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ATTACHMfAsT X Original Articles -> A' _ 0 \r >/ J`i' The Mortality Experience Journal ol Occupational Mej dicine 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 tetrachiorodibenzodioxin in a trichlorophenoL process -accident at the M onsanto Com pany *plant in Nitro. West Virginia. O ne hundred and twenty-one workers w ho developed chioracne resulting from this acci dent on M arch 8, 7949, werese/ected for study. Follow-up of this group was 1 0 0 % complete. The standardized mor tality ratio for all causes of death was shown to be 0.69. with 32 deaths observed and 46.47 expected. For the categories of malignant neoplasms and circulatory diseases, the standardized mortality ratios were 1.00 and 0.68, respect/ve/y. 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 neoplasm s 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. The results of tb/s study will be incorporated with those of a larger study which will include plant workers ex posed in the course of 2,4,5-tricb/oropbenoxyacetic acid production during the period 1943 to 7969. 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* T1 from 2.4.5-trichlorophenol (TCP). The most consistent clinical finding is chioracne. a skin disease characterized by com- From the Department of Medicine and Environmental Health. M o m an to Company. BUQ N Lindbergh Blvd. S t Loun. M O SJ166 ( M i Zack. EpKlemtotoinitL and the Inititute ot Environmental Health. Ketterwiy Laboratory, the Uniwennv ot Cincinnati M edical Center. Cincinnati. O H 4S2&7 (Or Suikmd. Oirectort 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.1 Chioracne has been shown to be essentially due to 2,3,7,8-tetrachlorodibenzodioxin (TCDD).J a byproduct in the synthesis of 2.4.5-T. The sub ject of this paper is the chronic health effects of exposure to TCD D. as reflected in the mortality experience of a cohort of Monsanto Com pany workers who developed symptoms of chioracne following a trichlorophenol pro cess accident at the Nitro. West Virginia: plant in|l949. 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 vyas'ap* plied and. when the pressure reached the desired point the autoclave was vented. O n M arch 8,1949. about six months after production start-up. a violent reaction and decom position occurred when temperature and pressurej 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 eve and respiratory tract irritation, headache, diz ziness and nausea, and a severe irritant reaction of the ex posed skin. After these initial symptoms subsidejd. the chioracne and other symptoms became evident. Ashe and Suskind*"* examined a total of 12 more severely afifected workers on three occasions during the period of 1949 to 1953. Another 26 persons with chioracne, apparently not related to the accident, were also examined in 1953. The 000209 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. O n examination, all of the cases had chloracne. Several were severely hyperpigmented. especially on the face. O f the six workers ex amined in 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 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. N o 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 Suskind are consistent with those which have been reported in other industrial*episodes which occurred subsequently.' The acute health effects .of T C D O exposure are described in the literature,7-bur 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 neoplasms.1'11 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 T C P '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. O f the six cancer deaths, three were from stomach cancer in the age group 6069. 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 a l* 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 in 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 T C D D exposure to animals has been more extensively studied. T C D D toxicity has been thoroughly reviewed.7 Chronic toxicity to T C D D 1 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 C D D to rats is associated with an increased incidence of neoplasia, in one study, the oral administration o f T C D D produced an increase in hepatocellular carcinomas and squam ous cell carcinomas of the lung, hard palate/nasal turbinates, or tongue.'1 In another study, T C D D fed to rats produced tumors in 3 0 % of the test animals.11 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 w ho 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 twentv-one white males were included in this studv -- 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. A n analysis of the chloracne cases and exposures not associated with this accident but rather with the normal TCPf'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 M on son 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 studv cohort was assumed to have entered the studv on M arch 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 ceiO iu Q a 3 ^ 9 o b - %1 Table 1. -- Observed and Expected Deaths Among 121 Males Exposed to Tetrachlorodibenzodioxin In a Trichlarophenol Process Accident. Cause ah causes or aeatn All malignant neooiasms Buccal cavity and pnarynx (Digestive organs ana oentoneum Sfomacn Liver All outer digestive organs Resoiratory system Lung All other respiratory organs Skin Genitourinary organs Lympnatic ana hematoooietic tissue Other sites Diseases ot the nervous system ana sense organs Diseases ot the circulatory system Arteriosclerotic heart disease. including coronary heart disease All other disease al the circulatory sysiem Diseases of me resoiratory system Diseases of the digestive system All other ciseases External causes of death ICQ No. (Eighth Revision) 140-209 140-149 150-159 151 155-156 -- 160-163 162.163 -- 172.173 185-189 200-209 -- 320-389 390-458 410-413 ' , -- 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 t ~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 SMH .3;' 1.00 r t t t f 1.66 1.75 t t! ri ri t' r 0.68 0.73 t r t f r 'p < 0.05 tless man 5 ooserveo deaths tained. The underlying cause of death was coded to the 8th .Revision of the International Classification of Diseases. Adapted'1 by an experienced nosologist Results A ll 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 shovyn 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. j There were 17 observed deaths from circulatory diseases with 25.01 expected. The standardized mortality ratio for circulatory diseases was low at 0.68. j 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 studv 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 2, -- Cancer Deaths Among a Cohort of 121 Males Exposed to Tetrachlorodibenzodioxin in a Trichlorophenol Process Accident. Year of Birth 1909 1910 1911 1922 1915 1920 1919 1907 1910 Year of Hire . 1943 1927 ' 1939 1945 1939 1946 1943 1943 1939 Year of Death t962 5 % 1970 1964 S 3 1973 1970 1978 A ? ^ 1973 S e/ 1971 c / 1978 6 ^ Death Certificate Statement of Cause of Death Lung cancer (162.1) Pulmonary carcinoma (162. t) Bronchiogentc carcinoma (162.1) Broncniogemc carcinoma (162.1) . Lung cancer (162.1) ` Malignant fibrous histiocytoma ot soft tissue origin (173.9) Hodgkin s disease (201.0) Lymphatic leukemia (204 9) Acute myelogenous leukemia (205 0) 'Smoking nistory was aotamed oy interviews with former co-workers at tne aeceaenis Journal of Occupational Medicine/Vol. 22. No. 1/January 1980 Smoking History* Cigarettes Cigarettes Cigarettes Nonsmoker Cigarettes Cigarettes Cigarettes Pipe Cigarettes i ' i 1 , 1 1 1 000211 ; 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 C D D m av be more definitely evaluated. The authors wish to thank M rs lanet Yung. M r Randy Pwolet, and Mrs Phyllis Korte for their assistance with the data collection References 1 International Agency for Research on Cancer (ARC Monographs on the Evaluation ot the Carcinogenic Risk of Chemicals to Man. Vol 15. Some Fumigants, the Herbicides 2.4-0 and 2.4,5-T, Chlorinated Dibenzodioxms and Miscellaneous Industrial Chemicals Lyon* IARC, 1977 2. Kimmig | and Schulz KH. Occupational acne (so-called chloracne) due to the chlorinated aromatic cyclic esters. Dermaro/ogica 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. July 1953. 5 Suskind RR. Chloracne and associated problems. Report to the Conference of the National Institute of Environmental Health Sciences on Chlonnated Dibenzodioxms and Dibenzofurans, April 3. 1973. 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, lanuarv 11. 1978 7 Young AL. Calcagm JA. Thalken CE. et al The toxicology, en vironmental fate, and human risk associated with herbicide jorange 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 I 8. International Agency for Research on Cancer Long-term hazards of polychlorinated dibenzodioxms and polychlorinated j diben zofurans IARC Internal Technical Report No 78'001. Lyon, 1,978 9. Iirasek L. Kalensky |, and Kubec K. Acne chlonna and "porphyria cutanea tarda during the manufacture of herbicides Cesk Dermatol 48.306-317. 1973. j 10. Iirasek L. Kalensky I. Kubec K. et al: Acne chlorina. porphyria cutanea tarda, and other manifestations of general poisoning during the manufacture of herbicides. II CesfcJOermatof 49:145*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-trichlorophenoxvacetate Prac Lek 26.332-339.1974 j 12. Kociba RJ. Keves DC. Beyer IE, et al; Results of a two-year chronic toxicity and oncogenicity study of 2.3,7.8-tetrachlorodibenzo- p*dioxin in rats Toxicol Appl Pharmacol 46.279-303.1978. I 13. Van Miller |P. Lalich )]. and Allen |R: Increased incidence of neoplasms in rats exposed to low levels of 2.3.7.8-tetrachlorodibenzo- p-dioxin. Chemosphere 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, PHS Publication No 1693. Washington: U.S Government Printing Office, 1977 Future Risk In the industrial countries we have grown rich during the age of hierarchical business corporations, in which each executive arranges what the man below htm will do with his hands, all the way down to the man turning a screw on the assembly line. Now, two rather fundamental things have happened. First, we have begun to realize that workers in rich countries don't like working in such places. Secondly, the rich countries are moving out of the postmanufacturing age. but thev still have great hierarchical cor porations in which executives sit behind their desks trying to arrange what the man below will do with his imagination. This no longer works. New. forms of business organization will have to be found, probably changing big corporations into confedera tions of entrepreneurs. The firms and countries that will go bust in these circumstances are those that try to replace hierarchical corporations by even more ossified forms of hierarchy -- say. by deciding that you mustn't have a boss trying to arrange what free men do with their imaginations, but can have a trade union committee doing so in stead. -- From "U nitJ S la t Can K w o Crow ing -- And Lead -- It it Wnht*%" bv Norman M at rat* in Smtrntoman. lulv 197b 000212