Document MJgMZovqxrRbOw0wkYeDxj527

n DRAFT j-s. r\ D L' DRAFT CRITERIA DOCUMENT FOR VINYL CHLORIDE o 0 FEBRUARY 1984 HEALTH EFFECTS BRANCH CRITERIA AND STANDARDS DIVISION OFFICE OF DRINKING WATER U.S. ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460 SL 110855 0 TABLE OP CONTENTS Page I. II. III. IV. V. VI. VII. VIII. IX. X. XI. SUMMARY 1-1 INTRODUCTION II-l PHYSICAL AND CHEMICAL PROPERTIES III-l PHARMACOKINETICS IV-1 A. Absorption IV-1 B. Metabolism IV-5 C. Excretion IV-8 HUMAN EXPOSURE* V-l HEALTH EFFECTS IN ANIMALS VI-1 A. Acute/Chronic Effects VI-1 B. Teratogenicity VI-3 C. Mutagenicity VI-4 D. Carcinogenicity VI-6 HUMAN HEALTH EFFECTS VII-1 A. Non-Carcinogenic effects VII-1 B. Carcinogenic effects VII-6 MECHANISM OF TOXICITY VIII-1 RISK ASSESSMENT IX-1 QUANTIFICATION OF TOXICOLOGICAL EFFECTS X-l REFERENCES XI-1 Prepared by the Science and Technology Branch SL 110856 EPA's Carcinogen Assessment Group (CAG) have recently recalculated their excess carcinogenic risk estimates resulting from lifetime exposure to vinyl chloride through the drinking water. CAG based their preliminary revised risk estimates (1984) on the Feron et al.(1981) study. The total number of tumors, considering tumors of the lung and liver, in rats exposed through the diet were used to calculate the excess cancer risk. They calculated that consuming 2 liters of water per day having a vinyl chloride concentration of 1.5 ug/1, 0.15 ug/1 and 0.015 ug/1 would increase the risk of one excess cancer per 10,000 (10~4), 100,000 (10"5) or 1,000,000 (10"6) people exposed, respectively, per lifetime. SL 110857 I. SUMMARY Almost 7 billion pounds vinyl chi rid nr produc d* in the United States annually. Most emissions into the environ ment originate from manufacturing plants Which use the compound f r the production of polyvinyl chloride resins. The predomi nant route of exposure to the public living near these plants is through inhalation* While the principal source of vinyl chi ride exposure for most Americans is probably from polyvinyl chi ride food containers. This source contributes approximately 1 ppb to the diet. Vinyl chloride has also been found in drinking water. Three national surveys of drinking water have demonstrated the presence of vinyl chloride at very low levels (ug/1 range) in a small number of supplies. Upon ingestion, vinyl chloride is rapidly absorbed from the gastrointestinal tract and is distributed to the liver and ther organs. Several pathways may be involved in vinyl chloride metabolism, which occurs primarily in the liver. The toxicity f vinyl chloride appears to be attributable to its enzymatic c nversion to reactive polar metabolites such as chloroacetaldehyde or tihloroethylene oxide. Several of these suspected meta bolites are mutagenic. While vinyl chloride itself is not, accord ing to available information. At low doses (e.g., 1 mg/kg) the metabolites of vinyl choride are primarily excreted in the urine. SL 110858 At high dos a (e.g.* 100 mg/kg), moat of tha advent ia expired aa vinyl chloride. Acute and chronic expoaure to vinyl chloride can reault in toxicity in experimental animale and humane. In animals, an inhalation expoaure of approximately 100*000 ppm reaulta in death within aeveral hours* with autopsies revealing c ngeation and edema of the lungs and hyperemia of the kidneys and liver. Test animals exposed to an inspired air concentration below 100 ppm exhibit no pronounced adverse health effects. Vinyl chloride does not appear to be terato genic in rats or rabbits* and insufficient data exists to evaluate the teratogenicity of vinyl chloride in humans. Studies on humans working ih vinyl chloride plants sug gest that systemic toxic effects that are noncarcinogenic in nature can be demonstrated at exposure levels below 50 ppm. Some plant workers may have been exposed to concentrati ns exceeding 1000 ppm and occasionally approaching 10*000 ppm before OSHA standards were instituted in 1974. At these levels* workers manifested dixziness* headaches, and/or uphoria. Long-term exposure to these levels in vinyl chlor ide plants have resulted in a number of diseases (i.e.* acroosteolysis* pulmonary insufficiency)* cardiovascular and gastrointestinal manifestations* and disturbances of the central nervous system. Unfortunately, data regarding SL 110859 1-3 dose-r spons r lationships in humans ar vary scarca because f the virtual absence of air measurements of vinyl chloride in the work environment before 1974. Vinyl chloride is a proven carcinogen in mice, hamsters, and rats. Animal studies have shown that vinyl chloride pro duces tumors of different types at different sites, and that th incidence and relative distribution are influenced by dose, age of the gnifcal, and species and strain of animal used. Angiosarcomas of the liver were found in all animals studied, vh reas some types of tumors such as brain tumors, hepatomas and lung tumors were observed in one type of animal only. A dose-response relationship was observed in most experiments. Inhalation studies have shown the lowest dose of vinyl chloride xposures to have a carcinogenic effect to be 50 ppm. A recent ly completed ingestion study demonstrated the occurrence of hepat ic angiosarcomas and pulmonary angiosarcomas in rats at levels of 5.0 mg/kg bw/day or more, and the increased incidence of foci of cellular alteration and liver cell tumors at the lowest exposure level of 1.7 mg/kg/ bw/day. Human data have been primarily obtained from workers xposed to vinyl chloride. A number of epidemiologic studies have linked vinyl chloride with angiosarcoma and other forms of neoplasm. The reported frequency of angiosarcoma of the liver is especially noteworthy because this is a very rare SL 110860 1-4 type of cancer (25-30 cases/year In the United States), and it is reasonable to infer a causal relationship between exposure to vinyl chloride and the development of this tumor. Through 1977, a total of 64 eases of liver angiosarcoma hav been identified worldwide among vinyl chloride-exposed indus trial workers. Although rare, the carcinogenicity of vinyl chloride to humans is unambiguous. * The International Agency for Research on Cancer (IARC) analyzed the available data and concluded that exposure to vinyl chloride results in an increased carcinogenic risk to humans. The organs most likely to be affected were the liver, brain, lung and hemato-and lymphopoietic systems. The National Academy of Sciences (1983) also examined the data and concluded that vinyl chloride is an established carcinogen in humans and animals with older animals and females appearing to be more susceptible. The National Academy of Science (NAS) and EPA's Carcin ogen Assessment Group (CAG) have calculated projected incre mental excess cancer risks associated with the consumption of a specific chemical via drinking water by mathematical extrapolation from high-dose animal studies. Using the risk estimates generated by the NAS (1977-1979) where the linear non-threshold multi-stage model was utilized, the range of vinyl chloride concentrations were computed that would nomi- SL 110861 1-5 7 nally increase the risk of one excess cancer per million (106), per hundred thousand (10^), or per ten thousand (104) p ople over a 70-year lifetime assuming daily consumption at the stated exposure level. From the MAS model it is estimated at the 95% confidence limit that consuming two liters per day over a lifetime having a vinyl Chloride concentration of 100 ug/1, 10 ug/1 or 1 ug/ would increase the risk of one excess cancer per ^0,000, 100,000 or 1,000,000 people exposed, * r spectively. Using the revised CAG approach and the multi stage model, it was estimated at the 95% confidence limit that consuming two liters per day over a lifetime having a . vinyl chloride concentration of 200 ug/1, 20 ug/1 or 2 ug/1 would increase the risk of one excess cancer per 10,000, 100,000 or 1,000,000 people exposed respectively. The numerical differences observed after utilizing the MAS and CAG risk estimates are due to the selection of data for use i in the model. The MAS based its calculations on an ingestion study by Maitoni et al. (1975) in which rats were exposed to vinyl Chloride by gavage. While the CAG used the same Maitoni t al. (1975) study but based its estimate upon the increased incidence of total tumors in rats exposed to vinyl chloride through inhalation. SL 110862 II. INTRODUCTION Vinyl chloride has bssn used for ovsr 40 years in the production of polyvinyl chloride (PVC), the most widely used Material in the Manufacture of plastics throughout the world. About 251 of the estiMated 18 billion pounds of vinyl chloride produced worldwide in 1972 was Manufactured in the United States (Berk* et al., 1976). Between 1968 and 1973, vinyl r* chloride production in the United States rose 14% annually, reaching a production level of nearly 7 billion pounds in 1978 (U.S. Int. Trade Comm.)* This increase in vinyl dhloride production was due to the growing dependence of virtually very branch of industry and coamierce upon products and components fabricated from polyvinyl chloride (U.S. EPA, 1974). (For the location of vinyl dhloride and polyvinyl chloride manufacturing and processing plants in the United States in 1978, refer to Figure II-l.) Vinyl chloride is not known to occur in nature (National Academy of Sciences, 1977). The compound is synthesized as chi rinated olefinic hydrocarbon monomer from petrochemical fe dstock and chlorine. In 1975, vinyl chloride emissions in the United States were found to originate from three major sourcesi (1) 17 plants Where vinyl chloride was commercially synthesized (about 11 percent); (2) 41 PVC plants where the vinyl chloride monomer was used in the production of PVC SL 110863 FIGURE II-l Locations of Vinyl Chloride and Polyvinyl Chloride Plants in the United States (Milby, 1978) i SL 110864 Vinyl Chloride Plant Location "Polyvinyl Chloride Plant location SOURCE* S1U. 0PUERTO RICO IX-2 resins for various industrial purposes (about 85 percent); (3) about 8*000 PVC fabricating plants (U.S. CPA* 1975b). Vinyl chloride and polyvinyl chloride are used as raw materials in the rubber, paper, glass and automotive indus tries. In addition, vinyl chloride and polyvinyl chloride are used in the manufacture of electrical wire insulation and cables, piping, industrial and household equipment, medical supplies, food packaging materials and building and construction products. Polyvinyl chloride and vinyl chloride copolymers are distributed and processed in a variety of forms, - including dry resins, plastisol (dispersions in plasti cisers), organosol (dispersions in plasticisers plus volatile solvent), and latex (a colloidal dispersion in water used to coat paper, fabric or leather). SL 110865 III. PHYSICAL AND CHEMICAL PROPERTIES The structure of vinyl chloride is as follows: H2C CBC1 Molecular Weight * 62.5 Vinyl tihloride is higlhly flammable (limits of inflamma bility: 4.00-21.70%) and in sufficient concentrations (at least 1200-2000 ppm) has a sweet, pleasant odor. The compound has a boiling point of -13.3*C. Thus, at standard temperature * * and pressure, vin^l chloride exists as a gas. Vinyl chloride is nly sparingly soluble in water (0.11 g/100 g water at 28aC), but is soluble in alcohol and very soluble in ether and carbon tetrachloride. The specific gravity of the chemical is 0.91; thus it would tend to rise to the surface of water. The vapor density of vinyl chloride is slightly more than twice that of air (CRC Handbook of Chemistry and Physics, 1978-1979; Braker and Mossman, 1971). s The above information indicates that vinyl chloride is volatile and readily passes from water into the gas phase under most laboratory and environmental conditions. This was confirmed in experiments where 16 mg/1 vinyl chloride was added to distilled water in beakers and the concentration d termined with time (U.S. EPA, 1974). The data indicate that if first order kinetics are assumed, the volatilization half-life in quiescent water (unstirred) is 290 minutes and SL 110866 III-2 in continually stirred water ia 25 minutaa. Billing, at al. (1975) found aimilar valuaa for tha atirrad water. As Billing, at al., note, predictiona of vinyl chloride Ions from water at relatively high concentrationa (e.g., 1 ng/1) ay not reflect tha aituation at vary low concentrations. Volatilisation appears to be the seat significant process \ in the loss of vinyl chloride fran the aquatic environment (Hill, at al. ,;.1976).. Once in the atmosphere, vinyl chloride undergoes rapid photochemical oxidation (Gay, at al.,1976; Lillian at al., 1975). i SL 110867 IV. PHARMACOKINETICS A. Absorption and Distribution An investigation by Duprat et al. (1977) indicataa that inhalad vinyl chlorida is rapidly absorbed by the lungs and immediately accumulates in tha livsr. In this study, rats were sxpossd in a chamber to 20,000 ppm vinyl chlo rida for 5 minutes, and then the distribution of radioactive vinyl chloride in tha various body organs was determined. After 10 minutes exposure, radioactivity was found in the liver, bile duct, digestive lumen, and kidneys. With increas ing time (up to 3 hours), activity was detected in the urinary system, salivary and lacrimal glands, shin and thymus. Using male Wistar rats, Withcy (1976) determined that vinyl bhloride is rapidly absorbed from the gastrointestinal tract following gastric intubation of aqueous solutions c ntaining up to 2.0 mg/ml vinyl chloride. Vinyl chloride uptake by this route was extremely rapid; peak concentrations were found less than 10 minutes after the dose was administered. In a study by Watanabe et al. (1976a), rats were given single oral doses (gavage) of 0.05, 1, or 100 mg/kg of 14C- vinyl chloride dissolved in com oil, and the routes and rates f limination of activity were followed for 72 hours. The percentage of the dose expired as vinyl chloride was 1, 2, and 67%, respectively. The disposition of vinyl chloride to SL 110868 IV-2 various organs and tissues was also determined. The liver was found to retain the greatest percentage of activity at all dose levels, three to five times the percentage found in muscle, lung or fat (Table IV-1). The investigators concluded that the fate of vinyl chloride following oral administration is a dose-dependent saturable process, with the saturation of the vinyl chloride-metabolizing enzymes occurring at a concentration between 1 and 100 mg/kg. In an inhalation study by this group (Watanbe et al., 1976b), rats were exposed to 10 or 1000 ppm *4C-vinyl chloride for 6 hours and the routes and rates of elimination of 14C activity were followed for 72 hours after termination of exposure. Like the gavage study, animals were sacrificed aft r 72 hours and samples of tissues collected for analysis of 14C activity. Table IV-2 indicates that, similar to the gavage study, the liver retains the greatest percentage of vinyl chloride (or metabolites) at the dose levels studied. How ver, no saturation of vinyl chloride metabolism is discernable between 10 ppm and 100 ppm in this study, in contrast to the gavage experiment. In another report, Bolt et aK (1976) studied the tissue disposition of ^4C-vinyl chloride in rats. Immediately after exposure by inhalation of 50 ppm vinyl chloride for 5 SL 110869 TABLE IV-1 Percentage of the Administered l*c Activity per Gram of Tissue After Administration of,(1*0 Vinyl Chloride by Gavage to Male Sprague-Dawley Bats* (Watanabe et al., 1976a) Tissue Liver Skin Carcass Plasma Muscle Lung Pat 0,.05 Dose (ma/kq)d *L.Ci 0.172 0.025b 0.070 + 0.023 0l`02l + 0.007 0.041 + 0.004 0.028 0.003 0.050 + 0.003 0.030 + 0.004 0.182 0.005 v 0.076 + 0.010 0.046 i 0.002 0.053 + 0*007 0.031 + 0.003 0.061 + 0.003 0.045 0.008 100 0.029 + 0.002 0.010 + 0.002 0.007 + 0.001 NDC 0.006 * 0.001 0.011 + 0.001 0.006 + 0.001 * Remaining in the body after 72 hr. M an + SE* five rats per dose c Not detectable above background d Vinyl chloride dissolved in corn oil SL 110870 IV-4 TABLE IV-2 Percentage of **C Activity per Gram Tissue 72 hr Following an Inhalation Exposure to (1*0 Vinyl Chloride For 6 hr in sale Sprague-Dawley Rats (Watanabe at al., 1976b) Percentage **C activity Exposure concentration Tissue10 ppm1000 ppm Liver 0.139 + 0.009* (0l35)c 0*141 7 -0.009b 0.145 0.008* (9.63)C 0.165 7 0.009b Shin 0.072 + 0.004 (0.18) 0.073 7 0.004 0.115 + 0.010 (7.64) 0.131 7 0.011 Carcass 0.048 + 0.004 (0.12) 0.049 7 0.004 0.049 + 0.004 (3.26) 0.056 7 0.005 Plasma 0.051 + 0.001 (0.13) 0.052 7 0.001 HD*3 Muscle 0.052 + 0.005 (0.13) 0.053 7 0.005 0.038 + 0.003 (2.52) 0.043 7 0.003 Lung Fat 0.065 4- 0.007 (0.16) 0.066 7 0.007 / 0.026 + 0.006 (0.07) . 0.026 7 0.006 0.046 + 0.001 (3.06) 0.052 7 0.001 NDd Kidney 0.079 + 0.003 (0.20) 0.080 7 0.003 0.057 + 0.005 (3.79) 0.065 7 0.006 * Expressed as percentage of total 14C activity per gran of tissue. Oncorrected for expired VC: dpn per o tissue total dpm recovered Mean + SE from four rats. b Expressed as percentage metabolized 1*C activity per gram tissue. Corrected for expired VC: dpm per q of tissue Total dpm recovered minus dpm of expired VC Mean + SE from rats. c Microgram equivalents vinyl chloride per gram of tissue. 4 Not detectable, detection limit for plasma and fat was 3 ug/g of tissue (3ppm) SL 110871 IV-5 hours in a closed system, the percentage incorporated as 14Cradioactivity per g tissue was highest for kidney (2.13) and liver (1.86). The percent of incorporated activity was 0.73 for the spleen and 0.17 for the brain. Forty- ight hours after the beginning of exposure, labeled material could still be detected in these tissues. The percentage .absorption of vinyl chloride from the * ; human gastrointestinal tract has not been established. B cause of the lack of data on percent absorption from the gastrointestinal tract, the risk calculations in this document will assume a 100% absorption factor. B. Metabolism Metabolism of vinyl chloride occurs primarily in the liver by microsomal enzymes. There is strong evidence that the toxicity of this compound is attributable to its enzymatic oxidation to reactive polar metabolites. Several of these suspected metabolites are strongly mutagenic, while vinyl chloride itself is not (Bartsch and Montesano, 1975). Exposure to vinyl chloride leads to the reduction of non-protein sulfhydryl levels in rat liver, suggesting that the metabolites of vinyl chloride conjugate with glutathione and/or cysteine (Hefner et al., 1975a). Hathway (1977) reported in vitro depurination of calf thymus DNA by chloroacetaldehyde identical to that observed in hepatocyte SL 110872 IV-6 DNX following administration of vinyl chlorida to rats in vivo. This soggaata that vinyl tihloride matabolitaa may intaraet with aoma purina and pyrimidina raaiduaa of DNA, providing a poaaibla axplanation for tha onooganic propartiaa aaaoeiatad with vinyl chlorida. In a raviaw of tha litaratura, Bartach and Montaaano (1975) raport two poaaibla bitransformation achamaa - one * involving alcohol dehydrogenase (Schama I) and tha othar involving tha mixed function oxidase system (Schama II). Thaaa ara indicated below* Schama I: Schama II* C1HC-CH2----->C1H2C-CH20H---> C1H2C-CHO--->C1H2C-COOH o C1H*CH2--->LH2C-CHCl3--->C1H2C-CHO--->ClH2C-COOH Evidence for biodagradation involving tha alcohol dahydroganaaa pathway includas data Which demonatrates that pr traatmant of rata with either ethanol or pyrazole (an inhibitor of alcohol dehydrogenaae) inhibita the metabolism f vinyl Chloride (Hefner at al., 1975a). Thara is also ampla evidanca that tha mizad function xidase (MFO) system is involved in the metabolism of vinyl chlorida. Pratreatment of rata with phanobarbital, which which inducas the MFO system, also enhances liver toxicity of vinyl chloride (Jaeger at al., 1974). Rat liver microsomes catalyze the covalent binding of vinyl chlorida matabolitas to SL 110873 rv-7 protein and nucleic acide (Kappus et al., 1975; 1976); chloroethylene oxide, Which ie thought to be formed by the MFO system, nay be the primary microsomal metabolite capable of alkylating these intra-cellular macromolecules (Laib and Bolt, 1977). Several pathways may be involved in vinyl chloride metab olism, the predominant one depending on dose. Hefner et al. (1975) performed an inhalation study in which rats were xposed to vinyl Chloride concentrations ranging from 50.5% to 1167.0 ppm for 12 months time. The rate of metabolism, as determined by measuring the declining level of vinyl chloride in the chamber atmosphere, was three times greater for seven separate exposures ranging from 50 to 105 ppm than it was for five separate exposures ranging from 220 to 1167 ppm. This indicated that the predominant pathway at the lower concentrations, probably involving alcohol dehydrogenase, is saturable between 105 and 220 ppm. This group also found vidence that oxidases in the microsomes may be involved in metabolism at high level exposures* In another study. Bolt t al. (1977) subjected rats to an inspired concentration f 14C-vinyl Chloride ranging from 200 to 1200 ppm in a closed system, and measured the rate of decrease of vinyl chloride levels in the chattber atmosphere. This group calculated that saturation of the vinyl chloride-metabolizing enzymes of the rat is achieved at 250 ppm. SL 110874 rv-8 C. Excretion Excretion of 14C activity within 72 hours following a single oral dose of **C-labeled vinyl chloride (0*05, 1.0, or 100 mg/kg) is shown in Table IV-3 (Watanabe at al., 1976a). As the dose increases, a Markedly greater proportion f vinyl chloride is expired unmetabolixed, While the percent age of metabolite .in .the urine decreases substantially. *' ' t Again, saturation Xinetics are suggested. The table also indicates that Metabolites of vinyl chloride are predominantly excreted via the urine. Administration of vinyl chloride by inhalation produced almost identical results (Watanabe et al., 1976b). Two major metabolites in the urine are identified r# as indicated in Table IV-4. Buchter et al. (1980) examined the metabolic elimination of vinyl chloride in Rhesus monkeys. Rhesus monkeys were placed in a closed exposure system into Which vinyl chloride was inj cted, and air samples taken to determine the decline of vinyl chloride in the gas phase of the system. The results showed that the metabolic elimination of vinyl chloride in Sh sus monkeys is a dose-dependent, saturable process, as in rats. Elimination was shown to obey a first-order law SL 110875 IV-9 TABLE IV-3 Percentage of Administered i*c Activity Recovered Poliowing a Single Oral Dose of Vinyl Chloride8 (Vatanabe et el., 1976a) Dose (mg/Icq) Expired: 0.05 v 1.0 100 jL--^^i As VC As C2 1.43 + 0.13.b 2.13 + 0.22 8.96 7 0.59 13.26 7 0.47 66.64 + 0.67 2.52 7 0.13 Urine 68.34 + 0.54 59.30 2.75 10.84 + 0.95 F ces 2.39 + 0.52 2.20 + 0.39 0.47 + 0.06 Carcass and tissues 10.13 + 1.93 11.10 + 0.47 1.83 + 0.14 Cage wash6 .0 0.84 + 0.45 0 T tal recovery .* 91.25 + 2.47 88.83 + 1.98 82.30 + 0.43 8 Percentage of dose excreted over 72 hr. Only the activity associated with the expired VC can be attributed to VC per se. b Mean + SE five rats per dose. c Distilled water wash of metabolism cage at termination of the study. SL 110876 IV-10 TABLE IV--4 l^C-containing Urinary Metabolites from Male Sprague-Dawley Rate Given Vinyl Chloride by Gavage* (Watanabe et al. 1976a) Compound vDose (mg/kg) 0.05(4)* 1.0(5) 100(5) A) N-acetyl-S-(2hydroxyethy1- cysteine) 30.4 + 2.0C B) Thiodiglycolic acid 25.6 + 1.9 C) Unidentified 38.6+2.9 Total 94.6 36.2 + 3.9 23.7 + 1.1 34.5 + 4.6 94.6 29.1 + 2.0 25.4 + 0.9 36.6 + 2.0 91.1 a Metabolites were separated and quantitated by high pressure liquid chromatography. Values are expressed as percentage of total urinary radioactivity. * ( ) * Number of animals per dose c Mean + SE SL 110877 IV-11 below 200-300 ppm, end At high concentrations the maximal velocity of metabolic elimination'of vinyl chloride was about half that of rats when related to kg body weight. Green and Bathway (1975) measured the excretion of 1*Cvinyl chloride administered to rats by intragastric, intravenous (femoral vein), or intraperitoneal routes. Two d ses were used* 0.25 mgand 450 mg/kg. The results are shown in Table IV-5. During the first 24 hours after treatment, more than 90 percent was excreted from the animals for all three routes. Significant differences were noted, however, in the manner of excretion for the 0.25 mg/kg dose. For the intragastric route, 71.5% was excreted in the urine, whereas 99% was exhaled from the lungs when vinyl chloride was administered intravenously. For the intraperitoneal route, 43.2% was exhaled while 41.5% was excreted in the urine. At the higher dose (450 mg/kg), over 90% was exhaled as vinyl chloride in both intragastric and intraperitoneal administered rats. The intragastric values are consistent with the values reported in the oral studies performed by Watanabe et al., (1976a) (see Table IV-3). Withey and Collins (1976) have developed a statistical model for use in equating oral dose levels of vinyl chloride to inhalation exposure levels in rats, using blood level SL 110878 SL 110879 IV-12 TABLE IV-5 (Green and Hathway, 1975) OP RADIQACTIVnY IN RMS, GIVEN A SINGLE 0Q6E OP l1*01 VINYL CHLORIDE ce each dosed l.g. with 250ug of (1*0 vinyl chloride per kg in com oil solution, and another 4 rats were each llarly with 450 sg of Il4c|vlnyl chloride per kg. 4 rats were each injected in the fssoral vein with 250 ug of 1 chloride per kg in N-(0-hydroayethyl)lactailde. Pour rats were each injected i.p. with 250 ug of (1*C|vinyl per kg in H-iS-hydroxyethyl) lactamtde, and another 4 animals were each injected similarly with 450 mg of 1**01 rids. Time (h) Radioactivity excreted (t of does)* ` ___________________________________________________ Intraaastric Exhaled air Urine Pjpoes Vinyl 002 chloride Intravenous ** Exhaled air ____________ Urine Peces Vinyl chloride 002 Intraperltoneal Exhaled airUrine Vinyl C02 chloride Peoes I 0-24 3.7 + 1.2 12.6 4 1.1 71.5 4 5.0 2.8 4 2.5 99.0 4 0.8 0.1 0.5 0.1 43.2 4 4.6 10.3 4 2.2 41.5 4 4.8 1.6 24-48 0.9 " 3.3 1.6 w 0.T 1.6 0.2 40-72 0.3 0.2 Total 3.7 4 1.2 13.5 4 1.3 75.1 4 4.2, 4.6 4 3.0 99.0 4 0.8 0.1 0.5 0.1 43.2 4 4.6 11.0 4 1.2 43.1 4 5.7 1.8 1 0-24 91.9 4 2.5 24-48 48-72 * Total 91.9 4 2.5 0.6 0.1 0.7 4.5 4 2.3 0.4 0.8 " 0.3 0.1 5.4 4 2.2 0.7 96.2 4 4.1 0.7 - 96.2 4 4.1 0.7 2.5 4 0.9 0.1 0.1 2.6 4 0.9 0.1 shown are the 4 8J>. of IV-13 tints curves. The suth rs conclud d that "if th total daily liquid intake contained 20 ppm vinyl chloride, then the area * g nerated under the blood level tine curve, for rats, would b equivalent to an inhalation exposure of about 2 ppm for 24 hours." Thus, according to this model, inhalation exposure is ten tines more efficient than oral exposure. \ I SL 110880 V. HUMAN EXPOSURE I Humans may be exposed to Vinyl chloride In drinking water, food, and air. Detailed Information concerning the occurrence of and exposure to vinyl chloride in the environment Is presented In another document entitled "Occur rence of Vinyl Chloride In Drinking Hater, Food, and Air" (Letklewlcz et al. 1983). . This section summarizes the pertinent information presented in that document in order to assess the relative source contribution from drinking water, food, and air. Exposure Estimation This analysis is limited to drinking water, food, and air, since these media are considered to be general sources conmon to all individuals. Some individuals may be exposed to vinyl chloride from sources other than the three considered here, notably in occupational settings and from the use of consumer products containing vinyl chloride. Even in limiting the analysis to these three sources, it must be recognized that Individual exposure will vary widely based on many personal choices and several factors over which there is little control. Where one lives, works, and travels, what one eats, and physiologic characteristics related to age, sex, and health status can all profoundly affect daily exposure and intake. Individuals living in the same neighborhood or even in the same household can experience vastly different exposure patterns. Unfortunately, data and methods to estimate exposure of identifiable population subgroups from all sources simultaneously have not yet been developed. To the extent possible, estimates are provided of the number of individuals exposed to each medium at various vinyl chloride concentrations. The 70-kg male is used for estimating intake. a. Water Cumulative estimates of the U.S. populations exposed to various vinyl chloride levels in drinking water from public drinking water systems are presented in Table V-I. The values in the table were obtained using Federal Reporting Data Systems data on populations served by primary water supply systems (FRDS 19S) and the estimated number of these water systems that 1 SL 110881 Table V-I. Total Estimated Cumulative Population (in Thousands) Exposed to Vinyl Chloride in Drinking Hater Exceeding the Indicated Concentration System type Humber of people served in U.S. Cumulative population (thousands) exposed to concentrations (ug/i) of: (thousands) "TITO >5 >10 >20 >3o ~T?o >50 >60 ">70-- Groundwater Surface water Total (% of total) 73,473 140,946 214,419 (100X) 1,063 859 1,922 (0.9%) 591 118 118 118 118 00 000 591 118 118 < 118 118 (0.3%) (0.1%) (0.1%) (0.1%) (0.1%) 118 0 118 (0.1%) 118 0 118 (0.1%) 0 0 0 (0.0%) CO tr* o 0GO0 (sj contain a given level of vinyl chloride. An estimated 1,922,000 individuals (0.9% of the population of 214,419,000 using public water supplies) are exposed to levels of vinyl chloride in drinking water at or above 1.0 ug/1, while 591,000 Individuals (0.3%) are exposed to levels above 5 ug/1. It is estimated that 118,000 individuals are exposed to levels greater than 60 ug/1. Of the approximately 1.3 million people exposed to levels ranging from 1.0 to 5 ug/1, 0.9 million (65%) obtain water from surface water supplies. All exposure to vinyl chloride in drinking water at levels above 5 ug/1 is expected to be from groundwater sources. No data were obtained on regional variations In the concentration of vinyl chloride in drinking water. The highest concentrations are expected to occur near sites of polyvinyl chloride production. Daily intake levels of vinyl chloride from drinking water were estimated -using various exposure levels and the assumptions presented in Table IV-II. The data in the table suggest that the majority of the persons using public drinking water supplies would be exposed to intake levels below 0.028 ug/kg/day. Table V-II. Estimated Drinking Water Intake of Vinyl Chloride Exposure level _ _(ug/l) 2i.o >5.0 >10 >50 >70 Persons using supplies exposed to indicated levels % of Total Population population 1,922,000 0.9% 591,000 0.3% 118,000 0.1% 118,000 0.1% 0 0.0% Assumptions: 70-kg man, 2 liters of water/day. Intake (ug/kg/day) 20.028 >0.14 >0.29 >1.4 >2.0 An indication of the overall exposure of the total population to vinyl chloride can be obtained through the calculation of population-concentration values. These values are a summation of the individual levels of vinyl chloride to which each member of the population is exposed. An explanation of the derivation of these values is presented in Appendix C. Population- 3 SL 110883 concentration estimates for vinyl chloride in drinking water were 1.1 x 107 ug/1 x persons (best case), 1.5 x 107 ug/1 x persons (mean best case), 2.3 x 10 ug/1 x persons (mean worst case), and 2.3 x 10 ug/1 x persons (worst case). Assuming a consumption rate of 2 liters of water/day, population-exposure values of 2.2 x 107 ug/day x persons (best case), 3.0 x 107 ug/day x persons (mean best case), 4.6 x 10 ug/day x persons (mean worst case), and 4.6 x 10 ug/day x persons (worst case) were derived. b. Piet No data were obtained on levels of vinyl chloride found in foods in the United States. Therefore, no estimates of the daily intake of vinyl chloride from the U.S. diet could be made. c. Air Exposure to vinyl chloride in the atmosphere varies from one location to another. The highest level of vinyl chloride reported in the atmosphere was 2,100,000 ng/m3 (2,100 ug/m3) (Lillian et al. 1975 cited in Brodzinsky and Singh 1982). High levels, averaging greater than 15,000 ng/m3 (15 ug/m3), have been detected in other areas. Normal levels, however, are somewhat lower. Brodzinsky and Singh (1982) calculated a median air level of 0.0 ng/m3 (0.0 ug/irr) in each of three types of areas: rural/remote, urban/suburban, and source dominated. The monitoring data available are not sufficient to determine regional variations in exposure levels for vinyl chloride. The daily respiratory Intake of vinyl chloride from air was estimated using the assumptions presented in -Table IV-III and the median and maximum levels for vinyl chloride reported above. The estimates in Table IV-III indicate that the daily vinyl chloride intake from air for adults in rural/remote, urban/suburban, and source dominated areas is 0.0 ug/kg/day. In contrast, the intake calculated using the maximum vinyl chloride level reported is 690 ug/kg/day; few if any persons are believed to be exposed at that level. The values presented do not account for variances in individual exposure or uncertainties in the assumptions used to estimate exposure. 4 SL 110884 Table V-III. Estimated Respiratory Intake of Vinyl Chloride 3 Exposure (ug/nr) Intake (ug/kg/day) Rural/remote (0.0) Urban/suburban (0.0) ^ ) Source dominated (0.0) * Maximum (2,100) 0.0 690 Assumptions: 70-kg man, 23 m3 of air inhaled/day (ICRP 1975). SUMMARY Table V-IV presents a general view of the total amount of vinyl chloride received by an adult male from air and drinking water. Two separate exposure levels in air and six exposure levels in drinking water are shown in the table. Since no data were obtained on levels of vinyl chloride in foods in the United States, the contribution of vinyl chloride in the diet to total vinyl chloride exposure could not be assessed. The data presented have been selected from an infinite number of possible combinations of concentrations for the two sources. The actual exposures encountered would represent some finite subset of this infinite series of combinations. Whether exposure occurs at any specific combination of levels is not known; nor is it possible to determine the number of persons that would be exposed to vinyl chloride at any of the combined exposure levels. The data presented represent possible exposures based on the occurrence data and the estimated Intakes. The relative source contribution data are based on estimated intake and do not account for a possible differential absorption rate for vinyl chloride by route of exposure. The relative-dose received may vary from the relative intake. In addition, the relative effects of the chemical on the body may vary by different routes of exposure. Brodzinsky and Singh (1982) calculated a median urban/suburban air level of vinyl chloride of 0 ug/m3 based on air monitoring data. Assuming an air level of 0 ug/m3, d-inking water would be the predominant source of vinyl chloride exposure all drinking water levels above 0 ug/1. An accurate 5 SL 110885 Table V-IV. Estimated Intake of Vinyl Chloride from the Environment by Adult Males In ug/kg/day (% from Drinking Water) Concentration in drinking water (ug/1) Rural/remote ^ Concentration in air Urban/suburban Source dominated (0.0 ug/m3) ___ J Maximum (2,100 ug/m3) 0 0.0 (-) 690 (0%) 1.0* 0.028 (100%) 690 (<0.01%) 5.0b 0.14 (100%) 690 (0.02%) 10c 0.29 (100%) 690 (0.04%) 50d 1.4 (100%) 690 (0.2%) 7& 2.0 (100%) 690 (0.3%) Intake from each source (see Sections 5.1-5.3): Water: 1.0 ug/1: 5.0 ug/1: 10 ug/1: 50 ug/1: 70 ug/1: 0.028 ug/kg/day 0.14 ug/kg/day 0.29 ug/kg/day 1.4 ug/kg/day 2.0 ug/kg/day Air: 0.0 ug/m:*: 0.0 ug/kg/day 2,100 ug/m* 690 ug/kg/day Food: Not included *1,922,000 individuals using public drinking water systems are estimated to be exposed to levels _> 1.0 ug/1 (0.9% of population using public water supplies). ^591,000 individuals using public drinking water systems are estimated to be exposed to levels > 5.0 ug/1 (0.3% of population using public water supplies). c118,000 individuals using public drinking water systems are estimated to be exposed to levels > 10 ug/1 (0.1% of population using public water supplies). d118,000 individuals using public drinking water systems are estimated to be exposed to levels > 50 ug/1 (0.1% of population using public water supplies). eNo individuals using public drinking water systems are estimated to be exposed to levels > 70 ug/1. 6 SL 110886 assessment of the number of individuals for which drinking water is the pre dominant source of exposure cannot be determined from the data since specific locations containing high concentrations of vinyl chloride in drinking water and low concentrations of vinyl chloride in ambient air and food are unknown. t 7 SL 110887 VI. HEALTH EFFECTS IS ANIMALS A. Acute/Chronic Effects Acute toxicity teats with vinyl chloride were carried ut by Patty et al. (1930) of the Bureau of Mines, Department of Commerce. Single exposure of guinea pigs to vinyl chloride gas, 10 percent in air (100,00 ppm), resulted in narcosis and .death within 30 to 60 minutes. Inhalation of lower concentra- . \ ti ns resulted in ataxia and narcosis. Pathological findings at necropsy were congestion and edema of the lungs and hypere mia of the kidneys and liver. A number of investigators have made similar observations when examining the acute inhalation effects of vinyl Ohloride in mice, rats, guinea pigs, rabbits, cats, dogs (Peoples and Leake, 1933; Lester et al., 1963; Mastromatteo et al., 1960; Haley, 1975; Prodan et al., 1975). In animal studies, LC50's at 2 hours ranged from 117,500 ppm / for mice to 230,800 ppm for rabbits. Marsteller et al. (1975) reviewed and summarised the findings of previous studies on vinyl chloride exposure in laboratory animals. Torkelson et al. (1961) exposed test animals to concentrations ranging from 50 to 500 ppm. Rats xposed to 100 ppm (2 hours/day for 6 months) were judged normal on the basis of appearance, mortality, growth, hematological examination and other factors. However, a SL 110888 VI-2 alight iacrtai* in the liver weight was observed. Rats* guinea pigs, rabbits, and dogs expoied to 50 ppm (7 hours/day, 130 times in 189 days) appeared to be normal in appearance, sertality, and growth, and the increase in weight of the rat livers did not occur at this concentration. Basalaev et al. (1972) administered gaseous vinyl Chloride to rats and rabbits at a concentration of 0.03-0.04 mg/1 for 4 hours/day for $ months. CardiWascular disorders, changes in the bioelectric activity of the hypothalamus, hyperadrenalinemia, osteoporosis and resorption of bone tissue were observed. Jaeger (1975) conducted experiments with rats to d tannine the interaction between vinylidene chloride (1,1DCE) and vinyl chloride. In this study, hepatotoxicity was measured by the elevation of serum alanine-c^- ketoglutarate transaminase (ART)." When fasted rats were exposed to 0.02% (V/V), 1,1-DCE, serum ART activity was elevated about 50fold, two hours after the termination of a 4-hour inhalation exposure. No elevation was observed when 0.1% vinyl chloride was administered alone. When the two chemicals were administered simultaneously at the levels indicated, no 1 vation of serum ART occurred. Thus, the vinyl chloride was protective. These two monomers are used together in the production of vinyl copolymers, and exposure to both agents in the workplace was reported by Kramer and Mutchler (1972). SL 110889 VI-3 B. Teratogenicity John et al. (1977) examined the foots of vinyl chloride inhalation on the fetuses of nice, rata, and rabbits. The pregnant animals were exposed 7 hours daily to oncentrations of 50 or 500 ppm for mice and 500 or 2500 ppm for rats and rabbits. Mice and rats were exposed on days 6 to 15 of gestation, and rabbits on days 6 to 18. * * * Ho teratogenic effects were observed at 2500 ppm in rats and rabbits, except that a greater incidence of dilated ur ters were noted in rats. Indeed, vinyl chloride exposure at this level actually decreased the incidence of certain skeletal anomalies in rats compared to controls (e.g., delayed ossification of the bones of the skull, and unfused centers of ossification of the skull and stemebrae). Mice w re the most sensitive to vinyl chloride. No teratogenic effects were noted in the fetuses of mice exposed to 50 ppm, but a significantly greater incidence of unfused stemebrae and delayed ossification of stemebrae (no. 5) and bones of the skull were observed among litters of mice xposed to 500 ppm compared to unexposed controls. Enbryotoxic effects were not generally noted, but some d crease in fetal body weight and crown-rump length was observed in rats and mice. SIj 110890 Radix _t al. (1977a) did n t obsarv gross (nonmicro- a seopic) abnormalities in tha offspring of rats exposed 4 hours daily on tha 9th to tha 21st 'day of gastation by inha lation of 600 or'6000 ppm vinyl chlorida. A small incraase in tha incidanea of minor skslstal abnormalitias, including wavy ribs, extra 14th ribs and dalayad calcification of small bonas, vara obsarvad in tha offspring of tha axposad animals. Bowavsr, tha invastigators concludad that such a small incidence* is difficult t\> distinguish from a sporadic occurranca, and should ba considerad to be skeletal variants and not malformations. Groups of pregnant CF-1 mica, Sprague-Dawley rats and New Zealand White rabbits vara exposed to doses of vinyl chloride ranging from 50 to 2500 ppm by inhalation. Exposure to these concentrations of vinyl chlorida did not causa any significant embryon/al or fatal toxicity and was not teratogenic in any of tha three species tasted. (John at el., 1981). C. Mutagenicity Vinyl chlorida is mutagenic in a number of biological systems. The mutagenic action of vinyl Chloride appears to b dependent upon its metabolic conversion to Chemically r active metabolites (a.g., chloroethylene oxide, 2 chloroacataldahyda). Tha mutagenic affects of vinyl chlorida have been demonstrated in: (1) metabolically activated systems SL 110891 VI-5 using Salmonella typhlmurlum (Barts ch et si., 1975; McCann t al., 1975; Elmore art al., 1976; Rannug at al., 1974; Garro at al., 1976) developed by Anas at al. (1973) in which tha ganatic indicator rafars to histidina prototrophy by base-pair substitutions, or by base-pair inaartiona or deletions; (2) Esdheridiia coll K12 bioauxotrophic strain with back nutation systam arginina + (Grain at al.. 1975); (3) savaral specie* o yaast inducing forward mutations and gene '\ conversions at specific loci (Loprieno at al., 1976, 1977); (4) in garm cells of Drosophila (Verburgt and Vogel, 1977) and (5) Chinese hamster V79 cells (Huberman et al., 1975). The literature on the mutagenic effects of vinyl chloride were reviewed by Bartsch and Montesano (1975). The mutagenic activity of inhaled vinyl Chloride (3000, 10,000 or 30,000 ppm for 6 hours a day for 5 days) was assessed in infertile male CD-I strain slice with the dominant lethal assay (Anderson at al ., 1976). At these concentrations, vinyl chloride was not mutagenic as judged by scoring of post-implantation fatal deaths, pre-implantation egg losses and reduction in fertility. Positive control tests indicated that the dominant lethal effect was expressed in the CD-I mice used in these experiments. Anderson and Richardson (1976) conducted a cytogenic study investigating mutagenic effects in the bone marrow SL 110892 VI-6 c 11s of rats after exposure to paradichlorobenzene at various dose levels. In this study, benzene and vinyl chloride were us d as positive controls. The results of the vinyl chloride c ntrol shoved that vinyl chloride was effective in producing chromosome damage in rat bone marrow after the multiple exposure regime. D. Carcinogenicity Evidence .has been accumulated in recent years impli** eating vinyl chloride as a human and animal carcinogen. The first four human Cases of liver angiosarcoma in workers employed by a vinyl Chloride plant were reported by Creech and Johnson in 1974. The first experimental data on the carcinogenic effect of vinyl chloride in rats were published by Viola et al., in 1971; preliminary results of an investi gation concerned with the oncogenic potential of vinyl chloride ** in experimental animals followed (Maltoni and Lefesiine, 1974). Th se initial reports spurred a series of retrospective epidemi- logic investigations of workers in the vinyl Chloride industry and supportive experimental studies in animals* Several compre hensive reviews and symposium proceedings have been published on the subject (e.g., Selikoff and Rammond, 1975; Proceedings of the Royal Society of Medicine, 1976; U.S. EPA, 1975c; Milby, 1978). SL 110893 V/ In animal studi s. Viola _t al. (1971) r port d th carcinogenic raaponae of male rats (AR/XRE Wistar strain) xposed to vinyl chloride by inhalation (Table VI-1). Skin tumors were first noted at approximately 10 months* tumors in the lungs and bones were observed at about 11 months. Caputo et al. (1974) exposed male and female rats (A and IRE Winstar strain) by inhalation to various concentrations of vinyl chloride Carcinomas and sarcomas were observed * in all groups except those Exposed to 50 ppm (Table VI-2). As can be observed, a dose response relationship exists between exposure of 50 to 20.000 ppm. Tumors appeared between 8 and 13 months from the beginning of the inhalation treatment. These investigations also exposed rabbits by inhalation to 10.000 ppm vinyl chloride for 15 months (Table VI-2) and reported the occurrence of lung and skin carcinomas. Recent inhalation studies with albino CD-I mice and CD rats (Charles River Breeding Lab) confirm the carcinogenicity of vinyl chloride at concentrations as low as 50 ppm (Lee at al.. 1977. 1978). Liver angiosarcomas as well as other forms of cancers were found in both species. An extensive examination of vinyl chloride in experimental animals has been conducted by Maltoni (1981). A summary of these results are presented in Tables VI^3 - VI-19. Vinyl SL 110894 VI-8 chloride ni shown to cause tumors in all th animal systems t st d (i.e.* mice* rats and hamsters) both through inhalation and ingestion exposure. A clear-cut dose-response relationship was shown to exist* with carcinogenic effects being seen at exposures as lew as 50 ppm. Newborn animals appeared to be especially sensitive to the development of hepatocarcinemas and angi sarcomas and carcinogenic effects on the embryo via the plac nta were demonstrated. Table VI-20 indicates the tumor i types that have been correlated to vinyl chloride exposure in xperimental animals. TABLE VI-1 Oncogenic Effects of inhaled Vinyl Chloride (Viola et al., 1971) C nc. VC (ppm) 4 hrs/day* 5 days/wk 12 months Number Rats Skin Epider moid Carci nomas Lung Adenocarci nomas fc Squamous cell Carcinomas Bones Osteo~ chondroma 30*000 No treatment 26 25 17 - 6 - 5 SL 110895 VI-9 TNZ VI-2 Inridanoe of Tutors in Rats and Rabbits ftqcaafl to Vinyl Qilaride by Iitialation (Cguto at al., 1974) % (Pf") 4 hrs/day 5 <SRys/wk 12 sooths * of Animals Liw Angiosarcams Cholangiams 20,000 10,000 5,000 2,000 500 50 No Traatnant 10,000 No Treatment t * Rats 150 200 200 200 150 200 / 200 Rtibbits 40 20 31 15 12 10 4 - - - ling Almolar Carcinoma 21 16 4 8 - - 6 Skin Squanus Call Car^mom Acanthom Other 67 7 34 8 20 2 66 3-- -- 12 - SL 110896 n If VI-10 Table VI-3 fnirtetSIL* I n" nr f**IVVT--^ iwmm Yl MF nr ST 141 LA SLAB ELA he "?L *ST Ma.Wa StT h4At Tn W.T 4U MJ SLT tat |U JAS AT At AS nm At U AUW) otm AW) am At AT At asm '* At .At . <AUMt9) w AW) LT .AW) LT V 14 AW) AW) AW) AT LT LT AW) AW) At AAWt) mm At AW) LT AWm ) At sen LT AW) LT AW) At AW) At AW) LT am m At aum AW) Mlt AW) Wt am At am LT am SLT am At AW) AT MmW) m m tAT atm ILt am At AW) AT MW) At AW) A4 aw) LT aw) LT OtD) A4 aw) LT aw) LT aw) * LT (M0) At AM ) S3 aLw7) (MO) S4 CWt) u (MO) tti At * * * OAW4 ) LT AW) CxsamvkT Wtot t VC M Mr 10.000, 000. XS00. 100. BO. d 10 ffK 4 MWy. dayaMwk, hr M WMkt BHiiiWrfuiUiiO Table VI-4 ; herbwirt* Aa/mb tth an* JSSSL I Wtj^ n iwm m mJT MM) rm- Bs^e*1Mew Zyetal SUr U7 IfT ST LAS LA SLAB ELA SL GLC* EpT FfcAAc ST At SLT tt.0 AS At At it it - AS At m A0 a* SLT Wt atom) mow) At anmm aim At aim - mm At Aim STJ At At * anmm ai/ut) - At - MOW) A1S0) MOW) A4 Wilt) A4 Main aLnTm A0 Wilt) At At At At OAW) Q/m aeuo) aim a/im) (4/1X0) (4/1X0) 1AT SLt Ll Aim) Ll Ll L< 1.0 Aim Aim) a/iss> 0/1S5) EapoMD* tgr inkalatte to VC fe air at W0,110,100 pw 4 te/dajr, t Mja/WMk, fcr B vmIb. Spnfiw-bMrtqr nu, It wd T, 1> Sources Meltonl, 1981. SL 110897 VI-11 Table VI-5 m* Anfaait wttA tinan. * JS2SL Tm Mm le*> WwAfii Ka bafaal da wm XT IT LAS LA BLAB SLA mm BL BL GLCa EpT TaAAc t moj ia aas LT IT M LT OMR (MR am am am - LT am 114 mm aLm7 114 OMO) as OBO) *Expara by Muilatka t> VC to air * 10^00 ppm 4 Mqr, f aH " ' ` " iv tt vatb. Spncoa-Swritj nu, V ad F, 17 Table VI-6 toaMm.1 juvault *fch xaacn, * XT IT LAS LA. SLAB ELA 444 j? ai a? ai aT~ 04BM) (MM) (MM) CUBM) Fort- lUnKfav> Nnn>- Zjrnbal Bon anwnari) airy BL BL GLCa EpT PaAAc XT T5 I ai to aJ tii OBM) OBM) aim)OBM) (CBM) . .. 1.0 104 ant) oo) 4*pamb7taMiattatoVCtaafr*Mffm4te^,4m'aaai>rlZvMkt.Sp(ic<MDavfe7nu.X*S,,U*mksflld. tmJu aftar 1C imd W)nrt--*) Source: Maltoni. 1981. SL 110898 TABLE VI-7 tms.* 1 r "r *ir T VT Ul LA AJ M4 44 U SLT AS onm LI U SAM) 0019) B4 BA 147i flj \ arm ;*rttgr. QAM) 14 wm L? O|O|lt) u QAM) QAM) lit 14 QAM QAM 1L0 QTA20) *74 SIAM) Ml 02/119) 12.7 OIAM Lt 14 anso) nu, M cad F, 12 TABLE VI-8 i Source: M&ltoni; 1981- # SL 110899 VI-13 TABLE VI-9 % btu 2SL Fan- Uto- XT BT LAB LA ELAS ELA s: tr BL Zytobal GLCa Ude EpT PaAAc UyMnippB HIBnOrimt* JV V^ (MOVOT pp* w AtoinO Al lu AS Al Al 4LT 4At 4LO SA2 AS 0/1-18) aA/uSt) aAuSs) AS a/n LT mm to * LT MIS) a/AuSs> LT arm AS armm AS an*uj V to aaAsSo) to a/AiAsSo) to T4 (BUUS) mso> AS W4i1lt) MIS) m to AS (B1U) (4A/14U) AS mu) LT mso) AS Mit) L7 mu) U.0 as/iu) IAS asaso) 1A4 asait) ai/AuSs) 4Lt asj AS arum AS onm LT arm LT arm to AS a/iso) aArmSm to aaLsTo) oAaSis) o/AisSo) aAatoSis) (nATit) M MSO) OA/ISU) AS mu) AS MSO) m1mASt) 1A0 (MSO) IAS 414 to dto to A4 OS27) to At AS Ti MZ7) (AST) (17AZ7) ----Jlf fatalanonto VC to afr U.0W. tOOO, ppn; 4 today, S dayetowk,: fcjMMk, te 0 mtw (gnopa III nrf TV) ar 4 Mday, AMt Mkbr, M --1 ** "--*--** *--- --- if------ - T~J ^i~rirlBiM) (fnapa I and 11) or 1 to/day, 4 VI) (100 to). Spngue-Dawlay in, TABLE VI-10 IT R 14S U ELAS ELA Fen- ManNaptoo-N< TjmhaT Skin *--* ar>' BL BL GLCa EpT PaAAc XT I AT it nm AT sr v Al A1 turn At (UU AS (1/90) AS Ml) A4 MS) Al (1/32) A0 (1/SI) Al ) 10 (1A1) A2 a %nwn to Galatian to VC ta a* M,000. at* 000vpe ef tavadm; 4 krfday fer 1 veek (Ben l&h te 18th day of wtfnancy} nna-Dawky ma. X aad F. It v^a Jd (towdanl Bnodon (pa^a 1 d ) and ofliprinc* (rapa III and m Baauluaftar S4S Source: Maltoni, 1981. SL 110900 VI--14 TABLE VI-11 Mr IT LAS LA TW* Anfaiwh wtth i Fan- --*apt- Kiphn Naan- Zymbol SUn Hamath marj ELA Mw BL BL GLCa EpT PaAAc KT I MUMypft r n" BT Bt m SB M|Mm0v_ ^hAbi) IF flOOlyMi ***** BU * Ml US su OMO * U 14 \ 0*M) OMO BU Bl 14 14 14 4TA OMB (MB (MB OMB OMO) - 11 IS (Mi) CUM) - 4J 4.1 OMB W4B * 14 (MB _______________ i to VC to afr at 10.000 oad <000 ppm. 4 hrUty. t AtyVwtk. fcr i mb (from 14oy to I waaki of ip). pncw-Dnrky nto, M anl Tt C vaaka old Onodarn) I tad II) and atwbon (gnvpo IU wd XV). Kooulto afUr 1141 TABLE VI-12 1 rs-JT wnpm mjm *vr "vr XT |M ms SIT ms ms HT us IT US ms us US UT IT US LAS ms zt) 1LS am us am UT am> IT o*o LA T.T am is am) - ITT.' Ammali with apery 4 FanKoto- Kn- ZymboJ SUb JU. BL GLCa EpT PaAAe is am) AS OBB -- IS om> IT IT (LOT) DOT) IS OBB It BOB AS OBB * - IT OBD T.T OBB ' T.1 om U.1 aim is OBB) 4.0 DBS) -- is OBB - aTi.m4 T.T am - - - A0 am) m aIiTm - m - " MB S urcst Maltoni, 1981. I SL 110901 VI-15 TABLE VI-13 T1 wbMaf^i *i aa LAS an mo Ctoataippa TXT.* A-Wl. , FataBap* Napfar* Nnm- tab! LA ELAS ELA tw BL BL GLCa EpT hiAt L0 am LO am L0 am aLmO - - aLm0> LI am) am) varta. Wtaar nta, M, IS va*a aid Baarta aft* 1S4 *i TABLE Vf-14 % Faw LA LAS ELA lfT EpT FiAAe MlO SLT 100.0 S7J CUM) 0.7 asm SI.1 OMO) turn asslmo aLTm 10.7 mm aSLmT u aum am aIiSmA LT am aLmS LT am Ui am a1LmT M LT am aTm.1 aSsLm1 SLS asm aTm.l L0 am LT am) L0 am L0 am 1L1 arm> CTJ aom) aOsmJ ) OLS aim a1LmS> 1LS am a1LmS) SLO asm> 11.7 am LS 0u40) . OflO) LT am> LS am ILO am SLO asm u am> LT am) L7 am) LT am LT am) SLT M.T AT aaso) LT a/uo) W.0 avuo) aLmT 0) LS OMO) Earn fax Mabtiw a VC a ab 1110.000.0000. ISOO. MO. 1F, 11 vaakaaid. XaaaluafUrSI' * ------------- - S urcai Maltoni, 1981. % SL 110902 VI-X6 TABLE VI-15 tin* 1 ,*B1^ Mp IT WOrTyp aowyps jp Ji KT w US U >u iWfcht 5i 3ft OKI V oa IT urn r* hue ljJyT SM M A) A| SOS ao Ai os MU A l Al ao oum AT 800) u 000) u O0O) AT asm AT amm * U am _ u amm m aAmT AT amm -- MS m (AT am 07 am su am aams as am u am AT am u am aMmlS cams) u am as am aams 1A0 aomo am u am aaosm M7 am A7 am asoum ao am u a--m 00.7 OT0O) aaom ao am 1A7 (MO) u MS ao am (400) 080) u 10.0 ao am (100) (MO) 00 OT * 0.7 mm AO am AO 800) Ml am II VC A 0r m. >0,000,4000. goo. SOO, no. mi 0 : 4 ketiqr. I ** >0 Gotten M.U *vmtoZtu SSS^vtrSonHi'lEiffiOn* IV,MO; On* V, M* Gmp VI. SAS; QfMp VII. TABLE VI-16 tDlwaBlL* fpmMO MT IT us Aaamb whh tnaar % Fm- u s= IMwVia* Cymbal Sttn tentieh nary XUS EU BL BL 6lc EpT hAAe XT aooi*f c ID >y< 07 SU SLS AT is AS - U 0700) am am am am SU ITS MS - - - AT asm am ao ao * AS is am am M7 as - - - m - - IS O0O) AS 800) IS (100) * AS 800) IS (100) AO (400) 7.S (MO) A7 800) IS IS - AO am (100) (400) --`T~*^`Tl"riittrrT~**inr~k,,j,1~ftf,yr>~'ifritffr tftW ITflmrttrifYf>inf] TwrtiTwrtn]- l Mk SfnflhDnlQ ntt, II ail f, IS mb dl Iwhi aftc US mb (and ttapriMMl fr" Sourest Maltoni, 1981. SL 110903 TABLE VI-17 I "JT* "Sf* timer. % rt> R lit U ELAI BU SE-tr C* EpT VMJU KT K7 tu u 0040) AT - *7 anm anm IM at 17 AT - A7 (IA4ft QA4B o/mo ttl u U- tt to ww anm o*/io> - 0.7 ls s.7 o/io) enoj m/mr - 0.7 t.7 M o/uo) (vuo) iivm Oteat 1M * .* at . .\ 17 wm U 4.7 (B1W) 0/150) Expaaan by tofoatta (Macktea)aTVC to Or* at LO, 04.0.0-f* ba* teR*. ama Mtr. ** fpngu>DBwlap nta, V an4 F, W waaka all Baaadto attar r tor 5 w* TABLE VI-18 ltir ST* I Uat'O n ttafxl ni tSBfXl IV MT BT 1U mo M.7 ms 1LT' 1U mo mo u SL7 LAS - Atenb wfchunon. t Fart- SE"rLA ELAS ELA Nro Eynbal Skin BL GLCa EpT PaAAc LB LB 0*6) 0*6) LO LB OSS) os 0*8) - Lt " - - - Lt U te OtNe ) LB te te 0*0) 0) - LB * AO AO OSS) 0*6) 0> 0*6) 1.0 OSS) SI fjcfttmt by tevpartamaal wjoelion rf VC. iS mg to Or* aO a ml), tit tew, at tn menOi kimk or amt only. Ctniw-Dovlfy nu. M and F, 17 waaka aid. Bantu alter 144 wita toad tt aapateteX S urc: Maltoni, 1981. SL 110904 VI-18 TABLE VI-19 sr* t Un 0 Ond tn ftoaiAn Aataakvbbtaean.* Fan- M STMT BT US LA ELAS ELA Man* Znabal 1 BL GLCa Skto Eff FaAAc 7 MJ ns - * m * - u " * - 4.0 m on BS SAT - -U am -U (HD - aLmS) Sank* aftor 14t wwfci toad efngpmmmX Abbreviation! used In tmblee* T Ct tpT Ffc Ac Ad Ail MT IT LAS LA has AAwami to i--Bg--t tmafnrmattow tamen (total If Mt atoarwtot cpadflad) SaigB tom (total If Mt athtnria* apadBad) Uwmluaw-- NqftrxvBL Mwc BL A A*toMaatfc hjpwiJtoto to Snr t At Ai*iafahtlr 4yiptodatof Stop **A Waoplntk aadiJw afSwr M-typ. Kodnlar byparvMarflfev th3> PMftaad lOTaqjMla rflHw 44 444 Source: Maltoni, 1981. # SL 110905 VI-19 TABLE VI-20 Tutors Presently correlated to VC Exposure (by Inhalation) on Experimental Rodents ________________________________(Haltonl, 1961) ________________________________________ Species Angio sarcomas of liver Tutors of brain Tutors of lung Lym phomas and leu kemias Hepa tomas Angio sarcomas Nephro blastomas oeous. cuta neous car- ' cinemas Other cuta neous epi thelial tuaors stomach papillomas nary and car cinomas thorns He not Rat ^ House 1 Hamster | + + + + 4 4 (+) * 4 (+) <> 4 4- <) 4 (+) (+1 4 ( Itro1 o <D O VI-20 Maltoni (1981) concludes from the avallabia data that vinyl tihloride nay produce tumors of diffarant typas at diffarant sitas and that tha incidanca and ralative distribution ar graatly influancad by dose, aga of tha animal# and spacias and strain of animal used. j A racantly completed study by Feron at al. (1981) examined th oral toxicity of vinyl chlorida in Wistar rats. This study was carried* ou t oyar tha l&feapan of tha rats# and consistad of incorporating polyvinyl chlorida powdar containing * a high content of vinyl chlorida monomar in tha diat# or using gastric intubation of a 10 vinyl chlorida monomar in soyab an oil. Tha vinyl chlorida monomar dosas (actual exposures) vara 0# 1*7, 5.0 and 14.1.mg/kg bw.through tha diat or 300 mg/kg bw by gastric intubation. Tha results showed that rats xposed to vinyl chlorida monomar at levels of 5.0 mg/k9 bw day or more demonstrated hepatic angiosarcomas# pulmonary angi sarcomas# and at tha higher levels# a few primary extrahepatic abdominal angiosarcomas. At tha lowest exposure 1 val of 1.7 mg vinyl chlorida monomar/kg bw/day# liver-call tumors and an increased incidanca of foci of cellular alteration w r noted. (Tables VI-21 and VI-22). SL 110907 VI-21 VI-2 L- Type and incidence of treatment-related histopathologic*! changes in the liver of rate exposed wally to VCM ____________________________(Ftercn at al. , 1981)______________________ Incidence of change Type of change* Treatment group (mg VCM/kgyday)... Males 1.7 5.0 14.1 300t ;0 1.7 5.0 14.1 3001 Clear-cell fod l No. of rata examined... 10 0 1 No. of rate examined... Clear-cell fod Basophilic fod Eosinophilic fod Neoplastic nodule Hepatocellular cardncna cystic proliferation of bile ducts 9 1 O 0 0 0 0 No. of rates examined...55 Clear-cell fod 0 Baeo|iilic fod B Eosinophilic foci 3 Neoplastic nodule 0 Hepatocellular carcinoma 0 Angioearoum 0 Led after 26 wk 10 --1 I -after 52 dc 9 10 1" 0 -- -- 10 9 9 -- 0** 0 0-- -- 00 0-- -- 20 0-- -- 10 0-- -- 10 0-- -- 00 0-- killed in extremis ot terminally 58 56 59 55 57 58 9** 16*** 21*** 9 4 24*** ie 21* 22** 12 0 33*** 23*** 27*** 33*** 11 8 35*** 1 7** 23*** 3 2 26** 12 8** 1 0 4 o 6* 27*** 27 0 0 10 10 -- 5** 2 -- -- -- -- -- -- '10 8** 4 5** 2 1 4* 8 0 1 0 0 0 0 59 22*** 17 20* 39*** 19** 2 57 36* * 28*** 29*** 44*** 29 ** 9** 54 10 19 6 2 0 29 SL 110908 TABLE VI-21 (Continued) VI-22 Proliferation of atypical sinusoidal cells only Extensive necrosis Cysts Livei'-cell polynoiphian Centrilobular degeneration Focal hacmatopoiesie 2 4 2-. 4 0 0 0 4 3 16* 0 1 4 8 4 28*** 0 0 7 23*** 16*** 42*** 1 10** 6 21 3 36 1 8 *4 .5 9 34 1 1 6 6 30*** 51* 2 3 3 19*** 41*** 38 3 1 4 27 ** 49* * 41 1 6 7 24 3 41 18 12 ^Specific Vpi^nmlinlor lesioM wm classified according to Squire ft Levitt (1975). fThe figures of this group were not evaluated statistically because no oorresfonding control group was Included in the stud/. (Not examined. The Initial nsiber of aninals was 60/eex/group. A number of rats could not be examined beaadse of camibalimn or advanced autolyeie. Values maxked with asteriks differ si^iificantly fran those of the controls acoording to the Ai-square test* *P<0.05 **P<0.01| ***P<0.001. SL 110909 VI-23 THUS VI-22- Site, type and incidence of tianours in organs other than the liver* in rate exposed orally to VCM Jfo --------------- over 2-5 yr (Feron etal.,1981)______________________________________________________________ Incidence of tumours Site and type of tumour Treatment group (mg VCM/kg/day). Males 0 1,1 5.0 l4.1 300+ 5 1.7 5.6 14.1 mI Effective no. of rats... No. of rats with prinary tunoura Lungs Angiosarocma Adencnn Zynfcal glands Squanouu-cell cardnoma * Adencnn Abdanen Mesotheliara Angioearoam |Fibarosaroara Oeteosarcara Isaraam Reticulun-cell sarccna 'Sciwann-cell tumour1 Unclassified Spleen Haorangioendotheliosarcana Lynphcearocna Nose Squamous-cell oarcinam Brain Granular-cell nycfolaabora Oligodendroglioma Plexus pepillara Glial-cell tumour Ependymoma Mesodermal tumour Pancrean Adenoaardnara Thorax Mesothelicma Thyroid Parafollicular-cell adamra Parafollicular-cell cardnara Follicular-cell adencma 55 58 56 59 55 57 38 50 49 52 44 54 0 0 4* 19*** 19 0 0 0 0 a.. 1 0 0 0 2 0 10 0 0 0 O' 00 3 1 7 8 11 0 0 0 0 10 0 0 0 3 01 0 0 0 *0 10 0 0 3 1 00 0 1 0 0 10 0 0 0 0 00 0 0 0 0 02 0 1 0 0 00 0 0 0 0 00 0 0 01 00 1 1 00 00 1 0 00 00 0 0 00 00 0 0 2 0 10 0 0 01 0 0 0 0 10 0 0 0 0 00 0 1 1 0 00 0 0 12* 10 00 10 3 10 01 37 00 01 58 59 56 55 01 00 00 00 6* 3 00 20 00 01 00 10 00 0 .0 00 00 10 00 10 00 00 00 21 00 10 3 00 00 57 54 57 47 5* 23 00 01 01 30 21 00 10 00 00 00 00 00 01 00 00 00 00 00 00 00 00 00 20 00 10 SL 110910 VI-24 TMU VI-22 (continued) Site and type of tumour Incidence of Unours Hales ~ Females Treatment group (mg VCM/kg/day) 0 1.7 5.0 14.1 300t 0 1.7 5.0 14.1 300t Adrenals Cortical adenana FbaeochronDcytcra Pituitary Adenana Carcinoma Blood Leukemia Heart Endocardial disease* Haemangioendotlieliosarocna Kidwyn Nephroblastoma Clear-cell tisnour Lipcmatoue tumour Unclassified epithelial tunour Thymus Fibrosarocm Reticulun-cell earccne Mesenteric lymph nodes Reticulun-cell sarocma Skin Squamous-cell cardncma Subcutis Fibroma Fribrosarucma Mesenchymal tumour Skeletal nuscle Rhabdcmyouaroara 18 11 12 1 1 2 1 1 0 0 0 0 0 0 2 2 0 0 0 25 17 21 8 25** 0 6 1 01 02 00 00 00 01 00 10 00 00 33 11 11 00 00 10 9 26 4 62 2** 0 14 0 03 1 31 2 11 0 00 1 00 0 00 0 00 0 01 0 00 0 10 0 10 1 00 1 13 0 01 0 01 1 11 3Q 20 12 16 10 a2 21 00 Q. 0 00 00 00 00 00 11 00 00 31 10 00 00 17 14 02 5* 3 00 01 01 00 00 10 00 00 0 :0 00 00 10 00 00 00 00 tC-O1 O 'sO VI-25 TABLE VI-22 (continued) Site and type of tumour (mg VCM/kq/day) Males Incidence ot Tumours ftrolea 0 1.7 5.0 14.1 300t 0 1.7 5.0 14.1 300* Skull Osteoma Mesendtynnl tumour 1 00 0 00 0 00 00 0 0 0 0 0 .% 0 0 0 Ear region Adenocarcinoma c# unknown origin 0 0 1 0 0 0 *.0 0 0 0 Urinary bladder N, Unclassified epithelial tumour 0 0 1 0 00 00 0 0 Preputial glands Squamous-cell cardram 00 1 0 00 00 0 0 Mammary glands . Adenoma | Fibroadenoma Adenocarcinoma 'Anaplastic cardram 00 00 01 00 0 0 0 0 0 00 00 2 0 0 0 21 25 12** 4** 7 2 03 S4 7 7 0 00 01 0 0 Tastes Interstitial-cell tumour 30 0 11 X Uterus Adenocarcinoma Malignant fibroadencnatous tumour Leiomyoma 6 31 1 0 0 10 0 0 0 01 0 0 Cervix Mesenchymal type of tumour Adenocarcinoma 2 01 0 0 0 10 0 0 Ovaries .Theca-cell *mrr 0 0 10 0 $A small umber of primary liver tumours unrelated to treatment were found in several groups. These tumours were one Kupffer-cell sarcoma( three reticulum-cell sarcomas, two fibrosarcomas* one haonangioendcthelicma and one mesenchymal tumour. |The figures for this group were not evaluated statistically, because no corresponding control group was included in the study. SL 110912 In several cases the neoplastic character of the lesion was doubtful. Values naiiced with asteriks differ significantly from those of the controls according to the chi-square testi *P<0.05; **P<0.01 ***P<0.001. VI-26 Ftron t >1. (1981) concluded that vinyl chloride monomer is a carcinogen When administered by the oral route/ and that th tumor response seems to shift from the exclusive development of angioearcosms at very high levels to the exclusive induction f hepatocellular tumors at low levels of exposure. Feron et al. have also initiated a similar lifespan oral carcinogenicity study with vinyl chloride in rats, using three different dose * 1 vels (0.017/ 0.17 and 1.7 mg' vinyl chloride monoraer/kg bw day) and two control groups. This study is currently in pr gress and the results are not yet available. / SL 110913 VII. HUMAN HEALTH EFFECTS A. Non-Carcinoganic Effects ' Vinyl Chloride can produce a number of pathological consequences in humans in addition to its carcinogenic effect. These effects can be from acute or Chronic exposure to vinyl chloride. Unfortunately, data regarding dose-response relation ships in humani are very scarce because of the virtual absence of air measurements of vinyl Chloride in the work environment of vinyl Chloride manufacturing and polymerisation plants before 1975 (Mancuso, 1975). According to OSHA (39 FR 12342, April 5, 1974), several facilities revealed vinyl chloride concentrations for some job classifications as high as 229 ppm. Rowe (1975) commented that before 1960, a few jobs resulted in exposures in the range of 100 to 385 ppm, but these measurements /could be high because the method of quanti fication measured total halogens rather than vinyl chloride al ne. Nicholson et al. (1975) reported that vinyl chloride in polymerisation reactors may often have exceeded 1000 ppm and occasionally may have approached 10,000 ppm before OSHA standards were instituted. At these levels, workers experienc d dissiness, headaches and/or euphoria during work periods. Several instances of acute exposure have occurred in vinyl Chloride plants. Deaths of two Canadian workers were SL 110914 VI1-2 reported by Dansiger in I960 following acute exposures to vinyl chloride gee. At autopsy, there was congestion of the liver, spleen and kidneys* In another study reported by Suciu et al. (1975 ), exposure of workers to high concentrations of vinyl chloride produced euphoria. Intoxication and narcosis. In this study, the investigators found a dose-response relationship f r acute and subacute cases of "occupational disease" from air concentrations ranging from 2,298 mg/m? (about 900 ppm) t about 100 mg/m^ (about 40 ppm). In another investigation, Spirtas et al. (1975) conducted a survey of 200 vinyl chloride workers and 89 rubber plant workers (controls) where information was sought on the frequency f eight symptoms, including dizxiness, loss of consciousness, h adaches, etc. The vinyl chloride workers were categorised into low and high exposure groups. Because the exposure limits had been markedly decreased a short time before the survey, the high exposure group consisted of workers who were exposed to vinyl chloride concentrations of over 200 ppm before the standard, and 20-30 ppm subsequently. The low exposure group consisted of workers Who were exposed to 0-50 ppm before the standard and 0-10 ppm subsequent to it. Examination of the differences among the three groups indicated a statistically significant dose-respenee relationship for five of the eight symptoms (i.e., frequency of symptoms in the high exposure group < low exposure group < rubber workers), and SL 110915 VI1-3 a similar but. non-significant tr nd in two of the remaining symptom categories. Thus there appears to be a dose-response relationship between certain acute synqptosns (predominantly neurological) and level of vinyl chloride exposure. The data als suggest that vinyl Chloride levels below 50 ppm can produce health effects. ** ' .* The earliest reports of hepatotoxicity in vinyl Chloride workers were noted by TribuXh 'et al. (1949); however* the effects were attributed to plasticisers added in the manufac turing process. The observed concentrations of vinyl chloride ranged from 1 to 470 ppm. Since that time* impaired liver r function has been noted by other investigators (Marstellar et al.* 1975; Lilis et al., 1975; Popper and Thomas* 1975; Ja ger* 1975). Another effect from chrpnic vinyl Chloride exposure is a c ndition known as acroosteolysis* Which involves bone lesions in the distal phalanges of the hands and feet and scleroderma-like skin lesions. Also associated with this condition are Raynaud's syndrome* pseudoclubbing of fingers* and numerous other symptoms. Many cases of acroosteolysis have been reported and Characterised and most involve autoclave workers in vinyl chloride plants (Wilson et al.* 1967; Dinman _t al.* 1971; Barris and Adams* 1967; Lilis et al.* 1975). SL 110916  VI1-4 Other long-term effects Induce disturbances of the central nervous system, pulmonary Insufficiency, cardiovascular manifestations, and several gastrointestinal symptoms (Miller _t al., 1975j Suciu et al., 1975). These and other vinyl chloride-induced health effects are reviewed in the New York Academy of Sciences report "Toxicity of Vinyl Chloride-Polyvinyl Chloride" (Selikoff and Bammond, 1975). . \ Reproductive effects have also been noted. According to a study by Infante (Infante, 1976; Infante t al., 1976a), the incidence of birth defects for three small communities in Ohio in Which vinyl chloride polymerisation plants are located were significantly higher (P<0.001) than those in either the counties in Which these communities are located r the State of Ohio in general. Significant excesses were observed for clubfoot and defects of the central nervous / system, upper alimentary tract, and genital organs. A follow up study by Edmonds et al. (1975) identified a moderate increase in central nervous system malformations, but no association c uld be found with vinyl chloride exposure. In another pidemiologie study by Infante et al. (1976b), there was a significant excess fetal loss (P<0.05) in wives Whose husbands were vinyl Chloride polymerisation workers compared to controls (wives of polyvinyl Chloride fabrication and rubber workers). The Infante studies suggest an association between vinyl SL 110917 VI1-5 ehl ride end birth def ct*/fetal loee, but th y ere not yet supported by enimal deta. Cytogenic studies have also been conducted. Picciano et al. (1977) reported no statistically significant differences in chromatid and Chromosomal aberrations or proportion of abn rmal cells, in a group of 209 vinyl Chloride exposed work rs. Thesg workers were exposed for periods ranging from '' ' \ 1 t 332 months to time-weighted average (TWA) levels of vinyl chloride ranging from 0.3 to 15.2 ppm. Killian et al. (1975) have also reported a lack of evidence for excess chromosome br akage in a population of vinyl Chloride exposed workers. In c ntrast, Ducatman et al. (1975) and Purchase et al. (1975) # hav reported increased incidence of chromosomal breakage among vinyl chloride exposed workers. Heath et al. ('1977) examined cytogenic effects in three gr ups of industrial workers: PVC polymerization workers (presumed high exposure), PVC processing workers (presumed low exposure) and rubber and tire manufacture workers (presumed n gligible exposure). Actual vinyl chloride levels were not measured. Chromosome breakage in all three groups was signi ficantly greater than in non-industrial controls, and overall breakage levels were simlar in all three groups. The authors concluded that other agents in addition to vinyl Chloride may cause cytogenic damage in workers employed in the rubber/ plastics industry. ________ SL 110918 VI1-6 B. Carcinogenic Effects The primary affact, associated with vinyl chloride exposure In man la an increased risk of cancer in several rgan systems including engiosarcosia of the liver. Human data have been obtained primarily from occupational exposure of workers to vinyl Florida. Epidemiologic studies of^vinyl chloride exposed workers have focused on cases of angiosarcoma of the liver, a type of cancer Which occurs infrequently in the general population, about 25*30 cases per year in the United States (Heath at al., 1975). Because of its rare occurrence, it is possible to infer a causal relationship between exposure to vinyl chloride and the development of this tumor. The epidemiologic evidence linking vinyl chloride to other types of cancers is more t nuous. 1 The first study associating vinyl chloride exposure in humans with cancer was conducted by Creech and Johnson, 1974. Three cases of angiosarcoma in workers at a polymerisation plant in Louisville, Kentucky, were described. The remaining portion of this section describes some of the epidemiologic studies linking vinyl chloride with angiosarcoma and other types of cancer. SL 110919 VI1-7 Tabershaw and Oaffay (1974) conductad a vitality study of vinyl Chloride workers. Mortality calculations included only those workers Who could be traced, i.e*, 7,128 of 8,384 workers* These individuals were from 33 different facilities and all had been exposed to vinyl chloride for at least 1 y ar. The man employment duration for the group of workers under study was 80 months. Among the workers, there were 854 with exposures of 20 year*, or longer and 1,640 exposed * / 15 or more years. Compared to the general male U.S. population, the overall mortality rate among vinyl Chloride workers was found to be lower, i.e., 75 percent of the expected rate. The favorable ov rail mortality rate is a phenomenon commonly observed in working populations. Stenderized mortality ratios (the ratio of the number of observed deaths in the study population to the number of deaths expected in a comparable population) for malignant neoplasms increased with increasing exposure level and/or longer duration. In the group identified as the high exposure group, there were increases in liver cancer (primarily angiosarcoma), respiratory system cancers, and brain cancers. These differences were not statistically significant. Dew Chemical Co. (Bolder. 1974) conducted a mortality study of 594 workers in a single plant exposed to vinyl chloride SL 110920 between 1942 end 1960. Workers w re assigned to exp sur groups based on the highest level of exposure for at least 1 w aonth (low group - TWA less than 25 ppm vinyl chloride* intermediate - 25 to 200 ppm TWA, high - 200 to 300 ppm TWA). Also included in the high group were workers normally exposed to 25 to 200 ppm TWA who were also frequently exposed to xcursions of 1000 ppm. Total mortality was 91 percent of xpected among/.the vinyl Chloride exposed workers. No deaths du to liver cancer were reported, and only 13 cases of n oplasms were reported as opposed to 15.4 expected. However, nine of these malignancies occurred in the high exposure group, as compared to 5.1 expected (the author stated that due to the small number of deaths, this difference was not tested for significance). Eight of these malignancies were in workers with 15 or more years of exposure. t Monson et al. (1975) conducted a proportional mortality study of workers from two vinyl chloride plants Who died between 1947 and 1973. Death certificates were obtained for 142 out of 161 workers (88%) Who died within this time period. Deaths attributable to cancer were 50 percent higher than xpected (a statistically significant difference). A 900 per- c nt increase in cancers of the liver and biliary tract was noted (five angiosarcomas). Excluding angiosarcoma, a 275 percent excess in numbers of cancers was observed. Two brain SL 110921  VI1-9 tumors (320 percent excess) and 13 lung eancars (60 pareant azc as) wara obsarvad. In addition, tha ovarail cancer death rata increased during tha period. Nicholson at al. (1975) studied a group of 257 workers (of whom 255 wara traced) exposed to vinyl chloride for at 1 ast 5 years subsequent to 1946. Their mortality status was evaluated begin* nin' g 1i 0 years after start of employment until * 1974. Exposures were estimated to often exceed 10,000 ppm. Among the 24 deaths were three cases of angiosarcoma of the liv r. Preliminary findings indicated a 25 percent increase in deaths over the expected number and a 131 percent increase in all cancer deaths, although neither of these increases was statistically significant. The National Institute for Occupational Safety and Health (NIOSH) conducted a study Which involved 1,294 individuals who were exposed to vinyl chloride for at least 5 years, and f r whom at least 10 years had elapsed since initial employment. A total of 136 deaths were reported versus 126.3 expected (not a significant difference). A 49 percent increase over the expected number of cancer deaths was noted, a statistically significant factor. A statistically significant excess number of deaths occurred for brain and CNS cancer, respiratory system cancer, and biliary and liver cancer (Waxweiler et al., 1976). SL 110922 VII-10 Ott et *1. (1975) have re-examined much of the mortality data raportad toy Tatoershaw and Gaffay (1974) and hava includad mora claarly defined exposure lavala and .follow-up of former company employees. Tha baaic findings remain unchanged; no incraaaa over expected in malignant naoplaama was found in tha loir axposura group (TWA from 10 to 100 ppm) and an increase in deaths due to malignant neoplasms was observed in the high exposure group.(TWA of greater than 200 ppm). * ,* * Chiazse at al.(1977) hava raportad a cross-sectional mortality study of 4#341 employees from 17 PVC plants who died between 1964 and 1973. No angiosarcoma deaths ware identified. Total cancer deaths increased in White employees (especially due to cancer of the digestive sytam). In white women enplayees, deaths from cancer of the breast and urinary organs w re greater than expected. In contrast, in a mortality study of 7,000 British woxXers exposed to vinyl chloride between 1940 and 1974, the investigators found no evidence of increased cancer mortality other than from liver cancer. In this study, four cases of malignant liver tumor were diagnosed, and two of these were confirmed to be angiosarcoma. Both cases were in men exposed to high levels of vinyl chloride (Fox and Collier, 1977). SL 110923 VII-11 In addition, Byran at al. (1976) traead 750 of 771 Swedish vinyl chloride plant workers. A four- to fivef Id incraaaa over azpactad in pancraas and livar tumora was found, and two caaas wara diagnoaad as angiosarcoma. The number* of othar tumors did not deviate significantly from expected. i Tan cases of.hepatic angiosarcoma have bean found among the relatively small work force employed at a vinyl chloride polymerisation plant in Quebec. This is the largest number of cases to be diagnosed in a single plant (Makk et al., 1976). As a result, Delorme and Theriault (1978) have retrieved more detailed information on these employees. The authors suggest that the cases of hepatic angiosarcoma appear to be associated with high vinyl chloride exposure levels and vertime work hours. Mo correlation was found between occurrence / f this tumor and alcohol consumption or cigarette smoking. In workers engaged in the polymerisation of vinyl chloride Who were studied by Popper and Thomas (1975), the characteristic hepatic fibrosis was present in all cases of angiosarcoma. Although the relation of fibrotic lesions to the development of angiosarcomas requires further study, a transition from th fibrotic stage tc angiosarcoma is suggested by the focal proliferation of the sinusoidal lining cells and of the SL 110924 hepatocyt * that ara n in th fibrotic stag but which bac maa avan more pronounced in tha initial stages of angio- oar oma development. Thasa findings auggaat that tha fibrotic Xaaions without angiosarcomas, fraquantly obaarvad in workers exposed to vinyl chlorida (Lilia at al., 1975), night ba tha prastaga of davaloping naoplastic lesions. Tha diagnosis of tha fibrotic lasions in thasa workers nay imply a longar , latency pariod for tumor initiation basad n a lower exposure level. Tha series of changes observed in tha liver appear to represent a multi-centric development of angiosarcoma and ara similar to tha Changes induced by Thorotrast and inorganic arsanicala (Bark at al.. 1976). In tha most recant update of tha BIOSH register (Spirtas and Kaminaski, 1978) a total of 64 cases of hepatic angio sarcoma have bean identified worldwide among vinyl chlorida exposed industrial workers. A listing of all documented cases by country is presented in Table VII-1. The number of cases per year is depicted in Figure VII-1. Of the 64 cases. 23 have been reported in the United States. The authors reported that both the age at diagnosis and the latency period for cancer induction appear to be increasing. They suggest three explanations for these phenomena: (1) early cases may have heavier exposures; (2) the initial cases represented more biologically susceptible individuals; SL 11092 VI1-13 and (3) random fluctuation. If tha trand of increased age at diagnosis and the longer latent period for hepatic angiosarcoma induction are indeed related- to lover levels of ccupetional exposure, then the latent period for cancer induction as a result of these low levels of exposure may be longer than previously anticipated, i.e., it would be many years before the ultimate outcome of these exposures will be known. \ It has been hypothesized that inhalation of low levels of vinyl chloride by the general public in the vicinity of vinyl 6hloride/PVC manufacturing plants could be responsible for an increased risk of angiosarcoma of the liver development. * Brady et al. (1977) examined annual rates of hepatic angio sarcoma from 1970 through 1975 in residents of the State of New York (excluding New York City). Exposures to arsenic, / vinyl chloride, or thorium dioxide were suggested to be significant factors in the etiology of these tumors. Direct exposure to these agents could not be demonstrated in 19 of the 26 study eases. Five of the 19 patients lived closer to vinyl chloride plants than did their matched controls. This may lend some support to the idea that "indirect modes of xposure, not specifically related to occupation, might be important in the etiology of this disorder* (Brady et al., 1971). SL 110926 VI1-14 The International Agency for Research on Cancer (1979) x&mlned the available data on humans and concluded that ex posure to vinyl chloride results in an increased carcinogenic risX to humans. The organ systems most liXely to be affected were the liver, brain, lung, and hemato and lymphopoietic systems. \ # SL 110927 TABLE VI1-1 Angiosarcoma of the Liver in Vinyl Chlorids/PVC Worker (Spirtee end Kaminski, 1978) Oocntry Case NO. Birth Date let VC Of PVC Exposure Diagnosis of Angiosarcoma Belgium Canada Canada Canada Canada Canada Canada Canada Canada Canada Canada Czechoslcr/akia Czechoe lcrrakia Fed Rep Germany Fed Rep Germany Fed Rep Germany Fed Rep Germany Fed Rep Garnery Fed Rep Gsrmany Fed Rep Genrany Fed Rep Germany Fed Rep Germany France France France France France France France France Great Britain Great Britain 01 01* 02* 03* 04* 05* 06* 07* 08 09 10 01* 02* 01* 02* 04 05* 07* 08* 09* 10* 11* 01* 02 03* 04* 05* 06* 07 08* 01* 03 00-00-00 12-15-13 03-06-14 08-26-19 04-05-19 05-07-11 12-15-19 11-09-19 05-13-20 07-19-21 05-16-15 00-00-28 00-00-26 06-04-30 07-26-31 09-04-30 01-01-32 09-29-26 10-19-17 12-13-34 07-25-29 12-29-36 04-15-24 06-03-11 00-00-19 01-27-27 01-29-38 04-14-34 00-00-27 04-01-34 04-20-01 06-02-37 00-00-00 00-00-44 00-00-43* 00-00-41 00-00-45 00-00-44 00-00-47 00-00-46 00-00-61 00-0046 00-00-53 00-00-57 00-00-51 10-01-56 10-14-57 04-16-57 12-16-62 04-15-54 04-19-54 12-02-59 10-10-55 01-02-61 01-0046 07-06-59 00-00-46 10-19-49 00-00-65 00-00-58 07-01-50 05-23-57 00-0044 02-00-66 00-0000 0000-55 00-0057 00-00-62 00-0067 00-00-68 00-0071 00-0072 00-0073 00-0074 00-0076 00-0073 00-0066 09-19-60 09-25-70 00-0074 00-0075 00-0075 00-0075 06-16-76 06-28-77 00-0077 02-18-67 01-0075 01-0075 01-04-76 04-0076 09-0076 07-0076 12-03-76 12-0072 12-0074 Age at Diagnosis 00 41 43 42 48 57 51 53 53 53 61 46 40 38 39 44 43 49 58 42 47 41 43 63 55 49 38 42 49 42 71 37 Years from 1st Exposure to Diagnosis 00 11 14 21 22 24 24 26 12 28 23 16 15 12 13 17 13 21 22 17 22 16 21 15 29 26 11 18 26 19 28 09 Total Years of Exposure 00 11 14 20 22 05 23 25 05 26 14 16 15 12 12 17 12 12 21 15 22 10 19 12 29 26 10 17 23 19 22 04 Date of Death 06-29-76 09-02-55 12-21-55 03-22-62 01-21-68 07-05-68 04-10-71 12-24-72 06-12-73 09-04-74 04-00-77 00-00-74 00-00-66 01-25-69 12-14-71 11-25-74 01-09-75 11-13-75 12-25-75 Alive 06-28-77 03-07-77 02-19-67 01-24-75 06-29-75 01-04-76 05-13-76 09-12-76 07-02-76 01-30-77 12-00-72 12-24-74 SL 110928 TABLE VII-1 (Continued) Country Case Birth No. Data 1st VC of PVC Exposure Diagnosis of Angiosarcoma Age at Diagiosis Years from 1st Exposure to Diagnosis Total Years of Exposure Date of Death Italy Italy Japan Norway Sweden Sweden Sweden U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. Yugoslavia Yugoslavia 02* 03* 01 01* 01* 03* 04* 01* 02* 03* 04* 05* 06* 07* 00* 09* 10* 11* 12* 13* 16* 17* 10* 19* 20* 21* 22* 23* 24* 25* 01* 02* 11-13-29 03-14-20 00-01-22 12-23-15 06-23-27 06-10-10 11-16-14 10-17-23 00-19-33 05-25-15 01-15-24 01-25-12 11-23-28 05-03-22 05-06-20 11-00-31 00-16-13 05-27-09 11-17-18 12-01-21 11-04-27 05-06-31 04-22-28 00-00-15 00-31-17 09-02-09 1002-23 0000-23 05-07-17 08-07-10 04-05-14 11-15-31 0000-57 00-00-53 04-00-53 03-00-50 08-14-51. 05-00-47 00-00-46 12-09-48 11-15-55 11-28-45 07-06-52 06-19-44 01-17-62 08-27-44 10-07-46 05-28-45 06-12-51 10-14-46 09-13-49 12-11-42 05-00-50 06-23-55 09-15-54 00-00-43 00-00-55 12-00-46 07-11-47 09-00-58 00-00-39 02-0047 00-00-53 0000-50 12-13-72 07-10-75 08-21-74 *12-20-71 00-00-74 03-19-76 05-12-77 03-03-73 " 05-00-70 12-19-73 00-19-67 04-09-64 02-00-74 00-00-68 08-00-61 03-01-74 05-00-68 03-00-70 05-02-69 05-00-74 00-00-69 10-11-74 00-00-75 06-19-75 01-30-76 00-00-77 01-00-76 04-06-73 05-27-77 03-10-77 04-00-73 07-12-73 - Total Reported Cases 64 43 55 52 56 43 65 62 49 37 58 43 52 46 45 41 43 55 61 50 52 41 43 46 60 58 67 52 50 60 67 59 42 15 22 22 22 19 29 31 *. 24 14 ; 28 15 20 12 24 ^15 29 17 23 20 32 19 19 21 32 21 30 29 15 38 30 20 23 06 21 22 21 10 21 31 21 13 20 15 20 12 17 15 24 17 23 19 26 04 19 . 11 22 18 21 28 14 26 20 20 18 12-00-72 07-10-75 10-24-75 01-04-72 10-20-70 03-19-76 05-12-77 03-03-73 09-20-71 12-19-73 01-07-68 04-09-64 07-24-75 03-23-68 00-29-61 03-00-75 05-10-68 t03-16-70 05-02-69 07-04-74 03-27-69 Alive 11-02-75 04-06-76 01-30-77 01-02-77 12-04-76 04-06-73 05-27-77 03-10-77 04-00-73 07-12-73 SL 110929 Figure VII-1 Numb r of cases of vinyl chloride/PVCf related angiosarcomas r ported to NIOSH by year of diagnosis (representing only 63 of the 64 cases known to NIOSH since information on diagnosis is missing for one case) (Spirtas and Kaminski, 1978). VIII. MECHANISMS OF TOXICITY The mechanism* of non-carcinogenic injury of vinyl chlorida ars not known* It is theorised that the toxicity of this compound is attributable to its enzymatic oxidation to reactive polar metabolites# possibly chloroethylene oxide or chloroacetaldehyde (see Pharmacokinetics section). Ward et al. (1976) hypothesized that an immunological mechanism is responsible for the non-carcinogenic pathological ff eta of vinyl chloride exposure. According to this model, . a metabolite of vinyl Chloride binds to plasma protein, pr ducing an antibody response. The antigen and resulting immunoglobulin interact to produce a soluble complex which causes vascular occlusion, platelet aggregation, and other adv rse effects Which explain the observed syngatoms of the dis ase. An investigation of workers with "vinyl chloride disease" showed the presence of circulating immune complexes in 19 of 28 patients. Abnormalities were also detected in some workers exposed to vinyl Chloride who had few or no overt clinical signs. Over the past several decades, scientists have conducted a great deal of research in an effort to establish the mechanism(s) by which Chemical substances exert their carcinogenicity. The somatic cell mutation theory of carcinogenicity suggests that for a carcinogenic response to occur, an irreversible change must occur in the cell which SL 110931 VIII-2 results in proliferation of a neoplasm. This Chang r fleets a mutational event in the DKA of that cell, suggesting that the diemical carcinogen must interact directly with or otherwise alter the DHA to intiate the change. In recent years, however# some substances have been shown to be carcinogenic# but by mechanisms in which there apparently is no direct interaction with or alteration of the DMA of the cell by the ...substance. Presumably# these compounds are not capable of ' initiating the alteration of a normal cell to a neoplastic one, but can facilitate expression of a neoplastic response in lat nt cells. On the basis of these purported differences in mechanisms, carcinogens now are often classified into two broad cat g riest genotoxic and epigenetic or nongenotoxic. The mechanisms by Which a compound exerts its carcinogenicity rarely can be determined by the chronic testing of whole animals such as is done in the NTP bioassay. Thus, a large number of short-term in vitro and in vivo assay systems have been developed for the purpose of elucidating mechanisms. Since most of the in vitro testing systems measure mutational events, and many carcinogens are mutagens, it is suggested that positive results in certain of these test sytems indicate genotoxicity. The decision as to whether a substance is g notoxic may be made qualitatively on the basis of several crit ria: 1) a reliable, positive demonstration of genotoxicity in appropriate prokaryotic and eukaryotic systems in vitro: SL 110932 VIII-3 2) studi s n binding t DNA and 3) vidanc of biochemical or biologic consequences of DNA damage (Waiaburgar and Williams, 1981). Ho aingla taat systam appaars eapabla ,pf datacting all carcinogans that ara ganotoxic. Therefore, a number of aci ntiata hava propoaad tasting battarias auch that raaulta from aach taat within tha battary Whan evaluated aa a whole, will allow ona to alake a conclusion about tha mechanism of carcinoganicity of a particular 'compound. Vinyl chlorida has * not baan ayatamatically studiad in any spacific battary of tests, but has baan avaluatad in a numbar of taat ayatama that hava baan propoaad for inclusion in ona or mora battarias. Tabla VIII-1 aummarisaa soma of tha mutaganicity studias on vinyl chi ride which hava demonstrated the chemical to hava ganotoxic pot ntial. Tha studias hava baan dividad according to tha thr a criteria for genotoxicity (Waiaburgar and Williams, 1981) outlined above. Whan considering all of tha data on vinyl Chloride, it is probable that vinyl chloride exerts its carcinogenicity through ganotoxic mechanisms. SL 110933 TABLE VIII-1 - Results of Viiyl Chloride Hitagnldty Studies A. A--ay system a--ulta In Vitro prokaryotic and eukaryotic systems Metatoolically activated Salmonella tychinuriun systnn (Ainas) + Bartach at al., 1975 NoCam at aI7, 1975 Haora at aT, 1976 tamug at at, 1974 Garxo at aTT 1976 Eecherihia coli X12 i-rpMo Crain at al., 3975 Yeast t'* dam oalls of Droeochilia Chinese hamster V79 calls \ + Lcprlano at al, 1976, 1977 Verburgt and Vogel, 1977 Hubernan at al., 1975 B. ENA Binding Studies Mouse tissues (brain, lung, liver, kidney, splaan, pancreas and tastes) in vitro + (Irreversible binding to R9A and DNA) Bazgnen, 1982 Rat liver ndcroacnas, reconstituted cytodirana P-450 system and isolated hepatocytes t Rat liver ndcroaomas with NADER + (Irreversible bindina to protein end ENA) Guengaridh at al., 1981 + (Alkylation of R3A) Laib and Bolt, 1977 C. Biochemical or biologic cansecruences of ENA damage Bona narrow call* of rata (in vivo) + (Chranoaon Anderson and Rihardson, 1976 Bcna narrow oella of Chinaae hamsters (in vivo) Baalar and Rdhrtaorn, 1960 aiatar^diiaiati^ Culturad peripheral lynphoeytaa in humna (viiyl chloride exposed workers) + (Chronosanal abnormality Purchase at al., 1978 Purchase at al., 1975 Ducatnan at al., 1975 SL 110934 f OfC 22 1983 IX. Quantification of Toxicological Effects for Vinyl Chloride The quantification of toxicological effects of a chemical consists of an assessment of the non-carcinogenic and carcino genic effects. In the quantification of non-carcinogenic ffects, an Adjusted Acceptable Daily Intake (ADI) for the chemical is determined. For ingestion data, this approach is illustrated as follows: ADI * (NOAEL or MEL in mq/kq)(70 kg) (Uncertainty factor)(2 liters/day) The 70 kg adult consuming 2 liters of water per day is used as the basis for the calculations. A "no-observed-adverse-effect level" which is the highest reported long-term dose observed not to produce any adverse effect or a "minimal-effect-level" which is the lowest studied concentration at which adverse h alth effects were observed is determined from animal toxicity data or human effects data. This level is divided by an uncertainty factor because, for these numbers which are d rived from animal studies, there is no universally acceptable quantitative method to extrapolate from animals to humans, and the possibility must be considered that humans are more sensitive to the toxic effects of chemicals than are animals. For human toxicity data, an uncertainty factor is used to account for the heterogeneity of the human population in which persons exhibit differing sensitivity to toxins. The guidelines set forth by the National Academy of Sciences (Drinking Water and Health, Vol. 1, 1977) are used # SL 110935 IX-2 in establishing uncertainty factors. These guidelines are as follows: an uncertainty factor of 10 is used if there exist valid experimental results from studies on prolonged ingestion by man, with no evidence of carcinogenicity; an uncertainty factor of 100 is used if there exist valid results of long-term feeding studies on experimental animals, or in the absence of human studies valid animal studies on one or more species, no indication of carcinogenicity; and an uncertainty factor of 1000 is used if there is no long-term or acute human data, scanty results on experimental animals and no evidence of carcinogenicity. In the quantification of carcinogenic effects, mathematical models are used to calculate the estimated excess cancer risks associated with the consumption of a chemical through th drinking water. EPA's Carcinogen Assessment Group has used the multistage model, which is linear at low doses and does not exhibit a threshold, to extrapolate from high dose animal studies to low doses of the chemical expected in the environment. In order to predict the risk for humans from animal data it must be converted to an equivalent human dose. This conversion includes correction for non-continuous animal fe ding, non-lifetime studies and for the difference in size. The factor that compensates for the size difference is the cube root of the ratio of the animal and human body weights. It is assumed that the average human body weight is 70 kg SL 110936 IX-3 and that the average human consumes 2 liters of water per day. The multistage model is then fit to the equivalent human data to estimate the risk at low doses. The upper 95% confidence limit of this estimate is used. Excess cancer risk rates also can be estimated using other models such as the one-hit model, the Weibull model, the logit model and the probit model. Current understanding of the biological mechanisms involved in cancer do not allow for choosing among the models. The estimates of incremental risks associated with exposure to low doses of potential carcinogens can differ by several orders of magnitude when these models are applied. The multistage model does not necessarily give the highest or lowest risk estimates at low doses. Whether it is the most conservative, least conservative or predicts a risk in the middle of the range of risks predicted by other models is chemical specific. The scientific data base, which is used to support the estimating of risk rate levels as well as other scientific endeavors, has an inherent uncertainty. In addition, in many areas, there exists only limited knowledge concerning the health effects of contaminants at levels found in drinking water. Thus, the dose-response data gathered at high levels of exposure are used for extrapolation to estimate responses at levels of exposure nearer to the range in which a standard SL 110937 IX-4 might be set. In most cases, data exist only for animals; thus, uncertainty exists when the data are extrapolated to humans. When estimating risk rate levels, several other areas of uncertainty exist such as the effect of age, sex, species and target organ of the test animals used in the experiment, as well as the exposure mode and dosing rates. Additional uncertainty exists when there is exposure to more than one contaminant due to the lack of information about possible additive, synergistic or antagonistic interactions. A. Non-Carcinoqenic Effects Vinyl chloride has been shown to have non-carcinogenic ffects in animals and humans. Acute and chronic toxicity studies have shown the major effects to be congestion and edema of the lungs and hyperemia of the kidneys and liver. Other non-carcinogenic effects have been noted, includeing disturbances of the central nervous system, pulmonary insufficency, cardiovascular manifestations, gastrointestinal symptoms and acroosteolysis. Acute toxicity tests with vinyl chloride were carried out by Patty et al. (1930). Single exposure of guinea pigs to vinyl chloride gas, 10 percent in air (100,000 ppm), resulted in narcosis and death within 30 to 60 minutes. Inhalation of lower concentrations resulted in ataxia and narcosis. Pathological findings at necropsy were SL 110938 IX-5 congestion and edema of the lungs and hyperemia of the kidneys and liver. Mastrometto et al. (1960) exposed mice, rats and guinea pigs in an inhalation chamber to 10, 20 or 30 per cent vinyl chloride in air for 1-30 minutes. The principal pathological changes observed were pulmonary edema and hemorrhages, and congestion of the liver and kidneys. In a chronic inhalation exposure study (Torkelsen et al., 1961), rats, rabbits, guinea pigs and dogs were exposed repeatedly for up to six months to 50, 100, 200 or 500 ppm vinyl chloride in air. Detectable changes occurred at all but the lowest concentration. Rats xposed to 100 ppm (7 hours/day for 6 months) were judged normal on the basis of appearance, mortality, growth, hemato logical examination and other factors. However, slight increases were found in the average weights of the livers of male and female rats. Rats, guinea pigs, rabbits and dogs exposed to 50 ppm (7 hours/day for 6 months) appeared to be normal in appearance, mortality and growth, and the increase in weight of the rat livers did not occur at this concentration. At higher doses, pathological changes were increasingly more pronounced. Basalaev et al. (1972) administered gaseous vinyl chloride to rats and rabbits at a concentration of 0.03 - 0.04 mg/1 for 4 hours/day for 6 months. Cardiovascular disorders, changes in the bioelectric activity of the hypothalamus, hyperadrenalinemia, osteoporosis and resorption of bone tissu w r observed. # # SL 110939 XX-6 Feron et al. (1981) carried out a lifespan oral toxicity study of vinyl chloride in rats. Vinyl chloride monomer was incorporated into the diet, or gastric intubation of a 10% vinyl chloride monomer solution in soya-bean oil was used. Groups of 60-80 male and 60-80 female Wistar rats w re exposed to 0, 1.7, 5.0 and 14.1 mg/kg bw vinyl chloride in the diet, or 300 mg/kg bw by gastric intubation. A variety of carcinogenic and noncarcinogenic effects were observed at all dose levels. At the 14.1 and 300 mg/kg doses, shortened blood-clotting times, slightly increased -foetoprotein levels in the blood serum, liver enlargement and an increased haemato poietic activity in the spleen were observed. Non-neoplastic liver lesions consisting of pronounced swelling, discolora tion and altered consistency of the lobes as well as nodules and nodule-like processes were observed. At the lower dose 1 vels of 1.7 and 5.0 mg/kg bw, histopathological changes in the liver were observed including clear-cell foci, extensive necrosis, cysts, and liver-cell polymorphism. Suciu et al_. (1975) examined exposure of workers to vinyl chloride at high concentrations. Air concentrations ranging from 100 mg/m3 (40 ppm) to 2,298 mg/m3 (900 ppm) produced euphoria, intoxication and narcosis, in a doseresponse relationship. In an epidemiological investigation, Spirtas et a_l. (1975) conducted a survey of 200 vinyl chloride workers and 89 rubber plant workers (controls). The vinyl SL 110940 IX-7 chloride workers were categorized into low and high exposure groups. The high exposure group consisted of workers who were exposed to concentrations ranging from 20*200 ppm and the low exposure group consisted of workers exposed to 0*50 ppm vinyl chloride. Information was sought on the frequency of eight symptoms, including dizziness, nausea, h adache and weakness. The results showed a statistically significant dose-response relationship for 5 of the 8 symp toms when comparing vinyl chloride workers with rubber workers, and between high and low exposure vinyl chloride workers. A similar but non-significant trend in the remaining symptoms categories was also noted. B. Quantification of Won-Carcinogenic Effects In the calculation of an adjusted ADI, a chronic study in which animals or humans are exposed to the chemical at various dose levels with a no-observed-effect-level or a minimal-effect-level being identified is used. Ideally, the study should use the oral route of exposure. For vinyl chloride, the toxicological studies which fit some of the above criteria are the Feron e al. (1981) and Torkelson et al. (1961) studies. The Torkelson et al. (1961) study examined vinyl chloride inhalation exposure in rats, rabbits, guinea pigs and dogs at various dose levels. At 100 ppm, the only adverse effect noted was the slight increase in the weight of the livers in the rat, and not in the other species. SL 110941 % % IX-8 Thus, a minimal-effect-level of 100 ppm could be used for the derivation of the an adjusted ADI. However, a major limitation of this study is that inhalation exposure was used, which presents problems in terms of conversion factors n eded to convert from inhalation to ingestion exposure. In the Feron et al. (1981) study, carcinogenic and non-carcinogenic effects were observed at all dose levels. At the lowest dose of 1.7 mg/kg bw, a variety of effects were reported, including narcosis of the liver, liver cysts and nodules. It is not possible to identify a no-observedadverse-effect-level from this study, as effects were seen at every dose level. However, 1.7 mg/kg/day may be used as a minimal-effect-level for the purpose of calculating an adjusted ADI, using an appropriate safety factor to account for the fact that the no-observed-adverse-effect-level is below this value. Using this study, the calculations are as follows: (1.7 mg/kg/day)(70 kg) 0.06 mg/1 (1000)(2 1/day) Where: 1.7 mg/kg * Minimal-effect-level from Feron et al. (1981) study 70 kg * Average body weight of adult human 1000 * Uncertainty factor; animal study where no-observed-adverse-effect-level was not identified 2 liter * water consumption per day for an adult human Thus, the adjusted ADI for vinyl chloride using non-carcinogenic data and 100 percent exposure from drinking water would be 0.06 mg/1. This numb r should b appropriately reduced if 110942 IX-9 there is shown to be significant vinyl chloride exposure from other sources, such as food and air. C. Carcinogenic Effects Vinyl chloride has been shown to have carcinogenic effects in animals and humans. Viola et a_l. (1971) reported the carcinogenic response of male rats (AR/IRE Wistar strain) exposed to vinyl chloride by inhalation. Rats exposed to 30,000 ppm vinyl chloride for 4 hours/ day, 5 days/week for 12 months, demonstrated an increased incidence of skin carcinomas, lung adenocarcinomas and bone osteochondroma over controls. Caputo et^ al. (1974) exposed male and female rats (A and IRE Wistar strain) by inhalation to 0, 50, 500, 2,000, 5,000, 10,000 and 20,000 ppm vinyl chloride. Liver angiosarcomas, lung adenocarcinomas and skin squamous cell carcinomas were observed in all groups xcept those exposed to 50 ppm. Tumors appeared between 8 and 13 months from the beginning of the inhalation treatment. A series of inhalation and ingestion studies examining the carcinogenic effects of vinyl chloride have been conducted by Maltoni (Maltoni, 1981). Vinyl chloride was shown to cause tumors in all the animal systems tested (mice, rats and hamsters) both through inhalation and ingestion exposure. In one study, Sprague-Dawley rats were exposed by SL 110943 % % % IX-12 1 ast 5 years, and for whom at least 10 years had elapsed since initial employment. A total of 136 deaths were reported versus 126.3 expected (not a significant differ ence). A 49 percent increase over the expected number of cancer deaths was noted, a statistically significant factor. A statistically significant excess number of deaths occurred for brain and CNS cancer, respiratory cancer, and biliary and liver cancer (Waxweiler et al^, 1976). According to the International Agency for Research on Cancer (IARC, 1979), vinyl chloride is a human and animal carcinogen. IARC's evaluation of the chemical is as follows: "Vinyl chloride was tested in rats by oral, subcutaneous and intraperitoneal administration and in mice, rats and hamsters by inhalation exposure. Following oral and inhalation exposure, vinyl chloride was carcinogenic in all three species, producing tumors at different sites, including angiosarcoma of the liver. Vinyl chloride was carcinogenic in rats following prenatal exposure. A dose-response has been demonstrated. Vinyl chloride is a human carcinogen. Its target organs are the liver, brain, lung and haemo-lymphopoietic system. Similar carcinogenic effects were first demonstrated in rats and were later confirmed in mice and hamsters. Although vidence of a carcinogenic effect of vinyl chloride in humans has come from groups occupationally exposed to high doses of vinyl chloride, there is no evidence that there is an exposure level below which no increased risk of cancer would occur in humans". SL 110944 IX-13 D. Quantification of Carcinogenic Effects In the quantification of carcinogenic effects for vinyl chloride, many studies were considered in performing the carcinogenicity risk assessment. In particular, human data exists for vinyl chloride and it would be advantageous to use such data in the risk assessment procedure. However, the human studies available do not provide dose-response data that is needed for the calculation of the risk values, and thus human data were not used for the risk assessment. EPA's Carcinogen Assessment Group (CAG) and the National Academy of Sciences (NAS) have used the linear multistage model to calculate the projected excess cancer risk resulting from lifetime exposure to vinyl chloride through the drinking water. The CAG numbers were calculated assuming consumption of 2 liters of drinking water and 6.5 grams fish and shellfish per day, and were published in the Ambient Water Quality Criteria Document for Vinyl Chloride, U.S. EPA 440/5-80-078. For vinyl chloride, CAG used the incidence of total tumors in rats exposed through inhalation (Maltoni et al, 1975) to calculate the excess cancer risk. They calculated that consuming 2 liters of water per day having a vinyl chloride concentration of 200 ug/1, 20 ug/1 or 2 ug/1 would increase the risk of one excess cancer per 10,000 (10"4), 100,000 (10"5) or 1,000,000 (10") respectively, per lifetime. There are several problems with the data used by CAG in risk estimation. The major problem is that inhalation data were us d, and the relationship between oral and inhalation exposure toxicity is not well understood. SL 110945 T- % % IX-14 NAS'used ingestion data from the Maltoni et al_. (1975) study in their calculation of excess carcinogenic risk numbers. In this study, rats were given vinyl chloride in olive oil by gavage, four or five times per week for 52 weeks and held for their life span. This experiment was not completed at th time NAS performed its computations, but the available data did indicate the development of liver angiosarcomas and other tumors in rats exposed to 16.65 mg/kg. The NAS made the decision to use this study because it was felt that the limited gavage data were still superior to completed inhalation studies for assessing risk by the oral route. The NAS have calculated that consuming 2 liters of water per day over a lifetime at a vinyl chloride concentration of 100 ug/1, 10 ug/1 or 1 ug/1 would increase the risk of one excess cancer per 10,000 (10-4), 100,000 (10~5), or 1,000,000 (10") people exposed, respectively. The NAS have published these calculations in Drinking Water and Health, Vol. 1, 1977. The major problem with the NAS data is that the Maltoni experiment was not completed at the time the risk calculations were carried out, and thus the data cannot be considered definitive. However, since that time the Maltoni experiment has been completed, and the NAS (Drinking Water and H alth, Vol. V, 1983) reexamined the data and decided to continue using their 1977 risk estimates. Thus, the NAS risk estimation uses ingestion exposure and represents the best estimate of the carcinogenic risk from exposure to vinyl chloride that is availabl at this time. Using the SL 110946 IX-15 NAS data,, the excess cancer risk concentrations associated with 10-4, 10-5, and 10-6 excess risk rates are 100 ug/1, 10 ug/1, and 1 ug/1, respectively. The World Health Organization has not calculated an action level for vinyl chloride. An EPA Health Advisory number for vinyl chloride also has not been calculated. Vinyl chloride has also been demonstrated to have interactions with other chemicals. Ingestion of ethanol was shown to increase the incidence of liver tumors in rats (Radike et al., 1977) and vinyl chloride was demonstrated to have protective effects when administered with 1,1-dichloroethyl ne (Jaeger, 1975). In the quantification of toxicological effects for a chemical, consideration should be given to subgroups within the general population which are at greater than average risk upon exposure to the chemical. For vinyl chloride, animal studies have indicated that older individuals, females, n wborns and alcohol consumers may be particularly sensitive to the effects of vinyl chloride. SL IIO947 EPA's Carcinogen Assessment Group (CAG) have recently recalculated their excess carcinogenic risk estimates resulting from lifetime exposure to vinyl chloride through the drinking water. CAG based their preliminary revised risk estimates (1984) on the Feron et al.(1981) study. The total number of tumors, considering tumors of the lung and liver, in rats exposed through th diet were used to calculate the excess cancer risk. They calculated that consuming 2 liters of water per day having a vinyl chloride concentration of 1.5 ug/1, 0.15 ug/1 and 0.015 ug/1 would increase the risk of one excess cancer per 10,000 (10"4), 100,000 (10-5) Qr 1,000,000 (10-6) people exposed, respectively, per lifetime. SL 110948 -r % X. REFERENCES American Public Health Association. 1975. Population residing near plants producing vinyl chloride. Ames, B.N., W.E. Durston, E. Yamasaki, and F.D. Lee. 1973. Carcinogens are mutagens: a simple test system combining liver homogenates for activation and bacteria for detection. Proc. Natl. Acad. Sci. 8:2281-2285. Anderson, D., M.C.E. Hodge, and I.F.H. Purchase. 1976. Vinyl chloride: dominant lethal studies in male CD-I mice. Mutat. Res. 40:359-370. Anderson, D. and C.R. Richardson. 1976. Paradichlorobenzene: Cytogenic Study in the Rat. 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