Document dYzOLpZ7m896bx3rXL16LdJGQ

71'j i ^ 7 Human Health Effects of 2,4,5-T and Its Toxic Contaminants R. R. Suaklrxi, MD, V. 3. Hartrberg, PhD A clinical epidemiologic study was conducted to dstsnnlns ths acute effects of this agent, which have long-term hsalth effects of workplace exposure to the process of manufac `been repeatedLv observed in humans, turing tha herbicide (2,4,5-trlchlorophenoxy)*cetlc ad d Including contaml- include chloracne,,>*the most consist- nanta such aa 2,3,7,8-tetrachlorodlbenzo-p-dloxln. Tha population con slatad ent clinical marker, liver function of two cohorts: 204 claarly axposad and 163 not exposed. Among tha impairment,1** peripheral neuropa- axposad, clinical svidanca of ehtorecne parslatad In 65.7% . Nona of tha not thy>l>` nervousness and irritability.1"* expoeed axpsrisncsd chloracna development. An association was found personality changes.1,0 porphyria cu batwaan tha parslatanca of chloracna and tha praaanca and savartty of tanea tarda.0'' and hypertrichosis and actinic alaatoslo of tha skin. Thara Is an association batwaan axposura and Kyperpigmentation.^-' Elevation of tha history of gastrointastinsl tract ulcar. Pulmonary function valuaa among levels of blood cholesterol.**1 triglyc thosa who wars axposad and who currently amokad wars lowsr than thosa erides,* gamma-glutamyl transcend- who war not axposad and who currantly amokad. Tha data assembled In tha Haas (GliTF),1 and alkaline phospha study Indfcata no svidanca of Increased risk for cardiovascular dlsaasa, tase have been reported. hepatic dlsaass, ranal damaga, or c antraI or parlpharal nsrvous ayatam * Toxicologic studies of TCDD in ani probisms. mals have revealed hepatotoxic ef (JAMA 1084:251:2372-2360) fects,**" teratogenic* effects,'01 sup pression of cell-mediated immunity in mice and guinea pigs," and the induc THE HERBICIDE (2,4,6-tnchIoro- enced acute symptoms characterized phenoxy)scetic add (2,4-T), first by skin, eye, and respiratory tract marketed in 1948, was used widely irritation, headache, dizziness, and until 1970 in large-scale fanning, nausea. These symptoms... subsided family gardens, forest management, within one to two weeks and were and weed control along roadsides and followed by an aeneform eruption, railroad rights-of-way. severe muscle pain affecting the The medical and adentitle commu extremities, thorax, and shoulders, nity was alerted to health problems fatigue, nervousness and irritability, arising from exposure to the manu dyspnea, complaint of decreased libi facturing process of 2,4^-T following do, and intolerance to cold.1An exam a process seddent (runaway reaction) ination of the workers in 1949 that occurred in a plant in Nitre, revealed a 1severe and generalized ,,WVs, on^jLreh_8,19^.' The accident aeneform eruption (chloracne), hepat- involved a kettle in which tiiInter-, 7 c *WOugemmti" pOTpheriti'new tiap mediate trichlorophenol was .being- delayed prothrombin *time, and in synthesized. Those employees in creased total serum lipid levels. By tion of hepatic carcinoma in rata.1* Some of the clinical reports have been concerned with the association of cardiovascular disease* and an increased risk for cancer in popula tions exposed to TCDD.IU* Several comprehensive reviews on this entire subject have been published.,w> A mortality analysis of workers exposed to the runaway reaction materials was conducted. Aa of 1979, the Standardized Mortality Ratio (SMR) for all causes of death was 0.69, with 32 deaths observed and .46.41 expected^orjths^cstegories of cancer'and circulatory diseases, the SMRs were 1.00 and 0.68, respective volved in tha deanup of the building 1953, those symptoms and findings ly " and the repair of equipment experi- Taierrabia to the nervous system ana A CLINICAL STUDY Frarn V toWtoto of D ii lro iw n S f Hm S i, LWvwWty al O ncfcwS U oJeol C ent*. n <pWS rsquatoa to krwHbta of D n Vonw ntol K e ftw to g Laboratory (H o. 6 6 ), 3 33 3 Gdon Aw, Ctnctorw. OH 483eT (Dr SutoVxQ. liver had subsided. The chloracna. 'although much improved, persisted.' In 1957, 2^,7,8-tetraehlorodibenxo- A-dioxin (TCDD) was identified as a toxic and acnegscie contaminant of trichlorophenol synthesis.1 The tub- la Jana 1979. a clinical examination program was conducted th at included the active and retired employees of the Hitro, WVa, plant, who were exposed to tha 2,4,5-T process between 1948 to 1969. The objective of the examination program waa 2372 JAMA. May 11, 1084-- Vof 261, No. 18 2.4,6-T-- Suskfod & Hertzberg i > to determtne possible increased risks, on a was carried out by the Lipid Research dence in conimgency..uhle3 were used to long-term basis, for adverse cutaneous, Division (a National Institutes of Health compare the two exposure groups snd the pulmonary, cardiovascular, gastrointesti Center) of the University of Cincinnati nal (Cl), hepatic, renaJ, neurological, Medical Center using methods of the three chloracne categories with respect to frequency of abnormal findings on phyai- behavioral, and reproductive effects; ef National Lipid Research Project," includ cal examination; pulmonary function Lest, fects on lipid metabolism and the possibil ing determination of plasma cholesterol, and lipid analyses.' Fisher' exact test was ity of increased risks for cancer. The plasma triglyceride, plasma high-density also used to' compare the two exposure population included those exposed to the lipoprotein (HDD cholesterol, and esti groups with respect to reproductive find process accident as well as those erposed mated' plasma low-density lipoprotein ings. Mantel-Haenszel analysis" was used to normal manufacturing processes and (LDL) cholesterol values. Pulmonary func Lo compare the exposed group with the not included chemical operators and service tion tests, ECG, chest roentgenogram, and exposed group with respect Lo frequency of employees, such as pipefitters and me nerve conduction velocity measurements, abnormal findings on physical examina chanics. The conLroi group consisted of performed by the method described in tion after adjustment for age group (<S0 current or former employees of the same Coodgold and Eberstein,** were done at the and :50 years) and with respect to fre : plant who. according to interview work time of the physical examination. The quency of abnormal findings on pulmo history and personal work records, were nerve conduction velocity measurements nary function test or abnormal plasma never associated with the 2,4,5-T process were obtained for most subjects from the lipid levela after adjustment for smoking or its materials. peroneal nerve for motor and the aural status. Logistic regression analysis" was S ubjects of the Study nerve for sensory function. used to detect associations of exposure Clinical laboratory analyses included with abnormal' findings on pulmonary I ? L A The total number of subjects examined blood calcium, phosphorus, blood urea was 436, There were 419 white males, five nitrogen, 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, albumtn/globuten white females. One subject among the lin ratio, total bilirubin, direct bilirubin, 419 was exposed to the runaway reaction SCOT, SGPT, alkaline phosphatase, iron, residue in 1949 as a child. The seven total lipids, sodium, potassium, chloride, nonwhite males, ten white females, and CGTP, complete blood cell count and dif the white male exposed as a child were ferential cell count, thyroxine radioimmu rcluded 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 coproporphy- not include work in the 2,4^-T production nn and roporpbvnn values. (Values were process. They are not included in this ' determined fmn| single void sample; nalyria. The remaining 367 subjects were "hence, the memomenta cannot be re Irjignated by exposure as follows (1) garded as valid.) function test after adjustment for pack years smoked. Log linear models" were used to detect associations between the three chloracne groups and abnormal plas ma lipid levels after adjustment 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 56.7x0.7 (XSE) years and 46.2x1.0 years, rpoaure without qualification: 204 sub jects who were involved in any aspect of Analysis of Data respectively (P<.0001). The two groups were found to be significantly the production of 2,4,5-T, including main Data from questionnaires and the sub different with respect to employment tenance from 1948 to 1969; and (2) no ject's medical history worn coded by status and highest educational level exposure: 163 aubjeets' currently or for assigning numerical values to the re achieved (Pc.OOOl). In the exposed merly employed a t 'the tame plant but : : never, aasociated with any aspect of 2,4,5-T production or maintenance of the produc tion facility. All living employees, active, retired, or sponses given. The subject's medical his and not exposed groups, 34.8% and tory and findings were coded using the 13-5%- were retirees and 9.8% and Systematized Nomenclature of Medicine" System. Laboratory data were eDtered as received.-Data were keypunched and veri ' 0.6% were terminated (left voluntari ly or laid off), respectively. Among terminated, aa determined from company fied. The computer data were compared the exposed and not erposed groups, records, were aaked to participate. To with the original files for accuracy. The 9.4% and 1.2% reached no further L constitute cohorts of the target sample Statistical Analysis System** computer than the eighth grade, respectively; site, all those who volunteered participa package was used for data analysis. As the 7Z4% and 56.8% had some high tion in the study were examined: thus, it was not possible to randomize the selec tion of participants. Of the living exposed personnel, approximately 61% voluntarily participated in the study, as did approxi mately 46% of the living not exposed analysis progressed, editing continued to ensure the greatest possible accuracy. Multiple linear regression analysis" was used to compare the exposed group with the not expoeed group and to compare the three chloracne subgroups with respect to school education, respectively. Among the not exposed, 42.0% attended col lege, some to completion, while among the exposed, only 18.2% attended college. , . personnel The, only mortality data avail- plasma -lipid-lavels,.. pulmonary ..function ble for analysis a t the time a t this study values, clinical laboratory values,-and Alcohol -and Smoking; ' - .......r were for personnel who were exposed to nerve conduction measurements after ad History of alcohol consumption was the runaway reaction materials." justment for covariable*. The corariables not found to be significantly different Clinical Examination The interviews and clinical examination with informed consent were conducted during the week July 11 to 18, 1979. in Winfield. WVa. were age is the analysts of clinical labora tory values and nerve conduction measure ments, age and smoking status (never, former, and current) in the analyses of pulmonary function values and age, and amoking status and alcohol status (never in the two groups. 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 The routine laboratory.analysia of blood used, formerly used, and currently used) in icantly longer than the not exposed - and urine warn"completed by Metpath. the analyses of plasma lipid values. Fish by 19 pack-years (.0001<P<.001). Blood plasma lipid -fraction examination er's exact test" and the x` test for indepen Among former smokers, the exposed JAMA, M ay 11. 1 9 8 4 -- Vol 2 61. No. 18 2 ,4 .6-T -- SuakJml & H eftzbafp 2 373 group had smoked longer thao the noL exposed group hy seven pack-years T a b U t . -- H iatory of M adical ProW tona v E a p o a u ra S ta tu a a n d try A ga (.O S c P c .lO ). T h is reflected the tenyear age difference between the exposed and the not exposed group. H istory of M sdlcal Problem s H M ory C M oracnaft E arn -- *. % |n -J 0 4 )- 80.3 Mot Sapoaad. % (h-143) '0 ,0 A ga < 8 0 jrr, % T jpoaad (-81) 78.8 ` Not F .a p o a a d (n-10O J 0.0 Aga * 8 0 p , \ gapoaart (-183)* 09.8 Hot Expoood* < * - 3 ) 0.0 The comparison of the exposed and not exposed cohorts for self-reported history of illness 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 to r* Skin c a n car H yparM ntoont * Angina B Coronary artary r tta O iiH Uppar gaafroinlaattnal tra d lAOarf 9.0 3.0 34.8 7,4 10.S 20.7 79.8 2.5 24.8 0.1 0.1 5.5 17.7 0 .0 21.8 5.9 2.0 13.7 43.0 1.0 10.0 1.0 0 .0 7J 5.3 38.8 7.9 ' 13.8 5.0 ' 23.0 9.8 4.8 38.1 14,3 IS.B 8.4 about the history of chloracne were determined on the basis of statements Carrear at a J U N * '* Uni 3 .0 1 J 0 .0 0 .0 1 9 ' 3 J from subjects that an acnelike erup tion called "weed bumps" appeared after an assignment to a 2,4,5-T pro *0>>a ot Ota 2 0 4 o b ra d dd not eom pata th a tn lan n o w /p fty iicaJ .M m nanon p ro g ram b u t h ad a docum arriad o d m a n 'i corroanaation d av n lor cM oracna. t ^ < . 0 0 0 1 ; P v a to a tor UarHa^ H aankia4 com p * n o o o t a a p o a a d r n o t a a p o a a d croa* g a atra ta . ( . 0 1< P < . 0 f i : in x p o aa d ; young v oW. by F ta n a r'i a a a c i la to ; 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 1.001 < P < . 0 1 : P v al a tor U am a t-H a an atat o o n o a n a o n ot a i p o a a d y no a , pen ad ac ro o a a g a atra a . 0 3 < P < . I 0 ; In a a p o a a d . y o in q v o to , by F iatiar'a a a a d (aal. ^ P < . 0 0 0 l : in no a a p o a a d . yoerig v o to , by F iab ar'a a a a d taaf. ,OGl C P C .O I ; in n o t a a p o a a d , young v Oto. try R a t W a a u c i la a t. **Vt th a a a p o a a d p o p , H aflrtar c a n o ', to o ; o oton c a n o a r, to ra ; p ro a la ia c a n c a r, o n a ; n th a not a rp o n a d gnoup. btaddar c a n car, orta; m atanom a. orta. histories. In the not exposed group, a history of acne vulgaris was reported more frequently than in the exposed Tabla 2 .-- Complaints ot Norvouartaaa and Saauaj Proclama to Examining Ptiyaician or (nlarviavvar 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 Corn p lain ! rpnaad. v (o--3D3) Mot eapoaad, % ( -te s ) Apa < 8 0 y r, % Hoi fygm ad fjpnaad (N-81 <n-10O) Apa & 6 0 y r, % ' Not Expoood Eapoaarf ( n - 1S2) (n--S3). the exposed group. When the medical aruriaty / dagraaaion * 18.3 11.7 7.8 15.0 19.0 8.4 history of the exposed and not Oaeraaaad B d o ttt r5 5 T } 18.3 19.8 1 0 ` 40.B S t.7 exposed was compared for two age groups younger than 50 years v 50 kfnpotanci, no4 oltW M H pacMtodll (<''' 27,0 J 11.7 7.8 2.0 14.2 27.0 years or older, a history of coronary artery disease and of hypertension were related to age, not exposure. * ,O 5 < /1< .1 0 : In axpoaad. young ve to , by R afta r1 aaa ct la a t. t. O O K K . C l; to r lia n ta l H aa n a ia l com pa/toon a t aapaaad to n e t arp n aad acroaa aga a tra ta . (Mlt/^ c .0 0 0 i: In nor aapoaad. young v o id , try F W a t'i m e t |.O O K P < .O t; In a n jo e e d . young v o id , by Raher* e xa ct te a t. Among the not exposed, angina was A O O O K /V C .O O t; In aypoaad. y o io g v e to , b y ra to r* aaaet le a l. significantly related to age; in the history of upper GI .tract ulcer, how by the older age group (Table 2). depression/anxiety.for exposed over ever, exposure, not age, appeared to As noted in Table 1, the reported not exposed. Although the sample size be a factor. history of skin cancer, hypertension, was sufficient to detect crude differ Closer examination of onset of angina, coronary artery disease, and ences between the two groups with ulcer in relation to exposure revealed cancer of all sites (except skin) was respect to complaint of impotence, the six subjects whose symptoms oc not found to be significantly associ difference disappeared when age was curred before exposure. There were ated with exposure. The sample size considered. also four subjects whose symptoms obtained was sufficient (at signifi The exposed population was catego occurred while they were receiving cance level of .05, power of .80 [proba rized into three subgroups, ie, those corticosteroid therapy or high doses bility of detecting a true difference]) who never had chloracne develop of aspirin or that were attributed to, to detect a fourfold increase in skin (n-2S), those who had a history of chronic alcoholism. If these ten sub cancer, a twofold increase in hyper chloracne only '(n-69), and those jects were omitted from the analysis, tension, a threefold increase in angi whose chloracne persisted (n"107). there remained statistically signifi na and coronary artery disease, and a When the histories of medical prob cant differences between the exposed sixfold increase in cancer of all sites lems were examined in relation to and not exposed groups (16.6% v (except skin) for exposed over what chloracne status, hypertension and 5.5%; P^.01 on age adjustment). was observed in the not exposed. As coronary artery disease were found to The complaint of loss of libido noted in Table 2, the complaint of be age related, not chloracne related. occurred more frequently in the nervousness/depression/anxiety and Histories of skin cancer and angina exposed group than the not exposed the complaint of impotence were not were not statistically significant group. When age was considered, the related to exposure. The sample size when related to chloracne or to age largest number of complaints of lose was sufficient to detect a twofold within the chloracne groups. While it of libido or impotence were reported increase in complaint of nervousness/ would seem (Table 3) that skin cancer 2 3 7 4 JAM A. M ay n , 1004-- Vol 25 1 . No. 16 2.4,5-T -- Susfctnd & Hertzbero L. Table 3 .-- H istory o l M e dica l Problem a v C hloracne S tatua in Exposed O nly and by Age CM orecne Stall*, X C*Yi.T. !I '*'. : H tilo rf" Acna woman* SUn cancer H yparleniont Angina Coronary artery dieeeeet Upper gaahux H eilx m I tract lAoer Cancer ot * n ie s (except akin) M alory O n ly (n - a ) a.a 6.0 35 3 5.0 8.8 ie.2 44 Current ( n - 107) a.s 3.9 38.3 10.3 14.0 35.2 2.8 Ha H ia to ry (n -2 B ) 75.0 3.6 17.0 0.0 3.6 14.3 00 M ta fo ry Only (n -1 9 ) 16.8 0.0 6.3 0.0 6.3 a.3 0.0 Age < 5 0 yr Current (**-33) 6.7 0.0 34.8 13.0 0.0 21.7 0.0 No M alory (n -1 2 ) 33.3 0.0 ia.7 0.0 0.0 a.3 0.0 M alory Only (**-62) 4.8 7.7 44.2 7.7 06 10.2 5.6 Age S SO j t C urre n t (n -S 4 ) 6.0 3.6 30.3 0.5 17.0 26.2 3.a No H istory <n-16) 18.8 ' 83 - ia.a,' 0.0 6.3 18.6 o.o "AJ eom panaona ot m e ffve* eN o raen e u l t g o o M , both tor th e total group and tor tha two a g e groupa, w ere found to b e not aignifteanl by y ' laaf tor in dapandanca ri connngancy labia*. | l < F < ,0S lor hiatory onty. yoing old by y* laat for independence in contviQency l*b*ee. t 0 5 < P < . 10 tor cixrenl, young void by j 1 laal tor mdependenea in contingency labia*. i` is related to age in the three chlor- arne groups, the number of persons 'J ,n> in the age group younger than SO years was too small to achieve statis tical significance. There was no asso ciation between the history of upper Tabla 4. -- Significant Clinical Findings y E xposure S tatus and by Aga Finding Expoaad, %, (n-203) Expoaad. % (n-163) Age <SO yt, % Expoaad (n-51) Not Expoaad ( n - 100) Aga i a p , \ Hot Expoaad Expoaad ( n - 152) (n -6 3 ) GI tract ulcer and chloracne status CNoncn*" 52.7 0.0 45.1 0.0 55.3 0.0 ii 1 (Table 3). While the number of subjects reporting history of cancer (other than skin) was small, all of them were found in the group aged 50 years or older, and the percentage in the exposed group was not 31gnlflbAnEIy Acne vtAgartattf Actinic aiaaioeie'^ 17 BaaeJ pel a p M o n e f ( Peyronie's < * aee^ MnuOam 2.0 SO 1 6.0 dJ> 6.4 11.7 30.1 4.3 0.0 1.6 7.6 37.3 2.0 O. 3.0 16.0 0.0 1.6 16.0 66.4 40.2 0.0 8.6 11.1 0.0 r T q p 0.0 1.0 5.0 3.2 */*<.0001; F vaiua for Uardaf Haanaiaf oompanaon of exposed y not axpoaad taroaa aga strata. t.0 6 < F k<.tO ; P v-aJua for Mantaf-Haanaxaf oompanaon of axpoaad ynot axpoaad across aga strata. I.O O O K fK .O I; In axpoaad. yowtg y old, by Fiabar'a a sect laal. different from that in the not exposed group (Table 1). The three blatfiiir I.O O K P C .O I: In not axpoaad, ytxng void, by R abat's axact laal. 1.000t< P < .0 0 1 ; P valua for Mental Haanaxat oompanaon ot axpoaad y not axpoaad acroas aga', cancers were reported by persons f.O O O K /^ .O O l; In axpoaad. young r e d . by Fisher's axact laal. y; txposed to p-aminobiphenyl, a rubber M P<.OOOI; In not axpoaad. young old, by Rahar'a exact laat. additive that was also made in the plant. 52.7% still had chloracne, 62.6% were acne vulgaris is usually very oily or Physical Examination Results mild cases, 33.9% were regarded as greasy. In the case of chloracne, the moderate, and 3.8% were severe. skin surface is usually dry. Persons There seemed to be no difference in The diagnoses of chloracne and with acne vulgaris, exposed to chlor- blood pressure findings between the acne vulgaris were made by qualified acnegens, may experience the devel exposed and not exposed group. The dermatologists. The criteria for diag opment of chloracne. The lesions of ? criteria for determining normal for nosis of chloracne include the initial acne vulgaris may increase in severity *j combined systolic/diastolic values appearance of comedones, milia, or and lesions may develop in sites not were less than 140/90 mm Hg for epidermal cysts on the malar, temple, usually or previously affected by acne subjects aged 59 years or younger and and periorbital areas that may subse vulgaris. l>'vi than 160/95 mm Hg for subjects quently involve other areas of the Among the exposed, 59.1% were K(;d GOyears or older. For diastolic face, the neck, forearms and arms, found to have actinic elastosis in al imc, less* than 80 mm Hg was con and scalp and genitalia. The scrotum contrast to 30.1% among the not sidered normal. Diastolic values of SO and penis are commonly affected in exposed. There was a significant dif to 89 mm Hg for ages 59 years ^and persona whose clothing becomes ference in the occurrence of actinic i- younger and 80 to 94 mm Hg for ages heavily contaminated by the acnegen- elastosis between th exposed and not 60 years and older were considered ic material. Lesions may become sec exposed in both age groups even i borderline. Diastolic values of 90 mm ondarily infected, especially on the though age is a factor in this clinical I* Hg or greater for ages 59 years and trunk, forearms, and genitalia. By finding. Three cases of Peyronie's younger and diastolic values of 95 mm contrast, acne vulgaris that usually disease were observed among the 204 ? Hg or greater for ages 60 years and starts in adolescence 8 seen as exposed. All of them had chloracne at older were considered high. inflamed papules, pustules, and come some time and they were all older The significant clinical examina dones, on the perinasal area, cheeks, than 50 years. Peyronie's disease is tion findings as related to exposure chin, neck, and back. It rarely, if ever, characterized by induration and scar status and age are found in Table 4. starts on the malar or periorbital ring of the corpus cavernosum of the Of those who were clearly exposed. areas. The skin of the affected sites in penis, producing distortion on erec- v: JAMA, May 11, 1084-- Vol 25 1 , No. 18 i** 2 .4 ,6-T -- Suskind & Heftzbaro 2 3 7 5 Table 5. -- Significant Clinical Finding v C hloracne S ta tu s in E xposed Only an d by Aga Fin J n q Acria nAoana * Acanta 'til S a u l C-4 aormaloma Payrorta'a dNaa MrsulNfllt Mfotory Only, % (n -e a ) 1.5 47.1 5.0 a.s 0.0 Currant, 41 f a - tor) 0.0 74.0 0.4 0.0 10.3 Ho Htatory. (-2S J 10.7 30.0 3.0 0.0 0.0 A ge < 9 0 yr, 41 HUtory Onty (* -1 0 ) 0.3 31.3 0.3 0.0 0.0 Current (n-23) 0.0 50.3 0.0 0.0 0.7 He Malory ( a - 13) 35.0 0.3 0.0 0.0 0.0 Age aSO yr, X Htatory (Wy (n-S J) 0.0 51.0 50 3.0 0.0 C tm nt (n-64> 0.0 70.0 10.7 1.3 <0.7 He H tilorf (n-101 0.0 43.0 0.3 0.0 0.0 * .0 K R < .Q 5 ; tar OvaraI dHfaraoc a a baO aaan tn a fftrae tfifo racn e categora ta a g a 40 y a a rt or yma^gar. by y* ta at for fodaoandanca in oontm gancy labtae. t.0 0 0 1 < R < . 0 1 ; tar ovara I ctlfai a o c a a b a f a a a n tb a rh ra a c h to ra c n a e a ta g o rla a in a g a 0 0 y a a ra or ofoar. by y* la s t ta r in d a o a n d a n c a in coo tin o an cy fib * aa. 1.01 < P < .O f. fo c u r a r a c f ta ra c n a . y o v O r e t d . by F ta b a r'a a a c t la st. |. O S < / 1< .iO ; in n o N arary of ch fo rec n a. y o u tg r o k l , by FiaN ar'a a u c l toar. Table 6 .--Exposure v Plasme Upids Expoaed Not Expooad Plaante U pid* O o U titid rn^yoartaa L ow ^antify km crgiairt tfiofoelarof 1V jn-danaay Ipognotain eJ4atan4 n X=se 300 311.1513.53 300 I4S .S 0Z 7.44 100 130.74 Z 3.40 300 40.03 0 .0 1 % Out of Rang* 7.5 14.3 7.7 0.0 n XzSC. 1S3 304 0 7 X 3.97 1S3 150.03 Z 7 .7 3 150 127.00 Z 3 .0 0 103 44.23 z 0.77 X Out of Range* 10 4 19.0 0.3 10.4 P V alue NS KS NS NS "O afereoca rang* tar plasm a eh o lailaro l. trigtycarida. an d fow -danaity Egoprotaat tfio laataro f w ar* d a f n a d a a laaa tn a n th e a g a -a p a c ite OOth p arca n td a a a d aiam w iad by tha K ahonal Lipid R ee aarcfi Prot'acf. R a fa ra n c a ran g * for high-danarty Ip o o ro lain cTtoiaatarof v a r a d efin ed a a ab o v e tb a ag a -a p a o A c le n m p * rcan t4 a aa d alao ran ad by th e M abonsf Lipid R a a a a rc h P rotect. lion. 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 tailors* skin). 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. Ptaama Uplds Plasma cholesterol, triglyceride, LDL cholesterol and HDL cholesterol were classified by age-specific percen tiles as determined by the National Lipid Research Project data." Plasma cholesterol, triglyceride, and LDL cholesterol valoes were classified as out of range 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 size 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 adjusting for smoking status, no significant differences were found. The mean Upid 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 status, there was a sig nificantly greater number of subjects with low HDL cholesterol levels in those with persistent chloracne than in those with mhistory 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 Upid values, the same adjust ments described previously were per formed. No significant differences were found. Log linear models were used to detect association between frequen cy of out-of-range lipid values and chloracne atatua 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 6 JAM A, M ay t l , 1064-- Vot 2 5 1. No. 10 2.4,6*T-- Su kind & Hartzberg Tabl 7.--CMoftcna Slatua in Exposed Only v Plawrta Up*da Rmim LW Chef1roi TrtQfyoeride Lm-d*ni(y Upog*<M*ai cftoteaieroif fegnovfwTjr ipoprwiei Cfioieaiarot* Watery Only X Out A Xxse at Rang* 07 2 IS. 10 X4.67 1i.a 07 144.00 X 14.M 7.6 M 142.64 X4.00 15.2 67 46.04 1.17 3.0 Currant X Out n Xxse . el Ranga* 106 210.2 3 X3.17 4.6 106 163.64X0.30 10.1 103 134.48 x 2.66 2.9 106 44.03X1.31 14.3 He'Htatnry X Ou n XxSC ' et Roogof. : 26 204.06x 7.13 7.1 2fl 140.1 IX 1036 14.3 27 130.00 X7.06 7.4 2S 47.76X3.31 7.1 'R a la ra n c a n n Q * i Iw p laam a che*aelerel. tritfy e e d a . a n d lo w e a o a rty WpopriTtatn etiotoalarol a w tfaAnad ta a a th a n Dm a g * -* p * o 6 c OOtf paroanM a aa dalarm nad by ti*a NattonaJ U pid R aaaaro fi P ro jac l. fla Ja ro n e * ra n g a a tor higft-danaiTy Kpopraiatn d y jJa a la rc t w a ra d afin ad a a abb* tt*a ag a-ap acrflc lantti p a rc a n rta aa dalarm inad by tha National Upid R aa aard l Prci aet. t P < . 0 I 8 : t o com paring freq u an e y o* owl-Of-rtnQa tr r a ta in tb a rtv aa e N o racn a groupa. tP<.O S; tor com pastng freq u an e y at OtA-ct-tano* laveie tn Ihe Ihraa cM oracna groupa. with chloracne status (.OKPc.QS), two exposure groups after adjusting rotic changes and pleural thickening and the degree of association did not for the effect of smoking (Table 9). No differences between the groups vary significantly by smoking status. difference was found between the two seemed to be age related, not expo-' (3) Out-of-range LDL cholesterol val exposure groups with respect to sure related. ues were associated with chloracne FEFu.,, percent predicted. Percentstatus (.01<P<.05), and the degree predicted values for FEV,/FVC and Neurological Findings and Narva of association did not differ signifi FVC were significantly lower in the Conduction Velocity Measurements cantly by smoking status. exposed group. Furthermore, there When exposed and not exposed Pulmonary Function Examination was a significant interaction between groups were compared for frequency smoking status and exposure with of abnormal findings on neurological Both forced expiratory volume in respect to FEV, percent-predicted examination, no differences were 1 s (FEV,) and forced vital capacity (FVC) were considered abnormal if values. When adjusted group means for each smoking status exposure found. Nerve conduction velocity measure the observed value was less than 80% combination (Table 9) were examined ments require controlled atmospheric of the predicted value of Morris. A to determine the nature of the rela conditions and uniform conditions of ' FEV./FVC percentage less than 70% tionship, no significant differences testing.' Ambient and body tempera was considered to be abnormal. The were found between exposed and not tures were recorded. With the tech forced midexpiratory flow rate exposed workers who never smoked o r* nology employed, it was at best a (FEF,,.,,) was considered abnormal if the observed value was less than 70% who formerly smoked. Among current smokers, however, there was a signif screening procedure. All subjects reporting diabetes or of the predicted value of Morris. icant difference between exposed and reporting a high weekly alcohol Consistent differences in abnormal not exposed workers with respect to intake (^35 oz. of alcohol per week) pulmonary - function valnes (FEV,, * FEV, percent-predicted values. were eliminated from the data analy FVC, FEV,/FVC, and FEF,,.,,) were found when the exposed and not Clinical Laboratory Findings sis. After these deletions, there were 278 with complete sural and 294 with exposed groups were compared (Table With regard to clinical laboratory complete peroneal examinations re 8). Among current smokers, there was determinations other than plasma maining. The data from the nerve a significant difference in frequency lipids, no significant differences were conduction velocity studies were cor of abnormal pulmonary function val detected between exposed and .not rected for body temperature accord ues between* the exposed and not exposed groups. There have been ing to the deJesua1' method. The age- exposed groups, but there were no reports of abnormal levels of alkaline adjusted values are presented in differences among persons who have phosphatase, SCOT, SGPT, and Table 10. No significant differences formerly smoked or among persons GGTP in other populations exposed to were found when the two exposure who have never smoked (Table 8). Logistic regression was performed TCDD for short or long periods; how ever, no differences were found in groups were compared or when the three chloracne groups were com to evaluate, the.relationship between frequency of abnormal pulmonary these' cohorts ten to 30 years after the last date of exposure. pared. ----- function values and exposure after adjusting for pack years smoked. Odds ratios are given for these ECG and Roentgenographlc Findings Reproductive Effects Information on reproductive fac parameters in Table 8. Exposure sig No differences were observed in the tors and birth defects was elicited nificantly increased' the odds for ECG findings when the exposed and from the male participants. Neither abnormal pulmonary function values not exposed groups were compared. physician nor hospital records were even after adjustment for pack years When the chest x-ray film findings in available to confirm the information. smoked. the exposed group were compared A comparison between the exposed The means of the percent-predicted with those in the not exposed group- and not exposed groups, for pregnan aloes were compared between the and separated by age, the arteriosde- cies, live births, infant deaths, mit- May 11, 1 0 8 4 -- Vd 2 5 1 . No. 18 2 .4 ,5 -T-- Suakind & Hertzberg 2 3 7 7 Tabla 9 .-- Expsure Group M aane ol Per cent-Predictad Pulmonary Function P aram eters Adjusted lor Sn^oking S tatua Function P aram eter FEW,' FVC* FEV./FVC % S--uUrif Statua Never F orm ar P anni Total CltoMd Sse 107.123.06 101.432.03 09.832.22 (.39 1.43 93.73 1.17 70.490.03 101.00*4.02 Hoi Expoeed lise 106.933.03 <04.902.16 <02.332.66 104.42 1.67 97.60 US 79.930.00 109.104.30 F NS N3 0.0006 0.0104 0.0064 0.0002 MS ' r FWi W c i i M lorcad ax p in to ry votom a In I i : FVC. I m d vital c a p a c ity ; F E F ,,.,,. fo rced m idaxpiratory How rata. Tab*# 10.-- M ain Narva Conduction Velocity* for the Exposure Groups and lor tha Chtoracne Subgroups . Category Expoaadt SSC(n) Mat Expoeed S 3E (/0 CMpmene. hiatery orVyf XSE(n) CWomove. curar* 2 SC (nj CNonma, na ,ar XS(n) Ulnar 50.00 2 JO (9) 01.91 2JO (91 50.92 6.02 (3) 67.BS 4.11 (8) 92. 10 0.00 (t) n*------ ^ 1-M*V- QPa ran aal Sural 41.77 0.47 ( 100) 42.00 0.49 ( 160) 42.02 a 62 (1641 41.49 0.64 ( 126) 40.00 0.77 (60) 41.14 0.90 (61) 41.38 0.00 (M> 41,37 0.78 (74) 40.81 1.12 (24) *' 41.23 1.30 (26) `A d iu M d lor *g. n o i aagnifcant lo r ocviiparfcan o( i ip ow d a rth n o i aapoaad w illi m ap ac l to ukrvar, paranaal, and ttn fc and d io lo r oom padaon o f tho B m a cN onacrta c H ija r iM M i ra ap n to lin o r, p a n n a a l, and a n i. ditions, at the same plant and/or other plants, between the late 1930s and 1979. Rubber processing chemicals iden tified by the subjects as other expo sures included diphenylguanidine, the benzothiazolesulfenamides, deriva tives of m-cresol, p-phenylenediamine derivatives, and 4,4-dithiodiraorpholine. Additional chemicals named were ethyl parathion and methyl parathion, phthalic anhydride, <r- and p-dichlorobenzene, a- and p-nitrophenol, toluene and mercaptobenzothia- zole derivatives of tetramethylthiuramdisulfide, and trimethylquinoline components. Seventy-nine subjects, or 21.5% of the 367, reported n-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 p h y si cian. The data relating this exposure to 2,4,5-T are described n Table 12. carriages,' birth' defects, and still births is listed in Table 11. There Other Work Exposures of the Study Population were no significant differences in t Other than 2,4,5-T and ita interme these parameters between the ex diates and/or contaminants, all of the posed and 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 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 3 7 8 JAM A. M ay I I . 1964-- Voi 2 5 1 . No. 18 2 .4 ,5 -T -- SuaWrvd & H ertzberg (ou*. tfy ) i M n d d H ide*, OonQwWai h r * t x * i e . 0bs*-uc9v cM * cta erf i r t w y a . dU> locrf. :o n g m t* J */wrt Wg. > n a n l i o d m j m , Down* t ^ n t n i w , hem ie, an d angiom a. tIn irta not aaooaad. faporlad birth d i l i . u Inc** MAd*. oongarrfta l a n o m a i t t trf wym. pcfvyw c <*>*, d t M M , an tral M b , eb a tn jeth m d a ta e ta o irln a n r ra d . c* jO to o l, a b a a n o a o tingara, o o n o o n aai d'*ochon o b ^ a . c r ane hygrom a, Om d i' i i f n d g n a , an d Sarnia. I f h a g r l a a n u a a in r u n b a r (IS O v 20rf tor a a p o a a d an d t&S v 183 tor not t j p o a t r f ) a ra du* to m an W w M r a antOaaa or m an who d d not rta p o n d (tw o n an ra* p o n d * ra In 9 m n o t a tp n a tr t. thraa In lh* a a p o a a d ). tFlgura* ara rmrfuaty ax d u aira. United States, particularly for long- may have been exposed to 2-A5-T, the term follow-op, randomization and contaminant TCDD, and other chemi participation requirements for pris cals varied markedly. Subjects re- tine epidemiological protocols are ' ported exposure to the 2,4^>-T process rarely satisfied. In this study it was for as little as one month to as long as not possible to match the exposed and 20 years, and exposure was often not exposed groups demographieflily intermittent over a period of years. It on basis of age, employment status, was difficult to accurately designate and education level. Although the two the duration of exposure for many of groups were defined on the basis of these persons. The data do not pro-* definite exposure to 2,4*&-T process" vide characterization of incidence or and no evidence of exposure to dose-response relationship. anywhere in the plant, no intorma-" Data obtained* from interviews and tion was available about levels o f' clinical examination! conducted by 2,3.7,&-TUUU in the worX environ different physicians have inherent ment or in the trichlorophenoi that biases. Nevertheless, the available was produced or In ihe final product,' populations provide useful informa ^ r5 -T . Sint .y w was used ubiqui- tion on the prevalence of biologic tousiy^ia a weed killer In many gar effects in the population exposed, as dens and farms,, the possibility of compared with those who were not exposure to some TCDD between IMS exposed to the 2,4^-T production. and 1969 exists for both groups. There A comparison of manifestation of is current analytical Information effects to TCDD toxidty in humans demonstrating that dioxins including as observed in this population with 2,3,7,8-TCDD may also be present in those observations made in experi tbe community environment in By ' mental animals most also consider ash and, flue gases1" 1 from incinera the acute, subacute, and chron tion of domestic garbage and indus ic effects in humans already re* trial chemical wastes.*"* ported.1'**" The degree to which each subject The subacute effects of TCDD tox- Icity in the group of exposed persons as described in the reports cited in the references were characterized by cutaneous, hepatic, and peripheral nerve damage. In other populations, where hepatic changes were observed as a clinical subacute effect, elevated levels of SCOT, SGPT, and GGTP were reported." *" Doses of 1.0 *ig/ kg/diy 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~levulinic add.1* The effects on the thymus have not been noted io humans, although there have been some reports of elevation of alkaline phosphatase and AALA levels in 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. Tetracblorodibenzo-p-dioxin was found to ioduce cancer of the liver, lung, palate, and nasal turbinates in rats.'4An 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 lation. Cancer of tbe liver was not observed in this study population, nor was an excess of drrhosis noted. High doses of TCDD (30 ppm), administered orally or subcutaneous ly, in pregnant mice' and rats may increase the inddence of cleft palate in mice and cystic kidney in rats." No teratogenic effects were observed in rabbits receiving 10 to 40 mg/kg of 2.4.5- T containing 0.5 ppm of TCDD or in rats receiving 1 to 24 mg/kg of 2.4.5- T with the same TCDD content.1* It has been demonstrated that hyper plasia and ulceration of the gastric mucosa occur in monkeys after lethal doses are administered.* In this study population, a statistically significant increase in the history of upper GI tract ulcer was found . when the exposed were compared with the not exposed. Birth defects as reported by partic ipants in this study showed no differ ences statistically between the ex posed and not exposed groups. In rhesus monkeys receiving 500 parts per trillion of TCDD, early abortions and inability to conceive were ob served.*" 1These effects have not been * * * * * , M ey 1 1 , 1084-- Voi 26 1 , No. 18 2 ,4 .6-T -- Suekind 1 Hwizbeco 2 3 7 9 observed in this study population. This study indicates that the pilose- baceous effects of exposure to the 2.4,5-T process were persistent in S3% ot those exposed. The effects of the person' Ida Blanch Suekind; Pam W inner. C arol W arre n ; C h ar lotte O abom*, RN: La* R afalaa. PhD ; 0 - o El Dolio: A. B. S m ith . WO. Gao nr* W. H a m b ric k . J r, MD: C hari* L Haton. U D , W ayoa El B aum an. WD, and Daojl F. Richfield. UD. 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 Rotoron co a 1. Aaha W, Sunkind RR: Chloracne a m of tba U ooaanto Chemical Company, Nitro. Weal Virginia, in R iporta o f ih* F ettering Laboratory, 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 elastosis with the occur rence and persistence of ehloraene. This can be interpreted aa increased susceptibility to LTV radiation dam age. There was an association of history of upper GI tract ulcer with exposure. University of Cincinnali, Orto bar 1949. April 1950, July 195X Z Kim m if J, Srhiilx KJL Cbiorioatad aro m al ic cyclic atb ar aa a catiaa of so-called chlorscn* N atururi**m *chafien 19S7;44:337.33X X Goldm ann PJ: EUtramaly avvera chloracne du to tri ehioro phenol decomposition products: A contribution to tba parsa problem. Arheiteraed Soeiolm ed A rbeitahyg 19727:12-18. A Jiraack U Kaienslry J, Kobeck K, et ai* Acs* chlorine, porphyria cntaoaa tarda and other m anifestations of general io lorica Liao duriog the maoufactor* of herbiddea. part Z Ceri Dermoiof 1974:49:145-157. 5. Croi* KJ>. Chloracne--an up to date aaana- 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 who chloracne per raeoL A aa Qcewp H yff 1978^1297-298, 6. O liver RU: Toxic effects of 2JL7.8-iitr- chlorodibem o-l.i-diorin in laboratory worker* B r J Ind M od 1975;349-5A 7. Bleiberg J, Wallen U, Brod k in R. et al: Industrially acquired porphyria. A rch D erm atol 19649:793-797. 8. Poland AP, Sm ith D. Metter G. et ah A health su rw y of worker* in a Z*-D and 2 4 J-T plane W ith aperial attention to chloracne, porpbyria cutanea tarda, and psychologic parame ter*. A rch E n v iron H ealth 197122316-327. 9. May G: Chlorscne from the accidental pro duction of tetnchlorodibeoxo-^-dioxin. B r J Ind Mod 197290276-283. 10. G upta BN, Voa JG . Moore JA . et al: Pathological efforts of XX7,S-letr*chlorodibn10-r-dioxia in laboratory anim ala /Tataro H ealth P rrrpect 1973*125-140. IL Scbwetx BA. N o m a JU . Sparachu GL, et ai* Toxicity of chlorinated dib*iuo-*-diorin E nviron H ealth P trip s c f 1973*87-99. sisted, there was a higher frequency of low HDL cholesterol values. 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 exposure groups with regard to plasma lipid and lipo 11 Vm JO , M oon JA . ZlaU JG: Toxicity of 13.73-tatrachlon>dib*Bxa-*-diox)n (TCDD) in CS7B1/6 mica. Toxicol A ppi P harm acol 1974; 29:229-241. IX Jones G: A hirtochemleml etndy of the li*er lesion induced by 23,73-tctnchlorodibenxo-pdiorin (dioxin) In rata. J PatKot 197B;116;101- 105. .... IX Courtney CD, Moore JA: Teratology stud ies with 2,4-trlchlorophnoxy acetic acid and X 3.73-tetracb lo rod!bearo p dioxin. TVxrieoi A ppi protein values. There was an association-of altered pulmonary function values, especially FEV--in those who were exposed and who currently smoke. This suggests Pharm acol 1971*0*96-401 11 Sm ith PA, S chw rti BA. Nitaehke KXh T eratogenicity of 23,7,8-tetrschl orodi baoxo-edloxin la CP-1 ratea. Toxicol .A ppi PKormaeol ' 1976*8:517-62X 16, Korib* RJ. Keyes DG, Beyer JE . et el: Resulta of a two-y*ar chronic toxirity and onoo- the influence of the number of pack genicity etsdy of 2A 73datrachiorod)beasn-r- years smoked as well as exposure. dinrin la rata. Toxicol A ppi P harm acol 1972; 46:279-3GX - There was no evidence n thin stndy - 17.. Axeiaon O, Sondali L* Herbicide xpoeura. - 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. Thia tody waa supported in p a rt by grants from the National Institute of Environm ental H ealth Sciences (ES-00169) and th e Moni an to Company and funda 0/ tba Inatitnta of E aviroam antal HaaJth. In valuable u d i U a e i In carry!Of out tba exam ination waa provided by m any m ortality and tum or Incidence An epidemiologi cal InreetigaHoei on Swedish railroad workera W ork E n vi ron H ooltX 1974JL21-2&. IX HardeU L: M alignant lymphoma la histio cytic type and axpoeurs to pbenoxyacetic adds or chlorapktteli. Lanaet 1979**6-56. 19. Young AL* Calcagni JA . T halkea CK. e t al: The Toxicology, E nvironm enta l F ata, an d H o m an R ich o f H erbicide Ora090 and I ti Associated ' D ia n a , technical report TR-78-92. Baal report. Brooks A ir Pores Baa, Tax. US A ir Force Occupational and Environmental Health Labo ratory, 1978, pp 1-247. 20. JR B A ssodata: R enino t f L iterature 0 //erbicida, Including P K rncxy H erbicide and A toonatod O u m iu Washington, DC, Veteran* A dm iniitntioo Dept of Urdicine and Surgery, October 1981. Zl. TV* H ealth Effort* o f 'A f/ent Ora no* ` and Polychlorm atnd D ioxin Contaminant*. Chicago, American Medirai Aaeodatiou Council oo Scien tific Affair, October 1981. pp 1-37. 2Z Lack JA . Suakiod RR: Tba m ortality erp*- riaoce of worker* expo* id to Letrachlorodibeu- odioria in a in c h loro phenol prooeea accident. J Cbcvp Med 1960.22:11-14. ZX The L ipid Research Clieic* P opulationj Studio* Boole The /Y m lm o e Study, AoprogotM D irtrfaulion < f L ipidx. Lipoprotein* an d Selected Variable* in t l /forth A m ericas Population*, Dept of Health, Educalioo, and Welfare publica tion (N1H) 79-1627. N adeaal loetitutea of Health. 1979, vol 1. 24, Coodgold L. Eberatain A: Elortrodiognoot* q f H rurom uaculor Diooaoua, ed X Baltim ara, W'dliama A Wilkins Co, 1972, pp 97-145. 25. 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