Document pmO26e1rmnzZ7365bwJEVor1X

clinical symptoms, in order ot relative frequency.4 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 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.3s * 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 ot 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 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,7 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 * Of 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 al9 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 intw'oot 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 ot TCDD exposure to animals has been more extensively studied TCDD toxicity has been thoroughly review-ed7 Chronic toxicity to TCDD is manifested by liver necrosis, thymic atrophy, and deple tion of the lymphoid organs Two studies indicate that 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 13 In another study. TCDD fed to rats produced tumors in 38% of the test animals 13 Neoplastic nodules and cholangiocarcinomas ot 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 follow'ing 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 w-ho 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 subiect of a future paper. The data were analyzed by the modified life-table method using the updated Monson program 14 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 Suskind T ab le 1. -- O b serv ed and Exp e cted D eaths A m ong 121 M ales E xp o sed to T etra ch lo ro d ib en zo d io xin in a T rich lo ro p h en o l P ro c e ss A c cid e n t. s < - Cause All causes ot death AH malignant neoplasms Buccal cavity and pharynx Digestive organs and peritoneum Stomach Liver All other digestive organs Respiratory system Lung All other respiratory organs Skin Genitourinary organs Lymphatic and hematopoietic tissue Other sites Diseases of the nervous system and sense organs Diseases ot the circulatory system Arteriosclerotic heart disease, including coronary heart disease All other disease ot the circulatory system Diseases of the respiratory system Diseases ot the digestive system All other diseases External causes ot death ICO No (Eighth Revision) " t___________________ v. i 140-209 140-T49 1 150-159 151 :> 155-156 -. 160M63 ' 162.163 ' 4. A 172.173 185-.189 v 200-209 --` ' ,5 320.389 : 390-458 ) , 410-413 , . 460-519 ** 520-577 1 ; -- ,. 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 1*J * % ; ;; SMR 0 69` 1 00 f 1 f s t -, - t 1 66 1 75 f f f t f t c 0 68 0.73 . t f t t t *p < 0.05 tLess than 5 observed deaths tamed The underlying cause of death was coded to the 8th Revision of the International Classification of Diseases, Adapted15 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 w'ere five lung cancer deaths versus 3.02 expected and one skin cancer death with 015 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... . * f'# 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 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 T ab le 2 . -- C a n c e r D eaths A m ong a Cohort ot 121 M ale s E x p o se d to T etra ch lo ro d ib en zo d io xin in a T rich lo ro p h e n o l P ro c e ss A ccid e n t. Year of Birth 1909 1910 1911 1922 1915 1920 1919 1907 1910 Year ot Hire 1943 1927 1939 1945 1939 1946 1943 1943 1939 Year of Death 1962 1970 1964 1973 1970 1978 1973 1971 1978 Death Certificate Statement of Cause of Death Lung cancer (162.1) Pulmonary carcinoma (162.1) Bronchiogemc carcinoma (162.1) Bronchiogemc 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) ` Smoking history was obtained by interviews with former co-workers ot the decedents Journal of Occupational Medicine/Vol. 22, No. 1/January 1980 Smoking History* Cioarettes 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 TCDD on mortality By augmenting these data with the results of comparable mortality studies, the long-term effects of TCDD may be more definitely evaluated The authors wish to thank Mrs lanel Yung, Mr Randv Picolet. and Mrs Phyllis Korte lor 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-D and 2.4.5-7. Chlorinated Dibenzodioxins and Miscellaneous Industrial Chemicals Lyon, IARC, 1977 2 Kimmig ) 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. |uly 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 lomt Conferente. National In stitute of Environmental Health Sciences International Agency for Research on Cancer. Lyon France lanuary 11 1978 7 Young AL. Calcagni |A. Thalken Cf et al The toxicology, en vironmental fate, and human risk associated with herbicide orange and its associated dioxin U S Air Force Occupational and Erv vironmental Health Laboratory Report OEHL TR-78-92 Brooks Air Force Base. Texas. 1978 8 International Agency for Research on Cagcer Long-term hazards of polychlorinated dibenzodioxins and polychlorinated diberv zofurans IARC Internal Technical Report No 78/001. Lyon. 1978 9 lirasek L. Kalensky |, and Kubec K Acne chlorina and porphyria cutanea tarda during the manufacture of herbicides CesA Dermatol 48 306-317. 1973 10 lirasek L, Kalensky J. Kubec K, et al Acne chlorina. porphyria cutanea tarda, and other manifestations of general poisoning during the manufacture of herbicides II CesA Dermatol 49 145-157. 1974 11 Pazderova ), Lukas E. Nemcova M, et al Chronic poisoning by chlorinated hydrocarbons formed in the production of sodium 2.4.5-tnchlorophenoxyacetate Prac LeA 26 332-339. 1974 12 Kociba R), Keyes DC. Beyer |E. et al Results of a two-year chronic toxicity and oncogenicity study of 2.3.7.8-tetrachlorodibenzop-dioxin in rats Toxicol Appl Pharmacol 46 279. 303. 1978 13 Van Miller |P, La lie h |J. and Allen |R Increased incidence of neoplasms in rats exposed to low levels of 2.3.7.8 tetrachlorodibenzop-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 E igth 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 14 Mortality Experience of Workers Exposed to Tetrachlorodibenzodioxin/Zack and Suskind