Document 5LJv1DO4jzvxxLwGBNE2d7JbD

'f[/a 7 Human Health Effects of 2,4,5-T and Its Toxic Contaminants R. R. Suakind, MD. V. S. Hertzberg. PhD * A clinic! e p id e m io lo gic stu d y w a s c o n d u c te d to determ ine the acute effects of this agent, which have long-term health e ffe c t* of w o rk p ie c e s x p o s u r s to the p r o c e s s o f m an u fa c oeen repeatedly observed in humann, turing the h e rb ic id e (2,4 ,S-ti1c h Io ro p h e n o x y > e c e tic a c id In c lu d in g co n ta m P include chlorscne,'*' the most consist- n a n ts su c h a s 2 ,3 t7 ,S-fstrachlorodU >anrop-<Jloxin* T h a p o p u la tio n c o n sla ta d ent clinical marker, liver function o f tw o c o h o rts: 3 0 4 clea rly e x p o s e d a n d 1 6 3 n o t a x p o a a d . A m o n g tha impairment-1** peripheral neuropa- e x p o se d , clinical a vid a n c a o f c h lo ra c n a p ars! atad In 5 5 .7 % . N o n a of tha n o t thy,'*` nervousness and irritabilitYttJ a x p o sa d a x p a ria n c a d c h lo ra c n a d a v a lo p m a n L A n ae eo ctetion w a s found personality changes. * porphyria cu b atw a a n tha p e rsiste n c e of c h lo ra c n a a n d tha p ra a a n c a a n d sa va rity o f tanea tarda/ ,J and hypertrichosis and actinic ala ato s is o f tha akin. T h a ra la a n a s so c ia tio n b a t w a a n a x p o s u ra an d Eype rpigmetation.^' Elevation of tha htatory of gaatrolntaatinal tract ulcar. P u lm o n a ry fu n c tio n v a lu e s a m o n g levels of blood cholesteroL**1 triglyc thoaa w ho w ara a x p o s a d a n d w h o cu rra n tiy s m o k e d w a r a lo w a r than thoaa erides,* gamma-glutamyl transpeoti- w ho w ara n o t a x p o s a d an d w h o c u rra n tiy a m o k a d . T h a d a ta a a a a m b la d In tha Haae (GGTP),' and alkaline phoapha- stu d y Indicate n o a v id a n c a of In c ra a a a d risk fo r c a r d io v a s c u la r d lsa a sa , tase have been reported. h apatic d lsa sa a , renal d a m a g e , o r co n tra ! o r p a rfp h a ra l n a rv o u a ayatam ' Toxicologic studies of TCDD in ani problem s. mals have revealed hepa totoxic ef (JAMA 1 9 6 4 ;2 5 1 :2 3 7 2 -2 3 8 0 } fects,'***' teratogenic effects,"" sup pression of cell-mediated immunity in mice and guinea piga,u and the induc THE HERBICIDE (2,4>triehlorophenoxy)acatic add (2,4,5-T), first marketed in 1948, was used widely until 1970 in large-scale fanning, family gardens, forest management, and weed control along roadsides and railroad rights-of-way. The medical and scientific commu nity was alerted to health problems arising from exposure to the manu facturing process of 2,4^-T following a process acddent (runaway reaction) that occurred in a plant in Nttro, ^WVa, onJdarchJS, 1949.' The accident^ involved a kettle in which th~inter-. T mediate trichlorophenol was . being- synthesised. Those employees in volved in the cleanup of the building enced acute symptoms characterized by skin, eye, and respiratory tract irritation, headache, dizziness, and nausea. These symptoms subsided within one to two weeks and were followed by an acneform eruption, severe muscle pain affecting the extremities, thorax, and shoaldan, fatigue, nervousness and irritability, dyspnea, complaint of decreased libi do, and intolerance to cold.' An exam ination of the workers in 1949 revealed a *severe and generalized acnefonn eruption (chloracne), hepatic'enIaVi^mm,~p^pheral"'nearitia^"' delayed prothrombin time, and in creased total serum lipid levels. By 1953, those symptoms and findings tion of hepatic carcinoma in rata.1* Some of the clinical reports have been concerned with the association- of cardiovascular disease* nn .increased risk for cancer in populs 'd ona exposed to TCDD.'_,J>* Several comprehensive reviews on this entire subject have been published.'*" A mortality analysis of workers exposed to the runaway reaction materials was conducted. As of 1979, the Standardized Mortality Ratio (SMR) for all causes of death was 0.69, with 32 deaths observed and _46.41 expected-JFor-the^categoriea of cancer' and circulatory diseases, the SMRa were 1.00 and 0.68, respective ly." and the repair of equipment experi- froni to* WwMtoto of DnVww--wtoi Ori- W V V o ' C W * rw * >UcScW C oU r. FWprtn* ragmea to VwStoto oI EflWnmwSal H a * h , KWMftog Laboratory (Ha. S e t 3 2 2 3 CSwi Av. Q n d n n a e. OH *43 T r SuHdrtok Teieftable to he perrons system and liver bad subsided. The chloracna. "although much improved, persisted.' In 1957, 2^7,8-tetrachlorodibenxo- p-dioxin (TCDD) was identified as a toxic and acnegemc contaminant of trichlorophenol synthesis.1 The sub A CLINICAL STUDY In Jana 1979. s clinical examination program was conducted that included the active and retired employees of the Nitro, WVa, plant, who were exposed to the 2,4,5-T process between 1943 to 1969. The objective of the examination program was 2 3 7 2 JAMA, May 11, 1 0 8 4-- Vot 2 f ll, Mo. 10 2.4.6-T-- SuakJnd A Heftzbwy <'r+i jTjWM1 ' --!' nu rr i> r' 1I*^ * to determine possible increased risks, on a was carried out by the Lipid Research long-term basis, for adverse cutaneous, Division (a National institutes of Health pulmonary, cardiovascular, gastrointesti Center) of the University of Cincinnati nal (Cl), hepatic, renal, neurological, Medical Center using methods of the behavioral, and reproductive effects; ef Nations! Lipid Research Project." includ fects on lipid metabolism and the posaibil- ing determination of plasma cholesterol, ily of increased risks for cancer. The plasma triglyceride, plasma high-densi ty population included those exposed to the lipoprotein (HDL) cholesterol, and esti process accident as well as those exposed mated* plasma low-density lipoprotein to normal manufacturing processes and (LDL) cholesterol values. Pulmonary func included chemical operators and service tion testa, ECG, chest roentgenogram, and employees, such as pipefitters and me nerve conduction velocity measurements, chanics. The control group consisted of performed by the method described in current or former employees of the same Goodgold and Ebersiein." were done at the plant who. according to interview work time of the physical examination. The history and personal work records, were nerve conduction velocity measurements never associated with the 2,4,S-T process were obtained for most subjects from the or its materials. peroneal nerve for motor and the sural nerve for sensory function. S ubjects o f the Study Clinical laboratory analyses included The total number of subjects examined blood calcium, phosphorus, blood urea was 0 6 . There were 419 white males, five oilrogeo, creatinine, blood urea nitrogen/ black males, one male of Hispanic descent, creatinine ratio, uric acid, glucose, total one male of American Indian descent, and protein, albumin, globulin, albumin/globu* * ten white females. One subject among the lin ratio, total bilirubio, direct bilirubin, 419 was exposed to the runaway reaction SCOT, SCPT, alkaline phosphatase, iron, residue in 1949 as a child. The seven total lipids, sodium, potassium, chloride, nonwhite males, ten while females, and GCTP, complete blood cell count and dif [he while male exposed as a child were ferential cell count, thyroxine radioimmu excluded from this analysis. There were noassay, and thyroxine-binding globulins. also 51 subjects whose possible exposure Urinalysis included routine examination was limited, poorly documented, and did as well as determination of coproporpaynot include work in the 2,4^-T production nn and aroporohvnn values. {Values were [imerss. They are not included in this ' determined from a single void aample; aoAlysia. The rem aining 367 subjects were hence, the measurement! cannot be re I*1jignated by exposure as follows: (1) garded as valid.) posure without qualification: 204 sub jects who were involved in any aspect of Analysis of Data the production of 2.4,S-T, including m ain Data from questionnaires and the sub tenance from 1948 to 1969; and (2) no ject's medical history were coded by exposure: 163 subjects currently or for assigning numerical value* to the re m erly employed a t the same plant but sponses given. Tbs subject's medical his v never, associa ted with any aspect of 2,4,5-T tory and findings were coded using the production or maintenance of the produc Systematized Nomenclature of Medicine11 tion facility. System. Laboratory data were entered as All living employees, active, retired, or received. Data were keypunched and veri term inated, as determined from company fied. The computer data were compared records, were aaked to participate. To with the .original files for accuracy. The constitute cohorts of the target sample Statistical Analysis System" computer i**. ill those who volunteered participa package was used for data analysis. As the tion in the study were examined: thux, it analysts progressed, editing continued to was not possible to randomize the selec ensure the greatest possible accuracy. tion of participants. Of the living exposed Multiple linear regression analysis" was personnel, approximately 61% voluntarily used to compare the exposed group with participated in the study, as did approri- the not expoeed group and to compare the m itely 46% of the living not exposed three chloracne subgroups with respect to ._f*T*QoncL.Th(Lonly mqrUlity. data avail-_ p la s m a lip id U v ri pu l m n n a r y fn ru -tie n . aibls for analis a t the tim e of thia study values, clinical laboratory values, - and were for personnel who were exposed to nerve conduction measurements after ad the runaway reaction materials." justment for covariables. The corarisbies Clinical Exam ination were age in the analysis of clinical labora tory values and nerve conduction measure The interviews and clinical examination ments. age and smoking status (never, with informed consent were conducted former, and current) in the analyses of during the week July 11 to 18, 1979, in Winfield, WVl The routine laboratory analysis of blood and urine was`completed by Metpath. Blood plasma lipid fraction examination pulmonary function values and age. and smoking status snd alcohol status (never used, formerly used, and currently used) in the analyses of plsama Upid values. Fish er's exact test" and the x' teat for indepen JAMA. May U , 1&S4-- Vol 2 6 1 , No. 18 dence in contingency ta b ! were used to compare the two exposure groups snd the three chloracne categories with respect to frequency of abnormal findings on physi cal examination, pulmonary function lest, and lipid analyses. Fisher's exact test was also used to compare the two exposure groups with respect to reproductive find ings. Msntel-Haenszel analysis" was used to compare the exposed group with the not axposed group with respect Lo frequency of abnorm al findings on physical exam ina tion a fte r adjustm ent for age group (< S0 and ^ 5 0 years) and with respect to fre quency of abnormal findings on pulmo nary function test or abnormal plasma lipid levels after adjustment for smoking status. Logistic regression analysis" was used to detect associations of exposure with abnormal findings on pulmonary function test after adjustm ent for pack years smoked. Log linear models" were used to detect associations between the three chloracne groups and abnormal plas ma lipid levels after adjustm ent for smok ing status. RESULTS D em ographic Inform ation Demographic data of the 367 white males were examined to determine potentially confounding variables. The mean ages of the exposed and not exposed groups were 56.7 0.7 (X iS E ) years and 46.2l.Q years, respectively (P<.0001). The two groups were found to be significantly different with respect to employment status and highest educational level achieved (^<.0001). In the exposed and not exposed groups, 34.8% and 13.5%- were retirees and 9.8% and 0.6% were terminated (left voluntari ly or laid off), respectively. Among the exposed and not exposed groups, 9.4% and 1*2% reached no further than the eighth grade, respectively; 72.4% and 56.8% had some high school education, respectively. Among the not exposed, 42.0% attended col lege, some to completion, while among the exposed, only 18*2% attended college. . ^ -- A lc o h o l-a n d S m o k i n g -- - ..... . History of alcohol consumption was not found to be significantly different in the two group. When smoking status (current, former, or never) was used as the criterion, no differences were found. Among current smokers, the exposed group had smoked signif icantly longer than the not erposed by 19 pack-years (.0001 < f >< .001). Among former amokera, the exposed 2 ,4 .6 -T -- SuakJnd A Bwrrzbsrg 2 3 7 3 group had smoked longer than the not exposed group by seven pack-years (.05<P<.10). This reflected the tenyear age difference between the exposed and the not exposed group. HIlory of Medical Problem The comparison of the exposed and not exposed cohorts for seLf-reported history of illoese is given in Table 1. Chloracne was reported only in the exposed group: 86.3% in the exposed v 0.0% in the not exposed. The data about the history of chloracne were determined on the basis of statements from subjects that an acnelike erup tion called "weed bumps" appeared after an assignment to a 2,4,5-T pro duction area. Records of the medical department of the company and the state Workmen's Compensation Bu reau stating that the person had chloracne confirmed many of these histories. In the not exposed group, a history of acne vulgaris was reported more frequently than in the exposed group. This information was based on the story of adolescent acne before employment at this plant. A history of upper GI tract nicer was reported almost four times more frequently in the exposed group. When the medical history of the exposed and not exposed was compared for two age groups younger than 50 years v 50 years or older, a history of coronary artery disease and of hypertension were related to age, not exposure. Among the not exposed, angina was significantly related to age; in the history of upper GI tract ulcer, how ever, exposure, not age, appeared to be a factor. Closer examination of onset of ulcer in relation to exposure revealed six subjects whose symptoms oc curred before exposure. There were also four subjects whose symptoms occurred while they were receiving corticosteroid therapy or high doses of aspirin or that were attributed to. chronic alcoholism. If these ten sub jects were omitted from the analysis, there remained statistically signifi cant differences between the exposed and not erposed groups (16.6% v 5.5%; P^.Ql on age adjustment). The complaint of loss of libido occurred more frequently in the exposed group than the not exposed group. When age was considered, the largest number of complaints of loss of libido or impotence were reported T a b le t . -- Hilory o l M e d ic a l Problem a v Eapoeus S la lu * svd try A g e f a tory Chlosaenel t Acne tnAgerief*^ Skin a n e w Hyp-rtanaan* Aston* tt Comnwy vtw y ff w y H Upper o*tfom-- a r f 1 treci lA c es f Canoes of 4 edee** (except aAVO X (e-204}* 643 9. 3.0 3-4. a r.4 lo.a Mot Cxpoeed, X ( A - 143] `o 0 to .a 2.5 24.8 0.1 81 A ge < 8 0 yr. X fjQ need (n -a tl 8.3 17.7 0.0 21.0 5.0 2.0 Mot tzpoeed {-too) 0.0 43.0 to 10.0 t.O 0.0 Ape i 80 yr, X Cxpoeert (n-163)* 80.5 7.2 5.3 34.8 70 13.0 Not I tp im t {A-OE3) 0.0 O.S 4.0 341 14.3 16.0 20.; 5.S 13.7 S.0 23.0 0.4 ao U 0.0 0.0 3.0 3 J *O n o t ff*e 3 0 4 >ut>fcii dd ot Como**!* irve tniesv'eoSpfryeical TWNehon p ro g ram bkri h e d a d o c u m e n te d O 'fa n in 'a o o m p e itte h o n rt* n tor cftforacna. f # * < .0 0 0 1 : P i l l a tor U e n tw-H aanaSel co m p an ao n oS a i p o i a d noi e ip o e e d aesoee ge a rrata. ( .0 1 < A < . 0 8 : id ip o e e d ; y o m g r 0*1. by F ia tw 'a a a a c i laat 1.001 < A < Q t: P vakr* lar l4*mel*Haenare4 oom panaon oI ip o e e d * not ampoaad acroaa ap a atraa. 1 .0 5 < /* < . to-, In a a p o a a d . y o m g r 0*d, by F u l w 'i a u c i la a t. tP < .O O O i: n n o t a a p o a a d . y o u y j ir o*d. by F iab a r'a a s a d laat. 0 0 1 < # * < .0 1 : in n o t a a p o a a d . y o m g 0*d. by F 'a r w 'a a a a c l laat. * *tn tn a a a p o a a d ^ u p , toUddar c a n e e s , two; oo4on c a n e e s , tn raa; p re e ta le c a n c a r, o n a ; n tria n o t arp o n a d proa, btaddar ca n car, ona: m atanom a, ooa. * .0 5 < / 1< .1 0 ; h aapoaad. young roM , by F W w - aaaci leal. t .001 < # * < .0 1 ; for l.UnlM M aanajal compartaon oS aapoaad to not a i poa a d croaa apa atraa. *#*<.0001: v not aapoaad. yixxig r * t by Ftahar'i a a a a laaL I.O O K P C .O l: In aapoaad. young r C*J, by H ahar'a a t a d teat. .OOOl< # * < .0 0 1 ; In aapoaad. y tw ig re d , by Fiaftar' a a a d taa. by the older age group (Table 2). As noted in Table 1, the reported history of skin cancer, hypertension, angina, coronary artery disease, and cancer of all sites (except skin) was not foand to be significantly associ ated with exposure. The sample size obtained was sufficient (at signifi cance level of .05, power of .80 (proba bility of detecting a true difference]) to detect a fourfold increase in skin cancer, a twofold increase in hyper tension, a threefold increase in angi na and coronary artery disease, and a sixfold increase in cancer of all sites (except skin) for exposed over what was observed in the not exposed. As noted in Table 2, the complaint of nervousness/depression/anxiety and the complaint of impotence were not related to exposure. The sample size was sufficient to detect a twofold increase in complaint of nervousness/ depression/anxiety for exposed over not exposed. Although the sample size was sufficient to detect crude differ ences between the two groups with respect to complaint of impotence, the difference disappeared when age was considered. The exposed population was catego rized into three subgroups, ie, those who never had chloracne develop (n**23), those who had a history of chloracne o n ly '(n-69), and those whose chloracne persisted (n" 107). When the histories of medical prob lems were examined in relation to chloracne status, hypertension and coronary artery diseaae.were found to be age related, not chloracne related. Histories of skin cancer and angina were not statistically significant when related to chloracne or to age within the chloracne groups. While it would seem (Table 3) that akin cancer 2 3 7 4 JAMA. May t l . 1004-- Vol 2 5 1. No. IS 2 ,4 ,5 -T -- SuaJtlnd & H e tlzb e rg `Vij. v/ ;i I A*' /i f T a b la 3 . -- Hi a lo ry o l M Jcal P ro b la tn a v C M o/ftcn S t a t u t to E i p o i e d O nly a n d b y Ag * C taofacna Slatua, X Hilory* Acn* *v*g*n* Stan cancar M ypao*a*Jont Angna Coronary anary cSaaaaat Upoar g a ilto in ta w w a l tra ct tAoar Cancar o a l a itii (aieatif ik n ) M alory O nly (a- 1 ) 0,0 S.B as a S.B 8.0 10.2 44 C urrant ( t l - 1071 a .s 2.8 38.3 10.3 4 .0 2S.2 2.8 Ko H talory (n --101 25 0 30 17.0 0.0 3.0 14.3 00 M alory O nly ( n - 10) 10 0 0.0 o.a 0.0 0.3 8.3 00 A < 5 0 yr C u rran t --2 3 ) 0.7 0.0 34 a 13.0 00 21.7 0.0 Ho H U Iory (a --131 33.3 0.0 18.7 0.0 00 8.3 0.0 H U lory O nly (n --621 30 7.7 44.3 7.7 08 10.2 58 A g a 5 0 yf C urrant ("--*) 0.0 3.0 30 3 0.5 17 0 2 2 3a Ho M talory (-IS ) io .a 03 18 8 . 0 .0 8.3 18.8 00 *AJ c o rro a n ont o [fia [Twaa cfitaracrv* C alag o n aa, botft (or (fw (M il QrouO an d tor ftv two a g a g reco i . --a lo en d 19 b a not *tarfta a n t try j ' laal for rta a o a n d a n c a n connnQancy labia*. t 0 1< /* < .0 5 to N n o ry onTy. y o co g VOid by j* la al ta r in g a g a n d a n c a in cor>t^jarvry laW aa. I 0 5 < e < . 10 lar CLvtam. young v o ta try * ' la al for rta a p a r ta a n c a n co n rm g an cy la ta a i. is related to age in the three chlorarne groups, the number of persons m the age group younger than 50 years was too small to achieve statis tical significance. There was no asso ciation between the history of upper GI tract ulcer and chloracne status (Table 3). While the number of subjects reporting a_ history of cancer (other than skin) was small, all of them were ' A f'lund in the group aged 50 years or^ older, ami tKe percentage in the exposed group was not UgHlfl6ioEIy different from that in the not exposed ~jp-oup (Table lj. The three bladder cancers were reported by persons imposed to ^-aminobiphenyl, a rubber additive that was also made in the plant. Physical Exam ination Results There seemed to be no difference in blood pressure findings between the exposed and not exposed group. The criteria for determining normal for A combined systolic/di&atolic values were leas than 140/90 mm Hg for subjects aged 59 years or younger and ''ss than 160/95 mm Hg for subjects ;,K''d 60 years or older. For diastolic alnnc, less' than 80 mm Hg was con sidered normal. Diastolic values of 80 < * to 89 mm Hg for ages 59 years and i' younger and 80 to 94 mm Hg for ages k. 60 years and older were considered borderline. Diastolic values of 90 mm y Hg or greater for ages 59 years and t younger and diastolic values of 95 mm Hg or greater for ages 60 years and older were considered high. The significant clinical examina tion findings as related to exposure status and age are found in Table 4. Of those who were clearly exposed. ?. JAMA. May 11, 1 0 6 4 -- Vol 2 5 1 . No. 18 Tabla 4 .-- Significant Clinical Findings y E ap o su ra S ta tu s and by Age FVtaHrfl CNoracrv* * Acna n A g u ttfll AcTirac a U a l o a ta l ^ ir 4n - - *-J o a l ip r f a A r r r a 9 Mayroree** i i i ^ - Hb-wtflani EigoA od, X (a- 2C 3) 52.7 2.0 50.1 S.fi rp 8.4 Hot E tpoM d, X ( A - 183) 0.0 11.7 30.1 4.3 0.0 1.8 A ga < SO y t, % A g a i VO yr. X C iPO M d I n - 31) 45.1 7.8 37.3 2.0 0.0 3.0 Hot 6g p o * a C iP O M d ( n - 100) (n --152) 0.0 55.3 180 0.0 100 68 4 0.0 6.8 0.0 C O D 1.0 5.0 H al C tpaM d ( a --83) 0.0 1.8 40.2 11.1 0.0 3.2 * P < ,0 0 0 1 ; P vakja tar U*nr* Ha a n a l al oom panaon o a rp o a a d v noi aap o aad croma a g a atraa, f , 0 f i < ^ < . 1 0 ; / ' v*kiA ta r M antaA -H aanual o o n ^ a n a o n o a a p o a a d v n o a a p o a a d a c ro a a a g a a tra a , 1.0001 < / * < .0 i : h am poaad, y s u ig ro ta , by FW iar'a am ad laal. |,0 0 1 < /* < .0 1 : in no a z p o a a d . y o u n g r ota. by FcaNar' am ad la a l, 1.0001 < F < .0 0 I ; P vala tar M anta! IU vnaral com ganaon o aapoaad v not aupoaad acroaa ao a ^ .O O O K /^ C .O O I: In a ip o a a d . y o u n g r e t a , by R aTiar' a s a d ta ta . * A < . 0 0 0 1 : In n o a r g o a a d . yocnQ r o t a , by R a h a r 'a a a a d la a i. 52.7% still had chloracne, 62.6% were mild cases, 33.9% were regarded as moderate, and 3.8% were severe. The diagnoses of chloracne and acne vulgaris were made by qualified dermatologists. The criteria for diag nosis of chloracne include the initial appearance of comedones, milia, or epidermal cysts on the malar, temple, and periorbital areas that may subse quently involve other areas of the face, the neck, forearms and arms, and scalp and genitalia. The scrotum and penis are commonly affected in persona whose clothing becomes heavily contaminated by the acnegenic material. Lesions may became sec ondarily infected, especially on the trunk, forearms, and genitalia. Gy contrast, acne vulgaris that usually starts in adolescence is seen as inflamed papules, pustules, and come dones, on the peri nasal area, cheeks, chin, neck, and back. It rarely, if ever, starts on the malar or periorbital areas. The skin of the affected sites in acne vulgaris is usually very oily or greasy. In the case of chloracne, the skin surface is usually dry. Persons with acne vulgaris, exposed to chloracnegens, may experience the devel opment of chloracne. The lesions of acne vulgaris may increase in severity and lesions may develop in sites not usually or previously affected by acne vulgaris. Among the exposed, 59.1% were found to have actinic elastosis in contrast to 30.1 % among the not exposed. There was a significant dif ference in the occurrence of actinic elastosis between the exposed and not exposed in both age groups even though age is a factor in this clinical finding. Three cases of Peyronie's disease were observed among the 204 exposed. All of them had chloracne at some time and they were all older than 50 years. Peyronie's disease is characterized by induration and scar ring of the corpus cavernosum of the penis, producing distortion on erec- 2.4,5-T -- Suskind 4 Hmb*rg 2 3 7 0 5T a W a . -- S ig n if ic a n t C lin ic a l F in d in g r C h lc x o c n o S t a t u s in E x p o s e d O n ly a n d b y A g a F ln cV - Acn* vvAOena' 1Acarac Wi i Kxm *J 1 BaaaJ Cat eorttietem Ptynn*'* Hntti tarauflam t W atery O nly. X (a-M l I.S 4M 3.0 2.0 0.0 Cim m L X (a - (071 0.0 74.B 6.4 0.0 i a .3 Ha W atery. X (n -U ) 10.7 26.6 3.6 0.0 0.0 A ga <30 yt . X W atory O n ty ( n --16) 6.3 31.3 6.3 O.a 00 C te ren rt ( n - 23) 00 36.3 0.0 0.0 6.7 Ho W atery ( a - 12) 23.0 6.3 00 0.0 0.0 A ga 30 y r. X H Htory O n ly (n --83) 0.0 S t.a 36 3.6 00 C tera-f ( n - 64) 0.0 7g .a 10.7 1.2 10.7 Ho W alorr (n --161 0.0 4 3 .a 63 0.0 0.0 * .0 1< R < .0 3 : tar w i l <JW rtnoM bf w t t n tfw aa cM o racn e c a te g o ric h a g e 40 y -- ra or y o in g a r. by y* iM l (or In c o n ln g a n c y la w . 1.0001 < R < . 0 1; lor w t l did ---t i c b * t* n th a ttv e a cM o racn a c i l t g o r t M In 1 9 6 0 y a a ra or o tear. by y* 1-- 1 lor In d rp a m t W i In eo n tm g a n c y lab<*4 . 1.01 < /* < .0 3 : in a r r a n t cWorocn, yo^ng *e*d. by Frana#*! a axel tl. | . 0 6 < / 1< . 10; In n o (--Tory c4 cXaaracr--. you n g r o U . by F>ftr'a a u d M . Table 6.-- Exposure v PIaamt Upids Expoeed Not E xpoaed PI-- hi (Jo4da Ov*ealero1 TrVyeerkSe Le---dene*y b o o p ro ta n ctxA atlaro! ign-dan**y fcjotxTj--i encix (arql n Zrse 200 71 1 .1 3 x 2 .3 3 200 140.66x7.44 106 1 3 8 .7 4 x 2 .4 0 200 46.63 O .SI X Out ot Rang* 7.3 14.3 7.7 9,6 A XI S t 163 2 0 4 OT x 2.97 163 SB 6 3 X 7 .7 3 139 1 2 7 .0 8 x 3 .6 0 163 4 4 .1 3 0 .7 7 X Ckrf o t R k o g t* IO 4 10.0 6.3 10.4 R V atea NS S3 M3 MS 'H *rance rang for ptaam a tfip la ila rp l. tn g rycenda. an d to--"d a n a d y EoO0te(e*i c#iO*t4rcl --a r a d a lin -d a a H aa (Kan tb a a O * -a p a a l< OOlti parcanrA a 4a M lanw iad by (ha N adonaf Lipid fle a -- r d i P rotect. R a la ra n c e ran g lor hagft-deneify teoprcrtaan e ro la a ta rc t -ara OaAnad a a a t v (Tie a g e -e p -o A c lan tft p e rc e n t* a a dalarm nad by m* Naoonal U p d flaaaareh Proaecl. tion. As noted in Table 4, there was no association of findings of basal cell epithelioma and hirsutism with expo sure. The sample size was sufficient to detect a threefold increase in basal cell epithelioma and a fourfold in crease in hirsutism for exposed over what was observed in the not exposed. Table 5 identifies the clinical find ings in the exposed population in relation to chloracne status. In these groups, actinic elastosis was found preponderantly in the subjects with persistent chloracne (74.8%), but it also occurred significantly in those with a history of chloracne only (47.1%). Of the exposed with persist ent acne, 10.3% were found to have malar hirsutism: nine of these 11 cases occurred in the group older than 50 years. Actinic elastosis is a problem found in persons of light coloration exposed over many years to sunlight (eg, far mers' skin and aailon' slcin). It is characterized by swelling and frag mentation of the elastic tissue ele ments of the dermis. There was an association of actinic elastosis with chloracne. It seems that the percent age of persons with severe actinic elastosis was related to presence of chloracne and that it is more severe when found with chloracne. Plasm a Lipids Plasma cholesterol, triglyceride, LDL cholesterol and HDL cholesterol were classified by age-specific percen tiles as determined by tbe National Lipid Research Project data." Plasma cholesterol, triglyceride, and LDL cholesterol n in es were classified as out of rang if they fell above the 90th percentile; HDL cholesterol values were classified as out of range if they fell below the tenth percentile. The frequency of out-of-range lipid find ings was compared for exposed and not exposed groups (Table 6). No significant differences were noted. The sample aixe was sufficient to detect a twofold increase in the fre quency o f . out-of-range cholesterol, triglyceride, LDL cholesterol, or HDL cholesterol values for exposed over what was observed in the not exposed. After sdjusting for smoking status, no significant differences were found. The mean lipid values were also com pared'for the exposed and not exposed groups (Table 6), and no significant differences were found. When the lipid levels of the exposed group only were examined in relation to chloracne atatus, there was a sig nificantly greater number of subjects with low HDL cholesterol levels in those with persistent chloracne than in those with a history only of chlor acne or those who never had chlor acne (Table 7). There was a greater number of persons with high LDL cholesterol levels among those who had a history only of chloracne than those who had chloracne currently or never. The mean lipid levels for these three chloracne groups were also compared (Table 7), and no signifi cant differences were found.' After adjusting for age, height/ weight, smoking status, and alcohol status, no significant differences were found between the two exposure groups with respect to mean lipid values. The interaction of smoking status and alcohol status was also added to the model, and no differ ences were found between the two exposure groups. To detect differences between the chloracne groups with respect to mean lipid values, the same adjust ments described previously were per formed. No significant differences were found. Log linear models were used to detect associations between frequen cy of out-of-range lipid values and chloracne status in the exposed group only, adjusting for smoking status. Findings are as follows: (1) Out-ofrange cholesterol or triglyceride val ues were not associated with chlor acne status. (2) Out-of-range HDL cholesterol values were associated 2 3 7 8 JAM A, May 11, 1084-- VoJ 2 5 1 . Wo. 18 2,4,S-T-- Suakind A HartzbefQ I* Tabl* 7.--Cftlo*C/v Sirut in Exposed Only v PIma Lip*da r w n Lipid GT<e**Mroi Lowdanarfy hpoorol**i CMMIIHdl High-d*n*ffr igopnmin dSoiwIeroJl WhMy Only ft ! K ar 313.10 X*.B7 or 144.00 s u .a a % Out of Rang* 11.0 7.5 M 143,04x4 SB 15.3 ar 4S.B4S 1.17 3.0 Cumnt a Ztse 100 310.33x3.17 100 1S3.84xB.39 % Out ol Renga* .a IB. t 103 134 45 x 3.04 3.B 100 44.B3X1.31 14.3 Ho Htatary ft XM ' X Ou o iUor. 30 304.90 x 7 .13 7.1 78 140.1 i x l a s s 14.3 37 130.90 X7.00 7.4 7B 47.78x3.3t 7.1 '( W t f M M rano* fcv p4*ama Cho*-- IfO *. Ingfycorf. and lOw-dOTt/fy kfmorotwn d W e e le ro l w * daftrm ) k * u th a n th * o * - e * o 8 e OOth pareanM * dai*rm in*d by th* K cAonet UpM H w i r r t Pro jo ct. R tla ra n c ran o * for h*sv-d*n**y fcpopro<*i cfw***1* rti M r * 0*A n*d abov tf x ao*-o*CTAe larwri p * o > n tt aa 7 O atarm nad by tha Kartonal L M R aaaartft Protect. T P C .O lfl: for co m p arin g Fr*quocy o 0w1-o-rnQ lava la in th a th raa cM oraona PTXjO I for oom pertng h * q u a n c y o o u t-o -tan g * lav**a tn tha Ifv*a eN o racn * group. } with chloracne status (.01 C-PC.OS), two exposure groups after adjusting and the degree of association did not for the effect of smoking (Table 9). No vary significantly by smoking status. difference was found between the two (3) Out-of-range LDL cholesterol val exposure groups with respect to ues were associated with chloracne FEFu.,, percent predicted. Percent- status (.01<P<.05}, and the degree predicted values for FEV/FVC and of association did not differ signifi FVC were significantly lower in the I cantly by smoking status. exposed group. Furthermore, there was a significant interaction between V Pulmonary Function Exam ination smoking status and exposure with S Both forced expiratory volume in respect to FEV, percent-predicted 1 s (FEV,) and forced vital capacity values. When adjusted group means (FVC) were considered abnormal if for each smoking status exposure the observed value was less than 80% combination (Table 9) were examined S of the predicted value of Morris. A to determine the nature of the rela * FEV/FVC percentage less than 70% tionship, no significant differences was considered to be abnormal. The were found between exposed and not forced midexpiratory flow rate exposed workers who never smoked or (FEFm ) was considered abnormal if who formerly smoked. Among current the observed value waa less than 70% smokers, however, there was a signif of the predicted value of Morris. icant difference between exposed and Consistent differences in abnormal not exposed workers-with respect to pulmonary - function values (FEV,, FEV, percent-predicted values. FVC, FEV,/FVC, and F E F ^ ) were found when the exposed and not Clinical Laboratory Findings exposed groups were compared (Table With-regard to clinical laboratory 8). Among current smokers, there was determinations other than plasma a significant difference in frequency lipids, no significant differences were of abnormal pulmonary function val detected between exposed and .not ues between - the exposed and not exposed groups. There have been erposed groups, but there were no reports of abnormal levels of alkaline differences among persons who have phosphatase, SCOT, SGPT, and formerly smoked or among persons GGTP in other populations exposed to who have never smoked (Table 8). TCDD for short or long periods; how >. Logistic regression was performed ever, no differences were found in to* evaluate, the.relationship between these cohorts ten to 30 years after the frequency of abnormal pulmonary last date of exposure. :function values and exposure after adjusting for pack years smoked. v Odds ratios are given for these EC Q and Roontganographlc F in d in g s parameters in Table 8. Exposure sig No differences were observed in the nificantly increased' the odds for ECG findings when the erposed and abnormal pulmonary function values not exposed groups were compared. even after adjustment for pack years When the chest x-ray film findings n smoked. the exposed group were compared The means of the percent-predicted with those in the not exposed group- values were compared between the and separated by age, the arterioscle rotic changes and pleurai thickening differences between the groups seemed to be age related, not expo sure related. Neurological Findings snd Narva C onduction Velocity Maaauram anta When exposed and not exposed groups were compared for frequency of abnormal findings on neurological examination, no differences were found. Nerve conduction velocity measure ments require controlled atmospheric conditions and uniform conditions of testing. Ambient and body tempera tures were recorded. With the tech nology employed, it waa at best a screening procedure. All subjects reporting diabetes or reporting a high weekly alcohol intake (^35 ox. of alcohol per week) were eliminated from the data analy sis. After these deletions, there were 278 with complete sural and 294 with complete peroneal examinations re maining. The data from the nerve conduction velocity Btudies were cor rected for body temperature accord ing to the deJesus11 method. The ageadjusted values are presented in Table 10. No significant differences were found when the two exposure groups were compared or when the three chloracne groups were com pared. -- Reproductive Effects Information on reproductive fac tors and birth defects was elicited from the male participants. Neither physician nor hospital records were available to confirm the information. A comparison between the exposed and not exposed groups/or pregnan cies, live births, infant deaths, mii- 'U u A. w y n . 1004-- Vol 2 51 . No. 10 2 .4 ,5 -T-- Sua kind & H i r t ib v g 2 3 7 7 Tabla 9 .-- E xposure G roup M u n s of P w con I-Predicted Pulm onary F unction P aram eters A djusted for Srpoking S tatu e Function Parem elof F E V ,- SU tue FVC* FV./FVC % F^n-r,* Total Em oM d X ise 1 0 7 .1 2 *3 .0 8 101.43 2 .0 3 0O .0 3 2 2 J Z2 99.39 2 1.43 B 3.732l.17 70.40 2 0.03 1 0 t.0 0 2 4.03 Hot EiTOM d Xsc 105.S3 2 3.03 104.00 2 3. I S 102.33 2 2.86 104.42 2 1.57 07.00 2 I J 0 70.03 2 0.S 100.10 2 4.30 MS H3 0.0000 0.0 IS4 0.0004 0.0002 MS FFV, in tfc a la s to rc ed a x p n l o r y volum e b i t : FVC. to re a d vHai c a p a c ity : FEFj.. toroed midej^aratory rale. T a u 10.-- M o a n N a rv a C o n d u c tio n V a lo c fty * fo r (h a E x p o o w a G r o u p s a n d lor tha CM oracrva Subproupa, . Category Lupo dt X 2SC& 0 tot D p o -- d K x S E (n) CN oraova, history ontyf X 2 5C (n) OVorama, cvrw d K xseoo C N o re o a , na.ar X tSC (n ) U ln a r 50 .0 0 2 3 .3 (0) 0 1 .0 1 2 * J O (0) 50.03 2 8.03 (3) s r . 0 0 2 4.11 (Q) 53.10 2 0.00 (1] M aria T n t a d N re m d 41.77 20 .4 7 (100) Sw at 42.00 2 0.40 (ISO ) 43.52 2 0.53 (134) 4 1 .4 0 sO .S 4 (128) 40.00 2 0.77 (50) 4 1 J 0 2 O .6 O (001 41.14 2 0.00 (51) 41.37 2 0.78 (74) 40.61 2 1.12 (24) *' 4 1 .3 3 2 1.30 (26) *A 4 u a*ad lor aoa. t P a o x a la not aigniBce nt lor o o m p td ta n of wrtTi not axpo aad with reepect to b e r , peroneal, and n t . and aleo tor comperteon of the three cfterec n o th r e a p e d to l4ner, pero nea l, an d a v a l. carriages, birth defects, and still births is listed in Table 11. There Other W ork E xp o su re * of th * Study Population were no significant differences in \ Other than 2,4,5-T and its interme these parameters between the ex diates and/or contaminants, all of the posed aod not exposed cohort. No workers in the study were exposed to data were available on age of wives of multiple, chemicals and industrial workers. processes under varying working con- 2 3 7 0 JAMA, May 11. ID04-- Vol 2 6 1 , No. t 8 ditiona, at the aune plant and/or other plants, between the late 1930a and 1979. Rubber processing chemicals iden tified by the subjects aa other expo sures included diphenylguanidine, the benxothiaxolesulfenamides, deriva tives of m-cresol, p-phenylenedi&znine derivatives, and 4,4-dithiodiraorpholine. Additional chemicals named were ethyl parathion and methyl parathion, phthalic anhydride, <r- and p-dchlorobenzene, a- and p-nitrophenol, toluene and mercaptobenzothiazole derivatives of tetramethylthiuramdiaulfide, and trimethylquinoline components. Seventy-nine subjects, or 21.5% of the 367, reported in-plant exposure to p-aminobiphenyl, a known bladder carcinogen, during the course of their employment. These subjects are peri odically examined in a clinical sur veillance program established by the medical department of the company. Subjects reported the exposure and the monitoring program during the interview and to the examining physi cian. The data relating this exposure to 2,4,5-T are described in Table 12. COMMENT In any interpretation of the medi cal significance of data elicited from this study, it is essential to consider the characteristics of the cohorts as well as the strengths and weaknesses of the design of the study. With all industrial populations at risk* in the 2.4.5-T-- Suafdnd & H em barg t- & T abto 1 1. -- E x p o s u re v R e p ro d u c tiv e FWvJVvja Aeproductfv* H ilofT (lpO M 4` (rv-1*ax .Mo4 E x r o e e d t (e-IM fl city in the group of exposed persona as described in the reports cited in the references were characterized by cutaneous, hepatic, and peripheral P re g n tn a n Iln n W g .i rwto pa 1.000 p fto w n a lM L-- b n M StfUrTM r*e (mt 1,000 I im to M ess M 10HJ4 S7S 11 ia.7T 420 SI ita se . 373 S un nerve damage. In other populations, e where hepatic changes were observed MS as a clinical subacute effect, elevated e levels of SCOT. SGPT. and CGTP MO were rep o r te d .D o s e s of 1.0 Mg/ CMa In 4 weafca rala par 1.000 M bfrth* C M *w i tatoi 1*91 d a fe o e nrt par 1.000 P-- bfcVw ir 2o .s e i* 11JO .. a t a.oo it 20 4S MS ee*> MO tha n p o M d , reported b H i d alri3 a tnduda apew bMd, tnapeortVad c a r J a c k w m J . pytorte in J H M n M leeocM . c o n j* r ii hy*-ooe*i, obstru ct* Patoct oi v irw y Vec*. ctok to , c ix W i J h a it leg , m o m i M e t a r r v n . D oam 'a e y r* * * * , herrPa, a n d i n g o m , kg/day in rats will induce altered liver function, elevation of alkaline phosphatase, lymphoid depletion of the thymus, and increased excretion of urinary porphyrins and A-amino"Tevulinic acid." The effects on the T*- I f a a p o a a d. w p a r u d brttl fil li e(a InctuPa ^ I n e t i1 a . oonoarWaJ m a i a l u r y e , pulfCV^ C ir V w y d t a a M , antrW w a p , o o e tr u c flv # d a f a c ta orf ir t n * r f k e d . cfuQ t o , i t r o a ViQ ara. o o n o a n e a i < t*tocahon N ^ a , c y a a c h ^ u n , Do-- i 'a ayrvkrvna. a n d harraa. I P -- CHlarancea in ravnOar (1SB r 0 4 lor a a p o a a d an d I I S 103 tor n en o o o e d ) -->ara dua to m a n --r *3 thymus have not been noted in humans, although there have been some reports of elevation of alkaline v a r a C fbtfaaa or m a n arfto t*d n e t ra a p o o d (tw o n o r r eau m r t an In ff*a n ea p o aart. f f w a In th e n p o a r i f l . phosphatase and AALA levels to long term exposure." Elevation of alkaline phosphatase levels was not observed in those who were examined in 1949, 1950, or 1953' or in this study popula tion ten to 30 years after exposure. Tetrachlorodibenzo-p-dioxin was found to induce cancer of the liver, lung, palate, and nasal turbinates in rats." An excess of cancer of all sites was not observed in the mortality analysis of the group exposed to the runaway reaction materials,11nor was an increased prevalence of cancer of all sites observed in this study popu United States, particularly for long- may have been exposed to 2,'CS-T. the lation. Cancer of the liver was not term follow-up, randomization and coafxminant TCDD, and other chemi observed in this study population, nor participation requirements for pris cals varied markedly, Spbiecti re was an of cirrhosis noted. tine epidemiological protocols are ported exposure to the 2 ,0 -T process High doses of TCDD (30 ppm), rarely satisfied. In this study it was for as little as one month to as long as administered orally or subcutaneous not possible to match the exposed and 20 years, and exposure was often ly, in pregnant mice* and rats may not exposed groups demographically intermittent over a period of years. It increase the incidence of cleft palate on basts of age, employment status, was difficult to accurately designate in mice and cystic kidney in rats." No and education level. Although the two the duration of exposure for many of teratogenic effects were observed in groups were defined on the h**i nf these persons. The data do not pro rabbits receiving 10 to 40 mg/kg of definite exposure to 2,<5-T process' vide characterization of incidence or 2,4^-T containing 0.5 ppm of TCDD and n ^ yidence of exposure to dose-response relationship. or in rats receiving 1 to 24 mg/kg of anywhere in the plant, no inlorma-* Data obtained from interviews and 2.4J5-T with the same TCDD content." tion was available about levels of clinical examinations conducted by It has been demonstrated that hyper 2,3,7,8-TCDD"7n the work eaviron- different physicians have inherent plasia and ulceration of the gastric `ment or in the trichlorophenol that biases. Nevertheless, the available mucosa occur in monkeys after lethal was produced" or In ihe final product,' populations provide useful informa doses are administered." In this study Since ,4,0-T was used ubiquX- tion on the prevalence of biologic population, a statistically significant tou2jTas a weed killer in many gar effects in the population exposed, as increase in the history of upper GI den! and farms, the possibility of compared with thoee who were not tract ulcer was found when the t; exposure to some TCDD between IMS exposed to the 2,1^-T production. exposed were compared with the not V; -' and 1969 exists for both groups. There A comparison of manifestation of exposed. is current analytical Information effects to TCDD toxicity in humans Birth defects as reported by partic demonstrating that dioxins including as observed in this population with ipants in this study showed no differ ^3,7,8-TCDD may also be present in those observations made in experi ences statistically between the ex the community environment in fly mental animals must also consider posed and not exposed groups. In ash and, flue gases1" * from incinera the acute, subacute, and chron rhesus monkeys receiving 500 parti tion of domestic garbage and indus ic effects In humana already re per trillion of TCDD, early abortions trial chemical wastes.*" * ported.'^ and inability to conceive were ob b" The degree to which each subject The subacuta affecta of TCDD tox- served,*" 1XheM effect* have not been t` *3S: JAMA May 1 1 . 1084-- Vol 261. No. 18 2 .4 ,6 -T-- SitoJdnd 1 HertZDecQ 2 3 7 0 observed in this study papulation. This study indicates that the pilose- baceous effects of exposure to the 2,4,5-T process were persistent in 53% of those exposed. The effects of the kind of care received by the various subjects may be a factor in persist ence. Since biopsies of the size required to identify and measure TCDD were not available, the pres ence of TCDD or its metabolites as a factor in persistence could not be ascertained. There was an association of actinic elastoaia with the occur rence and persistence of chloracne. This can be interpreted aa increased susceptibility to UV radiation dam age. There was an association of history of upper Cl tract ulcer with exposure. It was not possible to ascertain a designation of ulcer by site without GI roentgenography or endoscopic information. Among the exposed group, ten subjects reported surgical treatment of the ulcer, while none of the not exposed group reported surgi cal treatment of ulcer. These data are suggestive of association with expo sure; no definite conclusion can be drawn because of the qualified nature of the data. The association of upper GI tract ulcer with exposure warrants additional study with an appropriate ly designed protocol. Among those whose chloracne per sisted, there was a higher frequency of low HDL cholesterol vajuea. Among those with only a history of chloracne, there was a higher fre quency of high LDL cholesterol levels. There were no differences found between the two erposure group* with regard to plasma lipid and lipo protein values. There was an association of altered pulmonary function values, especially FEV--in those who were exposed and who currently smoke. This suggests the influence of the number of pack years smoked as well aa exposure. ... There was no evidence in this study . that exposure to the 2,4^-T process is associated with an increased preva lence of cardiovascular disease, he patic disease, renal damage, CNS or peripheral nerve problems, reproduc tive problems, or birth defects. Thim tody w as a a p p a ru d la p a r i by [ r u t s from lb* N ational [nrtituU of Environm ental H ealth Sdencsa (ES-00159) and the H ooaanto Company aad fusda of tba loadtnta of E a n ro o m eoUJ H ealth. Invaluable i h Ii I m m in carry in g out lb exam ination * u pnrvidsd by m any p * n o o t Ida Blanch* But kind; Pam Wjn n*r. C arol W ai-reo; C h a r lo tu O iborne, RN; L*-v Rafale, PhD . 0 * o & Dolio; A. B. S oiilb. UD, G eorgs W. H am brick. J r, UD; C harla* L H taton, UD; W eyoe El B aum an. UD. aad D an n i F. Richfield. UD. R afarancai t. Aab W. Suakiod RR: Chloracne a m of Lha Montante C hem ical C om pany, NO-o. W rit V irginia, in R eport* o f A* K e ttm .n g Laboratory. U n iv e rsity of C in c in n ati. O ctober 18*9, A pril 1950. Ju ly 1953. 2. K iram ig J , Sehulx KJL CbJorioaLad a ro m a t ic cyclic a tb a r aa a c u im of so-called chiaren n a U a h tru rito m ie k a fle n 1957;44:337-333. 3. G o ld m a a n P J: E x tre m e ly ever* ehloreco* dua to triehloropheool daenotpoeitioo products A c o n trib u tio n to lb p t n u probi to. A rbraom ^d S ocialised A rnttA pp 19727:12-18. A Jiro a ek L, K a irn e k y J, Knbeck K. I aL A sia cbIorina, porphyria chiama tard a and other m an t i n t a Uona of general intoxication during lb* m a n u fa c tu re of b e r b id d n . p a rt 2. C*i D erm ato l 1974;49:145-157. S. Crow fCD; C h lo ra c n * --ao up to d a u a***-*. raeaL d a a O ocnp H vo 1978:21`-297-298. fi. O liver R II: T oxic fleet* of 2 J .7 2 -t irs - ehiorodi be tu o -l.i-d io x in in Laboratory workrro. B r J Jnd At* d 1975:22*9-50. 7. Bleiberg J, Wallen U. Brodtin R. *1 at Induatrially acquired porphyria. A rch Dermatol 196*29:733-797. 8. Poland A P. S m ith D, M atter G, et a t A h ealth w m j of w orker in a 2.4-D aod 2..5-T p la n e W ith apodal co n atio n to chloracne. por p h y ria c u ta n e a ta r d a , a nd peyebologie pararne- Lara. A rc h E n vi ro n H ea lth 197122316-227, 9. May G: C hloracne from the accidental pro duction of tatnchJorodibeoxD -e-dioxin. B r J in d H ad 197220275-283. 10. Gupta BN, Vo* JG, Moors JA, at al: Pathological effect* of 22.72- tetrodi Iorod beoxo-e-dodn in laboratory animala Tavircm H v o llk P w rrpm i 1973;5:125-140. 11. Schwetx BA, Noma JU. Sparscbu CL. t a t Toridty of chloHoaled d ib e n w e -d io rin a E n v iiv n ita liA P ei rym d 19732:87-99. 11 Vo* JG, Moors JA. Ziaid JG: Toxidty of 2 2 .7 2 - la tn cb lo ctx lJb asx o -e-d iad a (TCDD) in G57B1/6 mien. T erricci A p p i P h a rm a co l 1974; 29:229-241. 13. Jones G: A blato cb em lcal tody of lba Urar lesion iodnond by 2 2 .7 2 -L e tra c b lo ro d ib a n a o -^ dioxin (dioxin) la ra ta J P a lh d 1978;11&:10110S. 1A Courtney CD. Uoore JA: Teratology (tudI .with i*2-tricbloropbaooryaeatie add and 22.72- U tra c h lo rodibanxo-ydioxin. Tbsiool A ppi P h a rm a co l 197120396-401. IS. Smith PA. Sehwati BA, Nitschka KD: Tsratogsnidty o f 2 2 .7 2 -la tra c h Jo ro Hjb a nro-edioxin la CP-1 mica. TarvcxJ A p p i PAorm ocof `lB7fi2& 517-523. IS Eodba RJ, Kays* DG, Beyer JE, et al Resulta of a two-year thro ole toxidty and on* (e n id ty atody of 22,T2-t*tnchlorodibnao-edioxin In reta. Toxicol A p p i P harm acol 1978; 4&279-303. - 17. 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