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differ* limate. 'i pneu- ithologi .-mok- | i I Environmental Health Perspectives Vol U, op 8-9i. 1981 Observations of the Site-Specific ' exper- {Carcinogenicity of Vinyl Chloride nee on ito Humans-ure on ,e onco* i which iby Peter F. Infante* ilogical i` part ilust in e*. Our - of the s \ I 1 ; A review of epidemiologic studies of workers exposed to vinyl chloride (VC) was conducted. Some of these studies comprised small cohorts and thus were insensitive in the evaluation of carcinogenic response for sites that do not demonstrate a high relative risk. Other larger studies used methodology and design that precluded an interpretation of the results. Such t-rs. to I ticks. i | limitations were acknowledged by some authors. Use of restrictive disease ruhrics also lead to the submerging of sites that would have demonstrated significant excesses. For example, some investigators analyzed data for liver cancer deaths with the board category of digestive system cancer deaths, while others combined data for CNS cancer deaths with the broad cateogry of "other and unspecified cancer," and most studies analyzed information for lymphatic and hematopoietic system cancer deaths with all 1,'iiWs Of nviron. tssays of 'i'>nde' tNTM . D. U | data combined. Only four of eight studies reviewed could demonstrate a significant excess of liver cancer among VC-exposed workers--a site confirmed in humans by 1974. In contrast, five of | eight studies appear to demonstrate a significant excess of CNS cancer mortality. Workers ' exposed to VC also demonstrate a significant excess of mortality for lung cancer, while (he data for lymphatic and hematopoietic system cancer are suggestive. Interpretation of cancer of the Ilatter systems may have been clarified if investigators had not analyzed their data by broad disease classifications. i XT on the mmittee. , In 1930, shortly after vinyl chloride (VC) was Introduced into commerce, VC toxicity was rerted in experimental animals (f). Over the next decades, study throughout the world indicated riat employment in the VC industry was associated jrth a wide range of toxicity in humans. This I toxicity has included nonmalignant pathologic efjkts or symptoms, involving (but not limited to) e bones, liver, central nervous system (CNS), lings, and blood (2). l Between 1970 and 1974, experimental bioassay l yrnonstrated VC*induced cancer in multiple or- ons including the liver, brain, lungs and lymphatic ..-tem U, h). This carcinogenic response has been observed in several species, given a wide range of doses, by various routes of administration. Between 1973 and 1977, several epidemiologic studies were undertaken to assess the site-specific cancer risk among workers exposed to VC. For this presentation, findings of these studies will be limited to an assessment of cancer of four organs or organ systems in humans. These same sites are known to be associated with nonmalignant VCrelated disease or symptoms in humans and cancer in experimental animals. Liver Cancer in Humans I *0tfce of Carcinogen Identification and Classification, Health * vc.dards Programs, Occupational Safety and Health AdnmiisItr.ion, t! S Department of I,abor, Washington, D C Hi 10 'e views expressed in this paper do not necessarily represent (tiatof the Occupational Safety and Health Administration. Table 1 shows a summation of data from the epidemiologic studies as related to liver cancer. Some authors did not present site-specific analyses for liver cancer deaths. Therefore, the most specific information available is presented. Waxweiler et al, (.)) conducted a cohort study of workers who had been exposed to VC in the U.S. ''lives (October 1981 89 A i i OLI 6920 . *, Table 1. Epidemiologic study results ,,f Vl'-exposcd workers as related to biliary and liter or digestive system eaneer Heath1 for the.- Investigation Site (thserved Deaths Expected * authors r recently SMR short to Waxweiler et al. (.5) Total cohort Latency > 15 yr Byren el al. (6) Total cohort Latency > 10 yr Fov and Collier (71 Total cohort Plant #2 > 15 vr Seven other plants Monson et al. (9) Total deaths Tabershaw and Gaffey (9) Total cohort Highest exposure. > 5 yr employment Buffier et al. U0)d Biliarv and liver Liver and pancreas Liver Biliarv and liver Digestive organs This stal 7 0.6 1155* t as to otl 7 0.4 1606" Monso tality st 4 0.97 413b * plants w 4 0.68 589" studied eight <le 4 1.64 244 versus 0 3 0.13 2308" Taben 1 1.51 66 $ cohort st industria 8 0.7 19 21.7 U.0ht data sep. deaths 6 94 i category 11 7.5 151 Table 1* | from dig* the highi Ott et al. (lir years of EEH (12) Total cohort Latency > 20 yr Digestive organs p < 0,01. l,p < 0.05. 'Proportional mortality study risk ratio. dNo liver cancer identified among 8 cancer deaths. 'No liver cancer identified among 20 cancer deaths. 29 40.8 9 13.6 cancer d< 71 1 of the oh 70 i Howev submerg. t in the an Of the 1 f noted th. f these live II according An add it for at least five years and who had achieved a some overlap in reporting. There were four! were idei period of ten or more years since initial exposure liver/pancreatic cancer deaths observed, compared . was publ (latency). On the basis of seven liver and biliary to 0.77 expected (p < 0.02). An additional death 1 been cat* cancer deaths that fit the cohort definition, the study demonstrated an 11-fold to 16-fold excessive risk of death from cancer of this site among VC-exposed workers. These findings represent an underestimate of the risk because seven additional individuals who died from liver/biliary cancer at the plants being studied were not included in the from liver angiosarcoma was identified as having ! occurred after the study cut-off date and thus was not included in the study. j Fox and Collier (7) studied U.K. workers ex : posed to VC. In eight factories studied, the;. ! observed a total of four liver cancer deaths a; 1 compared to 1.64 expected. Three of these death* J primary under ca cirrhosis This st ent limit; diagnosis result in analyses. Of these latter seven cases, four individu occurred in factory 2, where only 0.13 would ha\- risk. An a. als diagnosed with liver angiosarcoma were still been expected (p < 0.01). The authors stated thati*. f that may i alive at the study cut-off date, while two individuals was difficult to identify angiosarcoma of the livei | this study who died from biliary cancer had incomplete infor from death certificates (the usual method o` I determina mation on length of exposure to VC. A seventh individual did not fit the study cohort definition as he was exposed for only three years. He died from liver angiosarcoma 17 years after his initial expo sure to VC. Byren et al. (6) conducted a cohort study of all Swedish workers ever employed in positions where exposure to VC could have occurred. The investi gators combined deaths from cancer of the liver and pancreas because they believed that there was 90 identification), since some of these deaths wen; classified as primary, some as secondary liver t cancer, and others were not certified as cancer s deaths at all, ; The results from the Fox and Collier stud) ' probably represent an underestimate of the ob- j served risk of death from cancer for the follow inr reasons: (1) 75% of the study cohort was employe'; for less than ten years; (2) only 8% of the cohor * was employed for more than 20 years: and (3) ever i Environmental Health Perspective ? exposure followup uals with the study studied h of the he; ately stat be worth; tally sign Buffler October 1 IK 1 iicer death*. SMR 1155* (1)06* 413b 389* 244 2308" 66 11.0bt 94 151 71 70 ore four compared nal death is having t hus was rkers ex* ied, they leaths as se deaths "ild have -ed that it the liver lethod of >ths were ary liver as cancer ler study f the obfollowing employed ho at ia en i for those who completed 20 years of service, the lUthors stated that "because their service has only recently been completed, the follow-up period is too ;hort to evaluate the carcinogenic effect of VCM." This statement obviously applies to the liver as well >s to other sites. Monson et al. (8) conducted a proportional mor tality study of 161 deceased workers from two plants where VC was used. These plants were also studied by Waxweiler et al. (3). They observed eight deaths from liver and biliary tract cancer versus 0,7 expected; the risk ratio was 11.0. Tabershaw and Gaffey reported the results of a cohort study of workers exposed to VC in 33 U.S. industrial facilities. The authors did not analyze the data separately for liver and biliary cancer. Thus, deaths for these causes are accounted for in the category of digestive organ cancer. As noted in Table 1, for the total cohort there were 19 deaths from digestive organ cancer and 21.7 expected. For the highest exposure cohort, with more than five years of exposure, there were 11 digestive organ cancer deaths observed versus 7.5 expected. None f the observations are statistically significant. However, the risk of liver cancer in this cohort is submerged by including data for this cause of death m the analysis with digestive organ cancer deaths. Of the 19 digestive cancer deaths,' the authors noted that seven w'ere from liver cancer. Two of these liver cancer deaths w'ere listed as angiosarcoma according to the diagnosis on the death certificate. An additional four deaths from liver angiosarcoma were identified in this cohort by the time the study was published in 1974. Two of these deaths had been categorized by death certificate diagnosis as primary liver cancer, and two had been certified under causes of death other than cancer, i.e., cirrhosis of the liver and hepatoma. This study again demonstrates one of the inher ent limitations of epidemiologic studies (incorrect diagnosis in relatively rare causes of death) that result in an underestimate of the relative cancer nsk. An additionaltKtor, indicated by the authors, that may have led to an underestimate of the risk in this study was that the group with no vital status determination, 15% of the population, began their exposure ten years before the group for whom followup was completed. As a result, some individ uals with longer latency periods were omitted from the study. In addition, 57% of the cohort actually studied had less than 15 years of latency. Because of the healthy worker effect, the authors appropri ately stated that SMRs higher than expected may be worthy of attention even if they are not statisti cally significant. Buffier et al. (70) and Ott et al. (11) did not -'pvctivw j October 1981 1 observe any liver cancer deaths among eight and twenty deaths, respectively, in their studies. An unpublished study conducted by Equitable Environmental Health (72) reported the mortality of a cohort of workers from 37 U.S. industrial facilities. This study included data for the facilities studied by Tabershaw and Gaffey (9), Data were not analyzed separately for liver cancer. However, the category of death from cancer of the digestive organs, which includes liver cancer deaths, indi cates a deficit of mortality. As shown in Table 1, even for those individuals who had achieved 20 or more years of latency, the SMR was only 70. It is somewhat unusual to observe such a deficit of mortality among workers who had achieved such a long latency period. Brain Cancer in Humans Brain cancer also has been associated with expo sure to VC. A summary of the results of mortality studies is shown in Table 2. Although the number of cases upon which observations were based are small, Waxweiler et al. (5) and Byren et al. (6) demonstrated significant excesses of brain cancer. The relative risks were five and six, respectively. Waxweiler et al. (5) also noted an unusual distribu tion in the cell type of brain cancer. Of 10 brain cancer deaths identified among the VC-exposed workers, nine (fiU'/i) had a histologic diagnosis of glioblastoma multiforme. The tenth case had no confirmation of cell type. The authors contrasted this high proportion with that of the Yale autopsy series in which 33% of primary intracranial neo plasms were glioblastoma multiformo. Fox and Collier (7) observed two brain cancer deaths as compared to 3.7 expected for the entire cohort. For those cohort members categorized as having high exposure, one brain cancer death was observed versus 0.4 expected. Monson et al. (8) demonstrated a fourfold risk of brain cancer. Tabershaw and Gaffey (0) categorized brain can cer with "other and unspecified causes of cancer death;'' therefore, it is not possible to determine the actual brain cancer risk identified in this study. Since the Tabershaw and Gaffey study (9) was a subset of the EEH study (72), the latter study was used to estimate the expected number of brain cancer deaths in the former study under the as sumption that the age distributions were similar. The proportion of expected brain cancer deaths from "other and unspecified cancer deaths" m the EEH study (72) was then applied to the expected from this same category in the Tabershaw and fit OLI 6922 f Tahir 2. Epidemiologic studv results of \ ('-exposed workers as related to central non oils system. Investigation Site (ibsorved Deaths Expected SMK WaxwMiler et al. (.) Total cohort Latency > 15 yr Bvren et al. tS) Total cohort Fox and Collier (71 Total cohort Highest exposure Monson et al. (,t) Total deaths Tabershaw and Gaffey (9) Total cohort Highest exposure. > 5 yr employment All exposure levels Buffier et al. (JO)1* Ott et al. U/> Total cohort Total cohort EEH if*) Total cohort Brain and ('NS Brain Brain Brain Other and unspecified Brain All sites other than digestive and respiratory Brain Brain and CNS */i s. 0.05. hProportional mortality study risk ratio. 'Estimated. dNo brain cancer identified among 8 cancer deaths. 0.!* 329 0 fi 498" 2 0.3 612" 2 3.7 55 1 0.4 278 5 1.2 4.2*'b 17 11.8 155 7 3.5 204 6 2.4' 250* <5 6.8 88 2 o.r 286 12 5.9 203* Till; Investigation Waxweiler et Total cohot Latency > Byren et al. Total cohot Fox and Coll. Total eohoi Highest ex Monson et al. Total death Tabershaw at Total cohor Highest ex > 5 yr ei Buffier et al. Total cohor Long expot Short expo Ott et al. Ui Total cohor EEH (12) Total cohor Highest exMedium e. Low expost */> < 0.05. ''Proportlor Gaffey study (9). As a result, 2.4 brain cancer deaths were estimated to have been expected and compared to six observed in the study. This difference is significant. Buffier et al. (10) did not identify any deaths from brain cancer in their small cohort. Ott et al. (11) did not analyze their data separately for brain cancer, but rather included brain cancer deaths w-ith cancer deaths from "all sites other than digestive and respiratory." Therefore, using an analytical tech nique similar to that described above, the propor tion of expected brain cancer deaths among "all sites other than digestive and respiratory" from the EEH study (12) was applied to the expected in the study by Ott et al. ill). As shown in Table 2, there was a resultant estimated 0.7 brain cancer deaths expected as compared to two observed. The excess risk is estimated to be about threefold. The EEH study (12) also demonstrates a significant excess brain cancer among workers occupationally ex posed to VC. In summary, the data for brain cancer appear to be more consistent between studies than the data for liver cancer, although the magnitude of the excessive risk is not as great for brain cancer. 92 Lung Cancer in Humans Table 4. Epit As showm in Table 3, Waxweiler et al. (>> observed 11 lung cancer deaths as compared to 5.T expected (p < 0.005) for cohort members who had achieved 15 or more years of latency. The author? ' also noted what appeared to be an unusual distribu- 1 tion in the histologic types of lung cancer. Of eight histologically confirmed lung cancer cases, five J were classified as large cell undifferentiated, and; three were categorized as adenocarcinoma. These cell types are different from those usually associ- ated with a cigarette smoking etiology, i.e., small j cell undifferentiated and epidermoid carcinomas. > With the exception of the study by Fox and Collier (7), the remaining studies show excess risk,' i of lung cancer ranging from 7 to 200%. However. > the reservation expressed by Fox and Collier (7), a.1 mentioned earlier, about the short period of followuf j limits the interpretation of their study. This con- j cern is supported by the observation that the SMR ' for total mortality was only 75, 75% of w hat would; be expected on the basis of comparison to th 1 standard population. Environmental Health Perspective ^ Investigation Waxweiler et Latency > Fox and Colli Monson (40 Tabershaw & Highest exp-1 employmt i EEH (ftp I Latency > 2d Intemation, `'lntematior 'Proportion As show Buffier et dose-respo and lung c; gorization was used i with cautit October 19 MR J4 Ij*1 V* >5 4 2" b 35 '1*4 `,n* *0 i Tabic 3. Epidemiologic itudy results of VC-exposed workers as related to respiratory system cancer deaths. ! `.'.vestigation Site Observed Deaths Exacted SMR I Vtxweiler et al. (5) ' Total cohort j latency > 15 yr Respiratory 12 7 7 156 11 3.7 194" S;Ten ec al. (6) Total cohort Lung 3 1.8 168 Fox and Collier (7) Total cohort Highest exposure Lung 46 51.2 2 3.7 90 54 Munson et al. (d) Total deaths Lung 13 7.9 1.6b 'ibershaw and Gaffey (9) Total cohort Highest exposure, > Syr employment Respiratory 25 23.9 112 12 8.5 144 Safller et al. U0)d Total cohort Long exposure duration Short exposure duration Lung 5 1.7 289* 4 1.05 381* 0 0.45 -- Ottet al. (11) Total cohort Respiratory 7 5.8 121 EEH ill) Total cohort Highest exposure Medium exposure Low exposure Respiratory 45 44.3 107 7 5.1 141 19 17.0 116 19 22.2 92 `p < 0.05. "Proportional mortality study risk ratio, Table 4, Epidemiologic study result* of VC-exposed workers as related to lymphatic and hematopoietic system cancer deaths. t al. (J) red to 5.7 who had f author* l distribu. Of eight tses, five ated, and uu. These llv associi.e., small inomas. Fox and .cess risks However, lier (7), as >f followup This eon. the SMR hat would m he rspectives Investigation Site* Waxweiler et al. (5) Latency > 15 yr fox and Collier (7) Munson (d) Tabershaw & Gaffey (9) Highest exposure, > 5 yean employment EEH US') Latency > 20 year* (200-205) (200-205) (200-207) (200-205) (200-203. 205) (200-203, 205) `International Classification of Diseases, 7th Revision. `International Classification of Diseases, 8th Revision. `Proportional mortality study risk ratio. Observed 4 3 9 5 6 4 11 4 Deaths Expected 2.50 1.70 9.01 3.4 6.06 1.84 10.36 3.10 SMR 159 176 100 1.5* 106 222 112 136 As shown in Table 3, data from the EGH (12) and judgment. The study by Buffler et al. (10) is IBuflfler et al. (10) studies suggested a qualitative fee-response relationship between VC exposure and lung cancer risk. However, retrospective cate- particularly noteworthy; within a small cohort of only 464 workers, a fourfold risk of lung cancer was observed. When the investigators examined the | gorization of high, medium and low exposure, as effect of smoking, under the extreme assumption ; '.tas used in the EEH study (12), must be viewed that those with unknown smoking habits were j with caution because of the subjective nature of smokers, the data still demonstrated a significant October 1981 93 14 * 1 OLI 6924 excess of lung cancer (;> observed versus l.'ts expected.) Cancer of the Lymphatic and Hematopoietic System in Humans Table 4 summarizes data on cancer of the lym phatic and hematopoietic systems among workers exposed to VC. The relative risks for various studies ranged from 1.0 to 2.2. and none of the results demonstrated a significant excess. Although somewhat suggestive, the data need to be further analyzed by latency period and exposure levels combined. Analysis of data separately for lym- nhatir raniprs anH Ipukpmia miffht also IpaH tn meanmgiui ooservauuns. Summary In summary, epidemiologic evidence demonstrates that the carcinogenic effects of VC in humans extend beyond the liver. The brain and lung should also be considered target organs. Some studies indicate that the lymphatic and hematopoietic sys tems are also involved. These observations in humans are supported by studies demonstrating the induction of cancer of these same sites in experimental animals. l'idil. Ib-ulth Itcpi l.'i: 1!HL'1-|!I71 il'rtin '2 sclikulf. I J. ;uii! lljmiiuiiul, L. v' , Kil>. Tnxivilv nf vuiy. chloride-polyvinyl chloride. Ann. N.Y. Acad. Sci. 246:12T (1975). 9, Viola. P. L., Biogotti. A., and Caputo, A. Oncogeru, responses of rat skin, lungs. and bones to vinyl chloride. Cancer Res. 91: 516-519 (1971). 4. Maltoni, C, Lefemine, G., Ciliberti, A.. Cotti. G and Carretti. D. Carcinogenicity bioassays of vinyl chlondt monomer: A model of risk assessment on experimental bases. Environ. Health Perspect. 41: 3-29 (1981). 5. Waxweiler, R. J., Stringer, W., Wagoner, J K., Jones, J.. Falk. H., and Carter, C. Neoplastic risk among worsen exposed to vinvl chloride. Ann N.Y. Acad. Set. 271. 40-te (1976). Byren, D., Engholm, G.. Englund. A., and Westerholm.P. Mortality and cancer morbidity in a group of Swedish VCM and PVC production workers. Environ. Health PerspetL G M Vi Fox, A. J., and Collier, P. F. Mortality experience <f workers exposed to vinyl chloride monomer in the manefac ture of polyvinyl chloride in Great Britain. Brit, J. Ind. 8. Monson. R. R., Peters. J. M., and Johnson, >1. N. Prupor- tional mortality among vinyl-chloride workers. Lancet t 397-398 (1974). 9. Tabershaw, I. R., and Gaffey, W. R. Mortality study k workers in the manufacture of vinyl chloride and iu * polymers. J. Occup. Med. 16: 509-518 (1974). 1 !10. Buffler. P, A., Wood, S.. Eifter. C., Suarez, L.. and Kiiiaa, D. J. Mortality experience of workers in a vinyl chloride monomer production plant. J. Occup. Med, 21: 195-3B ff (1979). 4 11. Ott, M. G., Langner, R. R. and Holder. B. B. Vinyl chloride exposure in a controlled industrial environment. A long term mortality experience in 594 employees. Arch. Envina Health 30: 333-339 (1975), 12. Equitable Environmental Health. Epidemiological study rf vinyl chloride workers. Prepared for Manufacturing Chem ists Association, 1978. 4 01 Vir T1 darn exp< We- stud chrr. trib: vrj worl 11 stud the' plar