Document YrE44vRMbjk7xQXzMnRD1xxp0

Occupational Hazards of Vinyl Chloride and Styrene Trends in Cancar Mortality Among Workers in the Synthetic Polymers Industry William J. Nicholson, Paul K. Henneberger and Diane Tarr POccupational Hazards in the VC-PVC Industry William J. Nicholson, Paul K. Henneberger end Herbert Seidman Occupational Hazards in Production of Processing of Styrene Polvmers - Epidemiologic Findings William J. Nicholson and Diane Tarr Lectures presented at a course on occupational hazards of plastics and synthetic elastomers, Institute of Occupational Health, Helsinki, Finland, November 22-27, 1962 Published In: Industrial Hazards of Plastics and Synthetic Elastomers Eds. J. Jarvisalo, P. Pfaffli, H. Vainid (1984) Progress in Clinical and Biological Research: Volume 141 Alan R. Lias, Inc., New York, pp. 65-78, 155-176,263-278. ENVIRONMENTAL SCIENCES LABORATORY MOUNT IINII SCHOOU o* MSOieiN* O* T*< C'TV wNtwelTV O* NW YO* 05384 15 OCCUPATIONAL HAZARDS IN THE VC-PVC INDUSTRY William J. Nicholson, Paul X. Henneberger and Karbart Seidman. Environmental Sciences Laboratory, Mount Sinai School of Medicine of CUNY, New York, New York 10029 (VJN, PH) and American Cancer Society. 4 W. 35th Street, New York, New York 100D1 CHS). INTRODUCTION V On January 24, 1974, The Vail Street Journal publish ed an article describing the occurrence, of three, deaths from heaangiosarcoma. of the liver among.polyvinyl chloride (PVC) production workers at the B.F. Goodrich Tire and Rubber Company plant in Louisville, Kentucky. This announ cement shattered the^ Relatively complacent view toward health effects associated with plastic production in general and PVC.production in particular. At the time, U.S. and Western European production of vinyl ehloride (VC) exceeded 6 x lO.metric tons. Numerous mortality and clinical studies were undertaken in the major producing countries in an attempt to establish the extent of the carcinogenic risk and to identify clinical parameters useful for surveillance of exposed groups. Because of the immediate concern in 1974, most of these studies were com pleted between 1974 and 1977. Several reviews and sympo sia on human health effects from VC exposure have been published recently. A superb one is by Laibach and Marsteller (19S1). .. The exposures were high that led to the disease observed in these various studies. Typical concentrations in the industry were estimated to be about 1,000 ppm prior to 1955, from 300-500 during 1955-1970, end from 100-200 during 1970-1974 (Barnes, 1976). Howsver, variations from such exposures would, have occurred in specific plants (Rowe, 1975). While historical avsrsgo exposures were generally less than .1,000 ppm, peak exposures often ex- -V x .. :'ki' .. needed 5*10,000 ppn (where worker* lost consciousness) and, on occasion, 40,000 ppm (where plants exploded). During 1074, exposures were reduced to about 10*20 ppa in the U.S. industry (Jones, 1981) end even further, follow* ing the promulgation of * 1 ppe standard by the Occupa tional Safety and Health Administration in 1974. MORTALITY STUDIES OF VC-EXPOSED WORKERS Table 1 shows the populations observed and the follow19 characteristics of twelve cohort studies of vinyl chlo ride exposed workers. The studies were independent with the exception that the portions of the population reported in thp Equitable Environmental Bealth Study (1978) were included in sotse other U.S. studies. The proportionate mortality study of Monson at al (1974) is not included as the VC-exposed individuals studied therein were Included in the cohort Mortality study of Waxweller et al (1976). The site of the cohorts varied^greatly, from 255 in the study of Xicholson et al (1975) to 9,677 in the Equitable Environaental Health study. A notable feature of all of the studies is that the populations followed were rela tively young or recently employed, even though aany plants la the studies started production in the 1940s. Most workers were hired after 1950, when U.S. and Western European production increased sixfold in ten years (Hlcbolson and Henneberger, 1983). Thus, few deaths occurred aaong aost of the groups observed and data on effects 25 or aore years froa onset of exposure are li mited. The total mortality exceeded 10% of the observa tion cohort in only three studies. Further, the inclusion of recently employed individuals or those with short employment diluted the effects froa VC exposure. Only five studies Halted consideration to individuals with more than one year of exposure. In all cases, however, some Individuals with aore than 20 years from onset of employment were available for observation. The follow-up' teraioated in the aid-1970s for all studies. Table 2 eoapares the results for eancer of all sites and chronic liver disease in all 12 studies. Cancer la elevated in aost of the studies, although it does not achieve a 0.05 level of significance except in the studies by Waxweller et al (1976) and Blcholson et al (1975). In the study by Ott et al (1975), a highly exposed subgroup with 15 years latency had 8 eancer deaths compared to 3.2 \ URL 05385 Table 2 ~ Obaarend and axaectad death# enetic tIbtI chloride exposed workers la Wiln etndiot fearer of all altea - Send* Obeer. Bertaael at al : 30 Baffler sc al 5 yr. latency tyrea ec al kid ec al 'I 6 - 39 Equitable Fes A Collier 139 115 haauda Xlehelaoa Ott at al IS yr. latency lalal at al S 9 13 9 94 Theriault * Allard 20 Waxveiler at al 33 15 yr. latency 31 Ixeee. 30.9 S.19 4.34 36.44 141.39 126.77 3.8 3.9 ' 16.0 9.2 90.6 16.37 23.9 16.9 SMB 97 _ 194% 13$ "* 96 104* 91 138 230 81 98 112* 122 lift 184tt dlaeaaa Deeche Obaar. J&ESfc 3 0- SKR - 0 14 1 5 1 3 26.49 2.68 1.00 <0.6) 2.7 36++ 37 300* 167 111 14 18.4 -2 4.0 82 30 * Adjuated (it uaknewn cwu of daath ( > taclMtk as a pereeacaie of 0.8. ntu f * < o.os *+ t < 0.01 a 901 af central regulation *cually high UAL 05387 expeeted (p < 0.05). The absence of significant findings in other studies aay be sttributed to their low power. The study of Bertezzi et el (1979) asy be biased because of low follow-up in the group, fourteen percent of the population were untraced and person-years at risk were calculated for these individuals as if they were alive. The low SHE of 44 for all causes of death suggests that proportionately aore deaths occurred in untraced groups than in the traced. The studies by Buffler et al (1979), Byren et al (1976), Masuda (1979), and Theriault and Allard (1981) had very few deaths available for analysis. That of Ott at al (1975) also was Halted by the number of deaths and further by virtue of a study group with rela tively lover exposure (through better Industrial hygiene control). Vhile having aore death* available for analysis (136), the study by Duck et al (1975) was significantly < fi , diluted by the inclusion of many individuals with very short and recent periods of exposure. Turning to chronic `liver disease, one reaarkable finding is the absence of significantly elevated surtality from this cause in most of the populations under observa tion. The only study vith a significant elevation is that of Hasuda (1979) in which five deaths from chronic liver disease occurred where only one was expected. However, this must be considered in the light of an equally high mortality from liver disease (6 observed vs. 1.4 expected) in a comparison population followed for control purposes'. Five of 42 deaths from chronic liver diseeae sean in the study by Bertaxxi et al (1979) are unusual, but the limi tations of this study and lack of details make evaluation difficult. The generally benign results in other studies contrast sharply with the severe liver disease from VC exposure documented in clinical studies (Harsteller et al, 1975). Hepatomegaly, hepatic fibrosis, portal hyper tension, and bleeding esophageal varices have commonly been found in individuals heavily exposed to VC, even without concomitant exposure to alcohol. Table 3 lists the mortality data for primary cancer of the liver and biliary passages and for cancer of the lung, trachea and bronchus. In the esse of liver cancer, > the overall data are consistent and dramatic. Hemangiosareomss of the liver were found in eight of the twelve studies. In each of the eight, a very large and highly significant SMR for liver cancer wes seen. Methodological limitations can account for negative data in the other four studies. The large SMR'a observed, however, arc largely the result of low values for the expected number of esses rsther than a high incidence of observed cases. Only 29 separate liver hemengiosarcomes were identified in ell twelve studies. vJu..Ai the overall excess number of deaths from liver end biliary cancer in ell studies was 47, some heaangiosarcemas may not have been identified. The low numbers must^also be considered in light of the limited follow-up times^in moat studies. * ' The evidence for'tong cancer is less clear. There is an elevation in some studies, but at s level that does not achieve statistical significance, except in the 15 year latency population of Waxveilcr et el (1976). This, in pert, may be the result of the low power of many of the URL 05388 If %- .< sv. "*L :.S'& V< 20 JO c b :r *k. a.ilWirC-:. o. Table G#s^* * ..Jpoti .>. aa i Cheereed m4 ytt< 4a*rttt tm wlMm --mm *->t< , '-#' fttadv ^ ^Cmn of the las. 1*~* 4 biliary mWj kruttl Jb&* J8L <i.o>* Itaaaafi**' Jffi. www__ 2b__ I9L____ SL tioo)w>4 (7.7)* (91) Mllu 5 y. lUHcr lyt 10 yt. latency Sack 19 yt. Utocy t^ulukU 15 yt. latency In aad Calllar 15 yt. latency Nlchslaaa Ott talal Theriault 15 yr. lataacy Uaawallar 15 yt. lataacy 10 1 ) 0 u 10.17) 0.97 0.46 -- V;4 113 519 0 (4-5) 0.71 (221) 5 {l 3*3 2 0.9 (0.12) (0.5) 0.9 (0.5) 0.6 0.4 197 (1500))*+* - .-"Mi 0 3 0 1523 /*' (1600)1f*ll*?. ,*' 1155 1606 T- 6 ' 2, 6 1.TJ 1.49 . 1.78 219* 261 188 16 15.53 14 10.69 45 41 46 21 44.29 37.0 31.23 26.0 1 (0.1) 0 (1.1) *(57) 5.2 22 24.6 2 5.76 2 4.23 12 7.7 11 3.7 103 131 10? 111 90 109 (123) --' 77(96?) 95* 33 47 136 19*t Total of mbduplicated haaaa|loaarea*f 29 :*x . < 0.05 :1 * < 0.01 < 0.001 *< All ml(Ud liver aancar (uthi. laeludlat thoee eatabllehed by ntUm af all avallafela lafenutlaa., ( ) tnyrtad death* aatiaeted aa the bail! af 1950-1969 U.(. adjected rataa. ICO 155/ZC0 1*0-203. ( ) Ispaeted death* aaclaatatf aa the,heal* af aatleaal ate adjusted rate*. 1CD 162-163/1CD 140-205. 0m henauglesareeua oceurrad la a WC fabricator. Include* cancer af the peacre**. Adjaatad far anhaowa cansa* af death. y"'* " '. i ' %; \ *h CP <P \ \ ' : *. U. *3 studies. Only two have sn 80% power to detect ta overall risk of 1.5 (Beaumont and Breslov, 1981). Of signifi cance, however, are the very low SMR's la the groups studied by Theriault sad Allard (1981), Reinl, et al (1979), and Nieholson et al (1975), cohorts that would be expected to sunifest a high risk on the basis of the many heaaagiossrconas that were fouad. The four largest studies, although in sooe cases United by inclusion of short-term and recently alloyed workera, also are note worthy for the SMR's dose to 100. Where available, data on subcohorts with longer latency (> 15 yr) suggest some increased risk. Waxveiler et al (1981) undertook a detailed analysis of the exposure of those with lung cancer in their previ ously published study (Waxveiler et al, 1976) in an at tempt to identify particular etiological agents. The analysis used a serially additive expected dose nodel (Smith et al, 1980) in which a dose measure during each year of exposure was accuaulated for each study individual for a variety of potentially carcinogenic agents. The emulative doses for those with lung cancer were coopered with those of other individuals in the plant under study. The results showed that the greatest correlation of lung cancer was with exposure to FVC dust.-Secondarily, expo sure to vinylidene chloride appeared to be important, but only for large cell and adenocarcinoaa. The serially additive dose for VC nononer differed little in those with lung cancer coapared to others in the plant, except, possibly, for large cell cancera. URL 05390 Thus, evidence to date does not establish that VC nononer is an Important lung carcinogen in exposed worker populations, although it is recognised that limited long term obaervation has so far been available. In all stu dies considered here, a slight deficit of cases was seen compared to the nus&er expected. In the subcohorts with more than IS years from onset of exposure, an overall excess of 10% was observed. If, in addition, one consi ders a "healthy worker effect," any excess lung cancer would still be considerably less than the excess of liver cancer. A qualification to this conclusion is that no study specifically considered cigarette usage. If cigar ette smoking was much- less common among VC workers than the general population,J higher SMR's would have been seen if smoking specific'* data were available. ' However, this - . -# 7 " "8 9 ' *' "22 possibility is. unlikely, considering the aeny different populations studied. The uncertainty in human data ia lee reflected in animal studies. - Increased lunt cancers have been seen in mice but not in rats or hamsters (Maltoni et al, 19S1). Table 4 shovs the results for brain and central nervous system cancers and for cancers of the lymphatic and hematopoietic systems. Cancers of the brain and central nervous, system were significantly elevated in a number of studies, although the results differed consider ably across studies. Again, negative data may be simply the result of limited long-term follow-up or the low power of tfee study. In such cases <. the information is only sufficient to set an upper limit on relative risk of brain cancer. Zn contrast to lung cancsr, however, the largest study group has s significantly elevated risk of brain and central nervous system malignancy. As with lung cancer, the data on brain and CNS cancer in animals are equivocal, leuroblastomas and brain malignancies are observed in rata exposed to VC, but not among mice or hamsters (Maltoni et al, 1982). The human data are also mitigated by the recent finding of brain and central nervous system tumors in a variety of chemical plant exposure circumstances (Alexander et al, 1980; Selikoff et el, 1982). Excess brain malignancies, but not the etiological agents, have been identified in several Texas and Louisiana chemical/ petrochemical plants. VC exposure.vas documented for some caaea, but it could not explain tike overall findings. As individuals in many of the VC studies considered here were exposed to other chemicals and petrochemicals, the pos sible role of these agents cannot be excluded. Further, it has been suggested that some working groups, with employer-paid medical plans, may have better case ascer tainment than, ia generally available (Greenwsld et al, 1981) and, thus, more brain malignaneias identified. In any ease, the number of excess malignancies of the brain and central nervous system (approximately 10) in sll studies is considerably less than the number of hemangiosarcomas identified in the same populations. Similar results arc obtained for malignancies of the lymphatic and hematopoietic system. Here again, the analysis is limited by the few deaths and disparate re sults which occurred in different studies. Overall, there would appear to be an elevated risk, but the influence of % <> Table & Observed and wtettd dsatbs froa selected causss Cancer of the brain 4 central nervous svstea Obeer. Exeect.. SHE Bareaasi 1 CO.g)** 123 luffler lyres Duck Equitable 0 (0.1) - 2 0.33 4l2t -- - 12 3.90 203* Fcx 4 Collier 2 3.64 35 Maauda 0 (0.13) - Meholson 1 (0.1) (1000) Ott 1 0.4 (250) tain! 2 1.3 162 Theriault 0 0.6 - Vaxveller 3 13 yr, latency 3 0.9 329. 0.1 49IT Cenesr of the lmohaele and hanateooleelc svstaa Obser. beset. SMI 4 (3.0)* (133) 0 (0.5) - 0-- - 20 17.01 124 9 9.01 100 0 (0.3) - 2 (0.4) <300) 1 <1.) (43) 13 7.7 214++ 1 1.47 40 4 2.5 139 + e 0.03 tt 0.01 * ( ) Expeetsd estlaeted fro the ratio of ago standardised 0.3. raui ICO 193/ICO 140-203. * ( ) Expeeted estimated free the ratio of 1930-1949 0.3. rotas ICS 200-205/ICS 140-230. confounding exposures precludes definitive statements. The overall excess of such malignancies (about 10) is also much less than those from primary hemangiosarcomas of the liver. EFFECT OF REDUCTION OF EXPOSURE TO VC URL 05392 As mentioned previously, most mortality studies followed populations only to the 1972-1975 period. No data exist on the risk to previously exposed populations after cessation of exposure in 1974, although hemangiosar comas have been noted among retirees. We have recently completed a follow-up through 1981 of the population reported in 1975 (Nicholson et al, 1975) to determine whether a high risk of liver cancer contiiuies, following significant reduction in exposure. The original group :2L employed at a VC polymerIsation plant In tfiagara Falla, Haw Tork, has been expanded by 40 additional workers, all exposed for flee years, who achieved ten years from onset of exposure subsequent to April 1974. Additionally, 195 individuals employed at a* VC polymerisation plant in South Charleston, Vest Virginia, with Five years of exposure and ten years from onset in December, 1966, were identified and traced through 1980. Table 5 lists the observed and expected deaths by cause for both groups with the deaths occurring after 1974 separately identified. (These are preliminary data; full nsu 5 Ofeaarvad tad txpccttd duthi *oo| vlsyl cfclerlda polTiitiutlM votkifi effiy rftgaagu, isei) Cwm s< <mh All (MIU 2* All ttUW 1 UM hln/mm 0 l Bnla 1 Uwr 1 2 >mwu 1 Cirrhosis of llvsr 1 Cardiovascular dlmi 13 tml 20 44 t IS 22 2J 01 36 12 01 12 S 21 40.17 9.01 1.29 1.39 0.23 0.19 0.55 0.50 1.41 19.M 101 177* 02 214 303 315Se 545* 200 142 106 South OlTlAttBtt. ev (V * 1951 Qacmbtr 1, 11 - SMte^M 31, 1910) Obtarrad 66-9i 91-40 Total All (UMt 14 All ukw 2 t 1 CatM/mtia 0 Srsla 0 Unt 0 tyabhsaa 0 fwtwii 0 Cirrhosis Unt 0 Csrdlsvasealar disease 10 a 0.05 bps 0.001 * 9 * 0.0001 22 M 10 12 12 00 00 44 00 1. 1 1 1 10 20 i 44.74 10.65 4.07 l.tf 0.43 0.23 0.59 0.67 1.S1 27.24 SMS 0 113 49 -- 1739* -- 150 55 73 % URL 05393 I 9 1 , pathological review of all available specimens baa not been completed.) Among the 44 deaths that occurred in the Hlagara Falla cohort, 6 were from primary cancer of the liver, including 5 hemsngiosarcomas. Three of the heasn* gioaarcoaaa occurred -in the period prior to 1974 and 2 subsequently. Similar findings occurred among the smaller group in Vest Virginia. Here, of 36 death*, 4 vere from hemangiosarcoma, all of which occurred subsequent to 1974. Thus, the risk of neoplastic VC disease continues uadiainished, even though exposures to the monomer have been significantly reduced. The combined data from both groups are shown in Table 6 and demonstrate an excess risk of cancer, which is totally accounted for by the enormously increased risk of liver malignancy observed in each time from onset of exposure' category. The excess lymphomas which achieved significance at the p < 0.05 level in the Niagara Falls group lose significance when combined with the data from South Charleston. A deficit'of lung cancer was observed in both study groups and brain malignancies were about equal to the number expected.. . It is not certain whether the results of these two plants will be reflected in the results of other plants in future years. The South Charleston plant was the first facility to commercially produce VC. The New York plant opened immediately following the cessation of Vorld War - 21. Thus, we are observing effeets in populations that include many individuals with long times from onset of exposure. There is no information on whether the expo* sures in these two plants were significantly different from those of the majority of other VC polymerisation facilities. It is known that pre-1974 exposures in the New York plant were sufficiently high to cause loss of consciousness to some individuals (4.5% of those examined in the clinical survey of 1974) (Lilia et el, 1975). MORBIDITY AND CLINICAL FINDINGS AMONG VC-EXPOSED WORKERS Clinical abnormalities from VC exposure predated by 25 years the docwaentatlon of its carcinogenicity. Vari ous VC-relatedabnormalities vere reported in Eastern European literature, including hepatomegaly (Trlbukh et al, 1949), angioneuroais (Filatova and Gronsberg, 1957), osteolytic lesions of distal phalanges (Smirnova, 1961), Raynaud's phenomenon end aclerodesmalike akin lesions (Suciu et al, 1963). - However, VC disease ves not seri- URL 05394 Table 6 OfeMrvd nd wwet<j dwthi mom vlnr! chlorldo wad worktn in aw polturiutlan facillclo* br tin from OMit of wwmn Tmi alac* Mutt of axpomin Casas of death 10 - 19 20 - 29 i 30+ Total 9924.J!SU All eseaas All eanear 24 19.12 . 7 a.72 Loaf 1 1.26 Liver 2* 0.08 Iraia 1 iTWhm 2 Cirrhosis af liver 0 0.27 0.76 Cardloveseolar 14 6.74 4tiu fatsos Tun 2924 Obs. -fiSr 4*"' J&u 30 34.S3 28 31.64 9 7.98 12 8.03 1 2.98 2 3.08 3* 0.18 * 3 0.17 00 1 0.46 0 0.41 3 1.24 0 0.87 13 17.38 12 16.40 2730 1404 0ba._gag_. .80 83.61 28 19.64 4 7.31 10 0.42 1 0.76 3 1.14 3 2.83 41 42.73 *- 93 142 33 2381 132 263 103 96 a. bauA|ieitreu b. 4 haaaatlaaarcoau aad 1 hifitnu ously considered la the Vest until the published descriptiea of Raynaud's syndrone, acroosteolysis, aad pseudoscleroderna in two Belgiua VC reactor cleaners (Cordier et alf 1966)* Additional cases were soon noted (Wilson et al, 1967) and a comprehensive* epideniologicsl study of 5,011 0.8. workers employed in production aad polymerlsstloa was undertaken. Zt shovedthat 11.9% had possible X-ray signs of aeroostoolytla, compared with 3.2X in a Hichigen general population control group, with TL defi nitely hawing Raynaud's phenomenon or X-ray evidence of acroosteolysls (Dinman et al, 1971). The conditions were elearly associated with the cleaning of reactors, in which a heavy exposure to VC occurred. Only one ease of Ray naud's phenomenon occurred among 557 workers employed in PVC fabrication. During the early 1970'a, VC liver disease was de scribed in detail by Harstaller et al (1973, 1975). Observations on selected workers showed hepato- and sple nomegaly to be eosBon. Peritoneoscopy and guided liver biopsy identified severe portal hypertension in sons, generally without cirrhotic fibrosis, although perlsinusoldal and fecal or diffuse capsular fibrosis were cemmonly seen. The portal hypertension could lead to bleeding esophageal varices, with possible fatal consequences. In heavily exposed individuals, the portal hypertension and hepatic fibrosis often progressed after cessation of exposure (Martin et el, 1974). The histology of malignant and nonmallgnant liver disease has been veil described by Popper and Thomas (1975; Thomas et al, 1975), who suggest ed the possibility of an interrelationship between hemanglosarcoma end the "proliferation of sinusoidal lining, cells and hepatoeytes seen in VC fibrosis. Laibach and Harsteller (1981) have also noted that the vast majority of heaangiosarcoBS cases have appeared on a background of some degree of hepatic fibrosis. The implications of these suggestions for a hemangiossreoma dose-response relation are uncertain. During 1974, extensive studies were undertaken by the Environmental Sciences Laboratory of the total workforces of three polymerisation plants in the states of New York, Michigan and West Virginia. The results from the New York plant (Lilia et al, 1975) indicated the presence of acroosteolysis in heavily exposed individuals. Hepato- and splenomegaly or hepatic tenderness was commonly observed and associated vith duration of exposure and elevated alkaline phosphatase levels. Sixty-four of 354 had an enlarged or tender liver or spleen end of these, 41% had elevated alkaline phosphatase. Liver function teste were not pertlculerly revealing, axcept for a correlation of elevatad alkaline phosphatase levels' vith duration of exposure. Additionally, carcinogenic embryonic entigea titers were slightly higher among vinyl chloride exposed groups then in a smoking matched control population (Anderson et el, 1978). Tamburro end Greenberg (1981) have evaluated the effectiveness of federally* mandated screening tests for vinyl chloride exposed workers. Figure 1 shows the re sults on specificity end sensitivity for 78 individuals vith hepatic status * determined by biopsy* 3CG elesrsnee had the highest combined sensitivity and specificity, vith 8GPT the second most useful test. 'Elevated alkaline phosphatase had the greatest specificity of ell tests, particularly for chemically-induced liver injury, but was lacking In sensitivity. SOOT and GGPT were of limited use because of their low specificity for chronic liver disease. They recommended the-use of ICG clearance for screening, to be followed vit^ alkaline phosphatase determinations for those vith altered clearance. 20 SSS SENS an spec B S4S i URL 05397 A? , SCOT SCPT,.,. 6CTP - TESTS ICG -0.5 Figure It Sensitivity and specificity of various biochemical screening tuti and their sensitivity and specificity sum values (S 4 S) based on 78 vith biopsy documentation of their hepatle status. Three of the seven individuals vhe died after 1974 vith hemangiosarcoma in the previously described mortality followup were examined in 1974. One, who died 22 months after examination, had no noteworthy abnormalities on examination (alkaline phosphatase vas 88, slightly high). A second, who died three years after examination, had a slightly enlarged, palpable liver (11 x 6 cm) vith normal blood counts and chemistry. Only one of the above drank alcohol at all and he only drank 2*3 beers/month. The third, vho died 22 months after examination, had a slight ly enlarged liver (11 x 8 cm) and spleen (13 x 8 cm), and slightly elevated alkaline phosphatase (93), SCOT (52) and CEA (4.7). Thrombocytopenia vas also present (75,000). X data are available on later clinical parameters, but the above results are clearly not sufficiently specific for Identification of a special risk. Pulmonary abnormalities also have been associated vith VC/PVC exposure. Small opacities, predominantly . irregular, of profusion 1/0 or greater were found in 20 of 1,216 workers employed at PVC production in an Italian plant (Hastrangelo et al, 1981). .All had been exposed to high levels of PVC dust (>10 mg/m**). Lilis et al (1976) :9 reported that approximately 20% of VC/PVC workers with high exposures to PVC dust bed abnormal X-rays, which correlated with duration of exposure and, also, with cigarette seeking. In contrast, only 4.7% of individuals in a PVC plant with low dust levels had abnonaal X-rays. In addition to "typical pneumoconiosis," a granulatoeous reaction to PVC dust has been reported (Arnaud et al, 1978)* Hiller et al (1975) have observed pulmonary func tion abnormalities (a reduction in the ratios FEV./PVC and HKF/predicted UHF) in both smokers and non-smokers heavily exposed to PVC dust (and also to VC monomer). Haltoni and Lodi (1981), observed greater percentage of abnormal spu tum cytological results among VC exposed workers compared to several other groups of manufacturing workers or miners. Only workers in the chromium industry demonstrated a greater proportion of abnormal cells. Ducatman et al :(1975) have observed an increased frequency of chromosome abnormalities in the lymphocyte cultures of VC workers. Host of the abnormalities were "unstable" changes, such as fragments, dicentrics, and rings. This was confirmsd by Purchase et al (1978), among others. Some of the group studied by Purchase were resam pled 18 and 42 months later (Anderson et al, 1980). In those studied during January 1976, the frequency of abnor malities was lncrsasad in those who continued VC/PVC employment, but decreased in those who left the industry. In January 1978, no increased frequency wae found in any worker. The authors attributed the decrease to the reduc tion in VC expoeure. HEALTH HAZARDS IN THE PVC PROCESSING INDUSTRY Prior to identification of htmangiosarcoma in VC polymerization worksrs, little effort was made to control either the concentration of residual monomer in PVC dust or exposures to dust and VC that occurred in the various forming operations, of the PVC fabricating industry. VC concentrations in excess of 10 ppm occurred frequently. Vhile these concentrations were significantly lower than these of the polymerization industry, the much greater employment in the proceesing industry (hundred! of thou sands va. tens of thousands in the polymerization work) raised concern for population health effects, particularly for malignant disease'for which no threshold was known. However, only two hemangiossreoaas have been documented in URL 05398 - -i 'ir. .s * -30 m ** the PVC processing industry, one ea accountant in e plant PVC fabric and one ih~,aa Italian plant making PVC eaeka. A third caae nay have^ occurred la an electri cal wire lneulatorv but' the pathological dlagnoaia la uncertain (Lloyd, 197$)/ This la. in coatraat to 65 caaea known to have occurred anong polynerinatloa workera (HIOSH, 1962) This la aosevhat eonfortlag and indleatea a slgni- ficaatly lower total VC-related aeoplaatic riak anong fabrication workera. However, It ahould be noted that caae finding la likely to be poorer in thia group than in polymerization workera. A proportionate mortality etudy baa been conducted of 4,341 death* of foraer enployeea of 17 PVC fabricator* (Chiazze Jr., et al, 1977). The direct PMR'a auggested an exeats in total caneer mortality anong both white aen and white women with the major exceaaea concentrated in can cer* of the dlgeatlve organa. An excess of breast cancer was also teen in women, but not confirmed in a case-con trol study (which was of very low power and could only detect a threefold increased risk) (Chiazze, Jr, et al, 1960). The results of the proportionate mortality study must be considered cautiously. .. In such studies, elevated cancer risks and are typically seen because of a "healthy worker effect," which leads to a reduction in cardlovascular deaths relative to those of eaneer. If PCUR's (proportionsto caneer mortality ratios) had been calculated, rather than FMR'a, digestive cancer would still be elevated but not at an 0.05 level of significance. Interest ingly, an excess of stomach eaneer was seen la the propor tional mortality study of Baxter and Pox (1976). SUMMARY Overall, the results of the analysis of 12 studies of VC production and polymerisation workers demonstrate an enormously elevated risk of liver malignancies, the possl- _ billty of a twofold Increased risk of brain and central nervous system tumors and perhaps, also, of malignancies of the lymphatic and hematopoietic system. However, the role of other egents cannot be excluded in the etiology of nonhepatic malignancies. Bronchogenic carcinoma does not appear to be increased from exposures to VC monomer, although e relationship to PVC dust , was suggested in one etudy. These conclusions must be considered in light of limited data on workara followed more than 25 yaara from "'Cp as onset of exposure. Considering the numbers of observed end expected deaths in all studies, it would appear that the excess of malignancies at nonhepatic sites is less than the excess of liver .tumors. Data presented elsewhere in this volume (Nicholson and Henneberger, 1983) suggest that exposure reductions in 1974 may have virtually elimi nated the VC-associated risk of liver cancer . if the current U.S. standard is met. To the- extent that VC exposure is associated with other cancers, a similar risk reduction would be expected. 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