Document 3QE1mEa2OrpLMk2qoo5rkV8o0

R&S 028747 V manifest ners, that *o go in u. ) on right n is one of d file no . Environmental Health Perspectives Vol. 52, pp. 61-66.1983 Toxicity of Vinyl Chloride and Poly(vinyl if the risks e program >r putting he discushe schizo-1 when, if tcs expectare public ,e field ex! we recogut I would s' question o concern- , pie doubly ng. I think pendentlv ei^^ical-- i<^rela-ii^eto ock goes up. down. So I icy biologi- Chloride): A Critical Review by Joseph K. Wagoner* In 1974, vinyl chloride (VC) was first reported in the open scientific literature to induce angiosarcoma of the liver both in humans and in animals. Additional research has nowdemonstrated the carcinogenicity of VC to other organs and at lower concentrations. The target organs for VC now clearly include the liver, brain and the lung, and probably the Ivmphohematopoietic system. The evidence for a carcinogenic risk has been extended to jobs associated with poly(vinyl chloridel exposure. Cases of liver angiosarcoma have been reported among individuals employed in PVC fabrication facilities and an epidemiological study has demonstrated a significant association between exposure to PVC dust and the risk of lung cancer mortality. Cases of angiosarcoma of the liver also have been reported among individuals living in near proximity to vinyl chloride-poly(vinyl chloride) plants. An association between PVC dust and pneumoconiosis also has been demonstrated. On the basis of findings, prudent control of PVC dust in the industrial setting is indicated. Laboratory Bioassay In 1971,44 years after vinyl chloride was intro duced into American commerce 11), 24 years after vinyl chloride was shown to cause cardiac arrhythmia in experimental animals (2>, 22 years after vinyl chloride was reported to be associated with hepatic abnormalities in workers in a Rus sian plastic factory (3>, 14 years after toxic angioneuropathy was noted among workers exposed *0 vinyl chloride below the then Russian maxi mum allowable concentration of 390 ppm (4i, 11 years after the vinyl chloride production process was associated with a severe neurologic disorder `h Minamata, Japan (5). 10 years after vinyl chloride at concentrations down to 200 ppm were Sported to cause centrilobular granular de generation of the liver ifii and 5 years after vinyl chloride was shown to induce acro-osteolysis in Workers cleaning reactor vessels 17*. Viola et al. reported the induction of tumors of the skin. 'Ung and bone in rats exposed by inhalation to 30.000 ppm of vinyl chloride. These oncogenic findings have been interpreted y some to have elicited little response because Consulting Epidemiologist s:)H) Currleigh Parkway. ^Pnngfield, VA 22)52. the testing was conducted only at unrealistically high dosages bordering on the lower explosive limit of vinyl chloride (9). In reality, however, such was not the case. In May of 1971, Viola had presented to several U.S. companies unpublished findings of an increased incidence of tumors in rats exposed to vinyl chloride concentrations down to and including 500 ppm < JO*. Additional ongoing studies involving vinyl chloride expo sures of 20,000, 10,000, 5,000, 2.000. 500 and less than 500 ppm were also described to those same companies. In like manner. Maltoni, in 1972. upon noting angiosarcoma of the liver and cancer of other sites in rats exposed by inhalation to vinyl chloride at lower concentrations, also had transmitted his findings to the Manufacturing Chemists Association in the United States and to several chemical companies in Europe ill i. Gov ernment. labor and the independent research community were first informed of the expanding carcinogenic properties of vinyl chloride in Janu ary of 1974. when representatives of industry announced having found liver angiosarcoma in three workers who had cleaned reactor vessels as part of their employment at a single vinyl chlo ride polymerization facility in the United States. Almost simultaneously, findings of the induction of liver angiosarcoma in rats exposed to vinyl chloride were made public. 00002* FlH-* P 62 J. K. WAGOXER The carcinogenic properties of vinyl chloride were further clarified in 1974, when Caputo et al. (12) reported an increasing incidence of liver an giosarcoma with an increasing dosage of vinyl chloride. Among rats exposed to vinyl chloride by inhalation, the incidence of liver angiosarcoma was 39c at 500, 5% at 1,000, 6% at 5,000, 8% at 10,000 and 12* at 20,000 ppm. Among controls not exposed to vinyl chloride, liver angiosarcoma was not found. In that same year Maltoni and Lefemine (13) also reported the induction of tu mors in mice, hamsters and rats exposed to vinyl chloride by inhalation. The spectrum of induced tumors included angiosarcomas of the liver, ade nomas and adenocarcinomas of the lung, neuro blastomas of the brain, lymphomas and carcino mas of other sites. Vinyl chloride in that study was shown to induce liver angiosarcoma in rats at 50 ppm of exposure. Keplinger et al. (14) in that same year also reported the induction of liver angiosarcoma in mice exposed to 50 ppm of vinyl chloride by inhalation. Subsequently, Holmberg et al. (15) reported the induction of hepatic and extrahepatic angiosarcoma in mice following in halation exposure to vinyl chloride at 50 ppm. Shortly thereafter Maltoni (16) extended the car cinogenicity of vinyl chloride to lower levels of exposure. Vinyl chloride administered by inhala tion was shown to induce tumors at a variety of sites, including liver angiosarcoma at 25 ppm and mammary carcinomas at 25, 10, 5 and 1 ppm. Recently Maltoni (17) reported the induction of hepatic and extrahepatic angiosarcoma at 10 ppm of vinyl chloride. Epidemiology Occupational Exposure: Vinyl Chloride Production or Polymerization In 1974, the same year that the public was first informed that vinyl chloride induced liver an giosarcoma and cancers of other sites by way of experimental bioassay, epidemiological studies also were reported demonstrating an excess of cancer of multiple organs among workers occupa tionally exposed to vinyl chloride. Tabershaw and Gaffey (18) reported that cancers of the buccal cavity and pharynx, digestive tract (primarily liver angiosarcoma), respiratory tract, central nervous system (primarily brain) and the lym phatic system were excessive among workers in the United States having been employed for at least one year in plants producing and/or polym erizing vinyl chloride. Monson et al. (79) in that same year reported the results of a proportionate mortality analysis of 161 deceased workers ha ing been employed at one of two plants in tl United States producing and polymerizing vin chloride. The specific sites of cancer with th greatest excess were the liver and biliary trac with an 11-fold excess; the brain, with a 4-fol excess; the digestive tract and the lung. In 1975, Nicholson et al. (20) published a stud of cancer mortality among 257 individuals occu pationally exposed to vinyl chloride for at least years, with the initial exposure having occurred more than 10 years in the past during employ ment in a U.S. plant polymerizing vinyl chloride A 2.3-fold excess in deaths from cancer of all site combined was demonstrated with three death due to hemangiosarcoma of the liver. In that sam< year, Ott et al. (21) reported the mortality experi ence of 549 individuals occupationally exposed tc vinyl chloride-poly(vinyl chloride). Whereas nc angiosarcomas of the liver were found, an^Kest of all malignancies combined was reportedfl^P>n those workers classified as having been RTghl> exposed when contrasted with workers of ali other exposure intensities. Among the nine can cer deaths in the highly exposed group of workers, four were due to lung cancer. In a discussion o( the limitations of the study, the investigators noted that the majority of workers in the category "other than highly exposed" had less than one year of work experience in departments with ex posure to vinyl chloride-polyvinyl chloride. Duck et al. (22) in 1975 reported that a study of 2100 employees of a vinyl chloride polymerization plant in the United Kingdom revealed no excess of total or cause-specific mortality. In addition to reporting no excess of cancer mortality. The in vestigators reported an inverse relation between vinyl chloride exposure and cancer mortality, i.e., as the duration of exposure to vinyl chloridepoly(vinyl chloride) increased, the risk of cancer decreased. The results and conclusions of that study were adjudged by Wagoner et al. (23> to be spurious and due to the use of faculty analytical methodology. Upon reanalysis of the data in that study. Duck and Carter (24) reported an in creased risk of cancer of the digestive system among workers observed 15 years or more after onset of exposure to vinyl chloride-pol]M^ 1 chloride). Subsequently, Waxweiler et al. (25) reported the results of a retrospective study of mortality among a cohort of 1294 workers occupationally exposed to vinyl chloride in the United States. Since occupationally induced cancers often take years to become clinically manifest following ex posure to carcinogens, the study was restricted to TOXICITY OF VINYL CHLORIDE AND PVC 63 ___} individuals with 5 years or more of employ liver cancer was shown for each group of workers ed in departments and jobs directly involving whether exposure to vinyl chloride was judged to rity) chloride exposure and with 10 years or more have been high, medium or low. The authors tltpoed time since onset of initial exposure. Spe commented that, although there were no data cific jobs and departments with vinyl chloride from the study to support an excess mortality exposure were determined following a walk- from cancers other than of the liver, the period of thtvogh survey and review of the manufacturing follow-up of the workers was too short to permit a ud> Hftcees, engineering controls and air-sampling clear evaluation of those carcinogenic effects at reti 5to for the plants studied. When analyses were that time. baaed on the total study cohort, only two major Epidemiological investigations have now causes of death were in excess: nonneoplastic clearly demonstrated that laboratory bioassay respiratory disease (6 observed vs. 3.4 expected) findings were predictive not only for the carcino tod all malignant neoplasms combined <35 ob genicity of vinyl chloride, but also for several of the served vs. 23.4 expected). The latter excess was target organs. On the basis of these results, the ctatistically significant at p = 0.05. When analy IARC (29) in 1979 concluded "Vinyl chloride is a me tes were made according to site of malignancy human carcinogen. Its target organs are the liver, tod latency (interval since onset of exposure), an brain, lung and haemo-lymphopoietic system " excess cancer mortality was found for four organ-, systems, i.e., central nervous system, respiratory system, hepatic system and lymphatic and hema topoietic system. The excessive mortality was sta Occupational Exposure: Poly(vinyl Chloride) Packing and Fabricating tistically significant for three of the four organ Christine et al. in 1974 reported (30) two histo- systems, i.e., cancer of the central nervous, the pathologically confirmed cases of hepatic an m- respiratory and the hepatic systems, among giosarcoma in Connecticut among individuals r*. workers who had been observed 15 years or more who had been employed in industrial facilities since onset of exposure. During the course of the that used poly(vinyl chloride). One of these indi study by Waxweiler et al., an evaluation was viduals, a 47-year-old man, had worked for the made of the pathologic data underlying each neo previous 10 years as an accountant in a factory plasm identified. Of the 14 cases of liver cancer producing vinyl sheets and processing poly(vinyl identified, 11 were diagnosed as angiosarcoma. Of chloride) resins. This individual had frequently ten cases of brain cancer identified, nine were visited the plant's production area. The second shown to be glioblastoma multiforme in type. individual, a 61-year-old man, had spent 25 years ir Furthermore, of eight lung cancer cases histologi in an electrical plant operating a machine that cally confirmed, all were large cell undifferenti applied poly(vinyl chloride)-containing plastic to ated or adenocarcinoma in type. wires. In 1977, Baxter et al. (31), in a review of 14 Byren et al. (26) in 1976 also reported a statisti cases of hepatic angiosarcoma diagnosed in Great cally significant excess of liver-pancreatic and Britain during 1963-73, noted one case who had brain cancer deaths among 771 workers employed worked on a process which used poly( vinyl chlo in a Swedish vinyl chloride/poly(vinyl chloride) ride) as a raw material. production plant. These investigators reported In 1975, Selikoff wTote to NIOSH suggesting that this excess appeared within the first 5 years that appropriate precautions be taken to avoid after onset of exposure to vinyl chloride. the inhalation ofpolylvinyl chloride) dust, both in 1977, von Reinl et al. (27) reported the the packaging and transport and in its handling results of a study of cancer mortality among 7021 during the manufacture of poly<vinyl chloride) males employed in the production and polymeri- products. Selikoff based his suggestion on the retion of vinyl chloride. When compared to the results of studies by Lilis et al. (32) and Miller et mortality experience of the West German male al. (33) showing radiographic and pulmonary Population, vinyl chloride-poly<vinyl chloride) function changes among vinyl chlorides~poly(vi exposed workers experienced an excess of cancer nyl chloride) workers and on the findings of a cf multiple organs, i.e., liver, lung, brain and the poly(vinyl chloride) inhalation toxicologic study ympatic and hematopoietic system. Fox and Col- by Frongia et al. (34). This latter investigation ler (28) in 1977 also reported the results of the showed that rats and guinea pigs, exposed in the study of cancer mortality patterns among 7561 same occupational setting as workers who were ^Cales who, at some time between 1940 and 1974, employed in filling sacks with poly) vinyl chloride) employed at one of four plants producing powder, subsequently developed alveolar reac P*y<vinyl chloride). An excess mortality from tions and septal thickening. This investigation R&S 028749  1 * I 64 1 A w.\<;n\KR po.-ed workers seem to indicate a pattern^^fcor, also showed that 7 months after their initial exposure, both species exhibited granulomatous neoplastic effects, a granulomatous reaction u changes, with fine granules observed intracellu- polyi vinyl chloride) dust, with inclusion of poh larly. Agarwal et al. '3.5' in 1978 demonstrated ivinyl chloride' particles in macrophages and hi- that intratracheal administration of polyivinyl tocytes, and associated interstitial fibrosis chloridei dust in rats resulted in an increase in The long-term carcinogenic effect, with a sig the activity oflysomal enzymes, interstitial fibro nificant increase in lung cancer also is of concer; sis and granulomatous lesions surrounded by fi In 1978, Waxweiler et al. (40) reported the resuh broblasts, reticulin and collagen fibers. Pulmo of a study of lung cancer at a single vinyl chli nary disorders possibly associated with exposure ride-polyi vinyl chloride) facility. One objective o; to polyivinyl chloride) resins produced by the this study was to determine whether there was an emission process might by expected, as dust sam excess risk of lung cancer of a particular histolog- ples taken by NIOSH during the bagging of poly- ical type at the plant. A case control study showed (vinyl chloride) resin have shown concentrations a clear excess of type 3 (adenocarcinoma) and type ranging from less than 1 up to 19 mg m1, with 4 (large-cell undifferentiated) lung cancers in about 90*7 of the particles being smaller than 2.5 cases occurring among plant employees as com pm and lOOfr smaller than 7 pm in diameter. pared to other lung cancer cases from the same In 1978, Arnaud et al. (36) reported a case of hospital of diagnosis, matched for age and calen pneumoconiosis in a 53-year-old man who had dar period of diagnosis. The authors noted that been exposed to polyi vinyl chloride) in the bag adenocarcinomas of the lung, accounting for a ging area of a VC polymerization plant. This minor proportion of this excess risk, have been patient presented with exertional dyspnea, pul shown to be at most only weakly related to ciga monary function changes, and chest radiographic rette smoking; some studies have shown no asso abnormalities. Electron microscopy of lung tissue ciation at all. The authors also noted that large obtained by drill biopsy showed foreign particles cell differentiated carcinoma of the lung, in the macrophages that were identical to polyi vi accounting for the vast majority of the excess nyl chloridei powder viewed under the electron lung cancer risk, is the only major histol^cal microscope. In vitro incubation of polyi vinyl chlo type that has never been related to cijj^Bhe ride) powder with human lung macrophages smoking by epidemiologic study. Thus, thereon- showed that the macrophages engulfed the pow cluded that cigarette smoking was not a major der to give an appearance similar to that seen in confounding variable in the study. vivo. The authors noted that the histological le A further study was made by Waxweiler et al. sions in this patient were identical to those re to test w-hether one or more chemicals used at the corded by Szende et al. (37), who diagnosed ad plant were responsible for the excess of lung can vanced pneumoconiosis in a 31-year-old man cer of types 3 and 4 or for the excess of only type 4. secondary to the inhalation of polyi vinyl chloride) A model was specifically developed for this pur dust. Szende et al. also reported that microscopic pose. The sensitivity and specificity of the model examination of polyi vinyl chloride) dust particles was demonstrated by its confirmation of the rela showed them to be morphologically similar to tionship between angiosarcoma of the liver and particles found in the patient's lungs. - direct vinyl chloride exposure. The authors re Results of epidemiologic studies by Vertkin and ported that of all 19 chemicals used at the plant, Hamontov (33) and by Mastrangelo et al. (39) polyi vinyl chloride) dust was the only chemical further support the role of polyi vinyl chloride) in for which they found a statistically significant the etiology of pneumoconiosis. A total of 1216 association with lung cancer mortality and specifi employees of a polyi vinyl chloride) production cally with large-cell undifferentiated lung cancer. factory in Italy underwent chest X-ray examina The studies mentioned above suggest that the tions. Of 731 examined individuals with exposure excess lung cancer risk in the vinyl chloride- to polyi vinyl chloride) dust, 20 were diagnosed as polyivinyl chloride) industry is related to expo having pneumoconiosis. All of these individuals sure to polyi vinyl chloride) dust. That the dust had worked 5 years or more in departments clas itself or as a carrier of residual vinyl chloride sified as having polyi vinyl chloridei dust pollu monomer is a factor in the etiology of lung cancer tion. No cases of pneumoconiosis were observed seems biologically plausible. Polyi vinyl chloride) among the 485 examined individuals who worked dust particles are known to be often in the respi in areas free of polyi vinyl chloride) dust. rable range--that is, less than 10 pm in diame The effects of vinyl chloride-polyivinyl chlo ter. Almost all polyi vinyl chloridei particle^M> ride) exposure on the respiratory system of ex- duced by the emulsion system, one of the syi^Bs R&S 028750 R&S 028751 TOXICITY OF VINYL CHLORIDE AND PVC 65 at the facility studied by Waxweiler et al., are in within 1 mile of any facility polymerizing vinyl the respirable range. These particles could easily chloride or fabricating polyivinyl chloride). These settle in the lung and conceivably by themselves study findings are supportive of the role of in cause lung cancer. However, it is known that direct modes of vinyl chloride exposure in the vinyl chloride monomer becomes entrapped in etiology of liver angiosarcoma. poly(vinyl chloride) dust and can be released slowly over time. Thus it is also possible that Summary poly(vinyl chloride) dust particles in the lung could slowly release vinyl chloride monomer to small adjacent areas of the tissue, prolonging the contact time of that chemical with tissue. On the basis of these findings, one must seri ously question the safety of the current OSHA standard for polyivinyl chloride' dust, i.e., a stan dard which treats poly)vinyl chloride) as a nui sance dust. Adenomas and adenocarcinomas of the lung, angiosarcomas of the liver and of other sites, lymphomas, mammary carcinomas, neuroblasto mas of the brain, in addition to various other tumors have been induced in mice, rats and ham sters exposed by inhalation to vinyl chloride. In addition vinyl chloride when administered by in halation has been found to induce hepatic and extrahepatic angiosarcomas at concentrations as Community Exposure to Vinyl Chloride low as 10 ppm and mammary carcinomas at even lower concentrations, i.e., 5 and 1 ppm. 'Several mutually confirmatory studies, using Christine et al. (30) reported two cases of he the retrospective cohort method, have shown an patic angiosarcoma in Connecticut having a prob increased risk of liver angiosarcoma and cancer of able residential exposure to vinyl chloride. One other sites among employees of vinyl chloride individual with hepatic angiosarcoma lived polymerization facilities. The full magnitude of a 2 miles of the plant producing polyivinyl this site-specific cancer risk among employees of *de)-coated wire, while the second individual vinyl chloride polymerization plants will only be within 0.5 miles of a plant producing vinyl determined following full lifetime observation. sheets. Each of these two plants also had a case oNf evertheless, studies already have shown that hepatic angiosarcoma among its labor force. Nei for liver angiosarcoma the excess risk is approxi ther of these residential cases was known to have mately 11 to 16 times that of the general popula had occupational exposure to vinyl chloride or tion. For brain cancer the excess risk is 4-fold. arsenic or diagnostic exposure to thorium dioside, The role of indirect modes of exposure to vinyl the only three agents known to cause hepatic chloride has now been shown to be associated angiosarcoma in humans. Baxter et al. (3/>. in with an excess risk of cancer. Several cases of 1977 reported another case of liver angiosarcoma liver angiosarcoma have been reported among in Great Britain who had lived for 6 years within individuals living in close proximity (less than 2 half a mile of a plant manufacturing polyi vinyl miles) to facilities polymerizing vinyl chloride or chloride). On the basis of these observations, fabricating polyivinyl chloride). A recent epide Brady et al. (41) in 1977 undertook a study in miological study has demonstrated that 50** of New York State of 26 confirmed cases of hepatic females with liver angiosarcoma (5 101 lived angiosarcoma. Controls comprised of individuals within 1 mile of such industrial facilities, who had an internal malignant tumor other than whereas none of their matched control did so. primary liver cancer were matched with index Experimental bioassay and epidemiological cases on the basis of age at diagnosis, race, sex. studies have shown a high concordance for the place of residence and vital status. This study carcinogenicity of vinyl chloride, specifically for showed a statistically significant association be liver angiosarcoma. This excess of liver angiosar tween angiosarcoma of the liver and direct occu coma has been shown to persist from the polymer pational or therapeutic exposure to arsenic itwo ization of vinyl chloride to the residence in near cases), vinyl chloride <three cases' and thorium proximity to such facilities. dioxide (two cases'. In addition, this study demon Both experimental and epidemiological data strated that of ten female cases of liver angiosar indicate that PVC dust is probably associated coma (no direct occupational or therapeutic expo with respiratory effects, both neoplastic and non sure to vinyl chloride, arsenic or thorium dioxide' neoplastic in nature. 9^Hived within 1700 ft of a vinyl chloride poly'^^^arion plant and four lived from 500 to 4500 REFERENCES ft of a poly(vinyl chloride' fabrication plant. In contrast, none of their matched controls lived 1 L'.S Tariff Commission Census of Dyes- and of Other Synthetic Organic Chemicals, 1927 Tariff Information Series No. 37, U S. Government Printing Office. Washing Wagoner, J. K., Infante. P. F. and Saracci, R V.ny( ton. DC. 1928, p, 139. chloride and mortality Lancet 1 194-195 19761 Oster. R. H.. Carr. C. J.. and Krantz, J. C Anesthesia Duck. B. W., and Carter, J. T. Vinyl chloride and morcaj. Narcosis with vinyl chloride. 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Duck, B. W., Carter, J. T.. and Coombes. E. J. Mortality study of workers in a polyvinyl-chloride production plant. 41. Brady, J. S., Likeratore, F., Harper. P,, GreeniwwaaJMA.!I- "JBurnett, W., Davies, J. N. P., Bishop. M., Polan, A Vianna, N. Angiosarcoma of t.ie liver: an epidemio Lancet 2: 1197-1199(1975). survey. J. Natl. Cancer Inst. 59: 1383-1385 119771. 1