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American journal of Industrial Medicine 18:19-24 (1990) Liver and Biliary Tract Cancer Among Chemical Workers Gregory G. Bond, PhD, mph, Elsie A. McLaren, rn, Fred L. Sabel, ms, Kenneth M. Bodner, msph, Thomas E. Lipps, md, and Ralph R. Cook, md, mph A recent cohort mortality study of male, hourly wage employees of a large Michigan chemical production and research facility had found a greater than expected number of deaths coded to liver and biliary tract cancer. In response, an additional investigation was then undertaken of the 44 liver and biliary tract cancer deaths observed between 1940 and 1982. A random sample (N = 1.888) of subjects was selected from the total cohort (N = 21.437) to serve as referents. Company work history records were used to classify cases and referents by work area assignment and potential for exposure to 11 selected chemical agents which have been shown to produce cancer of the liver or biliary passages in experimental animals. Statistically significant associations in both positive and negative directions were found for several work areas within the facility. A sug gestive association was found for vinyl chloride monomer, based on five cases with presumed exposure. Key words: carbon tetrachloride, epidemiology, methylene chloride, retrospective studies, vinyl chloride INTRODUCTION A recently conducted cohort study of the more than 37,000 male employees from Dow Chemical's Midland/Bay City, Michigan, production, research, and head quarters units showed more deaths than expected from cancer of the liver and biliary passages (SMR= 140. 95% Cl = 99-191) among hourly workers [Bond et al.. 1987], No data relating to personal or occupational exposures were collected as a part of the original study. This was by design since it was not feasible to collect such comprehensive information on all workers. This paper describes the results of a follow-up investigation which used a hybrid study design involving a modification of the traditional case-control method [Kupper et al.. 1975). \ Depanmem ot Epidemiology. Health and Environmental Sciences. The Dow Chemical Company, Mid land, Ml (G.G.B.. K.M.b'.. R.R.C.). Medical Depanment. Michigan Division. Dow Chemical U.S.A.. Midland, Ml (E.A. McL.. T.E.L.). Industrial Hygiene Services. Michigan Division. Dow Chemical U.S.A.. Midland. Ml (F.L.S.). Address reprint requests to Dr. Gregory G. Bond. Department ot Epidemiology, Health and Environ mental Sciences. The Dow Chemical Company. 1803 Building. Midland. Ml 48674. Accepted for publication February 7, 1990. s 1990 Wilev-Liss. Inc. R&S 143238 20 Bond et al. METHODS AND MATERIALS Death certificates ol all male, hourly employees who died during 1940-1982 (N = 6,259) were reviewed tor a statement of primary liver cancer, cancer of the liver not specified as primary or secondary, or cancer of the gallbladder or bile ducts (ICDA-8 codes 155-156 and 197.8) mentioned anywhere on the document. This identified 44 cases, of which 11 were coded to primary liver cancer. 14 to cancer of gallbladder or bile ducts, and the remaining 19 to cancer of the liver not specified as primary or secondary. From the cohort of male, hourly employees (N = 21,437) who composed the original study population [Bond et al., 1987], a random sample (N = 1.888) was chosen to serve as referents. Company work history records were used to classify employee exposures by work area assignment (Bond et al., 1985. 1986) as well as by potential for exposure to 11 chemical agents chosen because they had been shown to produce cancer of the liver or biliary passages under experimental conditions in animals (Chu et al., 1984: Haseman et al.. 1984; NTP. 1985: Wilbourn et al.. 1986]. Visits to the Medical Department by the cases were reviewed by a nurse co-investigator (E.A.M.) to ascertain a historv of excessive alcohol use or hepatitis, as they are established risk factors for prime, liver cancer [Falk. 1982], This exercise was of limited usefulness, however, owing to: 1) the unavailability of medical records for those subjects who erminated their employment prior to 1947 (N = 24); and 2) a lack of information concerning any post-employment illnesses among the workers. Risk ratios were computed adjusted for birthyear by using the Mantel-Haenszel (1959) procedure. Analyses which additionally controlled for period of hire showed similar results to those which controlled only tor birthyear and are not presented. Likewise, analyses of the primary liver cancers separate from the gall bladder/bile duct cancers did not reveal additional information and are not shown. Ninety-live per cent test-based confidence intervals were calculated about the risk ratio estimates [Miettmen. 1976], RESULTS Analyses by work area assignments (Table 1) showed the cases were signifi cantly less likely to have held assignments in electrochemicals or organic chemical production, but were more likely to have held assignments in office maintenance (RR = 3.6: 959c Cl = 1.4-9.1). A positive association with assignment to polyvinvlpolyvinylidene chloride production did not reach statistical significance (RR = 2.0: 95% Cl" = 0.9-4 6). There were no statistically significant trends apparent when analyses were ma. c of duration of assignment within work areas: however, the idds ratio for an assign ment ol five or '"ore years to polyvinyl- 'Ivvinylidene chloride production was 3.7 (95% ( . = ().' 4.6) based on the conn.outton of two cases. Assignmei.. ,) polyvinvl-polyvinylidene chloride production areas was explored further in Figure 1 via a plot of the "attributable fraction" [Goldsmith et al., 1980] for each year during the period 1940-1980. The peak "attributable fraction" occurred in 1952. a year in which four of the seven cases assigned to these areas were all employed, no two in the same plant, however. None of the chemical agent comparisons revealed statistically significant dif- R&S 143239 Chemical Worker Liver/Biliary Tract Cancer 21 TABLE I. Age-Adjusted Risk Ratios for Analyses bv Major and Minor Work Areas: Study of Liver and Biliary Tract Cancer Among Chemical Workers. Midland. Michigan. 1940-1982* Exposure trequencies t</f) Major/minor work areas Cases (N = 44) Referents iN = 1.888) RR 95Vr Cl Administration 0 0 5.8 -- 0.0-1.5 Manufacturing Agricultural chemicals Herbicides Insecticides inorganic chemicals Ammonia 68.2 9.1 68 4.6 47.7 0.0 75.7 26.2 17.1 9.7 40.0 10 0.7 0.4-1.3 0.4 0.1-1.0 0.5 0.2-1.6 0.6 0.1-2.4 1.1 0.6-2.0 -- 0.0-8.4 Brine Brominated products 6.8 4.6 0.9 0 3-3.0 4.6 5.9 0 9 0.2-3.7 Calcium/magnesium 9.1 12.5 0.7 0.2-1.8 Caustic Cellulose products Electrochemicals 4 6 1 9 2.1 0 5-9 5 2.3 7.6 0.4 0.1-2.5 0.0 10.2 -- 0.0-0.8 Metal fabrication Organic chemicals Acrylamide Alkyl benzenes Chlorinated benzenes 22.7 36.4 0.0 0.0 0.0 16.8 56.8 2.1 3.9 3.6 1.1 0.6-2.2 0.5 0.3-0.9 -- 0.0-4.0 -- 0.0-2.2 -- 0.0-2.3 Dyes Fabricated plastics Glycols Halogenated hydrocarbons 6.8 6.1 0.7 0.2-2.3 6.8 16.5 0.6 0.2-1.9 0.0 1.8 -- 0.0-4.7 4.6 7.7 0.4 0.1-1 6 Ion exchange resins 2.3 2.0 1.2 0.2-8.7 Latex 2.3 2.7 0.8 0.1-6.2 Olefins 4.6 2.5 1.5 0.3-6.7 Phenol derivatives Polvstvrene 6.8 13.0 0 4 0.1-1.4 6.8 15.0 0.5 (l 1-2.0 Polvvinyl-polyvmylidene chloride Unknown manufacturing 15.9 0.0 10.1 2.0 0 9-4 6 1 0 -- 0,0-8.4 Research Service Animal handling 15.9 65.9 0.0 22.8 0 8 0 3-1.8 59 8 l.l 0.6-2.0 0.6 0.0-14.0 Boiler shop Construction 4.6 3.4 1.0 0.2-4.1 13.6 13.6 0.7 0.3-1.7 Electric shop Engineering Garage Lead shop Lubrication 2.3 2.8 0.9 0.1-6 4 2.3 1.6 1.7 0.2-12.5 0.0 2.5 -- 0.0-3.4 0.0 0.3 -- 0.0-28.0 0.0 0.4 -- 0.0-21.0 Machine shop Maintenance Material handling Office maintenance Paint shop 4 6 4 2 0.9 0.2-3 5 4 6 8.6 0.4 0.1-1.6 11.4 8.1 1 4 0.5-3.7 11.4 3.3 3 6 1.4-9 1 4 6 7 9 0.6 0.1-2.5 Pipe shop 9.1 10.3 0.8 0.3-2.3 Plant protection Power Road and yard mtc. Shops-steel & instrument Waste management 9.1 5.6 1.1 0.4-3.2 2.3 7 1 0.2 0.0-1.3 4.6 2.0 2.2 0.5-9 6 6.9 2.3 > i 0.7-7.5 0.0 1 2 -- 0.0-7 0 Well services 0 0 0.1 -- 0.0-83.8 'Workers may have been assigned to more than one work area during their employment and thus may be counted more than once in the table R&S 143240 22 Bond et al. o 1 (J o 05 o oo 1950 1960 CALENDAR YEAR 19 70 1 960 Fig. 1. Study of liver and biliary tract cancer. Attributable Traction tor assignment to polyvinyl-polyvinylidene chloride areas in each year during 1940-1980. ferences (Table II). The highest risk ratio (RR = 2.2; 95% Cl = 0.9-5.8) was for presumed exposure to vinyl chloride based on the contribution of five cases. There were no statistically significant trends for analysis by duration of exposure to any of the 11 agents, although in many instances there were too few exposed cases to permit meaningful conclusions. Likewise, there were no statistically significant trends ap parent when analyses were made bv estimated dose of exposure. DISCUSSION The present investigation revealed a statistically significant positive association with assignment to office maintenance, and some marginal associations with polyvinyl-polyvinyltdene chlorine production. The association with an assignment in office maintenance is curious, since this type of work is not generally considered hazardous. In fact, it was a common practice to assign to that department any workers who were not considered medically fit to work in more strenuous jobs. Company medical records were available to review for four of the five cases assigned to office maintenance, and revealed that two of the men had been hospitalized' for chronic alcoholism, suggesting that this finding may have resulted from confounding. High levels of vmvl chloride exposure have produced a specific hazard of angiosarcoma of the liver in some work forces [Doll. 1988]. In the present study, five of the seven cases of liver and biliary tract cancer who held assignments in the polyvinyl-polvvinylidene work area were considered to have had the opportunity for exposure to vinyl chloride monomer. There was no evidence that any of the five cases experienced angiosarcoma; however, pathology reports and/or medical records were R&S 143241 Chemical Worker Liver/Biliarv Tract Cancer 23 TABLE II. Age-Adjusted Risk Ratios for Analyses by Selected Chemical Agent Exposures: Study of Liver and Biliary Tract Cancer Among Chemical Workers. Midland. Michigan. 1940-1982* Exposure trequeneies I'/f-l Agent Cases (N = 44> Referents IN = 1.888) RR 95# Cl Carbon tetrachloride Chlorodibenzo-t p)-dioxins Chloroform Ethylene dibromide Ethylene dichloride Methylene chloride Perchloroethvlene Polychlorinated biphenyls 1.1.2-Trichloroethane 2.4,6-Trichlorophenol Vinyl chloride 11.4 2.3 4.6 2.3 6,8 4.6 13.6 0.0 0.0 0.0 1 1.4 20.0 9.1 67 7.3 14.6 8.9 11.3 1.2 0.5 0.9 7.8 0,5 0.2-1.4 0.2 0.4-1.4 0.6 0.2-2.7 0.4 0.1-3.0 0.4 0.1-1.3 0.8 0.2-3.6 l 8 0.8-4.3 -- 0.0-7.0 -- 0.0-16.8 -- 0.0-9 3 0.9-5.8 'Workers may have been exposed to more than one agent during their employment and thus mav be counted more than once in the table. available to confirm the diagnosis for only two of them. Table HI presents some descriptive information concerning these cases. By virtue of the time period in which they worked and the nature of their jobs, each of the men was considered to have had the opportunity for high levels of exposure to vinyl chloride monomer, with peak exposures probably exceeding 1.000 ppm. Although two of the cases had spent more than 20 years each in areas of potential vinyl chloride monomer exposure, the other three had very brief exposures on the order of one to several months. Of interest, none of the other chemical agents suspected a priori as potential risk factors was shown to be statistically significantly associated with liver or biliary tract cancer. It may be that some of the agents are weak carcinogens, but this study could not explore that hypothesis. An examination of the upper limits of the 95% confi dence intervals about the risk ratios presented in Table II shows that the study apparently had sufficient power to rule-out modest increases in risk for several chem icals (i.e.. carbon tetrachloride and ethylene dichloride), but only relatively large increases in risk could be excluded for others. Some misclassification of exposure may have occurred: however, the availabil ity of industrial hygiene data from the distant past for many of the plants at this production site should have reduced this possibility considerably. If misclassification did occur, and was non-differential, the tendency would be to diminish the strength of the associations. ' ACKNOWLEDGMENTS The authors gratefully acknowledge technical assistance from Tom Bradley. Wendy Dahar. Mike Dupuis, Stan Gorgacz, Harold Hoyle, Bruce Houtman. Carl Mueller. Gordon Roush, Dan Schmidt. Belinda Sconichini. Tricia Stirrett, and Mike Stricter. They also thank Diana Diamond for help with preparation of the manuscript. R&S 143242 24 Bond et al. TABLE III. Descriptive Data on Five Cases Presumed to Have Been Exposed to Vinyl Chloride Monomer: Study of Liver and Biliary Tract Cancer Among Chemical Workers, Midland. Michigan. 1940-1982 Case no. i Year lirst exposed 1943 Year last exposed 1943 S 1943 1943 3 1950 1970 4 1946 1967 5 1952 1952 Duration ot exposure (yr: mo) 0: <1 o. 3 20: 0 Year ot death I960 1964 1976 Job classification Assistant operator Janitor Operator 20: 8 1980 Operator 0: 2 1972 Handyman/ packager Best diagnosis (source)"1 Adenocarcinoma of common bile duct (DC) Carcinoma ol liver (DC) Hepatocellular carcinoma (PR) Intrahepanc bile duct cancer (MR and PR) Cancer of liver (DC) JDC = death certificate. MR = medical record. PR = pathology report. REFERENCES Bond GG. Flores GG. Shellenberger RJ, Cartmill IB. Fishbeek WA, Cook RR (1986): Nested case- control study of lung cancer among chemical workers. Am J Epidemiol 124: 1:53-66. Bond GG. McLaren EA. Cartmill JB. Wymer KT. Sobel W, Lipps TE. Cook RR (1987): Cause-specific mortality among male chemical workers. Am J lnd Med 12.353-383. Bond GG. Shellenberger RJ. Flores GH. Cook RR. Fishbeek WA (1985): A case-control study of renal cancer mortality at a Texas chemical plant. Am J lnd Med 7:123-139 Chu KC, Cueto C. Ward JM (1984): Factors in the evaluation ot 200 National Cancer Institute Bioassavs. J Toxicol Environ Health 14 621-639 Doll SR (1988): Effects of exposure to vinyl chloride--An assessment ot the evidence. Scand J Work Environ Health 14:61-78. Falk H (1982): Liver. In Schotienteld D. Fraument JF (edsl: "Cancer Epidemiology and Prevention." Philadelphia: W B. Saunders Company, pp 668-682. Goldsmith OF. Smith AH, McMichael AJ (1980): A case-control study ot prostate cancer within a cohort ot rubber and lire workers. J Occup Med 22:533-541. Haseman JK, Crawford DD, Huff JE. Boorman GA. McConnell EE 11984): Results from 86 two-year carcinogenicity studies conducted bv the National Toxicology Program. J Toxicol Environ Health 14:621-639 Kupper LL. McMichael AJ. Spirtas R 11975): A hybrid epidemiologic siudv design useful in estimating relative risk. J Am Statistical Assoc 70; 351:524-528. Miettinen OS (1976): Estimabilitv and estimation in case reterent studies. Am J Epidemiol 103 226-235. National Toxicology Program (NTP) (1985). NTP Technical Report on the toxicology and carcinogenesis studies ot dichloromethane in F-344/N rats and B6C3FI mice (Inhalation studies) NTP-TR-306 (board drain v Wilbourn J. Haroun L. Haseltine E. Kaldor J. Partenskv C. Vaimo H (1986): Response of experimental animals to human carcinogens; An analysis based upon the IARC Monographs programme Car cinogenesis 74 853-1863, R&S 143243