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Air Product* *nd cticcnieala, Ine. AIR JPRODUCTS 27 February 1986 Or. Has Shah Chemical Manufacturers Association 2501 M Street, N.W. Washington, O.C. 20037 Dr. Roy Gottesman The Vinyl Institute Wayne Interchange Plaza II 155 Route 46 West Wayne, NJ 07470 Sirs: You may wish to bring the attached paper to the attention of your various comnittees Interested in vinyl chloride health effects. It describes VC as the only recognized central nervous system carcinogen. Ve-ey^truly yours John T. Barr, Manager Regulatory Response JTB:pbr 0608c Enclosure: Moss, 3. Toxicol. Environ. H. 1^ 703-711 {1985) VVV 00000236^ m OCCUPATIONAL EXPOSURE AND BRAIN TUMORS Andrew R. Moss _ University of California, San Francisco. California wptdem/oiogicsi 0 f in OCCudationsi fnk of bmn w has been m row tndvstncs wjert cncmica/ are ftfce/v, mow irccflriv m a of profpecrr^e ituowj in r/ie perrocfte/rifca/ ^dusr/v, Hflwwe/, orr/y rn r/ae case or vmvt Cftfonde exposure nAS Aft occupAttOnai eentrai nervous svstem CArzrnogen been tPen* itfted. This repctT reviews f/re foove/^enct or epitfeirwotojica/ a/rc /afroraforv eii* tfence rrt eiu&//s/)ed cAe occupatronav fa/o/togrmoty or vutvi cin<j cusses m detAti the current evidence for an qccs/pdfion^/ rjjjfc of brain tumors in me petrocnemtcil incastty. INTRODUCTION Primary brain Tumors of the glioma series, which make up about half of all brain tumors, show a male-to-female ratio of about 1.5 to 1. Brain tumors in general appear to be increasing in incidence among older cohorts (Waxweiier et al., 1933). Thus brain tumors in general, and glioma series tumors in particular, are sometimes considered as a priori irfceiy suspects in the search for occupationally related tumors. Furthermore, gliomas can be produced experimentally in rats bv at least four groups of experimental chemicals: aromatic hydrocarbons, jv-nitroso compounds, tnazenes.and hydrazines. More recently, brain tu mors including gliomas have been shown to be produced by inhalation in rats by three industrial chemicals, bis(chloromethvl) ether, vinyl chloride, and acrylonitrile IMaltoni et a)., 1982). These experimental results, together with the established history of brain-tumor carcino genesis in vinyl chloride workers, have led many researchers to iend at least preliminary credence to reports of brain tumors occurring in other industries where there are chemical exposures. Most recently, a series of studies have suggested excess risk of brain tumors in the petrochemical industry. Evidence suggesting an excess of brain tumors has now been re ported for at least tour occupational groups: rubber workers (begin ning with Mancuso's investigations in the 1950s), chemists, vinyl chio- TSi* research was SUOMnefl in part bv gram 1 ROT OH 01337 from trie Ninon at tn.druc,Occupational iaretv and Health. Requests mr rectum snouid be Tern to undrew nt. tics*. Epiemiot<jcv jna inn-TM Health. UC5F. 5ao Francisco Ceneral Hostxtal. 395 Porrero Avenue. 3td*. hO. J,n u - =ii * r:;i- cisco. Caiiiorma SiHO. 703 lotinut 04 Tmicotocv and Ettvinximental Health l (>:71I3-- 71 ]. [ '"I-, Cnovrirnt a i^SS bv Hemisphere PublWime CuipnratJiHi VVV 000002365 704 A. K. MOSS ride workers, and petrochemical workers. However, the convergence of epidemiological and laboratory investigations that is usually ac cepted as the informal criterion of proof in such situations Has been hard to demonstrate (see, e.g., Cole and Merletti, 1980; Doll and Peto. 1931). Thus, Mancuso's original observations in the rubber industry were not fallowed by the identification of any specific carcinogen, and the existence of an occupational risk of brain tumors in rubber workers is currently open to doubt (Mancuso, 1982; Symons et aL. 1932). Braintumor risk in chemists has been shown only in a series of Swedish studies, and as yet no likely carcinogen has been identified (Olin and Ahlbom, 1932). The convergence of an epidemioiogically identified risk and a suspected carcinogen has been demonstrated only among vinyl chloride workers. Thus Cole, in his surveys of occupational carcino genesis, recognizes only vinyl chloride as an established industrial brain carcinogen (Cole and Merletti, 1930). Doll and Peto, more con servatively, admit the brain only as a "possible" site of occupational carcinogenesis (Doll and Pero, 1981). The history of vinyl chloride as a central nervous system (CNS) carcinogen is discussed in the next sec tion. Historically, the establishing or occupational or environmental risks has often been a complex and drawn-out process, sometimes requiring decades for the development of a consensus on a particular exposure. Thus although the issue of excess risks of brain tumors in rubber workers is currently in debate, the persistence of reports of brain tumor excesses in this and other industries has. as it were, promoted brain tumors to the top of the fist of tumors that may be associated with important occupational risk (along with lung cancer, leukemias and lymphomas, primary liver cancer, and, more recently, melanoma). This was the situation in 197B when a duster of brain tumors was reported in petrochemical workers in Texas, initiating a major wave of research into the subject. The petrochemical research is also reviewed in this article. VINYL CHLORIDE AS A BRAIN CARCINOGEN Cole observes that occupational carcinogens are usually recognized because they generate an unusually high rate among a small exposed population, and because they produce tumors that are otherwise un usual (Cole and Goldman. 1973). Vinyl chloride (VO is the classic case of a carcinogen that has such an effect, producing in workers exposed to high levels of the gas the very rare angiosarcoma of the liver {ASL). The first reported case of ASL in a vinyl chloride worker was diagnosed at the B. F. Goodrich company in Louisville, Kentucky, in Mav, 1970: the second in March. 1973: and the third, at autopsy, in December, 1973 (Heath et al., 1976). Since the incidence of ASL in the United States VVV 000002366 OCCUPATIONAL EXPOSURE AND BRAIN TUMOflS A ro3 t \ t tt j was Then 20-23 cases/yr, the appearance of 3 cases among a small group of workers prompted considerable concern. Furthermore, concurrent studies by Viola (1971) had shown skin, lung, and bone tumors in rats exposed to VC by inhalation. {Viola's carcinogenesis studies were reportedly an outgrowth- of his work on acroosteolytis in VC-exposed workers. Hepatitis-like liver changes had been reported as early as 1949 (Nicholson, 1977).]. Following Viola, Maitoni demonstrated angiosarcomas in rats exposed to VC in 1972 (Maitoni et al.. 1952). This result was communicated to the Manufacturing Chemists Association, which following the dis covery of the third case at 3. F. Goodrich, made public the finding of three cases of angiosarcoma in VC-exposed workers in the Wait Street journal. With this announcement, a major effort began to study vinyl chloride workers, including a National Institute of Occupational Safetv and Health (NIOSH) follow-up study of 1294 workers with extensive VC exposure in four plants. A concurrent histopathology study reviewed tumors reported on death certificates of ail workers in the four plants. The NIOSH study, published in 1976. showed very high relative risks in the category "biliary and liver cancer." The relative risk was 11 for workers with 10 or more years of exposure and 16 for workers with 15 or more years of exposure. Furthermore in the concurrent histopathology study, 11 of 14 reported liver and biliary cancer cases on death certificates were ASL (Waxweiier et ai., 1976). TTiese observations have remained the primary epidemiological basis for the assertion of the carcinogenicity of vinyl chloride. However the study also observed a significantly increased relativerisk for brain tumors, with 3 observed and 0.6 expected among workers exposed more than 15 years. At the same time Maitoni (1976a) reported that brain tumors as well as ASL could be produced in rats exposed to VC by inhalation. Furthermore the NIOSH histological study showed that 9 of 10 brain-cancer deaths in the VC worker cohort were glioblastoma multiformes (the most commoniy occurring tumor in the glioma series). This proportion was thought to be unusually high. [However, it has been shown that the expected proportion of glioma-series tumors in such a series depends heavily on the number diagnosed at autopsy (Schoenberg et ai., 1978)]. These results were sufficient for the devel opment of a reasonable consensus that brain rumors as well as ASL were associated with VC exposure. The primarv evidence in the deveiopment of the consensus was the correspondence between the human data and the laboratorv inhalation studies, in which the exposure levels were thought to be dose to human occupational exposures, (see. e.gWagoner and Infante, 19//). Vinvl chloride is the onlv occupational chemical carcinogen for which a correspondence exists. Waxweiier et al. (1983) also note that in the 9 glioblastoma multi forme cases identified in the VC workers histology study, the average : : > > I 1 ; j. . j j ; i. f [ j ` VVV 000002367 TO* A. L MOSS time since first exposure to vinyl chloride was 21 vr. Thus the epide miological observation of risk may have followed the oncogenic expo sure by a generation, and the circumstance of exposure could well have changed by the rime the risk was recognized. This long latency period is characteristic of occupational carcinogenesis. The excess risk of mesothelioma in asbestos workers, for example is not general Iv ob servable until 20 yr after exposure (Selikoff, 1977). The long latency pe riod has important consequences in the case of brain rumors, which are not rare tumors. The identification of VC-produced brain tumors, currently the only accepted example of occupational CMS carcinogenesis, offers same important lessons for studies of other industries. First, vinyl chloride was identified as a CNS carcinogen because it produces, as its primary effect, the extremely rare ASL. The excess risk of brain tumors would probably not have been recognized if it had not "piggybacked" on the rarer tumor. Second, the brain was only recognized as an additional site of carcinogenesis because comparable ranges of tumors were seen in human and animal inhalation studies. There is no other occupational carcinogen for which such a correspondence is currently known. Third, the number of tumors reported in the primary study was very small: there were 3 cases in the high-exposure cohort, and 10 in the concur rent hisropathology study. Fourth, the period between initial exposure and observation was so long that observed effects may in fact have been archaeology rather than epidemiology--the carcinogenic situa tion may well have no longer existed when the excess risk was ob served. BRAIN TUMORS AND PETROCHEMICAL EXPOSURE The intensive study of brain tumors in the petrochemical industry began in 1973 when as employee at the Union Carbide plant in Texas City. Texas, reported a newly diagnosed brain tumor to the local office of the Occupational Safety and Health Administration (OSHAJ. A joint study with the Oil. Chemical and Atomic Workers union (OCAW) and company representatives identified a total of 10 brain-tumor deaths and cases among workers at the plant (not including the original com plainant, whose tumor proved to be metastatic!. This number was suificienr for the OSHA office to request a formal study by NI05H. A joint study, with Union Carbide researchers, was initiated. A proportional monaliry studv of OCAW members in South Texas was alreadv in prog ress, and additional studies in other refineries and chemical plants were initiated over the next vear. However, in 1979 borh the Three Mile island incident and the Fed eral declaration of emergency status for the Love Canal area took place. VW OOOOQ2^363 OCCUPATIONAL EXPOSURE AND BRAIN TUMORS 707 and in the ensuing controversies over environmental carcinogenesis the atmosphere became polarized between industry and govern mental-unton forces. As a result, competing industry and govern ment-union studies were set up in several of the exposed petrochem ical cohorts in Texas'and Louisiana. When a meeting was convened at the New York Academy of Sciences in 1980 to review the studies, a total of eight were presented, four from each group. The four govern mental-union studies uniformlv indicated a twofold risk of brain cancer among petrochemical workers; the four industry studies untformiv failed to detect anv excess risk. "To the innocent observer." Science reported, "the crisp pattern of failing chips appeared at first sight to display blatant gerrymandering" fLewin. 1980). it was also true, however, that the range of methods and cohorts involved was consid erable and that there was extensive methodological disagreement. Reeve et al. (1985) reviewed the issues. The primary methodological questions were <1) the tendency of proportional mortality studies, as carried out by NIOSH, to inflate cancer risk, and (2) the tendency of industry-wide cohort studies, as carried out by the industry groups, to bury small groups of at-risk workers in very large cohorts. These issues were not resolved as, with the new Federal administration in 1981, NIOSH capacity to continue the epidemiology studies was lost. With no pressure from the regulatory side, the industry studies appear to have slowed down also. However, most of the oroportionai mortality studies were eventu ally converted to standardized mortality form, and a review of these studies is now possible. Savitz and Moure (1984) have recently reviewed the six prospective studies of refinery workers that were initiated bv labor--governmental and industry groups in 1979-1980. Table T is adapted from Savitz and Moure, with the addition of results from two studies of petrochemical plant workers, those of Waxweiier et al. (1983) and Reeve et al. (1983). [One studv, that of Thomas et ai. (1982): remains a proportional mortality rate study (PMR): the others use standardized mortality ratios.] All cohorts of petrochemical workers had low overall mortality, as is generally the case in studies of "healthy workers." and six of the seven for which all-site cancer mortality or incidence were reported showed lowered total cancer rates. [The exception was the PMR studv of Thomas et al. (1982).] However, brain-tumor rates were elevated :n all but two of the studies, the exceptions being the refinery-wide studv of Wen et al. (1983), which included salaried workers, and the industry wide study of the British petrochemical industrv by Rushtan and Alderson (1981). There was additional evidence of an association m mare detailed subsiudies. Thus Savitz and Moure H984) note that while Hants et al. (1982) report an overall relative risk of 1.02 tor brain tumors m their study of the Saton Rouge Exxon refineries, a more highlv exposed TABLE T. Reljnvt? Risk for Brain Cincer and Melanoma Prospective Epidcmiotogicil Studies Ot Reiinerv and Petroctiemical Woitifiu Study Theriault and Couiet. (15791 Suthton and Alderwn. nwn Schemenleid et *1. 11941) (mortHtyt SchonerrteW et *1. (1941) (incidence! Thomai et aj. (19522 iPMR) Hanit el at. (1942) Wen et ai. (19831 Wanveiler et ai. (19831 Reeve et *t. (1983) Alt dnctn XR AT 0.39 0.59 0,76 0.36 1-19 0.92 0.9S 0.51 N/A 2S T147 127 240 474 249 439 131 V/A Brain ax w 3.90 oao 1.S3 1.29 US 1422 - 0.99 iai 1.09 3 36 & 9 27 3 30 13 IS Mdinomi (U V 1.16 14 1.32 1.61 13 n 1.22 16 --- ---- * Adapted front Savin and Moure iT984i. * RJt. relative nsk: N. number. subgroup had a higher risk, in the Reeve et al. study or Dow chemical workers, while the overall relative risk was 1.09, the risk among workers hired before 1945 was 1.a3 (Reeve et al.. 1983). On the basis of the first six studies, Savitz and Moore comment that there was reasonably consistent evidence of a potential association between petrochemical exposure and brain cancer. The two chemicalplant studies appear to strengthen the association. In an independent review of all NIOSH investigations in eight in dividual refineries and chemical plants in Texas, Reeve et ai. (1983) note that inconsistencies remain in the piam-by-plam results, and that casecontrol studies within the studied cohorts show no consistent patterns of exposure. However the consistently elevated brain-tumor risk in the prospective studies appears sufficient at least for this line of research to continue. * Savitz and Moure note :hat melanoma risk is rarher consistent'v elevated in the studies of petrochemical cohorts, as well as brain-tumor risk. This result is of interest because of an emerging partem in recent studies of nuclear fabrication workers. Hadfimichael et aJ. (1983), in their study of the United Nuclear facility in Connecticut, observed rel ative risks of 2.40 for brain tumors and 2.12 for melanoma, against an Wv 000002370 OCCUPATIONAL EXPOSURE AND BRAIN TUMORS 709 all-sites relative risk of 0.33. Furthermore, Wilkinson et al. (1983) ob served a tripled risk of brain tumors at the Rocky Flats nuclear plant, and Austin (1981) observed a tripled risk of melanoma at the Lawrence Livermore laboratory. Attempts to explain these risks by radiation ex posures have proved generally unsuccessful: the similarity with the pattern of risk among petrochemical workers suggests that perhaps the cause is in some other aspect of the fabrication process. CONCLUSION Although this review suggests that the issue of brain tumors in pet rochemical wcrkers is at least worth further study, most of the pro spective studies appear to have been dropped. However, a second wave of large case-control studies of occupational exposure in brain tumors has now been set in motion (see Table 2). In these studies, all brain-tumor cases or deaths in a specific case-finding area over a spe cific period are interviewed, either in person or by proxy. These large studies may eventually resolve the issue of whether there is a genuine TABIE 2. Case-Control Studies Cotrent!v >n Progress ot Occupations! Exposure in Glkiitu Paitents Investigator Vumoef of Sumoer or Source 5ir- controls or cases Location Thomas. T. 1_.VC environ mental Epidemiology Branch Presion-Manin. S.. University or Southern California Mots. A. R.. University of California. San Francisco Buftler, P.. University of Teas Ahlbam. A.. Hudtnye University Hospital. Sweden Muucco. W.. Neuroi 00 cal Institute CBetia. Milan CNS CNS Glioma CfiORU 3*am Vlenmcfomir glioma 600 300 500 650 ISO 800 600 Death certificate New l*r$ew Launutu 300 Incidence Los Anceies Co untv 500 UCSF clinical cases and death California certificates an; Incidence Ccj^ioi levs jnrj lomwru ;oo Clinical Cases HvnOtn<*e in 2 hospitals t.WXJ Hospital cases Milan * From Muir and Wayner tI9WJ ana P, Bolder, personal communication VVV O0OQ023T1 710 A- t MOSS excess risk in petrochemical workers. [However, Cole notes that such large case-control studies are only effective when the exposed group makes up at least of the population studied (Cole and Coldman, 1975).] It should also be noted that while large case-control studies of brain tumors may identify industry-wide risk, they cannot, by their na ture. identify the partem of tumor sites associated with a specific ex posure. This latter information is generally accepted as important in establishing risk. In conclusion, the prospective studies of petrochemical worker co horts reviewed here suggest that there is an increased risk of brain tumors associated with petrochemical exposure, possibly accompanied bv an increased risk of melanoma. No evidence oi a specific carcinogen has been established, and while the current generation of large case- control studies will probably identify any overall risk in the industry, these studies will not identify the pattern of sires at risk. In the light of the consistency between the petrochemical worker studies and the recent nuclear-tabrication worker studies, there is an argument for a coherent program of prospective research in these cohorts* Other studies that could usefully be coordinated with such a program include a review of the specific-exposure inquiries in the petrochemical worker cohorts, an examination of the change in the incidence of glioma series tumors among all brain tumors, and an exploration of other associa tions between brain tumors and melanoma. REFERENCES Austin, D. F, 1481. Population-based lumof registries m me idenutication or occupational Caron- Ojtnt. Proceeding* of Itie 1980 International Symposium on Cancer. Sept. 14-IS. 7980. In Cancer: Achievements. Challenges and Prospects fatihc I980*. eds. i. H. Surctienal and H. F. Oetreen, rol. I. pp. 291-298. New Yoric: Crime and Siranon. Cole. P.. and Goldman. M. S. i?75. Occupation. 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A., jnd C!>bxw>- H. I. 1983. longnerm mortatiiv ituw qi oil reimerv woncers: I, vtorrantypr bourtv j.i-o i^ryd ivorker*. -WJ. /. tsdUK. Wilkinson. C. S.. V'oeiz. C. L.. Acauaveil*. I. F vinnaiiiv among plutonium and otner workers at a nuciear ^actiitv. Procruomes oi rhe Midvear Topical -Meetmg ot ;ne mmiih PhvsiC* Society, In epfaermo/yev Aooueo ro Hea/tn Phvstcs. COnF*3301C1. Jan. 9-- 1 4 1983 pp. J23-337. yvv QGCCQZ375