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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, \inyl chloride INTRODUCTION A recently conducted cohort study ot the more than 37.000 male employees from Dow Chemical's Midland/Bav City. Michigan, production, research, and head quarters units showed more deaths than expected from cancer of the liver and biliary passages (SMR=I40. 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 ol the traditional case-control method [Kupper ct al.. 1975]. Department ol Epidemiology. Health and Environmental Sciences. The Dow Chemical Company. Mid land. Ml (G.C.B.. K.M.bV. R.R.C.). Medical Department. Michigan Division. Dow Chemical U.S.A.. Midland. Ml lE.A. McL.. r.E.L.). Induslrial Hygiene Services. Michigan Division. Dow Chemical U S.A.. Midland, Ml (F L.S.I. Address reprint requests to Dr. Gregory G. Bond. Department of Epidemiology. Health and Environ mental Sciences. The Dow Chemical Company. 1803 Building. Midland, MI 48674 Accepted tor publication February 7. I WO c 1990 Wiley-l.iss, Inc. ft&S 142916 20 Bond et al. METHODS AND MATERIALS Death certificates of all male, hourly employees who died during 1940-1982 (N = 6.259) were reviewed for 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. I986| as well as by potential for exposure to 11 t-hemical 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.. 19861. 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 prim, liver cancer (Falk. 1982J- This exercise was of limited usefulness, however, owing to: I) 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 birthvear by using the Maniel-Haenszei (1959) procedure. Analyses which additionally controlled for period of hire showed similar results to those which controlled only for birthvear and are not presented. Likewise, analyses of the primary liver cancers separate from the gall bladdcr/bile duct cancers did not reveal additional information and are not shown. Ninety-five per cent test-based confidence intervals were calculated about the risk ratio estimates (Miettinen. |976|. RESULTS Analyses by work area assignments (Table I) 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 iRR = 3.6: 95cr Cl = 1.4-9.1). A positive association with assignment to polyvmvlpolyvinvlidene chloride production did not reach statistical significance (RR = 2 0: 957c Cl = 0.9-4.6). There were no statistically significant trends apparent when analyses were mu. e of duration ol assignment within work areas: however, the 'dds ratio for an assign ment of five or "ore years to polyvinyl-- lyvmylidene chloride production was 3.7 (95Cr t . = 0 4.6) based on the corn; .oution of two cases. Assignme. .> polyvinvl-polyvinylidene chloride production areas was explored further m Figure I via a plot of the "attributable fraction" [Goldsmith et al.. I980J for each year during the period 1940-1980. The peak "attributable fraction" occurred in 1952. a year in which lour of the seven cases assigned to these areas were all employed, no two in the same plant, however. None ol the chemical agent comparisons revealed statistically significant dil- R&S 142917 I R&S 142918 `C, r1 1 Chemical Worker Liver/Biliary Tract Cancer 21 TABLE I. Age-Adjusted Risk Ratios for Analyses by Major and Minor Work Areas: Study of Liver and Biliary Tract Cancer Among Chemical Workers. Midland. Michigan. 19-40-1982* Exposure irequencies (`ft Major/minor work areas Administration Manufacturing Agricultural chemicals Herbicides Insecticides Inorganic chemicals Ammonia Brine Brommated products Calcium, magnesium Caustic Cellulose products Electrochemicals Metal lubrication Organic chemicals Acrvlamide Alkvl benzenes Chlorinated benzenes Dves Fabricated plastics Glvcols Halogenated hsdrocarbons Ion exchange resins Latex Olefins Phenol denial no Polvsivrene Polwins l-pi'lys mslidene chloride Lnknown manulaeturing Research Service Animal handling Boiler shop Construction Electric shop Engineering Garage Lead shop Lubrication Machine shop Maintenance Material handling Office maintenance Paim shop Pipe shop Plant protection Power Road and sard mtc. Shops-steei iS: instrument Waste management Well serueos Cases ,\ - 44 > U.O 68.2 4.1 6.8 46 47.7 U.O 6.8 46 U1 4,6 2-3 0.(1 22.7 ?6.4 0.0 0.0 0.0 6.8 6.8 0.0 4,6 :j 2.3 4.6 68 s 1? 0 u0 15 o to,y (I 0 4.6 13.6 2.3 2.3 00 00 0.0 46 46 11 4 1 1.4 46 '/.I 01 2.3 40 64 00 00 Referents i,N = 1 .KBS) RR y5T Cl 5.8 75.7 26.2 17.1 4.7 40.0 1.0 46 5y 12.5 iy 7.6 m.2 16.8 56.8 2.1 3.y 3.6 6.1 16.5 1.8 7.7 2.0 2.7 2.5 13.0 15.0 III. 1 10 22.8 u.6 3.4 13.6 2.8 16 2.5 0.3 04 4.2 8.6 81 3.3 7.0 10. J 56 7.1 2.0 2,3 1.2 0l -- 0.0-1.5 0.7 0.4-1,3 0.4 O.I-I.O 0.5 0.2-1.6 0.6 0 1-2.4 l.l 0.6-2.0 -- (I.0-X.4 o.y 0 3-3.0 o.y 0,2-3.7 0.7 0.2-1.8 2.1 o 5-9 5 0.4 -- 0.0-0.8 l.l 0.6-2.2 0.5 o.3-o.y -- 0.0-4 0 -- 0.0-2.2 -- 0.0-2.3 0.7 0.2-2.3 0.6 0.2-1.y -- 0.0-4 7 0.4 0.1-1.6 1.2 0.2-8.7 0.8 0.1-6.2 1.5 ti.3-6.7 0.4 0 1-1.4 0,5 o 1-2,0 2.0 0 4-4 (1 -- (1 (t-N 4 <> X 0 }-\.X l.l 0,6-2.o -- 0 0-14,0 1 0 0 2-4 1 0.7 0.3-1.7 0.9 0 1-6,4 1.7 0.2-12.5 -- 0,0-3.4 -- 0 0-28 0 -- 0 0-21.0 o.y 0.2-3.5 0.4 0 l-l 6 1.4 0 5-3.7 3.6 1,4-4 1 0.6 0 1-2 5 0 8 o 3-2.3 l.l 0.4-3.2 0.2 0 0-1 3 1 s o 5-4 6 T S 0 7-7 5 -- 0 0-7.0 -- 0,0-83 8 'Workers mas hj'c been assignee 10 more ihan one work area during their employment and thus mas he .ountcd more man i'Hlc in ihe tame 22 Bond et al. RF A C G T fI G r-'--"----.................................................' T1 *.................................... 1 1--1------------'--'------ r i j40 1950 1960 1970 l 9 s U CALENDAR year Fiji. I. Study <>l liver and biliary tract cancer. Attributable fraction lor assignment to polyvmyl-polvvmvlidene chloride areas in each >ear dunni: ISMO^IVXO, Terences (Table II). The highest risk ratio (RR = 2.2; 95% Cl = 0.9-5.8) was Tor presumed exposure to vinyl chloride based on the contribution of five cases. There were no statistically significant trends lor 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 by estimated dose of exposure. DISCUSSION The present investigation revealed a statistically significant positive association with assignment to office maintenance, and some marginal associations with poly vinyl-poly vinvlidene chior-.e 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 vinyl chloride exposure have produced a specific hazard ol 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-polyvinylidene work area were considered to have had the opportunity tor 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 142919 Chemical Worker Liver/Biliary 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 irequencies i%) Agent Cases IN = 44) Referents (N = 1.888) RR 95% Cl Carbon tetrachloride Chlorodibenzo-lpl-dioxins Chloroform Ethvlene dibromide Ethvlene dichlonde Methylene chloride Perchloroelhvlene Polychlorinated biphenyls 1.1,2-Trichloroethane 2.4,6-Trichlorophcnoi X'invl chloride 11.4 2.3 4.6 Ss 6.8 4.6 13.6 (1 0 ().() (U> 11.4 20.0 9.1 6.7 73 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.I-.V0 0,4 0.1-1.3 0.8 0.2-3.6 1.8 0.8-4.3 -- 0.0-7 0 -- o 0-16 8 -- 0.0-9.3 1 1 0.9-5.8 Workers may have been exposed to more than one agent during their employment and thus may be counted more than once in the table. available to confirm the diagnosis lor only two of them. Table III 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 (he 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 briel 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 shoxxn to he statistically xigmticamlv associated with liver or biliary tract cancer, it may be that some ot 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 Hovle. Bruce Houtman. Curl Mueller. Gordon Roush. Dan Schmidt. Belinda Scortichini, Triciu Stirrett. and Mike Stricter. They also thank Diana Diamond for help with preparation of the manuscript. R&S 142920 24 Bond et al. TABLE III. Descriptive Data on Five Cases Presumed to Have Been Exposed to Vinyl Chloride Monomer: Studv ot' Liver and Biliary Tract Cancer Among Chemical Workers. .Midland. Michigan. 1940-I9H2 _______ Case no. Year tirst exposed Year last exposed Duration ol exposure <\r; mol Year of death Job classification Best diagnosis (source r` i 1943 1943 0: <1 I960 Assistant Adenocarcinoma operator of common bile duct tDO 1943 1943 0: 3 1964 Janitor Carcinoma ot lixer iDCi 3 1970 20: 0 1976 Operator Hepatocellular carcinoma (PRl 4 1967 20: X 19X0 Operator Intrahepaiic bile duel cancer (MR and PR) 5 1952 1952 0: 2 1972 Handy man/ Cancer ol liver paekayer iDC) `DC = death certificate. MR = medical record. PR = pathology report. REFERENCES Bond GC. Mores GG. Shollenberyer RJ. Curtmill JB. Fishbeck WA. Cook RR ( I9X6i: Nested easecontrol study ot iuny cancer among chemical workers. Am J Epidemiol 124; 1:52-60. Bond GG. McLaren EA, Cartmill JB. Wymer KT. Sobel W. Lipps TG. Cook RR (19X7): Cause-specific mortality amony male chemical workers. Am J Ind Med 12:353-3X3. Bond GG. Shellenberyer RJ. Flores GH. Cook RR. Fishbeck WA < 19X5): A case-control study ol renal cancer mortality at a Texas chemical plant. Am J Ind Med 7:123-139 Chu KC. Cueto C. Ward JM 119X41' Factors in the evaluation ol 200 National Cancer Institute Bioassays, J Toxicol Environ Health 14:621-639. Doll SR (I9X.X) 1.Meets ol exposure lo vinyl chloride--An assessment ol die evidence. ScunJ J Work Environ Health I46I-7X Falk H (19X2): Liver, In Sehottenleld D. Fraumeni JF (edsi; "Cancer Epideimoloyy and Prevention. Philadelphia. W B. Saunders Company, pp 66X-6K2. Goldsmith OF. Smith AH. McMichael AJ i 19X0): A case-control study ol prostate cancer wtthin a cohort ol rubber and tire workers. J Oecup Med 22.533-541 Haseman JK, Craw lord DD. Hull JE. Boorman GA. McConnell EE 119X4): Results trom 86 two-year carcinoyenieitv studies conducted by the National Toxicoloyy Proyram. J Toxicol Environ Health 14.621-6 61 Kupper LL. McMichael AJ. Spirtas R (1975): A hybrid cpidemioloyie study desiyn useful in estimattny relative risk, J Am Statistical Assoc 70; 351:524-528. Miettinen OS i I976i Estimabihty and estimation in case relerent studies. Am J Epidemiol 103:226-235. National Toxicoloyy Proyram i NTP) 119X51: NTP Technical Report on the loxicoloyy and carcinoyenesis studies ol dichloromeihane in P-344/N rats and B6C3FI mice iInhalation xiudicsi NTP-TR-306 (board drain Wtlbourn J. Haroun L. Haselttne E. Raldor J. Partensky C. \"jinio H I I9X6|; Response ol experimental animals to human carcinoyens. An analysis based upon the IARC Monographs proyramme. Car cinogenesis * 1X53-1X63