Document QkENa56RYJg0j4Qz3Kw7ZVXd6

R&S 113356 BIO-MEDICAL. RESEARCH DOCUMENT DESCRIPTION FORM 63 68 69 76 Duplicate.in all cards:--^ year as-1961- File number [Right justify [Numeric only] Author(s), as Last Name FS (No Punctuation) and coden for journal as JAMA preceeded by one blank space * ' /'---f* ` 40 41 i.-.rx' C ,A 77 78 Sub-Index Code 60 61 62 n 12 13 Title of Report; end with space-hyphen-hyphen-space. Follow with Index Terms * separated from each other with comma-space. Avoid other punctuation; do not abbreviate. l C 4K'4sU-.C- --------- T~ / , / 4 /7 /i' T4. l . ^ a 21 22 23 24 Source (Journal, Vol., Number, Pages, Date ) 12 -*tV*C- yW" ' /^-- --- . / ___ > 1/ '*--7 s ;--rw" "' * - V / L^*'/ / / 61 62 31 32 Brief Summary 12 10 SUMMARY: 61 62 61 62 63 64 ct . t OCCUPATIONAL EXPOSURE TO VINYL CHLORIDE ' / 't / -V. ' w PREPARED BT: Teresa McGrath, M.D., Special Studies and Services Branch. STATISTICAL EVALUATION: R. Kusiak. TMcGsJl October 1979 A IUDEX Background Animal Toxicology Human Toxicology The Experience with Vinyl Chloride in Ontario The Derivation of an Acceptable Occupational Exposure Level. Summary Conclusion Recommendations Page 22 2b 25 R&S 113357 T R&S 113358 CH2 = CH Cl vinyl chloride H \ C=C H H Cl BACKGROUND: Vinyl Chloride is a chemical used in the synthetic production of polyvinyl chloride - a widely used plastic material. It is produced by thermal dechlorination of ethylene dichloride or by hydrochlorination of acetylene. Under normal conditions vinyl chloride is a colorless, almost odorless, flammable gas with a boiling point of 13.8C. At higher concentrations it has a sweetish odor. It is virtually insoluble in water, but is soluble in alcohol, carbon tetrachloride and ether. It is usually stored and transported under its own vapor pressure. The explosive limits are to 22% by volume in air. The auto-ignition temperature is UT2.2C. an At concentrations of 6% and above, it is/anesthetic. Because of these properties, it was suggested for use as an anesthetic agent in the early 1930's. It was, however, found unsuitable because of its flammability. In 1930 large scale production of vinyl chloride was undertaken. At I this time it was believed to be one of the safest chemicals on the market. In 1937 Dublin (ll) reported two cases of acute intoxication in exposed workers, without serious consequences. In 19h9 Tribukh^"^reported problems in Russian workers in a plastics factory. Hepatitis without Jaundice, hypertension, anemia, chronic gastritis, skin and respiratory lesions were the main complaints. In 1958 Filatova^^reported toxic angioneurooathy in exposed workers and in 1965 Puskin (51) reported liver and biliary tract disease in Russian workers. In the mid 1960's several researchers reported Raynaud like changes and acro-osteolysis in vinyl chloride reactor cleaners.{6) (5*0 (62)^^ disorder subsequently became known as polyvinyl chloride 'disease.. Viola, ( 53 ) in an attempt to reproduce acro-osteolysis, found that vinyl chloride was capable of Page 2 inducing tumors in the exposed animals.' In 1973 reports from Germany described findings in exposed workers which included thrombocytopenia, splenomegaly, liver damage, circulatory obstruction and skin and bone alterations.(30) Despite all these reports vinyl chloride was still considered to be a reasonably safe chemical until 1973 when two cases of hepatic angiosarcoma, a rare Since then, 62 more cases have been reported, worldwide, in exposed workers. PHARMACOKINETICS OF VINYL CHLORIDE: Low doses of vinyl chloride are believed to be metabolized by a rapid metabolic pathway to polar products which are excreted predominantly in the urine. These products are thought to be derived after initial metabolism of vinyl chloride and subsequent conjugation of the products with glutathione and/or cysteine, by covalent binding with sulfhydryl groups. A small but significant amount is metabolized to COg and expired. An even smaller but significant amount of activity of labelled vinyl chloride appears to be retained, primarily in the liver (22) * but also in other tissues, for as long as 75 hours after exposure.. Very little is excreted unchanged in the expired air. Vinyl chloride binds to albumin and is transported by it. Albumin is synthesized around the portal vein. As the exposure dose of vinyl chloride increases and the detoxifying pathways are over loaded, one would expect more vinyl chloride to bind with albumin in the periportal area, 3ecause of its irritant properties local irritation may occur which may lead to subsequent fibrosis. The pathway of metabolism is thought to be as follows: H, C-C00H Mcr.cchloroacetic acid R&S 113359 R&S 113360 ! Page 3 Only small amounts, if any, of monochloroacetic acid are believed to be formed at lov doses, as chloroacetaldehyde rapidly reacts with the sulfhydryl groups of glutathione and cysteine. It is thought that when higher doses are encountered the primary pathway is saturated and metabolism takes place via other less rapid pathways. One postulation is that the accumulating 2 chloroethanol is oxidized by peroxidases and catalases with eventual formation of chloroacetaldehyde. Another is that direct epoxidation occurs with the formation of chloroethylene oxide, which subsequently rearranges to chloroacetaldehyde. Both the epoxide and chloroacetaldehyde are reactive metabolites, capable of binding with macromolecules, (RITA, DNA, proteins and lipids) with resultant toxic and carcinogenic effects. Animal studies indicate that a threshold may exist for the takeover by the secondary metabolic pathways, and that this threshold may be around 50 ppm vinyl chloride. Exposure of rats to concentrations of vinyl chloride of 150 ppm or greater resulted in a depression of the hepatic non protein sulfhydryl content, which is believed to be responsible for the detoxification of the metabolites. Exposure to 50 ppm resulted in an inconsistent depression, and exposure to 10 ppm caused no such depression. ANIMAL TOXICOLOGY: Acute Vinyl.chloride has a low acute toxicity. The acute ID, for rats (U8) 50 exposed by inhalation is U7,600 ppm, and for guinea pigs similarly exposed is 70,Q00ppm or greater.^^ Chronic Chronic exposure of guinea pigs to 100,000 ppm vinyl chloride by inhalation resulted in growth disturbances, and severe liver, kidney, spleen 1 and lung lesions. (1*9) s 3361 CAP.CIH0G3IIC ET7ECTS: Tumorigenesis has been reported in rats exposed to concentrations of ( 39) (**0) (58) (31) (32) or in excess of 50 ppm; in nice exposed to concentrations of or in excess of 50 ppm(39) (29) and in hamsters exposed to concentrations of or in excess of 50 ppm(.39) (32) Recent reports indicate that exp*osure to concentrations as low as 1 ppm have resulted in tumorigenesis in rats though there is no confirmation ( of this to date. The results of these experiments are presented in Tables I, II, III, and IV. These results suggest that the neoplastic response is related to the exposure concentration, the duration of exposure and possibly the strain of animal. Twenty two of fifty nine Sprague Dawley rats exposed to 500 ppm for 52 weeks and observed for 135 weeks developed tumors, whereas, sixteen and ten of similar si2e groups exposed and observed for similar durations to 250 and 50 ppm respectively, developed tumors. (Table I). Comparison of the total number of tumors observed in groups of Sprague Dawley rats exposed for 52 weeks and observed for 66 weeks, with the number in groups exposed for IT weeks and observed for 66 weeks, shows a difference of U versus 1 at 500 ppm exposure level and 3 versus 1 at 250 turn exposure level (39) (37) (Table IV), thus indicating a possible relationship between exposure duration and tumorigenesis. Ho tumors were observed in either group at 50 ppm at that stage of the experiment. A variety of tumors was observed in the various species of animals tested. Hepatic angiosarcomas were observed in Sprague Dawley rat3 exposed to concentrations of 50 ppm and over; in mice exposed to 50 ppm and over ar.d in hamsters exposed to 500 ppm. (39) Other tumors included nephroblastomas, brain neuroblastomas, skin tumors, pulmonary adenomas, mammary carcinomas and zymbal gland tumors. I 1 1 1 33 CO w CO C7> N> 1 1 1 1 1 % 1 a i i i i Page 5 Tumor induction was observed in mice and rats at the lowest reported dose tested - i.e. 50 ppm. A dose response function emerges from the animal studies for hepatic angiosarcomas in Sprague Davley rats between 500 and 50 ppm and for nephroblastomas in Sprague Davley rats between 250 and 50 ppm. Seven hepatic angiosarcomas were observed in the group of 59 rats exposed to 500 ppm; L in the group exposed to 250 ppm and 1 in the 59 exposed to 50 ppm. Six nephroblastomas were observed in the rats exposed to 250 opm and 1 in the rats exposed to 50 ppm. This will be discussed again in the section relating to derivation of a standard. None of the control rats or mice developed hepatic angiosarcomas or nephroblastomas. A transplacental effect was suggested by the finding of two subcutaneous angiosarcomas in the offspring of breeder rats exposed between days 12 to 18 of (37) pregnancy to 10,000 and 6,000 ppm vinyl chloride. Lee et al (32) studied the carcinogenic effects in mice and rats of exposu to vinyl chloride. Four groups comprised of male and female rats and mice were exposed to 0, 50, 250 or 1000 ppm vinyl chloride, six hours per day for 5 days per week. Four animals of each species, sex and exposure level were terminated at the end of 1,2,3,6 and 9 months. The surviving animals were terminated at 'l2 months. This excluded observation over the natural lifespan of the animals. The sacrifice schedule and the small number of animals, as well as other peculiarities of the study made the data unsuitable for the derivation of a safe exposure limit. It is of interest to note that hepatic angiosarcomas were observed in mice exposed to 50 ppm and in both species exposed to 250 and 1000 ppm. The number of tumors observed in both cases increased with the dose. Extra-hepatic angiosarcomas were observed in both species. Mammary gland tumors were observed in female mice but not in the control animals. It is difficult, however, to evaluate the significance of the development of any of these tumors in a quantative way, as already mentioned, because of the small number of animals and the sacrifice schedule. McNamara et al^ Page 6 undertook a lifetime cancer study in lice and rats exposed either to single doses of vinyl chloride monomer ranging betveen 50 and 50,000 ppm or to multiple doses of either 50 or 500 ppm with a total dose of 51000 ppm. Serial sacrifice was performed with final sacrifice at 20 months for the mice and 2k months for the ra.ts. The authors report no changes attributable to vinyl chloride in the rats but report an increased incidence of pulmonary adenomas in mice exposed to 500 ppm for 10 exposure periods. Progression to malignancy is reported in mice exposed subchronically to a total dose of 5,000 ppm.. The findings are however unconvincing as the tables do not adequately describe the findings reported in the text and the numbers that progressed to malignancy axe not significantly different from the numbers observed in the control group. No changes attributable to vinyl chloride exposure were observed in the multigeneration study on rats. The authors did not describe the. method * of selection of offspring for this study which encompasses four generations. As the number of offspring remains fairly constant some method of selection must have been used. R&S 113363 MUTAGENIC EFFECT ' Vinyl chloride has been found to be carcinogenic in animals. As many carcinogens are also mutagenic, and as it is currently believed that tumorigenesis may be the result of somatic mutation, studies have been undertaken to evaluate the mutagenicity of vinyl chloride and its metabolites, two of which are believed to be mutagenic (chloroethylene oxide and chioracetaldehyde). Mutations have been induced in vivo by vinyl chloride in yeast systems in host mediated assays (using mice as hosts), and in somatic cells of Chinese hamsters. ^ They have also been induced in vitro in bacterialand yeast systemsin the presence of liver microsomal preparations. 3oth metabolites have induced mutations in vitro in Chinese hamster V79 cells, the response increasing with the concentration of the metabolites in the medium. 1 ) Page 7 Mutagenic effects on germ cells have not been established by dominant lethal studies in rats and mice/ ^though in Drosophila, the number of recessive lethals was increased in subsequent generations following exposure. TERATOGENIC EFFECTS: There is no evidence at the present time to suggest that vinyl chloride is teratogenic in animals. Exposure of rats and rabbits to 2,500 ppm or 500 ppm and mice to 500 ppm, (28) 7 hours per day during organogenesis did not result in teratogenic effects in the offspring, despite slight maternal toxicity in the rats and rabbits at the higher dose and in mice at 500 ppm. Mice appeared to be more susceptible to the maternal effects of the compound. So other information has been located on teratogenic effects resulting from animal exposure to vinyl chloride. R&S 113364 HUMAN TOXICOLOGY: Acute Human Exposure Single exposure to high concentrations of vinyl chloride can result in euphoria, a feeling of inebriation, somnolence, narcosis and in some cases prolonged sleep. When acute exposures are repeated, headaches, irritability, Cb*) diminution of memory, insomnia, general asthenia and paraesthesia may develop. Chronic Exposure Exposure to vinyl chloride has long been associated with the development of toxic effects. The full implications were-not appreciated, however, until it became clear in 19T1* that some workers exposed to vinyl chloride developed hepatic angiosarcoma. Earlier reports had associated vinyl chloride with a variety of effects, amongst which were hepatic damage, gastritis, skin and respiratory lesions. Later it was found that workers exposed to high concentrations while cleaning reactors developed a disease involving skin, bone and blood vessels. This became known as "occupational acro-osteolysis". It was soon realised that there was in fact involvement of other organs and the syndrome subsequently became 1 commonly known as"vinyl chloride disease". Presently it is thought that exposure to vinyl in thft ^f u^*ur>** -- . . --* R&S 113365 Page 8 namely hepatocellular carcinomas, tumors of lung,lymphatic system, brain and possibly angiosarcomas in other sites. It is also postulated that exposure to vinyl chloride may induce an immune complex disorder vith multisystem involvement. ACRO-OSTEOLYSIS: Acro-osteolysis was the first well recognized toxic effect of vinyl chloride. Dissolution of the bones of the terminal phalanges of one or more of the fingers is accompanied by clubbing, swelling and shortening of the nail beds, and scleroderma-like changes of the skin. Associated closely with these changes are vascular changes ranging from slight narrowing to segmental occlusion or even complete absence of vessel filling. A classic Raynaud? sphenomenon is seen to develop frequently in workers with chronic exposure'. Lange et al(30) noted the occurrence of a thrombocytopenia which was the first objective finding inthe majority of cases. Ward(59) suggests that the thrombocytopenia observed may have been an "apparent" one. He postulates, that as the result of an immune response a cryoprecipitable complex is formed which is capable of initiating complement sequence with subsequent platelet aggregation,an apparent thrombocytopenia, fibrinogen/fibrin conversion and vascular occlusion. PULMCHARY EFFECTS OF VINYL CHLORIDE EXPOSURE: There are several reports of pulmonary changes associated with vinyl chloride exposure. Lilis et al(33) noted the presence of linear reticular and, less frequently, nodular opacities in chest X-rays of workers exposed to vinyl chloride many of whom had also been exposed to polyvinyl chloride dust in polymerisation plants. The prevalence of abnormal chest X-ray findings was related to the duration of exposure and to the exposure concentrations. It should be noted that age was unrelated to the prevalence of the changes, The prevalence of a positive smoking history was found to be related to abnormal chest X-ray findings in those with greater exposures. Pulmonary functions changes indicated a relatively high prevalence of obstructive changes in these workers. 3erk^ noted a significant reduction in forced vital capacity in a i ?age 9 30-year old patient with hepatic fibrosis who had been exposed to vinyl chloride. Miller^^noted a 57.8? impairment in pulmonary function, as measured by 1.0 FEV/FVC, in workers exposed to vinyl chloride monomer and polyvinyl chloride dust in a polyvinyl chloride plant in a heavily industrialized city. The impairment correlated with age and duration of exposure but was unrelated to smoking. Gamble(19)et al however, found no association between, exposure to vinyl chloride and decreased pulmonary function or increased respiratory Symptoms in workers exposed to vinyl chloride in the production of polyvinyl chloride resin and to polyvinyl chloride dust in the plastic products division of a plant. The finding of changes may well be consistent with other cellular and subcellular changes which have been seen in other organs of workers exposed to vinyl chloride and may add substance to the concept that exposure to vinyl chloride may result in a systemic disease with manifestations in many organs. Epidemiological studies have indicated a possible relationship between vinyl chloride exposure and the induction of lung cancers. This is discussed in the section on epidemiological studies. IMMUNOLOGICAL CHANGES: ' Ward et al(59) postulate that vinyl chloride disease is an immune complex disorder and that the immune response is initiated by the incorporation of vinyl chloride or one of its metabolites into protein synthesis to produce a haptogenic effect and the incitement of antibody synthesis. Antigen stimulates S cell proliferation and immunoglobulin production. Antigen plus antibody from a soluble complex which is cryoprecipitable and capable of initiating complement sequence with subsequent platelet aggregation, apparent thrombocytopenia, fibrinogen/fibrin conversion and vascular occlusion. Ischemia which follows, resuits in collagen biosynthesis. Collagen and complement interact causing further activation of the complement pathway. Ward studied immunological changes in workers in a vinyl chloride polymer isation plant where exposures had been high. Findings of hyperimmunoglobulinaemia, crvoclob'.il i 1,1*... r &S 113366 Page 10 decreased and B lymphocytes were increased* Circulating immunoglobulin complement vere seen. Fibrin - fibrinogen conversion and adherence to the vascular vail and narroving of the dermal vessels vith subintimal fibrosis vere seen. Removal of these workers from exposure did not influence the persistence of disease activity as evident by the presence of cryoprecipitate and conversion of complement. HEPATIC CHANGES ASSOCIATED VITH VTHYL CHLORIDE EXPOSURE: Some of the earlier reports from Europe indicated, hepatic effects resulting from vinyl chloride exposure. However.serious consideration was not given to the possibility of liver effects until the finding of hepatic angiosarcoma in exposed workers in 197U. Serk^et al reported the case of a 30-year old worker, who had been R&S 113367 exposed to vinyl chloride for 3h years cleaning reactor tanks. Persistent abnormal hepatic function tests and hepato splenomegaly were observed and finally a laparotomy was performed. The liver showed multiple areas of fine nodularity and fibrosis. The spleen showed lymphoid and reticuloendothelial proliferation. Removal from exposure was`ensured on his return to work. Follow up of 2h years later showed that liver function tests had returned to normal despite a possible progression of the hepatic fibrosis. (h7) Popper has described the pathological changes resulting from exposure to vinyl chloride and has observed that the changes are very similar to those resulting from exposure ta thorotrast or arsenicals. A precursor stage exists, characterized by a conspicuous subcapsular fibrosis, a non pathological progressive portal fibrosis and a borderline increase in intralobular connective tissue all associated with focal stimulation of the sinusoidal lining cells and the hepatocytes* This is frequently accompanied by splenomegaly and in some instances by a portal hypertension. Transition to angio sarcoma is preceded by focal dilatation of the sinusoids and even greater activation but dedifferentiation of their lining cells. It is postulated that this may result- from stimulation of hepatic and splenic cells by vinyl chloride vtin or i t*s + Vn-> i < * R&S 113368 Page 11 HEPATIC TUMORS: Since the first report of hepatic angiosarcomas in vinyl chloride exposed workers in 1973, more than 62 occupationally exposed cases have been reported worldv: in the literature, 10 of these occurring in Quebec. In all but one case (53)exposur had been to high concentrations, usually in excess of 100 ppm and frequently much i higher than that. Delormereported finding a hepatic angiosarcoma and a hepatocellular carcinoma in an employee exposed for 23 years to vinyl chloride. Histological evidence suggested coincidental development of both tumors as though in response to the same stimulus. He believes that a similar response by other cells in contact with the carcinogenic agent may result in tumors of other sites. This seems to be consistent with the findings of Maltoni in his animal studies. It also may explain, the finding of- angiosarcomas in more than one site in humans and the reports of epidemiological studies which suggest increased incidences of tumc^^of sites other than liver in exposed populations. AHCIOSARCOMAS OF OTHER ORpGA^NyS-; Popper and Thomas.report finding angiosarcomas in other organs in 3 patients with hepatic hemangiosarcomas. Duodenum was the site in one, lung in another and lung, heart, kidney and lymph nodes in the third. They were uncertain as to whether these were metastatic lesions, or whether there was multifocal primary involvement. In none was the spleen a site of angiosarcomatous change. (7) Couaerc et al report on a patient who presented with backache. .A tumor involving the posterior arch of Ath, 5th and 6th ribs was found to be an angiosarcoma. Further investigation revealed the presence of a hepatic angiosarccm- Multiple other sites were found on death following rupture of the liver lesion. These included vertebra and left adrenal. Again it is not known whether th i#as a case of multifocal primary sites or- secondary spread. TUMORS OF OTHER ORGANS: t, iomiological studies suggest a greater than expected incidence R&S 113369 Page 12 of tumors of the central nervous system, lymphatic system and lung in populations exposed to vinyl chloride. The evidence, though suggestive, is far from conclusive. These studies are discussed later in the text. EPIDEMIOLOGICAL STUDIES: As vinyl chloride is carcinogenic in both animals and man, and as it has been found to be mutagenic in bacterial test systems, several epidemiological studies have been undertaken in an effort to establish findings relative to such effects in populations exposed to vinyl chloride either occupationally or environmentally. Such studies include examination of peripheral lymphocytes for chromosomal abnormalities, cancer mortality in exposed populations, incidence of fetal loss in vives of exposed workers, incidence of congenital abnormalities in the offspring of exposed populations. As exposure concentrations are largely unknown, in most instances they have been estimated and hence reliable dose response functions cannot be derived. I. OCCUPATIONAL EXPOSURE: Chromosomal Studies Peripheral lymphocytes have been studied for chromosomal abnormalities in an effort to establish whether vinyl chloride induces such abnormalities in man. Some of these studies conclude that such changes are induced by vinyl chloride while others report negative findings (see Table- V). In the majority of these studies the study populations were very small and hence it is difficult to draw firm conclusions. The largest group studied, 209 men,was exposed to low concentrations of vinyl chloride, estimated to be between 12 and < 1 ppra.0/No chromosomal abnormalities were observed. Using the techniques described by the authors, Purchase^ noted a positive correlation between chromosomal aberration observed in the study group and the duration of employment, history of exposure to excursion levels and smoking. Again, however, the study group was small. Fleig ^ ^^reports positive findings only in workers who had symptoms of vinyl chloride disease, and in one patient previously treated for his hepatic angiosarcoma with chemotherapy. R&S 113370 Page 13 These results, whilst inconclusive, suggest that vinyl chloride may indeed he capable of inducing chromosomal. abnormalities, and that the effect may be dependent on the severity of the exposure experienced. Vinyl chloride, probably, is one of many agents capable of inducing somatic mutations. MORTALITY STUDIES IN VINYL CHLORIDE EXPOSED WORKERS: In response to the report that vinyl chloride was responsible for the induction of hepatic angiosarcoma in two workers in the 3.F. Goodrich plant in Kentucky in 1973 many studies vere set up to establish the role played by vinyl chloride monomer in the development of this tumor and whether in fact, it is responsible for the development of other tumors in exposed workers. All of the'studies undertaken have been carried out in the absence of definitive exposure data. Estimates of past exposures have been arrived at by using information from various sources. None of these are reliable enough to provide quantitative exposure data. In many cases exposure to copolymers of vinyl chloride, polyvinyl chloride and in some cases other chemicals occurred in addition to exposure to the monomer. As these studies lack quantitative data, they cannot be used to derive a dose-response function. However, the ,qualitative information that is forthcoming does give some indication of cause and effect relationships. Hepatic angiosarcoma is. the only tumor that has so far been definitely associated with exposure to vinyl chloride monomer in man. Available studies indicate that those workers who have developed hepatic angiosarcomas had experienced exposure to high concentrations of vinyl chloride in thl^pa^P (l)(55) (9)(^3) Frequently, they had been employed as autoclave operators or reactor cleaners, and experienced exposure concentrations in the hundreds and frequently in the thousands of ppms. (-4) Ott was, however, unable to find an association between malignancies of the liver and biliary tract and exposure to vinyl chloride, although, he did observe an association between exposure and deaths from all malignancies. Page iU (Ua) particularly in those vith an. estimated high exposure. Monson and. Peters and (61) Waxweiler also observed a relationship between deaths from all malignancies and exposure to vinyl chloride monomer. The importance of interval between initial exposure and the observation of (61) a tumor was illustrated by Waxweiler, who observed a significant excess only in tumors of the hepatic system at the first time-of observation (i.e. 10 years post initial exposure) as compared with significant excesses in tumors of brain and central nervous system, respiratory system and hepatic system when the (U2) . observation period was extended by 5 years. Monson and Peters report an increasing excess of deaths from all cancers over that expected during the 5 years of their study. (6l) (55)' Some studies have indicated an association between exposure to vinyl chloride and the development of brain tumors - particularly glioblastoma multiforme (6i) in type. Waxweiller's study suggests that the latent period for the development of tumors of brain is longer than that required for the development"of hepatic angiosarcomas. (55) Tabershav and Gaffey failed to find a relationship between the estimated dose and the development of these tumors. Both of these studies suggest ,a relationship between Yinyl chloride exposure and the development of respiratory R&S 113371 cancers. However, in neither study were the effects of smoking considered. Prom these studies we can conclude that high maximum exposure to vinyl chloride is associated with the development of hepatic angiosarcomas. An association between exposure and the development of tumors of the brain and respiratory tract is suggested but so far there is no proven cause and effect relationship. The possibility that the latent period required for the development of either of these tumors may exceed that required for the development of hepatic angiosarcoma is supported by the studies. If this is the case then it nay not be possible to draw conclusions about the role of vinyl chloride in the induction of these tumors until a lengthier observation period, if not lifetime observation, has elapsed. Page 15 STUDIES OK GERM CELL EFFECTS: The question of germ cell effects of vinyl chloride vas studied by (2*0 Infante et aJL. Gera cell effects on exposed males were taken to be expressed as fetal loss in the respective wives. The authors report an excess fetal loss in the group of wives whose husbands had had a primary vinyl chloride monomer exposure as compared with controls, whereas prior to exposure no such excess was seen. The results indicate a possible germ cell effect, however, the study has several shortcomings. The ages of the wives were presumed to be similar to the husbands' ages, a presumption which is not necessarily valid; details pertaining to conception, fetal loss, etc. were obtained from the husbands and no direct contact was made vith the wives. The interval between such episodes and the time of recall was not mentioned, but one would presume it would influence the quality of the information. Fetal death rates for wives of vinyl chloride monomer workers prior to exposure are compared with the rates for this group after exposure. The two rates are however not comparable as they have been adjusted to different standards; the first to the control before "exposure" and the second to controls after "exposure". II. ENVIRONMENTAL EXPOSURE; Much concern has arisen that populations residing in the vicinity of vinyl chloride plants may experience increased rates of (l)congenital abnormalities and (2) tumorigenesis in offspring. Several studies have been undertaken to evaluate such effects. The results of these studies are not unanimous and at the present time no firm conclusions can be drawn on either of these questions. R&S 113372 3373 CONGENITAL MALFORMATIONS: Infante et al^(26) studied the rate of occurrence of congenital abnormalities amongst live births in three Ohio cities, each of which housed a polyvinyl chloride facility. They observed that the rate of.occurrence of such abnormalities was significantly greater for each of these cities than the Ohio State rate. Comparison of the rate for each city with the rate for its corresponding county shoved that in two cases there was a significant difference. Such a difference was not observed when other city/balance df county rates were compared. When the data were analysed it was evident that significant excesses were seen for several abnormalities, one of which was defects of the central nervous system.. A further study of data on defects of this system included data from stillbirth records, as both may be closely connected. A significant excess of central nervous system defects was observed for one of the cities with a polyvinyl chloride facility. seen, in another of the cities. It is note worthy that no cases were , Although these findings suggest association between vinyl chloride exposure and an increased rate of occurrence of congenital malformations they are not conclusive. In an effort to examine the relationship between exposure to vinyl chloride and an increased rate of central, nervous system defects suggested by Infante's study, Edmonds et al undertook two studies. In the first they^^ compared the rates of occurrence of central nervous system malformations (I9T0-197*0 in two hospitals (one in Painesville* and one in Pittsburg both involved with the Birth Monitoring Defects Program) with rates for the respective states. Both cities had polyvinyl, chloride facilities. No increase was seen in the rates in the Pittsburg hospital, but there was an increase in the Painesvill* hospital. * Painesvili* was one of the cities studied bv Infants. When occupation and, place of residence of the families of these cases was analysed and compared with 2 control groups derived from the hospital registry, no association could he established between the cases and vinyl chloride exposure. The second (13) was a more comprehensive study using data on Kanawha County obtained from the Birth Defects Monitoring Program and from the State Department of Vital Statistics, for the period'1970-7^. Kanawha county was chosen because its rate of occurrence of central nervous system, defects for that period was significantly higher than national Birth Defects Monitoring Program rates for the same period. Two sets of controls were matched to the cases. Results of the study show no case-control differences regarding parents possible occupational exposure to vinyl chloride at that time or five years prior to the child's conception. It is interesting to note that several case families residing within three miles of the polyvinyl chloride plant were located to the North Sast of the plant and controls to the South West. Data on wind patterns and aiif pollution do not correlate with these observations. The observed clustering, of cases residing within three miles of the polyvinyl chloride plant is not satisfactorily explained by proximity to the plant. Consideration should be given to the fact that several sources of other chemicals are also present in I this geographical area, thus making it unrealistic to implicate vinyl chloride monomer as the causative agent in these cases. A. study conducted in Quebec(v56)'reports a higher frequency of birth defects in a community with a vinyl chloride polymerisation plant, than in a comparable city without such a facility. The ages of the mothers in both cities was comparable, however, occupational histories of the mothers were not considered. It is not possible to draw any conclusive association between the observations and vinyl chloride exposure, as the city which had the polyvinyl chloride facility had several other industries and hence exposure to many other chemicals was a re possibility R&S 113375 Page 18 It is interesting to note an increased frequency of malformations in the latter years of the study, when in all probability the levels of vinyl chloride had fallen. TUMORICENESIS: Saric et al (52) examined the incidence of malignant tumors of bronchus and liver over a four-year period (1968-1971) in a city with several industries, one of which was a polyvinyl chloride facility. They found that the incidence of both types of tumor was only slightly higher than expected, based on the incidence in Croatia over the same period. Ho cases of hepatic angiosarcoma, but eight cases of hepatocellular carcinomas were reported. However, no relationship was established between these cases and either occupational or residential exposure to vinyl chloride. One hundred and thirteen cases of bronchogenic cancer were reported. Ninety three percent of the 158 males and 1*75 of the 35 females in the study group were smokers, and 39!! were between 1*5-61* years and 585 were 65 or older. No relationship could be established between these cases and exposure to vinyl .chloride either occupationally or residentially. In Wisconsin residentstbetween 196** and 1976.ten cases of angiosarcoma of liver were identified. This is twice the expected rate based on estimates of the crude incidence of angiosarcoma of the liver for the entire United States^ These cases were scattered across the state;, the ages ranged from 36-71 years (mean 58); 9 were male and 9 white. One had a history of thorium di oxide exposure; two or possibly four had had an arsenic exposure; 7 of the 10 had lived on farms during their life. Only 1 had exposure to a vinyl compound - polyvinyl acetate, and 1 had lived near a chemical company which made plastics and resins. Page 19 (u) A study undertaken by 3rady at al indicated that the incidence of hepatic angiosarcoma in residents of New `fork State, excluding New York City, exceeded the incidence of such tumors in the total U.S. population (0.25 per million versus 0.14 per million respectively 1970-1975). Twenty six cases of hepatic angiosarcoma were reported to the Tumor Registry of the Cancer Control Brueau (N.Y. State Department of Health) in the years 1958 through 1975* Nineteen of these had no known exposure to any of the three agents known to induce such tumors (arsenic, thorium dioxide and vinyl chloride). Five, however, had lived for long periods (8-62 years) close to either a vinyl chloride or a polyvinyl chloride plant. In the other fourteen cases no pertinent' residential or occupational history was obtained. The authors remark that all matched controls* lived at a distance of more than one mile from the respective plants. However, the place of residence for the * 14 cases is not mentioned, nor is the question of wind direction, or other possible chemical exposure addressed. This study at best, indicates a possible relationship between ambient exposure to vinyl chloride and hepatic angiosarcoma induction. (26) (250 - Infante et al reported a greater than expected number of deaths from central nervous system tumors among residents of 4 United States cities combined (38 vs 24.7). Three of the cities had polyvinyl chloride facilities and 1 did not, but was 8 miles from one of the other 3 cities. Expected rates were based on the Ohio State rates. The Standard Mortality Ratios for cancers was increased in 2 of the cities. However, the number of cases involved was small and makes it impossible to draw any firm conclusion from the study. ^Controls were derived from the same Tumor Registry and consisted of cases with an internal malignant tumor, other than a primary liver tumor. 1 1 R&S 113376 R&S 113377 Page 20 THE EXPEP.IEHCE WITH VINYL CHLORIDE IN ONTARIO: Ontario has been involved in the production and polymerisation of vinyl chloride for many years. The first plant started up in 195^, a second in 1957 and a third in i960. Since 195^> as far as can he ascertained, approximately 1,000 workers have been exposed to the chemical for a period of 3 months or more. In the earlier years it is presumed that exposure concentrations vould have been high, with certain Job categories experiencing very high exposures. Once it was recognized that the chemical caused health effects, measures were taken to reduce exposure concentrations and when the chemical was linked to hepatic angiosarcomas in 1973, further steps were taken to reduce exposure concentrations even further. At the present time it is estimated by the companies that exposure concentrations run around 2-3 ppm for the majority of the time. Medical programmes were set up' by the involved companies as the need became obvious. Preplacement examination and regular assessment are undertaken by the plant physician. When workers retire or resign they are asked to notify the Ministry of Labour of their whereabouts and subsequent moves. The Ministry of Labour in cooperation with the companies, set up a nominal roll for all workers in the three major companies who were exposed to vinyl chloride for three months or more. When an employee retires or resigns from the company he is asked to notify the Ministry of Labour so that follow-up can be maintained. However, due to the human factor involved, this notification is less than 1005 and follow-up is thus incomplete. _ This must be remembered when one states that to date, to the best of our knowledge no cases of vinyl chloride induced hepatic angiosarcoma have been seen in Ontario. Also to be remembered is the small number of workers who would have a sufficient latent period for development of a hepatic angiosarcoma, the decreasing exposure concentrations over the years, the fact that one plant is an open one, the small number of workers in the annual work force and the even smaller number who would have had Jobs such as reactor cleaners. It is possible also that R&S 113378 Page 21 recognized cases of hepatic angiosarcomas were classed as such, only when reviewed with the knowledge of the association between vinyl chloride and this tumor. It may well be that ve` have Just entered into the time period when one would expect to see these tumors because of long latent period, and if, as the reported studies suggest, the latent periods for tumors of other organs are longer, we may still not have reached this time. While to date we are not aware of any cases of vinyl chloride induced tumors in Ontario, we must remember that this picture may change in the future. # i 1 1 Page 22 THE DERIVATION OF AJ3 ACCEPTABLE CONCENTRATION OF VINYL CHLORIDE FOR OCCUPATIONAL EXPOSURE: Ideally the derivation of an acceptable concentration for occupational exposure to vinyl chloride should be made using data from epidemiological studies which describe the dose response function in humans. In the case of vinyl chloride, this type of data are not available and it, therefore, becomes necessary to use animal studies which do provide quantitative data. In the case of vinyl chloride, the animal studies of Maltoni are the only ones suitable for this purpose and as such have been used exclusively for the derivation of an acceptable concentration of vinyl chloride for occupational Exposure. It must be recognised that when animal data are used for such a purpose many assumptions must be made. It has been assumed that no threshold exists; that the function is a linear one; that the effects observed at- high doses can be extrapolated to lower doses in the same species; that if the chemical is inhaled it is possible to extrapolate directly from animal to man; that the risk for both animal and man is similar,if a similar fraction of their life is spent in a smaller exposure concentration; that the latent period for the development of a specific tumor takes the same fraction of both species lifetimes if they have experienced .similar exposures; an acceptable risk has been taken to be 5xl0~^ per year. Based on the animal data and recognising fully the assumptions that have been made, it has been calculated that an acceptable concentration of vinyl chloride for the air in the workplace is 2 ppm. See appendix I. &s 113379 SUMMARY: Workers have been exposed to vinyl chloride since the early 1920's. Because of the large demand for its products, production has increased enormously since its introduction to the market place. Vinyl chloride was up to 1973, con sidered to be of low toxicity despite some published reports of toxicity in exposed workers,. Up to 197^ exposure concentrations frequently reached hundreds of ppms and often thousands of ppms as ascertained by reported acute effects. Once it was recognised that vinyl chloride was capable of inducing hepatic angiosarcoma in those exposed to it. th v--t---*- ........... ............ FL&S 113380 Page 23 Lovered. However, some of the workers had already been exposed to high concentrations of the chemical. Since 1973 it has been recognized that vinyl chloride has been responsible for the induction of hepatic angiosarcoma in exposed workers. Current information suggests that, in addition, tumor induction may occur in other organs and may include angiosarcoma of sites other than liver^hepatomas, tumors of lung, brain, respiratory tract, lymphatic system. Presently, however, hepatic angiosarcoma is the only tumor definitely associated with vinyl chloride exposure in man. The epidemiological studies suggest that in the cases known to date high and exposure concentration,/period between initial exposure and observation are related to the development of the tumor.. The lack of quantitative human data make it impossible, however, to derive a dose response relationship for this effect in man. Maltoni's animal studies have shown the indudtion of hepatic angiosarcoma in rats, mice and hamsters, with the former two species of animal developing the tumor at the lowest tested dose. A dose response relationship was observed for the rat over the three lowest doses tested. Tumor induction was also related to the duration of exposure and interval between initial exposure and observation. TuImors of other sites were also reported. Because the data from this study comprise the only quantitative data available, they have been used to derive an acceptable occupational standard for exposure to vinyl chloride. Besides carcinogenesis, exposure to vinyl chloride can result in a variety of toxic effects involving blood vessels, lungs, skin, spleen and liver. It has been suggested that these effects may be the result of an immunological response with multi system involvement. Immunological studies add some support to this theory. Vinyl chloride has been found to be mutagenic in bacterial- test systems. Chromosomal studies on human peripheral lymphocytes indicate a possible mutagenic t effect in man. Some reported studies indicate a possible germ cell effect on male workers exposed to the chemical. The studies are however, inconclusive. Page 24 Studies undertaken to evaluate the effects of environmental exposure to vinyl chloride suggest a possible relationship betveen exposure and increased incidence of tumorigenesis, especially of the central nervous system, and congenital abnormalities in exposed populations. Whilst these studies suggest such relationship they also are inconclusive. There have been, to the best of our knowledge, no known cases of vinyl chloride induced hepatic angiosarcoma among the estimated 1,000 workers exposed to the chemical in Ontario since the inception of the industry in 195^- However, as follow up has been less than one hundred percent and as the interval between initial exposure and observation may be shorter than the interval required for the development of tumors, particularly, if the group exposed is small, it may be too early to fully assess the full impact of vinyl chloride in the exposed population. R&S 113381 CONCLUSION: Epidemiological studies have demonstrated a definite cause and effect relationship between exposure to vinyl chloride and the development of hepatic angiosarcoma in exposed workers. In addition they suggest a relationship between exposure and the development of other tumors. As the exposure data are ill defined and frequently are only estimates using a variety of sources of information, the data arefar from quantitative and as such are unsuitable for use in the derivation of a dose response function and subsequently for the derivation of a safe exposure 'level. At best the data suggest that past exposure concentrations have been high for those who have developed tumors and that the interval betveen initial exposure and the time of observation may influence the observed response. The animal studies of Maltoni provide the only quantitative data available which is suitable for use in the derivation of a safe exposure dose. The utilization of animal data for such a purpose is not without problems. Many assumptions must be made and findings have to be extrapolated from animal to man. In view of the assumptions taken, a conservative approach must be adopted. n5in& such mnroach conRe,*V!,-* <\ ........ R&S 113382 Page 25 I a tumor by being exposed to 1 ppm of vinyl chloride is derived. 3y assuming an acceptable annual risk for man the exposure concentration which would incur this risk is calculated. Based on the experimental data and using the assumptions described, it was calculated that the risk resulting from lifetime exposure of workers to 1 2 ppm vinyl chloride would be acceptable. RECOMMENDATIONS: The time weighted average exposure limits shall be 2 ppm vinyl chloride. i i! !; tr I :i :, i* References 1. Anderson, D., et al. 1976 Vinyl Chloride: Dominant Lethal Studies in Male CD 1 Mice. Mutation Res. UQ: 359. 2 Anonymous, 1976. Morbidity and Mortality. Vol. 25: 8. DO C< CO 00 CO 00 CO 3. Berk, P.D. et al. 1975 Persistence of vinyl chloride-induced liver injury after cessation of exposure. Annals of M.Y. Acad. Sci.. Vol. 2L6, 70. L. 3rady, J., et al. 1977 Angiosarcoma of the liver. J. Natl. Cancer. Inst. 59 (5) 1383. 5. Byren, D., et al. 1976 Mortality and Cancer Morbidity in a group of Swedish Vinyl Chloride Monomer and Polychloride vinyl production workers. Env. Hlth. Perspect. 17, 167. 6. Cordier, J.M. et al. 1966. Acrosteolystset Lesions cutanee associees chez deus ouvriers affects au nettoyage d'autoclaves. Cahiers Med. Travai L: lL. T. Couderc, P.t et al. 1976 Angiosarcoma osseux Revelateur Dune tumour hepatique Chex Un ' Travailleur Expose Au Chlorure De Vinyle. Sem. Hop. Paris 52 (31) 1721. 8. Creech, J.M., and M.N. Johnson, 197^. Angiosarcoma liver in the manufacture of Polyvinyl Chloride. J. Occup. Med. 16: 150. 9. Delorme, F., 1978 Association of angiosarcoma of the liver and hepatoma in the vinyl chloride worker. Ann. Anat. Pathol. 23 (20) 105-U^. 10. Delorme, F., et al. 1973. Ten cases of angiosarcoma of the liver in Shawingan Quebec. J. Occup. Med; 20(5) 338.11 11. Dublin, L.I., and Vane R.J., 1933 and 19^1 a.c. MO Danziger H. Can. Med. Ass. J. 82:328: i960. &9B References 12. Ducataman, A., at al, 1975 Vinyl Chloride Exposure and Human Chromosome aberrations. Mut. Res. 31. 163.. 13. . Edmonds, L.D., et al. 1978. Congenital Central Nervous System.malformations and vinyl chloride monomer exposure: A community study. Teratology, 17, 137. 14. Edmonds, L.D., 1975 Congenital Malformations and vinyl chloride. Lancet No. 29 also Morbidity and Mortality 24 (29), 1975. 15. Filatova, V.S., et al. Hygienic characteristics of vinyl chloride. Gig. Truda Prof. Zabolevaniya. l6. Fleig, X., et al. 1978 Mutagenicity of vinyl chloride. External chromosome studies on Persons with and without vinyl chloride illness. Journal of.Occupational Medicine. 20 (8) 557-61. 17. Fox, A.J., et al. 1977 Mortality experience of workers exposed to vinyl chloride monomer in the manufacture of polyvinyl chloride in Great Britain. Sr. J. of Ind. Med. 34, 1. 18. Funes Cravioto, F., et al. 1975. Chromosome Aberrations in workers exposed to vinyl chloride. Lancet, 459. 19- Gamble, J., 1976. Effect of occupational and non-occupational factors on the respiratory system of vinyl chloride and other workers. J. of Occup. Med. 18 (10). .20 Greim, H. et al. 1975* Mutagenicity in Vitro and Potential Carcinogenicity of Chlorinated Ethylenes as a function of Metablic Oxirane formation. Biochem. Pharmacol. Vol. 24, 2013. .21 Heath, C.W., _ 1977. Chromosomal damage in Men Occupationally Exposed to Vinyl Chloride Monomer and other Chemicals. Env. Res. 14, 68-72. References 22. Hefner, R.E., et el. I9T5. Preliminary studies of the fate of inhaled vinyl chloride in monomer in rats. Ann. N.I, Acad. Sc. Vol. 246, p. 135. 23. Huberman, E. et al. 19T5. Mutation Induction in Chinese Hamster V79 Cells by Two Vinyl Chloride Metabolites, Chloroethylene oxide and 2 Chloracetaldehyde. Int. J. Cancer 16, 639. 24. Infante P., et al. 1976. Genetic Risks of Vinyl Chloride. Lancet 734. 25* Infante, P. et al. 1976. Mut. Res. 4l, 131. 26. Infante, P., 1976. Oncogenic and mutagenic risks in communities with polyvinyl chloride production facilities. Ann. N.7. Acad. Sc. 271 (49). R&S 113385 27. Inger-Lise, Hansteen, et al. 1978. Effects of Vinyl Chloride in Man. A Cytogenetic Study. Mut. Res. 51. 271. 28. ' John, J.A., et al. 1977 The Effects of Maternally Inhaled Vinyl Chloride on Embryonal and Fetal Development in Mice, Rats and Rabbits. Tox. and-App. Pharm. 39, 497. 29. Kelpinger, M.L. et al. 1975. Interim Results of Exposure of Rats, Hamsters and Mice to Vinyl Chloride. Ann. N.Y. Acad. Sc. Vol. 246, 219- 30. Lange, C.E., et al. 1975Further results in Polyvinyl Chloride production workers. Ann. N.Y. Acad. Sc. Vol. 246, 18. 31. Lee, C.C. et al. 1976. Inhalation Toxicity of Vinyl Chloride and Vinylidene Chloride in Rats and Mice. Pharmacologist 18 (2) 245. 32. Lee, C.C. et al, 1978. Carcinogenicity of vinyl chloride and Vinylidene Chloride. J. Toxi-oj.. and Env. Health: 4, 15. References 33. Lillis, R., et il, 1975. Prevalence of disease among vinyl chloride and polyvinyl chloride workers. Ann. N.f. Acad. Sc. Vol. 246, 22. 34. Lloyd, J.W., 1975Angiosarcoma of the Liver in Vinyl Chloride/Polyvinyl Chloride workers. J. of Occup. Med. 17, 333- 35- Loprieno, H., et al. 1976. Mutagenicity of Industrial Compounds, Vinyl Chloride, Styrene and their possible metabolites. Mut. Res. 38, 2, 114. 36. Magnusson, J., 1976. Mutagenic Effects of vinyl chloride in drosohilia melanogaster. Mut. Res. 38, 115. 37. Maltoni, C., 1975. Carcinogenicity Bioassays of Vinyl Chloride Current Results. Ann. N.7. Acad. Sc. 246. 38 Maltoni, C., 1977. Revised Vinyl Chloride Standards. Irk Industry, Chemistry and Engineering.13, August 1. 39. Maltoni, C.M., 1975The Value of Predictive Experimental Environmental Carcinogenesis. An Example Vinyl Chloride. Ambio.Vol. 4, 1, 18. 4o. McNamara, Vinyl Chloride monomer Inhalation studies (draft-unpublished). 4l. Miller, A., et al. 1975. Changes in Pulmonary function in workers exposed to vinyl chloride and polyvinyl chloride. Ann. N.r. Acad. Sc. Vol. 246, 42. Monson, R.R.4 1975. Proportional Mortality among vinyl chloride workers. Env. Health. Perspectives, 11, 75. R&S 113386 References 173387 Nicholson, W., et al. 19T5 Mortality Experience of a Cohort of vinyl chloride - polyvinyl chloride workers. Ann. N.Y. Acad. Sci. Vol. 246, 225. Ott. M. et al. 1975 Vinyl Chloride Exposure in a Controlled Industrial Environment. Arch. Env. Health. 30, 333. Patty, F.A. et al. 1962. Public Health Reports. U.S. Reprint No. 1405, 45 No. 34, Aug. 1930. a.c. IN Industrial Hygiene and Toxicology 2nd Ed. Vol. 11, Interscience. Picciano, D.J., Flake, R, Gay, P., Killian, D.J., 1977. Vinyl Chloride Cytogenetics. J. Occup. Med. 19 (8) 527. Popper, J., and Thomas, L., 1975. Pathology of Angiosarcoma of the liver among vinyl chloride - polyvinyl chloride workers. Ann. N.Y. Acad, Sc. Vol. 246, 268. Prodan, L., et al. 1975. Experimental Acute Toxicity of Vinyl Chloride. Ann. N.Y. Acad. Sci. Vol. 246, 154. Prodan, L., et al. 1975- Experimental Chronic poisoning with vinyl chloride. Ann. N.Y. Acad. Sci. Vol. 246, 159. Purchase, I.F., et al. 1978. Chromosomal Analyses in Vinyl Chloride exoosed workers. Mut. Res. 57, 325. Puskin, G.A., 1965. Liver and Sile duct disorders in workers engaged in production of certain types of plastics. Sov. Med. J. (Moskva) 28: 132. Saric, M., et al. 1976. Malignant Tumors of the Liver and Lungs in an area with a Polyvinyl Chloride Industry. Env. Kith. Persp. 17,' 182. Soirtas, R., 1978. Angie- ima of the liver in vinyl chloride/oolyvinyl chloride workers. *:r-r `fTOPH References JU.-..- Suciu, I., et al. 1967Study of disease caused by vinyl chloride. Med. Lavoro 58: 261. 55. Tabershav, I.R. and Gaffey, W.R., 197^. Mortality study of workers in the manufacture of vinyl chloride and its polymers. J. Occup. Med. 16(8). 56. Theriault, G.P. and Liasa Goulet. Birth Defects in a community located near a vinyl chloride plant. Unpublished. R&S 113388 57. Tribukh, S.R., et al. 19^9. Working conditions and measures for their sanitation in the production. cf .certain types of plastics. Gig. Sanit. 10:39- 58. Viola, P.L., 1970. Carcinogenic effect of vinyl chloride. X International Cancer Congress, Houston Abstr. Vol. 29. 59. Ward* A.M. et al. 1976. Immunological mechanisms in the pathogenesis of vinyl chloride disease. Br. Med. J. I. 936. 1 60. Watanabe, P.G. et al, 1976. Vinyl Chloride induced depression of hepatic iron protein j sulphydryl content and effects on Bromsulphthalein clearance. Toxicol. 6, 1. i 6l. Waxveiler, R., et al. Heoplastic Risk among workers exposed to vinyl chloride. . Ann. N.T. Acad. Sci. p. U0-k8. 62. Wilson, R.H. et al. 1967. Occupational acroosteolysis. Report of 31-cases. J. Am. Med. Ass. 201: 577. i ES3S1 ijfeBM hasss lawa fcaBt-i teaaai naa< TABLE I t e Exposure Exposure aid concentration duration ppm weeks. ats 500 52 Observation period weeks. Number of animals that developed hepatic angiosarcomas Latent period weeks. Humber of animals that developed nephroblastomas. 135 7 8l !| Latent period. Total number of animals that developed tumors (2) Ref. fi3wks 22 (3-1) .ts * .ts 250 50 52 135 52 135 li 1 79 6 135 1 BOwks 135wks 16 10 (3*!) (31) ts 0 0 135 0 00 0 No.\t (37) (1) S.D. - Sprague Dawley (2) ' Some animals developed more than one tumor. R&S 113389 R&S 113390 TABLE II (BT^) *al cies Exposure Number Concentration Number gf Exposure Observation Pulmonary- duration Period Tumors 3S 500 ppm 30 wka 1(1 wks 16 3 IS 250 ppm 30 wks 111 wks. 11 1 .3 50 ppm 30 wks Ill wk3 - \S 0 l - 111 wks 1 Latent Period 3*t 3*i - 39 Number of Mammary Cancers 2 6 Site of Latent other tumors and Period types 1| hepatic angio 33 sarcomas . 1 subcutaneous. 1 skin acanthoma Total number of animals with tumors. V 17 30 3 hepatic angiosarcomas. 1 hepatic angioma. 15 Ref (3$) (33) 7 35 2 hepatic (33) fibroungiomas. 8 2 subcutaneous angiosarcomas. 0- - 1 (37) Animal Species and Exposure N uiube r Concentration Golden Hamsters X 33 Golden Hamsters X 32 Golden Hamsters X33 Golden Hamsters X70 500 ppm 250 ppm 50 ppm 0 Exposure Duration 28 vks 28 wks 28 wks - TABLE III (BTfl). Observation Period 20wks Angiosarcomas Liver (l at later stage). 28uks 0 28 wks 0 2& wks 0 Site of other tumors and types. 1 lymphoma. 0 1 lymphoma 0 Reference ( 3s)) (3<j) (3$) (3`J> R&S 113391 R&S 113392 TABLE IV (BT3 + BT^) Animals Surviving Rats Exposure concentration weeks Exposure duration weeks. Observation During weeks. Animals with tumors. Ref. Sprague Dawley rats jc 5 It Sprague Dawley rats x 39 Sprague Dawley rats x 59 Sprague Dawley rats x 59 . 500ppm 250ppm 500ppm 250ppm 17 66 1 animal: lymphoma (3*t) 17 66 1 animal; - (33) nephroblastoma !| animals: 52 66 1 hepatic angio sarcomas - 3 <3?j) other types. 3 animals: 52 66 2 hepatic <3V) angiosarcomas - 1 other type jd studied. Exposure duration (range in years.) Exposure concentration (range in ppms). '3 ils from -t snt. l-2li years 2000 -80 ppm TABLE V Chromosomal Effects Significant' increase in breaks over controls. . ginal :S .ed ears later -Is from ;e plant. 1-26 years 2000 -00 ppm initially. 00 - lppm during the subsequent 2 to 2.5 yrs. No difference between study group and controls. rs ols ng of esenting mployment ous ^ No f exposure somal agents. l-20years Estimated as 12 -< lppm 9-29 years 20-30ppm at a. Lime of study but presumably higher in earlier years No significant difference between exposed group and controls. Significant difference between exposed group and controls. Comments Conclusions Ref. Comparison of the Vinyl Chloride Monomer is control groups mutagenic though a dose indicated similar response function could rates of chromosomal not be derived. breaks in both groups 27 * Vinyl Chloride Monomer at low doses may not induce changes. lit The highest frequency No conclusions can be of abnormal cell3 was drawn from this study observed in those as the groups are too with the shortest small. exposure. 2 cases did not vary from controls. 16 R&S 113393 TABLE V (continued) R&S 113394 E^xposure Lion studied. duration (range in years.) Exposure concentration (range in ppms) Chromosomal Effects Comments Conclusions Ref. iiers polyrhloride, rutory rs. ' side plant .)ls. 1-17 years (average 6-5 years). +500 ppra 2-15 years estimated (ave rage maximum 50ppm 9-5 years) -- A significant Increase was not observed jo either exposed groups. The severity of the lesions observed wns greater in the polyvinyl chloride workers than in the laboratory workers. All those exposed in polyvinyl chloride industry had been exposed to X-ray examinations in the recent past. /vinyl ride workers vinyl ride workers ufacturiug -ols .'vinyl ride workers t. rols plant - 6 if plant) 16-29 years (ave rage 2hyears). 21-29 years (ave rage 26years) 9-36years (average 25 years) l(-28years (average 15 years) "High" "Low" An increased frequency of breaks was observed In the three groups as compared with the control cases. There was little difference in the frequency of breaks between the three groups. none to vinyl chloride,but exposure to other chemicals occurred. none 500ppm or more. A significantly higher frequency of unstable , . changes was observed^ Break age rates did not vary with duration of exposure. This is a snail study group. The risk of such changes occurring a3 a result of exposure to vinyl chloride is low. 35 These results confirm that vinyl chloride monomer may be one of many causes of cytogenic damage. 21 These results indicate that vinyl chloride induces mutagenic effects. 12 :tion studied josed workers Exposure duration (range in years). 'Exposure concentration (range in ppins). ^ticlave kers. (ave rage) Ranges -- 10-7years c and Kr rS I chloride ators. (average) 1000-300ppm 32-7 years (19< 5-1970) (average) 6-3 years yvinyl ride cenance (average) 15-5 yrs 15-5 ppm (thereafter) TABLE V (continued) Chromosomal Effect Comments %H Conclusions Ref. 1 A significant increase was observed in the exposed groups as compared with the controls. Those with a history of short term exposure to the excursion values hod a higher percentage of abnormal cells. A positive The results indicate correlation was that vinyl chloride observed between induces mutagenic duration of employ- effects in exposed merit; smoking and workers. exposure to excursion values. 50 1 chloride tenance (average) 6-1 years illaneous . rols (average) 6-6 years - .er3 ynip toms) wn ure ored ure rols. not stated. 1000-150 ppm (assumed) 28 -< 1 ppm * No significant difference between exposed and controls. An increased rate of chromosomal aberrations was observed only in those with symptoms of vinyl chloride illness, (b it'S ymptoms ritrol A significant difference between workers with symptoms and control group. B&S 113395 R&S 113396 APPENDIX 1 R&S 113397 Calculation of an Acceptable Concentration of Vinyl Chloride In Air In che Workplace Daca The results of several animal experiments involving the Inhalation of vinyl chloride were used In these calculations. The-exposed animals were made up of six exposure groups of approximately equal numbers. Exposure levels were 50, 250, 500, 2500, 6,000 and 10,000 ppm of vinyl chloride. The control animals and all of the exposed animals were observed for the same time. In che case of che Sprague-Davley rats, which were exposed for 52 weeks, the animals were observed until all had died and, in all other eases, survivors were present at che end of che observation period. The daca used in the cal culations are in Appendix 2. and a more complete description of the experiments Is contained in reference 1. The data contained in reference 2 consisted of results obcained from animals which were sacrificed long before the end of their natural lives as well as results obtained from animals which were allowed to die naturally. Since, in the published reports, the results from the two groups were combined, any calculation based upon the data would under-estimate tumour risks. Hence, the data were not used. Methods of Results The relative frequencies of specific tumours in control animals and in all animals exposed to vinyl chloride were compared. Table 1 contains the probability that che tumour frequencies in control and all exposed animals were the same. Comparisons which were not statistically significant at che 5Z level were not reported. Also, the relative frequencies of specific tumours in control animals and in animals in the lowest exposure level were compared. Statistically significant differences at the 1Z level were found In Swiss Mice for mammary ,carcinoma, angiosarcomas of sices other chan liver and-ocher vascular tumours, and also all tumours. In all ocher cases, there were no statistically significant differences in tumour frequencies in control animals and in animals exposed to the lowest exposure level. Two methods were used to make estimates of the excess tumour risk factor. In che first method, it was assumed that the excess tumour risk corresponding to vinyl chloride concentration, C, was less than the risk,R, calculated using Che following formula: R * Ro x C Co where. Ro upper confidence limit of the excess tumour risk corresponding to vinyl chloride concentration Co. Co highest vinyl chloride concentration at which no excess tumour risk was discernible (no effect level). Excess tumour risk was che fraction of exposed animals which developed che tumour during the experiment less che fraction of unexposed animals which developed che tumour during the experiment. 2- The upper 957. and 99% confidence limits of excess tumour risk were used. The upper 957. confidence limit and the upper 997, confidence limit were calculated so that the probabilities chat the excess risk was, in fact, higher were 57. and 17. respectively. The factors Ro/Co were calculated when the tumour frequencies in control animals and in all exposed animals were statistically significantly different. Calculations concerning the risks of Zymbal Gland carcinoma were not reported because such glands are not present in humans. Table 2 contained the upper 95% and upper 99% confidence limits on excess tumour risks per ppm of vinyl chloride based upon the data observed at Che no effect level. In the second method, it was assumed chac the excess tumour risk depended linearly on Che concentration of vinyl chloride in air when the concentration was sufficiently low. Unweighted linear regression calculations were made in order to fit the observed excess risk to the following equation: R = AxC+B where R Excess tumour risk at vinyl chloride concentration C A Calculated slope of the regression line (excess tumour risk* per ppm of vinyl chloride). B Calculated intercept of the regression line (excess tumour risk at 0 concentration of vinyl chloride) C Vinyl chloride concentration in air (ppm). The calculations were made when the tumour risks in control animals 'and in all exposed animals were found to be statistically significantly dif ferent. As vill be shown later, the linear dose response function applied only over the lower dose ranges and therefore risk estimates derived from higher exposure groups that did no longer satisfy a linear dose response function were omitted from this calculation. The calculated slope of the regression line was an estimate of the excess tumour risk per ppm of vinyl chloride and the calculated intercept of the regression line was an estimate of the excess risk at zero vinyl chloride concentration. If the Intercept was not statistically significantly different from 2ero and the slope of the regression line was statistically significantly different`from zero then the data were compatible with a linear risk function with no threshold. A negative intercept which was statistically significantly different from zero together with a slope which was statistically significantly different from zero would indicate chat the data were compatible with a linear risk function with a threshold. In no case was the calculated intercept negative and statistically significantly different from zero. For mammary carcinoma in Swiss Mice, the Intercept was positive and statistically slgnlflcancly different from zero and the slope was not statistically significantly different from zero. R8tS 113398 3 Table 3 contained the calculated slopes of the regression lines and their upper 997. and 957. confidence limits, the range, of concentrations used in the calculations, the probability that the slope was zero,and the probability that the intercept was zero. The results were reported only when the slope of the regression line differed significantly from zero. The 957. and 997. upper confidence limits were calculated so that the probabilities thac the slope is in fact higher chan the upper confidence limits were 57. and 17. respectively. Figures 1 to 4 contained, plots of the regression Lines, 957. confidence limits of the regression line, 957. confidence limicd for data points'around the regression line, and the data points used in the regression calculation. It was apparent that tumour risks at "high" concentrations of vinyl chloride were not compatible with the linear regression line calculated from the risks observed at "low" concentrations. The following non-linear function was used in order to fit the observed tumour risks over the range of concentra tions used in the experiments. 66eVV R= jC vKxDr\ xAa xe-BxD LK x D if A x e -BxD -BxD if A x e <1 >1 where R * excess tumour risk D - concentration of vinyl chloride (ppm) K * slope of risk function calculated from risks at "low" concentrations of vinyl chloride A and B were fitted constants and Awas subject to the restraint that A must be greater than or equal to 1. In this non-linear risk function, che factor KxD represents the tumour risk at vinyl chloride concentrations D; the second factor, Axe~Bx^, represented the fraction of cells surviving the exposure to vinyl chloride concentration D; the restraint Axe"BxD>l indicated a range of concentrations at which no significant cell-killing occured. This risk function increased linearly at "low" concentrations, reached a maximum risk, and as concentration increases further, che risk function decreased. The function was fitted separately to che excess risk of liver angiosarcoma and to the excess risk of all tumours in Sprague-Dawley rats and in Swiss Mice. The risk of liver angiosarcoma in Sprague-Dawley rats was com patible vithche non-linear function. See figure 5. In the ocher cases, the data and che risk function were not compatible. 4 Calculation of an Acceptable Air Concentration of Vinvl Chloride The upper 99% confidence limit of the excess tumour risk factor 1 which was derived from the data observed at the no effecc level in SpragueDawley rats exposed to vinyl chloride for 52 weeks was used to calculate Che acceptable air concentration of vinyl chloride. This particular value was selected because it alone,among all the calculated upper confidence 1 limits of the excess tumour risk factors, was derived from data which rep resented lifetime tumour risks and also because it was derived by using * the more conservative approach which used data observed at the ,po effect 1 exposure level. The numerical value thus derived was 4.3x10*2 excess tumours per animal per ppm of vinyl chloride. In order to obtain the risk factor for humans, it was necessary to make an assumption. It was assumed chat the lifetime tumour risks were the same in man and the Sprague-Dawley rat when the same fractions of each species average lifetime were spent exposed to the same concentration of vinyl chloride in air. In this calculation, the average lifetime of the rat was taken to be 2 years(5). The fraction of the average lifetime spent in exposure by the Sprague-Dawley rat was calculated to be: 4 hrs/dav x 5 davs/week x 52 weeks = 6.0 x. 10 24 hrs/day x 7 days/week x 104 weeks The excess tumour risk factor when the duration of exposure was an average lifetime was calculated to be 4.3xl0~^ 7.2x10"^ per ppm of vinyl chloride in air. 6.0x10*2 The annual exposure duration for a worker was assumed to be 8 hours per day, 5 days per week for 52 weeks and the worker's average lifetime was taken to be 70 years. Hence, the fraction of an average lifetime spent in exposure during the course of one working year was calculated to be 8 hours/day x 5 days/week x 52 weeks 24 hours/day x 7 days/week x 52 weeks/year x 70 years 3.4x10"^ Hence, the lifetime risk when the exposure duration was 3.4x10"^ of an average lifetime was calculated to be R&S 113400 3.4x10" x 7.2xl0~ per ppm * 2.4x10" per ppm When the workers are exposed year after year to the same concentration of vinyl chloride, the annual risk resulting from the exposure will increase in successive years and approach a maximum value which Is equal to the lifetime risk from the exposure accumulated over one working year. Hence, the annual excess tumour risk for persons who are continually in exposure In che workplace to air containing 1 ppm of vinyl chloride will increase towards a maximum value of 2.4x10"^ per person or 24 excess tumours per year among 100,000 workers. I The annual acceptable risk for a worker was obtained by using the data of che International Commission on Radiological Protection (4; paragraphs 60 and 104) and was calculated to be 5x10"^ or 50 excess deachs per year among 100,000 workers. i Based upon che results of the above calculations and based upon the assumptions made, it was calculated chat chronic exposure in the workplace to air containing 2 ppm of vinyl chloride produced an annual excess risk,of at most ' 5x10'op 50 excess tumours per year among 100,000 workers. 3 R&S 113401 Discussion of Extrapolation Procedures Ac Che present clme, it appears chac chere is no completely satisfactory method of extrapolating tumour risks from the concentrations used in experiments to lower concentrations (3). The methods used in this report represent- the types of approach currently being used to extrapolate experimental data. In the first approach, Che calculation uses the risks observed at the no effect level. The no effect level is the highest concentration at which no excess tumour risk is discernible. The slope of the non-threshold linear function which passes through the upper confidence limit of excess risk at the no excess level is an estimate of the risk factor when the concentration of vinyl chloride is low. The effect of choosing the highest exposure level at which there is no discernible excess risk is to choose the smallest risk factor which is compatible with the data in a single exposure group. In Che second approach, it is also assumed chat the risk function is linear. In contrast to the first method, the data in several exposure groups are used in the calculation of the risk factor. In this approach, the hypothesis chac chere was no threshold could be tested when daca from several exposure groups were used. It must be pointed out chac many different risk functions would be compatible with the observed data and would provide very different estimates of the risk at low concentrations of vinyl chloride. Hence, the second approach is considered to be less conservative chan the previous one. The third approach attempted to show that the data.at all the exposure levels were compatible with a single risk function. When the results of the animal experiments were extrapolated to man, a number of additional assumptions were made: tumour risk increases in proportion to the duration of daily exposure; no adjustment for differences in species size is necessary if the exposure level is measured in terms of concentration in inhaled air; tumour risks are equal in two species when the same fraction of each species lifetime is spent exposed to equivalent exposure levels. In addition, these calculations do not take into account many ocher aspects of extrapolation between species which may be important (3). Summary , The calculation of the acceptable concentration of vinyl chloride in air in the workplace Was based upon the data observed in che Sprague- Dawley rats which were exposed for 52 weeks because chose daca alone represented lifetime risks resulting from chronic exposure over a sufficiently long period of time. The risk factor was calculated by using the data observed in Che control animals and in the animals exposed to the highest concentration of vinyl chloride at which there was no discernible excess tumour risk. This approach provided a more conservative estimate of che risk factor than chose approaches which used the data from several exposure groups. In Che calculation of the acceptable concentration of vinyl chloride in che workplace, several assumptions ve.re made. It was assumed that Lifetime tumour risks were the same in man and in the Sprague-Dawley rat when che same fractions of each species average lifetime were spent exposed to the same concentration of vinyl chloride in air. It was assumed that there was no threshold concentration of vinyl chloride below which chere would be no associated risk and that the relationship between air concentration of vinyl chloride and excess tumour risk was linear. The exposure duration for a worker was assumed to be 8 hours a day, 5 days a week, 52 weeks a year for a working lifetime. The acceptable annual risk was taken to be 50 excess tumours among 100,000 workers. Based upon the above assumptions che acceptable concentration of vinyl chloride in che air in the workplace was calculated to be 2 ppm. R&S 113402 -6 Conclusions: Based upon the calculations made and the assumptions stated, the acceptable concentration of vinyl chloride in air in the workplace is 2 ppm. 1 s 1 References 1, The Value of Predictive Experlmencal Bloassavs In Occupational and Environmental Carcinogenesis: An Example: Vinyl Chloride. Cesare Maltoni, Arabto, Vol 4, No l, 1975. 2. Carcinogenicity of Vlnvl Chloride and Vlnvldlne Chloride. C.C. Lee et al, Journal of Toxicology and Environmental Health, 4, 1978. 3. Estimation of Risks of Irreversible Delayed Toxicity, David G. Hoel ec al, Journal of Toxicology and Environmental Health, 1, 1975. 4.. Recommendations of the International Commission on Radiological Protection. Publication 26, Pergamon Press, 1977.5 5. The Rat Reference Tables and Data for the Albino Rat (Mus Norvegicus Alblnus)and The Norway Rat (Hus Norvegicus) H. N. Donaldson (editor), Philadelphia (1915). R&S 113403 M)m i- ssu H1 -'ABLE l; Comparison of Tumour Frequencies In Control Animals and In Animals Exposed to Vinyl Chloride in Air Experimental Animal Exposure Time(wk) Observation Time (wk) (l) Type of Tumour Probability of No Difference in Tumour Frequency in Exposed(2) Animals and Unexposed Animals Sprague-Dawley Rat 52 135 Zymbal gland carcinoma Nephroblastoma Liver Angiosarcoma .All tumours -2 1.07x10 1.75x10"* 5.33x10"* 8.87x10"' SpraRue-Dawley Rat 17 86 Zymbal gland carcinoma Brain neuroblastoma All tumours 8.95x10"2 1.38x10 1.31xlO-5 Swiss Mice 30 61 Liver angiosarcoma Pulmonary tumours Mammary carcinoma Vascular tumours of Other Types or Sites Epithelial Tumours of the Skin All tumours l.BBxlO-8 1.09x10-29 2.06x10"* 8.19x10"13 9.12x10"J 1.42xIO"J Golden Hamster 30 48 All tumours 1.98xl0"12 3 TES: (1) Observation time was the same for exposed and unexposed animals. (2) Exposure levels were 50,250,500,2,500,6,000 and 10,000 ppm of vinyl chloride in air (3) Results are reported when the probability of no difference between exposed and unexposed animals was less than 0.05. (A) Probabilities were calculated using the Flsher-Irwln exact probability method. Ak taa c imsb 'mm mk & I2& ^ lp SM fsa^is ^ lit Excel s Risk Factors forTn halation ot vtnyl un lor file; Results obtained Using A Single Exposure Croup R&S t13405 Experimental Animal Sprague-Daw ley Rat Exposure ObcervatIon Type of Tumour Time (wk) Time(wk)(1) 52 135 Nephroblastoma Liver Anglosarcoma All Tumours No Effect Observed Excess Level(ppm) Risk per ppm 50 3.4x10*2 50 3.4xl0-4 50 1.3x10 J Upper Confidence Limit on Excess Risk per ppm 957. 991 -I.6xl0~3 1.6xl0"3 2.1x10*3 2.lxlO*3 3.4x10*3 4.3xl0-3 Sprague-Dawley Rat 17 66 Brain Neuroblastoma All Tumours 500 0 500 4.6xlO"5 9.7xl0'5 l.3xl0"4 l.5xl0"4 l.6xl0"4 Swiss Mice 30 61 PulmonaryTumoura 50 -2.2xl0"4 Mammary Card- noma Liver Angiosar coma Angiosarcomas Other than Liver or Ocher vascu lar tumours 50** 50 50** 3.5x10"J 3.5xl0"4 3.9xl0~3 - Epithelial Tumoura of Skin All Tumours 250 50** 0 4.9xl0*3 5.2xl0~4 5.6xl0"3 1.6xl0*3 6.0xl0*3 8.2xl0-4 6.4xl0*3 2.2xlO"3 6.9xl0"3 2.0x10 6.9x10 3 3.0x10*2 7.8xlO_J Golden Hamsters 30 48 All Tumours 50** 2.6xl0"3 -3 4.6x10 5.5xlO~3 :ES: (1) Observation times for both exposed and unexposed animals were the same. (2) Results are reported only where there Is a statistically significant difference between exposed and unexposed animals (See Table 1). Results concerning Zymbal Gland carcinoma are excluded. (3) 957. and 997. upper confidence limits are calculated so that the probabilities that the excess risk per ppm Is In fact higher than the upper confidence limit are 5% and 1% respectively. (9) ** Indicates that there is a significant difference In tumour frequency between control gr up and lowest exposure group. fcaae* ~ 3; Risk Factors for Inhalation of Vinyl Chloride: Significant Results of Linear Regression Calculations R&S 113406 :>er lmental imal Exposure Time(wk) Observation Tlme(uk)(1) Type of Range of Concen Tumour trations Used in C aleulation(ppm) Slope of ReRegression Llne(Exceas Risk per ppm) Probability that Slope Is Zero Probability that Inter cept Is Zero Upper Conf .deuce Limit of Slope o : Regression Lin< i 95% 99% agueley Rat 52 .agueley Rat 17 135 Liver 0-500 Anglo- coroa Brain Neuro blastoma 0-10,000 All Tumours 0-500 Brain 86 Neuro 0-10,000 blastoma 2.4x10"*' -5 1.1x10 -4 5.1x10 9.2xl0"6 <0.01 >0.20 <0.02 <0.02 < 0.001 >0.50 >0. 20 >0.50 2.7x10"^ 3.2xlO_i| l.6xl0""* 6.9x10"** 2.0xl0"5 9.5xl0"4 1.2xl0"5 -5 1.3x10 (1) Observation time was the same for exposed and unexposed animals. (2) 95% and 997. upper confidence limits are calculated so that the probabilities that the slope Is In fact higher than the upper confidence limits are 5% and 1% respectively.3 * (3) Results are reported when the slope of the regression line is statistically significantly different from zero (p <0.05). EXCESS R IS K PER RNIMRL fig.I:EXCESS RISK OF LIVER RNGIOSRRCOMR IN S.D. RRTS:52 Wk EXPOSURE WITH 8SX COHFIBEHCE LIMITS * PPM OF VINYL CHLORIDE EXCESS R IS K PER RNIMRL R&S 113408 f1g.2:EXCESS RISK OF BRRIN NEUROBLRSTOMR IN S.D. RRTS:52 Wk EXPOSURE HITH 95* CONFIDENCE LIMITS PPM OF VINYL CHLORIDE a Ibhs9 fig.3:EXCESS TUMOUR RISK IN S.D. RRTS:52Wk EXPOSURE WITH 95X CONFIDENCE LIMITS is EXCESS R IS K PER RNIMRL PPM OF VINYL CHLORIDE R&S H3409 EXCESS R IS K PER RNIMHL R&S 113410 f 1 g . 4 : EXCESS RISK OF BRRIN NEUROBLRSTOMR IN S.D. RRTS:1? Wk EXPOSURE HITH 95X CONFIDENCE LIMITS PPM OF VINYL CHLORIDE Ossa lli^ fig.5:EXCESS RISK OF LIVER ANGIOSARCOMA IN S.D. RATS:52 HU EXPOSURE HITH 35 I. S9X CONEIOENCE LIHITS ON EXCESS RISK EXCESS R IS K PER RMIMRL PPM OF VINYL CHLORIDE R&S H3411 I R&S 113412 APPENDIX 2 > f.bl. 1. 8TI: Raiuiu .11.r 111 Hki (*n<l ol lh .ip.ilm.m) Antfflfli witn lumer* Treatment (*) VC iMOO oom VC MOO bo* VC 2304 esm VC too earn VC 230 oom VC M asm he irseiment Total Animal* (Sprague-Oawlay riu) ZymOsl gland carcinomas (c) Nephrobiaatomas (4) Tal.l 9 V 74 47 v 34 44 in Cor rected number <*i 41 40 59 fg 33 59 *44 * Average latency No. (d) time No. (weeks) il Z! !2 2J j7 ---- ---- 30 42 n -- -- 1 1 4 1 t 29 - - 28 V# (d) n <g r to 2 -- Average latency time (weeks) 59 71 43 40 :35 No. 9 <3 13 4 1 - 1* Angiosarcomas Uv*r (0 Average latency time (weeaa) 1 * 1 a :2 '7 i: :% 2 ' m Other tiles NO. 3 f'* 3 >0 3 m1 2 111 2 mi l .n) Sub* cutane Skin ous carclangto* nefflii mss NO. No. < 1 3* f -- t 3 1 1 1 4 1 -- - 14 2 It Hepe* toms* Brsm Qm*r type newro* no/or btaaio* mas ni* (g) No. No. No. : V - to) 1 i 3 91 2 i * :c) 3 -- ''i -- _ ; i -- -- ) -:t -- to j \ / 3 43 r.tal (h) NO. 31 31 32 n t 10. tu (a) Tho animats wero treated by inhalation for 4 hour* daily. S day* weekly, tor S3 Htu. (b) Animals alive after 39 week*, when the first tumor (a Zymbai gland carcinoma) wai observed. The percentages art referred to the correctad number. (c) MstastasM to lung. (d) Percentage of corrected number, (ej Metaststes to liver, lung, apteen and brain. jf) Metaataaea to iung, (gj Several caaea ot breaat fibroadenoma*. adrenal and pituitary tumor* (generally adenomaa) have not been considered, since thsif distribution m tba different group* com not vary. h) Several ammala with 2 or more tumor*. i) 1 angiosarcoma of the lies; 1 angiosarcoma of the nose: 1 mtra-ebdo* mtnai angiosarcoma (neat to liver). (j) \ angiosarcoma n aubcuianedua Hbroatng angioma; 1 ossifying parau't* cuiar angiosarcoma; t intra*abddmlnal angioaareoma (neat to liver). (k) 2 intra-aodomtnaf angioaarcomaa (i neat to spleen and I next to ovary): 1 ossifying angiosarcoma- of the nee*. (l) i pulmonary angiosarcoma; f angiosarcoma of ;ne utarus. (m) i mtfi'iscominai angiosarcoma (neat to spleen): i intrathorsetc ossify* mg angjosareama. fn) t (ntra*4sccminal diffused angiosarcoma, (O) 2 Zymbai gtand aevnomaa: 2 mammary carcinomas:/1 neurifemmomu* i ovarian C/ttoadanocarcinoma. (p) 4 Zymoai gtand adenomas: l salivary gland adenocarcinoma: 2 hopstfc and l ;sn:?nai angiomas. (d) \ Zymbai gland adenoma; t mammary carcinoma; 2 eoendymomaa. (0 1 mammary carcinoma; 2 lymphomas: 1 oulmonary fibrosarcoma. (s) 1 Zvmoat gtand idanoma: 1 mammary carcinoma; 1 iymonoma. (t) 3 Zymaal gtand adanomaa; 2 mammary carcinomas: t subcutaneous angtopareitoma; 3 uterine adenocarcinomas (1 with sarcomatous compo* nent). (u) t -nvaiive acanthoma of ZymbaJ gland: 1 subcutaneous fibrosarcoma: 2 cantonal vbroangiomaa. 3 uterine adenocarcinomas (1 w*m sarcomatous component) i uterine leiomyoaareoma; i ovarian fibrosarcoma; 1 put* monary rhabdomyosarcoma; t Iymonoma. Table t Experiment 8T3t Aeaultt after 89 weeks Treatment () VC 10000 ppm VC MB* m VC 13OQ ppm VC 100 asm VC 130 opm VC U asm No trsetmenl Tom Number el MiiMii (3prsgve*Otiwtey rstil Tats) Survi vors 30 9 40 13 0 33 00 V a 13 0 14 IW <ii 550 no Zymbai gtand carcinoma# 4 (181 * ( T) < ( 11 - -- -- H UH Nephrobla stoma# -- <: n -- 1 4) 11 4| -- f 21 ( i -- : n Number of animals with tumor* (b) Urr Angiosarcoma# OlKw III*. Brain neuro* btamtomss -- ' 1 -- 'Hi -- ( ) -- f 31 -11) -- -- -- 'Ml < ') ( 3) - I 3) - ( 3) - ( 1) - 1 i) < in -- 1 MJ) 0f n 2 ( 31 : i i) -- -- <0 (12) Other type and/or alto (e> Tsui l) 3 Ml S) 1 (m;) -- 1n 1 (it ( .1 1 HI ( 11 -- ( 3) 3 IV) ( 3) <1 MV) 3 ( *0) 10 ( 27) 1 ( at I ( 13) ill) 1 ( 3) 3 ( 2) M (<17) ` (a) Tho animals were treated by inhalation 4 hours daily. S hour* weofcty. for 17 weeks. (b) Between bracket* are recorded the tumor* found in experiment 0T1 after M weex*. (C) Several cases ol breast fibroadenomas, adrenal and pituitary tumors (generally adenomas) heve not been considered, since their distribution in the different groups does not very. (d) Several animats with 2 or more tumors. () < subcutaneous angiosarcoma. (0 i orbital angtcsarcom*. fg) 1 osraurfcwiar fibrosarcoma; 1 nasal papilloma: 1 renal adenoma. (h) t Zymoai gland fibroangioma; 2 sum carcinomas; t subcutaneous n* gtoma: i mammary carcinoma; t loreatomacn paoiMoma; t oraniai osteoma. (i) 2 lymonorras. (j) 1 Zymoai gtanc adenoma: t retrobulbar fibroma, (k) t Zymcst gtand adenoma; 3 lymphomas. R&S 113413 Table 3, Experiment BT7: Result* after <1 weeks Treatment (a) VC 10000 ppm VC uoo ppm VC 2500 ppm vC NO pam VC U0 pam VC 50 ppm He treatment* Telit Number of animals (Wtitsr ratal Total 3b 30 W CO 20 30 40 250 Survi vor* 8 13 S 18 18 22 34 117 Zymbat gland carcinoma* - ( 7) -( ') -( 1) - ( '1 . Nephrobia- ~ stomas < (3) -- (!) - (') Number of animal* with tumor* <bt Angiosarcomas Uver ' Other sites 0i 11 1 neuro blastoma* 1 (3) - (1) -(!) 1 --. -O) - (') -d) _ !W - (1) -- _ -- (101 1 (S) 3 f*l . _f.) <3) (a) Hie ammeis wers treated by inhalation for 4 hours daily, 5 days weekly, for 32 weeks. (b) Between brackets are recorded the tumors round M male Sprague* Oawiey rats ot the experiment STi, after 71 weens. (c) 2 Zymbai g'jnd adenomas, (d) 1 angioma of the caecum. . m . . . ? i Other type and/or site 1 to F) -- (1) - ItJ 1 (0) _ 3 (V) Total j i<) -- < i) -- ( 1 C i) 1 7 (33)