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J ! Scand J Work Environ Heoilh l! (1985) 165-- 171 Chloracne, "the hallmark of dioxin intoxication" by Raymond R Suskind, MD SUSKIND R. Chloracne. '`the hallmark or dioxin intoxication." ScandJ Work Environ Health 11 (1985) l$5_ 1 7 l. Clinical experiences and laboratory studies are described involving a population of workers ho were exposed in a plant making 2,4,5-irichlorophcnoxyacctic acid (2,4,5-T), including a trichloro- phenol runaway reaction. Workers were followed for a period of four years, and 30 years later a mortality analysis was done on those exposed to runaway reaction material to determine possible increased risks for causes of death. Subsequently, a morbidity study on 436 employees involving three cohorts was carried out to determine the long-term health effects associated with the production of 2.4,5-T including 2.3.7,8-tctrachlorodibenzo-p-dioxin (TCDD). The mortality and morbidity studies demonstrated that the standardized mortality ratio for all causes of death was 69, and for cancer at all sites and cardiovascular disease it was 100 and 68, respectively. The most significant observations emerging from the morbidity study were that 86 *Fo of the exposed persons developed chloracne at some time and that 52.7 `To still had chloracne on examination 20 to 30 years after the initial exposure. There appeared to be no evidence, on a long-term basis, of increased risks for cardiovascular disease, hepatic disease, renal disease, central and peripheral nerve problems, reproductive problems, or birth defects among the exposed and those who had chloracne among the exposed. Studies on the cell kinetics and pathogenesis of chloracne indicate that TCDD induces the modulation of undifferentiated sebaceous gland cells to keratinocvtes. This ac- :L-n ':su!:s in a d'-tanpearnnee eb~cer:-'i> :;r.c ; - : b ' s : c l ~ - v i e r e s and keratin cysts. Production workers nave the highest frequency ana severity of chloracne and systemic effects. Populations of users of 2,4,5-T rarely, if ever, develop chloracne, and there appear to be no well- documented systemic effects. Among populations which live in accidentally or otherwise contaminated environments, there are only a limited number of chloracne cases and no well-documented systemic effects. Sufficient exposure to TCDD can induce chloracne, but systemic manifestations such as peripheral neuritis and transient hepatic dysfunction occur only in association with and subsequent to the appearance of chloracne. Chloracne is the hallmark of TCDD absorption and biological response in humans. AVv terms: cell kinetics; subacute, long-term health effects; systemic associations; 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD. The term " chloracne" has almost become a house There are several known causes of acneform erup hold word since the beginning of the " Agent Orange" tions in the workplace. They include crude petroleum controversy and since the incident at Seveso. Occupa cutting oils, coal tar and its derivatives, and the chlo ' J tional physicians and dermatologists, however, have rinated aromatic compounds. Among the chlorinated been aware of this syndrome since 1897 when it was aromatic compounds, the most potent appears to be first described by Von Bettman. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TjCDD). The From the turn of the century to the early 1940s, other 21 isomers of this compound are less acnegenic. numerous reports were published describing an The rank order of their systemic toxicity in animals acneform eruption, sometimes associated with sys is better known than their rank order of Jacnegenicity. temic manifestations, in workers exposed to several Other chlorinated dioxins, such as penta-, hexa-, and chlorinated aromatic compounds. They included heptachlorinated dioxins, are also acnegenic. Some chlorinated naphthalene, chlorinated benzols, chlori of these are found as contaminants injpentachloro- nated diphenyls, chlorinated phenols, and other chlo phenol. In the case of the polychlorinated biphenyls, rinated hydrocarbons. These compounds were used the active acnegenic agent is presumed to be the chlo for insulating, fireproofing, and Degaussing cables rinated dibenzofurans. In the past fivejyears reports and as a dielectric in condenser manufacturing (5, 8, have been published regarding the acnegenicity of 9, 10, 11, 15, 17, 20, 24). In the late 1940s some of chlorinated azobenzene and azoxybenzene com these substances, especially the chlorinated phenols, pounds (12, 23, 25). These are also found as con were used as intermediates to make products such as taminants in the preparation of herbicides, in which herbicides, eg, 2,4,5-trichlorophenoxyacetic acid 3,4-dichIoroaniline has been used as in the prepara 12,4,5-T), the bacteriostatic agent hexachlorophene, tion of the herbicides diuron, linuron, propanil, and and the fungicide pentachlorophenol.. neburon. Hence, if the oxygen linkage of the dioxin is substituted with nitrogen, the chlorinated azo com 1 Institute of Environmental Health. University of Cincin pound continues to be acnegenic. nati, Cincinnati, Ohio, the United States. My own personal experience with TCDD began in Reprint requests to: Dr RR Suskind. Institute of Environ mental Health, University of Cincinnati. 3223 Eden Avenue. Cincinnati OH 45267, USA. October 1949, when my colleagues and ij. at the Ketter ing Laboratory, were asked to examine four workers who had become ill following an industrial process 165 : E' Oq'1-c 1 rZ , * , S - t t f C lc bIlMo rs t *- IiSrO" "i C a ar CV [ M O f O J C t t ' C at'fl s' 3 ICO'Li* ircnJo^cp^e"ii t i> Cl Cl cl; ci bJicntFf'dtilfnaQrolw, l Kfdroc^loric V a Cl i.butri nr V rtoo t Cl Cl Flgur* 1. Synthesis ol 2A5-trichlorophenoxyacetic acid and the condensation reaction of trichlorophenol to 2.3,7.8-tetrachlorodibenzo-p-dioxin. accident which occurred in March of that year in a plant making 2,4t5-T. A kettle, in w-hich trichloro phenol was being made, overheated and developed excessive pressure. Part of the contents was emitted through a safety valve and broken pipe connector in to the plant building and its surroundings. We did not know it at the time, but 2,3,7,8-TCDD was a tox ic component of the kettle contents. Figure 1 describes the synthesis of 2,4,5-T and the condensation reac tion of trichlorophenol to TCDD. The employees involved in the clean-up of that building and the restoration of equipment developed acute symptoms involving the respiratory tract; they also complained of skin and eye irritation, headache, dizziness, and nausea. These symptoms subsided within one to two weeks. They were followed by an acneform eruption; severe muscle pain affecting the ex tremities, thorax and shoulders; fatigue; nervousness and irritability; dyspnea; complaint of decreased libido; and intolerance to cold. The first four persons we examined had severe generalized chloracne (figures 2a, 2b and 2c), hepatic tenderness and enlargement, peripheral neuritis, a delayed prothrombin time, and an increase in total serum lipids (3). Transaminase tests were not developed at that time. Histological examination of a nerve biopsy in a worker with pedal sensory loss showed a myelin degeneration which we assumed was related to his neuropathy. The four were reexamined in six months, and even tually a total of 36 subjects were followed, in a series of examinations, until 1953 (26). By that lime, the symptoms and findings observed as initially referable to the liver and nervous system had subsided. There was some persistence of the acne, but considerable improvement was noted in most cases. A variety of treatments was used at the time by local physicians. It was in 1957 that the toxic contaminant of the 2,4,5-T process was identified as 2,3,7,8-TCDD. A considerable amount of research has been carried out in the last 15 years on the nature of its toxic action in animals. It is now known to be the most potent acnegen on record. One of our interests in the early 1950s was to deter mine which of the several trichlorophenol production processes were acnegenic and which were not. We were provided with trichlorophenol from three dif ferent processes. They included (i) sodium trichlorophenate from the process of the affected plant, (ii) the same material after distillation, and (ii) a sample from another company's process using dilution and filtration. The positive control substance was Halowax 1014, a mixture of hexa- and pentachloro- 166 c Figures 2 a. b &c. Examples of the severe generalized cnioracne seen in four persons examined in 19^9. naphthalene. Prior to this time, we had attempted to induce pilosebaceous changes in a variety of ex perimental animals, but were not successful. We were familiar with Dow Chemical's rabbit ear test. We did not believe at the time that the results were specific enough to translate into human experience. A study was conducted in 1953 with these materials. Our test subjects were 12 human volunteers. Each material was made up in a nonwater-absorbing vehicle (Plastibase5), which was not acnegenic, and, by testing the materials on ourselves and rabbits, we determined the threshold irritant and nonirritam concentrations of each of the materials. These materials were then applied in measured quantities to the flexural surface of the forearm of the subjects, daily for six weeks. The concentrations were as follows: (i) 3.5 %, (n) 7.0 ^o, (iii) 3.5 ^o, and Halowax 20 Three subjects were exposed to each material. The skin sites were examined daily for gross changes. Serial biopsies were taken on the subjects prior to exposure, at intervals during the exposure period, and finally six weeks after the last exposure. The subjects were given physical examinations and liver function tests prior to and at two-week intervals during the exposure and at 12 weeks after the ex posure. The sequence of cellular events in the evolution of chloracne, as induced by the material from the original plant process, are shown in the photomicrographs which are summarized in figures 3a, 3b and 3c. The first indication of change is hyperkeratinization in the sebaceous gland duct. This occurrence is followed by plugging of the follicular orifice, which occurs simultaneously with the alteration of the differentia tion process of the acinar cells. These cells, which are undifferentiated at the periphery, normally differen- 167 c B chloracncgens since 1941 and is snll widely used (1). Assessment of acnegenidty is made on the basis of clinical examination and histologic examination for epidermal hyperplasia, comedones, and epithelial cysts. c Several modifications have been suggested, including the use of the skin of the external canal of the rabbit, which is richest in sebaceous structures, instead of the pinna. Inagami and his colleagues (13) applied chlorinated biphenyl-contaminated rice oil respom sible for the Yusho epidemic in Japan to hairless mice and reported follicular hyperkeratotic changes in the sebaceous follicles. Recently, the hairless mouse was explored as a model for testing potential acnegens by Puhvel (22) using two different mouse strains. 2,3,7,8-TCDD was reported to produce all of the skin changes seen in chloracne in man, including hyperkeratinization of the stratum corneum and dis appearance of sebaceous gland follicles in the forma tion of keratin cysts. These occurrences were identical to those produced by Halowax 1014, which we studied as well about 30 years ago in humans. At least three groups have studied TCDD effects in monkeys. McConnell et al (18), after administering lethal doses of TCDD to Rhesus monkeys, observed the development of acneform lesions on the lips, re ---- > tention cysts of the Meibomian glands of the eyelids, facial alopecia, and loss of eyelashes. Allen and his group (2) observed similar changes in Rhesus mon keys who were fed a diet of 500 parts per trillion of TCDD for nine months. Such levels were found to be toxic for the animals, and the majority of them died. Unfortunately, threshold levels for acnegenidty in animals, as well as in man, have not been established. c Figures 3 s. b & c. Sequence of events in the evolution of However, the most heavily exposed populations, chloracne. which are industrial workers, demonstrate that chlor acne may be the only adverse clinical finding when the exposure is limited. On the other hand, following runaway reactions such as occurred in West Virginia, tiate into sebaceous or lipid-producing cells. The ef in the Netherlands, in the United Kingdom and in fect of the toxic agent is to cause the undifferentiated West Germany, it was only among some of the work cells to become kratinocytes, which produce keratin. ers who developed chloracne that involvement of The pathologist interprets this change as the other organ systems was observed. This also occurred disappearance of the sebaceous glands and the for in workers heavily exposed to the 2,4,5-T manufac mation of a closed comedone, frequently termed turing process but not to a runaway reaction, as in retention cysts. What is most interesting is that, in Spolano, Czechoslovakia. some cases, no matter what the original severity of Next I want to consider what is known about long the chloracne following the cessation of exposure, term health effects in humans. In 1978, we were able the complete pilosebaceous structure, including the to identify 122 workers who had been exposed to the sebaceous gland, is restored. The sequence of pi trichlorophenol runaway reaction which affected the losebaceous changes induced by the plant inchloro- original four. A standard mortality analysis was con phenate was the same as that induced by Halowax ducted on 121 workers in this group (30). As of 1979, 1014. the standardized mortality ratio for all causes of No abnormal clinical (other than the skin) changes death was 69 with 32 deaths observed and 46.41 ex or abnormal laboratory findings were observed in any pected. For the categories of cancer and cardiovascular of the subjects during the exposure or the follow-up diseases, the corresponding ratios were 100 and 68, period. respectively. Because of the small size of the cohort Now, what about experimental chloracne with and small numbers of deaths, the resuks cannot be TCDD in animals? The skin of the pinna of the regarded as conclusive, but they suggest no signifi rabbit ear has been used as a screening model for cant difference from expected death rates. Here is a 168 c cohort which was hcauly exposed 10 TCDD. Disabling health efrecis were observed in many but not all, acutely, subacutely, and subchronicaUy. If risk were substantial for hepatic, cardiac, or pulmonary disease and cancer, we should have detected it even in this small cohort. One of this group of 32 died of a malignant fibrous histiocytoma, originating in the skin. It is classified as a soft tissue sarcoma. Another, not in this accident group but exposed to the process and who had chloracne, died of a liposarcoma. The frequency data of soft tissue sarcomas for the general population is inadequate since those occurring in spe cific organ systems are classified under the Interna tional Classification of Disease number for tumors of the stomach or central nervous system or kidney or wherever they are found. The causal association of soft tissue sarcomas and TCDD is still to be deter mined. In June of 1979, we returned to the same plant and carried out a clinical study on 436 employees to determine and identify the possible long-term effects of chemicals associated with the production of 2,4,5-T, including TCDD, and to determine the in creased risk for the adverse effects which have been observed in the subacute phase in man, as well as those noted in experimental animals (27). The exami nation program attempted to determine possible in creased risks for cutaneous, pulmonary, cardio vascular, gastrointestinal, hepatic, renal and neurobehavioral problems, reproductive and birth defect problems, and effects on lipid metabolism. The population included those exposed to the process accident in 1949, as well as those exposed to the normal processes of manufacturing in the period 1948--1969, and it included chemical operators, ser vice employees, such as pipefitters, mechanics, etc. The controls (referents) wfere never associated in any way with the 2,4,5-T process or its materials. The cohorts consisted of the following persons: 204 ex posed, 163 not exposed, and 51 of questionable ex posure. In this study, we found that 86 <5o of the exposed had developed chloracne and 52.7 of the exposed, on examination, still had chloracne. None of the not exposed or the questionably exposed ever developed chloracne. There appeared to be an association between the persistence of chloracne and the presence and severity of elastic tissue degeneration of the skin, as found in actinic elastosis. There also appeared to be an association between exposure and the history of gastrointestinal tract ulcer. The occurrence of ulcers in the upper part of the gastrointestinal tract of the exposed was four times that of the not exposed. We also found that pulmonary function values among the exposed who currently smoked were lower than those who were not exposed and currently smoked. If one compared pulmonary function values of the exposed to those of the not exposed, there was a significant difference, and, when one considered pulmonary function in relation to smoking (past, present or never), it was only the present smokers who had a greater frequency of lower pulmonary function values. There appeared to be no evidence of increased risk among the exposed and those who had chloracne among the exposed for the following: car diovascular disease, hepatic disease, renal disease, central or peripheral nerve problems, reproductive problems, or birth defects. There was a significantly greater number of subjects with low levels of highdensity lipoprotein in those with persistent chloracne than in those with a history only of chloracne or those who had never had chloracne. However, when the mean lipid levels for these three chloracne groups were compared, no significant differences were found. Finally I would like to turn to the subject of how effects in production workers compare to those in other types of exposed populations. Populations potentially exposed to the chlorinated dioxins or dibenzofurans include production workers, formulators and users (sprayers) of herbicides, and those living in areas contaminated with the toxic agent through spraying or through inappropriate use of materials contaminated with dioxins. Among the production workers, the frequency and severity of chloracne is related to the degree and ex tent of exposure, and the systemic manifestations attributed to the exposure always follow the ap pearance of chloracne* The degree and extent of ex posure may also reflea involvement in a runaway reac tion as in one industry in the United States (30), in one plant in Germany (28), in one plant in the United Kingdom (16), and in one in the Netherlands (6). The systemic manifestations may be clinical, as in the case of peripheral neuritis, and/or determined by labora tory findings, eg, elevated lipids and liver profile enzymes. In workplace exposures in which the plant hygiene was relatively good, as in the case of a Mid land, Michigan, population, the frequency and severity of chloracne was low and systemic effeas infrequent. We now recognize that porphyria in humans, in cluding the cutaneous manifestations of porphyria cutanea tarda, have only been observed in two pro duction worker populations. These populations account for less than 10 Io of the production popula tion groups. They were the groups observed by Bleiberg and his colleagues (4) and subsequently by Po land and his co-workers (21) and the workers at Spolano reported by Jirasek and his colleagues (14). In both instances, it was a mixed exposure to 2,4,5-T and 2,4-dichlorophenoxyacetic acid processing. In the Spolano plant there was also a heavy exposure to pentachlorophenol. In the group studied by Bleiberg et al, of the 26 workers whose urine was tested for uroporphyrins, 8 had elevated uroporphyrins and 19 had chloracne. Three with elevated uroporphyrins had no chloracne. Exposure to relatively pure TCDD in a laboratory accident, reported by Oliver (19), did 169 I not produce porphyria. Another workplace exposure In summary, l have attempted to describe the which resulted in an 86 frequency of chloracne kinds of chlorinated hydrocarbon work exposures and systemic manifestations, including transient which result in chloracne and my own experience hepatic damage, as in the West Virginia group, did with TCDD-exposed work populations, including me c not result in porphyria. Among the sprayer user population in the United Slates, which started n 19-18. there have been no reports of chloracne or systemic effects. 2,4,5-T, which was known to contain varying amounts of frequency and severity of chloracne as a subacute or subchronic manifestation of intoxication. The in volvement of other organ systems which may be associated with chloracne, the cellular kinetics of chloracne, and the long-term effects in a substantially 2,3.7,8-TCDD, was widely used in large-scale farm TCDD-exposed population have been discussed. It ing*, family gardens, forest management, and for weed control along roadsides and railroad rights-of- has been demonstrated that production workers have the highest frequency and severity of chloracne. way. The extent of the human exposure in the United Some sustain systemic injury which, while temporary, States can be gauged by the statistic for the year occurs only in persons who have developed chlor 1964, in which 9.8 million pounds (about 45 104 acne. The populations of users which have been metric tons) were produced for domestic use alone. studied carefully rarely, if ever, develop chloracne, In the case of the most heavily exposed sprayers in and there appear to be no well-documented systemic Viet Nam, the Ranch Hand group of the Air Force effects. Among those populations which live in acci (29), a carefully conducted epidemiologic and morbi dentally or otherwise contaminated environments, dity study completed this year has demonstrated no well-documented studies show a very limited number evidence of chloracne and no conclusive evidence of with chloracne and no documented systemic effects. systemic problems. It is from these observations that one can state that chloracne is indeed a hallmark not only of TCDD Among the studies of populations exposed to a absorption and biological response in humans, but it contaminated community environment, those of Se- is also a hallmark of TCDD intoxication. veso and Times Beach, Missouri, contribute signifi cantly to our knowledge. The acute effects on resi dents and domestic animals living near the plant at Seveso, which experienced a trichlorophenol runa References way reaction, are well documented. The most signifi cant finding in humans was chloracne, especially in children. While some peripheral nerve and liver im 1. Adams EM, Irish DD, Spencer HC, Rowe VK. The response of rabbit skin to compounds reported to have caused acneform dermatitis. Ind Med Ind Hyg Sect 2 pairment was reported within the first two years after (1941) 1--4. c the incident, no chronic long-term systemic effects have been documented, and the study of these effects continues. The Center for Disease Control (CDC) 2. Allen JR, Barsotti DA, Van Miller JP, Abrahamson LJ, Lalich JJ. Morphological changes in monkeys con suming a diet containing low levels of 2.3,7,3-teirachlorodibenzo-p-dioxin. Food Cosmct Toxicol 15 and the Missouri Division of Health conducted a (1977) 401--410. clinical examination of residents in the heavily con 3. Ashe WF, Suskind RR. Reports on chloracne cases. taminated Times Beach area (7). No cases of chlor acne were found nor any increased disease prevalence Monsanto Chemical Company, Nitro, West Virginia. Kettering Laboratory, Cincinnati, OH 1949 & 1950. (Reports of the Kettering Laboratory December 1949 of any kind. & April 1950). We were curious about any unusual characteristics of the group of exposed workers who did not develop chloracne in our study. They constituted 14 <7o of the exposed. Their job categories included production operator, helpers, miller, dryer, grinder, bagger, mechanic, pipefitter, and process research chemist. 4. Bleiberg J, Wallen M, Brodkin R, Applebaum IL. In dustrially acquired porphyria. Arch Dermatol S9 (1964) 793--797. 5. Collier E. Poisoning by chlorinated naphthalene. Lan cet 1 (1943) 72--74. 6. Dalderup ' LM. Safety measures for taking dow n buildings contaminated with toxic materials. J Soc Ccneesk 52 (1974) 582--585. 616--623. Their duration of exposure ranged from 1.5 to 96 months. Their ages ranged from 36 to 68 years. Their life-styles and hygienic practices were different. Among those who had chloracne 16.5 % never smoked; 7. Donnel HD, Hoffman RE. Pilot study Times Beach Missouri. Presentation at meeting of AMA CSA Ad visory Panel on Toxic Substances, 13 December 1983. 8. Fulton WB, Matthews JL. A preliminary report on dermatological and systemic effects of exposure to among those who did not develop chloracne 39.3 never smoked. The frequency of using protective gear, washing, and bathing in this group appeared to be greater than among those who developed chlor hexachloronaphthalene and chlorodiphcnyl. Pennsyl vania Department o f Labor and Industry, Harrisburg. PA 1936, pp 1-- 15. (Special bulletin no 43). 9. FUSS. Chloracne. Tagung d Vereinig Suedwestdeutsch Dermat, Hcidelburg 1936. (Report 62). acne. These differences may or may not account for the difference in clinical response. I believe that, in this group, individual susceptibility may also have been a factor. 10. Good CK, Pensky N. Halowax acne ("cable rash"): A cutaneous eruption in marine electricians due to certain chlorinated naphthalenes and diphenyls. Arch Dermatol Syphilol 48 (19*13) 251--257. 11. Greenberg L, Mayers MR, Smith AR. The systemic 170 C I fi c*. effects resulting from exposure 10 certain chlorinated hydrocarbons. I Ir.J Hva Toxicol 21 (939! 29 12. Hill RH Jr. Kollen ZJ. Kimbrough RD. Groce DF. Needham LL. Tetraehloroazobenzene in 3.4-dichtoroaniline and ns herbicidal derixatives: Propanil. Jiuron, linuron. and neburon. Arch Environ Health 36 (1981) 11-- 14. 13. Inagami K. Koga T. Kkuch M. Hashimoto M, Taka hashi H. Wada K. Experimental study of hairless mice following administration of rice oil used by a Yusho patient. Fukuoka Igaku Zasshi 60 (1969) 548--553. 14. Jirasefc L. Kalensfcy J, Kubec K. Acne chlorina and porphyria cutanea tarda during the manufacture of herbicides: Part I. Cesk Dermatol 48 (1973) 306--315. 15. Kelley EF. Acne from synthetic wax (Halowax). Urql Cutaneous Rev 47 (1943) 238--239. 16. May G. Chloracne from the accidental production of letrachlorodibenzodioxin. Br J Ind Med 30 (19TM3) 276--233. 17. Mayers MR. Silverberg MG. Skin conditions resulting from exposure to certain chlorinated hvdorcarbons. J Ind Hyg Toxicol 20 (1938) 244--258. ' 18. McConnell EE. Moore JA, Dalgard DW. Toxicity of 2,3,7,8-ieirachlorodibnzo-p-dioxin in Rhesus mon keys (Macaco mulattoJ following a single oral dose. Toxicol Appl Pharmacol 43 (1978) 175-- 187. 19. Oliver RM. Toxic effects of 2,3.7,8-ietrachlorodi- benzo-l .4-dioxin in laboratorv workers. Br J Ind Med 32 (1975) 49--53. 20. Peck SM. Dermatitis from cutting oils, solvents and dielectrics, including chloracne. J Am Med Assoc 125 (1944) 190-- 196. 21. Poland A. Glover E. Kende AS. DeCamp M, Giandomenico CM. 3,4.3'.4'-Tetrachloro azoxybenzene and azobenzene: Potent inducers o f aryl hydrocarbon hydroxylase. Science 194 (1976) 627--630. 22. Puhvel SM, Sakamoto M. Ertl DC. Reisner RM. Har- k'xx mice as models fur chloracne: A study of cutaneous changes induced by topical application of established chloracnegens. Toxicol Appl Pharmacol 64 (1982) 492--503. 23. Scarisbrick DA. Martin JV. Biochemical changes as sociated with chloracne in workers exposed to tetrachloroazobenzene and tetrachloroazoxybenzene. J Soc Occup Med 31 (1981) 158--163. 24. Schwartz L. Occupational acne. NY State J Med 43 (1943) 1711-1718. 25. Sundstrom G. Jansson B. Renberg L. Determination of the toxic impurities 3.3',4,4'-tetrachIoroazobenzene and 3.3,.4.4'-tetrachlorozoxybenzene in commercial diuron, linuron and 3.4-dichIoroaniline samples. Chemo- sphere 7 (1978) 973-979. 26. Suskind RR. A clinical and environment survey, Mon santo Chemical Company, Nitro, West Virginia. Kettering Laboratory. Cincinnati, OH 1953. (Report of the Kettering Laboratory July 1953). 27. Suskind RR. Hertzberg VS. Human health effects of 2.4,5-T and its toxic contaminants. J Am Med Assoc 251 (1984) 2372--2380. 28. Thiess AM, Frentzel-Beyme R, Link R. Mortality study of persons exposed to dioxins m a trichlorophenol-process accident that occurred in the BASF AG on November 17, 1953. Am J Ind Med 3 (1982) 179-- 189. 29. US Air Force. School of Aerospace Medicine. Project ranch hand II: An epidemiological investigation of health effects on Air Force personnel following ex posure to herbicides; baseline mortaliy studies. Brooks Air Force Base. US Air Force School of Aerospace Medicine. Texas 1983. 30. Zack JA. Suskind RR. The mortality experience of workers exposed to letrachlorodibenzodioxin in a trichlorophenol process accident. J Occup Med 22 (1980) 1 1 -1 4 . 171 3