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Original Articles Reprinied Irom Journal ol Occupalional Medicine Volume 22. No 1. January 1980 The Mortality Experience J o u rn a l of Occupational M e d ic in e 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 trichlo rophenol prbcess 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 100% complete. The standardized mor tality ratio for all causes o f death was shown to be 0.69, with 32 deaths observed and 46.41 expected. For the categories o f malignant neoplasms and circulatory diseases, the standardized mortality ratios were 1.00 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 malignant neoplasms or diseases o f 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. The results o f this study will be incorporated with those of a larger study which will include plant workers ex posed in the course of 2,4,3-trichlorophenoxyacetic acid production during the period 1948 to 1969. 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 corrv (K* O rp jrtm m t o l tor jn d Enviro nm en tal H ealth. M o m m io C o m p a n y . ftOO N L in d b e rg h B l v d . S i l o u . t M O 63IW ( M i Z a c k . E p id e m o Jo ip itL and the In ititu te ol Enviro nm en tal H ealth. Kettering la b o r a t o r y , the U n iv e rs it y o l C in c in n a ti M e d ic a l C e n te r. C in c in n a ti. O H 452t>7 (O r Su ikm d . D irecto r) Journal of Occupalional 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),2 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 On March 8,1949, 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 uskind'~* 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 clinical symptoms, in order of 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 libido, 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 m 1949 and 1950. four had liver enlargement and one had sensory loss in one foot Liver impairment as in dicated by hepatomegaly, tenderness and soreness in the right upper quadrant and epigastrium and a delayed pro thrombin time, was observed.' 1* In 1953. four of the six workers examined in 1949 and 1950 were re-examined and six additional workers involved in the accident were also examined The findings in 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 4 The findings of the examinations by Ashe and Suskmd are consistent with those which have been reported in other industrial episodes which occurred subsequently1 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 TCDD which suggests an association between exposure and the subsequent development of a variety of neoplasms.*"" 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* 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. Iirasek et al* 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 bronchiogemc 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. TCDD toxicity has been thoroughly reviewed/ Chronic toxicity to TCDD is manifested by liver necrosis, thymic atrophy, and deple tion of the lymphoid organs Two studies indicate th a t'' chronic administration of low levels of TCDD to rats is associated with an increased incidence of neoplasia In one study, the oral administration of TCDD produced an increase in hepatocellular carcinomas and squamous cell carcinomas of the lung, hard palate/nasal turbinates, or tongue." In another study, TCDD fed to rats produced tumors in 38% of the test animals." Neoplastic nodules and cholangiocarcmomas 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 TCDD 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 t 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 niques and ascertained as of December 31,1978 For each person found to be deceased, a death certificate was ob- 12 Mortality Experience of Workers Exposed to Tetrachlorodibenzodioxin/Zack and Suskmd Tibia 1. -- Observed ind Expected Deaths Among 121 Males Exposed to Tetrachlorodlbenrodloxln In a Trichlorophenol Process Accident. Causa Ail causes ot death All malignant neoplasms Buccal caviiy and pharynx Digestive organs and peritoneum Stomach Liver All other digestive organs Respiratory system Lung All other respiratory organs Skm Genitourinary organs Lymphatic and hematopoietic tissue Other sites Diseases ol the nervous system and sense organs Diseases ot the circulatory system Arleriosclerotic heart disease, including coronary heart disease All other disease ot the circulatory system Diseases ot the respiratory system Diseases ot the digestive system All other diseases Exiernal causes ol death ICO No. (Eighth Revision) 140-209 140-149 150-159 151 155-156 160-163 162.163 -- 172.173 185-189 200 209 -- 320-389 390-458 4 10-413 -- 460-519 520-577 -- 800-998 Observed 32 9 0 0 0 0 0 5 5 0 1 0 _3__ 0 0 17 13 4 1 0 2 3 Expected 46 4 1 9 04 0 30 2 59 0.50 0.18 1.91 3.02 2 85 0 17 0.15 1 16 .0 .8 8 0 94 0 36 25 01 17.74 7.27 2.78 2.26 3.18 3.78 SMR 0 69* 1.00 t 1 t T r 1 66 1 75 t t t t t t 0.68 0 73 f t t t r _ p < 0.05 tLe ss man 5 observed deaths tained. The underlying cause of death was coded to the 8th Revision of the International Classification of Diseases, Adapted" 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 hematopoietic 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 apparenfexcess 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. The criteria for inclusion (presence of the workers at the 1949 accident and the subsequent occur rence of chloracne) limit the group to those with a signifi cant exposure at that time The latency period of 29 years \ Table Z. -- Cancer Deaths Among a Cohort ol 121 Males Exposed to Tetrachlorodibenzodioxin in a Trichlorophenol Process Accident. Year ot Birth -- 1909 --r 1910 1911 1922 -- 1915 1920 -- 1919 1907 .1910__ Year ol Hire 1943 1927 1939 1945 1939 1946 1943 1943 1939 Year ot Death 1962 1970 19640 1973 1970 19780 1973 19710 19780 Death Cerliticate Statement ot Cause ot Oeath Lung cancer (162 1) Pulmonary carcinoma (162 1) Bronchiogenic carcinoma (162.1) Bronchiogemc carcinoma (162 1) Lung cancer (162 1) Malignant librous hisliocyloma ol soil tissue origin (173.9) Hodgkin's disease (201 0) Lymphatic .leukemia (204 9) Acute myelogenous leukemia (205 0) Smoking history was obtained by interviews with lormer co-workers ol the decedents Smoking History* Cigarettes Cigarettes Cigarettes Nonsmoker Cigarettes Cigarettes Cigarettes Cigarettes^ 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 TCDD on mortality. By augmenting these 6. Suskind RR: Chloracne and associated health problems in the manufacture of 2,4.5-T. Report to the Joint Conference, National In stitute of Environmental Health Sciences, International Agency for Research on Cancer, Lyon, France. January 11, 1978. 7. Young AL, Calcagni JA. Thalken CE, et a l The toxicology, en data with the results of comparable mortality studies, the vironmental fate, and human risk associated with herbicide orange long-term effects of TCDD may be more definitely evaluated. and its associated dioxin. U.S. Air Force Occupational and En vironmental Health Laboratory. Report OEHL TR-78-92. Brooks Air Force Base. Texas, 1978. 8. International Agency for Research on Cagcer Long-term hazards The aulhon w tih to thank M n. U riel Yung. Mr. Randy PicoJeL and Mrs of polychlorinated dibenzodioxins and polychlorinated diben Phyllis Korte for Iheir assistance with the data collection. zofurans. IARC Internal Technical Report No. 78/001, Lyon, 1978. 9. lirasek L. Kalensky I, and Kubec K: Acne chlorina and porphyria cutanea tarda during the manufacture of herbicides. Cede Dermatol References 8:306-317. 1973. 1. International Agency for Research on Cancer IARC Monographs 10. lirasek L. Kalensky |, Kubec K. et al: Acne chlorina, porphyria on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Voi. cutanea tarda, and other manifestations of general poisoning during IS Some Fumigants, the Herbicides 2.4-D and 2.4.5-T, Chlorinated the manufacture of herbicides. II. CesJc Dermatol 49:145*157. 1974. Dibenzodioxins and Miscellaneous Industrial Chemicals. Lyon: IARC, 11. Pazderbva I. Lukas E, Nemcova M. et al: Chronic poisoning by 1977. chlorinated hydrocarbons formed in. the production of sodium 2. Kimmig j and Schulz KH Occupational acne (so-called 2.4,5*trichlorophenoxyacetate. Prac Lek 26:332-339.1974. chloracne) due to the chlorinated aromatic cyclic esters. Der 12. Kociba R), Keyes DC. Beyer IE, et al: Results of a two-year matologica U5;540-54(i. 1957. chronic toxicity and oncogenicity study of 2.3,7,&-tetrachlorodibenzo- 3. Ashe WF and Suskind RR: Reports on chloracne cases, Monsanto p-dioxin in rats. Toxicol Appl Pharmacol 46:279-303, 1978. Chemical Company, Nitro. West Virginia. Reports of the Kettering 13. Van Miller |P . Lalich ||, and Allen |R: Increased incidence of Laboratory. December 1949 and April 1950. neoplasms in rats exposed to low levels of 2.3.7.8-tetrachlorodibenzo- 4. Suskind RR: A clinical and environmental survey, Monsanto p-dioxin. Chemosphere 6:537-S44.1977. /- Chemical Company, Nitro. West Virginia. Report of the Kettering 14. Monson RR: Analysis of relative survival and proportional mor Laboratory. July 1953. tality. Comput Biom ed Res 7:325*332,1974. 5. Suskind RR: Chloracne and associated problems. Report to the 15. Eigth Revision. International Classification of Diseases, Adapted Conference of the National Institute of Environmental Health Sciences on Chlorinated Dibenzodioxins and Dibenzofurans. April 3, for Use in the United States. U.S. Department of Health. Education and Welfare, Public Health Service, PHS Publication No. 1693. 1973. Washington: U.S. Government Printing Office, 1977. 14 Mortality Experience ol Workers Exposed to Telrachlorodibenzodioxin/Zack and Suskind Px/7-W In 19$3. four of the six w orkers exam ined in 1949 and 19S0 wece re-exam ined and six additional w orkers involved in the accident w ere also exam ined. The findings in this " fa ter exam in ation indicated a general regression of both the cutaneous and noncutaneous symptom s w hich had been present earlier. A ll of the workers showed a m arked Im p ro vem en t in their skin lesions -- there w ere residua of the acne and a few active lesions. In a few cases, w orkers co n tin u e d to co m p la in of a ch e s and pains o f the lo w er ex' tremities"~ahd b ack, nervousness, excessive fatigue, and dyspnea. No clin ica l explanation for these com plaints co uld be m ade based on the results o f the physical ex am ination.* Journal ol Occupational M e d icin e January 1960 VoC 22 No. 1 0m \ Thirty-six persons were followed over a period of four years In very few cases workers continued to complain of mild pains, P *n 2 i nervousness, and faticue. Mild residua of acne were common. Presented a t the Jo in t Conference, National In s titu te o f Environm ental Health Sciences In t e r n a t io n a l Agency fo r R esearch on C a n c e r, WHO, Ly o n , F ra n c e , Ja n u a ry 11, 1978. All of the known therapeutic measures used by dermatol ogists at the time were not effective for acne. The cutaneous changes regressed slowly following removal from exposure. It was difficult to control the pain with common analgesics. Tranquilizers ware effective for the nervousness and irritability ^*hxrty-:six* (-36)-- persons-wer-e -examined- f o u r ..(4J-- yj^ars ._aJLtex,,the_ _ onset of the problem in the -plant, many of whom had severe symptoms initially. In only a few cases did workers continue to complain of pains., nervousness, and fatigue . There was no evidence of systemic disetase, but there was definite residua of the acne (scars and cysts). Presented a l NItHb conference, April 1973 Research Triangle Park, North Carolina