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Monsanto ________________________________________________________ DEPARTMENT OF MEDICINC & environmental health M onsanto Com pany 8 0 0 N. Lm dPargh B o ulevard S t. Lo u is. M isso u ri 63167 P h o n e : (31 -4) 6 9 4 - 1 0 0 0 ,, February 27, 1985 David P. Brown National Institute for Occupational Safety and Health Robert A. Taft Laboratories 4676 Columbia Parkway Cincinnati, Ohio 45226 MAR 4 10:5 Dear David: Enclosed is a photocopy of the report "Mortality of PCB Workers at the Monsanto Plant in Sauget, Illinois" by Judith Zack and David Musch. As far as I know, this is the final report, although the report was never published in the scientific literature. It was good hearing from you yesterday. I will be attending the NI0SH Dioxin Registry meeting in Cincinnati on March 14-15, 1985, and I- am looking forward -to- seeing: the old crew that-is still working-At N10SH. Sincerely, Enclosure c c : W .R . Gaffey Terry L. Leet Mortality of PCB Workers at the Monsanto Plant in Sauget, Illinois Judith A. Zack and David C Musch December 14, 1979 Page-1-: ^ ; Summary An historical prospective mortality study was conducted on workers exposed to polychlorinated biphenyls at the Monsanto Company plant in Sauget, Illinois. Eighty-nine workers exposed to PCBs for a min imum of six months during the period 1945 to 1965 were followed for their mortality experience. Observed deaths were not statistically different from expected deaths for any of the cancer sites examined. No deaths were observed from cancer of the liver or pancreas or from malignant melanoma. No excess was seen in deaths from liver cancer. A statistically significant excess of circulatory disease, exclusive of arteriosclerotic heart disease, was seen in white males. Background The term "polychlorinated biphenyls" (PCBs) describes a group of mixed chlorinated biphenyls which vary in consistency from light free-flowing liquids to crystalline and non-crystalline solids depending on the degree of chlorination. PCBs have been in commerical use since 1929. Their electrical properties, fire resistance, and inertness have made them popular for many applications. They have been used particularly in the production of electric capacitors and transformers and in the insulation of electric cables and wires. Reports of adverse health effects in man and carcinogenic effects in certain animals species prompted the National Institute of Occupa tional Safety and Health (NIOSH) to request that epidemiological stud ies be carried out on PCB-exposed worker populations. In a prelimin ary study of workers exposed to PCBs at the Mobil Oil Company plant in Paulsboro, New Jersey, Bahn reported an excess of deaths from malign ant melanoma and pancreatic cancer among research and production employ ees.^- At the same time, Roush reported the findings of a preliminary mortality study of PCB workers at the Monsanto Company plant in Sauget, Illinois (G. Roush, written communication, September 1976). No cases of malignant melanoma or pancreatic cancer were found. The accidental poisonings with PCBs in Yusho, Japan provide informa tion on the acute toxic effects of PCBs for man. PCB poisoning occur red following the ingestion of Kanemi rice oil contaminated with PCBs. The general symptoms of Yusho disease included neuroendocrine disturb ances, abnormal lipid metabolism, disturbances of the respiratory 2 system, acneform eruption, pigmentation, and ocular changes. Yusho disease, however, has also been attributed to the ingestion .of poly chlorinated dibenzofurans (PCDFs) present in the rice oil as PCB con taminant. The presence of PCDFs obscurs the relationship of PCBs to the clinical picture of Yusho disease. In 1976, the Monroe County Board of Health conducted biochemical tests among Bloomington, Indiana residents exposed to PCBs. Serum levels of gamma glutamyl transpeptidaise and plasma triglyceride levels were found to show a direct relationship t o `serum PCB levels. 3 In a recent study, Warshaw et al. evaluated pulmonary function in 243 .4 workers exposed to PCBs in the manufacture of capacitors. Thirtyfour of these workers (14%) were found to have abnormal forced vital capacity measurement. Of these thirty-four, twenty-seven demonstrated a restricted pattern of impairment with virtually no radiographic change. The relationship between restrictive spirometric impairment and dura tion of PCB exposure was not addressed in this study. Extensive studies of PCB toxicity for animals have been conducted and have been throughly reviewed.^ In a two-year chronic oral toxicity test of PCBs, no carcinogenic effects were observed in the rats and beagles tested. Hyperplasia, hypertrophy, extensive fibrosis, and several benign tumors were observed in the livers of the rats, but there was no evidence of malignancy of any of the test animals.^ Other investigators have reported liver tissue effects ranging from hyperplasia to well-differentiated hepatocellular carcinomas in rats or mice fed with various PCB-containing diets. Kimbrough fed rats PCBs and observed lipid accumulation, hypertrophy, and adenofibromas, .7 but no maligancies in the livers of the test animals. In a later - Page- -3 - experiment, the same researcher-reported the induction of hepatocellu lar carcinomas and neoplastic nodules of the liver.8 The literature on PCB toxicity points to several organ sites in man that could potentially incur toxic effects of exposure to PCBs. The present study represents a completed analysis of the preliminary study w of Monsanto PCB workers reported in 1976. This study will examine the mortality experience of PCB workers with particular attention given to overall cancer, liver and pancreatic cancer, and malignant melanoma. Population and Methods This study focused on workers exposed to polychlorinated biphenyls at . the Monsanto plant in Sauget, Illinois. PCBs were manufactured at this plant during the period 1936 to 1977. All male employees from the hourly roll who worked in the PCB department for at least six months between January 1, 1945, and December 31, 1965, were selected for study. During the period of study, the PCB process remained relatively unchanged. The process, in brief, involved the batch chlorination of biphenyls in the presence of iron and iron chloride catalysts. The crude mixture produced in the chlorinators was aerated, distilled, earth treated, filtered and transferred to storage tanks. No industrial hygiene data were available to quantify the PCB exposure levels. Through inter views with plant personnel, it was determined that exposure levels to PCB did not vary considerably within the PCB department. Therefore, all workers in the PCB department were considered to have common expo sure level. Other exposures in this department included hydrochloric acid, tri- and tetrachlorobenzene, biphenyl, and chlorine gas. The PCB worker cohort was identified from the p l a n t 's computerized work history system. Eighty-nine male hourly employees met the criteria for inclusion in the study. The vital status of each member was deter mined as of December 31, 1977, using standard followup techniques. A death certificate was obtained for each person found to be deceased. The underlying cause of death was coded to the Eighth Revision of the 0 International Classification of Disease, Adapted by an experienced independent nosologist. The data were analyzed by the modified life' table method using the Q Monson program. Standardized mortality ratios were calculated for IV nineteen selected cause-of-death categories. Mortality comparisons were made with the general U.S. population. Statistical significance was determined at the 5% level assuming a Poisson distribution. Results Eighty-eight of the eighty-nine members of the study cohort were traced. Fifty-eight were verified living and thirty were verified deceased by death certificate. The results of this vital status tracing are shown in Table 1. The person-years of observation contributed by the eighty-nine member study cohort are shown in Table 2. A total of 1800.1 person-years were observed at all ages. Most of these person-years were observed in the middle-age range with 1333.1 person-years (74%) observed for ages 35-60.' Table 3 categorizes duration of exposure to PCBs by vital status. For both living and deceased workers, the majority were exposed less than three years. The next frequent exposure class was for five or more years of exposure. The least number of workers fell in- the three to five years of exposure category. Overall, the average length of expos ure for living and deceased workers was similar with deceased workers having 3.7 years of exposure and living workers having slightly less at 3.2 years. The mortality experience for all males is summarized in Table 4'. The mortality of white and nonwhite males is examined separately in Tables 5 and 6. Observed and expected deaths and SMR's are shown for each of the nineteen cause-of--death categories examined. I 'V, ?. v.rage^.0 For all males, there were 30 deaths observed and 22.88 expected (Table 4). The overall SMR was 131. For malignant neoplasms, 8 deaths were obser ved with 4.46 expected. The SMR for all malignant neoplasm was 179. No deaths were observed from liver or pancreatic cancer or from malig nant melanoma. The SMR for lung cancer was high at 278. The only statistically significant difference seen in this table is seen for u diseases of the circulatory system, exclusive of arteriosclerotic heart disease. Nine deaths were observed with 3.98 expected, yielding a SMR of 226. Table 5 shows the overall SMR remains high for white males at 133. There were 4 deaths from cancer with 2.70 expected. None were from liver or pancreatic cancer or from malignant melanoma. The high S M R 's seen in Table 4 for lung cancer and the residual diseases of the circula tory system appear to be explained by the high S M R 's for these causes in white males'. There were 3 deaths observed from lung cancer with 0.94 expected, yielding a SMR of 319. For the category of circulatory disease, exclusive of arteriosclerotic heart disease, the SMR was 526 with 7 observed and 1.83 expected deaths. This difference was the only one of statistical significance in this table.* For nonwhite males, there were no statistically significant differences seen in Table 6. The overall SMR was also high at 128. Four deaths from cancer were observed with i.76 expected, but none from liver or pancreatic cancer or from malignant melanoma. Case histories for the eight cancer deaths are summarized in Table 7. Discussion The results of this study do not corroborate an excess risk of pancreatic cancer or malignant melonoma among workers exposed to PCBs as reported in the study of Mobil workers. Nor do the results uphold translating to man the outcome of animal tests, in which hepatomas have been associ ated with long-term PCB exposure. In this study, no deaths were ob i served from pancreatic or liver cancer or from malignant melanoma. The SMR for all causes was elevated from what one would expect in an industrial cohort. The high SMR for white males is, for the most part explained by the excess in deaths from circulatory -diseases exclusive of arteriosclerotic heart diseases. This cause-of-death category includes deaths from rheumatic heart disease, cerebrovascular disease, and other forms of heart disease, all of which are unlikely to be related to exposure in the workplace. It is urged that a larger study to be undertaken of the total Kruiranrich plant population to evaluate the overall risk of death from all causes and from cardiovascular dis eases .  v y -vi; is. References 1. Bahn Ak, Rosenwaike I, Herrmann N, et al: Melanoma after Expo sure to PCB's. NEJM 295:450, 1977 2. Kuratsune M, Masuda Y, Nagayama J: Some of the Recent Findings Concerning Yusho, in Proceedings of the National Conference on Polychlorinated Biphenyls, November 19-21, 1975, Chicago, EPA560/6-75y004. US Environmental Protection Agency, Office of Toxic Substances, 1976, pp 14-29 3. Morbidity and Mortality Weekly Report: Polychlorinated Biphenyl Exposure - Indiana. Center for Disease Control, 27 (12):99-100, 1978 4. Warshaw R, Fischbein A, Thorton J, et al: Decrease in Vital Cap acity in PCB-exposed Workers in a capacitor manufacturing facility. In Health Effects of Halogenated Aromatic Hydrocarbons, Annals of the New York Academy of Sciences, New York, 1979. Vol 320 5. International Agency for Research on Cancer: Polychlorinated biphenyls and Polybrominated biphenyls. Iarc Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Lyon, 18, October 1978 6. Kimbrough RD, Linder RE, Gaines TB: Morphological changes in liver of rats fed with polychlorinated biphenyls. Arch Environ Health 25:354-364, 1972 7. Kimbrough RD, Squire RA, Linder RE, et al: Induction of liver tumors in Sherman strain female rats by polychlorinated biphenyl Aroclor 1260. J. National Cancer Inst. 55:1453-1459, 1975 8. Eighth 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 9. Monson RR: Analysis of relative survival and proportional mortal ity. Comput Biomed Res 7:325-332, 1974 i Table 1 Polychlorinated Biphenyl Workers Results of Tracing as of 12/31/77 Total to be traced Status Known Verified Alive Verified Dead Death Certificate Death Certificate Found NotFound Status Unknown 89 88 58 30 30 0 1 Table 2 Person-Years of Observation Contributed by Workers Exposed to P C B 's by Five Year Age Groups Aqe in Years 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65+ . Total - All Workers Person-Years of Observation 11.4 63.8 142.6 222.5 283.2 325.3 294.5 207.6 134.0 115.2 1800.1 Table 3 Duration of Exposure to P C B 's for Workers by Vital Status Years of Exposure < 1 yr. Living N=58 20 Deceased N-30 5 Unknown N=1 1 Total N=89 26 1-3 yrs. 20 12 0 32 3-5 yrs. 64 0 10 > 5 yrs. 12 9 0 21 Average Length of Exposure 3.2 yrs . 3.7 yrs. 0.7 yrs. 3.3 yrs. Lifetime exposure prior to 1-1-66. I.C.D No. (Eiqhth Rev.) 140-209 140-149 150-159 155,156 - 160-163 162,163 185-189 200-209 - 390-458 410-413 - 460-519 520-577 - 800-998 Table 4 Observed and Expected Deaths, All Males Cause.of Death Observed All causes of death All malignant neoplasms Buccal cavity and pharynx Digestive organs and peritoneum Liver All other digestive organs Respiratory system Lung All other respiratory organs Genitourinary organs Lympatic and hematopoietic tissue Other sites Diseases of the circulatory system Arteriosclerotic heart disease All other diseases of the circulatory system Diseases of the respiratory system Diseases of the digestive system All other diseases External causes of death 30 8 0 1 0 1 4 4 0 1 1 1 16 7 9 1 2 2 1 Expected 22.88 4.46 0.16 1.33 0.10 1.23 1.53 1.44 0.09 0.51 0.40 0.53 11.17 7.19 3.98 1.27 1.20 2.40 2.38 SMR 131 179 - 75 - 81 261 278 - 196 250 189 143 97 226* 79 167 83 42 Number of persons observed = 89 * P <-05  v *r- Table 5 Observed and Expected Deaths, White Males I.C.D. No. (Eiqhth Rev.) 140-209 140-149 150-159 155,156 160-163 162,163 185-189 200-209 - 390-458 410-413 460-519 520-577 800-998 Cause of Death Observed All causes of death All malignant neoplasms Buccal cavity and pharynx Digestive organs and peritoneum Liver All other digestive organs Respiratory system Lung All other respiratory organs Genitourinary organs Lymphatic and hematopoietic tissue Other sites Diseases of the circulatory system Arteriosclerotic heart disease All other diseases of the circulatory system Diseases of the respiratory system Diseases of the digestive system All other diseases External causes of death 18 4 0 0 0 0 3 3 0 0 0 1 11 4 7 0 1 2 0 Number of persons observed ** 60 *p <.05 Expected 13.-53 2.70 0.09 0.75 0.05 0.70 0.94 0.89 0.05 0.28 0.28 0.36 6.82 4.99 1.83 0.73 0.75 1.10 1.43 SMR 133 148 319 337 -- 278 161 80 526* - 133 182 - "r V`f 'v i I.C.D, No. (Eiqhth Rev.) 140-209 140-149 150-159 155,156 160-163 162,163 185-109 200-209 390-458 410-413 460-519 520-577 - 800-998 T a b l e .6 Observed and Expected Deaths, Nonwhite Males Cause of Death Observed All causes of death All malignant neoplasms Buccal cavity and pharynx Digestive organs and peritoneum Liver All other digestive organs Respiratory system Lung All other respiratory organs Genitourinary organa Lymphatic and hematopoietic tissue Other sites Diseases of the circulatory system Arteriosclerotic heart disease All other diseases of the circulatory system Diseases of the respiratory system Diseases of the digestive system All other diseases External causes of death 12 4 0 1 0 1 1 1 0 1 1 0 5 3 2 1 1 0 1 Number of persons observed = 29 Expected 9.35 1.76 0.07 0.58 0.05 0.53 0.59 0.55 0.04 0.23 0.12 0.17 4.35 2.20 2.15 0.54 0.45 1.30 0.95 SMR f 128 227 -- 172 -- 109 169 102 - 435t 833 -- 115' 136 93 , 185^: 222i: -^ 105 y Race Nonwhite Nonwhite Nonwhite White White White Nonwhite White Table 7 Case Summaries of Cancer Deaths Amonq PCB Workers Year of Birth 1909 1913 1909 1893 1912 1916 1907 1906 Year of First Exposure 1942 1954 1951 1943 1951 1951 1945 1940 Year of Death 1959 1965 1968 1963 1968 1977 1964 1957 Duration Ever Exposed to P C B 's 1 yr., 1 mo. 7 yrs., 1 mo. 2 yrs., 4 moB. 2 yrs., 10 mos. 2 yrs., 4 mos. 2 yrs., 9 mos. 8 mos, 6 y r s ., 7 m o s . Death Certificate Statement of Cause of Death Carcinoma of colon (153.8) Carcinomatosis - ,, primary site kidney (189,0) Carcinoma of the lung (162.1) Carcinoma right lung (162.1) Cancer of lung (162.1) Carcinoma of lung (162.1) Multiple myeloma (203.0) Metastatic carcinoma carcinomatosis (199.0)