n iv ersity o f M ilan , Italy (Prof P. A. Bertazzi, M O ); N atio n a l In s titu te o f P u b lic H e a lth and E nvironm ental P ro te c tio n , B ilthoven. N e th e rla n d s (B. H. Bueno de Mesquita. M O ); M edical R esearch Council E nvironm ental Epidemiology Unit, U niversity of S o u th am p to n . UK (D. Coggon, M0); O n tario H ydro, T o ro n to . C an ad a (L M. Green. CPH); Institute of O ccupational H ealth. Helsinki, Finland (T. Kauppinen, PhO); D e p a rtm e n t o f P re v en tiv e M e d icin e and B io sta tistic s. U n iv ersity o f T o ro n to . C a n ad a (K. A. L'Abb, P h D ); Lund U niversity, S w e d e n (M. Littorin, MO); D anish C a n c e r R egistry, C o p e n h ag en , D enm ark (E. Lynge, PhO); M enzies School of H ealth R esearch, C asuarina. A ustralia (Prof J. 0. Mathews, M0); In stitu te of E nvironm ental H ygiene. V ienna. A u stria (Prof M. Neuberger. M0); H ealth an d S a fe ty E xecutive. B ootle. M erseyside, UK (J. Osman, MO); W e llin g to n S ch o o l of M edicine, N ew Z ealand (N. Pearce. PhO). Correspondence to Or Rodolfo Saracci, Unit of Analytical Epidemiology, International Agency for Research on Cancer. 150 cours Albert Thomas, Lyon 69372, Cdex 08, France. 17145 1028 THE LANCET VOL 338: OCT 26,1991 intermediates in the production of these chlorophenoxy herbicides and are also used directly for wood preservation. Both groups ofcompounds maybecontaminatedduringthe production processwith polychlorinateddioxins and furans, including tetrachlorodibenzo-p-dioxin (dioxin, TCDD), which is a widespread contaminant of the general environment.* Studies of cancer risks have revealed excesses for soft-tissue sarcoma and non-Hodgkin's lymphoma in populations exposed to chlorophenoxy herbicides, chlorinated phenols, dioxins, and furans during manufacture and spraying or after accidents.1-" In 1987 an International Agency for Research on Cancer (IARQ workinggroup concluded that therewas "limited" evidence ofhuman carcinogenicityfor chlorophenoxy herbicides and chlorinated phenols.27 A recent paper,*6 focusing on exposure in chemical plants to "dioxin", reported excesses for cancer of the respiratory tract and soft-tissue sarcoma, but could not exclude thecontributionofsmokingandother exposures in the workplace. We present here the first detailed mortality analysis of a large international cohort of workers (the International Register of Workers Exposed to Phenoxy Herbicides and their Contaminants) set up by the LARC in association with the US National Institute of Environmental Health Sciences (NIEHS). Results forsome cohorts inthe registerhave beenreportedearlier***-9-13but for different follow-up periods. Material and methods Study population T h e register incorporates information on 17 372 male workers, 1337 female workers, and 1 o f unknown sex, distributed among twenty cohorts from ten countries (table l). Since publication of the register population" m inor corrections have led to the exclusion o f 62 workers found to be ineligible. Workers from one British company which both produced and sprayed herbicides have been scparatedhere into two cohorts (14 and 20). T he register includes workers ever employed in production or spraying, accept in the cohorts horn Australia, Canada, and New Zealand, in which minimum employment periods of 1 year, 6 months, and 1 m onth, respectively, were specified. Eligibility of cohorts depended on the completeness at company level o f records identifying workers and on the ability to ensure tracing rates o f95% or mote. Follow-up for mortality was based either on computerised national record systems or on active follow-up procedures. Additional information on cases o f soft-tissue sarcoma and non-Hodgkin's lymphoma cases was sought horn medical records and cancer registries. Denmark, New Zealand, Finland, and Sweden provided incidence data horn population-based cancer registries. Person-years at risk were calculated horn 1955 onwards since only from that year were cancer-specific mortality rates available for all participating countries. Excluded from the analysis were 220 workers who either died or were lost to follow-up before 1955, 105 workers with unknown year of first exposure, 131 with unknown year o f birth, 1 with unknown sex, and 63 with other missing information. T h e 18 390 workers included comprise 16 863 males and 1527 females, and 307 488 person-years at risk were accumulated, with an average follow-up o f 17 years. Workers lost to follow-up constituted 5% o f the total cohort, and in no individual cohort did this proportion exceed 10%. Exposure assessment Questionnaires were constructed for factories producing chlorophenoxy herbicides or chlorinated phenols and for spraying cohorts. T hese were completed with the assistance of industrial hygienists, workers, and/or factory personnel. Industry and other production records were also used. Job histories were examined when available. Workers were classified as exposed, probably exposed, exposure unknown, or non-exposed: TABUE I--DESCRIPTION OF COHORTS IN INTERNATIONAL REGISTER Cohort No Type Period of of at Main chemicais subjects cohort Sex risk sprayed or produced 1, Australia 2, Austria 2177 159 3, Canada 4, Denmarfc* 1222 3843 5, Denmark 6, Finland 7, Italy 8, Italy 9, Netherlands 10, Netherlands 11, New Zealand 616 62 325 81 1167 1143 1038 12, New Zealand 780 13, Sweden 270 14, UK* 15, UK 16, UK 1531 145 1147 17, UK 18, UK 19, UK 20, UK 353 275 528 2013 s M 1955-83 2,4,5-T/2,4-D PC B 1971-88 2,4^-T/2,4-D MCPA/2.4.5-TCP 2,4-DCP s M 1955-82 2,4,5-T/2,4-D p B 1955-82 MCPA/MCPP 2,4-DP p B 1955-82 2,4-DP/MCPA p B 1955-85 2,3,4,6-TcCP p B 1970-86 2,44-TCP p B 1967-86 2,4-D/MCPA p B 1955-85 2,45-T/2,4,5-TCP p B 1965-86 MCPA/MCPP/2.4-D p B 1969-87 2,4,5-T/2,4-D MCPA/MCPB/ 2,4,5-TCP s B 1973-87 2,4,5-T/MCPA/2,4-D p B 1965-86 2,4-D/MCPA/MCPP 2,4,6-TCP p M 1955-87 MCPA p M 1960-85 PCP p M 1973-87 2,4-DB/MCPA MCPP/2.4-D/2.4- DP 2,4,5-T p M ..t-87 MCPB/PBA p M 1969-87 2.4-DP/2.4-DB MCPA/MCPP p M 1969-87 MCPA/MCPP/2.4-D 2,4-DP s M 1955-87 MCPA s- sprayers;p-production: PC-chloracne casesinproduction. M - mates: B bothsexes. tp2r.r4ocph-0laonrpo2ipc.h4ae-cdnidioc:xh2yl.o)4-ra-oc0pe8hteicno4ax-d(y2ad.cL4e-t2di.ci4c.h5t-oaTrcoPidp:h2en-(2o2.K4.4Y*.)05b-Pu<t`n"acn2ho-li(ocZrao4coi-dhd:eic2nh.o4lxo,5yro)--pTphf-oe(pn2ao.n4xoy.5i)c-add; MCPA- (4-chkxo~2-awthyi-phenoxy)-acebc acid; MCPP- 2-(4-chloro-2bmuetcahnyoti-cphaedndo:x2y.)4p-roOpCanPo-ic2.4-daicdhdJ;orophMeCnoPt8: 2.44-.5(-4T-cChPlo-.r2o.*42.-5m-tertichhylio-prohpehneonxoyl); 2*P3.C45.P6--WTpiCteinoPt-aac2lh.s4luo.6broj-etprchicteshnflroooir:mopPOh8eeAnnompl:hafeknaonxdZytb3hu.e4tU.y6nh-icTteaddCdKP.in-g2d.3o.m4.6w-eteretreaxcpholosreodpdhuenrionig; both production TFormuiators andspraying.. _ and packets 1982-87; handymen--1967-87:~ *process workers--1963-87. Exposed workers (n = 13482) comprise all known to have sprayed chlorophenoxy herbicides and all who had worked in any of the following departments at factories producing chlorophenoxy herbicides or chlorinated phenols: synthesis, finishing, formulation, packing, maintenance/repair, laboratory, chemical effluent/waste, cleaning, shipping/transportarion/stores/warehouse, plant supervision, cleaning during accident, and other and unclassified exposure. Probably exposed workers (n=41d) comprise all workers in cohorts 15 and 18; no job titles were available but it was judged that most workers would have been exposed. (Exposed and probably exposed are aggregated for some analyses, as indicated in the text.) Workerswith unknown exposure(n =541 ) had no information on exposure status. Non-exposed workers(n = 3951) were those never employed in the parts o f factories which produced chlorophenoxy herbicides or chlorinated phenols and who never sprayed chlorophenoxy herbicides came mainly from Australia, Denm ark, Netherlands, New Zealand, and U K (224, 1966, 1283, 214, and 180, respectively). Although not exposed to chlorophenoxy herbicides they were exposed to otha- chemicals, such as dyes and rodentiddes. Workers were also categorised as producers (12 492) and sprayers (5898). Exposed and probably exposed workers were also classified by groups of chemicals produced or sprayed (9377 chlorophenoxy herbiddes, 408 chlorinated phenols, and 4113 both) and within the manufacturing cohorts by department (3034 main production, 1522 VOL 338: OCT 26, 1991 THE LANCET 1029 TABLE II--MORTALITY BY DETAILED CAUSE AND EXPOSURE TO CHLOROPHENOXY HER8ICIOES AND/OR CHLOROPHENOLS. BOTH SEXES Cause ot death (iCO 8) fixposed All causes Malignant neoplasms (740-207) Buccal cavity and pharynx (140-149) Oesophagus (150) Stomach (151) Intestine, except rectum (152-153) Rectum (154) Liver, ^ llb b d d er and bileduct (15^-156) Pancreas (157) Peritoneum (158) Unspecified digestive organs (159) Nose & nasal cavities (160) Larynx (161) Trachea, bronchus and lung (162) Connective and other soft tissue (171) Skin (172-173) Male breast (174) Female breast (174) Female genital organs (180-184) Prostate (185) Testis (186) Bladder (188) Kidney (189) Brain (191-192) Thyroid gland (193) Other endocrine gland (194) Ill-defined sites (195,199) Lymphosarcoma (200,202) Hodgkins disease (201) Multiple myeloma (203) Leukaemia and alcukaexnia (204-207) Benign and unspecified neoplasms (210-239) Circulatory system (330-4S3) Respiratory system (460-519) Accidents, poisonings, violence (C80O-C999) Unknown causes 92* (88-96) (1870) 101 (92-110) (499) 116(58-207)///; 60(26-119) (8) 89 (64-121) (40) 113(81--154) (41) 110(70-163) (24) 44(12-113) (4) 112(73-164) (26) 156 (19-564) (2/ 331 (90-846) (4) 291 (60-851) (2) 145 (63-285) (8) 102(87-118) (173) 201 (55-515) (4) 32* (7-94) (3) 345 (42-1246) (2) 30(1-166)//; 94 (19-274) (3) 111 (75-158) (30) 225(90-464) (7) 80(42-136) (13) 97(48-173)///; 38* (14-82) (6) * 367 (100-940) (4) 462(95-1349) (3) 131 (83-197) /2 J; 97 (48-173) (11) 39(5-141) (2) 69(19-178) (4) 117 (70-186) (18) 199* (103-348) (12) 90* (84-97) (357) 72* (60-86) (I2S) 100<86-U6) (174) -- (SO) p<0*05. SMR (95% Cl) (no of observed deaths) Probate! exposed Non-exposed 122(93-158) (58) 129(74-210) (16) 0(0-1942) (0) 0(0-971) (0) 0 (0-305) (0) 0(0-479) (0) 179(5-995)//; 0(0-2170) (0) 185(5-1032)//; 0(0-12296) (0) 0(0-12 296) (0) 0(0-12 296) (0) 0 (0-3074) (0) 221* (110-395)///; 0 (0-7378) (0) 0 (0-2838) (0) --0- (0-3-6--889) (0) --- -- 0(0-671) (0) 0 (0-5270) (0) 227(6-1266)//; 0(0-1537) (0) 0(0-1025) (0) 0(0-12 296) (0) 0(0-36889) (0) 0 <0-802) (0) 0 (0-1476) (0) 769(19-4286)//; 0 (0-2838) (0) 0(0-1118) (0) 0 (0-2459) (0) U1 (72-165)/25; 95 (31-221) (S) 169 (55-394) (S) - ( . o> 103 (93-114)/J92; 99(81-120) (100) 59(2-330)//; 255 (83-595) (5) 85 (34-175) (7) 67 (22-156) (S) 43 (5-156) (21 83 (10-300) (2) 61 (13-177) (3) 0(0-1085) (0) 870* (105-3141) (2) 0(0-2170) (0) 90(2-502)//; 1400((01-0807-189)0/o) ;(40) 144 (30-422) (3) 0 (0-3689) (0) 114(31-293) (4) 89 (18-260) (31 40(5-143) (2) 0(0-444) (01 56(7-202)/2; 35(1-197)//; 86(18-250) (3) 0(0-1230) (0) 0 (0-1942) (0) 153(50-357) (5) 178(48-455) (4) 0 (0-332) (01 160 (19-578) (2) 88(18-256) (3) 317* (103-739) (5) 99(84-116) (162) 106.(69-156) (25; 108(77-146) (41) -- ( I t ) ------- Unknown 157* (119-203) (S7) 135 (72-231) (13) 667(17-3714)//; 0 (0-2170) (0) 0 (0-492) (0) 164(4-913)//; 238(6-1327)//; 435(11-2423)//; 0 (0-820) (0) 3333(84-18572)//; 0(0-18 444) (0) 0(0-36889) (0) 0 (0-3074) (0) 110(23-320) (3) 0 (0-12296) (0) 0 (0-2049) (0) 0(0-36889) (0) 0(0-1537) (0) 0 (0-753) (0) 217(6-1211) / / ; 0 (0-3074) (0) 0(0-1085) (0) 0(0-1366) (0) 556(67-2007) (2) 0(0-18 444) (0) 0(0-36 889) (0) 323(8-1797) (1) 0 (0-1757) (0) 0 (0-3353) (0) 0 (0-3074) (0) 0(0-1025) (0) 0(0-2306) (0) 113(64-183) (16) 191 (52-490) (4) 319* (182-518) (16) -- <D maintenance and cleaning, 1665 other, .1907 undassifiable). A substantial number of workers producing chlorophenoxy herbicides may also have exposed to chlorophenols (eg, p-chloro-ocresol) which are used as raw materials in the synthesis of chlorophenoxy adds. Exposure to the most toxic dioxin congener (2,3,7,8,-TCDD ) may occur during production of 2,4,5-TCP and 2,4,5-T, and during spraying ofherbiddes containing 2,4,5-T or its derivatives.1Facrories4,5,6,8,10,14,15,17,18,and20(n=6845)had other not produced 2,4,5-T or had produced very little ofit (around 10 tonnes per year during the study period). Workers in these factories were exposed to various chlorophenoxy herbiddes, chlorinated phenols, polychlorinated dibenzodioxins, and furans but were probably not exposed to TCD D . Thus within the register population it was possible to differentiate workers probably exposed to TC D D and workers probably not exposed to TCDD. Production acddents were known to have occurred in two cohorts (factories 7 and 9), 319 workers being exposed. There were 181 chloracne cases among workers in the cohort, 128 of whom came from cohort 2, which incorporated only workers diagnosed with chloracne. 9 production workers with a history of chloracne from exposure to polychlorinated dioxins in 1971-73 had a median levd of 340 pg TCD D per g blood lipids (range 98-659), higher than 4 unexposed workers from the same plant (median 18, range 8-28 pg/g) and 17 external controls (median 16, range < 5 to 23 pg/g) (M. Neuberger et al, to be published elsewhere.) Statistical analysis The person-years method was used to derive standardised mortality ratios (SMR) with 95% confidence intervals (Cl) based on the Poisson distribution." An excess or deficit of an SMR is regarded as statistically significant at p < 0-05 (two-tail) when the C l does not include 100. The WHO Mortality Data Bank was used to compute national mortality reference rates for sex, age (in 5-year age groups), and calendar period (in 5-year periods, except when such a period coincides with an ICD revision). Duration o f exposure was treated as a time-dependent variable in the allocation of personyears at risk. Poisson regression analysis was applied for selected sites." Coding Coding of underlying cause of death was done nationally. A conversion table has been prepared in 1ARC to allow the pooling of results over different ICD revisions.31-" About 40% of soft-tissue sarcomas (one of the a priori neoplasms of interest) develop in parenchymal organs3* and are not coded under ICD 171 (8th and 9th revision, "malignant neoplasms of connective and other soft tissue"). Histological diagnoses were not generally available and reference mortality rates are not available for sarcomas not coded as ICD 171. SMRs for soft-tissue sarcoma therefore relate only to sarcomas coded as ICD 171. Information on other sarcomas, identified from medical records and cancer registration, is presented but no statistical analysis was done. Results All-cause mortality was lower than expected from national rates (SMR=95 [95% Cl 91-99]). Among exposed workers, this was mainly because of low mortality for circulatory and respiratory diseases (SMR=90 [84r-97], SMR = 72 [60-86], respectively). Workers with unknown > 3 1030_________________________________________ T H E LANCET_______________ __________ VOL 338: O C T 26, 1991 if ,-'-5t & A r-, a n-_i ;} 3 * ! 1 : > T 1 TABLE 111--MORTALITY FOR ALL MALIGNANT NEOPLASMS ANO FOR SOFT-TISSUE SARCOMA ANO NON-HOOGKIN'S LYMPHOMA separately, both sexes All malignant neoplasms Soft-tissue sarccmas Non-Hodgkin's lymphomas - ft/Obs Exp SMR (95% Cl) Obs Exp SM (95% Cl) Obs Exn sCjilviOtn (/A30C70 V/**1iij Exposure Exposed and probably exposed Non-exposed Type o f cohort* Production Spraycn Chemicals produced or sprayed* Both Phenoxy Chiorophmols TCDD exposure* Probable Unlikely Years since first exposure * 30+ 20-29 10-19 0-9 Duration o f exposure* (yr) 20 + 10-19 1-9 <1 Department* Production Maintoiance Other exposure Unclassified 515 508-85 101 (93-110) 100 101-08 99(81-120) 253 258-91 98(86-111) 262 249-94 105(93-118) 112 106-70 105 (86-126) 384 385-28 100(90-110) 19 16-82 113(68-176) 236 215-12 110(96-125) 279 293-76 95(84-107) 74 88-60 84(66-105) 171 159-19 107(92-125) 170 166-49 102(87-119) 100 94-53 106 (86-129) 36 4217 85(60-118) 74 76-16 97(76-122) 234 230-54 102(89-115) 168 155-68 108(92-126) 62 60-38 103 (79-132) 40 42-02 95(68-130) 42 39-65 106(76-143) 107 114-10 94(77-113) 4 2-04 196 -53-502) 11 11-64 95 (47-169) 0 0-42 0 0-678) 4 2-25 178 (48-155) 1-03 973-541) 3 1-01 297 "41-868) 8 5-36 149 (64-294) 3 6-28 49 (10-140) 1 0-48 208-5-1161) 3 1-50 200 41-585) 0 0-06 0 0-6148) 4 2-37 169 (46--132) 7 8-96 78(32-161) 0 0-31 0(0-1190) 2 1-00 200 24-723) 2 1-04 193 *23-695) 5 5-76 87(28-203) 6 5-88 102 (37-222) 0 0-24 0 0-1537) 2 1-68 119(14-430) 0 0-52 0 0-709) 3 3-38 89(18-259) 4 0-66 606 165-1552) 5 3-94 127 (41-296) 0 0-50 0 0-738) 1 2-67 38(1-209) 0 0-15 0 0-2459) 2 0-29 690 -54-2491) 0 0-89 0 0-415) 2 0-59 339 -41-1125) l 1-02 98(3-546) 1 1-81 55 (1-308) 3 5-36 56(12-164) 6 3-35 179(66-390) 0 0-29 0 0-1272) 0 0-15 0 0-2459) 1 0-16 625 '16-3482) 0 0-35 0 -0-1054) 2 1-40 143 (17-516) 1 0-91 110(3-612) 3 0-90 333 (69-974) 2 2-08 96(12-347) 'Exposed and probably exposed workers are grouped together. ' exposure status had high all-cause mortality (table II), to be increased among sprayers (3 deaths, SMR = 297 especially for accidents, poisoning, and violence including [61-868]). All deaths occurred 10-19 years after first suidde(SMR=319 [182-518]). exposure, giving rise, for this rime interval, to a six-fold Table II gives SMRs (and 95% CIs) and observed deaths excess risk in the cohort as a whole (table III) and an even for major causes of death and for malignant neoplasms by greater excess among exposed sprayers (3 deaths, site and exposure for both sexes combined since only 10 SMR = 882 [182-2579]). No differentiation in risk was deaths from cancer were available for analysis among observed in relation to duration of exposure or probable .`'M!i '.a exposed females. Significant excesses were observed among males for malignant thyroid and benign and unspecified neoplasms in the exposed category, malignant neoplasms of TCDD exposure. 5 additional cases of soft-tissue sarcoma were recordedin cohort members who were alive at the end offollow-up or who had died with a certified cause of death trachea, bronchus and lung in the probably exposed other than ICD 171. These included 1non-fatal case in the category, and malignant neoplasms ofunspecified digestive non-exposed group. Details of all 9 cases are given in organs and benign and unspecified neoplasms in the table IV. non-exposed category; significant deficits were observed for malignant neoplasms of skin and of brain. Exposed workers had SMRs above 200 for neoplasms of M alignant lymphoma ' j. unspecified digesdve organs, neoplasms of the nose and nasal cavity, soft-tissue sarcoma, breast cancer (in males) and for neoplasms of the testis, other endocrine glands and thyroid. 14 deaths from non-Hodgkin's lymphoma (ICD 200, 202, 8th and 9th revision) were observed among men and 1 among women; 11deaths were in exposed workers, all men. Mortality for exposed/probably exposed workers was close ! Table III gives combined SMRs for exposed and to expected (SMR=95) with production workers having a probably exposed workers of both sexes, for all neoplasms, small statistically insignificant increase in mortality (8 soft-tissue sarcomas and non-Hodgkin's lymphomas. The deaths, SMR = 149)(table ill). 10out of 11 deaths occurred pattern of risk for all neoplasms by time first exposure did not indicateastronghealthyworkereffect, and mortality did more than 10 years after first exposure. 6 deaths occurred among workers exposedfor than a year, and no difference in not vary substantially between the groups examined. risk could be seen in relation to exposure to TCDD or type 'I! 1 Soft-tissue sarcoma ofchemical produced. The highest SMRamongproduction workers was for those in "other jobs" (transport/storage, laboratory workers, plant supervisors). 4 deaths from 4 deaths were observed, all among exposed male workers . non-Hodgkin's ly m p h o m a were observed among non- (table III). No increased risk was observed among exposed workers inoneDanish factory(cohort 4). Mortality production workers (1 death), whereas mortality appeared fornon-exposedworkers was higher than that ofall exposed m et 1?/4$ un: THF. I.ANCHT VOl. DX: o c r 26, llWI k> T ( 'D O . O il hi; i iKldiium;il registered cases o f soli-tissue sarcoma, identified from oilier morbidity or mortality records i 3 production workers, 1 sprayer, 1 noil-exposed) 1 was in j worker probably exposed to T C D D . 9 Green LM . A cohort mortalitv >iudv ol trcMry wnrkers excised to phenoxv acul herbicides. Hr 7 hut S Ud ll*oi ; 48: 2 3+ 3s 10 Hardell !.. Sandsirnm A. ^use-control studv Soli-iissuc sarcoma and exposure to phenoxv acetic acid'- or chloniphenols. Hr ^ ( .amer I97<i; 39:711-17. A small, non-significant increase in mortality' from 11.1 lardell L , Eriksson M , Lenncr P. I .ungren E. Malignant lymphoma and non-Hodgkin's lymphoma was observed among production workers, most deaths occurring more than 1.0years after first exposure. 6 out of the 11 deaths were in workers exposed for exposure to chem iols. especially organic solvents, chlorophenols aiul phenoxv acids: a uisc-cinurul study. Hr 7 ('am er 1981. 4.3: 169-76. 12. Duldcrup L M ./c llc n rjtli D. Dioxin exposure. 20 year follow-up. l^neet 1983; u: 1134-35. less than one year. O ther stu d ies1JJ' have, however, shown 13. Qiggon D . Pannett B. Winter P. Mortality and incidence of cancer at four risks associated with exposure to ehlorophcnoxy herbicides higher for non-H odgkin's lym phom as than for soft-tissue sarcomas. T h ere was no increase in mortality from factories making phenoxv herbiculcs. Hr J hid .Wed |9 0 j; 173-78. !4. H oar SK , Blair A. Holmes E'E. Boyoscn C D , Robe! RJ. Hoover R. EniumcnrJJ Jr. Agncutiural herbicide use and nsk of lymphoma ami soft tissue sarcoma. J A M A 1986.256: 1141--17 Hodgkin's disease, and the evidence for an association of 15. Hoar /.ham S. Weiscnburgcr [3D. Babbitt PA. Saal R(L Vaught JB. with exposure to ehlorophcnoxy herbicides has been weaker than that for non-H odgkin's lymphoma. We found increased risks for some uncommon neoplasms but these results are difficult to interpret because o f the small Clamor K P, Blair A. A case-control study of non-H txikin's lymphoma and the herbicide 2,4-diehlorophenoxyaccnc acid 2.1- D i m Eastern Nebraska, Iipidemtohxy 1900, 1: 44*i-5o 16. E'ingcrhut M A, Halpcnn WU. Marlow [)A . et ai. Cancer mortality m workers cxpsed to2.3.7,8-(ctrachlorodihen/o-p-dio.\in. .V IvatlJ M eJ numbers. Neoplasms o f the thyroid and other endocrine 1 9 9 |;.3 2 4 :2 1 2 -IH . glands have not been previously linked with ehlorophcnoxy herbicides in man but exposure to T C D D and chlorophenols have been a s s w jie d with neoplasms of the 17. Lilienfeld DU, Gallo MA. 2.4-D . 2.4.5-T and 2.3,7.H-TCDD: an overview. h'piJemtol Ri~r 1989; I U 28-58 IH. Centers li*r Disease (L>ntrol Preliminary report; 2.3.7,8ictrachlorodiben/o-p-dioxm, exposure to hum ans-- Scvcso, Italy thyroid and the adrenals tn mice and rats. " ill.U irK 1988; 48: 733-36 Interpretation of our findings will be easier when follow-up of this large cohort is longer-- ie, when the num ber of recorded deaths is greater. T h e pattern so far 19 Pearce N E, Smith AH, Howard JK. Sheppard RA, Giles H J, `League (LA. Non-H odgkin's lymphoma and exposure to phenoxv herbicides, chlorophenols, fencing work, and meat works employment: a casecontrol study. Hr J hui Med I98r>; 43: 75-8 3 indicates no increased mortality for neoplasms in general for 20. Persson B, Dahlander A, Frcdnksson M, Krage H N . Ohlson C -G . the most common epithelial cancers, and no clearly detectable excess for non-H odgkin's or for H odgkin's lymphoma. T h e significant six-fold excess of soft-tissue sarcomas occurring in the period 10-19 years since first .Axelson O. Malignant lymphomas and ecupacumal exposures. Br J hid.W ed 1989; 46:516-20. 21. Smith A H , Pearce N , Fisher D O . Giles H J. l eague CA, Howard JK. Soft tissue sarcoma and exposure to phenoxv herbicides and chlorophenols in New Zealand. J S a tl Cancer lust 1984; 72: 1111-17. exposure in the whole cohort, rising to a nine-fold excess in 22. Vincis P. Terracini B. Ccconc G . Cignetu A. Colombo E, Donna A, sprayers, is compatible with a causal role for chlorophenoxy herbicides, though not specifically for those probably contaminated with T C D D . Matli L, Pisa R, Ricci 1?, Zamm U. (tomba 1*. Phenoxv herbicides and soft tissue sarcomas :m female rice weeders: a population-based ' case-control study. Sc^nd J U"r/c Htmron Health 1987; 13: 9-17. 23. Wigle D T . Semenciw R M , Wilkins K . Riedel D . Rirtcr L .M o m so n H I, M ao Y. Mortality study of Canadian male farm operators: non- Supported by grant No l-ES-95276 of the US National Institute of Environmental Health Sciences. We thank line Johnson for his contribution `m semng-up the register and David H o d for support throughout the project; Hciko Beeher, M anlyn Fingerhut. and Paolo Boflecta for constructive HodgkuPs lymphoma mortality and agricultural practices in Saskatchewan;^ N*i(I Cancer lust 1990; 82: 575--82. 24. W iklund K , Dich J,^4olm I.-E . Eklund G. Risk of cancer in pesticide applicators in Swedish agriculture. H ' J Ind Sied 1989; 46: 809-14. comments on an earlier draft; David Marlow and William Parsons for help 25. Woods JS, Pohssar L, Sevnson R K , Hcnser LS, Kulander BG. Soft with planning the industrial hygiene investigation; Gilles Ferro for assistance tn data management, and Agnes Hanss-Cousseau lor manuscript tissue sarcoma and non-H odgkin's lymphoma in relation to phenoxv herbicide and chlonnated phenol exposure in western Washington. preparation. K.A. L A. was in receipt of a research fellowship from IARC 7 X ati Cancer Inst 1987; 78: 899-910 during pan of the work on this study 26. Zobcr A, Messerer P, Huber P T hiny-four-year mortality follow-up of BASF employees exposed to 2,3,743-T C D D after the 1953 accident. REFERENCES hit Arch Occup Ihnirtm Health 1990. 62: 139-57. 27. IARC M onographs on the Evaluation of Carcinogenic Risks to Humans. 1 International Agency for Research on Cancer. Some halogenated hydrocarbons and pesticide exposures. In: M onographs on the evaluation o f the carcinogenic nsk of chemicals to humans; vol X L l. Lyon: [ARC. 1986; 34b, 395. 2 Kcnazzi PA. Zocchetn C, Pcsaton ACL Guercilena S, Sananco M. Ten-year mortality study ot' the population involved in the Scvcso incident in 1976. A m ] F.pidtnnol 1989; 129: 1187-200. 3. KondCiG. W enersirocm N H . R oushG J,M cLaren EA, L ippsT E ,C ook RR. Cause specific mortality among employees engaged in the Overall evaluations of carcinogenicity an updating of IA R C Mouogr 1--42 'suppl Lyon: [ARC, 1987. 28. IARC Working Group. Phenoxv acid herbicides and contaminants description of the IARC International Register of Workers. A m J ind M ed 1990; 18: 39-45. 29. Coleman M P, Hcrmon C, Douglas A. Person-years 1PYRS): a Fortran program for cohort study analysis W H O IARC internal report no 39 0061. Lyon; IARC, 1989. 30. Checkoway H, Pearce N E, Grawford-Bmwn DJ. Research methods in manufacture, formulation or packaging of 2,4-dichlomphcnoxyacetic occupational epidemiology. New York. (Oxford University Press, 1989 acid and related salts. Br J hid M ed 1988; -15:98-105. 31. W orld Health Organisation. Manual ol the international statistical 4. Coggon D , Pannett B. W inter PD , Achcson ED, Bonsall J. Mortality of classification-ot diseases, iniunes and causes of death ,7th revision workers exposed to 2 methvl-4 ehlorophcnoxy acetic acid. Scatu! J conference]. Geneva: W H O , 1957. IVGrfr '.minm Health 1986; 12: 448-54. 32 W orld Health Organisation. M anual of the international statistical 5. Cook R R .B o n d G G , Olson R A ,O n M G .G ondck M R Evaluation of the classification of diseases, injuries and causes of death i8th revision mortality experience o f workers exposed to chlonnated dioxins. conference;. Geneva: W H O , 1967. Chemosphere 1986; 15: 1969-76. 33. W orld Health Organisation. Manual of the international statistical i \ o. Eriksson M , Hardell L.t Berg NO. Moller T , Axelson O Soft tissue sarcoma and exposure to chemical substances a case-referent study. Br classification of diseases, injuries and causes of death -9th revision conference:. Geneva: W H O , 1978 J bid M ed 1981.38: 27- 33. 34. Fingerhut M A, Halpenn W E, Honchar PA, Smith AB, (jro th O H , i 7. Eriksson M. Hardell L, Adami HO Exposure to dioxins as a nsk factor for soft tissue sarcoma: a population-bused case-control study. J S a il Russell WO. An evaluation of reports of dioxin exposure and soli tissue sarcoma pathology among chemical workers in the United States. 8 Cancer fntt 1990; S3: 486-90. . l.ynge E. A follow-up study of cancer incidence among workers m Scant! J Work Hminm Health 1984, 10: 299- 30 3 35. Hull" JE. Salmon AG, Hooper N F . /e ise L. U m g-ierm carcinogenesis manufacture of phenoxv herbicides in Denmark. H rJ Cancer 1985; 52: studies on 2,3,7,8-teirachlorodibcnzo-p-dioxin and hexachloro- 259-70. diben/.o-p-dioxin. ('ell Hud Toxicol 1991; 7: /-94. to get effective calcium antagonism w ith m inim al side-effects ! CA R D K N E * Abbreviated I'rry nbin): inform ation U ' e t : C h r o m s s ub s - l u c m . i -inl.i :> n . - J i t m 1i \ p c M i i i M O i i D o l a r e ^ iiij 1111 m. l " r vn < n s -,,hi >i irmiv: .loss .>i .`" m e : i .! :it: n i n e upv\.ifU t o .1 in. iMititiin >1 : 1 si In Ms ;>s ris'ii 'Un .1 i n m i l s ' : ....... ... . i o n >1 *i: rv' 0 ' -It m e 0 . 1 M Ut b e s i m .I . n i s s ........t f o l o i. n-M s! i. i. /n /j .in./ -i.:,', 1up.; i, I i mu. i ll s I 1 si ( h e n s .iff Mil t ut. it i o n V 1. 1-. :ti. ;l!) ,1 I mu.ills M i n e : si t . i n ' n l k i il l. uc m J i n i . m i m i i l ' s i >. lissluis 1 U ii.lt." V . f t 1* . iiiiiiriisl<-.{ siii.li r i > s . i : . M i s N ' :ii\i ss l u r e i ' t n . i l k ssilli l>s I n i`lo. Vs i> C " o n i r a - i n d i c a t i o n t : l ' i s e n n : . s m . i ' i . u u o m I K p e r ' C i i m i i v i t \ is> ifslipiiu isv: :o , nlo<nU' ^sls.HKssi is.' ii. .isiro.is W a r n i n g s a n d P r e c a u t i o n s : It ' s i i m i i h c iron . s .m .M s.s ks. rs :o 1 M U ' I M c i - l - .o l K s .l . i . s itu k i . i - H w U , >!,** M . r ( A K I ' l . M m i* : n i * s s|s r ; . ri, ,in : >1 i, i>i,. tm .s - *11111 l i n m u t o >>l 'l . i M t n c ills '! i;**. - ` f m o ' ' i ...... ... 'll. .loss \ s .-Isl ss sis nil. !'.s '. lists>11 HI pJI U III* 'Mill 1 l t l ' l o f \ >: >:r..ks ^ 'S ' .MM.........11 'il l s 'l l l. s s u li . I.'sli.,, 11: -.. p o o f . Ifsll.ls rCssTW Of lllip .tll S.! `Is }'.Ills ol i n I nos ........ M . . ; | . | . . ( ; ills ni- . .11 _ ': C>-s 111 . 11I1. Ilslllis . .nisi iil.issllis. . . n i s pin : . ol.. iss r> S i d r - c t l c c t s ..iiimj; In i.l.i. :n p s : ipli. 1 .s .Is -.s. . 1i 1s ii........ . I \ ' 11.ip : 1 101. 11 K 1: v ills r e ....... I m e : ii \ 1 lnn . l b Ml. . s o : , . o r . ri. . -I.......... Ii.: n u t . : ( N S .......................................... n r m u s p n.is n il. is ' > n . : 1 I. j m i o o s : >1 im p .i in m m it. |... . . \i>> . c i s w o . n i i s * , ups. : .1.. -.1 n . l o o r , Is i P r e s e n t a t i o n , b a s i c N ' H S i o m m s J p r o d u c t l i c e n c e n u i t i h r r v i V K I ' I M t . psuU ........ nis. iisliivnt :->,v . Iii.n i.l. m i '" in e I I'l "ijssf. HIV I SO.Iu; l . . . . 1 a > ' 1 1*1 ' 's*. Js'./.n ii.. ! I's r-s>11.11 t . .iin 1m in . ; I `tu.: I v . .ti. 1: l. .HI I -H ill. I ..........I'l ... :i. 's . I. S !'ll 11 III I. S ,.U . .lis I m ills i l . S \ n>. M :....... I Hs : 'ks M ! k l > \ R l M M ...... 5YNTEX DO ^ p h a r m a x ; ' o rtio i/itrm a a ; JS? IN H Y P E R T E N S I O N Cardene (nicardipine) An overall low incidence' of side-effects was confirmed in 10,932 patients w i t h ^ ^ hypertension and angina.1 --'V*T-' I f W hatever you give your h aem o ph ilia p a tie n t will help shape his future. You can now give him a high purity factor VIII derived from the plasm a of healthy U K donors, screened by the National Blood Transfusion Service. One that undergoes a unique and highly effective virus inactivation process.'-2-3 Quite simply, 8SM . The new high purity factor VIII from BPL. 8SIVL PURELY FOR QUALITY IM R IS LIFE 8 S M (High Purity Factor VIII) P R E SC R IB IN G INFO RM ATIO N Ind ica tio ns: Treatment of classical Haemophilia A. Do sa ge : Minor bleeds: 7-13 iu/Vg initially. Severe bleeds: initial dose 9-25 iu/Kg body weight For fuU instructions, including dosage for major surgery, se e Oata Sh e e t Adm inistration: Reconstitute Factor VIII in Water for Injection provided. Stow intravenous injection not exceeding 10ml per minute. Contra* ind ication s: Hypersensitivity to mouse protein. W a rnings etc: Contents should not be used if Factor V III vial does not oontain a vacuum or if the Factor VIII forms a gel or d o t The risk of transmitting viruses including those causing hepatitis and A ids cannot be entirely excluded. Side-effects: Specific hypersensitivity, occasional flushing, nausea. B P L IS A U N I T O F T H E C B L A increased pulse and headache may occur. Precautions: M a y contain blood group antibodies. Patients with A, B or A B blood groups should be monitored for sig n s of intravascular haemolysis. Antibody development should be monitored after treatment. Patients should be vaccinated against hepatitis B before commencing treatment Sterilised Water for Injection must not be injected on its own or for any other purpose than reconstitution of 8 S M . B a s ic N H S cost: 48p/iu. Presentation: Nominal 500iu or 1000iu /vial supplied with 5ml or 10ml Water for Injection. P rod uct Licen ce n u m b e r PL 08601/0015 (see Oata Sheet). Sterilised Water for Injections Ph.Eur., P L 1502/0003 (Phoenix Pharmaceuticals Ltd.. Gloucester. U.K.). Fud prescribing information and Oata Sheets available from: BPL, Dagger Lane, Elstree, Herts W D 6 30X. Tel: 081 90 51 81 8. R e fere nces: 1. Piszkiewicz 0, et al. Inactivation and removai ol hum an' immunodeficiency virus in monoclonal purified anti hemophilic factor (human). T h r w n t a ^ e ^ r d f c 1989; 55: 627*634. 2. Data on file. 3. G riff K ffle K r a M p ^ .c h a r a c t e fl sation of the Method M A H F p r p s p s 'le v in e p w to reduce the risk of v im s transmission, in Roberts H R (ed): Proceedings ot the sym posium on biotechnology and the promise of pure FVItl. Brussels, Baxter Healthcare Publications, 1989:69*85. A SPECIA L HEALTH AUTH ORITY WITHIN THE NHS VOL 338: OCT 26, 1991 THE LANCET 1031 Year Sex. of destht TABLE IV -- DESCRIPTION OF 9 CASES OF SOFT TISSUE SARCOMAS Cause of death iM iu iv y r.* Longest held jOu Years Years since first of XpuSUfe x p u s fe 1, Australia M ,46 <1980 Connective tissue lower limb (ICD 171) 2, Denmark M, 32 <1980 Connective tissue lower limb (ICD 171) 3, Denmark M , 34 Alive, Jan, 1984 4, Denmaik M, 47 <1980 lll-deftned cancer 5, Denmark M , 64 <1980 Prostate cancer 6, New Zealand M, 35 Alive, Ja n ,1988 7, New Zealand M , 55 1980+ Connective tissue upper limb (ICD 171) 8, UK M, 43 <1980 Connective tissue unspecified (ICD 171) 9, Denmark M , 56 Alive, Ja n ,1984 Fibrosarcoma of the hip Sprayer Neurofibrosarcoma, lower limb Mesenchymal sarcoma (possible Itposarcoma, retroperitonewn) Haemangjopericytoma, bade Leiomyosarcoma, prostate Production, transportation/scorage Production unspecified Production transporcarion/storage Production, transportation/storage Fibrous histiocytoma, lower limb Sprayer Neurilemmoma Spindle cell neurilemmomai sarcoma Sprayer Sprayer Leiomyosarcoma, larynx Non-ocposed 1 additional incident ca se occurre d after the end of fo llo w -u p in N e w Zealand. * C a s e s 2 . 3 .4 . 5 .8 . a n d 9 p reviou sly reported.2'4-7 f Precise year of death not provided for reasons of confidentiality. t H ist o io g y from c an ce r registration or medical records. H isto lo g y record not retrieved for c a se 1. 16 10 14 21 17 12 14 18 26 16 <1 <1. 8 2 12 12 <1 <1 workers, and similar to that of production workers (table III). The cases arose in seven countries. (Not included in table III are 3 cases in cohort members who were alive at the end of follow-up or whose certified underlying cause of death was not ICD 200 or 202.) Mortality from Hodgkin'sdiseasewas belowexpectation. Other neoplasms More than two-fold increases in risk were noted among exposed workers for several less common neoplasms, most ofwhich have not been previously associated with exposure tochlorophenoxyherbicides. 7deaths fromtesticularcancer were recorded, with at least a two-fold increase in mortality for the combined group of exposed workers (SMR=220 [89-454) and for the production workers (5 deaths, SMR=278 [90-648]). 5 deaths occurred 5 or more years after first exposure, and riskwashigher in workers probably exposed to TCDD (SMR=296) compared to those probably not exposed (SMR = 164). Thyroid cancer mortality was increased for the combined group of exposed workers (4 deaths, SMR=357 [97-914]), the excess applying both to sprayers and production workers, with deaths registered in three countries. 3 deaths from thyroid cancer occurred 10 or more years after first exposure, and risk was higher for workers probably exposed to TCDD (SMR=426) compared to those probably no- exposed (SMR=308). 3 deaths from neoplasms of other endocrine glands occurred m the UK with increased mortality for the combined group of exposed workers (SMR=454 [941328]), and separately in sprayers and production workers. Increased mortality fromneoplasms ofnoseand nasal cavity (3 deaths, SMR = 283 [58-827]) was similarly observed only in the UK, with the highest risk in sprayers. The mortality ofcases exposed through accidents was not increased either for all causes (33 deaths, SMR = 98 [67-137]) or for all neoplasms (13 deaths, SMR =120 [64-205]). Similarly, no increased risk was seen for chloracne cases for all cause mortality(13 deaths, SMR = 66 [35-113]) or for al neoplasms (5 deaths, SMR = 98 [32-228]). No deaths from soft-tissue sarcoma or nonHodgkin's lymphoma were observed in these groups, but the expected numbers were very low. Results were virtually unchanged when analyses were repeatedwith exclusionofall workers with less thanone year exposure. Analyses bytimesincefirst exposureand duration ofexposure forworkers probably exposed toTCDD didnot show any trends. Analysis using Poisson regression for all cause mortality, all neoplasms, soft-tissue sarcoma, and non-Hodgkin's lymphoma, did not reveal different partem of risk than that shown in the SMR analysis. Discussion The IARC register provides an opportunity to study, with a common protocol, the mortality experience of workers producing and spraying chlorophenoxy herbicides and/or chlorinated phenols in ten countries. This cohort study is the largest to have been done on these categories of workers. Nonetheless the attempt to associate risks with specific agents was only partly successful because there was often simultaneous exposure to several different chlorophenoxy herbicides or chlorophenols (table I) and to other pesticides, raw materials, intermediates, and processing chemicals. The risk specifically related to chlorophenoxy herbicides is best evaluated by looking at sprayers, who are exposed mainly to these compounds and, in smaller amounts, to other herbicides, and only to negligible amounts of chlorophenol impurities. Workers producing chlorophenoxy herbicides may also have been exposed to chlorophenols during the production process. It was not possible to identifya largegroup ofworkers exposed solelyto chlorophenols. The most toxic dioxin (TCDD) can be formed during production of 2,4,5-T or 2,4,5-TCP so the identificationoffactories which didnot produce 2,4,5-T or produced only very small amounts and of sprayers not using 2,4,5-T allowed a population to be distinguished in whichexposure to TCDD was unlikely(with the caveat that even occasional exposures to high concentrations ofTCDD may lead to accumulation of high tissue burdens18). A non-significant increased risk was observed for soft tissuesarcoma, the excess beingsignificant for sprayers in an analysis by time since first exposure. All 4 cases (in four countries) occurred 10-19 years after first exposure, a time shorter than that observed in Sweden10or the USA.16The increasedriskwas not confinedtoworkers probably exposed i7 m Bersatolofiiea, l *>95?) 5 ^ - T h i r t y - o n e c a s e s o f ehloracr.e were found among workers engaged in the production o f 2 ,^ ,5 - t r ie h lo r o p h e n o l and in the <r.version f the la t t e r into 2 ,A ,5-trich lorop h cn o x y a ce ti c a c i d and i t s e s t e r s . Animal experi.eer.ts,. c a r r i e d out by p a i n t i n g r a b b i t s ' e a r s , have shown th e e s u s e Di ehloracr.e t o be r.ot t r i c h l s r o p h e n e l i t s e l f , but t o x i c b y-p r od uc ts formed i n the a l k a l i n e h y d r o l y s i s of 1,2,l*,5-ttrachlorobcr.sene into 2,^ ,5-trichlorophenol. Compounds that may a r i s e i n t h i s p r o c e s s were s y n t h e s i s e d , and t r i - and te tr ach lorocib cr.zofuran and t e t r a c h l o r o d i ber.rodioxin were found t o be h i g h l y a c t i v e . Furthermore, 2 , 3 6 i 7 - t e t r a c h i o r o d i b e n s o d i o x i n was i s o l a t e d as a by product formed i n the manufacture o f t r i c h l o r o c h e a o l , and the p o s s i b i l i t y o f i t s formation from sodium t r i ch lorophen oxide was e s t a b l i s h e d . C h lo r in at ed compounds, used ns i n d u s t r i a l m a t e r i a l s or formed a s by p r od u ct s, occupy an important p o s i t i o n among t h e chemical and p h y s i c a l i n t o x i c a n t s capable o f producing acr.c and f o l l i c u l i t i s . * ** The f i r s t c o z e s caused by t h e s e compounds were boerved a t t h e b e g i n n i n g of the century with the introduction of the e le c tr o ly tic chlorine process. The view put forwdrd, and l a t e r c o r r e c t e d , by Kcrxhoincr, a c c o r d i n g to which the d i s c a o o i o caused by fr e e c h l o r i n e , hau l e d to the c o n f u s i n g but common d e s i g n a t i o n "c h lo r a c n c " . . Since the introduction o f chlorinated naphthalenes, uacd in various branches o f industry on account o f t h e ir u s e f u l p r e p e rtieo ( r e s i s t a n c e naphthalene d i s e a s e " ! , wlvich og.iin i s u n s a t i s f a c t o r y i n rainy r e o p e c t a . k 0173 1 Chlcracne hoc recen tly been observed in the sr.afacture o f pentjjchloroyhcnol. I t w i l l l a t e r be d i s c u s s e d s h o r t l y whether pentachlorophcr.ol i t s e l f i s to be regarded a s the i n t o x i c a n t proper in these c a s e s . *# l>* .. The c a s e s wheae c t i c l o g y i s aov d i s c u s s e d were found among v^rkars ir. a chemical p la n t i n Hamburg,. who were engaged i n the r-snufacture o f 2'it 5-t ric hl- 'vo ph cnol and i n i t s c o n v e r s i o n i n t o the h e r b i c i d a l ?!* 5 - t r i c 'hlr>r4:htfr>oxyaeetic a c i d and i t s e s t e r s . Out o f a t o t a l o f p? p a t i e n t s , 9 cho-cd s e v e r e , moderate, and 8 s l i g h t symptoms. The symptoms developed i n the summer and f a l l o f In the case of Bore h i g h l y exposed workers, f a c i a l d e r m a t i t i s accompanied by erythema ar.d s w e l l i n g appeared f i r s t , but withdrew l a t e r to g i v e way to a c r . e i f s r symptoms on the f a c e , then on o t h e r p a r t s o f the body as w e l l . Ir. most ccses, however, the history started not with acute dermatitis but with comedones and then p u s t u l e s , a f f e c t i n g the z y g c m a t i e - t e n p o r a l r e g i o n . The d e r m a t o l o r i c a l symptoms found on f i r s t examination c o n s i s t e d o f numerous comedones, r e t e n t i o n c y s t s , ra ng in g from the s i z e o f a pinhead to that o f a l e n t i l , f o l l i c l e s f il le d with hyperkeratotic m aterial, inflamed p a p u l e s , p u s t u l e s , and l a r g e r f u r u n c l e s . The f a c e , e x t e r n a l car, nec k, ar.d the nape were i n v a r i a b l y a f f e c t e d , s e v e r e c a s e s a l s o e x h i b i t i n g symptoms on the c h e s t , back, abdomen, e xtens or s i c e s o f arms and t h i g h s , and on the g e n i t a l s . The e f f l o r e s c e n c e was g e n e r a l l y s o dense t h o t p r a c t i c a l l y no f o l l i c l e remained u n a f f e c t e d . Vhcreas f a c i a l symptoms were mainly c h a r a c t e r i s e d by comedones and r e t e n t i o n c y s t s , secondary i n f e c t e d e f f l o r e s c e n c e ( f u r u n c l e s and p u s t u l e s ) was frequent on the nape and the trunk ( s e e }*igr. 1 and 2 ) . In a d d i t i o n to derm atological symptoms,, s e v e r a l p a t i e n t s developed ch ron ic b l e p h a r i t i s and c o n j u n c t i v i t i s . Host p a t i e n t s complained o f l o s s o f a p p e t i t e , d e b i l i t y , and weakness i n the l e g s , in o t h e r words, o f syiepto.T.G i n d i c a t i n g g e n e r a l i n t o x i c a t i o n . rig. n Tig. 2 Ho chan;* i n the l i v e r , k i d n e y s , c e n t r a l nervous s y s te m , end i n the hemopoietic system was f i r s t , found on thorough c l i n i c a l examin.sticr.. Son* p a t i e n t s had ar. a n c e i d a t y o f t h e g a s t r i c k u i s e . Owing * g c r e i s t e n t c o s p l a i r . t a , new a t o m i s t i c and n e u r o l o g i c a l e x a m in a t io n s were carrie d out on s e v e r a l p a t i e n t s a few weeks l a t e r , r e v e a l i n g iYccted liver in three eases. Detailed c lin ica l diagnoses w ill not hf>e vcr be d i s c u s c e d h e r e . The course o f the d i s e a s e was e x c e e d i n g l y lo n g and p e r s i s t e n t . Alth ea contact with the i n t o x i c a n t s had been d isc o n tin u e d , r e la p s e d dermato l o g i c a l sysptems appeared even 15 2C e o n t h s l a t e r , d e s p i t e i n t e n s i v e i n t e r n a l ar.d e x t e r n a l t h e r a p y . 1'tjolorv Ansal experiments were carried out with a view to c l a r i f y i n g the e t i o l o g y o f ehloraene by t h e . u s t o f r a b b i t s ' e a r s , on which Hofmann ar.d Neumann , Braur. , Landes , and o t h e r s had su cceeded i n i n d u c i n g symptoms by u s i n g c h l o r i n a t e d n a p h t h a l e n e s , th e symptoms r e s e t t l i n g those o f ehloraene i n man. In each c a s e the i n s i d e o f one car was painted daily with c p o ly g ly co l s o lu tio n o f the substance to be te s te d fer i t s chlcrac n e -in cu cin g a c t i v i t y , w h ils t the other ear, s e r v in g aa a c o n t r o l , was t r e a t e d with the s o l v e n t a l o n e . In eases o f p o sitiv e t e s t , f la t surface inflammation f i r s t developed i n 2 t o A weeks, fo ll ow ed a few days l a t e r by the appearance o f f o l l i c u l a r s w e l l i n g , h y p e r k e r a to s is, and s n a i l c y s t s ( s e e f i g . 2 ) H i s t o l o g i c a l exa.nir.stion showed a c a n t h o t i c e x t e n s i o n o f the e p i d e m i c , edema, and l o o s e , inf lamed c e l l i n f i l t r a t i o n i n the c u t i s . The f o l l i c l e s were distended and f i l l e d with k e r a to tic is a t e r ia l . Larger e y t t s were formed i n l a t e r s t a g e s ( s e c T i g . * 0 . fis- 3 P a b b i t ' s t a r t r e a t e d with a 0.15S solution of tctrachlcrodibcnso- dtoxin _ Histological picture of the r a b b i t ' s t a r shown i n F i g . J K \k having been used with s o r t than 100 s u b s t a n c e s i n the pnst two y e a r s , the rabbit-ear t e s t enables the chlorucnc-indueing A c t iv it y o f a oub*iancc to be a s c e r t a i n e d with high p r o b a b i l i t y . Th* f i r s t r e s u l t s were r e p o r t e d by one o f us*^ a t t h e 22? d Congress o:* ' Cermar. U e r x a t e l o r . i s i s i n V ie n n a. * I t was f i r s t shown t h a t , c ont r ar y . t o - p r e v i o u s a s s u m p t i o n s , 2 , ', 5 - t r i c h l o r o p h c r . o l war no t t o be e n r e i d e r e s a s ; t h e e h l c r a c n c - i n d u c i n g f a c t o r . T hi s merged ir o n 'hi o b s e r r s t i e n tlfcat the e xp ect ed symptoms wire not produced os t h e r a b b i t s ' t a r s with a 'jl* s o l u t i o n o f pure 2,*, 5 - t r i c h l o r o p h c n o l i n p o l y g l y e a l , b - t they were produced by th e t e c h n i c a l p r o du ct. S i n e * the s t a r t i n g m a t e r i a l , 1 . 2 , ^ , 5 - t e i r c t h l c r o b c n a e r . e , was i n a c t i v e bn the r a b b i t s ' e a r s , i t war t o be assumed t h a t the i n t o x i c a n t was among th e b y - p r o d u c t s formed ir. the olkaline hydrolysis of 1,2,A,5-tetr*chlorobcnser.e into 2,^ ,5-triehlcraphcnol. a Ol! U a + N. Oil ------- ^ 5-teirachlorobenaer.e C li^iJ-trichlcrc- Sir.ce the d i s t i l l a t i o n r e s id u e could not e t f i r s t be separated, s number o f such s y n t h e t i c compounds were s e l e c t e d f o r t e s t i n g , which were l i k e l y to be formed i n the h y d r o l y s i s o f te tr ach lc ro b cr .a ene a t 1cC C, th e s e compounds b e i n g the c h l o r i n e d e r i v a t i v e s o f diphenyl e t h e r or.d o f diber.2ofuran (d ip h e n y l c n e o x i d e ) . Whilst the c h l o r i n e d e r i v a t i v e s o f diphenyl e t h e r and u n s u b s t i t u t e d and monochlorir.atcd dibcr.sofuran were i n a c t i v e in th e animal experiments, t r i c h l o r c - and t c t r a c h l o r o d i b e n a o f u r a n r e s u l t e d i n the expe cted symptoms, even when they were s p p l i e d i n O.Cjr** s o l u t i o n s . In a d d i t i o n to the above symptoms, both compounds e x h i b i t e d s t r o n g h e p a t o t o x i c p r o p e r t i e s . The o r a l a d m i n i s t r a t i o n o f a c i n g l e dose o f 0 . 5 to 1 r.g/kg le d to s e v e r e hepatic c o n d itio n s in r a b b i t s . Jowover, c h lo r in a t e d dibcr.zofurans could not be d e te c ted as a by-prcduct l a the production. The c l i n i c a l examination o f a la b o r a t o r y a s s i s t a n t who de ve lo pe d a severe case o f chloracne After contact with tetrachlorodibenscaioxin indicated the p o s s ib le c a u sa tiv e function o f chlorinated dibcniodicsir.a (diphenylcne d i o x i d e s ) . Further exprimenta with r a b b i t s ' cars showed tetrachlorodibcnr.odioxins, especially 2,3,6,7-tetrachloradibcnsodioxin, t o bo very h i r h l y ctive. Three or four p a i n t i n g w i t h 0 , 0 1 - O.CC55* s o l u t i o n s , a p p l i e d a t i n t e r v a l s o f J to days , were found t o Vo s u f f i c i e n t to produce s ev e r e in in u vcatlon and f o l l i c u l a r h y p e r k e r a t o s i s . A s i n g l e doso o f 0.C5 - 0 . 1 mg/kg (per o s) r e s u lt e d in s ev e r e h e p a t ic c o n d i t i o n s , and, in c o s t c a s e s , in death within 5 to 20 dayn. Autopsy r ev e a le d distended n e c r o t ic t i s s u e s and engorgement o f the l i v e r . 47156  it 2: was shewn t h a t 2 , 3 : d 7 -t c tr a c h I o r e tl ib e n ; i. o d io x in can be fcre.cs from i-o molecules o f odium triel-lorcnhcnoxidc with the elim ination o f tvs e o l c e u l e s o f 7>*aCl. 2-to::c o v e r ; 2 , 36 7- t c t r a c h l creditor, sod 3 waj i s o l a t e d a s a by- product formed in the a l k a l i n e h y d r o l y s i s T t r i r a eh lore bens er.e i n t o t r i c h l o r o p h e n o i . T h is o b s e r v a t i o n l e a d s t o the c o n c l u s i o n th at t c t r a c k l o r o d i b e r . s o d i o x i n i s r e s p o n s i b l e f o r the or. fcascs o f chloracae i f not e n t i r e l y , c e r t a i n l y to o considerab le ex Ti sheuld be added th a t n e it h e r pure Z . ^ J - t r i c h l o r o p h c r . o l r.cr pure per.tachlercphenol c oul d ind uce the e xpe ct ed symptom on r a b b i t s ' e a r s . I t is therefore probable that thr reported1 cases of ehloracnc, c s i e n s i b l y r i s i n g a f t e r c o n ta c t with pentac'nlorophcnel, were caused net by t h i s compound, but l i k e w i s e by t o x i c .by - pr odu c ts , r e l a t e d to those examined in the present work, e s p e c i a l l y s i n c e pentachloropher.cl i s prepared from hex*chlorobenstne by oJ.kalinc h y d r o l y s i s , n slo g c u s ly to the preparation of trichlorophenol. `eremccs 1 K . t t '.x u n j I f . J . JUmrr; Jr.J. >|,,). Sug 70, I I * . 1951. 2 IT.; Ck)*i..e. fa iiia r. ..v l,rf;^ UMt. 195V i C x m m r r . ;/_ 21.1. Arbcil> > luin /rL fii* c l.u ii J. 74. 1955. i t l l t < t k t i m r r , X*_- M in c h . m r .|. 'S'tclir. JC. 273. 119?; Yc/io n d l. V I I . V;. D rim a l. C*. I l r c U 1901. 157. S //. 77 ,,, nil TT. / On,: 7.11. Arbcium ru.'ii'* A t lr.i*.CJiui j It';. 1957. i I* ./.., K .: D in a . ^ H 0 % Ji91, l? 3 l. S i Au/j, A . //..* V n r. X a i II. D u r k . D rn fiilu iik ^tii* K * ; r t 0 7V.cn v .m 75. hi 77. J. 1974. 7 ' 1 ' i j . L.: XU.. f , : K i . t . 315 u..d *97. 19.; 7, .14, J9*3; 7, !;1 , 1919. -- Tf'i u t r : Zbl. C cvtrl.ci.*ji< c i , ]00, 19)1. 7 . S c h u ls , K.H., Lecture d e liv e r ed * t the 23rd Congress o f Ceraar. D e r m a t o l o g i s t s , Vienna, Hay 23 - 27 195& |jP-oo) OCCUPATIONAL- ACNE .Translated from German '('Chloracne, i s o - c a l l e d ) `iby iJ.; ..Barandy B y K l m m i g ..& Schulz c .Derraato.log'ica.;l.T5, 5 ^ 0 , 1957 . A m o n g the.' 'different chemical'land, p h y s i c a l t o x i c a n t s whj /. caus.e; skin., acne., d n d follicultls.i 'to/a.'pathogenic extent, i chipr.inate.d.`products .'and byproductS..:ha've.;be'.en playing .an .. Important. -role. "' `; ' .'.'..The', first- s u c h cases.' pf- i l l n e s s e s 7,. i n d u c e d - b y .. c h l o r i n a t e d - m a t e r i a l s > . were.o b s e r v e d /ar.o.undi the end. of .. ; . the -century, in ^.connection :with,-.the"-newly ^introduced- process. . of. -obtaining c h l o r i n e t h r o u g h eiec-trolysi?./ Th e 'o p i n i o n ;. whi;cii ^Herxh e i m e r expressed,-'-but 'lateh'.''changed, :was that-. ' ...free,-;chl;ord1n e :,was; the cause,'of "l'lln'es's.es;,->and. l e d - t o the ' ..v . , . ' '... t . ' . . / . wide spread:',mi'sus e of the'word ''chl-orache:'''.in! German ` ' ,' j > * .'i. . . . . . ,'.* ' i ** : . 1 * / 1 . ; 'V ,V ... l i t e r a t u r e ' 1 i n c e u t h e - - I n t r o d u c t i o n o f ;.chlorinated:'naphthalene, ' -V - ; =`:'-v ^ \ ;' which,.'due.i to its. advantageous-.-|?echi?i'c.ai .properties- .(like '- '" a c i d resistance,-'.fire-water .repell'ency-i-good i s o l a t i o n ' capacity,-'etc.-);a p p e a r e d In "different''Indus trial'applica-:- ..'.Vi -.; .. ; , tIonsj." t h e / o c c u r r e n c e of ch-loracne/.'lalso-lias.increased. ': (.TeIe.ki,;Braun, '.Grimmer,etal) .Wauer.&.'-Teiekl identified.. .'. thes.e',-illnessesw i t h the q u i t e .I n a p p r o p r i a t e w o r d " D e r n a d i s e a s ', More ' c o n t e m p o r a r y are-' the ;:o b s e r v a t l o n s : of i n t o x i c a t i o n s . f r o m - p e n t a c h l o r o p h e n o l p r o d u c tion',,".' wher;e''pentachlorophenol . . ; In contac-t;'with' the skin, c.aused;;ch'lbrache-.: A l t h o u g h for ,. *. these-'c a s e s ,' the pentachloropehh.ol'.itself- c a n b e - r e s p o n s i b l e , . / we.-will, h a v e .to- c a r r y on f u r t h e r -i n v e s t i g a t i o n s = f '.* '. ::-- rxoxxrrd_ri. t I / w O A -- K -i J L 4 ' . , . ' .I :- v . ; ; ' ; ! 7 3 2 5 S i 171S8 -2 - .'Th'.actual-.pbservatlons-tol'.whid.h.:w 'by. experiments could ' .achieve '--were .'performed on wo'rkrg ;of yo'ne ..-of/the chemical. ' fact pries,.-Ifl' Hamburg, engaged; in. th .production 'of' ' 2 , h j 5-'*rCCP: and '.ics'endproduct-. !th e krb-ic ld' :2 i4,5 - 1rich! or o - :' ' - .--V':'-V ,\ . ,;y '..'.'phnoxyacetic 'acid"and its \e ter'syVt.-A; :t.o/tais'.of.3 1 p e r s o n s : became/.sick/ ;from. which '9 .showed;>ide'spradJ` heavy- deforma- :tins'j-':T4;-persons.* .general*:Qpn^i'ion.Sidqt-er^rated,and 8 . '; v 'iv*-'y-., y-.-: ..persons,'showed only minor.;changesw.'".' .-.' '. Th. clinical-. appearances; developed .'in:summer and Vautumn- of .`On one worker/'..obvdou'sly-;.heavily; exposed,-' ; symptoms-'appeared ,:flrst as'a:dermatitis.-on .:the. face, '' accompnied:by, erythema (redness} ,-'and, swelling'of the fape,/after}which-conditions/on ;;the/fac.e ,'acne. (like deforma-. ' . tions) 'developed. Still later., '.other' typs--pf'.pustules; formed, r In.most, cases/ the symptoms; appeared Vas`-blackheads .'in :the beginning^, while in the-:lattef:;.stk^eJ:.bolls developed." ;''on the cheekbone, region, without.'.acute.-dermatitis .-As-.-far-.as 'the first ;observations'yof,'these skin ' deformations,`are oneerned,.-they..''co'uld.. be.composed of 'Innumerable./blackheads, and/pr- retention-'.systems wit h size. ..varying-'from./pinheads/to lentil;;- of fplliQular ' .'-bond h y p e r k e r a t o s i s , of inflamed; boils'i-vpr/'.Qf 'f u r u n c l e s .. In;, ali.-c a s e s / -the inf e c t e d .parts; w r e ;t h e -face, earlobes,- ,; . . ' ` / . , .- ;i'.. ; ; .'. -,;-, ' . .. necks while '.in heavier cases,' the symptoms ..'spread on -, the. chest,-.-back, .abdomen, -sides/ .Upper/'ieg and on' genitals., ; :'in.'.general'-, ,:the a l l o c a t i o n s .of .thse ^eruptions were'.unusually 'thick, to such 'an 'extent: that-'hardly a * ;-3 S5 i s - ;* . ' 73 :2 5 7 17159 a.' follicle, ''remained undeformed."-While.;'m o s t b l a c k h e a d s V.\* ,arid retentlop systems have.;-:l?een;:.qbaerv.eidf;bri.,-.the face,. .' '' .types, o.f /secondarily infected-, eruption's/-('f.uihmcles) were . 1 , * *i.'* . ; . '* '1'1* *,'**^.*1* quite frequent', op the neck '.and'pn^.the'vtrxan^.l'of the bo4 y v ' Several-.patieri.ts.'.-- besideis'ithese*-skin',Reformations ^ -. developed- chronic' eyelid .c.onJunetiyiti?'.:'- Generally, \ .the 'other; c o m p l a i n t s of the.'patients.'were.-loss of appetite;,-;w e a k n e s s in t h e .l.ejgs-yahR/other;'s y m p t o m s which- 'y-'S'indicated.-aR-overall intoxication'.;. v; r' -The ^further, clinical^.examirta'ti'ohS; .reported d a m a g e - / . of. t'he/liver',. d a m a g e of c e n t r a l .-nervous .system a n d - d a m a g e ' " of, thp; blpod-rec.overy system, .alsp^, S e v e r a l 'patients' suffered.'hypoacidity (less.'acid): i n their'.'stomach Juice. ;' A,-week or so l a t e r , ' due' to ,, a g g r a v a t e d cases, in'te.rnar-'ahd n e u r o l o g i c a l examihation^-.; were..'resumed on. s e v e r a l / p a t i e n t s . This- time-,; 'indipatl'ans--.proved l i v e r ./ . . damage,1'i'n;'three-cases . We. ,'wlll;.not;.describe her e the.. . .details1 of .this c l i n i c a l r e p o r t . : : : . : Th.e- duration of the illness; .proved ;to.;be long and endurii' Although .'there was not any. contac.trwith.'the-.toxic-sub-, stances-,'-'despite .intensive;'lnterriai'.'ahd external therapy, even. 1 5 -:$Q months after the ;beginning-,,';marks 'qf skin deformations:kept appearing.. ."'I \ //Investigations '.of 'th,causer (ethiology) .'; Animal' e x p e r i m e n t s h a v e .been, 'conducted in o rder .'to flnd-.the'.toxic a g e n t c a u s i n g :the'.'illne.ss. As test objects, - i-, :: - i / ;7 s a ; lVl60 I -4- the rabbit/s ear.-was found '-'th-Ihost/aui'-tabie.; on which- i* ' '.. t 1 .*V. , V V J| '.*.*)<* .'.*'* !' ; Hoffman;, Neumann,.-Braun,. L a n d e s , ' . e b a ' l h a d -already ."worked; with;, chlorinated naphthalene',:paying/induced ... .'ap,pear*ai n*ce*s.';* si-.mlia' r to that/ of.'hvHnap :h.` io..'.r...a...c....ne. ;T he ' ** ' ' i * .internal'.surface'of one ear.-was/di'ly-i'treated by the. I*. ..* : '.substance '.'suspected as -the:'cause.;,of4chlorcne. The # ; substance.: was dissolved in ;'pbiygi'yc,olv//The.'.-other; ear :'V .. las- control--was- treated only-/with:'the.-'sdlyen-t. (polyglycol). .. .V,;',lri\:ppsitiy-e!'::cases; th/ tests, i*e's.ulted":first (within ' . "2-4 -weeks ), in-`flat -spread- inf lamination -and'.ays later; 'swollen follicles^:.hyperkeratosis ^ d . smailV.-cys'ts,'' ; ; H i S tolgical findingshaye-/been-:.-Acanthus, /like wfdenfng :pf.i.the pidemisyadma.ta'-ahd^c'ios.iy developed, cell infiltrations in the .cuticle-, .`'-the..:enlarged follicles. - were filled1with' keratoid m a t e r i a l i r V p l a t e r phases .. .thse'.-developed ,themselves'..into--eyh''.:iargr'::cysts . . /'As--the .a.lniost two years long research," carried on -with .more -than 1 0 0 substances .with-'the 'rabbit ear' test i , . indicated/'one can safely-m ake stat.nie'nfs .about' the ' ' ' -, . ' v.v :: . chloracne-causlngeffect of/certain'Materials-. ; "' -The-first'results preSenfedhby :u'sj'Vhad been reported; at. the 23rd-German Dermatological.-Congress-`in Wien (Schulz-). . The rep'ort .first pointed o u t 'that -it'i's'.hot.-the .2^ 4,5--' 'trichlorophenol which -is the', cause /aa/tyas.' originally :. .believed-/,'.because- treatment -with-.'ptire-...2 ,.4 /-5,frfcrlchTor..ophenol . 73259 171JB1 -5- - r (5# poiysiycqi-- solution) did not;..Show '.ahy.'.observable appearance's, 'op..rabbit *3 ear,'.'.but .treatment-.-With ' *t.-./ -t. . ' ' technical 'product': did cause/chldracre , Because the ; . .s tarting; product, 1 ,2 ,4, Srtetrachipr'obenzene' spread on'.the' rabbit 's ear has been without-e iffOct; we- h a d 'to assume that/-the. .toxicant'we'./aie1.'searching\f or- must. be. one ,'qf-th ,byproduct^, generated b y :alkaline:hydrolysis! from ,:1 ',2-,4> 5 - : 1 -,/-.,` .1` ' ! ' .`I'- .'v';' . ' .... 'te.trachlp.rpbenzene t o -forro^^4,5-;triehiqr.qphe.nol. ' /t- ..Because -.it:;wasn't possibl'e- -tolisolate; th e byproducts frorn.the'.'residue,'. we looked- for,'.cpmpQurids,-.-within- reason, " / =; - | V 1' : V '/'; \y\yy.'-. V.: ' ' that 'cduid/'forni''.from the 'Saponi'fIcat'lpn.-ofi `tetrachloro- benzene: .at ,i80C..' At first,1' t h e r e w a s .made..'available . to us- some ^chlorinated products-.Of;-diphenyl, e t h e r a n d "dibenze^uran. .' .'!' - ; - '. .'While t h e ;.'c h l o r i n a t e d 'derivatiohs.-ofI'dlphenyl ether, ?. nonsubSt.ituted ' * ,*. * a.ri,,d m o n o c.h*l o r in * a te d/' '* d i b e n z o f ur a n I n, the ' animal, t e s t - p r o v e d ineffective,' ith'e. trichl'qro :a n d . t e t r a c h l o t o d i b e n z o f u r a n in;-a boncenfrafeep-f 'O..05' already-.induced-described deformation's.'. B o t h of .these omp'ounds have- strong liver, p o i s o n i n g ' c a p a c i t y . ' One dose of. . 0:5-to. 'i.O'.' m g . per.kg b o d y W e i g h t talpen. O r a l l y by- the-' r a b b i t d / r e s u l t e d - i n s e r l o u s :/liver ^ i n j . u r i e s B u t - so far, 732S 0 17162 no-one.c o u l d ,detect chlorihated'ldifceriz-pfurane in the . /- }.byproducts .' " ;.\- '-V; : The `C l i n i c a l observation: of one.'-worker, w h o ' a f t e r the; exposure-: to; tetrachlorodibenzodib^ine 'became.. ; '.: - * - ; * : . ' ' s e r i o u s l y dll. of ;chloracne-,V^ointedv`i'to,!`,chlorinated . .- : dlbehhpdl'qxlne '(diphenylehe.dipiid-ej; ;a^;::art! i m p o r t a n t ' ' -causing ^agent.. .As further': studies Vindicated; t e t r a - ' v 1 :v . . chlorinated dibenzodioxlne; 'especially.:2y 3 ,6 -,7 -tetra- ` ;V : . ; ' c h l o r o d i b e n z o d i o x i n e , infe.c.ted;thev r a b b i t '? ;ear with' * V ; . an- unusually strong vigor Three -to,'four- times . brush ing.s w i t h . p . O l - 0.0055? solution-' Within- 3-4 'days.--. . ' ; v 1' v :v'- . were' sufficient.,to cause 3 e;rious ;;swe.iiings/'als.o abnormalities.' of fbll-i.cles, `accompanied- by ..hyperk-protitle.' deformations. - . One. oraliy-'.admlhistered dose! {'of- P.s0*>*:li0..i;.;mg/kg' body . . weight'.resulted'in heav-y liver-.injuries -'Most of 'the . j : animals.-'treated.': as above .expired-,; within-8 -2 0 .da y s :after .' f . ' ' i . . .* , ., , . 1 ,. i' i , . ' , . ' .. ..treatment. ; Autopsy found, extensive;-nd'cr.c?si,-s _and fatness of .t the- liver.;. '/ ' ". Meanwhilej.lt was chdmicali-y, Proven.-that 2> 3j 6/7- ' : :.- -i . .. - ' v. ' 1 " tet.rachi-orodibenzodloxlne-.'lt.seliif.qrms'-.-from', two m o l e c u l e s Na-triChlorophenate, splitting' dff' twp--,moiecules NaCl. ' '. ''.-. V -. . . Furthermore,- we, succeeded.in isolating ;2,3,6, 7-te.tra- 'chlorodibenzodldxine from 'the byproducts /-.-.produced by. the technical saponification:of-;.,hetrachiorobenzene to trlchlorpphenol-J. .On the ground-'-of .'thi'S'-ilnding,. we. are - ; able to ".conclude-.that this .t'etrachidr'odlbenzodl.oxlne is ; 73261 lVl63 i' t : -7- , . responsible ,- if.-not entlrely;j at-least essentially, for. the .observed -illnesses' due to chloracne. .V * , i In. conclusion, be reminded that .'application of pure'-2 ,4;5-trichlorpphenpl and p.entachlprophenbl on .rabbit-.' s- ears 'did not' induce' any described symptoms whatsoever.' -.Therefore, it .is highly probable that " the; published chloracne cases caused- by "pentachlorophenol (Header i ;B a b e r ).--actually iwere not'-cause'd--by "the 'compound itself)/.but likewise by tp^cic byproducts-,,- ' These byproducts were in. .the submitted substance (penta.) because the manufactur- .* ' i * ing process'of. pentachlorophenol .is =similar to the process of. irichiorophehol, an alkaline hydrolysis of hexa- chlorobenzene.. . , ,1 . SUMMARY ' Amongst .workers who are employed;'in the preparation of- 2,4,5^trichlprophenol and its 'transformation to 2 ,.4,5 -' trichlorophenpxyacetic acid or Its .esters, -31 cases-of- ' . ' , _ . * i i * "... sp-called; chloracne were seen. It'.`could -be 'shown . ._ experimentally 'by brushing -into'a rabbit'-'s--.ear, that it 1' ,i . ' ,* -..' 'i , Is not itrlchlorpphenol itself bub a'toxic product formed b y t h e ' a l k a l i n e h y d r o l y s i s ' o f 1 , 2, 4 , 5 , -tetrachloro'oenzene to 2 , 4 , 5 -brichl'orophenol w h i c h is- the ..cause- o f the chloracne. From the'.synthesised combinations,-which'-might come in questior t , 1 1* 3 -.and'4 'times c h l o r i n a t e d dibenzofuran. and- a lso t e t r a c h l o r o - b e n z o d l o x i n e p r o v e d v e r y active. 2-,'3,6,7 -tetrachloro.dibenzo- dioxine was .isolated out of the byproducts.and the possibility 1o f t s 'f o r m a t i o n from N a - t r i c h l o r o p h c n a t e is proved. 73262 1716 4 r ~T(J:I. E. Getzensas^r- Technical Subcommittee NACA Herbicide T H E D O W Committee CH EM ICA L M ID L A N D M IC H IG A N C' CO M PAN Y MAIN LABORATORY REPORT SHEET 5 March 1 9 to ' DATE charge. M AIN LAB. NUM BER . YOUR NUMBER DESCRIPTIOiNn v e s t i g a t i o n of method:-- ^or ;he d e t e r m i n a t i o n of 2 . 4 - P in the present cT c h l o r o p h e n o l s and/or' dth'er'~Tmpurities ANALTSES OR TEST The problem, as presented to this laboratory, was to develop a method.or methods of analyses for commercial 2,4-P and 2,^,5-T formu jlalior.s that will d e t e r m i n e the 2 , 4 - D a n d / o r 2,4., 5-T. content ; It was desired to have a m ethod or methods, preferably one which requires skill and equipment that are not too involved, that will determine only the respective phenoxyacetic acid in the event of possible adulteration, contamination, the use of a chlorinated s o l vent as part of the formulation or possibly the presence of other acid:-;. i The following report is based on the work done by this l a b o r a t o r y , at y o u r . r e q u e s t . It is o ur hope it will help towards solving some of the p r o b l e m s m e n t i o n e d a bove ;. / T h r o u g h c o - o p e r a t i v e a c t i o n w i t h o ther m e m b e r s of. the c o m m i t t e e perhaps, a set. of m e t h o d s c a n b e worked out that will meet the needs of the. Industry'. T his report is not ar. e x h a u s t i v e study of the p r o b l e m but it is o u r ideas and., a p p r o a c h based on the a n a l y t i c a l e x p e r i e n c e we have ha d w i t h 2 ,4-0 anc 2,4,5-T formulations; One..problem,. as we see it at present, is the determination: Of the 2 ,4-1) o r 2,4,5-T, e s p e c i a l l y 2 , 4 - p in the p r e s e n c e of u n r e a c t e d chlorophencls: Our analytical work with competitors' formulations has turned up a few that contain an excessive quantity of chloropher.ols that have appare n t l y been calculated as part of the total 2.4- D content. The AOAC methods, 5:ip3 and p.13^ (JAOAC, Vol'VIII, 1955) now being used, will determine the total organic acid content in.the case of amine formulations or the total chlorine content in the case of ester formulations. These totals will be calculated as 2.4- D cr 2,4,5-T respectively; The AOAC methods are entirely s u i l ^ able when a good grade of 2,4-D or 2,4,5-T acids are used to make the formulations. However, when a crude grade of acid is used AOAC method 5-155 falls down in that it shows a higher value for Y DS 00009969 UCMED 17.165 -2- _ 5 March thfev2,4-D-or 2,4,5-T content than- is actually present.' .The: re for-' thia is, that in a crude a c i d .some unreacted phehoQ.,3 2 ,:4 -f chlorophenol in the case of'2,4t B-,. has' not. been remo v e d ;and th compound is.acidic" enough to titrate with a base and-contains high: chlorine content. . I Amine Salt.Formulations .; The.-AOAC"taethod for 2,4-D and- its s a l t s M s gi ven--below: fc information purposes. \ 5.133.v- 2,4-BICHLOROPHENOXYACETIC. ACID" (2', 4 - D ) ' ' ( ^ W - O F F I C I A L (a) .'In preparations of free acid with-no::insoluble carrier.--Weigh 1 g sample into 250 ml.erlenmeyer,''dlssol in 7 5 ml'neutral alcohol, and tltr:. with 0.1 N NaOHyHusir. 1 ml phenolphthalein, 2 .1 2 (d).; (1 ml- 1 # a l e . -thymol-, phthalein soln may be substituted, -provided this lndiaa- tor has been used to stdze the: alkali.). .1 ml 0.1 N NaOH" = 0 .0 2 2 1 g 2 ,4--dichlorophenoxyacetlc acid. V (b) JIn herbicides containing free acid'and lnfeolubl carrier.---Weigh sample equiv. to 1 g of the: acid into:-v 250;ml .beaker, add 25 ml normal-.NaOH'and 50 ml.-HsO/:warnr1 and- stlr:1 5 min. to dissolve, acid, and .adjust to r o o m p . temp,,-.Filter thru paper into-250 ml separator and-wash h any lnsol.lmatter,',collecting washings .in separator.''* Neutralize contents'of separator with lO# H2S0j and 10 ' m l v'excess, and ext. with two. 75 ml-portions ether.i*.Corn-;' bine 2 ether exts.in separator,."wash f r e e 'from HaSO-^ -v with three -10 ml portions H2O/ and filter thru cotton':': pledget (previously, satd with ether) into 400 ml beaker.. . Rinse separator with' ether, and filter rinslngs-cthru, the cottoh Into beaker. To contents of beaker add 25 ml::, H 20;-and fevi boiling, c h i p s , evap.-on steam bath until -ca 25 thl'i'ether-remains,:and then remove balance of/ether at room tempv in air current. To resldual aq. soln.: a d d '100 ml-neutral alcohol and titr . with 0.1 N NaOH*'/ as in ( a $ . ; ,< (c*) Vln1herbicides containing salts of 2 ,4-dlchlorophenoxyacetlc acid.--Weigh .'sampleequiv. to ca .l g of / the free acid'and dissolve', in:-50 m l HaO. if lneol... carrier is present, filter thru paper and wash reaiduAt.:. Transfer clear soln to 250 ml separator, and proceed- ` ae In (b), beginning 'Neutralize contents of separator. Proposed Method for Amine Salt.' Formulations Perhaps; t h e :slmplefet method of analyzing for 2 , 4 - D acid in the presence 6 f 2,4-dlchlorophenol is:, to use the above AOACmethod a n d determine'.the end point with a different Indicator, or preferably'.by the -use of an electrometric titration.': The '" ' * DS 00009970 -.17166 -3 - ) 5 M a r c h 19 accorapar.lng curves (chart) show the effect cf the prese n c e of 2 , 4 -dichlorophenol w hen t i trating 2 , 4 - D c-. n t a i n i n g 2 , 4 - dichlcroiih- It can be seen the 2,4-D gives a sharp break from about pH 7 to pH 10 w i t h a m i d - p o i n t at pH .5- The Indicators n o w used, p h e n o l p h t h a l e l n (about p H 9) or t h y m o l p h t h a i e m (about p H 10), catch this break very nicely. As the 2 ,'4-dichlorophencl content : increased the break becomes less sharp. With 10% of 2,4-dichloro phenol added there is one break for the 2,4-D at pH 6 to pH 7 and t h e -2 .^ - d i c h l o r c p h e n o l continues to titrate and then g ives ancthe: break at about pH 10-. 5- What is proposed, is to titrate to an end point cf p H 7 potentiometrically, or use a suitable indicator, such as methyl red and calculate the per cent 2,4-D from this titration'. This end point m a y give s l i g h t l y l ower values f o r 2,4-7 or. a cids c o n taining no dichlcrophenol and slightly higher values for acids containing dichlcrophenol-. If the titration were continued from pH 7 to pH 1G one could tell w h e t h e r there was an y 2 ,4 - d i c h l o r o p h e n o l present by the nature of the break. If the break was sharp chlorcphenols could be assumed to be absent and the regular end point could be used for the c a l c u l a t i o n of per cent 2,4-D. Ir. the case of a large d i f f e r e n c e in t i t r a t i o n betw e e n p H 7 and pH 10. tie pH 7 end point could be used with the realization that some a c c u r a c y is forfeited for the benefit of screening out the chlorophenols. An inspection of the table given below and the a c c o m p a n y i n g curve will illustrate the above points; Table I Sample % 2 ,4-D pH at T h e o r e t i c a l % 2 , 4 - D % 2,4-] (Theory) end point at pH 7 at pH I Do w T e c h n i c a l 2,.4-D ir 2.5% 2 , 4-Dichloropher.ol a d d e d 99-4 96.? , 8,5 7-5 9 9 -C 96.5 99'.`7 100.4 h i 5.-2% 2 , 4 - D i c h l o r o phenol added 94.2 6.7 G4.5 101:9 IV 10..2% 2 , 4 - D i c h l o r o phenol added 89.3 7.0 89.3 103:4 TI Ester Formulations A question arises. Doe3 the unreacted 2,4-D 0r 2,4,5- T which is often present in ester formulations court towards the acid equivalent of the ester? We at Dow have been making a separate free acid analyses, when necessary, and correcting the total acid DS 00009971 17167 - if 5 M a r c h 195r equivalent for the free acid found. It appears that some companic are. c a l c u l a t i n g all the 2.4-D cr 2.4-,5-T present in their figures for pounds of acid equivalent per gallon as indicated by the anal> ses of their formulations.- The present AC AC method-for ester, f o r m u lations a p p a r e n t l y justifies this.. Hpwever, the d e t e r m i n a tion of free acid is a simple m a t t e r with most formulations. Propose! Method for Free Acid Content 1. Principle Th e free aci d present in e s t e r f o r m u lations is d e t e r m i n e d by. adding a sample of the formulation to alcohol and titrating the a c i d i t y with standard s c c i e m h y d r o x i d e to pH 7, 2. R e a g e n t s (a) S o d i u m hydroxide, 1.1 N standard solution. (t) Alcohol, 95^-. F o r m u l a 30 or F o r m u l a 2B, 3* Apparatus (a) pH meter. B e c k m a n L a b o r a t o r y M o d e l G, or its equivalent with a glass electrode and calomel reference electrode.. *'. procedure W e i g h a 10'. 0 g ram sample of the e s t e r f o r m u l a t i o n int o a 250ml'. be a k e r and add 100 ml-, of alcohol. T i t r a t e the free acid poter.ticmetricaliy with 0.1 N sodium h y d r o x i d e to pH 7- 5- C a l c u l a t i o n s (a ) 0._1 _H _NaOH _x_ %;0 > .00 free 2,^-D or (b) ml. 0.1 JC NaC H x 0. 0 2 5 0 x 100 1 '' % free 2 ;*,5-T Discussion Chloropher.ols have also been found by this laboratory in some e s t e r f o r m u l a t i o n s now :,r. the market. T h e s e f o r m u l a t i o n s a n a l y s e d in the o r c e r of 2 to 3% c h l o r o p h e n c l s on an e x t r a c t e d aci d basis by b o t h chemi c a l arid infra red m e t h o d s . This w ould raise the acid e q u i v a l e n t ar.aly-is of t h e 'f o r m u l a t i o n s a b o u t 1 to 1 .5# on the usual 3-3^ or ^.C- lbs. acid oq.. p e r g a l l o n formulation.- An extraction method is presented which could be used to supple ment the AOAC methrd when the presence of chlcrophenols is suspecte DS 00009972 17168 CD 5. 5. K a r o h :1956 This procedure is based on-the e x t r a c t i o n and isolation of the acid after the ester has been saponified followed by the acird-base titration. The same comme n t s a p p l y to this tit r a t i o n as t o `the tit r a t i o n in part I. It is r e c o m m e n d e d to the com m i t t e e that ;the f o l l o w i n g m e t h o d should be inve s t i g a t e d f u r t h e r as it appe a r s to wor k f a i r l y well'on .m a n y f o r m u l a t i o n s but one cannot be sure that 'it would work equally well on ail formulations.' The main difficulty arises In .trying to break the emulsions formed by wetting agents -whose c o m positions are unknown to the analyst. Perhaps through'co-operative effort this problem can be overcome. Proposed Extraction Method for 2,4-d in Ester Formulations 1. P r i nciple The 2 , 4 - D e 3ter p r e s e n t is sapon i f i e d with alc o h o l i c K O H solution. After evaporating off the alcohol1 the solution is a c i d i fied and the 2,4-D is extracted with methylene chloride which is evaporated off and the acid is titrated with 0.1 N NaOH. 2. R e a g e n t s (a) S o d i u m hydro x i d e . S t a n d a r d 0.1 N soluti-on. (b) M e t h y l e n e chloride, p r e f e r a b l y redistilled. (c) S u l f u r i c acid, reag e n t g r a d e , 1-4 dilution. ((d). Me thy i orange indicator. '(e)'.Methanol, ACS grade or other suitable alcohol. ((f) M e t h a n o l - K O H solution. D i s s o l v e 12-14 g rams of K O H in w a t e r an d a f t e r ..the s o l u t i o n has cooled'^to-room'tempe'rature d i l u t e to 100 ml. wit h m e t hanol. T h i s s o l u t i o n is s t a n d a r d i z e d 'a g a i n s t O . lN'HCl using phenolphthaleln indicator. 5. P r o cedure .'(a) W e i g h accurately, into a 125-ml. sotfhlet e x t r a c t i o n f lask approximately 2.5 grams of sample. Add a sufficient amount of m e t h a n o l - K O H s o l u t i o n to c o m p l e t e l y s a p o n i f y "the sample. (b) Add 25 ml. of m e t h a n o l and 20 ml. of w a t e r and a few boiling chips to the solution. Connect the flask to a water cooled condenser and reflux on a hot plate for 1.5 hours. '(c) R e m o v e the f l a s k f r o m the c o n d e n s e r a f t e r w a s h i n g d o w n with water and then cool. DS 00009973 17169 3 r 0 5 March .195 a(.i) T r a n s f e r the- s o l u t i o n to 400-ni. beaker, w a s h i n g out the e x t r a c t i o n flask with methanol. .Flac,.- the bea k e r on a steam bath- and evaporate off the methanol. .(e) Ccoi the b e a k e r and wash the w a t e r solution into a 3C0 ml. p e a r - s h a p e d s e p a r a t o r y funnel. Make acid tc methyl crange wit h 1: H 2S 0 4 . Asa 50 ml. of r e d i s t i l l e d met h y l e n e chloride and. shake ... thoroughly. A llow the layers to separate. Draw off the methylene chloride layer, and w a s h It w i t h 25 ml. porti o n s "cf- d i s t i l l e d H 2O to remove the m i n e r a l acid. Extract the w a t e r layer twic.e more w f 50 ml. portions of methylene chloride as above. Combine the washe; m e t h y l e n e chlor i d e layers in a 400-mld beaker. : Add 25 -ml- ofi.watei ciand a f e w . b o i l i n g chips and e v a p o r a t e " o f f the m e t h y l e n e c h l o r i d e a steam bath. . {f ) 'Cool t h e - w a t e r m i x t u r e and add ICO ml. m e t h a n o l `to -dissolve th-_ .c-x^racted acid. (g)'Ti t r a t e w i t h 0.1 N N a O H .taking readings at pH 7 an d p H 10. 0.1'N N a O H *. 0.0221 x 100 * 0 ^ ~ ~ r r -- = *.2 '4"D The fol l o w i n g .table s h o w s sthe. results o b t a i n e d by this method. Sample T a b l e II fc 2,4-p to pH 7 i . De w f o rr.u 1 a t io n . 2,4-n =. Zl.21 by s p a c il ic 0tion ana j.y:;is . ( saper if i vat lor.) . 24.5 24.4 l 2,4-p to pH 10 25-0 25.3 2. D-..W L\*rmu I->t ion wit h 5 v 2 4-dichicrophenoi ada-sd. 2,4-P = 2j.9^ ('-a leu la ted ) 24.1 24.1 30.8 30.8 After the acid has been extracted and dried the impurities p r e sent can alsc. ho d e t e r m i n e d by an infra-red o p e c t r o g r a p h i c anaivei: if the equipment is avallai i o . Ill The Determination of 2 , 4-Pichlorophenol in Form u l a t i o n of 2,4-D The m e t h o d p r e s e n t e d b e l o w w o r k s v e r y wel l with, a mine salt; formulations. With ester formulations some 2 , 4-dichlorophenol is indicated ever, on samp l e s that are k n o w n to c o n t a i n none.' T hus a value of up to 0.5 - 0.6;* does not a p p e a r tc be s i g n i f i c a n t in the cate of esters. The reason for the high values is not known as yet. Each constituent of an ester formulation was determined sepa r a t e l y without s h o w i n g the p r e s e n c e of 2 ,4 - d i c h l o r o p h e n o l but the f o r m u l a t i o n m a d e f r o m t hese m a t e r i a l s showed an aBJ2arent value cf Q,z%. DS 00009974 K-V, r t; v v- .. .v <* kk:'* 0 0 .....-v ._-._!L _____ _____ _______ 5 .Marsh 195 : Scope v Proposed Method x * .+' -t - * :r 4- UH . *< ' i- * This method is applicable to the determination of 2 f4~dichloro.phenol in" the presence of the oils,'amines/ esters, and wetting agents used in the various formulations of 2 ,4-D acid. Principle The 2,4-dl'chlorophenol is 6team-distilled frdm an aqueous acid .mixture and the distillate i3 collected in a receiver containing .ar aqueous base. T h e amount bf'ipdine that will react with the 2,4-d: i-chlorophenol, producing 2 ,4-dichloro-6-iodophenol, is determined. 3. Apparatus' /a) A standard steam-distillation-apparatus filled with a 500 ml. distillation,fTask. ... (b) Erlenmeyer,-flask, .500`ml. '/.s -- " \ 'U-. Reagents "^ .... (a) Sulfuric .acid,'approximately 2 N solution. Pour 56 ml., of concentrated'H2 SO4 {97$) into about 800 ml.,of/water and dilute the solution to 1 1 1 te^*. - -. . . * v*,T **,v~ k Uy (b) Sodium carbonate* approximately 1 N s o l u t i o n . Dissolve 58 grams of anhydrous sodium carbonate in about 400 ml. of water and dilute-the solution to 500.ml, '- 1' ' ^ <n* . - vt (c) Todine,- 0.1 N solution.. Dissolve 12.7 grams of Iodine, and 27'.9 grams of potassium ibdide in about 100 ml. of water and* dilute the solution to 1 liter'..4 . * *'* -^ ' ' '*--/* -V +' */ -. w s T i* - >r^'- .*>.'-a .rV.*k>-- / f . '(d) Seaium/ thiosulfaipfi-0.1 N standard. ''Elution. ' i' : r\ (e).Starch, 'indicator &olution. .Make a paste with 3 grams of soluble-starch, in-about /15vml .'of water and pour the paste ij/lto a liter of boiTins, wat e r . Stir the water yntil .the stanch .has : dissolved.'/ > j 1 1 ^ *r " sf:. .Sw --R4.r''*o*a"edui reX.-w\1,--V' rVrf>V./1" 'V-J >r .:;*t ;a^ place -.ili to :3 gfarns^of saraple weighed to the .nearest" mi 1 1 1 - .t. gram., in the*-5p0rml.,distillation-flask." Add 100 ml-''of 2 N aijlfurl TEJf-V -itdid ,ladid attfteh the Tl*asic7to the-distillation apparatus. * -j i` \4. - I (b) Place':5*0 ml\ o f .1 ^ .sodium carbonate in .the 5 0 0 - m l . ~ / Erlenmey^r X l a 3 k apd use*, .the fl^sk as. ttyecJ?*ceiver on the distilla- . V *y 1-v * ' i-r. ' 1 jttlioonn a/apopoaar^aatutise.. . ' * ' Mr * . . 'V'v 5W' -*;* . .. < C^3 f i -- d-* -.>vin 1.- . n 1. ^ - -T; :v^'' ' ' .: DS 00009975 . ^ 17l7i V-' :: . V / W ; , * . 'I uijgj-.*;_ virJL-'.i*r- * ` ; * -'-'Sftafgh-igOv ........ . - -**1 -;:`L r'J \ ing th distillate 'hhdet*.; the' tdiutfion^Efcand for.*'5. minut^/ then, acidify the solution with, io m l ' o f N sulfuric acid*-.' * 'r. v * - *\ W.,-.- , . .'. _ r-;, * . . ' ~ ` * > _i" '" A: <- :-," .-# k (e) .Titrate the'-exces3 iodfifte' w i t h 0 .1 N- soditn thiosulft/ using -strh indicator solution. v v ^ . ; . v >* '' j\ ... : ' (f) Perform a blank titration >ae^dllows:'. ^jllace 5*0 $&1-. f Q N aodium carbonate and 15Q:'mi.. of-water in. the rlenmey^;-flask.' ; 7 Pipette 25.0 ml. af -.O.J, N iodine intd^tfie flask arid let -th" sol- > v tion Starjd f.or.5 minutqs.- Theri acidify the iolupiqn wifch'iiLO of 2 N sulfuric acid-and., titrate .th^. iodine with*OM. N vsodim -thio sulfate , using starch indicator'`solution* -:. . +. . 'w * 6 .'Calculation .~ ;r- . >: 'i V *> V .* . ,X (.a) -'mX-. *6 .1 N sodiuft thlpefclfate'.`tblank titration) - >iV sodium thiosulfate (sample, titration) - m}. 0 . 1 )i iodine. ufc.e$ to react with the' 2 ,^-dlciUortjphenpl-. . . < `.jjL-f '- ( *> S . ^ M ? C 0 '*iz 7.- Notes y. : : 'f V*--' vi ' (a).. Th. reaction beiwet 2,4-dichorophhl .rid'-i'odini lt.-at''3^ Yellows': ' v^7 * * * -V- Siv-.;' * ,\ *'.J*"* .i S vtT' OH " ` OH C) > > r 2 . u : Cl ^V. XI.. . . -< . J v.'hi '*4ara >*- .. ... A ^ . .. ~ v.a, r L Jt . . ...... ; cric 3> .-V ? - *" -- . .1 . - ,, 1 <f%5 *<.1 ' ' ne mole 'Qf ftidijne La eaulvalht t l.inole^pf ?j4-dldhldr0phfhol * i \ 4*i - . .>^ :% ^ - ( b ) ;Tiite'anal ytlcal procedure 1 * Tnat, specific, for 2 ^rd^phlorii*' ^phenol. Many other, jphenfcls* vflJ, readt^eimiltfrly. /' ' '. 4 ;.* I rn 1 ''*' 'I y^ ''r***' ' V - W .* *V` ^'* ; (c):The simple .used for the- determination:- hou^d.not-contin ; over .0 , 1 5 jframs of '2 e4-dichlorcrphenol,;.-;.i . . .tj * ' ' 1.' . ` ' - . : " .v>rr-v,s>*-v.frl*. ' ' . V. /.*> ^ '8 . EitewCture flei'erence . ."V. $' ' \:.p- Kohn, Sus smarm, \ -'M^iohatoh. .*r** .. (1-925 7 .-7T.* - v" ' ,-4y ' . . fi IV Conclusions ,* ?>. 4; From the preceding w o r k ;it cajn'he ^aeen thrnt the preserioe'o di- chloro^hepols In amine typa^iorraulations ^can pe,, Peadily detetd or, DS 00009976 \v i 0, o' ; -9 - Si March 1956 analyzed to eliminate any contribution it would make towards the 2,4-D content. However, in the case of ester formulations, a small quantity of dichlorophenols, possibly up to 1# in the initial acid, might go,Ui\detected or give results whose validity could be questioned. v I t ~ appears that any gross contamination would be readily detected. The above methods are entirely chemical and should be able, to b performed by any laboratory now checking weed killers by the AOAC methods. Those laboratories to which an infra red spectrometer would be available (such as state labs with access to university facilities) have another method of analysis. Using methods I or II, the 2,4-D acid and accompanying impurities could be isolated, and an infra red spectrum of the acid would show the amount and identity of the impurities present. An infra red spectrum could also be made on the formulation and compared with a standard to detect any deviation. Some users are already doing this. V Suggestions for Further Work 1. It is felt that the method for esters presented in part II should be tried in the laboratories of the other members of the technical subcommittee. Special attention should be given to any modifications necessary in order to make the method applicable to formulations containing the various wetting agents used. 2. The method presented for phenols in part III is apparently not the approach the subcommittee wishes to take but it is presented here for information purposes and for the consideration of the sub committee. Some work would have to be done to refine the procedure to give better results with ester formulations. 3 It is also suggested that the methods presented be tried on 2,4,5-T formulations with the hopes that they may be applied with little or no modification. 4. Some work is being done with the infra red spectrophotom in analyzing ester formulations directly both qualitatively and quantitatively. A recent article on the subject appeared in the Ontario Research News, Vol. VII No. 2, April-June 1955 published by the Research Division, Hydro-Electric Power.Commission of Ontario, Toronto, Ontario, Canada. It was "Infra Red Analysis of Herbicides" by D. C. Cordingley. The Dow Chemical Company cannot assume any liability in . connection with the use of these methods. DS 00009977 17173 M TU rr^ rrr ">7 V i i ..."2 ru*aicmx>H&raEitc>txii 12 ' I . ' *. * ;..i ''* tCurvft.l,; Tcolm lb al' 2,^-0 .. ;. ..-2 .51 2 ,^-Olciilorphenol Added ' i "!` ITT ,*5'.2^',z V A-'Di<?hloraPhel Added- 11 r r , ; : i y `1 0 ;.^ '7 > -T )lc ip o r o p h ito l 'ASded !: :1 ' ' . , t ..................t *f 1 * p- f - . * . i f "j r^ii --f -- -- i ^ iirH > -v V / A ; N !:^CH :peK-'ifn 1- . .. - ' ' .i : ? ; , - -r . . ' V * X T. * DS 00009978 r* t October 29, 1962 Mr. P. W. Jarvis Dov Patent Kr. H. P. Wilkerson RKt Kixsd Alkyl Haters of P.,h-D and 2,h,$-T V are attaching eoplaa of K. S. Weiner's lettar of October $th and D. M. Warburton's letter of .September Uth on subject. Oversimplified, The Dor Chemical Cwnpany contends Diamond Allcall Company is infringing their patents which claim mixtures of various lamer alkyl esters of 2,1-B and ?,U,*>-T, in limited amounts, alone and in combination vlth a hydrocarbon oil, permit lover freesing point compoaltiaag. This subject has been under running discussion between our Patent Department and Cow'a Patent Department for alnoat s year now. At this point, Keasrs. Verburton and Vainer have recommended that ve take out a license under subject patent. I personally cannot agree with their recommendations end counter-Buggest we advise Dov our chemical know-how and, indeed, practice in this area predata the issuance of their patent and heoca we are exempted. I feel Dow ehoald also bs advised, in view of this and to pressrva present good relationship, ve are willing to accept a royaltyfree license position under this patent and by so doing acknowledge to outsiders we were operating under their license. Up conclusions are based on the following observational 1. Dov first ealled this patent to our attention the latter pert of 1961, immediately following the sale of Butyl-T Ester to the U. S. Anqr Chedeal Procurement District. The Chemical Procure ment bid invitation and specification clearly fall within tha realm of the Dow patent. At this time a rather complete examination of thla situation with Newark personnal indicated we not only practiced this eheedatry prior to the date of Dow's patent, but Ray Ouldl and others at that plant were willing to give dispositions to this effect. In addition, one of our lab notebooks confirmed this, unfortunately not specifically by date. A complete examination of old Koiker records was lmpossibla due to the loss of moat of those records during the i960 Newark explosion. Further an examination of Cleveland contract and purchase records did not turn up conclusive evidence which could be used to definitely establish our predating Dow's patent. Despite all of this, the key people involved express confidence of the validity of our position regardless of the absence of evidence to sake an air tight case in court. f* Dev's actions are not those of a corporation who is conplstsly confident of their own position. They Initially asked for St royalties and they later modified this to l-l/2> royalties with , a forgiveness clausa prior to November 1, 1961. Coat'd -- DS 000 mbi t 1^175 \ y" Mr F. W. J a rv is Doit Patent 2 ,October 29 1962 3 Thera is no uniforaity of opinion as to how such of our present so veil so historical production st Newark falls within the scope of this patent I am fearful acceptance of Low's current l-l/2$ royalty offering would literally leers us liable for this same royalty payment on the bulk of our total production at Newark I will be happy to discuss this subject further at your indication and I beliora It is safe to say both Messrs Warburton and Weiner will be happy to further expound their views. K. F. Wilkerson HPWivk enc* eci Mr B. M. Warburton - Concord Mr. H. S. Weiner R. A Ouldi - Newark H. R. Bvarson - Concord Hr. R G. Richards 05 0001 I U 5 _ m r n o r . c . ?... ^orr; ~ c.r.-t r Ir..nll . ry?-<-i v l o o r k ;;:>:\:': Jr Fk October 5/ 1962 iJ'.J! C7; Mr. M. F. Wilkerson Mixed Alkyl Esters of 2,1:--D and 2,li,5-T Mr. H* S. Weiner CCT 5 un ^ ___ ` _ ,.t ,, Ihis is in reply to your requea- for corn-rents on the subject :..c.uc oi 1. September lljth from Dick Warburton. 2,hThere is no question but that the production of mixed esters of 2, h-D and-- l-p,-T made against government order #BA 30-070-CKL-l635>, NY 2-612 within Bov patents. The subsequent negotiations with Dow were for uhe ; purpose of reducing any payments to them down to an absolute minimum (preferably zero) because of selling material that fell within their patent claims. The two arguments which were used in the discussions with Bow were: a. Bow had used a questionable technique in their enthusiasm for having the government specify material which fell within Bow's patents. b. Validity of Bow's patents may be voided if liti gation is pursued by Low. 5%Bow originally was pressing for a royalty of of sales together v_th -n annual minimum. At the end of the discussions, Dow became willing to accept 1*5%a license fee of with no annual minimum. This is a very reasonable Y^e for a specialty license. Although we have questioned the validity of Dow's patents, Dick Warburton has stated that we do not have adequate data to assure ourselves that we could break the patents. It would be fairly expensive to search cut addi tional information for use in trying to break the Dow patent, assuming that this information exists. For many years our Newark plant has been producing some materials which v_ might be questionably interpreted as falling within Dow's patents. If Dow vigorously pursued analysis of some of our field materials, they could make the situation uncomfortable for usj and they might use this approach if v:s antagonize them further in the particular area in question. Based on the information we now have on hand, I would recommend that we 1*5%accept the royalty fee on the complete block of Dow patents and assume that the only products which we have produced and are producing that fall within these patents has been the one specific government order in question. The agreement that Dow offers is cancelable at anytime at our desire; thus, at anytime we feel we have enough information to break the Dow patents we can cancel our agreement. Furthermore, the agreement which Dow offers, essentially overlooks any activity in the patent area prior to November 1, 1961. This means that even if Dow should decide at any future time that our normal production over the past many years infringes their patent, they still would not request royalty payments on any material produced prior tc DS 00011466 17177 Nr. K. F. Wilke rs on -2 - Cctcber 5, 1962 November 1, 1961, Her.:ever, if we did not accept their present proposal, Dow would not be subject to this time limitation. I am assuming that Dick Warburton will comment if he disagrees with the presentation in this memo. HSWtnk cc: Mr. B. M. Warburton H/ S, Weiner 1 DS 0 0 0 1 1 1 b 1 17178 THE August 31, 1962 DOW CHEM ICAL COM PANY ABBOTT ROAD BUILDINGS MIDLAND. MICHIGAN Mr. J. 0. King Diamond Alkali Company Union Commerce 3uilaing C l e v e l a n d .14, Ohio Dear Mr. King: Russ Ashworth has requested us to furnish you with a "complete" analysis of 2,U-Dichloropnenoxyacstic Acid. Our current sales specification has the following reauirements: 2, Dichlorcphenoxyacetic acid minimum Bromine absorption (calculated as 2,4-dic h l o r o p h e n o l ), maximum Pre ezing point, minimum f"' /-N/-* 0.53 135 c We are enclosing our analytical method number 21310 covering the determination of the above items. The Assay method shown is that recommended by the Association of Official Agricultural Chemists. The bromine absorption determines unsaturates 'which are reported as 2,4-Dichloropheno The freezing point determination of course is just another method of establishing a minimum purity. While not a part of the specification, the following impurities might be present in the amounts shewn. Inorganic chlorides, calculated as NaCL, could be present up to 0.15?$. The sodium salt of 2,4-D could be present up to 0.1?$. 'Water could be a maximum of 0.1?$. Diphenoxy compounds and trichlorcpnenoxyacetic acid if present will be found as traces. The items covered in this paragraph are not routinely determined on each lot and are not a part of the specification. We hope the above information will answer the questions which you have had. Very truly yours, W. J. McCoy Resale Products Section Agricultural Chemicals Sales eb DS 00025788 THE DOW CHEM ICAL COM PANY MIDLAND MICHIGAN M arch 26, 1958 ANALYTICAL M E T H O D M ethod No. 21310 2, 4-DICHLOROPHENOXYACETIC ACID A. Scope This method is applicable to the quality testin g of 2, 4-D ichlorophenoxya cetic Acid ( 2, 4-D) . P ro ced u res are given for determ ining the a ssa y , brom ine absorption, and freezin g point. B. Assay 1. P rin cip le The total acidity is determ ined by titration with standard sodium hydrox- ide solution and is reported as 2, 4-d ichlorophenoxyacetic acid. 2. Reagents (a) A lcohol, 95% ethyl alcoh ol (2 B ), n eu tra lized to the phenolphthalein indicator end-point. (b) Phenolphthalein in d icator, 1% solu tion in 95% ethyl a lco h o l. (c) Sodium hydroxide 0.1 N standard solution. Dilute 8 .0 0 gram s of 50% sodium hydroxide solu tion with r ec e n tly b oiled d is tille d w ater to one liter, and standardize against benzoic acid of known purity. 3. Procedure ( a) W eigh a one-gram sa m p le into a 250-m l. E rlen m ey er fla sk . D isso lv e in 75 m l. of neutral alcohol and titrate with 0.1 N standard sodium hydroxide, using one m l. of phenolphthalein indicator. (b ) O ptionally, the titra tio n m ay be follow ed with a stan d ard pH m e te r such as the B eckm an M odel H-2. A pH reading of 9 is used as the end-point. 4. Calculation ( m l. o f 0.1 N NaOH) x 0. 0221 x 100 = % 2, 4 -d ich lo ro p h en o x y a cetic'a cid . gram s of sam ple DS 00025789 1*7180 M arch 26, 1958 2- - Method No. 21310 C. Brom ine Absorption 5. Principle The sam p le is treated with an e x c e ss of brom ine from a standard brom ate-brom ide solution. The amount of bromine absorbed is calculated to dichlorophenol. 6. R eagents (a) Brom ate-brom ide, 0.1 N solution. D issolve 2 .8 gram s of reagent grade p o ta ssiu m brom ate and 12 gram s of p o ta ssiu m b rom id e in w ater and dilute to one lit e r . (b) Sodium thiosulfate standard 0.1 N solution . D isso lv e 25 gram s of sodium thiosulfate, Na2 S2 03 5H20 , and 0. 5 gram of sodium carbonate in one liter of w ater. Standardize against 0.1 N potassium iodate, according to the procedure given in Kolthoff and Sandell ( s e e 12). (c ) Su lfuric acid, 1: 4 so lu tio n in w ater. (d) P o ta ssiu m iod id e, 5% so lu tio n in w a ter. (e) Starch indicator solution. Mix one gram of soluble starch and five m g. of m e r cu ric iodide with a little cold w ater. Add m ore w ater to make a fluid suspension, and pour this into 500 m l. of boiling, d istilled w ater. Boil for s e v e r a l m in utes and then cool to room te m p er a tu r e . Keep in a g la s s stoppered bottle. 7. Procedure (a) W eigh a five-gram sam ple and tra n sfer it to a 500-m l. g la s s stoppered flask containing 200 m l. of w ater. Add exactly ten m l. of 0.1 N standard b rom ate-b rom id e so lu tio n , 35 m l. of 1: 4 su lfu r ic acid and sto p p er im m ed ia te ly . Shake v ig o r o u s ly for 15 seco n d s and allow to stand fo r tsn m in u tes. Add 15 m l. of 5% p o ta ssiu m iodide so lu tio n and m ix w e ll. T itra te the liberated iodine with standard 0.1 N sodium th iosulfate solution, adding a few m l. of starch indicator solution near the end-point. (b) Run a blank in the sam e way (w ithout any s a m p le ) . Subtract the sam p le titration volum e from the blank titration volum e to obtain the m easu re of bromine consum ed by the sam ple. 8. Calculation ('-n--e-t---m---l-.---o--f---0-.-1---N--- r--e--a-gaen t)---x---0-.-0--0--8--1-5- x 100 = % 2, 4-d ich lorop h en ol. gram s of sam ple DS 00025790 M arch 26, 1958 -3 - M ethod No. 21310 D. F reezing Point 9. Principle During the crystallization of a m aterial from its liquid sta te, a m axi mum tem perature is reached which is maintained for a period of tim e. This tem perature is considered the freexin g point and is an indication o f the purity of the m aterial. 10. Apparatus (a) T h erm o m eter, partial im m e r sio n , calib rated in 0 .2 C, range including 135 aC. (b) A gitator, nichrom e w ire with a 10-mm. diam eter coil at the low er end to en com p ass the th erm o m eter. ( c) T est tubes, 20 x 150-m m . and 38 x 200-m m . , P y rex . Support the sm a lle r tube con cen trica lly in the la r g er which se r v e s as an a ir bath. P a ss the therm om eter into the inner tube through a one-hole cork stopp er which is slo tted to p erm it m ovem ent of the w ire a gitator. 11. P roced ure ( a) Into the 20 x 150-m m . test tube, place su fficien t sa m p le that the m elt w ill co v er the th erm o m eter up to the im m e r sio n m ark. (b) A fter m elting the sam p le, place the tube in the air bath. A gitate continuously. A fter cry sta lliza tio n sta r ts, record the m axim um tem perature as the freezin g point of the sa m p le. E. Reference 12. L iterature R eferences Kolthoff, I. M ., and Sandell, E. B. , "Textbook of Q uantitative Inor ganic A nalysis, " Third Edition, Chapter 39, The M acm illan Company (1952) . ******* The analytical procedures given herein have been adapted from literature s o u r c e s or developed upon the b a s is of ex p erim en ta l data which a r e b e lie v e d to be r e lia b le . In the hands o f a qu alified an alyst they are ex p ected to y ie ld resu lts of sufficient accuracy for their intended purposes. H ow ever, The Dow C hem ical Company m akes no rep re sen ta tio n or w arranty w h a tso ev er con cern in g the p roced u res or r e su lts to be obtained and a ssu m e s no lia b ility in connection with th eir u se . U s e r s are cautioned to co n firm the su ita b ility of the m ethods by appropriate te s ts . Anyone w ishing to reproduce or publish the m a teria l in whole or in part should request w ritten p erm ission from The Dow C hem ical 1 7 Company. DS 00025791 N vaca <gtH D " 'j d f a m e a Eaters of 2 ,U-D and 2,Uj5-T 1* Butyl Ester 2. Isopropyl Ester 3 2-Ethylhexyl Ester U. Iso-Octyl Ester 5. Polyethyleneglycol Ester 6 . Butyoxyethoxypropyl Ester Amine Salts of 2,U-D and 2,U5-T 1 Dimethylamine salt of 2,h-D 2* Dimethylamine and Triethylaraine mixed salts of 2 ,ii-D and of 2,U,5-T 3* Triethylaraine salt of 2,U-D and 2,U,5-" U. li-01eyl-l,3-Propylenediamine salts of 2,U-D and 2 , k , $ - T 5. Isopropylamine salt of 2 ,ii*D and 2,ii,5-T 6 * Diisopropylamine salt of 2,U-D and 2,H,5-T 7* Trii3opropylaniine salt of 2,U-D and 2 Miscellaneous hormone formulations 1. Dimethylamine salt of MCP 2, Dimethylamine and Triethylamine mixed salts of MCP 3 Sodium salt of 2,U-D and 2,U,5-T lu Wettable powders of 2,2i-D and 2,U,S-T 5. Isooctyl ester of 2,U,?-TP (Silvex) 6 Dissolved 2,ii-D and 2,U,5-T acids in solvents and emulsifiers DS 00Q25792 Diamond Alkali Company / Subject have Individual customer presently hospitalized, who has written then stating that while using a knapsack sprayer charged with Gold Bear bfl he experienced spillage which saturated the ahailder strap of the sprayer* He adnrltta that he did not wash this material off and now is afflicted with a *poisos ivy* like skin eruption characterized by pustular inflanmation, itching etc* I briefly discussed bypertoratcei* and other forms of dermatitis sceetimes caused by chlorinated hydrocarbons Apparently this man is i seeking only advice in dealing with his problem and doea not anticipate ( legal action* In any rent, X told Swift: that since the inquiry was addressed to than, we would be disinclined to contact this person directly; however, we would be happy to contact Swift and offer any appropriate advice* I also pointed oat that we oaturally could not reccKmend oedioal treatment but perhaps could suggest a qualified specialist familiar with this disease Will you please forthwith see that D J. Campbell of the subject contacted relative to this problem* CLT/sb C> L*TR0PH DS 00022474 P" THE DOW CHEMICAL COMPANY November 22, 1966 POST O PP tC C SOX 312 MIOLANO, MICHIGAN 441 Mr. C. L. Dunn Synthetics Department Hercules Incorporated 910 Market Street Wilmington, Delaware 19899 // Dear Chuck: Enclosed is the draft of the proposed comments on behalf of the NAC ITFPHT, which we discussed by tlphon November 22. Although we have until December 8 to submit comments I would like ours to be mailed by Friday, December 2, to avoid any slip-up. Therefore, I will need your suggestions and those of the others receiving this letter early in the week of November 28. As discussed, we will not hold up the l e j t t e r for any dis cussions with FDA .and hope that our comments will provide the opening for a conference with the proper parties in FDA if we sense the need for one. I would suggest the telephone for comments, and for your convenience my telephone number is (area code 517) 636-5014. / Sincerely, -V -- Lypm., Cha-i-rman " Phenoxy Herbicide Tolerances Members ITFPHT Dr. L. L. Danielson Dr. W. L. Popham J. A. Noone abc Enclosure DS 00025741 17125 - DRAFT Hearing Clerk Room 5440 Department of Health, Education and Welfare 330 Independence Avenue Washington, D. C. 20201 Dear Sir: The National Agricultural Chemicals Association Industry Task Force on Phenoxy Herbicide Tolerances representing the basic manufacturers (Chipman Chemical Co., Inc., Diamond Alkali Co., The Dow Chemical Co., Hercules Inc., Monsanto Co., Thompson Chemicals Corp., and the Thompson-Hayward Chemical Co.) of 2,4-D (2,4-dichlorophenoxyacetic acid) herbicides; submits the following comments concerning the proposal published in the Federal Register of November 8 , 1966, pages 14359-14360, to establish tolerances of 2,4-D in or on certain grains by amending 21 CFR 121.142 and adding new sections under part 121. _____ . 1. The industry manufacturers and markets 2,4-D products registered by the USDA for uses on the grains listed which are not covered by the salt or ester forms given in the proposal. 2. In 121.142 as proposed there are certain items which we do not understand, or believe to be typographical errors : . In paragraph (b) (2) We are not familiar with the usage of "n" in the nomenclature: n-oleyl-1 ,3-propylene diamine. The "normal" configuration of oleyl is usually considered inherent. In paragraph (b)(3) the proposed list includes "isopropyl methyl octyl (isooctyl)," which would appear to lack necessary punctuation. We presume it should read "isopropyl, methyl, octyl (isooctyl),". DS 00025742 171ft -2- In paragraph (b)(d) we do not recognize the name "polyethylene glycol butyl ether" as an ester moiety of 2,4-D now being marketed. However, propylene glycol butyl ether esters are registered and marketed. Clarification of this apparent discrepancy is needed. In paragraph (b)(3) "tetrahydropropyl" as an ester moiety is unknown to us. However, the tetrahydro'furfuryl ester is one which has been registered and marketed. Clarification of this apparent discrepancy is needed. 3. Many of the salt and ester forms of 2,4-D now manu factured, registered, and marketed for use on grain are not covered by the salt and ester forms given in the proposal. Furthermore, it is likely that future avail ability and manufacturing economics will dictate the desirability of using ester and salt moieties other than those listed in the proposal. In order to overcome these two deficiencies in the present proposal, and to avoid a hardship on the industry with respect to their particular needs for latitude in the selection of economic 2,4-D forms for manufacture, and the hardship which could be worked on the farmer due to the lack of suitable and economic 2,4-D forms, we propose that the salt and ester forms permitted by the order follow a more generic description as follows: DS 00025743 17187 yw -3- 121.142 -----i'-U\ ______ (1 ) The inorganic salts, such as calcium, lithium, magnesium, potassium, and sodium. (2 ) Organic amine salts, such as alkyl, alkylene, or alkanol amine salts. (3) Organic esters, such as alkyl or alkoxyalkyl esters, or other esters as tetrahydrofurfuryl. The other, but much less preferred, alternative would be to amend the list of salts and ester forms according to comments received from individual companies for inclusion of the 2,4-D forms they manufacture and market. In view of the wide differences in the specific salts and esters listed in the proposal as published we can only assume that it was the intent of the proposal to provide for equal treatment of all of the 2,4-D forms now being used. We favor such an objective, but as pointed out the list falls short of including all of the 2,4-D forms now marketed and those that may be marketed in the future. We respectfully request that our proposals as set forth above be considered as means to accomplish the objective as we have interpreted it. Sincerely, G. E. Lynn, Chairman DS 00025744 17188 .^ ! CL COi:\'!>1*0SPIACI. IJ> I \ * 1 1 o r i <J / :i C o n i|> ; tny JOHN CORT, JR. / ji\O.V. E. L. CHANDLER CHLOROACNE - DOW MEETING cc: F. R. Kennedy - Mgr., Newark plant J. 0. King M. F. Wilkerson V '* ' 3/25/65 2k,On March Mike Kennedy and I met with two people from Hooker Chemical Co., 2,k,$two from Hercules, and with the Dow group to discuss the toxicological impurities associated with trichlorophenol and related materials. Dr. Rowe of Dow Chemical opened the meeting by stating that they had operated for 25 years without trouble; but, in the last year, they had 60 to 70 cases of chloroacne. Ten of these were moderate, and five to ten were extremely severe. Their approach was a qualitative one at first. They wanted to find the causative material, learn how to identify it, and try to avoid continual trouble with the unknown. They tested various materials from tar fractions and from, as they put it, "gunk", etc. They found that there are a number of suspect materials, probably 26 or 27; but the major "bad actor" that they identified and which seemed to consistently cause the problem was 2,3*7,8-Tetrachlorodibenzo p-Dioxin (symmetrical). Cl C l - VI ox fo This incidentally was previously listed as a suspect material by Cy Perkins of our company. A similar material is the unsymmetrical 1,3,7,8-TCDBD, also sometimes listed as 2,3,7,9-TCDBD. The Dow people used the white glove approach and found this contaminant on tool handles, benches, instruments, and other fomites. In test animals, they could consistently cause the symptoms to appear. Dr. Holder of Dow, one of their medical doctors, had excellent color slides of the various patients. The difficulty starts with multiple blackheads resulting in closed cystic structures which make the patient look like he needs to wash his face. The disease develops slowly, not appearing until six weeks to two months after mild exposure but appearing in five to seven days with very heavy exposure. One bench chemist has been under treatment for two years and his face is starting to show signs of clearing. Dr. Holder says that he believes this man's problems will be solved in another six months. Dr. Sadek, who does their micro scopic work in connection with their animal laboratory, showed photo micrographs of the cysts as they formed in the ears of rabbits. The cysts correlated with those found on the faces of the men. ns 0 0 0 1 2bI 5 1- 171SS  Chloroacne - Dow Meeting (ELC) -2 March 25, 1965 Basically, there is a carotinoid deposit in the hair follicles and oil ducts in the face. These eventually go from the blackhead stage to form a closed, heavy core deposit. The chemical cannot be found in the facial tissues or in the cores, but the problem still persists after exposure* The best description of the acute stage is that the facial tissues resemble the exaggerated surfaoe texture of an orange, rather glazed and marbly with the enclosed hard core deposits. A secondary symptom, which does not correlate directly with the amount of facial dermatitis, is a fatigue reaction where the employee is completely listless, tired out, and nearly incapacitated. A complete biopsy of liver, kidney, etc., shows no degeneration of major organs. A complete clinical examination of the patients showed no measurable affect on heart, blood pressure, respiration rate, blood sugar, etc. The fatigued patients seemed to be helped by heavy doses of vitamins, perhaps related in some way to the carotene metabolism of the body (involving vitamin A, eto.) An oral dose of 17 micrograms immediately killed the test animals. The Dow people did not lower this dosage to obtain an LD^q but decided that, when they can detect this compound, it should not be in the product. They found that, after exposure to the material, washing within 15 minutes did not help a great deal, but tdid slow own the speed at which the symptoms appeared. Washing after one hour was of absolutely no help whatsoever in reducing total dermatitis or speed of appearance of the reCtion. Moderate scrubbing with detergent does not remove this material. Extremely hard scrubbing can accomplish the task or the use of solvents, such as 1,1,1-trirhloroethene. Dow has developed a new analytical method in which they have confidence in their sensitivity to 1 ppm. They can only state in levels below this that some may be present below the 1 ppm. They stated that they have not used micro-colorimetric methods, fnd the electron capture tests that they ran made only a very slight improvemert in sensitivity with this compound. Their analytical chemist stated that the electron cell saturates because of the presence of other materials in high concentration compared to the dioxin. This material has some strange properties. It has a fairly high vapor pressure but nevertheless is quite persistent as a contaminant. It can be separated from benzene by boiling if it is not carried down to dryness. The Dow people are extremely careful in all of their work with this compound. They use PVC throw-away gloves, and all samples are burned in a special furnace which operates at 800F. These samples are sealed before going to the burner. They use bioassay methods on rabbits for qualitative checking only. The Dow people state that they intend to set a limit of zero with sensitivity of plus or minus 1 ppm on this material. They have analyzed materials from other companies, including our company, and have found amounts as high as 10 ppm in ^02,h,5-T acid and 20 to ppm in phenates. They have made a single application to the ears of test rabbits and found that 20 p^m will not give folliculitis. Forty ppm does give a slight effect, and 100 ppm ir severe. They have made repeat applications of from 10 to 100 ppb, and 25 of there treatments do not cause a response; however, 1000 ppb (l ppm) gives a slight rerponse with nine applications and a severe reaction with 11 applications. They conclude, therefore, that 1 ppm with repeat exposure can create a real problem. 1719D Dc-.-'s people outlined a method for extracting and running samples on 2.!,-5-T; ,',1;,5-TP; and phenols, it involves a chloroform extraction, followed by  Ch^L.roacne - Dow Meeting 3- Karch 25, 1965 a caustic wash, and a reduction by boiling to one-tenth the volume before putting it in the chromatograph. They have given the gas-liquid chromatography method to us, along with analytical-grade dioxin material. Mike Kennedy has these materials and intends to pursue the laboratory work necessary to ascertain where and how much, if any, of this dioxin appears in our 2,Ii,5-T process, The purpose of this meeting was obviously designed to help us solve this problem before outsiders confuse the issue and cause us no end of grief. Dow is sending the test results on our material to us, incidentally; and this will further check our technique, etc. Sincerely, O// ELCseen E. L. Chandler OS 0 0 0 I 2 b 1 1 171 SI . UO T-i 3 .//- B - / CABLEADORESOOWCHEMCO RANCH SALKS O P F IC I NEW YO RK CITY RAN FRA N CISCO PH ILA D ELPH IA LOS ANGELES W ASHINGTON SAIN T LO U IS CLEV ELA N D HOUSTON CH ICAG O SEATTLE D ETRO IT BOSTON The Do w Ch e m ic a l Co m pa n y MIDLAND MICHIGAN December 15, 1949 Dr. V. A. Drill Department of Pharmacology and Therapeutics Wayne University College o f ;Medicine 1512 St. Antoine Street Detroit 26, Michigan . . e o> sO Nl vO NO -a ci h ro C3 Dear Dr. Drill: We are sending to you under separate cover, samples of 2,4-D (2,4-dichlorophenoxyacetic acid) and 2,4,5-T (2,4,5-trichlorophenoxyacetlc acid) for use in the toxicological studies on dogs. The sample of 2,4-D being sent is regular production material assaying 98.5jf and having a freezing point of 13 2 *8*0 . m ---- .The sample of 2,4,5-T being sent is also regular production . material assaying 100^ and having a freezing point of 148.8*C. V Both of these materials are being supplied to you in the . acid form. Both are fairly soluble in olive oil and both can easily be put in aqueous solution with caustic. I believe you will find that a slight excess of caustic is required to put these materials in c solution and that onoe in solution, a large part of the excess alkali can be neutralized. Hence, for a 5.0# aqueous solution of the sodium salt of 2,4-D, the pH after solution 13 effected, can be adjusted down to 7.2 with HC1; with 2,4,5-T the final pH of a 1.0^ aqueous solution can probably be in the neighborhood of 10 . When 2,4-D or 2,4,5-T is used as an herbicide, the con centration usually ranges from O.l# to 0.2,4. The active material may be applied in any one of a number of forms depending upon the particular requirements of the Job. The most common forms are the sodium salt, alk&nol amine salts, and esters. Almost all the toxicological work so far reported deals with 2,4-D administered either as the free acid in oil or as the sodium salt in aqueous solution at a pH of 7.2. We have conducted a fair amount of toxicological work on the other forms of 2,4-D and also on 2,4,5-T in its various forms. We have observed that the form of the material makes little difference to warm blooded animals and that, acutely, there is not much difference between 2,4-D and 2,4,5-T. Dr. V. A. Drill Paga 2 December 15 1949 The toxicity picture as we have it is given in the following tabulations! ' Toxicity of 2,4-D when administered in Single Doses. Animal Route Rat Oral Rat Oral Mouse Oral Mouse Guinea Pig Sub-Cut. Oral Chicks Oral Source Approx. LD^Q (g ./ k g .) Lit. Na Salt Dow- Incomplete Na Salt Acid Isopropyl esterB Lit. Na Salt Dow - Incomplete Acid Lit. Na Salt 0.666 0.70 0 .5 - 0.6 0.5 - 0.7 0.375 0.3 - 0.5 0 .20 O O -nI 07 >-- * fo ca C7 Lit. Na Salt Dow - Incomplete Na Salt Acid Lit. Na Salt Dow - Just started 1.000 0.5 - 0.7 0.5 - 0.7 0.38 - 0.76 Toxicity of 2,4-D when administered in Repeated Doses. Animal Route Source Notes Dogs Sub Cut or I.V. Lit. Guinea Pigs Orally (/) Lit. Rats Mice Orally in diet I.P. Lit. Dow Lit. Na Salt 0.200 g.Ag./day-death in 2 da 0.100 g./kg./day death in 2-4 days 0.050 g./kg./day death in 3 days 0.025 g.As-/day marked affects Na Salt 0.100 g . A s . / a a y 10 times in 12 day was tolerated 0 .1 tolerated 0 .1 j -caused very slight effects 0 .03% clear No marked hlatopatholftglcal findings No neoplastic growths Reproduction O.&. , . 17 ' t i f , . Dr. V. A. Drill Page 2 Deoember 1 5 1949 Toxicity of 2,4-D when administered in Repeated Doses. - Cont'd. Animal Route Source Notes Chicks Orally Orally in Diet Lit. Dow O.O28 g . A s * 3 times/week for 4 weeks - O.K. 0.280 g .As* 3 timesAek for 4 weeks - growth depression 0.l for 1 week - O.K. 0.2jf for 1 week - O.K. except for slightly depressed growth rate. Toxicity of 2#4,5-T When Administered in Single Posea Orally (This Information is from our data and is not complete - We are finishing it.) Animal Notes O CO c: Rat Mouse Guinea Pig Chick LD50 for the acid lies between 0 .5 -1 .0 g./kg LD50 ?or the isopropyl ester lies between 0 . 5 - 1 . 0 g.As* LD50 for the acid lies between 0 .2-0*7 g . A s LD50 for the acid lies between 0.2-1.0 g./kg for both the acid and Na salt Work Just begun Neither 2#4-D nor 2,4,5-T are more than vary mild skin irritants even in concentrated form. In diluted form ready for use, they present no health hazard. Studies conducted upon guinea pigs by Hill and Carlisle on the inhalation of 2,4-dichlorophenoxy acetic acid dust, either wet or dry, but of unknown particle 3 l z e , indicate that the dust is not likely to cause systemic intoxication. This has been born out by our own e x perience with men handling the dust. The dust, however, is capable of causing irritation of the nose if the concentration in the breathing zona becomes sufficiently high. The following references may be helpful If you wish to consult the literature for a more detailed description of procedures, etc.s .Y . m, . ` DOW 7 5 1 2 9 V Dr. V. A. Drill Page 4 December 15# 1949 1. Toxicity of 2,4-Dichlorophenoxy Acetic Acid for Experimental Animals. Edwin V. Hill and Harold Carlisle (Camp Detrick* Frederick, MD.) J. Ind. Hyg. Toxicol. 29, 85-95 (1947) C.A. 41: 5217a (May 20, 1947) 2. Tolerance of Farm Animals to Feed Containing 2,4-Dichloro phenoxy acetic acid. J. V. Mitchell, R. E. Hodgson and C. F. Gaetjens (U.S. Dept, of Agr., Washington, D. C.) Animal Sci. 5, 226-32 (1946) C.A. 40 (17); 5198a (Sept. 10, 1946) 3 . 2,4-D Toxicity. I. Toxicity Towards Certain Species of Pish. Jos. W. E. Harrisson and Edward W. Rees (La Wall and Harrisson, Research Consultants, Philadelphia, Pa.) Am. J. Pharm. 118, 422-5 (1946) C.A. 41 (2529) (1947) 4. Effects of 2,4-Dlchlorophenoxy Acetic Acid on Experimental Animals. Nancy L. R. Bucher (Harvard University) Proc. Soc. Exptl. Biol. Med. 6 3, 204-5(1946) ,.C.A. 41: 808 (1947) Data on the acute oral toxicity of both 2,4-D and 2,4,5-T for dogs is lacking. Therefore, it is suggested that the acute oral tudis be started at your earliest opportunity so that information 'ill be available for choosing appropriate dosage levels for the 90 day feeding tests. In the single dose experiments we suggest that a notation be made regarding any symptoms exhibited at the various dosage levels, body weights for each day during 3 or 4 days immediately following administration and on alternate days during the rest of the 2 -week observation period. We do not feel that it is necessary to do any elaborate tissue studies on acutely dosed animals. We would, however, like to see animals that die and those that survive autopsled and the gross condition of the G.I. tract, liver, and kidneys noted. A few sections at critical dosage levels might also be desirable - at your discretion. 17196 DOW 7 5 1 2 0 8 Dr. V. A. Drill Page 5 December 1 5 , 19^9 In the 90 day feeding tests, we suggest that the material be administered with a part of the diet. Dosage levels cannot be decided upon until acute data is available. We would suggest that general ob servations, growth reoords, and perlodlo hematological examinations (initially, after 30 days, and after 90 days on the experiment) be con ducted during the experiment. At autopsy, gross and histopathologlcal studies on the liver, kidney, stomach, intestine, spleen, lung, heart, adrenal, testis or ovary, and p o s s i b ^ brain and vascular system are of importance. We believe that nega c1^^fliratngs at upper dosage levels make similar studies at lower dosage levels unnecessary. The requisition for this work has been approved and I will see that an appropriate check is deposited as before. If there are any details which are not clear or If any problems arise, please contact us at once. I regret that I did not have more time last week to spend with you. Nevertheless, I was very glad to get home early and avoid the snowstorm that settled on this area about 5*00 p.m. that evening. Please give my regards to Dr. Hays. Sincerely yours, THE DOW CHEMICAL COMPANY VKR/mg V. &. Rowe biochemical Research Department 171S7 DOW 510645 9u 4 Before attainting to o.uestion the validity of the roo.uirc~.ent for restrict ing livestock from sprayed areas for seven days following application it is necessary that we mako some reasonable assumption as to the amount of herbicide remaining on any edible forage in the treated area. In the special cr.se cf i right-of-way spraying this is an extremely difficult thing to do since much cf the material used is for the specific purpose of tree stump control ar.d as such does not actually come into contact with the livestocks normal forage. In a general review of the herbicidal literature the greatest application c rate found was 6.0 per acre (B). This value, as a maximum, has also boor, cited in correspondence from The New York State Cooperative Extension Service at Ithica ( James E* Dewey to Paul C, Couldin, `April 8 , 1966 ) and as such scons to be a more than fair amount to assume is being sprayed on the actual foragebearing portions of the right-of-way. (/aere comoutes to 6 2 ,$mgm/so. ft. and based on the data of Grigsby and Farwell 19 ) t-o 890 mgm 2,li-D or 395 ngn 2,U,5-T oer nound of forage. Just why the 2,ii-D, sprayed at equivilant rates oer acre, shows uo an a greater concentration in the forage is unclear but is probably related to the grasses greater absorption rate for this chemical. Grigsby and Farwells data on this V.. point is also somewhat variable with some tests showing only half as much (oCmnc) 2 ,Ii-D remaining in the crops. Since right-of-way spraying uses a mix-cure of both 2,1;-D and 2,U,5-T, some assumption is necessary as to how the 6 ocur.ds cf stray per acre is split between the two chemicals. For the purooss of calculation ic will bo assumed here that this split is 2:1 2,lj-D to 2,!i,5**T, since this arrange ment will favor that compound (2,U-D) which shows up to the greatest externa in the forage. Actually, I believe the NYSiT&G literature on the subject indicatec a cr.idominar.ee of 2,h,5-T. 171S8 9 f '9 0 T S ' A O a Based on the above assumption the amounts of chard.cal remaining Jr. ih 2}h-'0/!rforage arc- roughly 60Cmgm ar.d 120mgm/ 2,1:,5-" for a total oonc.utrni: of 720 mgm/?. Although 2,li-D and 2,u,5-'T differ somewhat in thoir iouicclogl properties it is veil rocognizea that either may be consumed by live atocl at : of lOOngm/kgm^for extended periods without inducing any ill effects in the animals (l^<2cl7)* In order for an average ruminant (770 ) to acquire this doseage ( which would cause him no harm ) he would have to injest the rather -flikely amount of 1;8.5 of sprayed forage per day. Even were an animal actually to acquire the above coseage, cr.d 'hie ^assumes that not only does he actually consume 1:8.5 # of forage nor d-ey but t: all of it comes from the sprayed right-of-way, there is ar.nle evidence in the literature to suggest that he could continue to do so for time -ericas greats: than 2 l/2 months (l5) before even slight evidences of damage were noticed. Obviously, long before this time period could ela-ise, the normal lose through evaporation, penetration in the soil and dilution by periodic raindal would act to reduce the concentration in the forage to the point that no car.~ whatever could possibly exist. Ihe above example should help to dispel any unfounded notions as to the toxicity of herbicides to grazing livestock and to put into proper persnecuive the obviously over-restrictive condition listed or. 2,1;-D labels. In essosir.j the forgoing remarks it should be borne in rind that the amount of herbicide (6-?/acre)chosen for the example is undoubtedly far- greater than the rare .'hieh would probably be used for forageablc areas on the right-of-way. Acverily mho rate of application of these chemicals is proportional to the amour.r of brash and undergrowth in the area and as such an application rate of p^'/ecre would indicate an almost comletely overgrown area with little if any available forage. (2) 171S9 In. addition to the above exannle, a perusal of the cxiscur., sc_on ^-- o literature discloses several points which argue against the necos? .y o* re stricting cattle from sprayed areas for seven days following application. 1. Because of the already mentioned dissipating affects of m o o_.cr.cnts on the concentration of herbicide remaining in the forage it is clear that tr.e greatest danger of livestock poisoning is of short duration- pernaps, **s only for the first week following the spraying treatment. 'While the above Q example has cite^evidence to show that even unusually hign concentrations c_ ^ O .herbicide are not harmful over extended time periods, there is also evidence to Ot * rf* indicate that livestock have enormous resi3tar.ee to very high doseages for short term exposures. Dr. V. K. Rowe (17) for instance has run experiments which show that single doseages of $00 and 10CO mgm/kgm of Esteron Brush Killer (1:1 2,L-D: can be invested by livestock without having mortal effects, -ver. at the lower concentration this would mean that a grazing cow could accidentally drink over two gallons of the NYSS&G mixed spray without suffering any ill effects. Gbviously, the possibility of such an occurrence is extremely remote but the example does indicate that the resistance of the livestock *wC shor"w ex*" posures is so great that even very sloppy handling of the spray materials should present no untoward danger to foraging animals. 2. Grigsby and Farvell (19) in a well documented-paper in 19$0 have roported a suco'esful experiment which should also Point out the cver-restrictivenoss of the directions on the 2,li-D label. In their tests cattle were fenced into small plots and forced to graze on land sprayed with 33 jl/acrc of both 2jli~D and 2,h,$-T for a period of two weeks. Despite the fact that the livestock were present when the snrays were anolied and had no alternative but to graze tho sprayed forage, they were ccr-^letely healthy at the end of the two '.:zz (3) 1 7200 DOW510648 period. The above reference is from the Quarterly Bulletin or the Michigan Agricultural Experiment Station and can certainly be considered tcbe unbiased. 3. Additional evidence for the low toxicity of herbicide! sprays e immediately following application can be gained from a paper by k.E. Coldsteir. and J.F. long (l6). These investigators actually sprayed 2,h-D and 2,L.,5>-? directly on livestock without causing any harmful effects. In another test cut forage was sprayed twice a day with the herbicides and then fed to the cattle without inducing any ill effects. The above exoeriment was continued for six straight weeks and still no illness was noted in the livestock. The above sit uation clearly represents a degree of herbicide accumulation which weald be un likely to be obtained in a field situation even immediately following a spray r.ding treatment and argues convincingly for both the short a long term safeness of 2,li-D and 2,1*,5-T. 00 BtSOISWOdf AT- tvc.ilf.tle editions of Chenictl Abstracts for the yerr IvCo vo re searched under the headings ,:ilerbicides = in mi.T_'.c,!, end "Jil;-: - Herbicides or residues In". One reference t.s .s found (73241 H {.) in the Aug. iO"-* oo.) and this nas in the last issue availsble on Oct. 10, 1066. Ho reference to the Klingiean (b) et al paper has as yet beer, indexed. Similarly r.o reference as yet exists in the abstracts for the related paper by Yip ar.d -.'ey (,cj -hi describes the analytical test method used by Klingran. The paper by Klingnnn has been analysed fer incorporation into the c literature study and also has been commented on as it relc tes to the case hand, references (a) arc (cj are being sought. through the hern Li errry at Cornell. (a) Cetsmin.-tion of 2 ,4-h t-.ssic.ues in /nine! Products. 0.0. Cross; ana J.B. Boners. Eull. Environ. Contain Toxic? 1 1 ('} 10-1-7 Hoc lbj Residues in the Forage and in j.'rcn Cove Grr-tin- 1nr.-_j- Treated r.-ith Zsters cf 0,4-D. sayton L. liir.grr.n, Chester 1. Gordon, George lip end H.P. Burchfield. eegs Vol. 1-1, p!24- 167 1366. (c) Analysis of 1,4-1 Residues in ''.ill-: end Fora`e . George lip or.d itonalc 2. L'ey,Jr. Weeds Vol. 14 pl7- 1063. 1720 2 ***' - DOW 1 252988 July 9 , 1 9 6 5 48640 Albert M. Kligraan, M.D., Ph.D. Department of Dermatology Hospital of the University of Pennsylvania 3 6 th and Spruce Streets Philadelphia 4, Pennsylvania Dear Dr. Kligraan: I am sending you under separate cover a small amount of 2,3,7,8 -tetrachlorodibenzo-p-dioxin This is the material which is a potent acnegen and is highly toxic. I have checked back on our figures and find that the. single dose oral DDcn rabbits is in the neighborhood of 10 0 ralcro- grams/kilograra, and we had or.e animal die which had received a single dose of 16 micrograms/kilograra. It is safe to say, however, that doses of 0.5 to 1. 0 mg/kg are always fatal, although deaths may be delayed for 10 to 20 days post treat ment. The typical clinical picture Is severe liver and kidney injury. o -Vi O vO PO In regard to the skin response on rabbits, we nave attempted to quantitate this by applying C.i ml of test solution to one to two square Inches of the surface of the inner face of the rabbit ear. ' Vie find that when "he total dose does not ex ceed about 0 . 2 of a microgram of -.-he acnegen, no follicular prominence or epithelial hyperpi_:.l.a develops. When the total dose 13 about 0. 5 bf a urogram on this area, the response is marginal; 1 to 2 mioregrams almost always proc :es a response, and 4 to 8 alcrograma usually produce a severe response. We have net as yet been able to quantitate the dose required to cause 5 C/I- mortality from skin exposure, but we are sure it is well above the total dosages noted above. In view of this information, it does not seem probable that the dosages shown Ln the accompanying suggested protocol for the human work would be likely to constitute any serious systemic hazard because the dose on a per kilogram basis would be far below that which produces any significant effect systeralcally ln the rabbit. I might add that the rabbit 1 far mere sensitive than the rat to this type of compound. Nevertheless, the seriousness of the consequences that might develop from testing with this type of compound require that we approach the matter in a highly conservative manner. It 17203 17204 DOW 1 2 5 2 9 8 9 A. M. Kllgman, M.D. 2 July 9, 1965 Is with this thought In mind that I have developed the attached protocol. The number of persons per experiment is your decision; I would suggest two as a starter. When applications are repeated, I would like to have them made on consecutive days, if it is convenient to do so. Although the time required to conduct these experiments will require several months, I believe it is the safe way to proceed, using a few people at a time with careful observations on each. The observations are to be made at your discretion, but I would urge routine SGOT's and alkaline phosphatases as a minimum. There is another item upon which comment should be made. I have indicated in the suggested protocol that a two week ob servation period should be used prior to starting the next series of experiments. This is because our experience with both animals and man indicates that there is an induction period. In a few instances, we believe an eruption in the human has developed four to six weeks post exposure. Also, we have had a few serious flare-ups which have developed within a matter of days, post exposure. I have compromised on a two-week observation period, but of course, any treated Individual should be watched for at least two months post test You asked about materials in which this test substance is soluble. I have indicated it is quite soluble in chloro form and benzene and slightly soluble in alcohol. I be lieve that a solution in pC/ 5 0 alcohol and chloroform would be quite appropriate for your work. In rogai'd to covering the exposed area, I would suggest that when the treated area has dried that it be covered ilgatiy with a gauze simply to keep the material from being brushed away or having a person contaminate his hands or clothing Inadvertently. I hope I have answered your questions, but if you have hny others, please do not hesitate to contact me. -sincerely yours, V. K. Rowe Biochemical Research Laboratory 1701 Building VKR/Jd Attach. co Medical Department : Gordon, Holcer, Kramer J. E. Peterson L. bilverstein H. R. Hoyle V. K. Rowe (2) To6.5-66631 -7 172" Quik Print INSTANT PRINTING & PHOTO COPYING 98 Prince Will>am Street, Saint John, N.B. E2L 283 (506) 634-8840 We can "Custom Print" Post-ItTM Notes fiV JI ftftA ft ... ask oursales rep. fordetails V%ftrmO O tr U rais<'<( a. q u a n d a ry aro u n d lli<' m u n t r y re g a rd in g d is p o s a l. T w ou ld In* (lie lirsf. In ad m it that. we. <! not have, an y e asy a n sw e rs fo r th is problem . T h e re , h a v e linen soim> reco n tm en datio n s m ade to me h,v statT as to w h a t we. m ig h t issue, p u h lid y , an d f have p e rs o n a lly tu rn e d them d o w n heeanse. (h e y lo not a n s w e r the question p ro p e rly . AAV. a re . th e re fo re , h o ld in g a. n a tio n a l co n fe ren ce on th e of ~.D .t id e in w h ie h we are h a v in g people come in fro m v a rio u s segm ents C D r in te re s t, i 11<IuI i u <r onservat io n is ts . lo d iscu ss th is p ro b le m , to look at the so lu tio n s that some people are try in g out in the S ta te s, and to see i f we ra n develop some g u id elin e s to solve, th is question o f d is p o s a l, not o n ly o f those w h ie h we are t r y in g to rem o ve fro m the. m a rk e t, hut- also ro u tin e d isp o sa l o f e,ontainers. T h i s is one actio n we are ta k in g in o rd e r to get- a t th is prob lem . W o admit- it is a p ro b le m . A ir. r .n 'K W iT . You say that yon suspended certain uses o f i.-I.-T because an im m inent hazard e xists, and you canceled ra th e r than suspended use on bind cro p s because. although a h aza rd existed in th at case, it w as not an im m in e n t h a za rd . T h a i sta te m e n t b rin g s to m ind several questions. F ir s t o f a ll, do you believe, you are required to suspend use o f an econom ic poison w h e n e v e r the. use in question create s an im m in e n t h a z a rd ? AVe kn o w yo u c a n n o t suspend u nless an im m in e n t h a z a rd e xists, but when an im m in en t h azard is present, are yo u required to suspend ? I>r. H .w i.n v . T do not see the d ilfere n cc. I f there is one. do you want to tell me? A ir . I h r n w i T . A n im m in en t h a za rd ve know is n ecessary fo r su s pension. W hat I am askin g is w hether il is alsosullieieut ? S e n a to r Il.u r r . lla v e von got that straig h t ? I >r. I '.w i .k v . I am m>| su re I u n d e rstan d the leg al d iffe re n ce . S e n a to r I I . x iit. !/( me sec i f I can slate it. We, are agreed that an im m in en t h a za rd is req u ired before von may su sp en d . I f an im u iin e iil hazard is present. m il-I vmi suspend ? M r. I '.w i.n v . I lo n e to ad m it I w ould be m ore co m fo rta b le i f I had a la w y e r s i ll i n g w ith me to a n sw e r that question because th e re m a y be a legal d is tin c tio n that I am l ot a w a re o f. S e n a to r Il.x irr. T h e o nlv th in g the qiic.-linn raises is w hether von are req uired by the law in llie e x c n l an im m inent h aza rd is disclosed to snspMid o r whet tie r you m e re ly m ay suspend i f th ere is an im minent h azard disclosed. M r. I ' .w i .k v . [ am not d e a r on that p o in t. w ill he honest w ith you. I am not clea r on that point. M r. Ih r K x v r r . A n o th e r question y o u r statem ent, b rin g s to m ind is e x a c tly what, the dili'orenro is belxveen an im m in en t h aza rd and just a p la in h a z a rd . AA'e ad ve rte d to the fact that C o n g re ss d id not define the d iffe re n ce . C a n yo u a rtic u la te the. d iffe re n c e as you see it an d ns yo u a p p ly it. in y o u r practice, in su sp e n sio n and c a n c e lla tio n ? D r . M v k k i .v . M ay I fr y and an sw e r to th at as n e a rly as I niav i p a ra p h ra se , th e one in th e d ic tio n a ry th a t I use,? I t seem s Unit, im m inent means som ething th reaten in g to happen im m ed iately. {'0 G 8 6 6 1 MOO 51 17207 Now, \vp, li,ave, of course, fri ve tIn* top priority, tlie liijrli priority, ili additimi lo lite, somethin}; 111rea ten in;; lo lnippcil iniiii<mlintel y to liny Inizimi to Immun health. Dr. Havi.kv. Tlnit is my iniderstandin<; of it also. .Mr. Hickwit. 'I'Iipii, in flip, ease of food products, if tlierc is a hazard, it is not an imminent one? Certainly one of tlie hazards wo aro con corned nlioiit, is tlr.it of liirlli deformities tlnit may lie oce.urnnj; riolit. now. llow would you respond lo that ? ('l'lio following informationy was subsequently received for llie record:) I I m p a r t m m n t o r Ac.iticiti.TUnr., flinen or i in: SixitsTAinr, Wnnhimjtnn, D.V., Jntll 1, JffiO. Scnnlor I'niup A. IIaiit, Chainini n, Snbeoniniiltcc on Energg, N atam i Ilrmarcr*, and (he Knviranmr.nl, Senato Cammrree Oontmillec, V. S. fienale, Wimhtnglim, D.U. D m a r S k n a t o r H a r t : In tlio tm n srrlp f. of tcsllin o ny preseli lofi tn .vini I liid lciilcd I wnM not clcn r nliont n i(tmstlmi yen nsltctl. Y o n r (incsllnii Telateli In tlie rci|iilrompTit of F I F R A to stiKiK-ml I f nny Imminent. Inizim i werp rmiml. O a r Olllco of Honorai Couiisol n dvlscs me tlia t tini Inw Is perm issive ami mit m nmlntnry on thla i>olnt. I t sla Ion, "T lm Soorolnry in ay, w licn lie flmls flint suoli action Is noco.ssary to |irovont an Iniinlnont lim am i to Ilio im lilic, l>y n rilcr, susppnfi Ilio registration of an conomie poison Im tnctlinloly." I rpcnminonil tlia t tlils clarificatio n lie nfifirfi to t lie record, nespcctfully suhmltted, Nun 11. rtAVI.KY, Director, Srirnrr. and Kdaralian. I ) r . R v i.im v . W e ll, let us look a t th is . A l A p r il 15 o r M a y 1. i f . fo r exam p le, fire, is planted in (lie sprin<r and lia n c s lc d ill I lie fa ll-- is so m e th in }; U nit m ifd it o ccur on t lie l ice d ia l w ill lie eaten (i m onths lienee, im m in e n t; is it Ih re a le n iu tr to happen im u ic d in le ly n o w ? S e n a to r I I a iit . I am triad .Mr. I '.ii k w i i is eondnel in*; I lie q u e stio n in ';. M r. H ic k w it . S ix n io n llis is md im m in e n l in y o u r v ie w . Is that, w lia l vo n a le s u rr:.res| n o ? D r . I '. m i:i.v . N o. s i r ; d ia l is not w lia l I am sa v in ;. M r. K u i, w i t . I lo w u h o iil .r>t W h e re w ou ld vou d ra w d ie lin e ? I) r . l i i i m .v . W e ll. I jruess I w ill mil oo beyond llie wnrtl " n o w ." Im m inenl h a z a rd m e a n s th re a te n in '; to happen im m cd iu lelv. M r. I ' u K w r r . In the case, oT fond c ro p s , w ill it a lw a y s he the case d ia l ih e y w ill lie. eaten fi m o n th s a f t e r s p r tiy iiifr w ith 2 . 1 .5 -T ? D r . I ' m .h i.v . N ot a lw a y s , th o ug h ,, ns I re c a ll, (lie r is k o f food crops for w hich there, are reristered uses. 1 th in k that tnkin; into account llie lim e o f the issuance o f cancel la I ion o rd e r and the sp e cific lis t o f final cro p s, as f a r as T re c a ll th em , d ia l is the case. M r. I ' u K w rr. Docs is fo llo w th at i f the evidence, were abso lutely d e a r d ial w henever we ap p lie d 2 .1 .5 -T to food crop s an il those food crop s w ere eaten, we slood a 75 percent chance o f a h ir d i d e fe ct o r, s a y , a 00 p e rc e n t ch a n ce o f a h ir th d e fe c t, (lin t the use on food cro p s w o u ld n o t c o n s titu te an im m in en t, h a z a rd to h e a lth and yo u w o u ld n o t he. a u th o rize d to fake, a c tio n ? D r . R .w r.r.y . I th in k w c are. gcttin<; h ack to w here we concluded th e he.nrin'rs la s t tim e . W c a re s p e c u la tin '; w ith o u t d a ta . I fin d it. v e ry d ifficu lt to develop a p recise percentage sta n d a rd w ith o u t h a vin g sonic eo n rrelc data in fro n t o f mo in ord er to m ake a jn d g m cnf. I>r. IlvKiii.y. M a y T g iv e yon a ta n g e n tia l a n sw e r and p o in t ag ain to a comment flin t D r. K a v lc y made w ith respect to o ur need fo r a u th o rity to make. a te m p o rary cessation o f m ovem ent while, we determ ine w hether or not an im m inent hazard would result? A n d if seems fo me fhe ease th at yon p ro vid e d w o u ld he. such a case. M r. l ' n 'K w rr. Y o n would have au th o rity to act? D r . I ' vr.m .v. W e do not now have a u th o rity in m y o p in io n -- not cle a r a u th o rity -- to act in such a ease. O b vio u sly, there w ould come a tim e i f we. were, su re o f the. h aza rd w hen such a u th o r ity co uld he exercised . A n d we w ould do w ell to w a rn , i f we could w a rn , o f im pending action. D r. R w i.r .v . I th in k w hat we are doing is p o in tin g up the diflie u lty in m a k in g th is kin d o f a decision. M r. Mi c k w i t . F t h in k it. c e r t a in ly does point, o ut th e d iffic u lty . T f im m in en t h a za rd is to he dc.lincd in te rm s o f m o n th s, o r less th an m o n ilis . and i f due process m a y ta k e as m uch as *2 o r > y e a rs , then c le a rly , if im m inent h azard is so defined, you do not have, adequate a u th o rity now to protect the p u b lic health. D r. liv K iu .v . AYe h clicve we need ad d itio n a l a u th o rity . We. said that e a rlie r. M r. K u k w i t . The. D a y s memo w h ich M r. W e ll fo rd re fe rre d to p re scrib e s c a n c e lla tio n in the. ease o f a reasonable doubt-'as to s a fe ty . Do yo n b elieve th ere is no reasonable doubt in the use oT 2,-1,fi- T on past m e lands ? D r . I 'w i .r .V . T h e w ord " iv a s iiiia h le " here, o f co urse, is siih ie e l to in te rp re ta tio n . A n d o u r in te rp re ta tio n is that there is not snllicient. e vid en ce to h a te reasonable do iihl in reg ard to range and p astureland : that is rie h t. .Mr. K ic k w it . Is th ere not a reasoiiahle douhf ahont the d e g ra d a b ilit y o f d io x in ? C an yo u say that it lias been proved beyond a reasoiiahle, douhf that d io xin is degradable? D r . F' v k k i .v . F>i\ K a v le y review ed the state o f o u r k n o w le d g e in the fo rm a l sta tem e n t. Aon w ill re ca ll that o u r k n o w le d g e at. the present tim e staled that photolysis occurred rath er q u ick ly in so lu tion exposed fo s u n lig h t. O ne m ay ra tio n a liz e , hut. one does not. kn o w , that the le a f su rfa ce a llo w s p h o to lvsis to take place. I n the so il s u r fa c e a p p a r c n llv d io x in is so hound that d e stru c tio n Foes not la k e p la ce . N e ith e r does it m ove. A m i. th e re fo re , hound to fho s u r fa c e , tin* h a z a rd is not im m e d iate. T h i s is as f a r as o u r knowledge) goes. A n d we are. seeking , as you w ell kn o w , to obtain know ledge as q u ic k ly and as th o ro u g h ly as we can in th is very d illieull. area. .A ir. K ic k w it . T arn not su re 1 h eard you c o rre c t ly so let me s u m m arize what I th in k you said. In so lu tio n , when subjected to a sun lam p , d io xin w ill degrade ra th e r q u ic k ly , lm t when hound to so il, when put. on s o il, even u nder a su n lam p it w ill not degrade ra p id ly . D r. B v rn r.v . That, is our inform ation c u rre n tly ; yes, s ir. M r. K ic k w it . A n d as to g rass, w hen you p u t it on g ra ss, we h ave no determ ination as yet? D r . B v r.rn / r. AA"c h ave no direct, d e te rm in a tio n ; n o , s ir . S 0E S6G rP " r,:j 172CB M r. H n n w rr. in ease, cun we sa y it lia s been proved l*yn<I a reasonable, doubt- th a t d io x in w ill d e g rad e w lie n put ou g ra ss? T h a t is a rh e to rica l question o f course. D r . I I a y i.k y . 1 f liin k we h ave to p u t th is in co n text o f the h isto ry o f the use o f the m ate ria ls. W e should recognize the wide num ber o f m a te ria ls in w h ic h d io x in s m a y he. present at. r e la t iv e ly low leve ls. C e rt a in ly , there has been sufficient p u b lic exp o su re i f d io x in s were accu m ulatin g over a long period o f ye ars fo r som ething to have happened. j It. is also indicative, that, when there have been problems with dioxins, we. have, been able, to pinpoint them immediately and correct them and eliminate those problems even in regard to the chloracnc. aspects of them. I think we have to weight this evidence along with all the rest, that we have. M r . I I u '.k w i t . I a o re c w ith y o n . D r. Ha v i.k v . T think the.ro is no basis for action at this point. M r . l i i i K w r r . 1' u t as you s a y we have, to w e ig h t the e vid en ce th a t you describe. W h a t I am a s k in g is whet her you believe, that th a t e vid e n ce is su fficie n t to s u s ta in the. b u rd en o f p ro o f-- w h ic h D r . H a y s h as stated is a. b u rd e n o f p ro o f beyond a reason ab le doubt---that d io x in is not. a, h a z a rd . D r . I '. a v i.k v . A r e yo u u s in g D r . H a y s ' w o rd s ? I do not h ave that- m em orandum in fron t o f me. Mr. I ' u'k w it . lie refers to live groups of actions, (iro up two is the grouii miller which cancellation would he. classified. And lie write- : T i n - : i ( t i t ` i H " h ` J i n i i M t ; i l ; r p i n**' w l n - f l fl t*;s<*n:iI*li* t l m t M o x I s t M its* l o !!.* if* !) t-r iIJi l i i i i H " - fl ;t ' r t| i Jl Is its tllrfrhMl r Ir ! . i l l i t ' l i n t n i . t i l v n- i . n l y . 1 |>r:i> i n r*. Dr. I '. 1 i i v. Vi-i. That i~ <1itli-r<-111 iban the way von staled itmi a f. mi mu c ago. Mr. I'. 11 i, n . Il h i I read "a lea oiiahlc iloiibl c \M - as I o sii fel v" as meaning when grouped with ill" a--nmplion that the hnrdeli of prool >, on |he lua mi fact u n r . which yon have staled is till* case, that the maim fact nrer must prove licvnml a I'ciroimdilr doubt that there is saTely. lie must elim m ale that doubt. I f be does not elim i nate il. we have a reasonable d"tib|, and .-ann-lial ion should ensue. Dr. Ha v i.kv. \ \ e. have, to come back to the slalcm enl 111:it we liavc Mot. found a basis for reasonable, doubt (bat (lie product as il is now registered and used is unsafe. M r. Jtir.icw iT. W h ich leads you to the conclusion that vmi have not loim d a basis fo r reasonable, doubt that d io x in on p a slu n T .m d is not degradable? D r . B v i- m .v . W e ll, t h a t DOlirJusion is hm| him* In w liir li I mTiI be le<| lieeause. in the, p ro cess o f d e te rm in in g w h e th e r o r not d io x in s e xist and in w ind, level th ey e x ist. Y o u reca ll that on the Tib o f A p r i l , w h ic h e v e r it. w a s, w hen wo w ere h ere, we entered in to the record first eonfirm d e xa m in a tio n o f curren t, levels oT d io x in s in li.l..r>-T w h ic h w e re on the. w h o le quite, lo w . T h o s e are a m a tte r o f record. So we have to fake into account first, w hat are (lie facts. A n d we m ust. I believe, d eterm in e the facts w ith respect, to w hether o r not. and lo w h a t e x te n t d io x in is p resen t. . 111 Mi- .1 ,i . jMimitdiv to no into it, any lu riu cr, bill I avoiiId like fo say tlnil if yon Iiatl no reasonable doubt 11s to dioxin's degradability, wlv n it you running these tests? I>r. Itvr.iu.Y. I would not go beyond Mu; furls. Wind, wo reported is Iliat in !Ui hours on tiro soil surface, avc found no evidence as to tlic degradability n sunlight. .Mr. Hii kavit. And yon have no ca donee as to tlie degradability of dioxin an g ra ss? I >r. Itvr.in.Y. 'I'ltal. is correct. .Mr. itii'i\wcr. And you have, no evidence as to the. dcgvadability of dioxin in cows, in cow tissue and in human tissue if humans should invest, produels which are the produce of those c.oavs? Mr. Ha y i.k y . I would hesitate, to say that we have to hare reason able doubt about a product before we make a scientific im piiry in regard to (lie phenomenon involved. I would hesitate to say that. Mr. lluuovrr. I withdraw that. I tut l will not withdraw my con- rlusioii that you have not proved In me beyond a reasonable doubt that I here is no bazard. Mr. Ha y i.k y . That is a judgment. Mr. Ihi'Kw iT. Applying; this same form of approach to -1). did mil the I >iiiilet ies Import -a v that 2. i I t wa- put ent iall v da ilifemi is { And is there any ditl'erenee between ti e term-; potentially dangcroii.s and reasonable dinilil a ; to sa fel v Mr. Mvkim.v. The fnllli.ll lr>o|d cm C lih -. 1 hrlii'Ar. a I ii--( nunte from tlie report whi> li rel'i-rred to is ic c e-ti-r.- of J. I M am i alo referred to lb te-a litters .->11ji--fi-i| |o I 11. pi-r in n iie b no inerease of abn urn la I Tel n s-s pi r lit ic r >'ill i I. .Mr. It Ml , ivrr. A ll' tlic.-e lin e r n-ed in ptud m l- euivenllv mi the market { I )r. Hy k iii.y . <Hi, yes. Mr. Ha y i.ky. Thu Department of Health. education. ami Welfare would be testifying; further in regard to J.l-M tomorrow. Mr. Itif'KAYiT, T h at is true, lint you do make the decision as to whether or not a product ought to hr canceled. I laioiv vou seek advice from flic. Department of II I'iW. Yon arc reipiired to. Hut as of noAV, yon have made the decision not to cancel `J.l-M . Therefore., f would like fo rile certain evidence which, again, in my mind creates n reasonable doubt as fo the safety of J .l- I) , perhaps only as to sa fete of t lie 2,-t-I) esters whirl yon mentioned, lint yon h a w admit led that these esters are presently in marketed products. I am told tlm l Mr. C la ra W illiam s at F M A is running; an experi ment on a strain of hamsters and has produced teratogenic, etfects. In (he. W hiteside article, it Avas staled (hat the incidence of hirlh defects avms higher than in the case, of c.nmpavahh. dust's of J .l.h -T . The Minueties data showed a. high incidence of abnormalities in the offspring of mice. F in a lly , Mr. Yorrctt's studies slow ed comparable abnormalities in chicks, comparable to I lose found in 2,l,i>-T. In light of this evidence, and in light of tlie. possibility that there may be dioxin in J .l- I) it Avould appear to me th a t the rec|uisife. reasonable doubt exists. l ) r . B v k k i.v . W e .ll. s i r , I hope and l (ru s t Huit. you \vm ask h h .^ qu estio n s when tlie ] I FAY w itn e ss is before yo u to m o rro w . Am i in the m eantim e, if. is o b vio u s. s i r , tlm t. we lu iv e not. (lie b a sis fo r re a so n able (loiil)f, sttflicicn f t<i w ;ir r ;in l. in o n r o|>inion the c a n c e lla tio n o f registered uses o f l i . I-D . M r. r .m is w r r . W liie li m enus Unit, yo u lu n e not. found :i reasonable (loulit. as lo t lie sa Tety o f _ M - D ill eurrent. uses. |)r. Kvr.in.v. Yes. M r. I '.K K W ir. Does (lie evid en ce I cited create a n y douhl w h a ts o ever in y o u r m ind f D r. R v is u .v . S ir , I lu n e review ed I lie evidence most ra re I w ily. T h e I Jep arl ment. lia s not found / siillicie n t b asis fo r e stab lish m e n t o f a reasonable d o n ili w a r r a n t in g the. ca n ce lla i ion o f `J.- l- D . A n d I co ncu r in that position. .Mr. Hick wit. O u r lir s l w itn e s s th is m o rn in g . M r. W r l l f o r d . sucr- geslcd that action to lim it the use o f 2 .1.-T w ould be in co m |d e le w ithout s im ila r action on S ilv e x , w hich is closely related lo '-?.l.a-T. M r. W e ll fo rd 's reasonin'.'' w as th at both pesticides lu n e g .l. - lri- chloropheiiol as an interm ediate product am i that d io xin s are form ed in producing th is interm ediate. I am in fo rm e d th a t D r. V e r r e t l's w o rk at F D A h as sh o w n S ilv e x to lie h ig h ly teratogenic to c h ick s. Ilo w w ould you an sw e r M r. M ell- ford's argum ent? D r . H v v .m .r. A g a in , r e fe r r in g to 11 F A Y the q u estio n , flu* p r e lim in a re in fo rm atio n that we lo n e w hich is lim ite d . I b elieve, to a s in g le eonlpjefe a ssa i' w ith -oon* c o n h n ir.il mu ' i f that a ssa y an d verb al rep o rts o f o th e r e x a m in a tio n - on :'.I..'i T . that cu rre n t m a n u fa c tu re is assum ed I n c o n ta m h -- Ilian ) ppm of let rncldorndih'ctiv.o- para dioxin. f I n o . ' t a d to tic c .r r / 'i.' 1 in m i a u - w r r hecau-c the e vid e n ce upon w h- h ' . d I . . . . : - . .11. I .C i : ! . I Soria . I ii. ioi < i.i \ o\ (> v. a it I re fe r. I sa id `J . l. - T . I am Mr. Hn m u i . Hot lie .n o h tin- n idem e is s m a ll, von re g a rd 1 ns proo I ).o i.m>1 a Ira -on.al ile doni it f D r . I ' v iu i.v . Heyond a iva -n n a b le dn iih l that w h a t, s i f t M r. Hu ixWi r. A s to I lie sa let v o f S ilv e x . I ) r . H vr.m .v. I have -aid there is sullicienl evidence, in in v o p in io n at- p resent a v a ila b le to e sta b lish a reasonab le doubt, o f the s a fe ty o f (he. reg iste red uses o f S ilv e x . M r. B in c w r r . I notice that S ilv e x is one o f the IS pesticides th a t von listed to be checked fo r d io x in content. D r . l! y i:i ;f ,v . Tf. is. ind eed, ft- is one o f the Ir ig r o u p in w h ic h in m y opinion m ost p ro b ab ly te tra d io x in w ill he present. A n d , th ere fo re . we are seeking to determ ine, w h e th er or not in fact it is present. M r. R ic k w it . A n d w hen do yon expeet the resu lts o f the. tests on th is and (lie o ilie r 17 p ro d u c ts ? D r . R vv.iu .y . 1 v e ry nnieh hope that, w ith in .1 m o nths, we w il l h ave com p leted at. least th e lirs l,g o - iiv o n n d on a ll o f the IS . M r. R u tv w it. W Iiv " m onths? D r . Hvi-.ui.v. 'W hy? M r. H ic k w it . I ask th is question from ignorance. - <Tj o CM r- I >r. /!> r.m.v. I i m d c r s l u m l . It is s i(111>I \` :i m ailer of (lu* rare and sophist ii*:i I inn of the method. I In- time rc(|iiim l lit g<4. I in- jolt done. Mc have Ittiill, Dr. Hayley has j)(iinlc<( oui, ;m isftl.-i( ifin l;il)<tr:il(>ry--l s:i y huill. I fli;i that to eipiipped ;m isolai inn l:ili(ir:ilory. M V have the seienl isls. MV wo, in I'.-Mi. romlv I" proceed. Tlio. lime. therefore, would lo I lie. lime re<|uired lo do llio analyses :md verify them. Mr. liri'Kw rr. Thanl,- von vrrv imicli. S o n iilo r H a r t . ( n ille m o n . (h a n k y o u . Il, h as lioon an in te re s tin g and iu fo ru u d ivo m o rn in g . ( 'o n g ra lu la l ions a g a in fo r tlio. e ffo rt that, y o u . I him s u re , p u t in to d e velo p in '!; and then p e rs u a d in g d e p art- n ien lal aeceplanre. o f (he suggested am endm enls. I hope im p ro ve ment in llia t. ltasie. la w soon w ill le w ritte n . 1 )r. I ' .w i .k v . T h a n k yo u , M r. ( 'h a irin a u . S e n a to r H art. MV. a d jo u rn , lo resum e to m o rro w a t 11 a .m . in the-m orning in the h ea rin g room o f the (.'om inittco on Commerce, 5110. (M ' h o re u p o n , a t 12 40 p .m .. th e h e a rin g recessed to reco nvene at 11 a .m . on T h u r s d a y , J u n e I S . !!)7 o .) 08( EFFECTS OF 2,4,5-T AM) RELATED HERBICIDES ON MAN AND THE ENVIRONMENT -1----- TH U RSDAY, JU N E 18, 1070 U.S. Sknatk, COMMITTK ON Ctl MKIM!K, SuiK'OiUMITri'.K ON Enkiic.y, NaTUR.U, Rksouim-kr, ANO Till'. JOWnVaIsIIhOiNnMgtKoNnT, ,D.C. 'I'Ik ! sn b co m m illc e m r.l, p u rsu an t. fo a d jo u rn m e n t, a t _11 : 55 a .in . in n iiiin r.110, Xe.w So o alc. Ollico. i 'm ild in g , H o n . P h i l i p A . H a r t ( c h a irm a n <>f (In- sn b co m n iit le e ) p re s id in g . I ' re.-enl : S e n a to r J l a r l . S o iia in r I I m :t . T I io oniinilloo w ill lie. in o rd e r. I.i l mo a lie in p t in ap o lo g ize lo I lie. w itn e sses w lio lia v c lioon in- cmm.i -ii i o n - I In llii- ; n i i ti ill o d e la y . A H ire lin g w a s c a lle d y e s lc r- dav n i I !-. I [loior.il o l ae.' ii'.- fu r in a .in . a n il I fe ll co m p elled In | , n : ( i l l . . I n ; li wo o "iild in u ia L'o 111i 11lt*-5 a lilil* m o le re s p o n sib ly :ii : . i - a l .i- \ a - i 'o iil ' I o i - ru n n i i c / c i ci \ b ody c b e 's b u sin e ss. | M' - I"ila v i- I ' m <1i ilign i-bed science a d v i s o r lo I lie. I'l. .I '. I >r. I mi I'.i 'l" o. statement o r dr. i.r.i: a. d.iRridge. science advisor to the ri:r.rim ::t and director, oitice of science and TECH NOLOGY: ACCOMPANIED BY DR. EDWARD J. BURGER, JR., TECHNICAL ASSISTANT h r . h r I '.iiim m .. M r. ( T ia ir m a n , I have. asl,-ed m y asso ciate , D r . Cni-yer. o f my ollico, lo accom pan y me. l i e is an .M .l). w ho has been follow ing the m a ile rs related fo health and the other e lle cls o f pc.-1 io ide.'. M r. C h a irm a n . I have, te stifie d before, th is com m ittee, on A p r i l 15 on the `2 .1 .5 - T s u b je c t, an d I am not sure, th e re is v e r y m uch to add lo w hai I said a t th a t-tim e , hut there, are, a few p o ints T w ould libo lo review and em p hasize. I re iewed I lien so m e th in g about th e h is to r y an d d e ve lo p m e n t and value o f I he use o f th is h e rb ic id e an d I used th a t re v ie w as a te xt from w h ich to d r a w w h a t T co n sid e re d to he. some, im p o rla u l g cn cra li/a lio n s about pesticides, and Illese are some o f (he m a ile rs I would libo lo repeat. Eel. me begin by p o in tin g out th a t 2 ,1 ,5 -T is a pesi irid a i chem ical w hich has been in tro d u ced in lc n lio n a lly in to m an 's su rro u n d in g s because, o f I he benefits presum ed (o fo llo w , it s pu rpo se w as lo serve as an a d ju n ct to o th er m eans o f weed and brush control in land am i (57) o 04 58 5!) 17211 w a te rw a y :m<l a g r ir iilt m ill m anagem ent. O v e r :i period o f 20 y e a rs it h as p ro ve d its u t ilit y so th a t we. ire, now in ;i p o sitio n o f re Ii fiv e dependence on I It is m a te ria l. However, especially in recent nionllis, we have begun to question in greater Mini greater leplli flic possible IniniMii IicmIHi cllccts of pcsliciilcs like. 2 .1 ,5 - T M in i this Iimk rc(|iiircd m greater sopliisticMlion in resciiivli Mild Ic*st injj; fInin wus previously I bought, adequate. T h e example, of co urse, wits (lie. J ' ioneties stu d y for the N n lio n n l C a n e c r In s f iln le . P re v io u s research on 2 .1 .5 - T lctd co ncentrn ted on the Mcnfe. toxicity of Mint compound mid Inid show n th is to be of ;i low level. T h e 1` ionelies study represented n departure in that it. in re s titu te d the potential o f the herbicide, to provoke tumors, birth defects nnd genetic Mlfer.'ition in appropriately exposed cxpcrimentMl a n im a ls . 2 .l.r ,- T emerged from th is s tu d y is 1 possible. teratogenic, agent. A s T have said, th is study wus u dcpurlure in Severn I wnvs. W hereas nearly ill of the background toxicology on pesticides had been performed ns purl, of the development process by the develop in '; company o r industry, th is study wus hiuuched nnd pnid fo r by the ( io\ernm eiil. I hinted ( hut this might represent m precedent. I f our society dcm.Miids u very high lend o f sophistical ion in ibis type of resenrcli, industry niny not be :d>lc to nll'ord the incrcMsed cost, o f develop ment nnd furl her development of vnlunhle new products m a y be discournped or provenled. lienee I suggested licit new w a y s of distrib ulinp I lie costs of (his work mny have to be found. Kxpendit ures of public funds iiid fovrrnm rnt participation in this resenndi m a y lie desiruble. I em p h a size d lic it it a n v p o in t in lim e , we find it d illic u lt to per. com p lete in fo rn c il ion about the I rue h aza rd s o f m iiv p e slicid e o r m y o ilie r (diem ieul su b sliin ce . T h a t is, reseu" eh in th is nrc.u ( ms in m iiv o th e r) Iims no finite, end p o in ts. Il m ny In k c lonp e x p e rim e n ts w ith m11 k in d s o f leve ls nnd ill k in d s o f o iro in .isln n ce s to im ik e n n v such a sse rtio n nnd one run n e v e r be sure. w ind, new reseurcli re s u lts w ill turn out. A s one p erfo rm s more rescai-cli to in ve stip n lc vurio u s hypotheses, one in e v ita b ly raises a d d ilm n a l i|iiestions-- ns w ell is unsw ers. I t fo llo w s fro m th is I I imI n n v re g u la to ry system fo r p i'stic id e s m ust be nlile. to neeommodnfe new ind unexpected in fo rn c itio n . I pointed out tlu it our present arrangem ent fo r reg ulation is not s n llic ie n tly fle xib le to reflect n ew in fo rn c il ion ms it encniM les fro m re se llre h . A p n in , these p o in ts w ere c Icmi I v illu s l r.-ilcd h v the ense o f 2.1.5-T. W in d I sa id in A p r il w us (h u t there, does not e x is t n. n ie c lc m ism w hereby the ( ovcriim ent. m ay exercise, p rm h sit nnd u n erp iivn eiilly e ll'e c tiv e re stra in t. te m p o ra rily on the. re ce ip t o f new , u nexp ected in form ation nnd possibly p re lim in a ry results and w h ile a w a itin g more definitive, conclusions. Til m a n y w a ys the F e d e ra l G o ve rn m en t did act, w ith d isp a tch in flic case o f 2 . l ,r>-T. A f t e r th e O cto b e r lit) announcem ent, about, r e s t r ic tio n s im posed on 2 ,t..ri- T a d d itio n a l research stu d ie s w ore Iiopun in a num ber o f apencies. These studies were in itiate d both bv the G o ve rn m en t and by in d u s try . T h e aitn in every case w as to co nfirm or e xten d the u nexp ected re s u lts o b tain ed I rum the. I ' iom l ii s- X a lio n a l C an cer In stil ute si udies. O ne o f llio new issues e xa m in ed in the new set o f invest ipal .on.; w as I hi', im p o rt 1 lic e o f im p u r it ie s p rese n t in m an y sam p le s ol 2.-1,n - T . It had been d isco ve re d (h at o v e r a p erio d o l y e a rs co m m e r ced 2,1.5-'!' contained v a ry in g am ounts o f a h ig h ly toxic im p u rily w h ic h w a s 1 m em b er o f a. f a m ily ol p o ly c h lo rin a te d d io x in s . .I w as o f obvious im port mice to asce rtain the re la tiv e eonl rib iilm u s o f the 2.4,5-T and the d io xin im p u rity as potential teratogenic npenls. T h e d io xin wus know n to be v e ry to xic. H ence Ib is (|iicslio n became part, o f the exp erim ental aim . F o rtu n a te ly , t.eriitopencsis is a re la tiv e ly acute a H air and e xp e ri m ents necessary to investip nte th is phenomenon are sh o rl-lcrn i exp erim ents. A n sw e rs w ere expected in a f a ir ly short, period o f lim e. Some, o f these, c o n firm a to ry e xp e rim e n ts w ere u nd ertaken b y one o f the. N a tio n a l In s t it u t e s o f H e a lt h -- th e N a tio n a l In stitu te , o f K iiv iro n m e iiln l H ealth Sciences. The, results of these experim ents w ere rep o rte d to yo u as fre sh out, o f th e la b o ra to ry at the. tim e o f the last, h ea rin g s. In b rie f, you m ay re ca ll, these results im p licated both 2.1.5-T am i 2,.`i,7,.8-tetrac.lilorod ibeii7,o-p-< lioxin as p o te n tia lly te ra to g e n ic in n a tu re . I 11 r a ts , o v e r th e sam e dose ra n p e , o n ly th e d io x in ap p eared to prod uce b irt h d e fe c ts. If. w as p r in c ip a lly on the. b a sis o f these re s u lts that S e c re ta ry H ard in , Secretary Fin ch and Secretary Ilic k e l jo in tly announced the. se rie s o f rest rie l io ns oil t he. use o f 2 .1 .n - T . These, w ere related to you by Ih cS u rp e o n G en eral, D r. Ste in fe ld . In b rie f, the p h ilo so p hy behind these rest rie l ions w as hoped-for pp >1cel ion o f w om en o f e h ild lie a r in g age. T h u s the D e p artm e n t o i \ :r ii 1111ore suspended the rc g i-l rat ion o f lu p in ! fo rim d a t n il* o i the " 11!;iIh w fo r uses aro un d the home and o f ill fo rm u la tio n s fo r use on lake . ponds an d d itch lu n iks. In a d d itio n , resist rat ions Mere c:in ci,||i,d fo r uses o f n n n ru |iiid fo rm u lai ions around the home am i o f a ll fo rm u la l ions fo r use on food 'Top-- intended fo r p u b lic no-mopl ion. H I Ibe total amomil- of J.l.a T ii ia| in t liis count r v fo r ill p u r poses it w as c s tim a lc d Ib at these rest r id in n s a p p lie d to about 20 percent--;tbe. 2<i percent o f the cases w h e re h u m a n exp o su re w as p o s s ib le . I fir m lv b e lie ve that. the. issues raised b y th e ease h is to ry w h ich T o utlined in A p r il co ntin ue to he p ro m in en t. In a w a y, i suppose, we can th an k the existence o f the questioning a b o u t2 .4 .5 -T for b rin g m g to o u r attentio n m atters such as the ones I have described. T h is study has served ns a most useful vehicle and we m ay learn some lessons fo r fu tu re stu dies. H o w e ve r, as I w arn e d , in v attem pt to a n s w e r the. rese arch q u estio n s raised w ill in e v it a b ly ra ise some, ad d itio n al questions. rs u g g e s te d th a t in som e w a v s w e w ere f a i r l y lu c k y in o u r i 11 vestipntions o f 2 .4 .5 -T . T h e issues h ave appeared h iir ly stra ig h tfo rw a rd and it. w a s p o ssib le to s t a r t c o n firm a to ry e x p e rim e n ts f a i r l v quick-h and to ;;cf. co n firm a to ry resu lts q u ic k ly . Y e t. w h ile th is ap p ea rs to lm vc been a modest, success s to rv , some m ay rig h tly a s k : S h o u ld n 't the k in d s o f exp erim ents w hich were S0G 866 rM9Sl (0 m ohili/.ed on I lie s|>nr o f Mi<'. m om ent fo r - J .l.fi- T h ave been a cco m p lish e d on ;t m ore s y s te m a lic b asis m il x v illu m t the s p irit, o f !i c r is is necessary to urge them on { F u r t h e r . <uu* ask w heth er o r not it m ig h t be d esirab le to su p p o rt ;i f a i r l y so p h ist h-ah d level o f in xcst ig a tio n fo r ;i In rjic iiiin il)e r o f p e srie id a l c h e m ic a ls - not ju st *2. I,.">-T. N o n -. 1 m id o ttie rs h ave o illin e d tin ' resenreli xvnrk on `2 ,1 ,5 - T nnd I lim e term ed it re h d ivo .lv s o p liis lic n lc d . V e t 1 w ill hitvo to n d m it tied there Inis hern utmost, no w o rk done, to e lu cid ate the in e ln h o lir h a n d lin g o f th is h o rh irid e ill fin* :tn i inn I o rg a n is m . T h e re is little knoxvn in liioelieniie:d term s o f the m echanism o f its actions an d (h e re is e s s e n tia lly no k n o w led ge, o f a n y possible, in te ra c tio n s between th is chem ical and other m aterials. In s im ila r fashion we arc p o o rly info rm ed about, the ch a ra cte r is tic s o f the dose-response re la tio n s h ip fo r v e ry lo w dose. le v e ls. T h i s , o f course, is the situ atio n w hich we lace in real life in the ease o f a v a rie ty o f e n viro n m e n tal a g e n ts --in c lu d in g p e sticid e residues. Ilc r o the problem is a s ta tistic a l one. In o rd er to d e rive m ean in g fu l an sw ers w ith any useful level o f confidence, very larg e colonies o f e x p e rim e n ta l a n im a ls must be tested, o fte n o x e r a. lo n g p e rio d o f tim e . I suggest, these co nim eid s to illu strate , that, there, am vario u s levels o f so phistical ion in research. Tn the rea lm o f p e stic id e s the level o f o u r rese arch a r liv if .ir s m a y not. have kept, up w ith the stall* o f that, art n o r w ith a co rre sp o n d in g Ir x c l o f (iiesl o ilin g to w h ich p o lic y m a k e rs and the p u b lic an*, now seeking answers. T h e v e ry e xcellen t report on re - e a i-!i needs co m p iled hv an a d v i so ry task force to the S a lin iia ' lu a ilu li- o f F .n x ilo iim c n la 1 H ea lth S c ie n c e s out lined llie -e research are as \ c r v w ell and v r r v e x p lic it ly . T h i s r e p o r t . I a m i n f o r m e d , is ju.<i m o w b e i n g p u b i c hed. A l l ol t h is -- n ion* s o p h istic a te d re se a rc h , m ore e x p e n s iv e resea fe ll, re-ean h sponsored b v tin* f ho .rnm enl - - w ill cost m o ney. A g a in . I re p e a l, il a re a lly se rio u s th ru st is taken ill I h is d ire c t ion xve ni.av be o b lig ate d to lie d new in s titu tio n a l ave n u es fo r a c c o m m o d a tin g (Id s rosea iv li since, as a p ar! o f the cost o f d evelo p m en t, (lie, b ill to in d u s tr y m ay In* h ig h e r than we m ight d esire. A ll o f ibis d ise ii--io n brings nic (nee ag a in to a point, w h ic h I m ade in m y prex iuiM te stim o n y and xvhioli I feel is xvorlh e m p h a siz in g . hih* xxe as a so cie ty lia x e recent lx* begun (o ask more, p e n e tra t in g q u estio n s about Mu* po ssib le adxer.-e h e a lth e lle e ls o f e n v iro n m e n ta l ag en ts ;( is nut c le a r I hat xve k n o w Imxv p e n e tra tin g th is quest Mining should lie or must be. \\ bat I sa id before w as that xve bad set o u r s ig h ts h ig h e r. W lia t. T sh o u ld ad d is that we are not su re Imxv h ig h th e y sh o u ld be set. F o r e x a m p le , up |o the present tim e xve lia x e been x x illin g to liv e xxitli a x-lcMi m uter w hich (he am ounl o f to xico lo g ica l research p e rfo rm e d on a p esticide xvas to some ex lent:, related to llu* p ro b a b il ity o l h u m an exp o su re . V ilh a lnxx* o r se e iiiin g lx' n e g lig ililc p ro b a b il it y <il e xp o su re , r e la lix e ly lit t le u n d e rs ta n d in g xvas so ugh t an d lit t le research xvas u n d e rta k e n , in fa c t, one co uld a rg u e th a t sin c e the a p p e a ra n c e o f residu es o f 2 .1 ,.">-T lia x e been rare, e v e n ts-- it is x-o.ry ra re to (m d m easurab le resid u es o f "2 ,!.u - ' l'. on food-- th e re fo re ono 60866f V. 01 , | j , | j,ni | i : m : I n k n o w t o n m u c h a b o u t , l In*. t o x i c o l o g y o f I In- I m i 'i .i - |.|c. N m v w e a re more, p u rl ir.nl:ir. I le d Ihat. w c sh o u ld ho more, rxplio.it about. assu m p tio n s su-h as Iho-o. I f (.hey a rc v a lid th e y w ill s t a n d o n t h e i r o w n merit.. I f they are. mil. v a l i d w o s h o u l d e h . i n re t h o r n . I a m h a p p y l o s a v t h a t , m y office is e x a m i n in g q u e s tio n s s u c h ns th ese a t th e p r e s e n t tim e. T hank you. S enator H art. S e n a t o r 11 act. T h a n k y o u . Y ou suggest. th e possibility! th a t th e d o v e rn m e n t m ay have to assume, a g re a te r role in an y te stin g are a b u t specifically in the m ai ler o f pesticides. J)r. D irJhunui:. Yes. ... S e n a t o r J I a u t . Y ou i n d i c a t e , t h a t , o t h e r w i s e t h e h i l l to i n d u s t r y m ig h t he h ig h e r th a n w e m ig h t desire, w hich I suppose, is a n o th e r w av o f s a y in g an in d u s try co u ld n o t afford it. J lo w should wo read that? D r. Dnlhimr.F.. W h a t J m e a n t to sav is if in d u s try is required to c arry on years o f very expensive research before any new product, c an lie m a n u f a c tu r e d , o b v io u s ly i n d u s tr y w ill n o lo n g e r he in te re ste d in m a n u fa c tu rin g new p ro d u c ts because, they co u ld not recover fho lo ss. 'T im s the. c o m m u n i t y , ( h e s o c i e t y w o u l d he. r o b b e d o f m a n y future, very valuable chem icals w hich society might, lind extrem ely im p o r t a n t f o r h e a lth a m i o th e r reasons. T o impose. Ibe, b u rd e n o n a p a r t i c u l a r c o m p a n y t h a t he. Io r e i t c a n m a r k e t , a p r o d u c t , i t m u s t undertake m illions and m illions of dollars m ore w orth of research t h a n 1 h a s in ( lie p a s t w o u l d s i m p l y s l o p t h e d e v e l o p m e n t o f n e w products. Therefore, it seem s to me only fair, since we w ant to protect N O 'idy as a w h o le h u t also to encourage, be.nelils to society, th a t S'l.T-iy as a whole, o u g h t lo particip ate, in th e cost o f d e te rm in in g v ' - ii i l l " d a m a g e s m n v h o n s w e l l a s w h a t I h e b e n e f i t s m a y he. S' " iio r li v e r . T h a t th e n w o u ld he y o u r basic, a n sw e r to (he 11*i <>r a r g u m e n t t h a t r e s e a r c h is j u s t a n o t h e r e l e m e n t o f t h e l:i' t(" ' '! (' -on. :I U . I 'i I I i . Vc . 11 . | | i. I : 11 t h e i i ' i t i i f t h e p r o d u c t s h o u l d h e a r t h a t c o s t a l o n g v. it h hi !, r i o i I Jr. D r Ih:tf",i . Dvre-llv. I am n ot sa y in g that, th e m am ifae- n r r rI s h o u l d n ol a l - o l.i-a r ` , . l a c l i a l r o - f ^ . J I,* s h o u l d m a k e s u r e l l . a l l h " p r o d u c t tl c i t h e i-: i,g fo m acl cl is not d a n g e r o u s ly poi o i i o i i ~. d o e s not h a v e " I n m u- n d v e r- e h u m a n h e a lth effects. Iiidii fry lioidd he re q u ire d to u n d e rta k e a re a s o n a b le set. o f e x p e r i m e n t - . a n d t h e y a l w a y s d o . i n a 1-'-u r e t h a t t h i s p r o d u c t h a s a r e l a ti v e l y g o o d s a f e l y f a c t o r . Dili it m a y l a | , c v e a r s t o lin d mil; lo w le'-cl a n d e asily h id d e n d a n g e r s w h ich sn in cliin rs m n v hecom e o b v i o u s o n ly w h en m ass ire. is u n d e r ta k e n . T o h e lp a v o id these, d a n g e r s T th in k some. I'Vdernl p a rtic ip a tio n in Ih e research p ro g r a m w ould he desirable. S e n a to r I r.wrr. D o y o u k n o w w h e th e r th e a d m in is /ra t ion in /e iid s to e m b a rk on b ro a d n ew research p ro g ra m s in th is a rea? D r . D i d 'icuioi--.. T h e r e are, s e v e r a l a g e n c i e s w h i c h are. d e v e l o p i n ' ' p la n s, p u rs u in g re search in th is a re a , a n d T believe, an a d v iso ry c o m m itte e o f (he. D e p a rtm e n t, o f I I E W h e a d e d b y D r . E in il M ralc 0 0 -2 0 2 -- 70------r, Od >H CM r- G2 is Minkin;; som e p ro p o sa ls to JITCW a b o u t su b s ta n tia lly e x te n d in '; ils research a n d te stin g activities in th is lield o f pesticides, a n d about, developin'; extensivo facilities, largo anim al colonies an d largescale testing equipm ent an d personnel, to carry o u t extended tests in th is field. T hese are recom m endations th at arc being form ulated and aro b e in g p ro p o se d to IliOW k I d o not. k n o w w h a t th e s ta tu s o f th e m is a t the. m o m e n t. S e n a to r Jl.u rr. It. is likely y o u w o u ld n o t h a v e th e fig u re w ith you, but. let. m e a s k t h e q u e s t io n . P e r h a p s it. c o u l d b o p r o v i d e d f o r t h e record an d I have no idea w h a t it w ill show . Put, w ould it be possible to id e n t if y th o se a c tiv itie s w h ic h are, n o t u n d e r t a k e n b y t h e D o p a r lin o n t o f D e fe n se that. are. com parable, to the. lino item research a n d d v e lo p m c n t that, is d o n e b y th e D e p a r tm e n t o f D e fe n s e ? T h e to t a l fig u re fo r re se a rc h b y the. D e p a r t m e n t o f D efense, is in th e ra n g e o f $7 billion a year. I low m uch are we sp en d in g in o th er research? D r. P u l 'nmm::. T h e to ta l F e d e ra l budget, fo r re se a rc h a n d d e v e lo p m e n t in th is current, y e a r is close to 17 billion. S e n a t o r 11 a i m '.. I n c l u d i n g t h e P O P ? D r . P u' I '. i.-iu o k . I n c l u d i n g t h e P O P . I f y o u l a k e out. s o m e w h a t o v e r $ 7 b i l l i o n o f P O P f u n d s , i t is $!> b i l l i o n t o $ 1 0 b i l l i o n in a l l o t h e r b r a n c h e s o f the. ( o v e rn m c n l. S e n a t o r II.\i:r. W r w ill let o th e r s ju d g e w h e th e r th e a llo c a tio n o f t h e r e s o u r c e s is o r is n o t p r u d e n t . I t h i n k it is g o o d t o h a v e i t i n the record. Y e s te r d a y we received te-1 ninny fro m th e D e p a rtm e n t, o f A g r i c u ltu re . W h e n w e th i n k about c h a n g e s in the. sv sle m o f p e stic id e research a n d c o n tro l we h ave to th in k about, c h a n g e s in th e basic, la w o f pesticide, re g u la tio n s . In c lu d e d in I lie (e.-lim ony y e s te rd a y f r o m the D epartm ent of A griculture were a num ber of suggestions and c h a n g e s t h a t th e y re c o m m e n d he made, in the. b asic act. A r c y o n fam iliar w ith Ihose suggestions? P r . I ) i ; I *i: 11w:i P r . J t n r g e r t o l d m e a b o u t , t h e m t h i s m o r n i n g a n d I h a v e a r o p y o f t h e m h e r e , a n d we. h a v e d is c u s s e d t h e m . T h e s e a r c in line w ith som e o f th e su g g estio n s w e h a v e h a d w ith A g ric u ltu re a n d o th e r agencies; nam ely, (hat. there is n o t sufficient flexibility in th e p resent, s ta tu te to lal;e. a s u ita b le a c tio n in a ll eases w h e re n e w in form al ion becomes available. S o m e tim e s new in form al ion like the I 'ionetics s ln d v is very s u g g e s tiv e bill, cannot, be s a id to be finally i-onclirdvc because, o f tins sm all n u m b er o f anim als and sm all num ber of rirrnm slanros in v olved a n d Ihe sepa ra Iion o f an im p u r ity m a v not. he latum care, of. It w ill frc q n e n lly h a p p e n t h a t yon w ill g e t p re lim in a r y s u g gestive. r e s u l t s n o t sufficient, t o a b o li s h the. use. o f a c h e m i c a l b u t siillicicnt. to lake. some, pru d en t, actio n u n til more, final re su lts h a v e been obtained. T th in k th e A griculture, su g g estio n s do move, in this directio n to give, for exam ple, w h a t they call p relim in ary suspension au th o rity . S o if a d a n g e r sig n is raised you take, prudent, te m p o ra ry action a n d continue further research. I f the fu rth e r research confirm s th a t safety is th ere a fte r all you can remove, th e suspension. I f f u r th e r research proves th e d a n g e r, th en p e rm a n e n t suspension can bo achieved. 0TER661 V O'5 S t- lK ilo r J I.MtT. I d i d n o t q u a r r e l y e s t e r d a y w i t h lice ] rl ::ni.l " f A g r ic u ltu r e 's int.ei p rr l a I ion o f th e basic. a ri. ( tv c r n ip h t I h a \ - i i i ' l . a s 'V e a l w a y s d o , to just-iTy w h a t w e d id , n a m e l y , those. o f u- "h<> w r o te . t.lio. l a w . I a m n o t c o n v i n c e d t l i n t t h a t s t a t u t e ^ p r o h i b i t s i h e D e p a r t m e n t o f A g r i c u l t u r e , w h e n , :is y o u s a y , t h e s ig n a l goes u p from suspending the m ark etin g of the product-- I am not sure that C ongress sh ould bo held to h av e said that, we ex clu d ed th e possibility of a tem p o rary suspension. J u s t as I was not yesterday^ T am not sure you arc not equipped, and did not plan to debate w hat lim its there arc under the existing law . ]) r . D u T 'iminr.. N o , I a m n o t a n e x p e r t o n th e q u e s tio n o f interpretation o f the law , b u t it h as sim ply been taken fo r granted, m aybe n ot p ro p erly an d m aybe u n d e r an in te rp re ta tio n that, should lie f u r th e r d ev e lo p e d , b u t it h a s been ta k e n Tor g r a n t e d t h a t p r e lim inary or tem porary suspension w as not provided for, explicitly a t least, in tho statu te. I f (lie law w ere in te rp re te d to allow this, it w o u ld be fine. S e n a to r ITaiit. I c a n n o t im a g in e th e re w o u ld b e a n y d id event criteria for a tem p o rary suspension than a suspension. I still have th e feelin g th a t th e su sp en sio n is n o t for a th o u s a n d y ears. I f you suspend an d then discover that y o u r alarm s w ere groundless, surely' you can unsuspend. T h a t w ould argue th a t you can tem porarily suspend. D r. D trU u m m . Tf th a t is th e case I th in k that, is fine. I t a p p a r e n tly needs to be made* m o re e x p lic it to th e people, w h o are, d o in g th e s u s pension b e c a u se th e y d o n o t feel t h a t I b ey h a v e t.liis a u th o r it y . S e n a t o r I Ta u t . C l e a r l y t h e y d o n o t . Are, you y e t in a p o sitio n to ad v ise w h e th e r y o u w o u ld s u p p o r t o r recommend su p p o rt of the suggestions fo r law changes m ade yestcr- d o v I-,- A g r i c u l t u r e ? D r. D i im iiu k . I th i n k it is f a i r to sa y t h a t w e w o u ld b elieve t' rl.- .. ,, ,, are t v proper i;-|.| m oves. A g a in , as I say, w e are n o t e x p e rts in th e legal field. W hat, w e trie d to d o is to find I h - ............ u i d t e c h n o l o g y t h a t is a p p l i c a b l e , a n d w o l e a v e it. t o I lie ( , ,|i --i ` 'id t h e l e g a l a u t h o r i t i e s t.o d e t e r m i n e w h a t s p e c i f i c r e g n h i l i.ii, a n d f a 11111 :irr> r e ' i u i r e d . I i v illI'Ul lliiu l: 11 a d d i l i n n a l l l - x i b i l i t d o e s principle, sound very d e s i r a b l e I n u--. - i m p l v I -- m - r e - e a r r h r e s u l t s , y o u k n o w , a n n e v e r th e final answ er mile Ihev are ex lrem elv conehr-i results of extrem e danger. I t is a lm o s t n e v e r p o s s ib le in s a v Ih il a ll t h e r e s e a r c h h a s b e e n d o ne, a n d if, p r o v e s t h a t t h e t h i n g is b u e v e r s a f e . S e n a to r irA irr. C o n v e rs e ly , fo re v e r a n sa fc. T here were several o th er suggestions th a t A g ricu ltu re m ade. O ne reg ard ed the ineffectiveness o f h an d lin g pesticide regulation by labeling. T h ey w ere g o in g to recom m end restrncl u rin g ^ th e law to re q u ire a g r a d in g by d e g re e o f th e h a z a rd s o i a pcst.ir.idc a n d to e n s u r e t h a t e x t r e m e l y h a z a r d o u s p r o d u c t s w o u l d b e p e r m i t t e d t o be, h a n d le d o n ly by in d iv id u a ls o r in stitu tio n s licensed to do so. D o von have any com m ent on th a t one? D r. D uDRim m . I th in k I have no very expert, com m ent except to note th e experience w ith in m y ow n fam ily th a t labels on packages 1721 CO It a r e n i t r i i n u t a d e q u a In l y r e a d a n d t h a t 1Ins l a b e l i n g p r o b l e m is a diibridi (me. S e n a t o r I I akt. A s A g r i c u l t u r e i n d i c a t e d , not, :i v e r y r e l i a b l e h a n d l e fo r pro tectio n a g a in st in ju ry In h ealth o r environm ent. W e ll , svo w o u ld hope, limi, y o u w ill lum i y o u r d i s t i n g u i s h e d scio n - filir. su|)|)orf. fo flic re c o m m e n d a lio n s U nit A g ric u ltu re h as m ade. A c o u p l e . o f o i l i e r q u e s t i o n s , a n d 111is? o n e s l o Ilio, d i l f e r e n t a c t i o n s fim i l u n e Iicon (ak o n w ith r e s p e c t lo p e s tic id e s o r h e r b ic id e s b y d i f ferent departm ents o f the G overnm ent. A grirnll uro suspended I th in k you said about 20 percent of the use o f LM.fi-T. J ) r . J > u B i ; i i m -,k . T d i d n o t i n t e n d l o i m p l y t h a t w a s a l l A g r i c u l t u r e . I s a i d (lie, t o t a l s u s p e n s io n m u m m i e d t o 2 0 p e rc e n t, o f the. t o t a l u se . S e n a to r Jl.wrr. It is m y u n d e rs ta n d in g that, th e D e p a rtm e n t o f D e fe n s e , lias s u s p e n d e d il e n t i r e l y I o n is e , in V ie tn a m . D r . D p l 'iuncn. T h a t is c o rre c t. S e n a to r ll.wrr. A n d lite D e p a rtm e n t of In te rio r very recently su sp en d ed it for use on p u b lir lan d s: lands in ils o w n ersh ip . I>r. Diflliunci'.. Yes. S e n a to r l l u r r . D o w do we e x p la in (lie di lie rent, re a c tio n s fr o m th e s c i e r a i d e p a r t m e n t s w i t h r ' " p r r l l o Mie s a m e p r o d u c t ? D r . .! r J '.imioi-.. I d o n o i k n o w Mia/ 1 c a n f u l l y e x p l a i n i t , I m t f l i c s i t Mat i o n i n m i l i t a r y o p e r a t i o n s is imi n e c e s s a r i l y the. s i t u a t i o n i n n o rm al peaceful o p eratio n s in Ibis conni rv. In m ilita ry operations, by necessily. lln -e eltemieals are d istrib u ted by a i r e r a l l . a n d it is not. a lw a y s easy Iti coni m l w h e re I b ey go h o w f a r a w a y t h e y b l o w o r c \ e u I'ual tin- a i r . r a l i is h i l l i n g I he. r i g h t targ el. T h erefo re I Iliink som ewh;i 1 m ore prudeiiee m ay be rrf|tiired. W h e n y o n a re d o in g if in a n o rm a l n ay. in ag rie n ll o ra l p ra c tic e o r land m anagem ent, you fluii llie m aterial does not rail be get on fuo no idr l i c r m or ops e o e r ar in ef y il o l u a r nd wa ll de ialc rs, o w sure, hich w ill e o n fa m in a to Ilio w a fe rs, o r gel on g e a r in g la n d s on w h ic h a n i m a l s w i l l he, g e a r i n g a n d t h e r e f o r e g e t i n t o m i lk ' o r m e a t . Im rlm ia tc ly 2 ,l.o -T d e g ra d e s q u ile ra p id ly . If is n o t like. D D T . Tf you sp ra y a pasture, w ith 'J.l.-T. essentially all traces o f it are g o n e a f t e r a b o u t Mirre, m o n i Its' exposure, to w in d , r a in , a n d sn n . T h e re fo re calile can quile safely graze, on g ra z in g land treated willi 2 .1.o-T a fte r f bis period. A l s o , i f it. g e t s o n l o u d i t is l i k e l y l o d e g r a d e p r e f f y r a p i d l y , film igli it is d e s ira b le lo b a v e no to le ra n c e fo r food, lini where, it is u sed in a r e a s w h e re Micro is n o him iati p o p u la tio n a n d w h e re Micro is no d a n g e r fit e o n la in in a l in g food o r w a te r. Mien a c o n tro lle d liso c a n be. e x t r e m e l y v a l u a b l e , a n d s i n e c . n o d a n g e r s w o u l d b e r e s u lt. i n g T lliin k it is p erfectly p ro p e r to b av e controlled use in Ibis c o u n try . S e n a t o r D . u r r . I V l i a t d o y o u s a y , t h e n , t o I n t e r i o r 's p r o h i b i t io n f o r use tm its lan d s? D r. Dt;I)i:mc.r,, I guess I ain n o t fa m ilia r w ith h o w extensive th a t use is. S e n a t o r IT.-wrr. I a m f o l d t h a t I n t e r i o r 's a c t i o n w a s t a k e n o n l y yesterday. D r. D i'Ifnm oK . I see. I a m not. f a m ilia r w ith the. b a c k g ro u n d fo r that action o r the extent of it; o r maybe, they found th a t oth er m a- ITe866 l tc r i.'ils c o u l d I >t! u s e d <111 | h i! 11ii: l a n d s <ii I r I l i a n ~ , l , h - J w h i c h w o u l d s e r v o I.lio p u r p o s e . I j u s t d o im l k n o w . S e n a t o r 1 l.\i!T. I '.til. 1 m i l l i - i b n l c s l o Hie. u n e a s i n e s s o f Lite p u b l i c m n l l i r lw lio u wo. so t h e s e s c e i n i i i y l v in; r e a d ions. D r. P n l 'mnoi:. T h i s is o n e o f fhe. v e ry d e lic a te filin g s (lint, fho G o v e r n m e n t f a c e s ; I.lr.it is, n o t l o o v e r r e a c t t o s i t u a t i o n s w i n c h w i l l d o d a m a g e b y o v c r r o a e t . i o n . I '.nl, Micro, is nil o p p o s i t e i n j u r y o f u n d e r reaction a n d n o t ta k in g p ro m p t o r adcmiat.o action wlion d a n g e r s arc. e v i d e n t . I w o u l d Tilce. l o d e f e r l o l l i o D e p a r t m e n t . o f th e in te rio r in th is ease, a n d willi y o u r perm ission, linvc tin t. Ide p a r t m e n t s n l u n i t a s t a t e m e n t f o r flic, r e c o r d . (T h e in fo rm at ion fo llo w s:) S tatkmk.n t on I ktkiiioii IT.st ii iiib I 'o i.icy Tin- Pi'imilinoiil or Iho I n fe r io r policy Rl.'ilcmcnt, Issued liv S ecrelary M i'kcl oil .lim e IS. d u e s iml. dl lTcr mil r k e d l y f r o m IIn* o n e H i n t Im s lieen f o llo w e d f o r Kevenil y e:o s. N ev ei l lieless, II. m i l l s s o m e eliem ieo ls mIioiiI wliieli w e l m v e r e e e l r e d n d d iliim :il d:il:i w l lliio I In* I a s i y e a r a n d r eeo "iii/,es I In- c o n c e r n e x p r e s s e d b y lcuIIrrhrpilnoiecaasyiona-onTenurleIeninpena'shcailoeiiieriyreiinewfrldoIe.arineolissppl,1ilIiof1frIesi.oeoiidolnsnirl|Klfi.lTsehiisailiir.miipeeaimel'1:eiils1e;od|let'ieelmonoIepIrtrfolsmssaeeioelnl|ijari|lsrirelfilirtufhoiiaeay'iliislaloliyltiieeietsofeahsvtnenmihaeIi|nlnIssIrveIsIashnayelyb!aoIoIlrhIlirmlmV.IlllieeynieOsseatoeeolMohplyensatammoe,rt.rIshiilesoetroioecrrfcrfoenysoennn|ilnfoinlpxlsg.so'idldo*l(ieinfirel.olr;iiiiiselxrietlaeee.iihiynlfldd'rpliiadlisl.iogoItis'1lhrlfilI*looalillii*ro'.ennrm11danHo1islrabi.'e.tooiJ.eIi-d.i.mnol..iI.eAln.l.nX.hIeel.otrdi-.n-s.vIiT.i.ldl.i.nIai.elimenrdAmisdnolilieelinionaofrsaSciirliIIslrrmoemt)nlavrIivliaI|ol..IOllliIoa1iwanIco1wnn-Vtfeiodsanulrdellsstses.aie-K.o.ee.'mr>lrlehn.lai'lIelelfliahiIleetay'lreo.plieM/.didin,i.islesIaullellJies.ribsdion|den.-lTlolblibsciathoeIllciido*sfsefl- S e n a l o r ll.MST. Y o u r e m i n d e d m e n f a (pic;.I inn I k ic k e d m y s e l f ycsicrilny fo r n o t Jiaviiur s-k ed tin- 1)oparl ment. of A g ricu ll uro wiI nesses, l 'o r h a p s yo u can help. Y ou m e n t i o n e d P U T . A s I re c a ll (lie. t e s li m o n y y e s t e r d a y , u n d e r the, F J F I t A A c t. a scien ce a d v is o r y r o im n if lr c is e sla b lislie d w h e n ( h e r e i s n. e a n e e j l a l 'uiii p e o e n l i i r e a i m e d at- a p r o d u c t . T h e y ex p la in e d Mint in (tie ease o f P O T th a t so m e six m o n th s h a v e passed since the. ea iie c lla lh m p r o c e d u r e w a s in i ti a te d a n d n o e o m m ille e s h a v e b een f o e iiie d : lien ee (lie, |iassao;e o f tim e, lia s b een e x te n d e d a t n m l iini'ill a s t b y ( h i s a m o u n t i l n r i n ; w i n c h , u n d e r t h e e a i i e c l l a l io n p r o c e d u r e s , m a r k r /i n g o f th e p r o d u c t goes oil. W h y th e fi-m onlh ric hly? P r. P i r.i.inm:. T c a n n o t e x p la in th a t. T d o n ot k n o w w h y lliern s h o u ld he a lo n g l a g hot w e e n these, t w o e v e n ts . 'I'lie. n n lv t i l i n g T c a n think' of is since, th e S e c re ta ry 's pesticid e a d v is o ry com m ission lias b o rn eonl im io n s ly at. w ork' o n tb e p e s tic id e p r o b le m , e s p e c ia lly w ith a t t e n t i o n (o D D T , t h e y w e r e d e p e n d i n ' ; o n it. t o e x a m i n e I b i s p a r ticular problem . S en ato r ir.u rr. T repeat., I sh o u ld h av e asked th em y esterd ay an d J d id not. J 'u t if th e y re a d so s tr ic tly Ih e s t a tu t e w ith respect, to suspension, T w ould assum e th e sam e strict, re a d in g w ould tell (hem th a t they cannot substitute th e M ra k C om m ission fo r tbe explicit s ta tu to ry re.rjnirem ent th a t Micro be a science b o a rd e stab lish ed fo r each of these products. , vH 04 I >r. D i r l ' c m c i :. I w o u l d a y roc. I t h i n k m a y b e ( lie l a w d o e s n o t so t a t i m e a t w liic li t l i o .s c i e n c e a d v i s o r y c o m m i s s i o n s l i a l l lie e s t a b l i s h e d . .S -nator J I art. N o ; it does not. I t w as assum ed th a t it w ould bo established a t least w ith all delib erate speed, an d G m o n th s seem s to be undue delay. J)r. D u I' rid cu. Y e s , I a g re e . W i t h y o u r p e r m is s io n , I w o u ld lik e fo a s k th e D e p a r t m e n t oC A g r i c u l t u r e to p r o v i d e a n e x p l a n a t i o n o f this ap p aren t delay. (T he inform ation follow s:) D epartment of Agriculture, Dr. I,ek A. Dunr.inoE, 7, 7370.O f f ic e ok t h e S ecretary, Washington, J). C. July E xeat tire Heardary, Connell on Environmental Quality, Executive Office of slcAelwvgpoenCteioooonariyrocaaosmmmiDorm(((<(t(ta((tovgms1<hdciyh;/ccadmIeriime)rt)/)>e)le)nint)h))m)yneaenhsoieeagimctqirsgNleTxinCSTlCPelCA.alDttut,MpieoystooewFoweonreoenefiuneneefDmeedwt'itecleseoon.oir.eerdillevtdieeecfyeiifeeomttlrlltniylroaelssirhnraolitameeSimoirnieoceioeneun;wlddttadntcltgfDiDat-rysphigedilsenreoniirlwae,u1anieitiyeefmeilngdnt)ntaiIft-lnrcisTeeiho,i.nicnnvfoioiRgnins-waartere,lgsidofmWnstinlsnsvesioeelwt-eeantoaasietdoaermahnrdioehaarlweolIrrhcstnianyinehinoaFrgyhseaistctmrt:|eltatlinteideumiiollocicldeoaciitie.lsiibmriolineclnteksaeleeJ|yseaaiimiwirig,rlsninpinIvlsnul.ncimvpoioelhlagiimmoestscegieterFinuoneyeieliiardwrd,iispiitauhdmitpsnelshefe.Dpnllrifeoprcsoieanbefttwepogrrf.weracoofmsCeromviirolrtferflcdellroIoeo.rimlyrioecsi,nheN.arvldedaorelrccelcqasooeAvnitrneohluspf,DhpuwcaepsiSmtteoeuisialuloIsraciiataleusmbItbntdpohlcfk.lnotHtafllilodgelemeaoidlnieptt.cdewfWunrni-htneriloitectihitloexnhhlUntmtsIcttypsephsaee-con(oaaoa,podalemlwtsdnaidls.ao,rwrentcqeinvedeyIcihlmodnentsulpilaitteiosirnmdhgherlptsioloeioncisnaetee:eemrotaawsffttiriynoJechsndentmitDhcmenhotrps:oededo-eldeyleiiecNpeoinmltptrdotelchAfohuIteosrap-stmawpiJieenoecieavtnrrtnSar.tanedeimteots.Dfnslrmb.1s.seveoesei)itArlri.edutteridttvtooess.nraooaeeeHhsfctled,tarsukaissstneaetieehsitbcnfrannvreroelhevwdsovgvtresaelleyheNiiaylvrodtmedapge,hafoooe.pIodeYdtnnnnswpsiDpHiro.eseadttDtnatdaoarwhhhshedrairelTtdereeeys,,lt Dim-tor, Sehnee anil Eilucntion. S e n a t o r U aiit. T w o u h l h o p e in e o m i e c li o n w illi Ih e c a n c e l l a t i o n p r o c e e d i n g o n U .l.ri -T a n a d v i s o r y e o m m i l l e e w i l l he, f o r m e i l w i t h less d elay . T h is next, question b ears d iroclly mi y o u r broad b a c k g ro u n d . O n e o f Ihe diiriciilfies in t Ids ii.lA -T s to ry w as the tliliii-nlly ex p erien ced in o b ta in in g in fo rm a tio n w hich m ig h t h av e heen o f p u b lic h e a lth s ig nificance. U n d e r w h at conditions do you su g g est scientific in fo rm atio n might, to be k e p t se c re t w h en a q u e stio n is ra is e d a s .to the. s a f e ty o f th e p ro d n e t? T>r. DuTlniricT:. T f y o u a r e t a l k i n g a b o u t s c ie n tific i n f o r m a t i o n , T <lo n o t t h i n k i t s h o u l d be, k e p t s ecret.. W h e n y o u are, t a l k i n g a b o u t inform ation having to do w ith the m an u factu re o f com m ercial p ro d ucts, th a t is a v e ry d iffe re n t s itu a tio n b ecause th e costs o f d e v e lo p m ent, testing and getting a com m ercial p roduct into production are STG8661 A* S I 3 .4 1 \i rv hit'll. Il i- <111i11' 11i'i11iir I!i:it ill'- 111:1111: i1I'll' I m > . . 1 ' " U> uuiii fi J m> ili;il jn> will !i;iii' :n <i| i| ->fImni y I i' 1>' i n-1'. IIn should have, :i p:iI<111. *ir :i pi"l''l imi l11' hi- m ' :-.'-a r }, ip r o d u c t so Ihal, lit1. r;m itimvit tin-, very large rust s to dcvr'"p it. Whereas, if lie. instantly published nil the in formal ion about 11*y-' to himIni this product so Mint ntliers would insliinlly si art making it. wit limit Ilie expense of development, this would obviously he ;m mi l:iir Kind of competition. Our whole system is bused upon the fuel, that inventors of new pit-esses and products have, probation to regain their investment and recover their costs. Therefore I think the publication anti the dis tribution of information with regard to the manufacture of products and materials is a proper trade secret. On the other hand, when it is clear that human health is at sf.ako I would assumo there should be mechanisms by which Government agencies in proper authority could he told something about the com position of the product, so that they would he able to dotermino whether or not there might he materials in the product which ought to be investigated for their harm. I do not know exact ly what the law is on this, but it would seem sensible. Senator H art. Your suggestion is that when a question of health is raised with respect to a product, data and information on the product, should be made available to the appropriate Government agency for its determination as to a question of health and safety? Dr. PuBmnor.. Yes, sir. Senator H art. That excludes, of necessity, the judgment and (lie comment of perhaps very gifted men and women of science, in ar riving at the determination of whether public hcnllh is or is not. in jeopardy. This is not. to suggest, that the appropriate agency lacks qualified and competent people hut surely they do not have a mo nopoly on that. I- Micro some way, notwithstanding the obligation to protect, trade se.'i11' and encourage invention and discovery, we can do a better job <( |"'nnilting the outsider, whether it is the head of (he cliemi'' *'.y di i.ii ini'-nl at. Cal Tceh or someplace else, being brought, in and liavin:- an >i|i|i>>rlunity to sharpen (lie judgment oi everybody? Dr. f)i-f'.ini.r:i:. Well, I think that the various advisory mechanisms available tn tin- various Government agencies ought, in general to accomplish that (ibjei-live. A science advisory group can he called in (o consult no a pai l ii nlar problem, on (be possible dangers of tlio particular rliemi.-als that happen to lm in a particular commercial product. I am sure Hull-they could tap the rest, of the scientific community t.o find out. whether ehemiral A or chemical B is of a nature that it would likely he harmful. Tliev do not have t.o reveal (he whole conposition of the product in order to say this product happens to con tain a certain amount of compound A, is there any evidence or any chance or any reason to believe that this compound A is harm ful. I think the knowledge of the scientific community could be ob tained. Senator ITatit. Should 1mobtained? Dr. D uB ridce. And should be, of course.  DOW- -412185 967. TERATOLOGY STUDIES WITH CHLOuODIHENZO-P-DIOXINS K,' D iane C ou rtn ey Primate and P e s t ic id e s E f f e c t s Laboratory Environmental P r o tec tio n Agency Research T riangle Park, North Carolina 27711 P lease send proof to: K* D ian e C ou rtn ey, PhD Environmental P rotection Agency ..... N ational Environmental Research Center . P r im a te f, P e s t i c i d e s E f f e c t s L a b o ra to r y R e s e a r c h T r i a n g l e P ark, t.'C 27711 ` .... _________- ............ - .......-- ..........................- .. P resented in part at.-the American Chemical S o c ie ty m eeting, W ashington, D.C., Sept. 1971. '' 17218 DOW 412186 ABSTRACT T eratology stu d ie s with. chlorodibcnzo-p-dio>:in compounds: Courtney, K.D. (1973). T o x ic o l. Appl. Pharmacol. 0 0 ,0 0 0 -0 0 0 . The o r a l a d m in is t r a t io n o f 100 or 200' p g /k g /d a y o f a m ix tu re o f ' 40% 2 , 7 d i c h l o r o - and 60% 2 , 3 , 7 t r i c h l o r o d i b e n z o - p - d i o x i n o r d o s e s o f 5 or 20 ng/kg/day of octa ch lo ro d ib cn zo -p -d io x in to pregnant D-1 m ice from day 7 -1 6 o f g e s t a t i o n d id n o t a f f e c t f e t a l v i a b i l i t y o r g r o s s m orphology. The o r a l or su b c u ta n e o u s a d m i n i s t r a t i o n o f 100 to 1000 pg/kg/day of 1 ,2 ,3 ,4 tetrach lorod ib en zo-p -d ioxin to pregnant CD-I m ice from day 7-16 o f g e s t a t io n was not t e r a t o g e n ic . In c o n t r a s t , the o r a l or su b c u ta n e o u s'a d m in is t r a t io n o f 25 to 200 pg/kg/day of 2 ,3 ,7 ,8 tetrachlorodibenzo-p-dioxin produced a high in c id e n c e o f f e t a l m o r t a l it y , c l e f t p a la t e and h y d r o n e p h ro sis. I M*x7V***''^M**#*,***,*H"*`l*'**,t.*,f**,**Vi:- V V 'rT ^\`< t' . * L * * i u.i I' * 172 jA '.' D O W 412187 2 and p a t h o l o g ic a l e f f e c t s has been p r e sen te d by Kimbrough ( 1 9 7 2 ) . P o s s i b l e mechanisms o f a c t i o n or a c t i o n s o f TCDD w ere s u g g e s t e d - A * a t a symposium on D i o x i n s (NIEHS C o n fe r e n c e , 1 9 7 3 ) . To d a t e , i t i s n o t known how many o f t h i s c l a s s o f compounds s h a r e t h e e x t r e m e l y t o x i c and t e r a t o g e n i c p r o p e r t i e s o f TCDD. T h us, t h i s s t u d y was undertaken to evalu ate the teratogen ic p o te n tia l in mice of other members o f th e c l a s s o f c h lo r in a t e d d ib e n z o -p -d io x in compounds. 9 MATERIALS AND METHODS Female CD-I m ice and p reg n a n t'C D -I m ice w ith known i n s e m in a t io n dates were procured from Charles River L a b o ra to ries, W ilmington, M assachusetts. D e te c tio n of a v a g in a l plug in d ic a te d day 1 o f pregnancy. The m ice, from a procurement bred a t th e same tim e , were randomly s e le c t e d and -assigned to c o n tr o l or exp erim en tal groups. The v a r io u s c h l o r i n a t e d d ib e n z o - p - d io x in s w ere prep ared and s u p p lie d by Dr. A. Pohland o f t h e Food and Drug A d m i n i s t r a t i o n ( P o h la n d and Yang,' 1 9 7 2 ). Compounds w ere a d m in is t e r e d o r a l l y or s u b c u t a n e o u s l y . O ral ad m in istra tio n was by means o f g a s t r ic in tu b a tio n u sin g a volume of 0 .1 m l/m ousc/day. The fo llo w in g s o lu t io n s were u sed f o r o r a l a d m in istra tio n . Dibcnzo-p-d.Loxin was d is s o lv e d in corn o i l . The o c tn c h lo r o d ib e n z o -p -d io x in was d is s o lv e d in 15Z a n i s o l e in c o m o i l . 17219- 3 The rem ain in g compounds were d i s s o l v e d in 57. a n i s l e in corn o i l . Compounds a d m in is t e r e d su b c u L a n e o u sly were d i s s o l v e d i n D.MSO . <*' ' employing; 0. 1/ uguiO/<ny In order to s e le c t dose le v e ls for the tera to lo g y stu d ie s, tl-e v a riou s c h lo rin a te d d io x in s were a d m in istered by g a s t r ic in tu b a tio n d a ily to fem ale CD-I m ice fo r 14 d a y s. They were ob served fo r an a d d it io n a l 7 days. For the te r a to lo g y s t u d ie s , compounds were ad m in istered from th e 7 th through t h e 1 6 t h day o f g e s t a t i o n - . T h e s e m ic e \>:ere s a c r i f i c e d on day 18 ex cep t th o s e r e c e i v in g o c t a c h l o r o d i o x in and .t h e ir r e s p e c t i v e c o n t r o l s . They w e r e s a c r i f i c e d on day 17 o f g e s t a t i o n . Upon s a c r i f i c e , f e t u s e s were weighed, examined and sto r e d in B ou in's s o l u t i o n u n t i l n e c r o p c ie d . The f o l l o w i n g c o n v e n t io n s were ob served in com piling data. I f a fet'us was e it h e r dead or resorbed,. i t was regarded as a dead f e t u s . Only l i v e f e t u s e s were examined for p h y sic a l a b n o rm a lities. A fe tu s was c l a s s i f i e d abnormal i f i t was. a l iv e and had a t l e a s t one type of anomaly (r e g a r d le s s o f t y p e ) . A f e t u s was s a id to have abnormal- k id n e y s i f a t l e a s t , one o f i t s k i d n e y s was a f f e c t e d . Tn c a l c u l a t i n g t h e r a t i o s o f l i v e r t o body w eight in the mother, maternal body w eight was d efined as the *d i f f e r e n c e betw een t h e w e ig h t o f t h e m other bn t h e day i t was k i l l e d and the gravid u t e r u s w e ig h t . M aternal w e ig h t g a in was d e f in e d as the d i f f e r e n c e in the co rre c te d m aternal w eig h t on the day i t was DOW 412188 bU I 17219 3 ;. ' The remaining compounds were dissolved in 57, anisolc in corn oil. Compounds administered subcutaneously were dissolved in DMSO %** employing'0.l/mouse/day. # ,. In order to select dose levels for the teratology studies, tie various chlorinated dioxins were administered b y gastric intubation daily to female CD-I mice for 14 days. They were- observed for an additional 7 days. For the teratology studies, compounds were administered from the 7th through the 16th day of gestation^ These mice were sacrificed on- day IS except those receiving octachlorodioxin and their respective controls. They were sacrificed on day 17 of gestation. Upon sacrifice, fetuses were weighed, examined and stored in Bouin's solution until necropsied. The following conventions were observed in compiling data. If a fet'us was either dead or rcsorbed, it was * regarded as a dead fetus. Only live fetuses were examined for physical abnormalities. A fetus was classified abnormal if it was alive and had at least one type of anomaly (regardless of type). A fetus was said to have abnormal- kidneys if at least one of its kidneys was affected. In calculating the ratios of liver to body weight in the mother, maternal body weight was defined as the difference between the weight of the mother bn the day it was killed ' and the gravid uterus weight. Maternal weight gain was defined as the difference in the corrected maternal weight on the day it was DOW 412189 ku 17220 DOW 4121.90 . /, 1 killed and its weight on day 6 of pregnancy. Averages were calculated for each litter, then across litters. Statistical analyses were performed using the student's "t" test. ' .RESULTS AND DISCUSSION -- The .results from treating female CD-I nice with various doses of .the different dibenzo-p-dioxins are presented in Table 1. Adminis tration of the compounds for 14 days at the doses indicated produced no lethal dose values. The dosages for the dibenzo-p-dioxin, dichlorodibenzo-p-dioxin, and octachlorodibenzo-p-dioxin are expressed as milligrams per kilogram of body weight per day while the others .are expressed as nicrograns per kilogram of 'body weight per dayi . The change in body weight'reflects the difference in body weight on the first day of the study to the last day which was seven days after the last dose. The only unusual value is from those mice which received 50 mg/kg of dibenzo-p-dioxin. Further study is needed to determine if this increase of. almost seven grams is real or not. Limitations of the supply of these compounds precluded further --* exploration of dose studies at this time. In general, none of the'.. "dibcnzo-p-dioxins studied were as toxic as. TCDD, the 2,3,7,8>'" tctrachl.orodibcnzo-p-dioxin isomer, and some of the compounds could be considered relatively non-toxic. 17221 d o w 412191 .a. 5 Toxicologic results of administering che various dibcn;:o-pdioxins to pregnant CO-1 i;iicc arc presented in Table ?.. The. diluent control solutions of 5% anisle in corn oil, DMSO or 15% anisle in corn oil did not adversely affect fetal aortalicy or fetal weight. The mixture of the dichloro- and trichlorodibcnzo-p-dioxin administered orally at doses of 100 and 200 aicrograms/kg/day had ` no.advcrse effects on the fetal and maternal parameters. The fetal weights of these two groups are higher than those of their respective controls. They are also higher than values which might be antici pated for a gestational day 18 mouse fetus. . It is assumed that 'these nice were very near tern since one member of the experimental groups-littered (omitted froa these data), and thus, these mice might be considered almost day 19 mice instead of day 18. * The, maternal weight gains of the experimental groups were slightly higher than the values of the control-groups, but these differences T7ere not statistically significant. This slight increase in maternal weight gain was also seen in mice treated with the 1,2,3,4 tetrachlorodibenzo-p-dioxin isomer administered orally at doses ranging from 100 to 1000 micrograms/kg/day. Whether or not'. this' increased weight gain is a true increase in weight or a manifestation .of edema needs to be explored since studies with- ~ TCDD produced marked maternal edema. In contrast, the subcutaneous administration of the 1,2,3,4 tctrachloro- isomer produced a slight decrease in maternal weight' gain compared to controls. The "niinei'.s.'wu.'!tr.u.'ar'.xm.'-.T.rr r.v-- .. r"7?;.<t TW.'.'.ftrif.C Mo n 6 difference in chase values war. not s t a t i s t i c a l l y s i g n i f c a n t . In marked contrast, TCDD adversely affected fetal weight and. mortality, and maternal weight gain at a dose of 100 micrograms/ . kg/day. Dose levels of ?.00 and 400 yg/kg/day produced generalized edema in the mothers, and vaginal bleeding after the sixth dose `with some mice aborting shortly thereafter. The increase in the ratio of liver to body weight seen in the mice receiving the lower doses either orally or subcutaneously is primarily due to an increase in the liver weight. The dose of 50 yg/kg/day produced a decrease in maternal weight gain, and at the tvo highest doses the obvious edema made it difficult to interpret maternal weight changes. The subcutaneous administration 4 of TCDD produced more fetal mortality at lower doses than oral *administration. This suggests that the bioavailability of a subcutaneous dose is greater than that of an orally administered dose. Treatment of ptegnant mice with octachlorodibenzo-p-dioxin at 5 ing/kg/day had no adverse'effects on fetal or maternal parameters. At a dose of 20 mg/kg/day, there was a slight reduction of fetal < . weight which was not statistically significant. Also, the reduction .. .....-- in maternal weight gain was not statistically significant due to a 17223 7 / v e r y l a r g e stan d ard deviat. io:i. Tlio i n c r e a s e i n th e r a t i o o f l i v e r t o body w e ig h t was p r i m a r i l y duo t o a lo a n in. body w e i g h t . F e t a l Mortality was not a f f e c t e d a t c i t h e r d o s e . All of the live fetuses were examined for malformations. These results arc shown in Table 3. oo The mixture of dichloro- and trichlorodibenzo-p-dioxin produced .a'slight increase in the number of abnormal fetuses. At the lower dose this was partly due to an increase in kidney malformations which were a mild form of hydronephrosis. Since most of these fetuses (9/10) were from one litter, and kidney malformations were not' observed at the higher dose, it is very doubtful that this malformation was produced by the compound under study. At both dose levels there was an increase in the incidence of clubfoot. This may reflect uterine crowding, since these fetuses weighed slightly heavier and the litters were slightly larger than'the controls. However, this does not negate a possible compound effect.- Hto CD CD The 1,2,3,4 tetrachloro- isomer did not increase the incidence of malformation at any dose level by either oral or subcutaneous administration. Since this strain of mouse has a tendency to 4J-spl^y --- clubfoot, the SK incidence of this anomaly observed at the 1000 ... ----------- microgram/kg/day done level needs further substantiation before * being accepted as a compound effect. av..v*s*>*^**rv. "TW *r>\**-*rt DOW 412194 8 In contrast TCDO produced many abnormal fetuses at all doses studied ana by both routes of ad::iin.iserntion.- The majority of the. malformations were cleft painter, and hydroncpbrotic kidneys, both unilateral and bilateral. A few other anomalies such as hydrocephalus and open eye. were occasionally seen. TCDD administered subcutaneously produced a greater teratogenic response at a lower dose than adminis tration by the oral route. Administration of the isomer by the subcutaneous route at the lowest dose produced about 87% abnormal fetuses per litter. This made it difficult to demonstrate a .dose related response since this is close to being a maximum response. At the higher dose with both routes of administration many fetuses were observed with marked edema and petechiae. The oral administration of 5 or 20 mg/kg/day of octachlorodibenzo- *' p-dioxin to pregnant CD-I mice did not affect fetal development morphologically. The only malformation detected in this group of fetuses was a single cleft palate at the low dose. ' CONCLUSIONS TCDD, the 2,3,7,8 tetrachlorodibcnzo-p-dioxin member of thirs- ... class of compounds was the most fctotoxic and teratogenic compound ___ studied. The related compounds were relatively non-toxic and were not teratogenic at the doses studied. . .............. .. . i - J.* Cl xt" DOW 412195 9 T! oral admin istirai; ion of 100 eu* 200 i:ii.cromm;/k /deiy of a mixture of 402 2,7 dlchloro- arid CO/! .2,3,7 triclilorod bc-nzn-p-d u:in to pregnant CD--1 mice from day 7 through 16 of gestation did not affect fetal viability or gross morphology. Tlic oral administration of 100 to 1000 microgrnns/kg/dny or the subcutaneous administration of 5C0-or 1000 niicrogrnms/kg/dayof 1,2,3, t\ tctrachlorodibcnao-p-dioxin to pregnant CD-I mice did not affect fetal viability or gross m o r p h o l o g y . The oral administration of 5 or 20 milligrams/kg/day of octachloro- dibenzo-p-dioxin to pregnant CD-I mice did not affect fetal viability or gross morphology. ' The oral administration of 25 to 200 nicrograms/kg/day of `2,3,7,8 tctrachlorodibenzo-p-dioxih, TCDD, to pregnant CD-I mice produced a high incidence of fetal mortality and malformations. The malformations were almost exclusively cleft palate and hydronephrosis. Maternal toxicity was evident at the higher dose levels with marked edema, vaginal bleeding and abortion. ACKNOWLEDGEMENTS: I gratefully acknowledge the technical assistance -- ------ of Mrs. J. Putnam and Mrs. M. Ebron. I also thank Dr. A. Poiiland of the Food and Drug Administration for the generous supply of dioxin compounds. ' '` 172 1 r** D O W 412196 10 Tabic 1. Oral Administration of Dioxins to Female CD-I Mice For 14 Days Compound Dibenzo-p-dioxin t' 2,7-Dichlorodibenzo-p-dioxin Combination of: 40/? 2-,7-Dichlorodibenzo-p-dioxir. 607 2,3,7-Trichlorodibcnzo-p-dioxin ?, 3,4-Te trachlorod ibenz o-p-d iox in 2,3,?, 8-Tetrachlcrodibcnzo-p-dioxin Octachlorodibenzo-p-dioxin . No. of Mice Dose/ Day No. Dead/ Change body Doses Wt. (gms) 6 1 mg/kg 6 10 6 . 50 0 0 1/14 +0.6 -0.3 +6.8 6 0.5 mg/kg 0 6 1.0 1/8 -0.1 +1.5 6 6 6 10 yg/kg 50 100 '.1/9 0 . 1/13 6 6 .6 6 5 yg/kg 10 '50 100 0 0 0 0 10 . 10 yg/kg 0 6 0.5 mg/kg 1/11- 6 0.75 0 6 1.0 0 +1. 2 +0.8 +1.-6 0 -0.2 ' +0.8 -0.9 '+0.1 +0.1 +0.7 -0.4 'g w n r ; **! 1 7 c i* .i 1722 DOW 412197 Ii i i v**.?rir <vt vtjm* :<** I c o l o 2. T o x i c o l o g i c E v a l e t i o n o f C h l o r in a t e d D i b e n z o - p - d i o x l n Compounds i n P re g n a n t CD-I Mice (Conpounds A d m in is t e r e d Cron Day 7 to 16 o f C e s t a t i o n ) D ib en ze-p -d io x in Compound j i Route 5% a n i s o l o s c o r n o i l j o r a l Dose/kg/day No. o f . L itters 0.1 ml/mouse 15 Av. 7. Fetal M ortality/ L itter 6 Fetal Weight (gns) X SD 1.02 0.16 Maternal Weight ^Can (g) X SD 3.5 1.93 Maternal Liver/Dody Weight x 100 TT SD 7.S 0.59 'tan i, r 2/3 mixture3 1 ,2 ,3 ,4 -te tr a c h lo r o ! i i j j . i i1 1 1 oral oral oral oral oral oral sube sube 100 pg . 200 Pg . 100 p g. 250 pg 500 pg- . 1000 pg . 500 Pg 1000 Pg 6 5 4 U 5 5 5 '' ' 6 3 5 10 20 5 10 . 7 2 1.36 1.25 1.C9 1.10 1.C3 . 1.03 1.24 1.31 0.13*** 4.6 0.19** 4.4 0.09 0.12 0.08 0.09 4.8 4.8 4.5 3.7 0.07 0.07 3.4 2.3 1.10 1.59 0.51* 1.44 1.56 1.31 0.S2 0.57 3.0 0.64 7.3 0.45 7 . 3 0-47 7.7 0.37 7. 8 0.43 . s. 3 0.53 7 . 6 ` 0.40 8 . 1 0.44 DMS0b ' sube . 0.1 n i/nouse 6 ( 2,3,7,8-tctrachloro oral 25 Vg * | oral . 50 pg oral 100 Pg 'i oral 200 Pg |1 o r a l 400' Pg 11 su be 1 sube 1t su be ' 11 su be 25 Pg 50 Pg 100 Pg 200 .Pg 7 7 6 6 5 5 6 6 6 14 6 13 14 87 97 36 56 72 76 1.19 1.13 . 1.01 0.95 d d 1.25 1.20 d d 0.17 3.1 0.13' 0.13 0.12 3.4 ' 3.4 2.1 d d 0.07 0.15 3.0 2.3 d d 1.96 7. 5 0.54 ' 2.20 1.07 3.57 3.6 9.4 7.8 d d 0.03** 0.44*** 1.C0 0.86 1.17 ' 9.7 9.0 d 0.42*** 1.09* i 15% a n i s l e : c o m o i l c o r a l 0.1 nl/mouse 5 8 0.61 0.05 O.ff 1 .4 7 6 .2 0 .2 2 1 pi pctachloro 1 oral 5 mg 6 14 0.60 0.05 0.3 1.40 6.6 0-22 \ t oral 20 mg 6 . 12 0.53 0.05 -0 .1 2.31 7.2 0.G0* I a m ixtu re = 40% 2 , 7 d i c 'n l o r o d i b e n z o - p - d i o x i n arid 60% 2 , 3 , 7 t r i c l : l c r o d i b c n z o - p - d i e x i n b 37:30 = c i r . e t r . y l s u l f o x id e \~ s a c r ific e d day 17 o f g e s ta tio n : a l l oth ers s a c r if ic e d day IS. \* . /. .. rs - n n: . .. o n*M i U w (> 4 1 .L ^ } Table 2. Toxicologic Evaluation of Chlorinated Dibonza-p-dioxin Compounds in Pregnant CD-I Mice (Compounds Administered from Day 7 to 16 of Gestation) r, p < hr' t Dibcnzc-p-dloxln Ccr-.pcur.d Roete Dose/kg/day No. o f . L itters Av. 7. Fetal M ortality/ L itter Fetal Weight (gns) X SD Maternal Weight ;Cain (g) X SD Mat c rr.al L iver /F.ody Weight x 100 *V SD . 52 a n is le :com o i l .oral 0.1 ml/mouse 15 6 1.02 0.16 3.5 1.93 7.S 0.59 C*2 r- tiK 2/3 nixture3 ` oral oral 100 pg . 200 Pg ? ** 1 ,2 ,3 ,4 -te tr a c h lo r o oral 100 pg oral 250 pg . oral 500 pg . i oral 1000 pg 6 5 4 4 5 5 3 5 10 20 5 10 . 1.36 1.25 1.09 1.10 1.03 1.03 0.13*** 4.6 0.19** 4.4 0.09 0.12 0.08 0.09 4.8 4.8 4.5 3.7 1.10 1.59 0.51* 1.44 1.56 1.31 3 . 0 0 . 4 / . J 0.4-5 7.8 0.47 7.7 0.37 7.8 0.4 3 V 3.3 0.58 ; D>S0b 11 s u o c . t1 su b e sube . ' 5 0 0 Pg 1000 Pg 0.1 nl/nouse 5 6 6 7 1.24 0.07 3.4 0.82 7 . 6 0 . 4 0 ` *- 2 1.31 0.07 2.3 0.57 8.1 0.44 14 1.19 0.17 3.1 1.96. 7.5 0.94 ' t 2 ,3 ,7 ,8 -te trachloro oral 25 Pg r oral . 50 pg 7 G 1.13 0.13' 3.4 2.20 3.6 0.63** 7 13 1.01 0.13 3.4 1.07 9.4 0.44*** t o r a l oral 100 pg 200 pg 6 14 0.95 0.12 2.1 3.57 7.8 1.00 6 87 d d d r | oral 400 Pg 5 97 d dd ! sube 25 Pg 5 36 1.25 0.07 3.0 0.66 ' 9.7 0.42*** J sube 50 pg i sube 100 pg *{1\ ! sube 200 Pg 15Z a n i s l e : c o m o i l c; o r a l 0.1 nl/mouse \ octachloroc i* oral 5 rtg \ ! oral 20 a?g 6 6 6 5 6 6 56 72 76 8 . 14 12 1.20 d d 0.61 0.60 0.53 0.15 0.05 0.06 0.05 2.3 d' d O.ff 0.3 -0 .1 1.17 1.47 1.40 2.31 u9 . 0 1 . 0 9 * d 6.2 0.22 6.6 0.22 7.2 0.G0* i a r.ixturo = 407. 2,7 dichlorodibcnzo-p-dioxin and 60 2,3,7 trichlcrodibcr.zo-p-diexin b D!i30 = dr.cthylsuloxide .\- \ sacrif.ice.d day 17 of gestation: all others 4s.a.c. rirfincr,e, d da^y 18.ai a '*.v _ o t f DOW 4121.99 T c b lc 3 . ' T e r a t o g e n i c E v a l u a t i o n o f C h l o r in a t e d D ib en zo-p- dioxin Compounds i n CD-I Mice D b cn zc-p -d io x in . 'Compound 5Z a n i s o l e r c o r n o i l 2/3 r.i::tutea ! 1 ,2 ,3 ,A tetrachloro- i i1* DMSO3 : 2 ,3 ,7 ,8 .tetrachloro- f * 15% c n i s o l e : c o m 1 I * 1 oil c octachloro-0 ! i Routc oral oral oral oral oral oral oral sube sube sube oral oral oral o r a l' oral sube sube sube sube oral oral oral Dse/kg/day * 0 .1 ml/rcouse 100 UB 200 UB 100 vg' 250 ug 500 vg 1000 ug 500 ug 1000 UB 0-1 ml/mouse 25 ub 50 ug 100 us 200 UB 400 US 25 UB 50 ub 100 UB 200 ug 0.1 irl/mouse 5 mg 20 tng No. o f L itters Av. No. Uve Fetuses/ U tter 15 6 5 4 4 5. `5 5 6 V 7 7 6 6 5 5 6 6' 6 5 6 6 11.0 12.3 .12.8 11.8. 11.5.11.6 .S 11.6. 12.2 . 11.3 . 10.9 11.0 9.7 1.5 0.4 7.7 5.3 3.5 3.3 11.2 ' 11.2 11.6 Av. Ko. Abnormal Fetuses/ L itter 0.8 3.2 3.8 0.8 0.5 0.2 1.0 5.4 1.0 0.2 4.6 8.1 8.3 1.5 0.4 6.7 5.0 3.5 ' `3 . 1 0 0.2 0 Z A notta licn /'i'o ta l rCtUSCS 1 Cleft T a la te Kidr.oy C lu b fo o t .0 1 4 0 10d 9 0 1 22 20 01 00 00 2 3 0 0 00 14 2 3 00 1 3 34 19 72 66 71 100 ICO ICO 50 3 7 13 14 50 . 82 53 ' 11 79 53 17 85 95 0 100 33 13 00 10 00 0 0 0 a m ix tu r e ** 4CZ 2 , 7 c i c h l o r o d i b c r . z o - p - d i o x i n and COZ 2 , 3 , 7 t r i c h l o r o d i b c n z o - p - d i o x i n 'b D>'iSO * d i r . c t h y l s u l f o x i d e c s a c r i f i c e d day 17 o f g e s t a t io n : a l l o t h e r s s a c r i f i c e d day 18 d 9/10 iron one l i t t e r o CT) 04 r- / 13 REFERENCES DOW 412200 1 . H e ib e r g , J . , W a lle n , >., P.vodkin, R. , and Appclbaun, I . , I n d u s t r i a l l y Acquired. P o r p h y r ia " , A rch. D e r m a to l. JS9, 7 9 3 - 7 9 7 , 1 9 6 4 . 2 . Courtney, K.D. and Moore, J . A . , " T e r a t o l o g y S t u d i e s w ith 2,4,5-T rich lorop hcnoxy. A c e tic Acid and 2 ,3 ,7 ,3 -T e tr a c lilo r o d ib e n z o p - d io x in " , T o x i c o l, and A p p lie d P h a m a c o l . 20,1 3 9 6 -4 0 3 , 1971. 3 . Higginbotham, G .R ., Huang, A.', F i r e s t o n e , D . , V e r r e t t , H . J . , R css , J . , and Campbell, A .D ., "Chemical and T o x i c o l o g i c a l E v a lu a tio n s o f I s o la te d and S y n th e tic Chloro D e r iv a t iv e s o f D ib en zo -p -d io x in " , N ature 22, 702-703, 1 968. 4 . ' Kimbrough, R.D. , " T o x i c i t y o f C h lo r in a t e d Hydrocarbons and R e la t e d Compounds", A rch. P a th . 9 4 ,. 1 2 5 - 1 3 1 , 1972. 5 . Neufccrt,,D. and D i l l n a n , " I . , "Embryotoxic E f f e c t s in Mice T reated w ith 2,4,5-T richlornphenoxy A c e tic Acid and 2 ,3 ,7 ,3 -T etra ch lo r o d ib en a o p - d i o x i n " , Naunyn-Schm Archi. P harm acol. 2 7 2 , 2 4 3 - 2 6 4 , 1972- 6 . Pohland, A.E. and Yang, G .C ., " P rep a ra tio n and C h a r a c te r iz a tio n o f C h lo r in a te d D i b c n z o - p - d i o x i n s " , J . Ag. Fd. Chem. 2(3, 1 0 9 3 - 1 0 9 9 , 1972'. '. : . 7. P o la n d , A., S m ith , D . , M e ctcr , G . , and F o s s i c k , P . , "A H e a lt h Survey o f Workers in a 2 ,4-D P lan t and a 2 ,4 ,5 - T P la n t" , Arch. Environ. Health 2 , 316-327, 1971. If ZZ t A\nn U 8. S parscliu, - C,L* , Dumi, F,L=, and Rovo,. V .K ., "Scudy o f clic TcraCogenieily of 2 ,3 , 7,8-T otrnelilnrodiboazo-p-diosin in clic Rat", / Fd. Cosmee. T o x i c o l . j>, /.0 5 -4 1 2 , 1971. i I t ' *rw\Nv/-n> 'liuovt'aijiv rijic ii ryrr*r.v.r rrr.* .v -- ....... . 17232 SUSPENSION OF 2 A 5 - T , SILVEX FOR USES ON: RIGHTS-OF-WAY FORESTRY' PASTURES NQI SUSPENDED FOR USE ON: RANGELAND RICE SILVEX ALSO SUSPENDED FOR: AQUATIC USES TURF AND LAWN USE OTHER CANCELLED 2 A 5 - T FOOD CROP USES EXCEPT RICE Original Articles DOW049918 Journal of Occupational Medicine The Mortality Experience January 1980Vot.22 No. 1 of Workers Exposed to Tetrachiorodibenzodioxin in a Trichloropheno! Process Accident Judith A. Zack, M .P.H , and Raymond R. Suskind, M .O. pwrwolooapArrnhkkteeesirnrntssaoNnwel dxihptparororood,dscieezWedesvesdetslootampVcteeoicrdtgrirdtaiacnechliniahtlyto.iorOaaraotcnndneatiehblhyeesrueinnssMzduowroledtanidnisosgaaxcnnifnrodtoonimtndwCuaethconttimstreyicdpa-ohacnolncoenyi- dent on March 8,1949. were selected for study. Follow-up owctaafilttithethygiso3rar2gietrisooduefpaootrhwf saaslmlo1caba0lsiug0es%nrevasencdotofmandnpeedloeaptt4ehla6. .sw4Tma1hsseessxhtaaponnewddcntaerdtcdo.iirzcbeFuedolar0mt.o6tohr9rye, d0armdozHye.eoniifss6osoaddee8wwurraa,isltooettsas.shrxrveeelkeiTiesstsneoyh,rpror,efsetewhfiolctrtwaehtherhttioiissiviestsvhueitnewicallmtsylasineyrt.upcddrhoBedsuoeaigmfeyalrrafdtchtotahahtaicozlnpslliulosaertesywdnnaetsfhnusrketomouyamodemsdfttobtxyetnobprhemtovewoemaresloawisairutclpymlflaroiagepsbdnranaapesteoloalrtiaebdeiisonntrsntehiisetzcoetrseteordrewnvadroxoeepecobcdoforchesfeptrseoiihaonnlsran1etrveesoac.ei0anmcddldgu0roils,srtbywhooaivetounith3oteanhprde0.rtl pthoosseedoifnatlhaergecor sutrusdeyowf h2i.c4h,5w-triilcl hinlocrloupdheepnlaoxnytawcoertkicersaceixd production during the period 1948 to 1969. o2hfia,nf4sAd.5ibn2-et.grw4ei.cnii5sdh-reclteorhpivrcloooahprrrltaihoeecerdtnoynepiono.hlfwae(aTonscCrokkuiPxnet)yer.dasiaTcsinhenedeavtisocsmelvucoebahsd-caatiicrdncauoctthnet(ees2hri.sim4ezt,eeaa5ndl-ntTthub)cfeyalficnfcfertoiouccmrmates-l From the Dto^rtmcm oi Medein and Environmental Health. Momamo Company. 00 N Lindbeffh Blvd. St loud, MO 63166 (Mi Zack. EptdemtoiotriU. and the Institute oi Environmental Health. Kettermf Laboratory, the Umvcmty oi CiiKinruo Medical Center. Cincinnati. OH 4S267 (Or. Suskmd. Deectort (cscjtfbtep1mpacoww1aaptamtcczpSreTiioehoyoeonedooi9hl,nlfortuounocChuis2moeemtoldhne5nrdlsePtsEaestwsrToidsp,tDoni,3cdoetksieph4rsktnoamrtepCretheece.hadhteDroisapisat,guohhnfadnlpstryo5DdpercdaAscen)esitennte,dasrtwrm,lm-ocesusonDvhoroi1oendrtn1taiciacneekieiceo"iyfoplosyfdm,d,onndsaNy*uslotitetenhcawewauwivtisrMacamatoaeofehepibntcaevhotncdthuhnanessnladtsxraefauyoeecrletlithetdsodteAr,yvsniaaiuphrparnhsoecarrsowanecrdsmlfvbepaeeenrohslni2etethftdeonoedeheueanfraeceatt6ldiplaraohhrntntdulotwcsenealrcaiesnoyhorillsr,eoretetanpuedacuuitwgistoeuaebcwdaacaordemtttcrtntpepdtrlhhchhefehtroicenedratoksttdohiNrtt.etensaeelraiadnecd-sCednreyoosreailsouOredninslk,lszem,rttcrfaerotoetinparriasseoioIeynodcnohxnadvowomwnfts2,ptu.dptrltnhocesn'reni,em.iaeyMrtresatioewhnp3eeaelometsednCoallroWhirsrnv.oeian.maswtitegiet7nsrsrophoehdevtritinnaiwdretahc,dheaiy-esierlrhiuvcf8tboysuaoeaoeonuhleisscrmeerehrs-nh1ollpebccrrlteatteottsi.xceshaw2ihneeghsfheabs8ortoaVedppiencbuTyrgetaedlaroceuo,rstuomroiirisrn1aetmrehhdtutrfalrirargostifsttesarraietotg9egkeexsohemomcaaocrhapucttnaflfeca4ieaescrhnrihacnrmehtrateoethbtlrirne9.ioaemselaenyciooiaetnasafufoas,rimcqpvhfeHenrndvlfsesimtdh,ier,itta2ngeoeulewle.vtehie,osdaeeoyTcoo.ebetxbe.epripf4.evdichsaphddtCrdnihdntpdoetsrlon,eoithvsSiepaaaorHee5erePgibeeudtdrtuooeaeptbpioynsh-avalne.rineetnefiyTbdnnlxhsimcdeponeaadftvltesoane.syiute1edlsarlrelidepnotoipApoizifrxlrdTroendsh9ncveaxeeemcotompfswyo1dnhemodh5omoeapoefp,hdt1is9fdteatufpe3aempwwlhncolhsoel,oo9eif4,y.,tseccoteo1souytneriecs4snappa9attno9tusTaxmdnfu9thnirttneeratnoneeeem4hhraitnihhiico.btiaotnzddpeondpxadn8dndeodssdetelt * Journal o< Occupational Medidne/Vot. 22. No. 1/January 1980 11 17234  e i6 6 W M o d . clinical symptoms, in order atrelative frequency,* included accidental industrial intoxication. acneform lesions; severe pains in muscles of upper and In 1976, a TCP process accident in Meda, Italy, resulted low er'extrem ities, shoulders and thorax on exertion; in the contamination of a large and densely populated fatigue; nervousness and irritability; decrease in libido; area.* A preliminary mortality study has been conducted dyspnea; vertigo and intolerance to cold. O n examination, in two o f the 11 towns affected. The overall m ortality rate x all of the cases had chioracne. Several were severely hyper- did not differ from that expected, but increases in deaths pigmented. especially on the face. O f the six workers ex from liver cirrhosis and leukemia were suggested. amined in 1949 and 1950, four had liver enlargement and The chronic toxidty of TCD O exposure to animals has one had sensory loss in one foot Liver impairment as in dicated by hepatomegaly, tenderness and soreness in the right upper quadrant and epigastrium and a delayed pro thrombin time, was observed.1* * In 1953, four of the six workers examined in 1949 and - been more extensively studied. TCD O toxicity has been thoroughly reviewed.* Chronic toxicity to TCD O is manifested by liver necrosis, thymic atrophy, and deple tion of the lymphoid organs. Two studies indicate that chronic administration of low levels of TCD D to rats is 1950 were re-examined and six additional workers involved in the accident were also exam ined The findings in this later examination indicated a general regression of both associated with an increased incidence of neoplasia. In one study, the oral administration of TCDO produced an increase in hepatocellular carcinom as and squamous cell the cutaneous and noncutaneous symptoms w hich had carcinom as of the lung, hard palatefnasai turbinates, or been present earlier. A ll of the workers showed a marked -tongue" in another study, TCD D fed to rats produced improvement in their skin lesions -- there were residua of tumors in 3896 of the test anim als." Neoplastic nodules - the acne and a few active lesions. In a few cases, workers and cholangiocartinom as of the liver were observed. continued to com plain of aches and pains of the lower ex The study reported here w ill examine the m ortality ex tremities and back* nervousness, excessive fatigue, and perience of a cohort of 121 em ployees involved in the ! dyspnea. No clinical explanation for these com plaints 1949 trichlorophenol process accident with special em could be made based on the results of the physical ex phasis on cardiovascular disease and on neoplasms, par am ination.* ticularly of the stomach, liver, lung, and skin. The findings c f the examinations by Ashe and Suskind are consistent with those which have been reported in Population and Methods other industrial episodes which occurred subsequently.1 The acute health effects of TCD O exposure are described in the literature.7 but little is known of the chronic effects. Severe! reports describe the occurrence of cancer and other deaths in workers exposed to TCDO which,suggests an association between exposure and the subsequent development of a variety of neoplasms.**' These reports, however, are generally of sm all groups of workers with relatively short periods of follow-up and are considered to in this study, the development of chioracne. a hallmark of TCD D exposure, was used to identify employees, for study. The study population consists of ail persons with chioracne w hich could be attributed to the 1949 TCP p ro cess accident One hundred and twenty-two employees who developed chioracne following this incident were identified from plant safety records dating to the time at the accident and from workmen's compensation and plant m edical records. O ne hundred and twenty-one be-preiiminary in nature, in a 25-year follow-up study, 17 white m ales were included in this study -- one female deaths were observed among a cohort of 75 Cerm an who was living as of the endpoint of the study was not in workers who had been involved in a 1953 TCP process cluded in this mortality analysis. It is assumed that all of accident* O f the 17 deaths observed (11-25 expected the skin disorders recorded in the plant records represent depending on the choice of a control populationl six true cases of chioracne and not other types of occupa were from cancer (four or fewer expected), five from car tional or nonoccupaticnai dermatitis. An analysis of the diovascular disease (as expected), two horn suicide (fewer chioracne cases and exposures not associated with this than one expected ! one from liver cirrhosis, one from a accident but rather with the normal TCP/2.4.5-T produc urogenital tract disease, and two from external causes. O f tion processes w ill be the subject of a future paper. the six cancer deaths, three w ere from stom ach cancer in The data were analyzed by the modified life-table the age group 6069. a number significantly higher than method using the updated Moroon program.1* In this expected. Two other cancer deaths were from o a tce ll method of analysis, the age-, race-, time- and cause- carcinom a of the lung and one was from adenocar specific m ortality rates for a standz/d ^JzLr-'tn (in *Ss cinoma of the colon. case, the population of the United States) are applied to A sim ilar accident occurred in the Netherlands in 1963 the person-years lived classified by age. race, and tim e A in a factory producing 2.4.5-T.* Eight deaths have- been standardized m ortality ratio was calculated as the ratio of observed among 93 exposed workers. Five or six of these the observed deaths to the expected deaths for 22 deaths w ere from cardiovascular disease. The proportion selected causes of death. The statistical significance of of deaths due to myocardial infarction was noted to be differences between observed and expected numbers was high. based on the Poisson distribution and statistical signifi Jirasek et al* '* and Pazderova" followed 55 of the 78 cance was determined at the 5 9 i level of significance. Czechoslovakian workers who were affected by chlor- For the purpose of analysis, each member of the study ic n e resulting from occupational exposure to 2.4.5-T and cohort was assumed to have entered the study on M arch pentachlorophenoi. In this study, five deaths were ob 8.1949, the date of the accident. The vital status of each served. These included two deaths from bronchiogenic member was determined using standard follow-up tech carcinom a (less than one expected! one from cardiovas niques and ascertained as of Decem ber 31.1978. For each cular disease, one from liver cirrhosis, and one from an person found to be deceased, a death certificate was ob- 12 MortaiityExperienceofWorkers ExposedtoTatrachtorodibenzodkwn/ZackandSuskind 17235 Tabla 1 . -- Observed and Expected Deaths Among 1 2 1 M ales Exposed to Tetnchlorodlbenzodloxin in a Trichlorophtnol Process A ccid ent Cause All causes o1 deatn All malignant neoplasms Buccal cavity and pharynx Digestive organs and peritoneum Stomach Liver All other digestive organs Respiratory system Lung Alt other respiratory organs Skin Genitourinary organs Lymphatic and hematopoietic tissue Other sues Diseases of the nervous system and sense organs Diseases of the circulatory system Arienuscferotjc heap disease, including coronary heart diseaso All other disease of (he circulatory system Diseases of the respiratory system Diseases at the digestive system All other diseases External causes ot death p < 0 .0 5 IL e ss than 5 observed deaths 8tDatiihsneeadsR.eesTv.hisAeiodunanpdtoeefdrly"itnhbgeycaaInnusteeexrpnoeafrtiideoennacatelhdwCnaolasssocsloiofdigceiasdttioton thoef 0wo3pptvsttRtthahrh..teerrae60iarbeeetcrATescl92hnlisituefvee.h1oelduil.leedee29wdtnamdsr..1xT.rol0iydp-rdatch4TfehmdeeEaibezshseacnelreite3uyetgcehttcxam2eldhehteeptsmwodsatiboremsyf.se1beac-otaeTrin2dostrlcfeniefd1higeerransddoterntnrlebtah.vlmurmaiymyeleneoTdinatdenwesyhwydtslemieededgtetrcnoaurreeaabnrseoeernemaatetikiohhgifdttworiifphohnocivsaincvelssarerrfa,etoerdcnrowseafriawirartfmfztlanioniuraenehfdsdesmicntdlocdiihlecfga4safedhrde6hmtmcfoleee.rioid4avbsaeiaf.aosw1eintrtlnntruihoahncgrtcgedsaaultesneyhxiyrlsrnamiiepfstadsrn.ywehoTcnphestciToimdahohsaattnhhhetobwatneiheodowl3tasnoesi0r.c2rctlnepy.oty1v1Tilsnmate.t5wwhwioossraiTatmseseemhenchubrorrxiaideheeseess;f ICO He. (Eighth Revision) 140-209 140-149 50-159 151 155-158 -- 160-163 162.163 -- 172.173 185-169 200-209. -- 320-389 390-458 410-413 -- 480-519 520-577 -- 800-998 Observed 32 9 0 0 0 0 0 5 5 0. 1 0 3 0 0. 17 13 4 1 0 2 3 Expected 46.41 9.04 0.30 2.59 0.50 0.18 1.91 3.02 2.85 0.17 0.15 1.18 0.88 0.94 0.38 25.01 17.74 7.27 2.78 2.26 3.18 3.78 SMR .6 9 * 1.00 f t t t 't 1.68 1.75 t f t t t t 0.68 0.73 t t t t t TdrhaieastTCbmeioahlaeasesfteoer2oesr.pswcouwiiiremt.echtmurice2laa5trti.is1o0es17rsuyeefdoxoiwbpsrseeiteacthhrstveee0eds.d8.cw8aTanhdesceexeaplsortethwacdstneeaddafta.trh0rods.m6iz8ae.rdceimrcguoivlreatantolirtiyny wwsrccptofDoeoealeroeuinltsnnTlrBarrscoccitketehileieuwvreeentccmsehr-xooacsus.uTepibeuoflopCoassNarconl.setetaDhteaofurrltvDtvTrlogtrhhihyeeetreh-eeyearedsetadscx,hst1oitenpset9rcgtuteeolwhh4errdoa)si9oeasotsyefelustreidamkdr,cpsrtieieceoa.wmitcsraethhsouietvdoetfhrlh.oeitkernsserTtrenadwdhrntigicsnicuaeanraavaoselciynnlentualessdnustptimtodetosshitginttheaonmoaocelnoblptyafteearhasledp(intougpphsedcsbnpreearoeesaaionfonsetnrwtmneedseqtslirninyudototnchuteelr3feeotednr2aao2nextyp9lcdgodsiotlere-faiyyecgtsaecsecpsnttaomreurhhiomernxfresssif Tabl* 2 . -- Cancer Oeaths Among a Cohort of 121 M ales Exposed to Tetnchlorodlbenzodloxin in a rrichtorophenoj Process Accident. Y ia ro t Birth 1909 1910 1911 1922 1915 1920 1919 1907 1910 Year at Hire 1943 1927 1939 1945 1939 1948 1943 1943 1939 Year at O uth 1962 1970 1964 1973 1970 1978 1973 1971 1978 Outh Certificate Statement ot Cause at Oath Lung cancer (162.1) Pulmonary carcinoma (162.1) Sroncniogemc carcinoma (162.1) Bronchiogenic carcinoma (162.1) Lung cancer (162.1) Malignant fibrous histiocytoma ot sort tissue origin (173.9) Hodgkin s disease (201.0) Lympnatic leukemia (204.9) Acute myetogeiMus leukemia (205.0) ' Smoxing nistory was obtained ay interviaws with former co-workers of the decedents Journal of Occupational Medicine/Vof. 22, No. 1/January 1980 - Smoking History* Cigarettes Cigarettes Cigarettes Nonsmoker Cigarettes Cigarettes Cigarettes Pipe Cigarettes 13 17238 DOW 049921 is longer than that of any previous study, and the follow 6. Suskind RR: Chloracne and associated health problems in the ' up is complete. Therefore, although the cohort is sm all, it represents the best opportunity so far to study the long term effects of TCD D on mortality. By augmenting these manufacture of 2.4,5-T. Report to the loirn Conference. Nadonai In-stitute of Environmental Health Sciences. International Agency for Research on Cancer, Lyon, Franc lanuary 1 1 ,197ft. 7. Young AL. Caicafro |A . Thaikan CE. at ak The toxicology, to- data with the results of com parable mortality studies, the vironmental fa t and human risk associated with herbicide orange long-term effects of TCD D m ay be more definitely evaluated. and its associated dioxin. U.S. Air Force Occupational and En vironmental Health Laboratory. Report OEHL TR-78-92. Brooks Air Force ftas Texas. 1978. PfoTrihJ* Kaurdtimonforttiall rtou thnfc M r* m u ik i J mthot dYauta*c* aMdar.ctRtoaai.irip Hcp iat and M r* ft. International Agency for Research on Cancan Long-term hazards of polychlorinated dibentodkjxms and polychlorinated dibmv zofuram . IARC Internal Technical Report No. 7SAX31, Lyon. 197ft. 9. lirasek L Kalensky I. and Kubec K: Acne chlorine and porphyria References cutanea tarda during the manufacture of herbicides. Cask Dermatol 4*306-317. 1973. 1. International an tit {valuation Ao ffttnhcyCaforcrinRoesjeenartcchRoisnkCaatnCcheermIAicRaCls M anotraphi to Man. VoL 15. Sons* Fumigant th* Herbiddas 2.4-0 and 2.4,5-T. Chlorinated 10. lirasek L Kalensky I. Kubec K. at a t Acne chlorine, porphyria cutanea tarda, and the manufacture of ohtehrebricmidaensi.feIIs.taCteiosknsDoefrmgeantoelra4l9p1o4iVso1n5in7g. 1d9u7r4in. g ibcnzodioxjns and Miscellaneous Industrial Chenucais. Lyon; IA RC 11. Pazderova I, Lukas E. Nemcova M. et ak Chronic poisoning by 1977. chlorinated hydrocarbons formed in the production of sodium 2. K'mg | and Schulz KH: Occupational acna (so-called 2.4,5-tnchiorophenaxyicetat Free Left 2*332-339,1974. Cmchhfm3eo.mrAhasictchineaeela)WC1odflmuSaocnp5da4tno0Sy-t.o5t4Nkh*ienitrd1o9cR.N5R7Wo: meRseatptVeoditrtgsioanrnioac.mMRaeotipcnocrnctsyec.colaifcsteheexMoKonent.tseaDrninetogn - IX Koebe R |. Keyes DC. Beyer |E . et ak Results of a two year chronic tonicity and onc ogencity stutfv of 2J7.S-teoachlorodibnnz p-diamn in n o . Toxicol Appf Pharmacol 4*279-303,1978. IX Van M iller IP. Laikh II. and Allen lit Increased incidence of Laboratory. December 1949 and Aphl 1950. neoplasms in rats exposed to low levels of 2J7.5-tetrichlorodiberao- 4. Suskind RR: A clinical and anvironmentai Chemical Company. Nitro. West Virginia. RapoR osuf rtvheey. Monsanto Kettering Laboratory, |u iy 1953. p-dtaon. Chemospfiere *337-544,1977. 14. takty. MCoonmspount RBRio: mAendalyRseiss of relative 7:32S-33X survival 1974. and proportional mor- . 5. Suskind RR: Chloracne and associated problems Report to the Conference of the National Institute of Environmental Health fo r15U.sEelgitnh Revision. Imemetianai Classification the United States. U.S. Department of of Disease Adapted Health Education Sciences an Chlorinated Oibenxodioaina and Dibenzofumn Aprd 3. and W eifar Public Health Service. PHS Publication N a 1691 1973. Washington: U J . Government Printing O ffice 1977. Fu iu re R isk In the industrial countries we have grown rich during the age of hierarchical business corporations, in which each executive arranges what the man below him w ill do with his hands, ail the way down to the man turning a screw on the assembly line. Now, two rather fundamental things have happened. First we have begun to realize that workers in rich countries don't like working in such places. Secondly, the rich countries are moving out of the postmanufacturing age. but they still have great hierarchical cor porations in w hich executives sit behind their desks trying to arrange what the man below w ill do with his imagination. This no longer works. New forms of business organization w ill have to be found, probably changing big corporations into confedera tions of entrepreneurs. The firms and countries that w ill go bust in these circum stances are those that try to replace hierarchical corporations by even more ossified forms of hierarchy -- say, by deciding that you mustn't have a boss trying to arrange what f r e e " - men do with their imaginations, but can have a trade union committee doing so in stead. - from -UiMKd S uus Cxn Keep Crawv, - And leed - It .1 W niws* fay Nom ao K iw . mSnwMomm. luiv 197 14 Mortality Experience of Workers Exposed to Tatracfttarodibenzodioxin/Zack and Suskind 17237 1- 9\ t x if Mortality Experience of Employees Exposed to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) DOW097720* Ralph R. Cook, M .D., M .P.H .; Jean C . Townsend, M .S.; M . G erald Ott, M .S.; and Lawrence G . Silverstein, M.S. c o This hort osftu67d ym adleesscirnibveoslv et hde inmao7r t9a6l4i t yc experience hloracne inc of iden a t. Presum ably as a result o f skin ab sorption o f the process contaminant, Z3J.8-tetrachlorodibenzo-p-dioxin (TCD D or dioxin), 49 o f these trichlorophenol production workers developed the skin condition. W ith in the lim itations posed by cohort size and length o f follow -up, TCDD does not appear to have adversely affected m ortality experience. Overall, four deaths occurred and 7.8 were expected. O f these, one death was due expected) and three deaths to cardiovascular were attributed to disease cancer ((37..86 expected). N one o f the findings were statistically sig n ific a n t at a = 0.05. Further fo llo w -u p is contem plated. VwdgepsaeereeuetrrxxeexvmnioueeecpppartiIrdqpesaetnookllsnouioulrtnesesoeemasnaeteturdythrlimsnttydorieiiin,etpenns7n*heealgghHasatmvtationtnnuoewewetvohodpaterehNheofrn1ldxrtotaersisheaCbaipttteord,shehnleDooixweietesecEoe,yfiCannortxxdeWreDrpicsoudonkxiohtnioefcievunpnsaaiewsedtdoteenitxtdrsyaAidad1paoeVu,tCwg9moelnlrliwadv6eeshrdisgytu4iuahenm.hteo.irarnfemtnierdroBnldtoihiatOTrgcermmhsteWe.hacathri7srageoaaalle,seitiunrtsueaaCtly1sdgftasovlmar9etoeeeyblh4ritmw,ofrtehj49ooeyafnaorpfllcp(ogisrUcwaHaturuaihn.oUvnetnEtSglherybelr.tiW.ehaSveemlsegce.w)aAdiemaro1cirsenhaw9dibtearsiicdgo7tovelieuee8finrFbooapnessfwseuorsrctlwoareaeirsinibeca6mnarr.dt1goeeeyssl,t vdb7cecutndcaa5hloxisyieioornrplupAnduCIoixxniooaradrctriihpovonusnal,ialoetldusly,s.coiol'ssouurnkrgeshtncccfeoisni.figeoctobi,edoscapnamlqriewictosealeAouihmoisntxnedfamolneiolteebrintaassaoororrnsodralecnuxscoomoocdigoithafrcsinfaneemleiherttbrreh,eytssua.cyhie1,nmhcTlehidfttolCaosihaToieusmaivSueDnhrnssneineienbD.tsdel1v2rdeaauiefq,astlfs3psseewusltaaoor,dicaa7oso,stsf,dnsppo8nptIvu.eotur,oh'waa-catcpnntehTerliceiyudtinfehseehti,olcroeatpafyltltsaocmchomrieuocohrenoxopabncnlogocssnhirsdtfdeitrtadycleoaesmtsrrdsontipiameaeiliixtvTlsrnb*xn-oieacdCaechcmmutennayDiodotbfntziialiDnsinfoioonodtnueitngx-enehopotnilidngaeieycsr-ft fro m D o w C hem ical U S A . M id lan d . M l 46 64 0 (D r C ook. Director. U S Area E pidem iology. M s Townsend. Epidem iologist. M ic h ig a n D ivision, M r Ott. Siostatistician. U S A rea Epid em iology, a n d M r Silverstein, R e se arch M an a g e r. U S A re a In d u stria l H y g ie n e ) M r O tt is c u rre n tly at the U n iv e rsity o ! M ic h ig a n . Sc h o o l o( Pub lic Health. D e p t of E p id e m iolog y sooocMimmbahhweTtnaulanpdyymbhaaeamebgdseTiTsessebpdtnstiorhoishieraelbniadnueoraceionrafnpaetdfqaythiliaidfscyeotzctsupuealiiiecasgrodoontsoeecetdt1hns-ndtaausnsiiarpo9t-ln,esirsothisea-ow6natlisdpyinndeaaxlb4(nsfih2aggdipttdiMdoce)ltnorohiiihwtoxttnabehsymaypeeaiwnhgtdyneuegtoermdeneeoeo.rpiprtJeecionnrsparforhtiAuinkoiodsotlaoionesgeecenentelnbehyxsehdwgdamdmepsaeesrliai1ogaaeostipitenoni9hrpssahnsoulexo6dclrunydopntcosiy4ohrsgehsgecue.netlikptnrleoiesileoonctetigrsnniwaasrxgonptsaoaermoicbeogcrp,fcpcfaelaareoirunrTnoortpscoibdliedeoooeCnanthomlae.erayfggandtDniderIntnyithcnctorDtngaiaieih2ttegateeotscs,.pinhe(lwa3sntauo1erseg,lseam)litnt7rtscihoehxssneft,thpwerpeoo8rdeiolmTlopzn-rboihvtnlseCrneforiiaiaeorgncnucodetDtonlxrhdhdrhduplaeimpDaafuuuoahec.onplspdcstwelhssicgtsTltteeontarleruijoekoeohorinmioarnaraisnirdbnneessll-.lt- 530 flprlntd front Journal of O ccu p allo n al M dl ein A u g u st, 1960. V olum 22, No. 9 pp. 530*532 J O M 1980 17238 . .t t Table 1. --Age Distribution ot 61 Employees PoEtmenptlioaylleydEIxnpoPsreodcetsosTACrOeaD. During 1964 by Job Category and by Oate First Exposure Group and Age Distribution Group 1. (High potential exposure) Total 20 - 24 25 - 34 35 - 44 45 - 54 55 - 64 Group 2. (Low potential exposure) Total 20 - 24 25 - 34 35 - 44 45 - 54 55 - 64 First Employed In Process A ru Prior to July to Total June 1964 December 1964 39 34 32 13 12 10 8 87 55 22 16 40 65 99 32 00 5 1 1 2 1 0 6 4 1 0 1 0 ( dw1de1hampmpttspcriia99hormooiuoiorogreitoe66onnssSnemcerhapn4v3uwsukestcielixp.it,roerdooentfhseetafurlydayunoyqTtlontye-ntisgerhumgnohdicendlerdiriyponrtsnpcoohoTJete(neJvmuufh3deuauakrrtunopp)esoeagegnnbesllsUoymvsememmhoulpnaencewsrattSnpwi1rnddonhDci.1idnl9becenioraTal.sew6oielertyswtuhttbec4eiVudseohrtoeseys,nwiis,geiibtenttmfahhhashaeuuald-eonaasnolbrartaxwncwDepivmtdpeponthsedeaee-ereredntaweeocatrcscpwhlxf3reidotefeftmoieuoor1prieourcmomssrssi,kofpdardscumtekeasboieo1etontbeidenunhe9pntonwtfdiddrume7ermnunateihimsav8nel1afapiaeieoni.lal9ewdllbggletion6ibasdeeFretqao6fey4ohcsteidr1-oyurnme.ssefuestslir.woidlppp*tgopmoiobfnefeemnlrmwwoiufemtoecienonemyioniinmdndlfpcneddirtaegcltlkhtewNetoiuh.ainoeesnpmyadooatmgd,theaTsrspveeaoeseerehedrbdnraitrdotsneemmuytahswedawaprnobnetietu,leernehhicdoeonrtocxxgiroeeyessrftt (tdRcabaeOapedatlrdopchoheoaicpmxlciueofysvoooeswncApnhpTfsestcpetypuvekeeheeetuo-hcrhosreal)gwp.neiolgcatran.entmidoshtsgotsteyrlesaeiAScelteaheoitn,ean-cndmeudumle-vilpfsf-docia.ffplnbtkesiaoari6omettntoetdeOoxawirlru1icnrndiateadiepgl.veoredfgsgilJsbaldonenin-mirTsupesdtootseegsateaihnhboeteioienufsxnohamdneeeaenanderopnotDldsstew-t1oossbwshosheoeeone9anresie,ssbgxeseewcf6seevweoupsrevoe4teseorwwneemsieaorhnp;vmmrurertremssoeleifeoavpsaptobruppdyrtuevtspleo.hkepoueoriosmdesblegrerborryoaratosrisrsts3nipm3yodmngoocabe,e.fu1efef8gnarsuraneatorov,vdlahtseevlcp1atcnnhleeeuteyerde.9ehtettgrvxdwpihdp,s7ossepspfauri,re8nidiewasttrasOiongsnhhoo,c,cntomfhmnaecbirantdin13jvsceieitoayolcfl.u0eepodiys61tnbsqnhicso,dns1m;hdwuogaweacoeaenf1apeaxt4tlJwfmawnhoaes4rtarisp39uevredetsifners4ealitaeooeyosod,hncti)tnffdiinpufhoetnftaneithe1aee1rmucfttoewdpehhiT9erx6bart=sc.peoe6pesstalistokeotcii4elotsebNnhoonhwth0,sivOlonystaeioce.luegeti0o7t.envahmna6earrhr5i.i2redee1e.ennrnee8l-,-.. ddf1mfopepspnaw1ytpccuEcHppiore9veeeioa9htoounmeofainegoarcr6eas6snsCClmsCknmrtvvaorihpefa4arccdu-4yncinykaaioeastrryprbll,gnrr,hr,iioteaeossosdorr.iieveeehaeebbtameelewchdtryneiodebnbatHnraoseenememontre31eeahr2y6dlpdiosooiaews..nn.dg.gnew0emTshafcof.aw.iib--ic,Nmn--nbTdenCnnnotfaHyso--heehettsennnCeoeroDtakhielrefek1hsiaoiaioTkiehTnDielnnfDbnne9aertwseolTehwhaggsthDcr6gdufsmrtrerh..oeanre,edhai4,ppt.iwceosdcgxh,ioseiIoirs2eniseahnnAaapneopaihkn1u4nshuvdllsssorsdelot4om1tbt1eecbt1u1soyduaahery9w9njorajia9ua9booreoneneaaco74yomwl7a-2rdjjpcftfadtrcg2ueo2ee:lht6i8etatorhota,ipa..xhghcbns.a.satwaepwnnabpttieay.hDgishDddann,dpcaoDippotoRnwureIretkuoaacsareerinr1ruwfaavrcenekokrkuarlciier9ormcgoanicpoemf,oerrckfni17poheanoeekflglacdyerdevg95rarnlerkghwpecac.oooitmd6c5tindieid3ieka3rhncasNnrgfs24a6cg51reroreihictga,4sstsnitopcdespniiodrrarhysnyghiepwueso.epgaohnmadgeeoeirlonccaetofmofedeyea1aftfacetuktsrerditreirwn8frerroihyacd5afsraisosaetsronoran,3hnaea,ocndaydetywli.rwshepsttnnthtre.,dneitiiipAsteaa1eeafieasvrvaiertthAotaeirr7rnshl.ueruerhbceleirsedrshlymdrcatteeuaHsudao.ehyewtw3tyatcawt.hitahieinphvgeoie5eaonyeaAsreareoDkensiiaeuwgdneesrgytrhlynfeyflhermgntsudcohaocesasedo,oohtrwswpaolraesdeoatoirwosemnhneiermahao2rnttbwsixinoedegensadsseana0aft. Ta3b1la, 21.97--8,Voitfa6l1anEdmEpmlDoypuelroeinysgmPe1on9tt6eS4n.ttaiatullyaETxhproosuegdhtoDeTcCeDmDber VEmitaplloaynmdent Statui Total Still working Retired Deceased Left company Deceased Alive Ns. of Employe* 61 40 11 4 '0 6 531 172 38 rNgctgptyerhrlaioitocolCniiorshumayearlpanosumaiecortnoeontwa4pnp1en.risth9et,doyh4e--c,on6onwmfrotdaadhThelusteehytaardpetpirfshn.aeeetesgacarHrtue.sfeeoabe.nIgtrnsjHhsdmee.iii1ecsveeNo9tedsd6fobm.ph4ie4neeao1ghrauk.1iaeoret9notHddw7pd,e6wafisso.syosehrspraiewnek3esvi0aenntehsdtygnaeee2ptavwy0hetreehisirgtalyfeohoherbpsr-aaumeterghtaxsdeeeqfptdiuoeonc.msarfount7hmihrlt1ideeis. t2yedcrteb5pcopaaocTetltafiaticrldDoynchhyeohoeehih,maxsaxber0nhoanfisi3ceesoeesalsbppTaolserney%eseirTlt1teroe,pmudxocrhheeooe7nsnheoctaldi9hsofarlelcdiuuiessweennso,efectaneasnaoo.i6cr8fsaeovsseltuueceytrcscadslov4-omT-slfandpcrpfnelrsechyiuenoiTdsatceansuineheetcteorotlteaaeepeofCsssttigoiilhdpe(artcdnsonuefpdnlosha,mtrcd.eh.iidlriDkaroc"ge1nocdidndnreetfuqoc0tluiuhtaheDn(laa,hgeywcsmmlapaue2r3McsrnaIaseftsataestytfntrtxohyi,loeiiiatdodrehreoxe,dn3ionnoswuhpesisenrrstussppderncdr,setgntacoahacytwadi7acnhtsieeniuesaecgdcnhsraheetsya,,toesooukceraotlnuau8dniauillstahwinsnitinrt.frbtooottrlorp-itmehthskistcddefertywttinoyoeadifimedqoseaheoeecocetslaeopufaha.,truaetdadpodaahaenhfrlpibspoeletetaoeelbWnontodtaoi)xhsesrhhlovpifxipldaiecanrtcotpnprtflomeaslteeeptuuiuhertedtilchuondeedvrreetowtealrndmmlitce.mkvymhlwdsruanelohsinvwonreytitfceoict2euOicsatrctfieodeisuorsoue.rvid,nheouieeo,nsolcecrrmtnnhrfdniv3euyrh;htgdltcusdtdcanaaAvddruecoier,oalmaeoen.oeirs7sinnieelimcrblanlarlcaarvdueodhslse,acdIrlaie"sdhtel8ntsmhtiniceaghovsevwolnaudtdelwnlu-tohehhleceoabnriresaoynitpumnicszntwyeaeimcfmrtreyrpea,dmdrpaaahtcooogirasctiuha-1esiseel1drdoyllora-ilpaftrtsteota.sne;letdh9,phciehrh6wrrtyhratluancrtfoesc6iui-etiyciehtsohontnoesati(dhiehlfpos4loaesitthseraafooornnrdhnhnwilpxilo,iesntfeolsoaioncvgwgosc,ilittp,ooa,nfscytonsssesyoxderiguooiegyepeenslsmoeceyuttorxiiogrnehnhhsceouvknyoadwrsacllenwtgciaeet,ntnyoeegosenntterieeeaefcubbepdan,pne.ae.grrrpoeoetds4sax,fatmsmeyooagetorebswrriudtFef)htcnespostnsttpse,feoIwiaensaeihoheeoufeidnsnaacvtozecfnfelsdedpbnadmrrfnpeiiiclcottctginddtealtsrsohthtehthttotatiooc-iea1iohgteeibhhhhciaouoepcaaaeyspwiitnx4)dnnhtnsesdeeyea"ltft,rr-.,ltrt dhuumctaends.to determine whether it is a weak carcinogen in Cddowa7etcspcdh.auhoixnrifeo8coeoperredTarncvxrvesceemhetcieiiecanrxidfllnsiiiuteosprolceelodssnaeraagedeitltigcnneloiovh)'gtis,tcaenvnnaehadhelannctdydpit,orslows)yodeoo.xcwiasiatifsfiuttFetnihsiitolonauntaheflhfgrnebcotritoiinotlvsaohaalehrlvedeovnlgletgeletrewanhsay,rramneosopa-iitunsttuheleoallupfo.pdixbrommof,wrto'pefsrafWieimeoectlt2saitcimcairtshu,eatoytt3ksanieimnotnol,uieelod7torcsineotxtt,ainyas8drptoarosl-e(e(cwiv3pt4ptpreriyenpaeoippeetdrsoedsrercaoneeaeoagribclpxacftdlrdeaiaepstrhcnuheteieilbcponotscodrryayofifveironoe.oinoet6nmcgernbcd1dccCocneshirihbneheemortulearaootnvmahvosdnssrnrtleuiat.haeeezntdmcnoasosuarnstuti1-iveahnhzisp.enl.sderddkes6-,.l The authors w ish to thank M s. M a x in e C oin for editing the m anuscript A ll correspondence regarding this report sh o uld include the reference num ber B-6OOO27-0O. N21CwH11ofwDl2rRtaeoa99940foeoheobretx7772489623411571rswraeweoi316::Sf......1k..0kcmln85re...s.t.e.iOeAOWePCBBSa1h9cTtivrrrSMKymste73oli5nuoltseeaostai.c.3-lte7xrvoonasiiar5acnid3frt:Siyo1icenneyMbn9Mfnhcn1:e9.cireent3yo7yddb6iE7wcSpGe-cil,mRa,aRPt9c1HN1Leeotso"AA1.l.h0rMr.o9rP::Rn:92P2o,iap4Tk:7uBe(7.c:l.Dc0-epSe4E91.Vsso97ooel1rTl9:c-.idSwK.,PgenisoD1r7e1omd.PeAelx)1an18Het:2exntiis9hBt.y6i|s0nntnai:Ecti7caeieC6r.htgncsh8Wsnyra-FisIhdieS.m1Wtndnh,DDflyt1IdooBgafaCa2o,nC6saer1fvcns,ufeadb7sCoc4M.toevdthrdu.dt.e.tlsM5eBaasihanedibf1Fn-to4mrulepeTeysoe9uetgdx6iyeaeees7afpdti:ielo6rhntnsoz28sfprhttf2ecesbn7.3hldCah.d|9pa.Zef3AE2tiroi.-chnr--,o.43,7kEr3kDemexFt9a0,e,ash,u.i87-n3eCstoWdnSeAr-Ae,Ou,ndr8rt.eo3at:rrettgbA-mrp1l,ecaftt.aePi9iexahers,Aglcli1nR7oai:itaacpiit9antmr8nsndeciyeEoE7sna.cs.hese5isnKcexduclIOTru.rhvopklaiiahiOttroarlcreLnrhsoteexaodaroicPdaeraooiindnon:ccenolsrf.igtnaoudgebAFheHC1dlacgnpieaoabe9vieenhngtsht7Meeaerewdtozedye9if,nrlomiifatfRoeyszth-elS-pAd.oR1tittcychohhuo-.:tde2a4Cpf1eectsa2vl-Me8-ishdrf:Ae.da:u"i3e1StirnSirocco1hymo6eovchccI6rxe,5xceeAiir-ati-Cdmeiys3nso1aEelMnae2ton6tlhnnccy7yinii8Aiinneyffncs.tf,. vf \ ' 532 17 c^SS T 'lM O O ASPLUNDH ASPLUNDH TREE EXPERT CO. 979 P. 0 . B O X 2 6 8 . D A N V IL L E . X Y 4 0 4 2 2 A R E A C O D E 5 0 2 > T E L E P H O N E 361-8811 GASTON ROSE Vice PRESIDENT September 25, 1978 Federal Register Section Technical Service Division (WH-569) Office of Pesticide Programs, EPA Room 401 East Tower 401 M. Street, SW Washington, D.C. 20460 Attn: 0PP 30000/26 Gentlemen: I represent the Asplundh Tree Expert Company in the state of Kentucky and have been Vice President for three years. I have been using 2,4,5,-T in Kentucky for the past 26 years to con trol brush on right-a-ways for the various utilities in the state. I started using it as a sprayman on a crew. It has been the most effective method of controlling brush along the right-a-ways, and I have seen no ill effects to wildlife or any other livestock. If 2,4,5-T is not to be re-registered, we will turn to hand clearing or mowing, which would cost us approximately five times as much. Neither of these methods would be nearly as effective as 2,4,5-T. Needless to say, I am very much in favor of 2,4,5-T being re-registered. Sincerely, :kh cc Wendell Ford Walter Huddleston Carol Hubbard William Natcher Romano Mazzoli Gene Snyder Dr. Tim Lee Carter John Breckinridge Carl Perkins Gascon Rose Vice President 17241 9 oO LETTERS RECEIVED -% 17242 8CSGTGMOCI ASPLUNDH ASPLUNOH TREE EXPERT CO. B LA IR M IL L ROAD. W ILLOW G ROVE. PA. 19090 A REA COO E 215 TELEPH O N E: 784 -42 00 1034 West Street, Amherst, MA 01002 October 13, 1978 Federal Register Section Technical Service Division (WH-569) Office of Pesticide Programs, EPA Room 401 East Tower 401 M. Street, SW Washington, D.C. 20460 ATTN: 0PP 30000/26 Gentlemen: As a Division Manager ar.d Vice President of ASPLUNDH TREE EXPERT COMPANY, I wish to acquaint you of my concern regarding the study by the Environ mental Protective Agency on the re-registration of the Herbicide .245T. I, as an employee and user of 245T, have worked closely with this material since 1949. I have had the responsibility of applying this material and assisting people in making decisions about its use. As an applicator who has used 245T to treat undesirable woody growth on Utility Rights of Way over a period of 28 years covering many thousands of acres of brush, I feel that you should be aware that during this period I have not received a claim from an employee or ex-employee of any health problem or am I aware of any that existed. I am sure that you are aware of the many discrepancies that exist in the newspaper, radio and television reports with unsubstantiated claims of health hazards. 245T, when properly used in the control of unwanted vegetation on utility company's Rights of Way, offer a substantial savings to the maintenance budgets. The alternative measures of control would multiply maintenance costs and thereby be directly reflected in utility rates. At this point in time, I an not aware of other chemicals or mechanical control measures that offer the benefits achieved by the use of 243T. 17243 CRSGTGMOO Federal Register Section Technical Service Division October 13, 1978 Page 2 As an active member of the International Society of Aboriculture, Western Mass. Shade Tree Association, Massachusetts Tree Wardens and Foresters Association and the Maine Arborist Association, I sincerely request chat you give serious consideration to the positive aspects of the use of the herbicide and use your influence to keep 2A5T as a tool for Right of Way brush control. Respectfully yours, Joffre G. Schnarr Vice President pc; Ken. Paul Tsongas Ken. Edward Brooke Hc*n. Silvio Conte Hon. Edward Boland Hon. Joseph Early Hon. Robert Drinan Hon. Edward Markey Hon. Thomas O'Neill Hon. John Moakley Hon. Gerry Studds 17244 1! CONTRACT0I1 1 Walqren Tree Experts, Inc. 2 Farrens Tree Surneons 3 Georqia ROW Construction 4 N. G. Gilbert Corp. 5 Davey Tree Expert Co. 5 Nelson Tree Service Inc. 7 Townsend Tree 8 Noxious Veqetation Control 9 Karl Kuemmerlinq Assoc. 10 Funk Bros. Tree Service II Noxious Veqetation Control 12 Bartlett Tree Expert Co. 13 U t ilit ie s Forestry Service 14 Bartlett Tree Expert Co. 15 Glume System Tree Experts 16 Trees, Inc. 17 Davey Tree Expert Co. 18 The Daltons of Indiana, Inc. h* <1 19 N. G. Gilbert Corp. O 20 Townsend Tree Service 00 21 A s p i n il f ill f i n i s h f n n f r n l f n 22 Shannon Tree Co. UTI Rhone 203-249-5266 -9Q4-Z43-2622 404-27B-6905 404-294-5490 216-673-9511 513-294-1313 614-593-6037 614-486-8994 614-471-4144 419-325-2113 814-623-6351 614-453-0653 814-765-7115 615-247-2154 713-782-9450 713-692-6371 214-593-3122 219-267-2460 317-284-4461 317-282-1234 317-482-2041 717-296-6351 Cfr-s \CT( Name-Ti tie of Person AES No Out Yes Copy Date Bruce Walqren x X 8-18 Gerald Farrens XX 8-18 James H. Hicks Bob Bowen Dick Abbot Paul Russell (spnt previnn ly) XX XX XX XX 8-18 8-18 8-18 8-18 Dent C. Dailey XX 8-21 Sally Watson Franklin N. Brown XX XX 8-18 8-18 Kenneth H. Funk XX 8-21 Walter Grobert XX 8-23 Burl B. Shreve S. J. Wayrynovic, James Davis web X X 8-18 Herb Merri11 XX 8-18 H. L. Graves, Gen. Mgr. Thomas Gunning Merle Talbot XX 8-23 Do n<it of rer sp 'ay x S<rvic k 8-25 XX 8-25 Lex Dal ton John Elsesser XX XX 8-18 8-24 Donald F. Townsend XX 8-21 Fernand Perras Walter Shannon, V.P. n r* XX XX 8-18 8-21 1 JTlL CO.^CTQ.- /' CONTRACTOR Phone 2 1 Arbor Tree Suroorv .21. Uavey Tree Fxpprt Co. I lt ilit v Tree Service Inc. 005-466-1239 415.443-1723 707-443-9794 26 Farrens Tree Surqeons 21 Farrens Tree Surneons 205-833-9079 404-636-1994 .2 Davev Tree Expert Co. ..ZD Wright Tree Service, Inc. 404-451-7913 515-277-6291 JO_ P liillin s Tree Experts Inc. 606-528-4145 - J L John Lucas Tree Expert Co. T2 Bartlett Tree Expert Co. 207-797-7294 703-343-9376 31 Nelson Tree Service 906-265-2618 _34_ .Tree-Preservation Co,, Inc,____________ 914-941-2600 ,,31 lewis Tree Service, Inc. Jfi. Monroe Tree & Landscape Service .31 J. Taylor Tree Surqery Jfl. Uavey Tree Expert Co. 1 L F. A. Bartlett Tree Expert Co. H* 40_ F. A. Bartlett Tree Expert Co. to "'U- Black Industries, Inc. Uavey Tree Expert Co. 716-684-0120 716-436-2900 914-895-3495 312-437-0911 203-323-1131 215-664-3200 919-4770485 704-596-8066 Stackhouse, Inc. -*3 14 U ...H __Too1a iQiistr-UcT.iQJ] C(L_ qiq-735-]704 919-273-6927 Name-Title of Person Richard 0. Alvares Euqene W. Haupt Jim Fox Marvin Humphries J. L. Arqo Tommy Davis Roy Gunson Ray Phil lips Henry Thibedeau C. L. Greqson Frederick Gault David Franklin Robert Howard Steve Kubber James W. Taylor Herbert J. Winters Robert A. B artle tt, J r . David G. Poe Craiq M. Black Gene Efird James R. Fdmnndsnn w. d. Pooie 2 G2 L I -^ AES No Out Yes Copy Date XX 8-21 X --SeHeottu1laauvertytr ce--- -- un-coii XX NOT USIN< X _ L i 5-T 8-21 8-21 XX 8-21 XX 8-21 XX 8-21 web X X X X 8-22 8-21 Se Mail i Off ce XX XX XX cb 9-1 8-21 8-21 8-22 XX XX NOT 1ISING X CHEI 11CAL > XX XX DO NIT US _JL_ X 2,4, J-T DO MJ SPIJHY W( IK 1 8-22 8-22 8-23 8-22 8-22 8-24 8-22 r UTil 11Y OpRAC1 uno 1 CONTRACTOR 45 Asplundh Tree Expert Co. 46 B a r t le t t Tree Fxoert Co. 47 Ilenkels & McCov. Inc. 4ft Southern U t i l i t y Const. 49 Nelson Tree Service. Inc. 50 Ilenkels A McCov. Inc. Rhone 617-032-5721 606-324-9414 215-646-0000 205-871-0410 419-433-6471 301-650-5522 flanio-Ti Lie of Person Patrick V. Smith Flmer W. Reynolds John J . Burns Melvin J. Uornberaer Herb .Dotson, Mqr. Joseph B. Dugan AES Mo Out Yes Copy Da to X X 0-23 yes X or XP : X Stun X 8-22 is 8-25 X X 8-22 X X 0-22 - X X 8-24 51 A g ricu ltu ra l Services, inc.______________ 612-330-5001 5? Davev Tree Exnert Co. 003-543-3029 53 Asolundh Tree Expert Co. 414-931-1610 54 CUSCO . 703-362-9210 55 love A A ssociates, Inc. 004-372-4941 . 56 l'Jes_Lv.ar-n Cnrp.._________________________ _ 004-023-2257 57 Chem-Spray 310-425-0671 Ted Meidnnfeller Ray Bannister & J . 0. Brooks Robert Wakefnrd Mr. Bob Sayre Wi 11 i ain Kp p I John (.lack) Onegy (sent previously) R. A. Rains v/cb X X 8-22 X X 8-24 X X 8-24 X X 8-25 X X 8-23 X X 8r24 _5Q. In d u stria l Heed Control ..a leeds. Inc. 60 'arker Layrie Tree Service 61 IcKibhon A McKibben 6? Jiem-Trol. Inc. 63 iadison Snravino Service 61 lute Tree Service M i ). I. Brown Tree Fxoert Co. 66 Nelson Tree Service ?lfl..?37-7755 012-440-5677 615-037-6565 717-323-0205 913-342-3006 405-237-0294 712-792-9009 615-037-6565 015-725-7269 .1 0 Richard John Uaronich cb DO I IT US X 2,4, i-T 8-24 John P. Lavne (sent previously) X X 8-24 B i l l McKibben cb X X 9-1 Bob Tolman (sent prev ) X X 8-25 Weslev Madison X ___s _ _ J h H _ 1 . J. Onto X. X 8-24, John P ("Parker*! lavne (sent prpvio s ljU x_ ___ 0-24.. Chuck Kaseno r( ^ ~ Hi r a CONTRACTOR 67 Chem-Aq _6 8 Nelson Tree Service (Main office) U 11U T yO i TRAL I ui\S l'iione Name-Titie of Person 318-9(11-0349 313-7P7-7W7 Russel Mier Vir l AES No Out Yes Copy Date cb cb -- 1 -- I'G Q i'TG M O C _ ____ ___ 1! ASPLUNDII REGIONAL MANAGERS 1 ATE (Conn.) 2 ATE (N.Y.) 3 ATE (Georgia) 4 ATE (Texas) 5 ATE (Virqinia) 6 ATE (Maryland) 7 ATE (Mass.) 8 ATE (California) 9 ATE (Maryland) 10 ATE (Florida) 11 ATE (Connecticut) 12 ATE (Pennsylvania) 13 ATE (Pennsylvania) 14 ATE (Minnesota) 15 ATE (North Ca;olina) 16 ATE (Ohio) 17 ATE (Oklahoma) 10 ATE (D .C.) 19 ATE (New York) 20 to ZJ\ o _2L ATE (Tennessee) flTF ( 111 i nni <;1 ATE (Kentucky) or^s. Phone ..#47 J30 052 m #42 #35 #45 #75 #38 #54 #46. #22 #34 #65 #50 #61 #40 #32 #57 #66 #59 \ l.i Name-Title of Person AES Mo Out Yes Copy DaLe B ill Neidiq, V.P. Fri Rpganr V.P isent previn K 1V/) XX XX Conrad Bostock. V.P. XX Richard A. Bates. V.P. XX Dan Cole. V.P. XX Bob Co llier XX Ed Cumminos. V.P. Jack Curtin XX X DO N)T US : 2,4, i-T Charles Dalton, V.P. XX Rick Dannenmiller XX Harold Duncan (Car #614) X B ill Eqqers, J r . XX Jerry Erickson, V.P. Paul Erickson XX XX Norman HoDe. V.P. X M0WI IG Dudley W. Jordan. V.P. XX Howard Kidder. V.P. Werner (Dutch) Lanqe Fred Mehre XX XX XX Ray Muse, V.P. Farl Reynold:, V.P. Gaston Rose, V.P. g Q T f i M O < 1 __JL_ XX XX --! 7-?S 8-3 8-3 8-3 8-4 8-4 8-3 8-4 8-4 8-3 8-7 8-3 8-4 8-4 8-7 8-21 8-4 8-3 8-8 8-t4 8-4 8-3 /' ASPLUNDII REGIONAL MANAGERS 23 ATE (Massachusetts) 24 ATE (California) 2b ATE (Florida) 26 ATE (Louisiana) 27 ATE (Indiana) 2M ATE (Texas) 29 ATE (New Jersey) 30 ATE (Florida) 31 ATE (Pennsylvania) 32 ATE (Texas) 33 ATE (Utah) 34 ATE (Washington) 35 ATE (Michigan) 36 ATE (Alabama) -i * Phone flame-Ti tie of Person m Joffre Schnarr, V.P. m Mel Sease, V.P. #55 Dallas Schiver, V.P. #58 Ray Spencer, V.P. #60 Bob Spudis, V.P. #69 Dick Troxell #27 Milton Walsh, V.P. #56 Sam Sandlin #23 Merle Weity, V.P. #71 Dwight Watkins #73 Lloyd Eqemo #72 Donald Kuhn #64 0. Dan Stewart 205-633-9037 (off. Roqer Ferry AES No Out Yes Copy Date XX 8-9 X NOT 1SING CIIEMI :al 8-3 XX 8-3 XX 8-3 XX NT1 surer X HERB CI DE 8-3 8-4 XX 8-3 XX 8-18 XX 8-4 XX 8-8 XX 8-3 XX 8-9 XX 8-8 XX 8-9 sj o_ 9 SGGT6 M OO DOW 9 1 3 5 2 S i-'-.'JSithV CONGRESS * ...r.r> d _ Sr.SSifJN OXI O. ( f * d p r ! .n'fnnturr. of Memt-pr) IN THE HOUSE OF REPRESENTATIVES March 13, 1978 M r. .--Eiraas...o f..G e o rg ia ---------; introduced the following b ill; which was referred to the Committee o n ..... ;y>.v <5--^! .To abolish the Environmental Protaction Agency **-fi ` .VK - .V-;. \. ;;E: y - j Be it eanacted by che'Senate and House of Representatives - ;'.A2 of che United Scaces of >America in Congress assembled,-.- -.Section 1. The Environmental `Protect ion Agency is hereby ;V;f: A '^abolished. All- functions\ \ activities"powers, and. ducies of- .Xhe Environmental Protection Agency are' terminated and shall ,not . ' -.be trahsferred- to any- agency o t .instrumentality of the United States';.'. Notwithstanding vany other provision of law, all regu- : iacionsi.. orders, rules,, determinations, contracts,' certificates, % j j '.-r-iicenses,' and privileges issued , made, granted, or allowed co -a. V 'i'*' x-:v * % `xi ,,.V-.-:'," *` -, / / J/S S /W 17252 ('? T 2 1 become effective by the Environmental Protection Agency on or 2 before the date of the enactment of this Act shall cease to have 3 effect. A Sec. 2. The Director of the Office of Management and Budget 5 shall cake such action as he deems necessary, in accordance with 6 applicable .laws and regulations, to conclude the outstanding 7 affairs of the Environmental Protection Agency, including matters 8 affecting personnel, contracts, assets, liablicies, property, 9 and records of the Environmental Protection Agency. 10 Sec. 3. Unexpended.balances of appropriations, authorize11 . Cions, allocations, or ocher funds related to the Environmental 12' Protection Agency shall be available for use by the Director of 13 the Office of Management and Budget until the end of che fifth 14 fiscal year after the fiscal year in which this Act is enacted. 15 ,,Such use shall be for che purposes for which the appropriations, 16 authorizations, allocations, or ocher funds were originally made 17 available, but only co the extent required to conclude che affairs IS of che Environmental Protection Agency pursuanc to Section 2. 19 After che period specified in the preceding sentence, any unex- 20 pended balances remaining shall be returned to Che general fund 21 of che Treasury. ; j/1// 17253 / June 23, 19/8 \ 9 cO>K*'>) O C CD I JO Mr. Tom Price KIRBY FOREST IH0USTRIE5 P. 0. 2ox 577 ~ Si-1 slice, Texas 77657 ' Oear Tom: _ ; ' in compliance with.your request, please find listed below the s ta tis tic a l information of Campbell Air Service, Inc, for the past 12 years or scoco/;: . aPsi\\aregRaerldesaseto: the use of 2,4,5-T for Rights-of-Kay .... , Srusn Control a'id To:ry Rights-of-li>y Crash Control 1) Average work days 'per crew per year 2) Average flig h t hours per crew per day 3} Average hours per day each crew member is in direct contact with chemical, including mixing and leading.. - 71 ? .51 4 Forestry Pine Release 1) Average work days per crew per year. 2) Average flig h t hours per crew per day 3) Average- hours per day each crew member is in direct contact with chemical.including mixing and loading 41 2.25 4 Please note that one crew working both rights-of-way and forestry would av?rage 112 clays per year and In our experience the maximum would not exceed 120 Jays or 4 months. 17254 2SCTGMOO Mr. Tom Price KIR8Y FOREST INDUSTRIES rage 2 June 28, 1973 For your further information Campbell Air Service, Inc, has not experienced any In ju rie s, nor i l l effects, to any employee, as a result of chemical usaage 1n our operations. Every precaution is taken to prevent spillage and leakage by maintaining a s t r ic t schedule of Inspections and maintenance. The ciieMical 1s transferred from it s original container to closed mixed tanks by means of suction pump and nose, where i t 1s mixed with water and subsequently delivered to saddle tanks on the helicopter, also by means of pump and hose. Also, I would liko to add that I personally have been using and in direct contact with this chemical for the past 25 years, and have experienced no i l l effects, whatsoever. I have 2 children and each of them have children, and there are no i l l effects to any, as a result of my experiences with the chemical I conclude, that after seeing first-hand the tremendous accomplishments thru the use of tnis chemical, that to question Its use is utterly ridiculous. Yours very tru ly , . CAMPBELL AIR SERVICE, INC. W. B. Rowe, S r ., President WGRSR:jw 17255 CAM PBELL AIR S ER V IC E, INC. P. . BOX 872 VIVIAN, LOUISIANA 71082 PHONE A/C 318 - 375-3207, 425-8218 r C u O ' C B . . C *. O A M O * * C Q I C S .ITC S. O C T * C " Ite* C O T C I U H " I t C O TO t e s o t 17256 OOW913524 Eastern S hore N atural G as C ompany P. O. BOX 615 DOVER. DELAW ARE 19601 August 23, 1978 Asplundh Environmental Services Mr. Jim S k e 1ton Benefits Letter Coordinator BI a i r Mi l l Road Willow Grov e, PA. 19090 Dear Mr. Ske1ton: We do not use Z,k,5~T RPAR. Sincerely yours, EASTERN SHORE NATURAL GAS COMPANY WM/kd Wayne M o r r i s Project Designer 17257 ssseiGMoa i ol> LETTERS RECEIVED 172S8 September 15, 1978 DOW913523 Mr. Dennis Holewinski, Manager ASPLUNDH Environmental Services Blair Mill Road Willow Grove, Pennsylvania 19090 Re: 2, 4, 5 - T (RPAR) I Dear Sir: i This letter has been prepared in accordance with your letter of August 4, 1978, regarding re-registration by EPA of 2, 4, 5 - T formulations. ARCO Pipe Line Company has not used this material i extensively in weed control on our pipeline rights-of-way, however it has been used on our pipeline station properties very effectively in control of broadleaf c vegetation over the last few years. Alternatives to the use of 2, 4, 5 - T formulations on our station properties would include the less effective ! use of diesel oil. 1 If 2, 4, 5 - T should not be re-registered, the economic i consequences would amount to the lower cost of diesel oil but result in the greater cost of labor in killing the weed roots which the diesel would not do. Sincerely.^ G. E. Clapp d' GEC:vrr AflCO Pipe Line Company A yr Approval To: Mr. Dennis Holewinski H andling C om m enta Inform ation S ig n a tu re u1-1 u1-- l We have not sent copies or this letter to EPD or State Representatives or Senators. You may do so if you believ that our comments are anpropriate. F ile Note A Return A s Requesteo nL J C ontact Me From : G. . C/aoo J 3 0 ' .-Q-A Date: 9-L5-7S 17259  ` , . .s 'i i . . . ... . : . . , :' ... ; - ' I't-r , , , ; . M ' V : . ' . .. _ 1 ; . ^ . - . r ' . '* Ii ' . . . : . i s , : . j j : . ' 1 . v .~ r: '' '-J:-,- " ' ` \ /..\S;;.\ 1*.".'! :: -- -- , > . \ 'X' ^ / riv -'.;,: . " . . t r *v . *. .` . *1''' * < -,l / A. j:^ . ". i - .* -. .` -/ 1 .r. . .* y/ y / ;*- *>* jv-i'-j,'-''`'..'`,'V1'-..-j1, * ' .V '-"r -..* :1`" S - i l f - . y ,. *w \\ - i - ;''-V.v.- ' .'v/i" ;;-s-i- : -:vV.:'f->- ' . :; / *' ''; ` `i */; -1 l".. 1 ^KV;,,v?.r;/; V A ? ! -i ; j _ , 1 , , '7V^:^y\v:- '-,.: ' >; -7-ii,' i >. .1 -'He ' .^']/f i'',.,'. '. . ` J ;i'''N"*c''- V `*:4 4^* t! '* j:; `"/;:* -VH a :'v' * i-^- /::.'-Xi ,;X' - .r'* ;;.-o : .:. *- //W`-'-7^ ^` -T. vf . li V. '. " ' '. 1 .'. "*' *'. -j* i*. -.Cnf - : : /vij*;'''.*! iv A i : H : / T > . . *} : ., ' ^ r-h .' _r!. : r , v ; r' .1 V ; : ' . " '< .'* Vv'VV\__. r .. w? ` T J ! -4 ' ' ' ?j ; +. ' : "XWX.. v:'- v-/- ! .. rv^'^ i^r. v.lUr^ ^ x ; : 7 x:,Vx:v"'.: : 'v . !". ,.iVV'.r -^sivvi-' .'i-:>-A;*-:.-1;1'.v *'* w ' /-; y \ ' ' V ;.<.* . '.v j' - 0BZLI -V . . > ..'' t j - i v is* p *(; ;*-i \`s : 'i. F'jr .V . y - `-'V i'- ;> 'vw^.. 'V .:?/ v <* / . ri -<-\' *.'^ 1 ' > ' . . ^` ^V : 1 ' V V->,-'-V, r irr' r . i f r 4 1 * . ' V i ' ' ' -.- l', .j - >'; :*' S* . .;; J '-..'.. r 4 .* ^>* * . . V i ''l ' \ * . * * '.i ,,^^ v-,y,.,*.(,,J/'i>/...!./i'f'.*..'.>*i.>-*'/:X -s .a -\; i;'i"ij'.7i-,V.'X! . n.;;, i,.;^rJ.--iV', ^ :v,i-1^^ ',;.- vt-'-vv l!v` 0'`1 7/ 1f i i*' ' , y., '..,, *. * c 1'-^" r *k ' ^ ; .it'1 1-' :- - .'vI ;..-.7-:;.' 'I- > *a' --.i./ . 't. )?i iV .':- r..y;-* ..... . ^ v:v .-''.^;v*3 A \Q O -^ ^ -i .-:^ix:- i W x v :^ - . .' '; .....! -, . ...' " ;i/. .>:'.. -J '. ' 17261 r n Pipeline or Contractor ' v 1- Phone l Buckeve Pipe Line 215-967-3131 2 ARCQ Pipe Line_________________________ 215-678-8005 3 C o n so lid a te d Gas Supply 304-623-3611 4 I. anre 1 Pipe Lin e 717-737-8611 5 Columbia Gas T ra n sm issio n ' 304-346-0951 6 T ra n s c o C o m p a n ie s I n c . _____________ 201-862-8600 7 . ARCQ. J i p o lin e C Q ____________________ 316-331-1300 8 A r - n rn P io n L in e Co. 713-923-3300 9 A V r o r n i! & Gas O.ompanv____________ 918-743-9148 10 M nhama-Tonn. N a tu ra l Gas Co._________ 205-383-3631 11 A1gnnrpiin Gas Transmission Co. 617-254-4050 12 AVtied Matprials Cnrp.__________________ 405-842-4403 13 American Natural Gas Service Co. H Ainom Pi De line Co. 313-965-8300 312-856-5.111 . 15 Apnllo Gas Co. & Carneqie N at'l. Gas 412-462-7121 16 Arkansas Louisiana Gas Co. 318-425-1271 17 Cambell Air Service 318-425-8218 10 American Petrofino Pipe Line Co. 915-263-7661 19 Ami noi 1 U.S.A. Inc. 713-686-9261 20 Amoro Gas Co. 713-948-2501 21 Anadarko Production Co. 713-526-5421 2_2_ Apro Pipe 1 ine. Inc.____________________ 316-442-3620 |M,( Name-Title of Person :rS AFS Mo Out Yes Copy Date F. Rornaker. Rea. Mar. !__ Christman, R/W__________________________ -_R jn e t Environmental____________________ 1. E. Johnson B. 01 lic e ; Ena. XX X No e>peril nce X D0 NCT US 2.,4 5-T XX XX 7-28 7-28 7-28 8-2 7-28 Jim Houston Gen. Clat.p, Fnv. Eng. H. 1. Mayes Donald F. Baker J. W. Solomon Wm. Lawson Truman Peek Vince Lajiness, Env. Wm. Domax B. F. Morton J. A. Irvin Jim Eakin cb X X 7-28 X OWN 0 R0 IS 7-28 X NO Cl EMIC IS 8-2 X X 7-28 X D0 NIIT US X 2,4, i-T D IIjT U S X 2,4, i-T X 8-2 7-28 8-4 X ROW )n Fa 'inland s 8-7 DO N)T US X 2,4, -T 8-2 X X 8-2 (sent pre1.) x X 8-2 Wayne Bartlett Harold Nissen Mr. Castil le, Envir. ^^ M C Richard Gains, or Clyde Anthen H. R. Ledeker X NO C IEMIC US X D0 F!)T Uil *Ox 1 A * \ -T ____ . X tN)50e fLlf'I3FMC TK /US Weed) Conl . 8-3 8-7 8-2 8-4 Q- 7 // 1` ipeline or Contractor Phone 23 Arapahn Pipeline Co. 303-842-2081 _24_ ArhiirHff Pippl i .0 918-560-6357 25 Arkansas-Oklahoma Gas Corp.____________ 501-783-3101 2f> Arkansas-Western Ras Co. 501-521-5400 27 Ashland Pipeline Co._____________________ 606-329-3333 1 28 Rarlger Pipeline Co. 312-439-0270 29 Belle Four.rheJIipeljne.Cq.._____________ 307-756-3292 _30_ pighpart frudp Oil Cnrp .________________ .918-582-7211 31 piarli 1akp PipelineCo._________________ 3.16-3.31 -13QQ 32 Rlark M p s a Pipeline- Ine._______________ 602-774-5076 crystal nil Company.... 318-222-7791 _ a i . ur-ro -Pipel ine--Corp_______________ :______ .505-398-6308 .J5_ Butte pippl inp Co 915-684-5511 _3_ LI U 1 * 1. AL 918-333-4111. 913-434-4832 ASL Cahot C n r p n r a t . i n n 806-669-2581 Calnpv Pine Line Co. 714-877-2414 Carolina Pipeline Company S J1 L C e n e x Pinpline ,_42_ Central Florida Pipe Line Co. 803-708-3220 40fi-252-9326 813-248-2148 . J L Chamnlin Petroleum Co. .M. Chandeleur Pipe Line Co. 4O5-233-7600 502-587-7531 Name-Title of Person AES Mo Out Yes Copy Date Mr. A. G. Sprawka . Charles Hoffman Lewis Belcher X DC T USI V 2 4 r -T No Sf ray 1rog. X Use [ rust* Hog 8-4 8-3 8-2 James Walker X Use [ rush Hogs 8-2 Clarence'A. Clark X Use [ rush Hogs 8-2 Merle Helqland Lvle Sessions, Supt. X Mech< nica D0~W n i s i X 2,4 5-T 8-2 8-4 Ralph Eaton X NO C EMIC IS 8-2 . John R. Sebastian J. G. Montfort C. A. Norvell Jim Waddell Georae Todd Joe Hicks R. A. Keaqy X X 8-2 00 N( T US X 2,4,! -T 0-2 R" 01 e kn iws ab jut X 2,4, -T 8-2 00 NliT US X 2,4,! -T 8-2 Up t( 1 Ind vidua 1 X Forei lan 8-4 DO NtiT US X HERB CIDE > 8-2 DO N<iT US X CHEM CALS 8-2 DO N(T US X HERB CIDE > 8-2 J. R. Scruoas. Maint. Sunt. cb Skin Maclnnis, P .L , Supt. Mr. Bratlie R. P. Rruhck X X 0-2 X ROW n cr jplanc 8-2 Mai tain X no :OWs 0-2 Rnhert. Crews Mr. Incjles _____ T ^ jC in A A O i 1 * No Exoericnee Not w i' ! 7ar.miA. iar 8-7 f "n ; II Pipeline or Contractor PEL' Phone 45 Charter Gathering Co. 713-923-3404 46 Chase Pipeline Co. 316r321-6380 47 Chevron Pipeline Co. 801-359-7761 46 Chevenne Pipeline Co. 307-634-2064 49 Chir.aD Pipeline Co. 312-885-5411 50 Cities Service Gas Co.___________________ 405-236-0601 51 C ities Service Pipeline Co.____________ 918-586-3750 52 Citrone11-Nobile Gathering, Inc. 205-433-6167 53 Clajon.GaS-CiL_____________________________ 915-336-3379 54 Clear Creek, Inc,_________________________ 316-263-8145 _55.. Coastal States Gas Producing__________ 713r627-3700 ._5_ -Them--Spray__________________________ ______ 713-486-1891 iZ _ Collins Pipeline Co, _aa_ Colonial p ip e lin e r n ___________________ _5i_ Colorado Interstate Gas Co. i _ si l\D 61 CO 6? Columbia Gas Transmission Commonwealth Natural Gas Corp. Continental Pipeline Co. 713^757-2131 404-261-1470 303-473-2300 412-228-3200 804-644-2931 713-956-1130 61 Cosden Pipe 1ine Co. 64 Crown-Rancho Pipeline Corp, 915-263-7051 713-224-8550 66 Cullman-Jefferson Counties Gas. 205-734-1911 -6C_ UelUJbrClir.okee.Coiinties Gas (list. 205-845-3731 's ^ r ^ TOR Name-Title of Person Mo Out Yes AES Copy DaLe Aubrey Williamson, Frank Smith Andv Hendricks Jerry Brower, Sr. Enq. C. E. Siemers Mr. Ed. Scott Mr. Turney Mr. Ansal Neal Don Smith X " use Chem Sprai/" 8-7 X DO NIT US Z A ^ >-T 8-4 X DO NIT US HERB CIDE 8-4 X ROWS on Past ire & Farms 8-7 X DO N)T US 2,4 , >-T 8-7 X DO NIT US 2,4, i-T 8-7 XX Mowi ig an 1 X Hand Cutt inq 8-7 8-8 Chas. Moody cb Dalton Alspaw J. C. Baker Steve Crosby J. L. Solomon cb X Own |n ROIs X DO NIT US 2,4, i-T X No Mlinte lance 8-7 8-9 8-7 F. .1. C o llin s. Mqr. ROW cb W. I . Blount Geo. Walz R. J. Godfrey Don Butter D. M. Bardwel1 cb X No S irayi ig ___ Jtow_ js/ye ir DO NIT US X 1 A >-T .......... cb 8-7 .8-7 J. D. Winzeried F. W. England Wm. A. Wri nht RTR T ___ x_ M C 1EMHI1L5-- . ___a ..Jto_l|EMIX JLQEi...__ 8ji7 O f! In n''' 1 M- i, - 1 r' t. Pipeline or Contractor I i r t i im i / l U i'I i I<ML 11Hi --7~N -- Phone Name-Titlo of Person AF.S Mo Out Yes Copy Date 67 Fas torn Shore Natl. Gas Co._____________ 302-734-7443 Wavne Morris X X 8-0 Fas torn Tpnnessep Nat.M. Gas Co. 69_. Dixie Pipeline Co. 70 Derby Refining Co. ,.ZI_ Delhi Gas Pipeline Corp. 615-63-35QJ_________ Rnht Rder 404-237-4636 .lim Mr.Galia 316-267-0361 0. 0. Adkins 214-747-0341 Pet.e nirkens _. . rtcb 00 F JT U5E X CHEF fCAL NO BRUSH X .CONTROL USE NO 1 X CHEMICALS 0-0 8-10 8-0 _2Z_ Fverqlades Pipeline Co. -Z i.. C ities U t ilit ie s Construction Co. 305-522-8464 305-525-7025. D. il. Stack X USE C3NTR7CT0R Suppl y 0n` y X Labor 0-8 8-8 _Z4_ Eureka Pipeline Co. 304-405-5540. R ill 1ytle _25_ Fuuitable Gas Co. 412-171-760Q 71im Nnel 76 n Paso Natural Gas. Co. 915-543-2600 0. N. Canfield J L L . FI Paso Products Co. 915-337-2011 .lnhn ! SFrnjplc - J L - Enterprise Pipeline Co._________________ 713-650-0100_________ Harnlri 1pp ,J Fxplorer Pipeline Co. 910-7.43-5393 G V Shaw cb No HE 1BIC1 DES X On RCNs 8-8 Don1" Knot X about 2,4 5-T 0-8 Use X Conio actor 0-0 Don't Knov Abou X 2,4 ,-T 8-9 Use Erush Hogs X Some Torde n 10- ; 8-9 m . Evynn Pipplinp Co._______________________ 713-656-3636 .Ina Unllrnpr X (he f ontr ctors 0-9 .HL Farm Ritrpan Oil f.n. JLL GrTTY Pipe Co. x to _i Florida Gas Transmission Co. ai >!* _0L Four Corners P.L. Co. -i. Fr io P peline Co. ; 812-030-4341 717-455-5500 310-942-6535 713-241-6161 713-223-4901 1r\hn Adame U F T^eker r arro l1 Pirh^rd Mr .Ip p Mims l.l IJ Uoiclpr .lr x_ X Hand ed bj X Foren en 8-9 8-9 __ __ XX _L2__ 0-9 X No Mi jluLj ance _ B.-9 ... ..06 Golden Eaole Refiniq Co. 213-777-0941 wch_ _iiZ Great, lakes Gas Transmission 313_Q45-Q/inn ..aa _Gre.at Ye H omstone Corp.________________ 910749=1660 _ .... p jq ^ T R A A O f1 wch . Do N)t Mai ntaii pc ' - II Pipeline or Contractor 89 Sant Fe (Gulf Cnetral) Pipeline 90 Hess Pipeline Co. 91 The A. S. Helbiq Co. 92 Gulf Enorqy & Development Corp. 93__ Gulf Refininq Co. dmH-LJM*-' ",UN lUK -- - r >1 -- Phone Name-Title of Person 918-585-2631 . 601-425-1(196 216-376-8116 512-828-0501 713-226-3448 Mr. F ile r or W. R. Keathly B illv Green Robt. Helbiq, Sr. M. B. Parks B ill Traylor AES Mo Out Yes Copy Date -X Use Rri h Ilf ns 8-9 rh rh rh 94__ Houston Pipeline Co. 713-654-6161 95 Hioh Plains Natural Gas. Co.___________ 806.323-6464 96 lliiskv Pipeline Co. .307-587-4711 Robt. Newell Paul Wilson Mr. Spear X IIke Mnwi ny---------- 8-9 Onl. Pas ure 1X Farm -and__ 8-9 X N o rush 8-9 96 Hydrocarbon Transportt ion Inc. 402-348-5371 (see reqional offices) 98 " "(Minneapolis) 612-884-2204 Mack Mickelberg, Eng. X X 9-10 99 " "(Midland. TX) 915-682-7964 I00_ " "(Liberal. KS) 316-624-1911 I0]__ " "(Great Bend, KS) 316-792-2161 !QZ_ "(Des-Moines. IN) 515-243-6139 103 Standard Oil (Ohio) _ 517,898.7971 lf)/l Standard Oil (Texas) 214-757-7110 105 Inland Gas Co.. Inc. -3 to 106 Interstate Storaqe & Pipeline Coro. 03 a \ I07_ yhaw!: Pipeline Corp . 606-324-7171 609-267-9100 316-267-0361 I0L I'.-meh Pipeline fn. 316-262-1408 IQiL Knnc ac -Mehra^l-a Nat 11 Ga<; Cn 402-462-2441 Kent Westl lii_ nrky Virginia Gas Co.________ 606-886-2311 Mr. Henman Jim Goodwin T. Moore Mr. Sampson B. E. Ashford DO 10T >E X 2,4 ,5-T DO 10T USE X 2,4 ,5-T x DO MOT 5E 2,4 5-T iLENO JRUSli X . PRO NO 3rusl X --Car iXfxL 9-9 9-9 9-10 -9.-1Q- 9-10 James James Philip A. Stricland Asburv Jenkins 0?.Qf! T 0 AAOfl --x__ V __M__ARcCPObp'tii-h.ai l-oannofTt t nr, 1__nL11 .......................... ................................ ................ 11 ,........... ...................... (JKt ' l u i L 1 J J I \ 7 ^ u r t " / u i | r^; - ................. ' a Pipeline or Contractor i l l Kaw Pipeline Co. (See Texaco) 11? Kenai Pipeline Co. (see Chevron) Phone 713-666-8000 415-094-0773 Name-Title of Person R. W. Olbrich Chas. Stevenson A -- - /^s AES No Out Yes Copy Date cb cb -- -- -- '^2 to 03 Cft --i Ta^CTCMOn DOW93514 0 3 1 0 -0 2 6 0 -7 4 4 0 (744) c. T I CK L E D A T E _________ June 2D, 197S 988 Office of Pesticide Program Technical Service Division Errvlrcrnentil Protection Agency 401 li Street, S,U. Washington, D. C. 204fl Gentlemen: The Pennsylvania. Department of Transportation has usei 2,4,5-T for may years without serious problems. 2,4,5-T hasproven to bs an economical and effective control far undesirable trees and shrubs growing along the Department's 45,000 alias of highways. Applications of 2,4,5-T include foliage brush spraying and damnrt basal application. Without 2,4,5-T, the Department would be forced to use other herbicides which have not had as widespread and varied use as 2,4,5-T. Substitute herbicides, in ever;' case, would cost the Department core ooney to achieve the sane results as 2,4,5-T. Sincerely, i nsideration. P l e a s e ensure that any further correspondence on this i ss ue Lears the identifying notation OPP-3QOOO/26 1 >ank you for your interest in the Office of P e s t i ci d e Programs' activities. |C Federal Register Section Information Branch Technical Services Division (U'H S6Q) Office of P es t i c id e s Programs, 'PA DOW913511 ROGER L MALLAR Commissioner STATE OF MAINE 9d^' DEPARTMENT OF TRANSPORTATION ST A T E O FFICE BUILDING AUGUSTA. MAINE 04333 May 25, 1978 fii y irii y i Douglas Castle, Administrator for Pesticide Programs US Environmental Protection Agency Washington, D.C. 2046Q Dear S ir: It is my understanding that an RPAR will be held in the near future involving the continued registration of 2,4,5-T. I also understand that arguments are being presented for and against the suspension of the use of 2,4,5-T during the RPAR period. I wish to be placed cn record an opposing any suspension of the RPAR period end request that your actions on this product be linitod to an RPAR review. Thank you for your consideration. Very truly yours, Department of Transportation Roger L. Mallar, Commissioner HCR/lov oc: T. Stone By: Martin C. Rissel Engineer of Maint. & Operations 172C8 R O G E R L. m A U a R 5TAT O F M A I N E DPARTMNT OF TRANSPORTATION 9 j 0 TRANSPORTATION BUILDING AUGUSTA.MAIN 04333 August 3: 1978 OOW913510 Mr. Jim Skelton Asplundh Environmental Services Blair Hill Road Willow Grove, PA 19090 Dear Sir: As requested in your telephone call, I have attached copies of the Maine Department of Transportation letters to EPA regarding the RPAR on 2 4 5-T. TMS:mc attachm ents Theodore M. Stone Landscape Architect Bureau of Highways 17269 O H M UUUU S Z ? ft H * l 9 7 * IOWA DEPARTMENT OF TRANSPORTATION 9 d j. DOW913509 August 3, 1978 Federal Register Section Technical Service Division (WH-569) Office of Pesticide Prograns, SPA Room 401 Bast Teuer 401 M Street SH 600 The Highway Division of the Iowa Department of Transportation as a positive program governing right of vay maintenance which recognizes the benefits accruing to the public in beautification compliance with state law regarding control of noxious weeds, and revintion of vegetative growths which would adversely effect rainage, sight distance and snowfall AS Chief Engineer with administrative responsibility over 10,000 miles of state highways requiring a maintenance budget'of $41 million, judicious expendi ture of funds for right of way preservation is necessary brush control program formerly utilized 2, 4 5-T principally to control volunteer growth after cutting brush However, when it was indicated that 2, 4, 5-T might be removed from the list of re gistered herbicides, we elected to discontinue the purchase and use of that chemical For the past six years Tordoa 10-K pellets, Hyvar X-L or Krenite has been utilized for brush control The substitute chemicals are affective and acceptable Under present circumstances no reason appears to exist for revising present maintenance practices, even if 2, 4, 5-T is re-registered. FHQickw Vary truly yours, / bcci Dennis Holewinski.Mgr. R. H, Given Asplundh Environmental Chief Engineer Services Blair Mill Road Willow Grove, PA 19090 DOW913508 9 JIJ 4738 wildrye Boise, Idaho 83705 August 7, 1978 Federal Register Section Technical Services Division (WH 569) Code No. 30000/76 Office of Pesticide Programs Environmental Protection Programs Environmental Protection Admin. Room 401 East Tower 401 M St. S.W. Washington, D.C. 20460 De'.ar Sirs: .. My first experience with the use of 2,4,5-t P was in Llie years between 1952-58 when I was working for the Federal Govern ment with responsibilities which included range-land improvement. We were able to increase carrying capacity as much as 400% with the use of the 2,4-D, 2,4,5-T sprays, usually applied by airplane. The Conservation Cost-Share Program of the government paid for about 50% of the cost of this woody plant control. Prior to this, our only method was by mechanical beating, etc. at a much greater cost while obtaining a much poorer quality job. Many thousands of acres were improved' in this manner and I have remained in the area since and have not observed any detrimental effects whatsoever, nor have I even heard the hint of any. At the present time I am responsible for right-of-way vegetation control. My estimate is that should we lose our use of 2,4,5-T for woody plant control, the cost would increase dramatically, about 1,000%. This would cause a very serious cost situation and could very well bring about unsafe conditions and deaths as a result.' We have struggled very hard tc held devn costs ar.d my is that the unfounded rumors, started probably by some uninformed or hysteria! persons, will not deprive us of this valuable material that we have worked with so very successfully over so many years. Gentlemen, please allow common sense and sound scientific reasoning, rather than fear prevail on this 2,4,5-T, RPAR issue. to Very truly yours, J. E. RINARD 17271 w_....j.. . .. .-r y*i"!i ua^ii ui i uic mWincc. Humber of acres in ycur systen )i ,^ 2 .Number of mi 1es in your systern . States in which you have riqht-of-way areas O';!*-'/, \ ih?3 Percentage of your total right-of-way acreage that is under some form of vegetation management proqram7 ^ / .V - v '-r. n- ~Oj_&rr,/ Number of right-of-way acres that were treated during 1977 A ro ;? / J -q -f. MECHANICAL METHODS USED FOR VEGETATION MANAGEMENT ^v a. Approximate percentage of total ROW acreage that is'treated by mechanical methods 1 ) ,c OSGTGMOn b. Percentage of these mechanically treated areas that were treated by the following methods: % of all mechanically treated acreage treated approximate cost with each method below per acre R oller chopping Brush raking Sheardozing Brush hog Mowing 7" Other methods MANUAL METHODS USED FOR VEGETATION MANAGEMENT a. ` Approximate percentage of total ROW acreage that is treated by manual methods L\ b. Percentage of these manually treated areas that were treated by. the . . ' - , following methods? % of a ll manually ' treated acreage treated' approximate cost . with each, method below per acre Chain saw cutting Trimming Girdling Other methods ___________ :___________________ U jcl /L 1----f w -a---' c/ 0 I A*/ _____________________ . ,-//i' ^ A J L CL--. CHEMICAL METHODS USED FOR VEGETATION MANAGEMENT a. Approximate percentage of total ROW acreage that is treated with brush r A n t i* n l r h o m i r a l e / / . a! a* '/- -------------- \r\ Vii * ..* `*0 ; ** i, .>` .-li V" ' A JL s 0OW913424 1018 June 1, 1978 Federal Register Section Technical Services Division (WH-569) Office of Pesticide Programs, EPA Room A01 East Tower Washington,DC RE: 2,4,5,T - Notice of Rebuttable Presumption _____ 43FR17116, et. seq., April 21, 1978 Dear Sir: The Detroit Edison Company has reviewed EFA's rebuttal presumption against registration of 2,4,5,T. The Detroit Edison Company conccnds that the studies referred to in the April 21st Federal Register Notice do themselves sustain the burden of proof that under commonly recognized practices of use, the anticipated exposure of 2,4,5,T, as it is now formulated, to applicators, users and local populations is not likely to result in any significant acute adverse or chronic effects. Detroit Edison contends that the EPA's determination is in error. Furthermore, Edison contends that 2,4,5,T is an economic and uniquely effective tool in controlling the growth of high growing tree species since it does not impact the growth of low growing trees, shrubs, herbs, and grasses. The Detroit Edison Company knows of no other herbicide which controls tall growing species while preserving a well-balanced monocotylcdonous environment. The banning of 2,4,5,T would have significant adverse impacts on both the coses of controlling tall growing species and on che eschtics of rights-of-way controlled in some other manner. The studies referred to in the April 21st rebuttal sustain the burden-of-proof that under commonly recognised practice? of anticipated exposure of l',4,5,T, as it is now formulated, to appli cators, uses and local populations is not likely to result in any significant acute adverse of chronic impacts. I refer to the bulk of the studies in the presumption rebuttal. These studies demonstrate that 2,4,5,T which contains less than .1 ppm of TCDD (as required by current U.S. Specifications) when applied or dosed to laboratory animals at rates comparable to the dosage 3nd exposure of humans is not likely to result in any significant adverse effects. The data presented (pg. 17119 F.R.) indicate that 2,4,5,T is not - -17273 OOW913425 Federal Register Section June 1, 1978 Page Two persistent and is readily metabolized by mammals. The data presented (pg. 17120 F.R.) indicate that there is no major problem of bioaccumulation of 2,4,5,T since it is neither strongly lipophilic nor hydrophilic. The EPA has errored in its conclusion chat 2,4,5,t exceeds certain criteria for r.isks. The error lies in the use of inappropriate data as "effect" levels. Test animals are exposed to more 2,4,5 .T/TCDD than would be expected as a normal exposure. Also, assumptions are made regarding application practices which are contrary to commonly recognized practices of use. The State of Michigan requires that applicators of any herbicide or pesticide be fully clothed. V.'e know of no application of 2,4,5,T done by persons having bare arms, hands, or legs. Examples of the use of in appropriate data are: 1. Third Summary of Scientific Evidence Relating to Rebuttable Presumption - Part 1(a) under oncogenic effects (pg. 17124 F.R.) In this study, The test organisms (mice) were fed higher levels than usual to assume for human consumption, since 2,4,5,T is not used on consumable crops. 2. In the same section, Part B (pg. 17125 F.R.) the test organisms (mice) were exposed to higher levels of TCDD (3X) chan the current formulations of 2,4,5,T contain. Therefore, the use of this study is unrealistic in looking at oncogenic effcccs. 3. In the same sections, Part 2 (pg . 17126 F.F..) acute r.vt a !itie to control organisns (rat.-.) -ere higher than test organism:, exposed to several concentrations of TCDD. Therefore, the test is not valid since the source of concrol mortality and subsequent test oncogenic responses may be due to pre-test history of the test organisms, or to poor holding techniques. 4. In the same section, Part 3 "Exposure Analysis", the hypothetical exposure analyses sec up a lisc of criteria which "a priori result in a rebuttable presumption. The use of a woman's weighc as the standard increases the potential exposure on a dose per weight basis. The exposed person is assumed Co have bare arms, hands, head, and sometimes legs. In addition, the aforementioned inappropriate data are used as "effect" levels. Lastly, che basis of the margin of saiecv is not explained and appears to be only a subjective appraisal of quantitative information. 17274 D O W 913426 Federal P.:lister Section June 1, 19 7S Page Three In light of the facts tha.t 2,4,-5,T docs not appear to result in any significant adverse effects and chac the banning of 2,A,5,T v:ould have significant adverse economic and aesthticconsequences , The Detroit Edison Company contends thaC the benefits from the use of 2,4,5,T far out-weights the risks associated with use and a pre sumption against registration (and use) should not be established. Sincerely, Dennis A. Leonard Environmental Affairs bcc: J. J. Gessner A. Heidrich, Jr. J. E. Knight P. J. Eisele DOW913421 1019 West Penn Power Company Part of the Alleghany Power Syetem C ab in Hill. Greanaburg. Pa. 15601 (412) 837-3000 June 2, 1978 Environmental Protection Agency Office of Pesticide Program Technical Service Division WH-569 401 M Street, S.W. Washington, DC 20000 Dear Sirs: 2.4.5-T Herbicide Review In response to your "Environmental News Release" of April 12, 1978, I will state the benefits of the present registered uses of 2,4,5-T by outlining the field problems that would result if the use of this herbicide was eliminated. Without the availability and use of 2,4,5-T as the backbone herbicide of the brush control program on the West Penn Power Company System, the effectiveness of herbicide solutions would be reduced. The hydraulic ground foliage method of applying herbicides containing 2,4,5-T in a water carrier will result in 957. or better kill of tall-growing tree species. Basal bark methods utilizing oil products as a carrier for 2,4,5-T can result in similar results where low brush density allows these methods to be used. Without the ability to use 2,4,5-T, the effectiveness of these methods would be 'reduced 30X to 507., resulting in unsatisfactory brush control. The use of alternative chemicals presently available would result in higher rates per acre and a greater use of more persistent materials. This course of action could easily increase off right-of-way damage along the edges of rights-of-way and would force the unnecessary introduction of a larger amount of herbicides into the environment. The cancellation of 2,4,5-T for use on rights-of-way will result in higher maintenance costs to obtain a lesser degree of control. The results obtained through the use of alternative herbicides could dictate returning to hand clearing. As a consequence, our present total annual vegetation control budget of $3.5 million would increase to $6.5 million if we were to hand clear those areas scheduled for spraying. This increase in expenditure would be compounded due to returning every six years to clear the brush. An example cf typical charges following initial clearing is as follows: 22tG T 6A A O a WEST PENN POWER COMPANT Environmental Protection Agency Page 2 June 2, 1978 Herbicide Treated Hand Cleared With Equipment 1973 1975 1979 1985 1991 1993 Clea red $100 80 --80 Cleared -- $ 400 400+ 400+ -- $260 $1,200 r Over the above 20-year portion of the line, the annual cost per r year with herbicides is the total cost of $260 divided by 20 years = $13/year. Without herbicides, the total cost of $1,200 divided by 20 years = $60/year. The differential of $47 when applied to the total acres underneath our transmission and distribution system would approximate an annua 1 increase in expenditures of $4 million. Assuming this amount of money was available, it would be highly questionable whether enough men and equipment would be available to perform this type of work. In addition, with each clearing the wildlife population and habitat will be adversely affected. It is interesting to note that workman's compensation races for brush cutters and tree trimmers are approximately three times greater chan the rates for herbicide spraymen, indicating a higher risk in using saws than in using herbicides. Utility right-of-way brush control depends largely on the use of 2,4,5-Trichlorophenoxyacetic acid alone or in combination with other herbicides. Therefore, the necessity for the continuation of the registered uses of 2,4,5-T is important to the safe, economical, and uninterrupted transmission and distribution of eleccrical energy. In working in the herbicide field as a research forester, in railroad vegetation control, and in my present capacity for a total oi 15 years, I have not become aware of any toxic effects to man or animals attributable to 2;4,5-T when used according co the label. As a practical observation, I have noticed the red-taiied hawk population increases around herbicide treated utility right-of-way. The increase in population and increasing number of nests on our structures indicate a high small animal population is present to support the increase in the hawk population. It is my sincere hope that facts such as chose mentioned above, magnified by similar conditions in 3,600 U. S. eleccric utilities, present the Environmental Protection Agency with a true picture of the potential economic and environmental repercussions which could result from cancelling the registration of 2,4,5-T. -Vr^ truly yours.- Peter E. Spangler System Forester L T) DOW913423 Environmental. P ro tectio n Agency Page 3 June 2, 1978 % S v :-c^ r .. ^ -- A nr s3# ^ . --j y W '- F . " S' .1 ( --.'S'-'< \L*3e - O fe -: CC: Hr. Douglas Cos t i e , A d m in istrator, EPA Hr. Edwin L. Johnson, Deputy A ss is ta n t A dm in istrator fo r P e s tic id e Programs, EPA Dr. Rupert C o u lter, OSDA Sen. Richard S . Scbwelkar Sen. H. John H einz, XIX Rep. Joseph S . Ansaeroan Sep. John H. Dent Sep. Joseph H. Gcydos Rap. WillLam F. Goodling Rep. W illiam S . Moorhead Rep. A ustin J . Murphy Rep. John P. Murtha Rap. Gary A. Myers Rep. E. G. Shuster Rep. Douglas Walgren BCC: Charles Beckwith, Dow Chemical Paul H. Johnston, Asplundh 5cr*J ALO i2JM A h c .i` .7'7 "Deo ix o T Z e-W i^ 53 ? it Owfc&7  0Ow 914314 M N 0 0 1 665 May 31, 1978 1706 TO: PROPONENTS OF PHENOXY HERBICIDES SUBJECT: GROUP MEETING TO COORDINATE EFFORTS ON RPAR FOR 2,4,5-T MEETING TIME AND PLACE: June 7, 1978 - 9:00 a.m Ramada O'Hare 6600 Mannheim Rd. Des Plains, Illinois Tel. (312) 827-5131 2,4,5-T is a useful and necessary tool for the following: 1. Right-of-way brush control 2. Rangeland brush control 3. Forestry 4. Weed control in rice In order to better coordinate the activities of these interests, it was thought desirable to assemble a group of individuals that could mobilize the necessary effort to respond to the RPAR. Reasons for the meeting: 1. Establish lines of communications among the key groups present. 2. Determine capabilities of each organization in regards to making key political and user contacts. 3. How to achieve maximum effect with the news media on forth coming benefit statements from user groups. 4. Review of RPAR process and the necessary jobs that need to be done. 5. Review of legal actions in various states regarding 2,4,5-T. Come prepared to participate by reporting what work your organization has underway and difficulties encountered to date. We will see you June 7. sj. H. Davidson Agricultural Products Department nc 17279 July 5, 1978 -J. V kJ THE DOW C H E M I C A L C O M P A N Y M ID LA N D . M ICH IG AN 48640 D. D. McCollister L. L. Smith M. L. Leng J. H. Davidson M. J. Traynor, 2020 J. A. Gray, 2030 O $ POLICY QUESTIONS ON THE ORGANIZATION OF THE 2,4,5-T RPAR REBUTTAL o to I am organizing the assembly of the RPAR document and have a couple of lA questions which must be answered by Friday noon, July 7th in order to schedule our personnel needs. -S> 1) Do you wish to include in the RPAR submission copies of the , 3 documents referenced in the RPAR position 'document when they are also referred to in our paper? We could instead give the bibliographic reference and cite the Position document reference number. 2) Do you wish to submit copies of references not directly cited in our papers? We can prepare a list of additional references which EPA would then be able to request and which we would likely be free to discuss if appropriate topics came up. We will need to know the overall organization of the document by the end of next week (July 14th), in order to answer such questions as: a) Should the references for each section immediately fellow that section, or should all references be compiled at the end? The former arrangement will allow us to compile whole volumes as the collections are completed. We can number pages using the section designation. b) Since the sections will vary in size, I do not believe we should tie our volume numbers and our section numbers too tightly together as some sections may require two volumes I suggest using Roman numerals for the volumes and capital letters for the sections. We can number our references D.r.l, D.r.2., etc. Attached is the proposed compilation schedule. Please reserve the morning of August 2nd to help us verify the accuracy of the 10 complete copies. Alice H. Morgan Government Registration Health & Environmental Research At tachment ebg 17280 /'/ , * ./ r . /C ..........*:.......... lOu D O W 798866 EVALUATION OF THE MUTAGENIC POTENTIAL OF 2,4,5-T AND TCDD IN RESPONSE TO A RPAR ON 2,4,5-T By B. A. Schwetz, D.V.M., Ph.D. Research Manager and K. S. R a o , D . V . M . , Ph.D. Research Specialist Toxicology Research Laboratory Health and Environmental Research Dow Chemical U.S.A. Midland, Michigan 48640 17281 Rodenticide Act (FIFRA), the basic environmental standard for major regulatory determinations is "unreasonable adverse effects on the environment". The term is defined in Section 2 (bb) of the act to mean "any unreasonable risk CO oo Op 05 social, and environmental costs and benefits of the use of any pesticide". The Environmental Protection Agency1s registration guidelines establish the data requirements for registration of a pesticide. Sections 162.84-1 to 162.84-5 of these guidelines establish the requirements for testing to establish the safety of compounds for mutagenic effects in order to register a compound. In making the determination that a rebuttable presumption has arisen, the registration regulations require the agency to take into account the type of effect, the statistical significance of the findings, and whether the tests were conducted in accordance with the material requirements for valid tests as recognized by experts in the field. Section 162.3 (y) of the registration regulations defines the term "mutagenic" as "the property of a substance or mixture of substances to induce changes in the genetic complement of either somatic or germinal tissue in subsequent generations". An important aspect of this definition is that the EPA considers the demonstration 17282 8868 humans. Multi-test evidence is necessary for assessing the mutagenic potential of a test substance since it is well recognized that it is unlikely that a single test system' is capable of assessing all potential types of genetic change with sufficient sensitivity and, in addition, incorporate the toxicological concerns relevant to mammalian physiology and metabolism, as well. Many new test systems have evolved in recent years or are in the process of being developed presently, especially in the area of in vitro short-term tests to evaluate muta genic and carcinogenic potential. Nearly all of these tests suffer from lack of validation between laboratories and across different classes of chemicals. Until a satis factory degree of reliability has been demonstrated for these tests, it does not seem appropriate to use the results of such tests for making critical regulatory decisions. For example, in regard to the microbial tests in particular, consideration must be given to the fact that it is impossible to simulate the route of exposure encountered by man in these tests, liver microsomes are not an accurate reflection of 17283 substances through disposal of the material or its metabolites, and the influence of dose level upon response is not inter pretable. Therefore, the usefulness of these test systems even for the process of defining the needs for further testing has significant limitations. CD toxicity (1). They concluded that there were insufficient data on the mutagenic potential of 2,4,5-T and TCDD, and that further testing was needed. Mutagenicity was not a trigger for the RPAR. The results of the laboratory tests to assess the mutagenic potential of 2,4,5-T and TCDD are summarized in Tables 1 and 2, respectively. Our review of the literature revealed considerable additional information to that included in the RPAR Position Document 1. TESTS IN NON-MAMMALIAN SYSTEMS Negative results were reported by Anderson et al. (2) in spot tests with salmonella; ten different phenoxyalkanoic acids and five commercial formulations containing these compounds did not increase the frequency of back mutations. A group of 110 different herbicides was evaluated for their ability to induce point mutations in one or more of four different microbial systems using histidine-requiring mutants of Salmonella typhimurium. The amount of 2,4,5-T used in the test plates was not indicated. 17285 2,4,5-T was found to be "doubtfully mutagenic only after activation". In the absence of enzyme activation, 2,4,5-T was not mutagenic in any of the five strains of organisms (TA-100, TA-1535, TA-98, TA-1537, or TA-1538). In the presence of enzyme activation, there was no increase in the number of revertants in the frameshift strains (TA-98, TA-1537, or TA-1538); the increase in the number of revertants in the base substitution strains (TA-100 or TA-1535) was less than two-fold. This increase of less than a two-fold magnitude was referred to by the authors as a doubtful mutagenic effect? increases less than two-fold are generally not considered to represent a positive response in this test. Seibert and Lemperle (4) tested 32 herbicides for their ability to induce mitotic gene conversion in a diploid strain of the yeast, Saccharomyces cerevisiae. The culture medium contained 1000 ppm 2,4,5-T; no evidence of mutagenic activity was found for 2,4,5-T. Shirasu and co-workers (5) conducted tests with the REC-assay procedure using H17 REC+ and M45 REC~ strains of Bacillus subtilis. The "dose" of 2,4,5-T was 20 yg/plate; no evidence of mutagenicity was found. v. 172SS not described in sufficient depth to critically review the procedures used. Another study in Saccharomyces cerevisiae RAD18 has recently been reported by Zetterberg (7). 2,4,5-T was found to be mutagenic at an acidic pH but not in solutions with neutral pH. 2,4,5-T concentra tions in the range of 0.02-0.06 mg/ml were evaluated over a range of pH values. The authors concluded that while 2,4,5-T caused mutations in acidic conditions, it was unlikely that mutations would be induced at neutral pH, such as would be found in gametes. Cells would apparently not take up the dissociated form of 2,4,5-T. Numerous mutagenicity studies have been conducted in the fruitfly, Drosophila melanogaster. In a study by Davring and Sunner (8) chromosomal defects in oocytes and nurse cells of Drosophila females were reported at very low concentrations of a commercial formulation of 2,4,5-T butoxyethyl ester. The significance of these observations 172&7 Several sex-linked recessive lethal studies have been reported in Drosophila. In a study reported by Mujumdar and co workers (10), Drosophila were given 2,4,5-T at concentra tions of 250 or 1000 ppm in their diet. A slight increase in sex-linked recessive lethals was found at the high concentration, 1000 ppm. In contrast to these positive findings, Vogel and Chandler (11) found no effect on the incidence of sex-linked recessive lethals in Drosophila given 2,4,5-T at concentrations of approximately 1000 and 2000 ppm in their diet. As already indicated above, Magnusson (9) found an increase in the incidence of direct recessive lethals in Drosophila given 1000 ppm 2,4,5-T in their diet. This was not accompanied by cytogenetic changes in the insects. * 172S8 S74 is based on forward mutations in the inserted DNA. There was no evidence of mutagenicity at 100 ppm of 2,4,5-T. TESTS IN MAMMALIAN SYSTEMS In addition to the above tests in non-mammalian systems, numerous tests have also been conducted in mammalian systems. Dominant lethal tests were performed in mice by Buselmaier (13) by injecting 100 mg 2,4,5-T/kg intraperitoneally. The males were subsequently mated during six weeks after treatment with untreated females in order to assess all stages of spermatogenesis. There was no indication of an increased pre- or postimplantation loss. Buselmaier (13) also tested for point mutations in the host-mediated assay using Salmonella typhimurium and Serratia marcescens. 2,4,5-T caused no effect at a dose level of 500 mg/kg. Thus, 2,4,5-T was found to be negative in both the dominant lethal test and the host-mediated assay. 1729 host-mediated assay by Styles (15), serum from rats treated with 2,4,5-T was used with his mutants of Salmonella typhimurium. No increase in the number of mutants was observed. The results of several cytogenetic studies appear in the 2,4,5-T literature. In a study by Yefimenko (16) rats were administered 2,4,5-T at dose levels of 0.001-1 mg/kg. Chromatid aberrations and chromosome adhesions were reported after a dose of only 0.01 mg/kg of the butylester of 2,4,5-T to male rats. This interpretation is based on the information contained in an English abstract and a translation of the original article from the Russian literature. In a study translated from the Japanese literature (Fujita, 17), the effect of 2,4,5-T on cultured human lymphocytes is reported. The concentrations of 2,4,5-T ranged from 0.025-25 yg/ml. Chromosome and chromatid aberrations were reported, but as mentioned in the RPAR position document 1, it is not possible to distinguish whether this was a toxic effect or a potential genetic effect of 2,4,5-T. 17290 were observed which may have been related to toxic effects rather than mutagenic changes. The judgment of the authors in their classification of aberrations has been challenged (Ramel, 19) and leaves the value of the data reported in this paper highly questionable. Another in vivo cytogenetics study was reported by Davring and Hultgren (20) in which mice were dosed with a commercial 2,4,5-T ester formulation. Chromosomal aberrations were observed in the mouse bone marrow cells in this study but close examination of the data reveals that the effects may well be caused by the solvent and/or emulsifier used in the herbicide preparation and not by the 2,4,5-T itself. The same preparation was used in Davring's experiments in Drosophila (8). UJ cn In addition to these published reports on studies of the mutagenic potential of 2,4,5-T, several additional pieces of unpublished data are included. An abstract published by Babbitt and co-workers (21) is attached regarding studies of the effects of 2,4,5-T on two human cell lines - spleen fibroblasts and lymphocytes. No data were included in the published abstract. 17231 in the overall assessment of mutagenic potential. In the case of 2,4,5-T, a study was conducted at the Dow Chemical Company in which Sprague-Dawley rats were maintained on diets providing dose levels of 2,4,5-T of 3, 10, and 30 mg/kg/day for three successive generations (22). Effects were not seen in this reproduction study which were suggestive of mutagenic effects of 2,4,5-T. If 2,4,5-T were a potent 0 mutagen which caused changes which were transmissable to subsequent generations, a reproduction study would reveal the effects of a potent mutagen. The results of this repro duction study, considered together with the rest of the data from all of the mutagenesis studies, indicate that 2,4,5-T is not a potent mutagen. At most, 2,4,5-T might be considered to have weak mutagenic potential. <1 The results of the mutagenicity studies on TCDD are summarized in Table 2. Hussain and co-workers (23) reported that TCDD was mutagenic by causing intercalation in bacterial systems. An increased frequency of mutations was found in E . coli Sd-4. No effects were seen in Salmonella typhimurium TA-1530, but increased mutation frequencies were seen in strain TA-1532, a 17232 on the effect of TCDD in the Salmonella tester strains developed by Ames (24) . No evidence of mutagenic effects was observed in these tests. CC Two different mammalian tests have indicated a lack of mutagenic potential for TCDD. Khera and Ruddick (25) reported the results of a dominant lethal study in Wistar rats that were dosed with 4 or 8 yg TCDD/kg/day for 7 consecutive days. The male rats were caged with untreated virgin females for 5 days during 7 sequential mating trials after dosage with TCDD. The dose levels administered were clearly toxic, since 11 of 20 and 2 of 20 male rats died after receiving 8 or 4 yg/kg/day, respectively. No dominant lethal effects were observed. An in vivo cytogenetics study in rats has been reported by Green and Moreland (26). In their study, rats were given 10 yg TCDD/kg orally five times in one week; additional groups of rats were given 5, 10, 15 or 20 yg TCDD/kg as a single dose intraperitoneally. Examination of the bone marrow of these rats revealed no increase in the incidence of chromosomal aberrations relative to control rats. Another unpublished study by Green is mentioned in a 17233 TCDD/kg twice weekly for 1J weess. " u x m . i c u :-- ... . of chromosome breaks occurred at dose levels of 2 and 4 yg/kg in male rats and at 4 yg/kg in female rats compared to the frequency of chromosome breaks at the lowest dose level. The results of this latter study are not available for review and inclusion in this response. CO The results of the mutagenesis tests on TCDD indicate that under some test conditions, this chemical may be mutagenic in microbes. In whole animal mammalian tests, TCDD has not been found to be mutagenic in the reports of studies that have been available for review. The recent data of Sidney Green's representing rats which were dosed on a subchronic basis with TCDD will need to be examined before a more definitive answer can be given regarding the mutagenic potential of TCDD in mammalian systems. Based upon the definition by EPA of the term "mutagenic" (the property of a substance or mixture of substances to induce changes in the genetic complement of either somatic or germinal tissue in subsequent generations), the results of studies of the mutagenic potential of 2,4,5-T do not indicate that this herbicide represents a mutagenic hazard. 17234 Heritable mutagenic changes induced by 2,4,5-T have not been demonstrated. GO O CONCLUSION In conclusion, numerous studies have been conducted to evaluate the mutagenic potential of 2,4,5-T and TCDD in nonmammalian and mammalian test systems. None of the studies in microbial organisms indicate a significant mutagenic effect,.for 2,4,5-T. One study in yeast indicated mutagenic changes at acidic pH's but not at a neutral pH as found in mammalian tissues. Positive and negative results were seen in studies in Drosophila. Tests in whole-animal mammalian systems have either indicated negative results (dominant lethal test, host-mediated assay and micronucleus test), or uninterpretable results (cytogenetic studies). Thus, 2,4,5-T is definitely not a potent mutagen and might be classified, at most, as a weak mutagen in some test systems. Additional data from one laboratory which have not been published are reported to indicate a positive cytogenetic change in rats dosed subchronically with TCDD. The final evaluation of the mutagenic potential of TCDD should take ^uix<=o<= u a^ u a^ x^ xMxL4.v^ j a o ^ u u m .^ M >*!^ t *>%4a 9w*1i%xcrxMx 4uxxcsyw Wu c uMuAuVMi c ^a v^ aa n1 a u ia W 1 c . 1. . . (1972) Evaluation of herbicides for possible mutagenic properties. J. Agr. Food Chem. 20_, 649-656 . 3) Ercegovich, C. D. and Rashid, K. A. (30 August 1977) Mutagenesis induced in mutant strains of Salmonella typhimurium by pesticides. 174th American Chemical Society National Meeting, Division of Pesticide Chemistry. 4) Siebert, D. and Lemperle, E. (1974) Genetic effects of herbicides: induction of mitotic gene conversion in Saccharomyces cerevisiae. Mutation Research 2_2, 111-120 5) Shirasu, Y., Moriya, M., Kato, Furuhashi, A., and Kada, T. (1976) Mutagenicity screening of pesticides in the microbial system. Mutation Research 40_, 19-30. 6) Fahrig, R. (1974) Comparative mutagenicity studies with pesticides. IARC (International Agency for Research on Cancer) Scientific Publications 10, 161-181. 17297 Hereditas 68_, 115-122. 9) Magnusson, J., Ramel, C., and Eriksson, A. (1977) Mutagenic effects of chlorinated phenoxy acids on Drosophila melanogaster. Hereditas 5, 121-123. 10) Majumdar, S. K. and Golia, J. K. (1974) Mutation test of 2,4,5-trichlorophenoxyacetic acid on Drosophila melanogaster. Can. J. Genet. Cytol. 16_, 465-466. 11) Vogel, E. and Chandler, J.L.R. (1974) Mutagenicity testing of cyclamate and some pesticides in Drosophila melanogaster. Experientia 3, 621-623. 12) Rasmuson, B. and Svahlin, H. (1978) Mutagenicity tests of 2,4-dichlorphenoxyacetic acid and 2,4,5-trichlorophenoxy acetic acid in genetically stable and unstable strains of Drosophila melanogaster. Ecol. Bull. 2_7, 190-192. 1728 98884 3 Zbl. 91, 311-325. 1 4 ) Jenssen, D. and Renberg, L. (1976) Distribution and cytogenetic test of 2,4-D and 2,4,5-T phenoxyacetic acids in mouse blood tissues. Chem. Biol. Interact. 14_, 291-299. 15) Styles, J. A. (1973) Cytotoxic effects of various pesticides in vivo and _in vitro. Mutation Research 21, 50-51 (abstract). 16) Yefimenko, L. P. (1974) Materials for assessing the gonadotropic and mutagenic action of the herbicide 2.4.5- T butyl ester. Gig. Tr. Prof. Zabol. 1, 24-27. (Pesticide Abstracts 1_, abstract #74-2885) . 17) Fujita, K., Fujita, H., and Funazaki, Z. (1975) Chromospheric abnormalities brought about by the use of 2.4.5- T. J. Jap. Assoc. Rural Med. 2A_, 77-79. 18) Majumdar, S. K. and Hall, R. C. (1973) Cytogenetic effects of 2,4,5-T on in vivo bone marrow cells of Mongolian gerbils. Journal of Heredity 64, 213-216. 17239 8885 of iji vivo bone marrow cells of Mus musculus induced with a commercial 2,4,5-T ester product. Hereditas 5^ 123-134. 21) Babbitt, B., Risch, S., Choffnes, E., Kalis, J., Zupanic, M., Boody, G., Benson, D., Spier, S., Kleese, R., and Wickstrom, J. (1972) Effects of 2,4,5-T on human chromosomes. Genetics 7^1, s3 (abstract). 22) Smith, F. A., Schwetz, B. A., Murray, F. J., Crawford, A. A., John, J. A., Koiba, R. J., and Humiston, C. G. (1978) Three-generation reproduction study of rats ingesting 2,4,5trichlorophenoxyacetic acid in the diet. R&D Report Dow Chemical Co., U.S.A., Midland, Michigan. 23) Hussain, S., Ehrenberg, L., Lofroth, G., and Gejvall, T. (1972) Mutagenic effects of TCDD on bacterial systems. AMBIO 1, 32-33. 24) Ames, B. N. (1974) Communication from Dr. B. N. Ames to Dr. P. C. Kearney. 17300 D O W 798886 25) Khera, K. S. and Ruddick, J. A. (1973) Polychlorodibenzop-dioxins: perinatal effects and the dominant lethal test in Wistar rats. Chem. Ser. 120, 70-84. 26) Green, S. and Moreland, F. S. (1975) Cytogenetic evaluation of several dioxins in the rat. Toxic Appl. Pharmac. 33_, 161. 27) Moore, J. A. (1978) Toxicity of 2,3,7,8-tetrachlorodibenzop-dioxin. Chlorinated Phenoxy Acids and Their Dioxins. Ecol. Bull. 27, 134-144. Iu\ CoO LO Test System Ames Test Ames Test -S-a-c-c-h-a-r-o--my<-c-e-s--c-e-r-e-v-l-s-l-a-e 4D. Bacillus 6ubclll6 E. coll (5-MT resistance) E. coll (Gal RS strain) Serratia marcescens (a 21 and a 742 strains) E. coll (strep, resistance) Saccharomyces cerevlslae In Vitro Cytogenetics (human lymphocytes) Saccharomyces cerevlslae HAD 18 TABLE 1 Summary - Laboratory Tests For Mutagenicity of 2,4,5-T Dose(s) Tested Results Comments Not stated A. 9 pg/plate 1000 ppm 20 pg/plate - 110 Herbicides were tested + Doubtfully mutagenic after activation - 32 Herbicides were tested - 166 Pesticides were tested *> - Reference Number RPAR Reference Number 2 Not listed 3 148 4 Not listed 5 Not listed ? 7 7 ? .02-0.06 mg/ml - 31 Pesticides were tested, very ^ little description of methods _ - J + Mutations only at pH < A.5; o.II r -If i n r < ; i p ^ ' 1 i*1 v ;i r n t M i C m l 6 Not listed H* si CO CD U3 Drosophila melanogaster (in vivo cytogenetics) Drosophila melanogaster (direct recessive lethal) Drosophila melanogaster (somatic mutations) Host-Mediated Assay and Dominant Lethal (mice) Micronucleus test (mouse) Host-Mediated Assay (salmonella typhimurium) 1000 ppm in diet 1000 ppm in diet 25-200 ppm In diet 100 mg/kg IP 100 mg/kg ? In Vivo Cytogenetics (rats) In Vitro Cytogenetics (human lymphocytes) In Vivo Cytogenetics (gerbils) 0 .001-1 mg/kg 10~7 -10_AM) (0.025-25 pg/ml) 10-100 mg/kg/day In Vivo Cytogenetics (mice) Not seated + 50Z Decrease in fertility at 250 ppm chromosome effects seen; unsubstan tiated in other tests 8 + Slight increase in sex-linked recessive lethals at 1000 ppm 10 No effect on sex-linked recessive lethals 11 Same sample used by Davring and Sunner (1971) 9 +- 9 Tested In genetically stable and unstable strains 12 --- 13 1 - Used serum from rats dosed with 2,4,5-T (abstract) + Abstract and translation only +? Not possible to tell If effect was mutagenic or toxic 15 16 17 70 & ig/kg + Questionable classification of aberrations Effect may have been due to solvent or emulsifier 18 20 172 178 Not listed Not listed Not listed Not listed Not listed Not listed Not listed 151 169 169 171 Test Svscea Pose >3 7seed isuLcs .bes Tese Not stated 110 H e r b ic id e s were te s t e d ho c l i s t %:d Aaes Test 1. 9 ,,g. p la te OoubcfuLLv c u c j ^ n u a f t e r accivaclon 1-3 S a o c ' n a r o s Y c e s c e r e v i s t a e D, LOUO pen 32 H e r b i c i d e s w ere t e s c e d Not listed r 20 place3JC.1-J SUOCiLid Ibo P e stic id e s were tasted Not listed E. c o l i v2-MT r e s i s t a n c e ) . C3 i ^j>il S a'CTj " ) j e r r acid rarcoscens la _l a.u a 7-2 sereins) lcrep. resi s t anee? Saccrarcrfoes c-areMitae in . i c r a .vcocenecie s \\:-jzan l--?nocyces> 31 P e s t i c i d e s w e r e t e s t e d . .:. l i t t l e d e s c r i p t i o n af -iet...uis HAJ 13aa c : : u r : r . v : a c e r o v l . ^ t a e Dr;sooni.a telano-Mst-jr (ettect in acienesLj; 0.01-0.Cr rc/di 130rr~ D rosjorila re lanosa?tar 1 >cx*Lir..sed r e c e s s i v e l e t h a l ) 2 3 0 , LC.'O r a in diet Drosaohila r.eiar.ocjs:er 3 . b, ril je:c-L;n.<ad recess.'.'e LethaL) (0 .9 2 , 1.31 rc.-r.L) Dro^oonilj -elan o g aster ( i n v lvc c y t o g e n e t i c s ; D rnsppnilj rr.el-iaogascer tract recessive .uthal) Drosophila m elanogastar (somatic su ta tio n s) H ost-M ediated Assay and Doainaac L ethal (alee) M icronucleus te s t (souse) Host-Mediated Assay ( s a l a o r . e l l a cyphirrer lura) LOGO ??*2 in diet 1000 poro in diet 25-200 pan in diet 100 mg/kg IP L00mc/ke In Vivo C y to g en etics ( r a t s ) La V i t r o C v c o c e n e c i c s (human lym phocytes) In Vivo C y to g e n etics (geroiis) 0.001-L a*/kg 10 1-10'*N) (0.025-25 ug/al) 10-100 mg/'<7''icy In Vivo C y to g e n etics (m ice) Not stated + i t 70 & 1)0 n ; / kg : t u c j C i o n s o n l y .\c pH < 1 . 3 ; m utations unlikely a: neutral :!i, a s m jia.meces 3 0 'j D e c r e a s e i n f o r c i l i t v i t 1:' :rr-. ohronosone e f f e c t s see n ; ;:nuo - t a n ti a te d in o th e r te s ts Slichc increase in sex-linked r e c e s s i v e L e th a L s a c 1000 yp-i No e f f e c t on s e x - L i n k e d r o c l e c na Ls arse sjmpLe used by O nvcinc and unner (1971) T e s t e d i n c u n e t i c a L l y s t n b L e a--d unstable strains I' s e d s e r u n f r o m r a t s d o s e d w i t h 2 ,1 ,5-r (abstract) A b s tr a c t and t r a n s l a t i o n only Not p3ssible to t e l l it e f f e c t was mutagenic o r toxic Questionable c la ssific a tio n of iberrations E ffect aay have been due to solvent or em ulsifier No c 1 i j ce d Not l i s t e d Nut i i - t e d `. , c L i s t e d Nat i i s c e a in TABLE 2 Summary - Laboratory Tests For Mutagenicity of TCDD Test System Dose(s) Tested Results TCDD : Non-Mammalian Mutagenic Tests Ames Test and E. Coli up to 4.0 pg/plate + Comments - Ames Test Not stated A memo to U.S.D.A. TCDD: Mammalian Mutagenic Tests Dominant Lethal (rats) 0, 4, 8 pg/kg - In Vivo Cytogenetic (rats) 0, 5, 10, 15, 20 pg/kg - High dose level lethal to some of the males Abstract plus text of oral presentation Reference Number 23 24 25 26 688864 8 0S I _ C'J ^ ~V .i- \ il- 0 6 8 8 6 wMw o n ----- f-7 " * 1,. r N ,t.. '< *- 1' ' ' ' i ' ' ^f , '^ 6 JXiXUX. y I< >J.- 'fUt-. ----xViyj TAHl.K *1 ^^ iX Ce/\ i (M. , A, w lU^a , A\., Summary - Laboratory Tests For MuLagenicity of 2,4,5-T Test System Dose(s) Tested Results Positive Mutagen Employed Comment s 2.4.5- T: Non-Mammalian Mutagenic Tests > . Ames Test Not stated Yes 110 Herbicides were tested r ^-Ujjuu,U1J. -.ay..aU-.^-c./,A,i,j^X |<VJyT. l'lio .. i M ii . i\ . HO^, / ^ - 3r Reference V O Andersen, K. J. et al. 1972 Che*\J. Agr. Food Ge i1. 20, 649 798891 Ames Test ""^^rosophila ( 4.9 pg/plate + Yes Doubtfully mutagenic after Lrcegovicli, C. D. and Rashid, K. A., 1977 activation (impubi islicd) f. w* frOtjW*4* ) 250 ppm + No 50% Decrease in fertility at Davring and Sufiner, 1971 250 ppm cliroipospnic effects Hereditas. 68, 115 1 j (^tW) xJi ^ ) D r o s o p h i l a ^ ^ l ^ d t i i l ^ ^ ^ * * ^ 250, 1000 ppm jU~ ^ ' + Vf r / .) JjAidfrjAuXd 6 h & jQ ) ****** 3 . If ,1 .1 p\h\ _ 2.4.5- T: Mammalian Mutagenic TesCs Host-Mediated Assay and /'IM ) Dominant Lethal (mice) ; `i P 500-1000`mg/kg IP Yes Ki seen *./ c"-'. '.<iJijji Sliglic increase in sex-linked recessive lethals .11 M Z'*-.\ Mujumdar, S. K. and Colia, J. K., 1974 Can. J. Cenet. Cytol. 16, 465 \l oyAs , ^ r' AL,i_/ j.i E . n t ji|kJ 'd ; Cs i ' G*' 11. No Buselmaier, Von W. et al, 1972 Biol. Zbl. 91, 311 \ In Vitro Cytogenetics i (liuman lymphocytes) J , , , In Vivo Cytogenetics (gerbils) f . > In Vivo Cytogenetics ' 7 (mice) io 7-io-S, (uui- ? t X ?+ U) No 10--100 mg/kg/day + at 70 & 100 mg/kg Not stated + No ? Not possible to tell if effect was mutagenic or toxic Fuji ta et a l . 1975 J. Jap. Assoc. Rural Med. 2\t 77 ! J a ^ j l O 1'' 0 ' y ( rii*(/ . r : ir ' L MujuimJar, S. K. and Hull, R. C. , 1973 J. Heredity 64, 213 r j, . ^ 1` \-)j / ,,()' 1 : Davring and llultgren, 1977 Hereditas^ 85, 123-134 XI %.o C *^sj- OOW 798892 ' -TTJjTHA^x^ yd ffrvprv**' fy " ^ n r ? 1. s h _^y nyy>-0 p m * 9 * ' 'Z i-b- w^nrtfV^T f f f l f * * 1" 7*^* Hippmpr>'^o p ^rg y 'jin ^^vtxWO-nO'o ^ 9QZ-S1. 8i ava mnrTrvrV3y V73^ m5 vV>^V s 6 D r- (^ ptr-vvyvOOTTJTjr^yTjrVrvtA^"/ ^ n ^t^vj^va/ Drynv4^xOV PVT*?*' =e ^| LhP) ^ vwx-ortlQ 7>tf yr^ry tyf-mA^ros 151 "7/ X a '' f p p " ? f ^ f T f 17 --^ Yty"*y ^^000| c yw'T^VTTT^/' ra/ wi^00^ ixi^itBiyVQ" y j - l o r o (^-rpjv} ^ n j v ^ ^ Qy^-Q / o-rvvv ^^ |W ^ fT T IT ^ *fi UM ^ - ff % y ji U 'Q Q TrtfrvT? ^ v \ (^_c (-jtoW ] YinTl^mvv0v3iRA</ (^lv hir \n^rrjTf vr^vTnp \J ORP7T^ ^ ' p r v < T*rnr`n tfn rp J i J yyn-rrv '-^ ^ 2 'V V TD ^jrV f } vyp-si/ ~ ^ y -yirm-iurvO' T rr> fc ^ '^ ? ( ^ S P i f c r q T 7^ ' * * " ? ) T 2 (^ r ^ q r lh L T Y~ I ? V ) t'^TTT^^VTrV/^' ^VT^^vVT^ >-*-07? C ^ r f ffy ) ^ P -a ^ rv ri/jjy . ) y ri iw 2 y y * ) J (~ f f f V . V- ' ^ z f X V 1 UOVY 7 9 8 8 9 3 c (Vf s 17309 TABLED ? Summary - Laboratory Teats For Mutagenicity of TCDD _________ Test System_________ l)ose(r;) Tested Resul ts Positive Mutagen Employed ______________ Comments_________ TCDD: Non-Mammalian Mutagenic Tests Ames Test and E. Coll up to A.G pg/plate + Ho - Ames Test Not stated - Yes A memo to USDA ____________ Kelerencu Hussain, S. e ail^ 1972 Ambio. 32-33 Ames, B. N., 1974 (unpubl islied) TCDD; Mammalian Mutagenic Tests Dominant Lethal (rats) 0, A, pg/kg In Vivo Cytogenetic (rats) 0, 5, 10, 15, 20 pg/kg In Vivo Cytogenetics ^ (rats) 0.001 - 1 mg/kg + No Highest dose level lerLal to some of the males fJiuANo Abstract - m i y ^ pAMiLttalLler^ t<0 Abstract and translation only Klieru, K. S. and Ruddick, . . A., 1973 Advances in Chemistry 120 70-84. reen, S., 1975 Toxicol. Appl. Pharmacol. 33. 161 Yeflutenko, L. P., 1974 Gig. Tr. Prof. Z.ihol. IB,' tinI to ^6886^ MOO j/c-aJL O