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Original Articles f The Mortality Experience January 1980 Vol. 22 No. 1 of Workers Exposed to Tetrachlorodibenzodioxin in a Trichlorophenol Process Accident Judith A. Zack, and Raymond R. Suskind, M.D. A standardized mortality analysis was conducted on workers exposed to tetrachlorodibenzodioxin in a trichlorophenol process accident at the Monsanto Company plant in Nitro, West Virginia. One hundred and twenty-one workers who developed chloracne resulting from this acci dent on March 8, 1949, were selected for study. Follow-up of this group was 70 0 % comp/ete. The standardized mor tality ratio for alt causes of death was shown to be 0.69. with 32 deaths observed and 46.41 expected. For the categories of malignant neoplasms and circulatory diseases. the standardized mortality ratios were 7.00 and 0.68, respectively. Because of the small size of the cohort and the relatively small number of deaths observed, the results of this study cannot be considered conclusive. However, it is important that no apparent excess in total mortality or in deaths. from ma//gnanf neoplasms or diseases of the circulatory system was observed in a group of workers with a high peak exposure to tetrachlorodiben zodioxin who were followed over a period of nearly 30 years. T h e icstrivro tJ^ T n rdy witt bp i r ^ yporate^w/t/vthose o f a larger study whicfr vrr&Tnc/ucfe p&wifvinSfUersex^^ posed in the course of~X4,5-trichlorophenoxYacetic acid production during the period 1948 tal969^^r7~^^ A wide variety of acute and sub-acute health effects has been reported in workers involved in the manufacture of 2,4,5-trichlorophenoxyacetic acid (2.4,5-T) from 2,4,5-trichlorophenol (TCP). The most consistent clinical finding is chloracne. a skin disease characterized by com- . .From the Depanmem of Medicine and Environmental Health. Monsanto Company. 600 N Lindbergh Blvd.. St. Louts. M O 63166 (M s Zack. Epidemiologist), and the Institute of Environmental Health. Kettering Laboratory, the University of Cincinnati Medical Cent, Cincinnati. O H 45267 (Or. Suskmd. Director) Journal of Occupational Medicine/Vol. 22, No. 1/January 1980 edones. cysts, pustules, and abscesses. Hepatic dysfunc tion. peripheral neuritis, disorders of fat metabolism, and porphyria cutanea tarda are other frequently reported findings in these workers.' Chloracne has been shown to be essentially due to 2,3,7,8-tetrachlorodibenzodioxin (TCDD),* a byproduct in the synthesis of 2.4,5-T. The sub ject of this paper is the chronic health effects of exposure to TCDD, as reflected in the mortality experience of a cohort of Monsanto Company workers who developed symptoms of chloracne following a trichlorophenol pro cess accident at the Nitro, West Virginia, plant in 1949. Production of trichlorophenol began in the fall of 1948 at the Nitro plant. In this process, the reactants 1,2,4,5-tetrachlorobenzene, sodium hydroxide, and methanol were all added to the autoclave. Heat was ap plied and, when the pressure reached the desired point the autoclave was vented. O n March B. 1949, about six months after production start-up, a violent reaction and decom position occurred when temperature and pressure within the autoclave became excessive. The relief valve opened and the fumes and tarry residues from the decomposed ^contents of the autoclave were discharged into the at mosphere and into the interior of the building. Employees who worked in the area of TCP production or were involved in the clean-up began to develop symp toms immediately following exposure to the material which was discharged from the autoclave. Symptoms in cluded eye and respiratory tract irritation, headache, diz ziness and nausea, and a severe irritant reaction of the ex posed skin. After these initial symptoms subsided, the chloracne and other symptoms became evident Ashe and Suskind1-* examined a total of 12 more severely affected workers on three occasions during the period of 1949 to 1953. Another 26 persons with chloracne, apparently not related to the accident were also examined in 1953. The 11 (13 clinical symptoms, in order ol relative frequency/ included acneform lesions; severe pains in muscles of upper and lower extremities, shoulders and thorax on exertion, fatigue; nervousness and irritability: decrease in Iihido. dyspnea: vertigo and intolerance to cold On examination, all of the cases had chloracne Several were severely hyperpigmented, especially on the face. Of the six workers ex amined in 1949 and 1950. tour had liver enlargement and one had sensory loss m one foot. Liver impairment as in dicated bv hepatomegaly, tenderness and soreness in the right upper quadrant and epigastrium and a delayed pro thrombin time, was observed.114 In 1953, four of the six workers examined in 1949 and 1950 were re-examined and six additional workers involved in the accident were also examined. The findings m this later examination indicated a general regression of both the cutaneous and noncutaneous symptoms which had been present earlier. All of the workers showed a marked improvement in their skin lesions -- there were residua of the acne and a few active lesions. In a few cases, workers continued to complain of aches and pains of the lower ex tremities and back, nervousness, excessive fatigue, and dyspnea. No clinical explanation for these complaints could be made based on the results of the physical ex amination/ The findings of the examinations bv Ashe and Suskind are consistent with those which have been reported in other industrial episodes which occurred subsequently.' The acute health effects of TCDD exposure are described in the literature/ but little is known of the chronic effects. Several reports describe the occurrence of cancer and other deaths in workers exposed to T C D D which suggests an association between exposure and the subsequent development of a variety of neoplasms1" These reports, however, are generally of small groups of workers with relatively short periods of follow-up and are considered to be preliminary in nature. In a 25-year follow-up study. 17 deaths were observed among a cohort of 75 German workers who had been involved in a 1953 TCP process accident.1 O f the 17 deaths observed (11-25 expected depending on the choice of a control population], six were from cancer (four or fewer expected), five from car diovascular disease (as expected), two from suicide (fewer than one expected), one from liver cirrhosis, one from a urogenital tract disease, and two from external causes. Of the six cancer deaths, three were from stomach cancer in the age group 60-69, a number significantly higher than expected. Two other cancer deaths were from oat-cell carcinoma of the lung and one was from adenocar cinoma of the colon. A similar accident occurred in the Netherlands in 1963 in a factory producing 2,4,5-.T/ .Eight deaths have been observed among 93 exposed workers. Five or six of these deaths were from cardiovascular disease. The proportion of deaths due to myocardial infarction was noted to be high. Jirasek et al1 10 and Pazderova" followed 55 of the 78 Czechoslovakian workers who were affected by chlor acne resulting from occupational exposure to 2,4,5-T and pentachlorophenol. In this study, five deaths were ob served. These included two deaths from bronchiogenic carcinoma (less than one expected), one from'cardiovas cular disease, one from liver cirrhosis, and one from an accidental industrial intoxication In 1976. a TCP process accident in Meda. Italy, resulted in the contamination of a large and densely populated area.* A preliminary mortality study has been conducted m two of the 11 towns affected. The overall mortality rate did not differ from that expected, but increases in deaths . from liver cirrhosis and leukemia were suggested. The chronic toxicity of TCDD exposure to animals has been more extensively studied. T CD D toxicity has been thoroughly reviewed.7 Chronic toxicity to T C D D is manifested by liver necrosis, thymic atrophy, and deple tion of the lymphoid organs. Two studies indicate that chronic administration of low levels of T CD D to rats is associated with an increased incidence of neoplasia. In one study, the oral administration of T C D D produced an increase in hepatocellular carcinomas and squamous cell carcinomas of the lung, hard palate/nasal turbinates, or tongue.11 In another study. TCDD fed to rats produced tumors in 3 8 % of the test animals.'1 Neoplastic nodules and cholangiocarcinomas of the liver were observed. The study reported here will examine the mortality ex perience of a cohort of 121 employees involved in.,the 1949 trichlorophenol process accident, with special em phasis on cardiovascular disease and on neoplasms, par ticularly of the stomach, liver, lung, and skin. Population and Methods In this study, the development of chloracne, a hallmark of T C D D exposure, was used to identify employees for study. The study population consists of all persons with chloracne which could be attributed to the 1949 TCP pro cess accident. One hundred and twenty-two employees who developed chloracne following this incident were identified from plant safety records dating to the time of the accident, and from workmen's compensation and plant medical records. One hundred and twenty-one white males were included in this study -- one female who was living as of the endpoint of the study was not in cluded in this mortality analysis. It is assumed that all of the skin disorders recorded in the plant records represent true cases of chloracne and not other types of occupa tional or nonoccupational dermatitis. An analysis of the chloracne cases and exposures not associated with this accident but rather with the normal TCP/2,4,5-T produc tion processes will be the subject of a future paper. The data were analyzed by the modified life-table method using the updated Monson program/4 In this method of analysis, the age-, race-, time- and causespecific mortality rates for a standard population (in this case, the population of the United States) are applied to the person-years lived classified by age, race, and time. A standardized mortality ratio was calculated as the ratio of the observed deaths to the expected deaths for 22 selected causes of death. The statistical significance of differences between observed and expected numbers was based on the Poisson distribution and statistical signifi cance was determined at the 5 % level of significance. For the purpose of analysis, each member of the study cohort was assumed to have entered the study on March 8,1949, the date of the accident. The vital status of each member was determined using standard follow-up tech- J37a,.Fjpr each '^e r^n ^o una to be dece^tf7^tfead>'certifrcatevvas ob- 12 Mortality Experience of Workers Exposed to Tetrachlorodibenzodioxin/Zack and Suskind Table 1. - O bserved and Expected Deaths A m o n g -121 M ale s Exp osed to T e lra ch lo ro d ib e n zo d in in ;. in a Trichlorophenol P ro ce ss.A ccid e nt. - Cause Ail causes ol oeatn All malignant neoDlasms Buccal cavity and pharynx Digestive organs anfl peritoneum Slomacn Liver All other digestive organs Respiratory system Lung All other respiratory organs Skin Genitourinary organs Lymphatic and hematopoietic tissue Other sues Diseases of the nervous system and sense organs Diseases ot the circulatory system Arteriosclerotic heart disease, including coronary heart disease All other disease of the circulatory system Diseases ot the lespiraiory system Diseases ot the digestive system All other diseases External causes ol dealh ICO-No!. (Eighth Revision), 140-209 140-49 lS-'X59 151*.- 155-J56 --, 160-153 " 16?. 153 -i- \ 172,173 185-,189 .. 200-209' -- 320-389 1: ' -* 390-458 ), ' 410-413 _ 460*519 520-5771 . 800-998 .. Observed 32 9 0 0 0 0 0 5 5 0 1 0 3 0 0 17 13 4 1 0 2 3 Expected 46.41 9.04 0 30 2.59 0.50 0 18 1 91 3.02 2.85 0.17 0.15 1.16 0.88 0.94 0.36 25.01 17.74 7.27 2.78 2.26 3 18 3.78 SMR - . .0.691.00 t t t -, t 1.66 1.75 t t f t t : 0.6B 0.73 t t -V : t t p < 0.05 tLess than 5 observen fleams tained. The underlying cause of death was coded to the 8th Revision of the International Classification of Diseases, Adapted11 by an experienced nosologist. Results All of the 121 members of the study cohort were traced. Eighty-nine were verified living and 32 were verified deceased by death certificate. The results of the standardized mortality analysis of the 121-member study cohort are shown in Table 1. The standardized mortality ratio for all deaths is shown to be 0.69, with 32 observed deaths and 46.41 expected. This is the only statistically significant difference shown in this table. There were nine deaths from malignant neoplasms with 9.04 expected. There were no deaths from stomach or liver cancer. There were five lung cancer deaths versus 3.02 expected and one skin cancer death with 0.15 ex pected. The malignant tumor was a fibrous histiocytoma presumably of dermal origin, which is rare. There were three deaths from neoplasms of lymphatic and hematoppietic tissue with 0.88 expected. There were 17 observed deaths from circulatory diseases with 25.01 expected. The standardized mortality ratio for circulatory diseases was low at 0.68. Case summaries for the cancer deaths are given in Table 2.,...- Discussion Because the study cohort was small and only 32 deaths were observed, the results cannot be considered con clusive. Nevertheless, the analysis of the mortality ex perience of these workers indicated no apparent excess of total mortality or of deaths due to malignant neoplasms or circulatory diseases. The TCDD-exposed workers in the present study repre sent the largest group ever investigated after long-term follow-up. T h e - ^ ^ ua^jop in c lu sio n ,(presence of. the t workej>. a t t h e ' the'subsequent occor ren c e d f l ^ ra t e group to those with s signify * cantex'pc5sure`at`that time. The latency period of 29 years Z . --Table Cancer Deaths Am ong a Cohort ol 121 M a le s Exposed to Tetrachlorodibenzodioxin in a Trichlorophenol P ro ce ss Accident. Year ot Birth 1909 1910 1911 1922 1915 1920 1919 1907 1910 Year of Hire 1943 1927 1939 1945 1939 1946 1943 1943 1939 Year ol Death 1962 1970 1964 1973 1970 1978 1973 1971 1978 Death' Certificate Statementof Cause of Death Lung cancer (162.1) Pulmonary carcinoma (162.1) Bronchiogemc carcinoma (162.1) Bronchtogenic carcinoma (162.1) Lung cancer (162.1) Malignant fibrous histiocytoma of soft tissue origin (173.9) Hodgkin's disease (201.0) Lymphatic leukemia (204.9) Acute myelogenous leukemia (205.0)1 Smoking history was obtained by interviews with lormer co-workers ot the decedents Journal of Occupational Medicine/Vol. 22, No. 1/January 1980 Smoking History* Cigarettes Cigarettes Cigarettes Nonsmoker `Cigarettes Cigarettes * Cigarettes Pipe Cigarettes 13 is longer than that of any previous study, and the follow up is complete. Therefore, although the cohort is small, it represents the best opportunity so far to study the long term effects of T C D D on mortality. By augmenting these data with the results of comparable mortality studies, the long-term effects of T CD D may be more definitely evaluated. The authors wish to thank Mrs lanet Yung. M r Randy Picolel, and Mrs Phyllis Kortr tor their assistance with the data collection References 1 International Agency for Research on Cancer IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man Vol 15. Some fumigants, the Herbicides 2,4-0 and 2.4.5-T, Chlorinated Dibenzodioxins and Miscellaneous Industrial Chemicals. Lyon, IARC. 1977 2. Kimmig I and Schulz KH Occupational acne (so-called chloracne) due to the chlorinated aromatic cyclic esters Der matologies 115 540-546. 1957, 3. Ashe WF and Suskind RR Reports on chloracne cases. Monsanto Chemical Company. Nitro, West Virginia. Reports of the Kettering Laboratory, December 1949 and April 1950 4 Suskind RR: A clinical and environmental survey, Monsanto Chemical Company, Nitro, West Virginia. Report of the Kettering Laboratory. luly 1953 5 Suskind RR. Chloracne and associated problems Report to the Conference of the National Institute of Environmental Health Sciences on Chlorinated Dibenzodioxins and Dibenzofurans. April 3. 1973 6 Suskind RR Chloracne and associated health problems in the manufacture of 2,4,5-T. Report to the loint Conference. National In stitute of Environmental Health Sciences. International Agency for Research on Cancer. Lvon, France. January 11 1978 7 Young AL. Calcagni IA. Thalken Cl. et al The toxicology, en vironmental fate, and human risk associated with herbicide orange and its associated dioxin U S Air force Occupational and En vironmental Health Laboratory Report OEHL TR-78-92, Brooks Air Force Base. Texas, 1978 8 International Agency for Research on Caijcer Long-term hazards of polychlorinated dibenzodioxins and polychlorinated diben zofurans. IARC Internal Technical Report No 78/001. Lvon. 1978 9 Jirasek L. Kalensky J. and Kubec K. Acne chlorma and porphyria cutanea tarda during the manufacture of herbicides Cesk Dermatol 48:306-317. 1973 10. Jirasek L. Kalensky J. Kubec K. et al. Acne chlorma. porphyria cutanea tarda, and other manifestations of general poisoning during the manufacture of herbicides II Cesfc Dermatol 49145-157. 1974 11. Pazderova I, Lukas E. Nemcova M, et al. Chronic poisoning by chlorinated hydrocarbons formed in the production of sodium 2.4.5-trichloraphenoxyacetate. Prac Lek 26.332-339.1974 12. Kociba R|, Keyes DC. Beyer JE. et al. Results of a two-year chronic toxicity and oncogenicity study of 2.3.7.8-tetrachlorodibenzop-diox in in rats Toxicol Appl Pharmacol 46.279; 303. 1978 13 Van Miller IP. Lalich JJ. and Allen |R Increased incidence of neoplasms in rats exposed to low levels of 2.3.7.8-tetrachlorodibenzop-dioxin Chemoipbere 6:537-544,1977. 14 Monson RR Analysis of relative survival and proportional mor tality Comput Biomed Res 7 325-332.1974 15 Eigth Revision. International Classification of Diseases. Adapted for Use in the United States. U S. Department of Health. Education and Welfare. Public Health Service. PH5 Publication No 1693 Washington U.S Government Printing Office. 1977 14 Mortality Experience of Workers Exposed to Tetrachlorodibenzodioxin/Zack and Suskind