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/ Original Articles i i Cancer Mortality of a Group of i Canadian Workers Exposed to I Vinyl Chloride Monomer G. Theriault, M.D.. Dr.P.H., and P. Allard, M.D., M.Sc. The present study was undertaken to find out whether there was an excess of cancer mortality from causes other than angiosarcoma oi the liver among a group of workers heavily exposed to vinyl chloride monomer (VCM). The mortality oi 451 workers exposed to VCM for more than five years was compared with that of 870 workers from the same company who had not been exposed to VCM. The ^ relative risk for digestive cancer was significantly higher than 1 (6.25. confidence interval 2.69 to 7 4.52) in the ex posed group. The standardized mortality ratio (SMR) for digestive cancer was also higher (SMR 259.26 p < 0.01) than that or the general population. No other cancer was in excess. Since the exposed workers are known to have had a cigarette smoking experience similar to that oi those who jvere not exposed, it is concluded that the association be tween lung cancer and VCM exposure, if present is indeed rather small. Several studies have demonstrated that vinyl chloride monomer (VCM) produces angiosarcoma of the liver among people exposed at work.'' There is. however, much controversy about the capability of VCM to gener ate other types of cancer in man. One author.* using a proportional mortality ratio technique, described ex cesses of lung cancer (observed. 13; expected, 7.9; obs/exp 1.6) and brain cancer (observed, 5; expected, 1.2; obs/exp 4.2) in a group of 161 workers from two vinyl chloride plants.* Another author.' who studied the mortality of a group of 1.294 American workers exposed to VCM. re ported excesses of lung cancer (observed. 11 expected. 7.5; SMR 194. p < 0.05) and brain cancer (observed, 3; ex pected, 0 6: SMR 498. p < 0.05) among men who had had From th* oi SoojI and Preventive Medicine School of Medicine Livjl Univertitv Ste-fov, Quebec Cjrwdj. CtK 7P* Thu fe^ejrcn fmjnced ojrtlv under Cr*n( No 780195 from |h< Conied de Ij Recherche en $4nte du Quebec their first exposure more than 15 years before their death. While most authors have not been able to document a significant excess of any other cancer in their studies, they have noted that such an excess may exist. In order to better document the cancer mortality asso ciated with exposure to VCM. the present study of the workers of the Shawinigan vinyl chloride polymerization plant was undertaken. The main objectives of the study were (1) to compare mortality among vinyl chloride workers with the mortality of workers from a nearby industrial complex; and (2) to compare the mortality of the VCM workers with that of the general population. The Shawinigan vinyl chloride plant opened in 1943 as an independent company which produced both VCM and PVC (polyvinyl chloride). In 1958. it was merged into an industrial complex (to be used as the comparison group) of which it became the Cana dian Resins Division. In the late 1960s. the VCM produc tion ceased and only the polymerization process con tinued operation. In 1972. this division was sold and again became an independent plant Over the years, the VCM and PVC productions fluctuated. The average annual work force at the plant was 225 men. In 1965. VCM pro duction was estimated at 90 million pounds and PVC at 60 million pounds.'" In 1977, PVC production was 22.3 million pounds." Since several episodes of unconscious ness among workers were reported, the level of VCM in the air at the workplace is believed to have been high dur ing this period. Ten cases of angiosarcoma of the liver have been reported since then.' The industrial complex from which the comparison group was drawn comprises several divisions; a carbide division which produces calcium carbide and acetylene black; a chemicals division which produces several chem icals derived from acetylene: acetone, chloral, butanol, acetic acid, acetaldehyde, several acetates, solvents and resins; a stainless steel division which consisted of a small foundry and a division formed in 1957. which produced Journal of Occupational Medicine/Vol. 23. No. 10/October 1981 671 Fig 1, -- Population undor study. sulfuric acid, chlorine and cyanide. This complex started operations in 1927; some ot its divisions opened at a later date; others closed in the late 1960s or early 1970s, The annual number of male workers averaged 1.000.'1 Methods Population Under Study. -- All production workers whose names appeared on the unions' lists or the com panies payrolls of the VC plant and the industrial complex between lanuary 1.1946, and December 31.1972. consti tuted the population under study. Several methods (old addresses, telephone books, Quebec motor vehicles bureau, inquiries with fellow workers and families, searches in homes for retired persons) were used to trace these men, 16% of whom were still working for the same companies. Once identified, the worker himself or his next of kin (spouse, child or close relative) was questioned at home or at work bv a trained interviewer. The ques tions permitted the reconstruction of a detailed occupa tional history within and outside the companies under study. Questions were also asked regarding smoking habits. For each deceased person believed to have been exposed to VCM, the occupational history was confirmed with the help of a fellow worker. The men whose number of years of work for these companies, as established through occupational histories, did not exceed five were removed from the study. The re maining population was then subdivided into three groups. The first group (known as the unexposed cohort) consisted of men who stated they had not been involved with the production of VCM or PVC. or both, for a period greater than five months. The second group (constituting the exposed cohort) comprised men who declared they had worked on the production of VCM-PVC for more than five years. Finally, the third group consisted of the men who had worked on the production of VCM* PVC for a period of six months to five years. This group was ex cluded from analysis because it neither fulfilled the definition of the exposed nor the unexposed cohort. Data Sources. -- The vital status of these men was established as of December 31. 1977. Causes of death were determined from death certificates. They were coded according to the 8th revision (ICDA) by one of the authors, who was unaware at the time of the coding as to which group the man belonged. For cancer cases, a histopathological confirmation was sought on autopsy, biopsy or cytology reports contained in the medical files at the hospital. Information on Queoec's population and mor- 672 Mortality of Workers Exposed to Vinyl Chloride Monomer/Th^riault and Allard R> these ones, he rethree ihort) lived eriod utmg thev more f the C for is exI the svas !eath were i the is to isto- PPSV the mor- llarO Table 1. -- Age Distribution of the Men in the VCMExposod and Unexposed Cohorts as of December 31. 1S77 (Deceased Excluded). Age 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 25 + TOMt Exposed No. % 00-- 1 03 23 7 1 75 19 1 96 24 5 102 26.0 53 13.5 30 7,7 6 1,5 1 0.3 392 100.0 Unxposd No. S 1 02 3 0.5 6 0.9 45 7.1 55 3 6 84 13 2 112 17 6 110 17 3 113 17.7 65 10.2 43 6.7 637 100.0 talitv by cause, age and sex was secured from Statistics Canada for the year 1971. In order to ensure the validity of the results, only the causes of death which appeared on the death certificates were used in the comparisons. Statistical Analysis. -- The results were analyzed using the "man-years at risk" method as described by Hill." The number of person-years of observation was established for each five-year age group and for each five-year period between 1946 and 1977. The mortality in the exposed cohort was compared with that in the unexposed cohort according to the method of relative risk. The tests of significance used were those of Mantel. Haenszel" " and Miettinen.'* 17 The observed mortality was also compared with the mor tality expected from the population of the Province of Quebec according to the method of the standardized mortality ratio ($MR).'* The test of significance used was the one described by Bailar and Ederer." Quality Control Procedures. -- A thorough occupa tional history was developed for workers who were ex posed within the VC plant. The questionnaires presented a detailed profile of the plant while specifying possible jobs within its maior units. Before the beginning of the Study, it was pre-tested with former employees. Interviewers who contacted the workers had received training by the same person and were supervised during the entire study. The completed questionnaires were re viewed weekly by one of the authors and missing infor mation was sought by telephone. Data entered in the computer were systematically checked against the origi nal questionnaires. Results As shown in Fig 1. the population under study originally comprised 1.659 workers. Of these. 48 men were untraceable. leaving the number in the studv population at 1,611 (or 97.1% of the original number). After the removal of the 156 men who had worked at the companies for a period not exceeding five years and the 134 men who had been exposed to VCM for a perod extending from six months to five years, the exposed cohort comprised 451 men and the unexposed one. 870 men. In the exposed cohort, the proportion of men who responded to the questionnaire for themselves was 84.3%. In the unex posed cohort, this proportion was somewhat lower at 68.2%. The age distributions of the workers in the exposed and unexposed cohorts as of December 31.1977, reveals that workers in the unexposed cohort (Table 1) were somewhat older. Since the industrial complex had been in operation for several years when the VC plant opened, the finding of older people in the latter cohort was predictable. Table 2 shows the distribution of the exposed workers according to their length of exposure and their observa tion period (time between first employment and end of follow-up). Among these. 81% (365 out of 451) had an ob servation period of 15 years or more. For 23% of them, the time elapsed between first exposure and the end of the follow-up period exceeded 29 years. The mean obser vation period for the exposed cohort was 22.6 years. Table 3 gives the diagnosis at death and the diagnosis after histopathological review of all the cancer cases found in the exposed group. On the death certificates, eight cancers of the liver were reported. The histopatho logical review reiected one of them as being a cancer of the sigmoidal flexure of the colon, but added another as an incorrectly diagnosed cancer of the peritoneal cavity. All eight cancers of the liver turned out to be angiosar coma of the liver. It is noted that two more angiosar comas of the liver were certified as cirrhosis on the death certificates and were considered as such throughout this study. Table 4 compares the mortality of the exposed workers with the mortality of the unexposed workers. The con fidence interval (95%) of the relative risk indicates that there is a significant excess of mortality due to cancers of the digestive system in the exposed group (RR 6.25, con fidence interval 2.69 to 14.52). There is no excess in the other causes of death. Table 5 shows the standardized mortality ratios (SMRs) for the exposed workers in comparison with the entire population of the Province of Quebec. The SMR for all causes is 83.02. thereby showing no excess of death in the exposed cohort. Although the SMRs for all cancers, respi ratory system diseases and digestive system diseases ex- Table 2. -- Distribution ol Exposed Workers by Length ol Exposure and Observation Period. L Expotur* (Yflinl 5- 9 10-14 15-19 20-24 25-29 30 + Total Obstrvitlon Porlod (Yurs) 5-9 10-14 15-19 20-24 30 23 7 40 -- 28 26 19 -- -- 17 35 -- -- -- 22 --- -- - --- -- - 30 56 50 116 Journal ol Occuoational Medicine/Vol. 23. No. 10/Ociober 1981 25-29 2 17 19 24 34 -- 96 30 + 4 5 a i5 33 33 103 Total 111 95 79 61 67 38 451 673 R&S 001665 Table 3, -- Age at Death, Diagnosis on Death Certificate and Diagnosis on Histological Review of the 20 VCM-Expcsed Workers Who Diad ol Cancor. Casa Number t Death Certificate Cancer ot the liver 1 Cancer ol the intestine 3 Carcinoma ol the tracnea J Angiosarcoma ol (he peritoneal cavity 5 Cancer ol the lung a Cancer ol the liver 7 Cancer ol the liver 8 Cancer ol the orosiaie 9 Angiosarcoma of the liver 10 Cancer ot Ihe oancreas 11 Adenosarcoma ol the intestine 12 Heoaioma 13 Cancer ol the liver !J Cancer ol me Dancreas 15 Chondrosarcoma 16 Hepatoma 17 Primary cancer ol the liver IS Cancer ol the digestive track 19 Cancer ol me biliary oucis 20 Lymphoid leukemia Histological Review Cancer ol me sigmoid llejure of me colon Metastatic cancer ol the colon Carcinoma ol the tracnea Angiosarcoma ol the liver (no review) Angiosarcoma of me liver Angiosarcoma ol me liver Cancer ol the prostate Angiosarcoma of (fie liver Eotifieiioma of ihe heao of ihe pancreas Adenosarcoma of tne intestine Angiosarcoma of me liver Angiosarcoma of tne liver Anaplastic epithelioma Qt tne pancreas Chondrosarcoma Angiosarcoma ot tne liver Angiosarcoma ot me liver Cancer ot the cecum Cancer ol me head ol the pancreas lymonoid leukemia Age at Death (Years) 73 56 50 4t 54 42 57 64 62 40 53 S3 53 59 43 48 S3 52 54 48 Total Exposure (Years 1 15 16 15 11 16 ;9 17 26 13 8 25 24 22 29 7 22 5 26 12 21 Latancy Period (Yeats) 28 17 15 11 16 19 23 29 23 13 28 24 23 30 10 22 12 26 12 2) ceed 100, they are not statistically significant. On the other hand, deaths by accident and violence are signitV cantly lower (p < 0.01). As for specific cancer deaths, a significant excess is noted for cancer of the digestive system only. This excess is accounted for exclusively by cancer of the liver (8 cases observed versus 0.14 expected, SMR 5,714.29). No other cancers are in excess. The cancer mortality among the workers who were still alive 15 years after their first exposure shows the same results as the mortality in the entire group, namely that onlv cancers of the digestive system are in excess in the exposed cohort (Table 6). Discussion Difficulties encountered in comparing the mortality of a group of workers with the mortality of a whole popula tion are well documented. They are termed: "healthy population selection effect," "survivor population effect."" "ethnic/cultural/social characteristics." They are believed to underestimate the actual mortality of a group of workers and therefore to underscore the effects of the risks to which these individuals are being exposed at work. There are no easy ways to avoid such`difficulties. One method would be to compare a group of workers with another group of workers with the same characteris tics except for the exposure to the risk under study. The problems encountered in so doing are no easier. Although the group most similar to industrial workers is probably another group of industrial workers from the same town, it is almost impossible to think of a group of industrial Table 4 -- Deaths Observed in the VCM-Exposed and Unexposed Cohorts. Age-Adjusted Relative Risks and Confidence Intervals ol the Relative Risk. Cause of Death All cancers (140-209) Mourn and onaryn* 1140-149) Oigeshvt (150-159) Respiratory (160-163) Bone, skin, connective (170-173) Urogenital (185-189) Eye. CNS (190-1921 Leukemia (200-209) Other cancers Cardiovascular Respiratory (390-458) (460-S191 Digestive (520-577) Accidents and violence (800-899) Others Total ' Significant according to Miemnen's lest17 (One cause unknown 674 He. of Cases Exposed Unexposed 20 52 02 14 9 2 20 22 17 02 14 06 25 124 6 15 4 12 2 15 2t 15 59 233 Relative Risk 1 48 -- 6.25 0.36 1 67 0 83 -- 1 15 -- 0 80 0 81 1 44 0 51 0 57 1 07 95 X Confidence Interval el Ihe Relative Risk 0.84- 2.61 2 69-14 520 08- 1 58 0 21*12.99 Q )0- 7 10 -- 0 07-17 80 _ 0,47- l 36 0.4a- 9 35 0,49- 4 25 0 21- i 24 0 14- 2 39 0 79- t 45 Mortality ol Workers Exposed to Vinyl Chloride Monomer/Thgriauit and Allard latency Period (Tearsl ~n 17 5 M 16 3 23 29 23 13 23 24 ,'1 3 0 22 1* 26 12 2t I ! ole popula- J: "healthy population " They are of a group ects of the vposed at lifficulties. >f workers haractenstudv. The Although probably me town. industrial I I j' j : ` ( / I ; ( j Allard l 7- Table 5. - Observed and Expected* Numbers ol Deaths In the VCM-Exposed t Cohort and Standardized Mortality Ratios (SMRs). Cause el Oealh All cancers Mouth ana onarynx Digestive Resoiratory Bone. skin, connective Urogenital Eye* CNS leukemia Other cancers Cardiovascular flesturaiory Digestive Accidents and violence Others Total (140-209) (140-1491 H50-159I (160-163) (170-173) (185-1891 (190-192) (200-209) (390-4581 (460-5191 1520-577) 1800-999) Observed 20 0, 14 2 2 ! 0 \ 0 25 5 4 2 59 Expected 16 37 0 64 5 40 5 78 0 38 J 33 0.60 1.67 0.54 31.67 3.21 3,85 10,58 5.40 71,07 smr 122.17 -- 259.261 34.60 526,32 75-19 -- 59.88 -- 78.94 186.91 103.90 18.90T 37.03 83.02 'ExoecteO numoers ootameo Irom 1971 males Queoec aeatn rates aooiied to oerson-years in eacn age grouo tp < 0 01" tone cause unknown workers not exposed to some kind of carcinogenic risks In the present study, the authors decided to compare the exposed workers with both the general population and a group of unexposed workers. It must be noted that among the unexposed workers, no causes of death were found to be in excess when their mortality was compared with that of the general population The comparison of the mortality of the exposed and the unexposed workers gave results similar to the one reached by the comparison with the general population. The number of cancer of the digestive system was signifi cantly higher in the exposed cohort. No other cancer was in excess and there even seemed to be a deficit (not statis tically significant) in respiratory cancers. Considering the fact that animals experimentally ex posed to VCM have developed not only angiosarcomas of the liver but also malignant tumors of several organs (skin. lung. bone. Zimbal glands, kidneys, mammary glands)'1 " " and since several epidemiological studies on VCM-exposed workers have found an excess of lung cancer,'* the results of this study of heavily exposed men are surprising. Three questions can be raised One con cerns the ascertainment of the population. In retrospec tive studies conducted from old company or union rec ords it sometimes happens that records of people who die or leave get lost. These losses could account for the low cancer rates observed. But this is a remote possibility, since the approach followed was a historical-prospective retrospective one, which began with old lists of workers composed in 1948 and 1952 and followed almost every one through time, adding new workers as they first ap peared on more recent lists. This was done without knowl edge of exposure to VCM. A second reason for low lung cancer rates could be a bias in the classification of persons as exposed or not ex posed The classification was made essentially on the basis of personal recollection for living persons and by family members with confirmation by co-workers for deceased persons To minimize such bias, much attention had been given to the occupational history (with indica tion of the buildings the subject had worked in) and workers with VCM exposure shorter than tive years were reiected. There remains the possibility that some of the men who died of liver cancer, had thev lived longer, might have developed lung cancer. The small size of the population under study increased the probability of not detecting an excess that was actual ly present. This was a case where "the number of person/ years at risk may be too small to detect an increased risk of cancer."" It was particularly true for rare cancers such as cancer of the brain and cancer of the lymphatic system. Inasmuch as cancer of the lung was concerned. Table 6. -- Relative Risks and SMRs lor Cancer Deaths Among Men Having an Observation Period of 15 Tears and More. Cancers All cancers Mouth ana pharynx Digestive Respiratory Bone. skin, connective Urogenital Eye. CNS Leukemia Other cancers (140-2091 (140-149) (150-1591 (160-163) (170-173) (185-189) (190-192) (200-209) No. 15 0 11 2 3 1 0 1 0 *0 < 0.01" Journal ol Occupational Medicine/Vol. 23, No. I0/0clober 1981 Relative Risk 1 30 -- 5 68 0 35 -- 0,82 -- 0.59 - 95 ft Confidence Interval ol the Relative fliik 0.97- 1.74 -- 2.72-11.58 0.25- 4 73 -- - -- - SMR 129 -- 281* 47 -- - - 675 R&S 001667 i the situation was somewhat different. When one applies the Quebec lung cancer death rate after adiustment for age to the exposed cohort, the probability of finding an excess twice as high as in Quebec was 73%. This proba bility would have been 99% had the excess been three times as great in the exposed group." In view of the fact that the smoking experience of the exposed workers was similar to that of the unexposed and considering that the subjects in this study are believed to have been heavily exposed to VCM, it seems reasonable to conclude that the excess of lung cancer associated with VCM exposure, if present, is indeed rather small. The authors with to exoress their gratitude to the following who contributed to thu ttuov workers, union representatives and management personnel of th* comoamet Canadian Reims and Chemicals. Shawmigan Chemicals. B F Goodrich and Gulf Canada, Drs H Itutra and I Fabia. epidemiologists, and Or F Delorme pathologist, for their help and advice, the several hospitals coo taeted and the several persons who assisted with the collection o> information jno the writing ot this article References 1 Creech |l |r and lohnson MN' Angiosarcoma of liver in the man ufacture of polvvmvl chloride / Occup Med 16 150-151, 1974 2 Tjbershaw IR and Caffev WR Mortality study of workers m the manufacture ot vmvl chloride and its polymers / Occup Med 16 509-510. 1974 3 Nicholson VV|. Hammond EC. Seidman H. et al Mortality experi ence of a cohort Of vinyl chloride polyvinyl workers Ann NY Acid Set 246 225-230. 1975 4 OuCk BW. Carter |T. and CoOmbes E| Mortality study of workers m a polwinyl-chlonde production plant Lancet 21197*1199. 1975 5 Bvren 0. Engholm C. Englund A, and Westerholm P Mortality and cancer morbidity m a group of $wedish VCM and PVC production workers Environ Health PenpeCt 17 167-170. 1976 6 Fox A) and Collier PP Mortality experience of workers exposed to vmvl chloride monomer m the manufacture ot polyvinyl chloride m Creat Britain fir / Ind Med 34 1-10. 1977 7 Oelorme F and Theriault C: Ten cases or angiosarcoma of the liver m Shawmigan, Quebec. / Occuo Med 20 336-340. 1976 6 Monson R. Peters J. and lohnson M, Proportional mortality among vinyl chloride workers. Lancet 2:397-398 1974 9 WaxweiJer |R. Stringer W. a no Wagner ||, NeooiastiC risk among workers exposed to vinyl chloride. Ann NY Acad Set 270 40-46. 1976 10. Special Report bv the Editors* PVC aims tor a bigger share m plastics. Can Chem Process 49 41*44 1%5 11 Conseil de?.Sciences du Canada: Vue d'ensemole des dangers de la contamination par le chlorure ce vmyle au Canada Quebec Science tSuppI) 1-24.1977. 12. LaRochelie F: Shawmigan deouis 75 an*. Ateliers de I'imprimene Publicite PJquet Enr. 1976. pp 497-525, 13, hill 10 Computing man years at risk &r f Prev Med 26 132*134. 1972. 14 Mantel N and Haenszel W Statistical aspects or the analysis of data from retrospective studies of disease / Natl Cancer Inn 22:710-746. 1959. 15. Mantel N* Evaluation ot survival data and two rank order statis tics arising m its consideration Cancer Chemotner Rep 50:163-170, 1966. 16. Miettmen OS. Standardization or risk ratios Am I Epidemiol 96 363-368. 1972- 17 Miettmen OS- Simple interval-estimation of risk ratio Am / Epidemiol 100:515*516. 1974 16. Caffev WR: A critique or the standardized mortality ratio. I Oc cup Med 3 157*160. 1976 19 Bailar 1C and Ederer F: Significance factors (or the ratio of a Poisson variable to its expectation Biometrics 20 639-642, 1964 20 Fox A| and Collier PF* Low mortality rates m industrial cohort studies due to selection for work and survival m the industry fir I Ptev Soc Med 30 22S-230. 1976 21. Viola PL. Cancerogemc Effect or Vmvl Chloride, Vol 29. X Inter national Cancer Congress. Houston. 1970 22. Viola PL. Bigotti A. and Caputo A Oncogenic response of rat skin, lungs and bones to vinyl chloride Cancer Rei 31 516-519, 1971. 23 Maltoni C and Lefemme C. Cancerogenicitv bio assays of vinyl chloride: Current results. Ann NY Acad 5cr 246 195-216, 1975 24, Wagoner |K Vinyl chloride and pulmonary cancer I fnv Pathol Toucol 1 361-362. 1976 25 Pell S, O'Berg MT, and Karrh B Cancer eoidemiologic iurvcik lance m the DuPont Company / Occup Med 20 725-740. 1978 Reducing Financial Risks There is too little evidence that the nuclear industry, which was never verv good at calculating its own interest, is seriously contemplating the effect of another Three Mile Island on its future -- or its fortunes. The industry has already returned to complaints that the safety bureaucracy is nitpicking it to death, running up construction costs and delaying licenses. The latest complaint is that, in the aftermath of the TMI accident. NRC diverted safety reviewers to deal with operating reactors and fell behind in ap proving new licenses. There is a kind of tunnel vision m the failure to see the connection between safety and the special financial risk involved in nuclear investment. To use the current energy crisis to avoid safety requirements is to ignore the fact that safety is essential to protec ting the heavy investment in nuclear power. Some hope lies in the fact that, although the mdustrv thinks safety requirements are a pain in the neck, they may be forced to look at them as an investment in financial public relations to alleviate the bankers' skepticism. -- Victor C'lmskv. Commissioner, the Nuclear Regulatory Commission at QvOted *n Notable and Quotable ' m the Walt $iteet /oumj, viav 21 676 Mortality of Workers Exposed to Vinyl Chtorice Monomer/Thdnault and Allard 00 l ! Mi j ii: Eliza' Th and t \ a rub thep previ lune j U.S. dead wale ing r ploy trow servi 3.3 t obse rubb Iron plac don ma> cier. deCi clar sen, ana wui exp for we 19; arr I Hu Ru *ut i irv i Jd