Document K070N0gK3MyRnGpzeVqgobK

R&S 001860 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. Sabei, MS, Kenneth M. Bodner, msph, Thomas E. Lipps, md, and Ralph R. Cook, md, mph A recent cohort mortality study uf male, hourly wage employees of a large Michigan chemical production and research facility hud 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 tor vinyl chloride monomer, based on live 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/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 el 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 ol a follow-up investigation which used a hybrid study design involving a modification of the traditional case-control method [Kupper ct al.. 1975]. Department ot Epidemiology. Health and Environmental Science'.. The Dow Chemical Company. Mid land. Ml (G.G.B.. K.M.B.. R.R.C.). Medical Department. Michigan Division. Dow Chemical U.S.A., Midland, Ml (E.A. McL.. T.E.L.). Industrial Hygiene .Services. Michigan Division. Dow Chemical U.5.A.. Midland. Ml (F.L.S.i. Address repnm requests to Dr. Gregory G. Bond. Department of Epidemiology. Health and Environ mental Sciences. The Dow Chemical Company. 1803 Building. Midland, Ml 48674. Accepted lor publication Eebruary 7. IWO c, 1990 Wilcv-I.iss. 1 iic. R&S 001861 20 Bond ei al. METHODS AND MATERIALS Death certificates of 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 IN = 21,437) who composed the original study population [Bond et al.. 19871. 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.. I986|. Visits to the Medical Department by the cases were reviewed by a nurse co-investigator lE.A.M.) to ascertain a historv of excessive alcohol use or hepatitis, as they arc established risk factors for prim, liver cancer [Falk. I982|. 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 birthyear by using the Mantel-Haenszel (1959) procedure. Analyses which additionally controlled for period of hire showed similar results to those which controlled only for 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 [Miettincn. I976|. 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 tRR = 3.6: 95T Cl = 1.4-9.1). A positive association with assignment to polyvinvlpolyvinvlidene 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 ol assignment within work areas: however, the >dds ratio for an assign ment of fixe or -'ore years to polyvinyl-- -lyvinvlidene chloride production was 3.7 (957c t . = t); 4.6) based on the corn: .ouiion of two cases. Assignme. > polyvinvl-polyvinylidene chloride production areas was explored further in Figure I via a plot of the "attributable fraction" [Goldsmith et al.. 19801 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 xvere all employed, no two in the same plant, however. None of the chemical agent comparisons revealed statistically significant dif- Chemical Worker Liver/Biliary Tract Cancer 21 TABLE 1. Age-Adjusted Risk Ratios for Analyses by Major and Minor Work Areas: Study of Liver and Biliary Tract Cancer Among Chemical Workers. Midland. Michigan. 1941)-1982'" Exposure frequencies t`f) Major/minor work areas Administration Manufacturing Agricultural chemicals Herbicides Insecticides Inorganic chemicals Ammonia Brine Brommated products Calcium; maunesium Caustic Cellulose product' Electrochemicals Metal fabrication Organic chemicals Acrylamide Alkyl benzenes Chlorinated benzenes Dyes Fabricated plasties Glvcols Haloeenaled hvdniearbons Ion exchange resins Latex Olefins Phenol dori\;ituo Polystvrene Poly vans l-polsv ms lidene chloride Cnknossn manutacturmg Researeh Service Animal handling Boiler sht'p Construction Electric shop Engineering Garage Lead shop Lubrication Machine shop Maintenance Material handling Office maintenance Paint shop Pipe shop Plant protection Posver Road and sard mtc. Shops-stecl & instrument Waste management Well services Cases iN = 441 DO 6X.2 4i 6.X 46 47.7 0.0 6.X 4.6 41 46 n,u 22.7 .'6.4 0.0 0.0 0.0 6.X 6.X 00 46 2.3 "I } 4.6 6.x 6 1$ 13.4 tl 0 13.4 fo.y 0.0 4.6 13.6 2.3 2.3 0.0 0.0 0.0 4.6 4.6 11.4 11.4 46 4.1 4.1 2.3 4.6 6.9 0.0 0.0 Referents tN = I.S8SI RR 45T Cl 5.X 75.7 26.2 17.1 4.7 40.0 1.0 4.6 34 12.5 1.9 7,6 10.2 16.X 56.X 2.1 3.9 3.6 6.1 16.5 I.N 7.7 2.0 2.7 2.5 13.0 i5.o 10.1 i it 22.x 54.X 11.6 5.4 13.6 2.X 1.6 2.5 0.3 0.4 4.2 X.6 X.l 33 7.4 10.3 5.6 7.1 2.0 2,3 1.2 ii. 1 -- 0.0-1.5 0.7 0.4-1.3 0.4 0.l-l .0 0.5 0.2-1.6 0.6 0 1-2.4 l.l 0.6-2.0 -- 0.0-X.4 0.4 11.3-3.0 0.4 o 2-3.7 0.7 ti.2-1.x 2.1 0,3-'* 5 0.4 tl. 1-2.5 -- 0.0-0.K l.l 0.6-2.2 i).5 0.3-0.4 -- 0.0-4.0 -- 0.0-2.2 -- 0.0-2.3 0.7 tl 2-2.3 0.6 0.2-1.9 -- 0.0-4,7 0.4 0.1-1.6 1.2 (I.2-X.7 O.X 0.1-6.2 1.5 u 3 -6.7 0.4 (1 1-1.4 0.5 n 1-2,0 2.0 O 4-4 6 -- 0 O-N 4 n.K H.3-1.X i.i tl 6-2.0 -- 0.0-14.0 1.0 0.2-4 1 0.7 0 3-1.7 0.4 0 1-6.4 1.7 0.2-12.5 -- 0.0-5.4 -- 0 0-2X.0 -- 0.0-21.0 0.9 0.2-5.5 0.4 0.1-1.6 1.4 0.5-3.7 3,6 1.4-4 1 0.6 0.1-2.5 0 X o 5-2.3 1.1 0.4-5.2 0.2 0.0-1 3 T "I 0.5-4 6 T 0,7-7 5 0,0-7.0 -- 0 0-X3 x 'Workers mas base been assumed to more than one ssork urea during their employment and thus mas be sottnied more than mite m the tabie. R&S 001862 Bond et al. 0 1 . O uw #_i t JA O --r 1950 --^--------1--1--t ............ 1960 calendar year ' *r' 1970 1 yau Fig. I, Sludv til liver and biliary iruci cancer. Attributable traction lor assignment lo polyvinyl-polyvinvlidene chloride ureas in each year during IUJO-Ivku. Terences (Table II). The highest risk ratio (RR = 2.2: 959c 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 lor analysis by duration ol exposure to any ot the I I agents, although in many instances there were too lew exposed cases to permit meaningful conclusions. Likewise, there were no statistically significant trends ap parent when analyses were made by estimated dose ol exposure. DISCUSSION The present investigation revealed a statistically significant positive association with assignment to office maintenance, and some marginal associations with polyvinyl-polwinylidene chlorioe 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 of angiosarcoma of the liver in some work forces (Doll. I988|. In the present study, live of the seven cases of liver and biliary tract cancer who held assignments in the polyvinvl-polvvinvlidene work area were considered to have had the opportunity tor exposure to vinvl chloride monomer. There was no evidence that any ot the live cases experienced aneiosarcoma: however, pathology reports and/or medical records were R&S 001863 R&S 001864 Chemical Worker Liver/Biliary Tract Cancer 23 TABLE 11. 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 trequencies (*) Agent Cases t.\ = 44) Referents (N = 1.888) RR 95* Cl Carbon tetrachloride Chlorodibenzo-(p)-dto\ins Chloroform Ethylene dibromide Ethylene dichloride Methvlene chloride Perchloroethvlene Polychlorinated biphcnyU 1.1,2-Trichloroethanc 2.4.6-Triehlorophenol Vinyl chloride 1 1.4 2.3 4.6 ^ * 6.8 4.6 13.6 00 U t) no 1 1.4 20.0 9.1 6.7 73 14.6 8.9 11.3 1.2 0.5 0.9 78 0.5 0.2-1.4 0.2 0.4-1.4 0.6 0 2-2.70.4 0.1-3.0 0.4 0.1-1.3 0.8 o.2-3.6 1.8 0.8-4 3 -- 0.0-7 0 -- II 0-16,8 -- o.u-v,;* 0.9-5 S Workers may have heen 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 for 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 (he 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 he 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 VSCc 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 misclassificaiion 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. Wendv Dahar. Mike Dupuis. Stan Gorgacz. Harold Hoyle, Bruce Houtman. Carl Mueller. Gordon Roush. Dan Schmidt. Belinda Scortichini. Tricia Stirrctt. and Mike Strieter. They also thank Diana Diamond for help with preparation of the manuscript. R&S 001865 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. I940-I9S2 Case no. Year first exposed Year last exposed Duration of exposure <vr: mol Year of death Job classification Best diagnosis i source r* i 1943 1943 0: < 1 I960 Assistant Adenocarcinoma operator of common bile duct (DC) 1943 1943 0: 3 1964 Janitor Carcinoma of liver iDC) 1950 1970 20; 0 1976 Operator Hepatocellular carcinoma iPR) 4 1946 1967 20: X 19X0 Operator Inirahepalic bile duet cancer i.MR and PRl 1952 1952 0; 2 1972 Handyman/ Cancer ol liver packager (DCl 'DC = death certitieate. MR = medical record. PR = pathology report. REFERENCES Bond GG, Fiores GG. Shellenbereer KJ. Cartmill JB. Fishbeek W.A. Cook RR 119X61: Nested casecontrol study ol lung cancer among chemical workers. 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