Document Z3wMR4XRL3dpXdqex6ejQ83d

F*l DRAFT PB84- 1 9 953 8 DRAFT CRITERIA DOCUMENT FOR VINYL CHLORIDE i FEBRUARY 1984 \ HEALTH EFFECTS BRANCH CRITERIA AND STANDARDS DIVISION OFFICE OF DRINKING WATER U.S. ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460 AP060t2253 t TABLE OP CONTENTS * Paa I. 11. III. IV. V. VI. VII. VIII. XX. 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 APOOOt 2254 III. PHYSICAL AND CHEMICAL PROPERTIES The structure of vinyl chloride!* as follow*i H2C " CBC1 Molecular Weight * 62.5 Vinyl chloride is highly flammable (limits of inflamma bility! J^0^21.?0t) 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# vinyl chloride exists as a gas. Vinyl chloride is only sparingly soluble in water (0.11 g/100 g water at 28*C), 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# 1978-1978; Braker and Mossman# 1971). The above information indicates that vinyl chloride is volatile and readily passes from water into the gas phase under most laboratory and anvironmental conditions* This was confirmed in experiments where 16 mg/1 vinyl chloride was added to distilled water in beaXars and the concentration determined with time (U.S. EPA, 1974). The data indicate that if first order kinetics are assumed# the volatilisation half-life in quiescent water (unstirred) is 290 minutes and AP000I2255 III-2 in continually stirred water is 25 J3 minute*. Dilling, et al. (1975) found similar values for the stirred water* As Dilling* et al.* note* predictions of vinyl chloride loss from water at relatively high concentrations {e.g. * 1 jng/1) may not reflect the situation at very low concentrations. Volatilisation appears to be the most significant process in the loee of vinyl chloride from the squatic environment (Hill* et al., :1976).. Once in the atmosphere* vinyl chloride undergoes rapid photochemical oxidation (Gay* et al.,1976? Lillian et al.* 1975). t j t APOOOf2256 At. high doses (e*g* 100 mg/kg), most of the solvent is expired as vinyl chloride* Acute and chronic exposure to Vinyl chloride can result in toxicity in experimental animals and humans. In animals, an inhalation exposure of approximately 100,000 ppm results in death within several hours, with autopsies revealing congestion and sdema of the lungs and hyperemia of the kidneys and liyar* Test animals exposed to an inspired *' *' \ eir 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 concentra tions exceeding 1000 ppm and occasionally approaching 10,000 ppm before OSHA standards were Instituted in 1974. At these levels, workers manifested dissiness, headaches, and/or euphoria* Long-term exposure to these levels in vinyl dhloride 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 ? l AP00012257 I* SUMMARY Almost 7 billion pounds of vinyl chloride ere produced* in the United Stetes annually. Most emissions into the environ ment originate from manufacturing plants Which use the compound for 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 chloride exposure for most Americans is probably from polyvinyl chloride food containers* This source contributes approximately 1 ppb to the diet* Vinyl chloride has also been found in drinking water. Three national surveye of drinking water have demonstrated the presence of vinyl chloride at very low levels (ug/1 range) in a small number of supplies* i Upon ingestion, vinyl chloride is rapidly absorbed from the gastrointestinal tract and is distributed to the liver and other organs. Several pathways may be involved in vinyl chloride metabolism, which occurs primarily in the liver* The toxicity of vinyl chloride appears to be attributable to its enzymatic conversion to reactive polar metabolites such as chloroacstaldehyde or chloroethylene oxide. Several of these suspected meta bolites are mutagenic, while vinyl chloride itself is not, accord- a ing to available information. At low doses (e.g*, 1 mg/kg) the metabolites of vinyl choride ere primarily excreted in the urine. APOOO12258 L o ca tio n s P o ly v in y l C h lo rid e o P f l V an i t n s y iln Ch th lo e rid e Uni t an ed d B t a t e s (M ilb y , 1978) AP00012259 XI-2 resins for various industrial purposes (about 85 percent); (3) about 8*000 PVC fabricating plants (U.S. EPA* 1975b)* Vinyl chloride and polyvinyl chloride are used as raw materials in the rubber* paper, glass and automotive indus tries. In addition* vinyl chloride end polyvinyl chloride are used in the manufacture of electrical wire insulation and cables* piping* industrial and household equipment* medical supplies* food pacfcmging materials and building and construction products* Polyvinyl chloride end 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)* t APOOOf2260 IV. PHARMACOKINETICS A. Absorption and Distribution An Investigation by Duprat at ai. (1977) indicates that inhaled vinyl chloride is rapidly absorbed by the lungs and immediately accumulates in the liver. In this study, rats were exposed in a chamber to 20,000 ppm Me vinyl chlo ride for 5 minutes, and then the distribution of radioactive vinyl chloride in the various body organs was determined. After 10 minutes exposure, radioactivity was found in the liver, bile duet, digestive lumen, and Sidneys With increas ing time (up to 3 hours), activity was detected in the urinary system, salivary and lacrimal glands, skin and thymus. s Using male Wistar rats, withey (1976) determined that vinyl chloride is rapidly absorbed from the gastrointestinal tract following gastric intubation of aqueoua solutions containing 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 wars given single oral doees (gavaga) of 0.05, 1, or 100 mg/kg of 14C- vinyl chloride dissolved in corn oil, and tha routes and rates of elimination 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 AP00012261 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 ^C-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 after 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. However, 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 al. (1976) studied the tissue disposition of l^c-vinyl chloride in rats. Immediately after exposure by inhalation of 50 ppm vinyl chloride for 5 , AP00012262 TABLE IV-1 Percentage of the Administered Activity per Gram of Tissue After Administration ef,,(Hc) Vinyl Chloride by Gavage to Male Sprague-Davley Rats* (Watanabe et al., 1976a) Tissue 0*05 Pose (mo/hq)^ 1.0 100 Liver Skin Carcass Plasma Muscle Lung Pat 0.172 + 0.025* 0.070 + 0.023 01*027 + 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 + 0.002 0.053 + 0.007 0.031 + 0.003 0.061 + 0.003 0.045 + 0.008 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. * Mean + SE, five rats per dose - Rot detectable above background * Vinyl chloride dissolved in corn oil APOOOt 2263 IV-4 TABLE IV-2 Percentage of 1*C Activity per Gram Tissue 72 hr Follotfing an inhalation Exposure to (1*0 Vinyl Chloride For 6 hr In male Sprague-Davley Rata (Watanabe et al.# 1976b) Percentage 1*C activity Tissue Liver Shin Carcase Plasma Muscle Lung Fat Kidney ExDosure concentration 10 ppm 1000 ppm 0.139 0.009* (0'.3S)c 0 -141. + 0.009b 0.145 + 0.008* (9.63JC 0.165 7 0.009b 0.072 4* 0.004 (0.18) 0.073 7 0.004 0.115 + 0.010 (7.64) 0.131 7 0.011 0.048 * 0.004 (0.12) 0.049 7 0.004 0.049 0.004 (3.26) 0.056 7 0.005 0.051 + 0.001 (0.13) 0.052 7 0.001 HD*3 0.052 + 0.005 (0.13) 0.053 7 0.005 0.038 + 0.003 (2.52) 0.043 0.003 0.065 4* 0.007 (0.16) 0.066 + 0.007 / 0.026 + 0.006 (0.07) ,, 0.026 7 0.006 0.046 4> 0.001 (3.06) 0.052 7 0.001 NDd 0.079 + 0.003 (0.20) 0.080 + 0.003 0.057 + 0.005 (3.79) 0.065 + 0.006 * Expressed as percentage of total 1*C activity per gram of tissue. Uncorrected for expired VC* dpm per q tissue total dpm recovered Mean + 8E from four rats. b Expressed as percentage metabolized 1*C activity per gram tissue. Corrected for expired VCt dean per o of tissue -Total dpm recovered minus dpm of expired VC Mean *_ SE from rats. c Hicrograra equivalents vinyl chloride per gram of tissue, d not detectable, detection limit for plasma and fat was 3 ug/g of tissue (3ppm) APOOOI2264 1-3 dose-response relationships in humans are vary scares because of 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 tumora of different types at diffarent sites, and that the incidence and ralative distribution ara influancad by .v dose, age of the fnimal, and species and strain of animal used. Angiosarcomas of the liver were found in all animals studied, whereas 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 jchjLoride exposures to have a carcinogenic affect to be SO. ppm, a recent ly completed Ingestion study demonstrated the occurrence of hepat-- -- I ` '* ie angiosarcomas and pulmonary angiosarcomas in rate 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 exposed 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 AP00012265 1-4 type of cancer (25 - 30 cases/year in the United states), and it is reasonable to infer a causal relationship betveen exposure to vinyl chloride and the development of this tumor. Through 1977# a total of 64 cases of liver angiosarcoma have been identified worldwide among vinyl ehlorlde-exposed Industrial workers* Although rare* the carcinogenicity of vinyl ehloride to humans is unambiguous* .\ The international Agency for Research on Cancer (XARC) analyzed the available data and concluded that exposure to vinyl chloride results in sn increased carcinogenic risk to humans. The organs most likely to be effected were the liver# brain# lung and hemato-and lymphopoietic systems. j The National Academy of Sciences (1983) also examined the data and concluded that vinyl chloride is an established carelnogen 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 chemieal 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 noroi- * AP000I2266 1-5 nally Increase the risk of one excess cancer per million (10*)* per hundred thousand (10s). or per ten thousand (104) people over a 70-year lifetime assuming daily consumption at the stated exposure level. From the NAS model it is estimated at the 95% confidence limit that consuming tvo liters per day over a lifetime having a vinyl chloride concentration of 100 ug/1, 10 ug/lorlug/ would increase the risk of one excess cancel per J.0,000^ 100,000 or 1.000,000 people exposed, respectively. 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 r --- - vinyl chloride concentration of 200 ug/1, 20 ug/1 or 2 ug/1 would increase the risk of one excess cancer per 10.00o\ 01!00,000 or 1,000,060 ~people' exposedT respectively. The numerical differences observed after utilizing the NAS and CAG risk estfmatas are due to the eelection of data for use s in the model. The NAS 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 et al. (1975) etudy but based its estimate upon the increased incidence of total tumors in rats exposed to vinyl chloride through inhalation. r AP00012267 II. INTRODUCTION Vinyl chloride bee been used for over 40 years in the production of polyvinyl chloride (PVC), the most widely used materiel in the manufacture of plastics throughout the world. About 25% 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 chloride production in the United States rose 14% annually, reaching a production level of nearly 7 billion pounds in 1978 (US. Int. Trade Coma.}. This increase in vinyl chloride production was due to the growing dependence of virtually every branch of industry and commerce upon products and components fabricated from polyvinyl chloride (U.S. EPA, 1974). (For the location of vinyl chloride and polyvinyl chloride manufacturing and processing plants in the United States in 197B, refer to Figure XI-1.) Vinyl chloride is not known to occur in nature (National Academy of Sciences, 1977). The compound is synthesised as Chlorinated olefinic hydrocarbon monomer from petrochemical feedstock and chlorine. In 1975, vinyl chloride emissions in the United States were found to originate free three major sources* (1) 17 plants Vhere vinyl chloride was commercially synthesised (about 11 percent) j (2) 41 PVC plants where the vinyl chloride monomer was used in the production of PVC APOOOf2268 IV-5 hours ia a closed system* the percentage incorporated as 1*Cradioactivity 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. Fortyeight 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. Because 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 ensyaes. There is strong evidence that the toxicity of this compound is attributable to its ensymatic oxidation to reactive polar metabolites. Several of these suspeeted metabolites are strongly mutagenic* while vinyl chloride itself is not (Bartsch end Mentesano* 1975). Exposure to vinyl chloride leads to the reduction of non-protein sulfhydryl. levels in rat livsr* suggssting that ths metabolites of vinyl chloride conjugate with glutathione and/or cysteine (Hefner at al., 1975a). Hathvay (1977) reported in vitro depurination of calf thymus DNA by chloroacetaldehyde identical to that observed in hepatocyte AP00012269 IV-6 DHA following administration of vinyl chloride to rats in vivo. This suggests that vinyl chloride metabolites may interact with some purine and pyrimidine residues of DNA, providing a possible explanation for the oncogenic properties associated with vinyl chloride. In a review of the literature, Bartsch and Montesano (1975) report two possible biotransformation schemes - one involving alcohol dehydrogenase (scheme Z) and the other involving the mixed function oxidase sygtea (Scheme II). These are indicated below* Scheme Ii Scheme II* C1HCCH2------>C1H2C-CH20H------>C1H2C-CH0------->C1H2C-C00H o C1H-CH2----->CH2C-CHCl3--->dH2OCHO--->C1H2C-C00H i Evidence for biodegradation involving the alcohol dehydrogenase pathway includes data Which demonstrates that prstrsatxDsnt of rats with either ethanol or pyrasole (an inhibitor of alcohol dehydrogenase) inhibits the metabolism of vinyl Chloride (Hefner et ml., 1975a). Thera is also ample evidence that the mixed function oxidase (MFO) system is involvsd in the metabolism of vinyl chloride. Fretreatment of rats with phenobarbital, which which induces the MFO system, also enhances livsr toxicity of vinyl chloride (Jaeger et al., 1974). Rat liver mlcrosorees catalyze the covalent binding of vinyl Chloride metabolites to APOOO12270 XV-7 protein and nucleic acids (Kappus et al., 1975; 1976); chloroethylene oxide, Which la thought, to be formed by the MFO system, may be the primary microsomal metabolite capable of alkylating these intra-cellular macroiaolecules (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 exposed 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 end 220 ppm. This group also found evidence that oxidases in the microsomee may be involved in metabolism at high level exposures. In another study. Bolt et al. (1977) subjected rats to an inspired concentration of l^c-vinyl chloride ranging from 200 to 1200 ppm in a closed system, and measured the rate of decrease of vinyl chloride levels in the Chamber atmosphere. This group calculated that saturation of the vinyl chloride-metabolising enzymes of the rat is achieved at 250 ppm. AP000I2271 IV-8 C. gxcrstion Excretion of activity within?2 hours follcwing a single oral doss of labeled vinyl chloride (0.05, 1,0, or 100 mg/kg) is shown in Tabls ZV-3 (Watanabe et al., 1976a) As the doss increases, a markedly greater proportion of vinyl Chloride is expired unmetabolised, while the percent age of metabolite.in,the urine decreases substantially, " * \ Again, saturation kinetics 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 as indicated in Table IV-4. Buchtsr st al. (1960) examined the metabolic elimination of vinyl chloride in Rhesus monkeys. Rhesus monkeys were plaeed in a closed exposure system into Which vinyl chloride was in jected, 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 chlorida in Rhesus monkeys is a dose-dependent, saturable process, as in rats. Elimination was shown to obey s first-order law AP00012272 1V-9 TABLE IV-3 ' Percentage of Administer** i4C Activity Recover** Poll owing a Single Oral Dose of Vinyl Chloride* (Watanabe et al., 1976a) 0.05 v Pose (mg/fcg) 1.0 100 Expiredt AS VC As CO2 Urine Feces Careass and tissues Cage wash6 Total recovery 1.43 4 0.13P 2.13 4 0.22 8.96 4 0.59 13.26 4 0.47 V in o +1 68.34 59.30 4 2.75 2.39 4 0.52 2.20 4 0.39 o CD* 10.13 + 1.93 11.10 4 0.47 .0 4 0.45 , 91.25 4 2.47 88.83 4 1.98 66.64 4 0.67 2.52 4 0.13 10.84 jr 0.95 0.47 4 0.06 1.83 4 0.14 0 82.30 4 0.43 a Percentage of dose excreted ever 72 hr. Only the activity associated with the expired VC can be attributed to VC per se. b Mean + 8E five rats per dose. c Distilled water wash of metabolism cage at termination of the study. APOOOf2273 IV-10 TABLE ZV-4 14C-cont*ining Urinary Metabolites from Mala Spragua-Dawlsy Rata Oivan Vinyl Chloride by Gavage* (Watanabe at al., 1976a) Compound iDose (ag/kg) 0.05(4)b 1.0(5) 100(5) A) H-acatyl-S-(2hydroxyethyl- cyeteine) 30.4 + 2.0 B) Thiodiglycolic acid 25.6 + 1.9 C) Unidentified 3B.6 2.9 Total 94.6 36.2 + 3.9 23.7 + ** 1.1 34.5 + 4.6 94.6 29.1 + 25.4 0.9 36.6 + 2.0 91.1 * Metabolite* war* saparatad and quantitatad by high pressure.liquid chromatography. Value* are axpraaaad as percentage of total urinary radioactivity. b ( ) Humber of animals par dose c Mean 4 SE o. CM AP00012274 IV-11 below 200-300 ppm, and at high coneantrations tha maximal velocity of metabolic alimination'of vinyl ehlorlda was about half that of rats whan ralatad to kg body weight* Green and Bathway (1975) Matured the excretion of 1*Cvinyl chloride administered to rats by intragastric, intravenous (femoral vein), or intraperitoneal routes* Two doses were usedj b.25 mg/k^ and 450 mg/kg* The results are shown in Table XV-5. During the first 24 hours after treatment, *re than 90 percent was exereted 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 lunga when vinyl chloride was administered intravenously. For the intraperitoneal route, 43.2% was exhaled while 41.51 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 Tabls IV-3)* Hithey and Collina (1976) have developed a statistical modal for use in equating oral dose levels of vinyl chloride to Inhalation exposure levels in rats, using blood level AP00012275 IV-12 TABLE IV-5 (Green and Hathway, 1975) OP RADIOACTIVITY IN RIOS' GIVEN A SINGLE DOSE OP (14ClVINYL OUORlDe re each dosed i.g. with 250ug of l^Cl vinyl chloride per kg in corn oil solution, and another 4 rats ware each tlarly with 450 ag of [Hc| vinyl chloride per kg* 4 rata were each injected in the fenoral vein with 250 ug of l chloride per kg in H-(O-^ydixncyethyl)lactaBid0. Pour rata ware each Injected i.p. with 250 ug of l^Clvinyl Mr kg in N-(0*hydrotcyethyl) lactawide, and another 4 aniaals were each injected aiailarly with 450 sg of |Hc| ride. -- . --- ............ -............. ' ' Tine (h) Radioactivity excreted (% of does)* * i Intraoastrlc Intravenous Intraceritoneal Exhaled air Urine Paces Exhaled air Urine Feces Exhaled air Urine Feces Vinyl 002 chloride Vinyl chloride 092 Vinyl 002 chloride 0-24 3.7 + 1.2 12.6 + 1.1 71.5 + 5.0 2.8 + 2.5 99.0 + 0.8 0.1 0.5 0.1 43.2 + 4.6 10.3 + 2.2 41.5 + 4.8 1.6 24-48 0.9 3.3 1.6 0.7 1.6 0.2 48-72 0.3 * '' 0.2 Total 3.7+ 1.2 13.5 + 1.3 75.1 + 4.2 4.6 + 3.0 99.0 + 0.0 0.1 0*5 0*1 43.2 + 4.6 11.0 +1,.2 43.1 + 5.7 1.8 0-24 91.9 4- 2*5 24-43 48-72 Total 91.9 + 2.5 0.6 0.1 0.7 4.5 + 2.3 0.4 0.8 0.3 0.1 5.4 + 2.2 0.7 * * 96.2 + 4.1 0.7 96.2 + 4.1 0.7 2.5 + 0.9 0.1 0.1 2.6 + 0.9 0.1 > shown are the asm + 8.D. of those nans. ooO ro hO IV-13 'tin* curves. The authors concluded that "if the total daily liquid intake contained 20 ppm vinyl chloride, then the area generated under the blood level time curve, for rats, would be equivalent to an inhalation exposure of about 2 ppm for 24 hours.* Thus, according to this model, inhalation exposure is ten times more efficient than oral exposure. v s / AP00012277 V. HUMAN EXPOSURE 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 Water, Food, and Air" (Letkiewicz 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 dally 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 1983) and the estimated number of these water systems that 1 APOOOI2278 ( Table .Y-I# Total Estimated Cumulative Population (In Thousands) Exposed to Vinyl Chloride In Drinking Water Exceeding the Indicated Concentration System type Number of people served in U.S. Cumulative population (thousands) exposed to concentrations (uqTI) of: (thousands) 2i.o >5 >10 >20 >30 >40 >50 >60 >70 Groundwater Surface water Total (% of total) 73,473 140,946 214,419 (100%) 1,063 859 1,922 (0.9*) 591 118 118 118 na 00 000 591 113 118.9 118 lie (0.3%) (0-1%) (0.1*) (0.1*) (oa%) 118 __ 0 118 (0.1%) 118 0 118 (0-1%) 0 a 0 (0.0%) APOOO12279 ? contain a given level of ylnyl chloride. An estimated 1,922,000 Individuals (0.94 of the population of^TlM19,00Q)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 (65S) 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/1) 2i.o >5.0 >10 >50 >70 Persons using supplies exposed to Indicated levels % ot 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 (uq/kq/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. Populatlon- 3 i AP00012280 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 10s ug/1 x persons (mean worst case), and 2.3 x IQ8 ug/1 x persons ^worsj) case). Assuming a consumption rate of 2 liters of water/day, population-exposure values of 2.2 x lo7 ug/day x persons (best case), 3.0 x 107 ug/day x persons (mean best case), 4.6 x 108 ug/day x persons (mean worst case), and 4.6 x 108 ug/day x persons (worst case) were derived. b. Diet No data were obtained on levels of vinyl chloride found In foods in the United States. Therefore, no estimates of the dally intake of vinyl chloride from the U.S. diet could be made. ^y^ 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 Brodzlnsky 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. Brodzlnsky and Singh (1982) calculated a median air level of 0.0 ng/m3 (0.0 ug/m3) 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 end the median and maximum levels for vinyl chloride reported above. The estimates In Table IV-III indicate that the dally 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 APOOO12281 Table Y-III. Estimated Respiratory Intake of Vinyl Chloride Exposure (ug/m3) Intake (ug/kg/day) Rural/remote (0.0) Urban/suburban (0.0) Source dominated (0.0) Maximum (2,100) ) ^ 0.0 90 Assumptions: 70-kg man, 23 ni3 of air tnhaled/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 fn 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 aifesorptiofurate 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. Brodzlnsky 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, drinking water would be the predominant source of vinyl chloride exposure it all drinking water levels above 0 ug/1. An accurate 5 APOOOf2282 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 Rural/remote v Concentration in air urban/suburban source dominated j ^ Maximum Cug/1)l!(0.0 ug/m3)(2,100 ug/m3) 0 0.0 (--) 690 (0%) 1.0a 0.02a (ioo%) 690 (<0.01%) 5.0b 0.14 (100%) 690 (0.02%) 10 0.29 (100%) 690 (0.04%) scfi 1.4 (100%) 690 (0.2%) 70e 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/m3: 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) b591,Q00 Individuals using public drinking water systems are estimated to be exposed to levels > S.O 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). ^118,000 individuals using public drinking water systems are estimated to be exposed to levels > 80 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 AP00012283 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. 7 APOOOt 2284 VI. HEALTH EFFECTS IN ANIMALS A. Acute/Chronic Effects . ^ Acute toxicity testa with vinyl chloride were carried out by Patty et al. <1930) of the Bureau of Hines, 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 concentre- 4.* / . \ tions 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 chloride in mice, rats, guinea pigs, rabbits, t cats, dogs (Peoples and Leake, 1933; Lester et al., 1963; Mastromatteo et al., 1960; Haley, 1975; Prod&n 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 summarized 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 exposed 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 AP00012285 VI-2 light increase in the liver weight wee observed. Rets, guinea pigs, rabbits, end dogs expofted to 50 ppm (7 hours/day, 130 times in 189 days) appeared to be normal in appearance, mortality, 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 ng/l for 4 hours/day for $ months. CardiWascular disorders, changes in the bioelectric activity of the hypothalamus, hyperadrenalineaia, osteoporosis and resorption of bone tissue were observed* Jaeger (1975) conducted experiments with rats to determine the interaction between vinylidene Chloride (1,1DCS) and vinyl chloride. In this study, hepatotoxicity was measured by the. elevation of serum alanine-el-- ketoglutarate transaminase (AKT)/ When fasted rats were exposed to 0.02% (V/V), 1,1-DCE, serum AXT activity was elevated about 50fold, two hours after the termination of a 4-hour inhalation exposure. JTo elevation was observed when 0*1% vinyl chloride was administerad alone* When the two chemicals were administered simultaneously at the levels indicated, no elevation of serum AKT occurred* Thus, the vinyl Chloride was protective* These two monomers are used together in fehe production of vinyl copolymers, and exposure to both agents in the workplace was reported by Kramer and Mutchler (1972). AP00012286 VI-3 B. Teratogenicity John et al. (1977) examinad the effoots of vinyl chloride inhalation on the fetuses of mica* rats* and rabbits. Tha pregnant animal* vara exposed 7 hours daily to concantratlons of 5Q or 500 ppm for mica and 500 or 2500 ppm for rata and rabbits. Kica and rats vara expoasd on days 6 to 15 of gestation, and^rabbits on days 6 to 18. f * * Ho taratoganie effect* ware observed at 2500 ppm in rats and rabbits# except that a greater incidence of dilated ureters ware 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 VCt - --Wiijw* *<*>*: . i u.-r Wi;r. * . . \-4j.fr* centers of ossification of the skull and sternebrae) Mice were the most sensitive to vinyl chloride. Mo teratogenic / effects were noted in the fetuses of mice exposed to 50 ppm# but a .significantly greater incidence of unfused sternebrae and delayed ossification of sternebrae (no. 5) and bones of the skull ware observed among litters of mice exposed to 500 ppm compared to uaexposed controls. Ssibryotoxic effects were not generally noted# but some decrease in fetal body weight and erown-rmqp length was observed in rats and mice. APOOOf2287 Vl-4 Radike #t al* (1977ft) did not observe gross (nonmicro- 9 scopic) abnormalities in the offspring of rata exposed 4 hours daily on ths 9th to the 21st Hay of gsstation by inha lation of 600 or'6000 ppm vinyl chloride. A small incrsasa in ths ineidsnes of minor skeletal abnormalities, including wavy ribs, sxtra 14th ribs and dslaysd calcification of small bonss, were observed In the offspring of the exposed animals* However, the investigators concluded that such a small incidence* is difficult t'b distinguish from a sporadic occurrence, and should be considered to be skeletal variants and not malformations. Groups of pregnant CF-1 mice, Sprague-Dawley rats and Hew Zealand white rabbits were exposed to doses of vinyl Chloride ranging from 50 to 2500 ppm by inhalation. Exposure to these concentrations of vinyl Chlorlds did not causa any significant embryonal or fetal toxicity and was not teratogenic t in any of the three species tested* (John et al., 1981). C. Mutagenicity Vinyl chloride is mutagenic in e number of biological systems* The mutagenic action of vinyl chloride appears to be dependent upon its metabolic conversion to chemically reactive metabolites (e.g., chloroethylene oxide, 2 chloroacetaldehyde ) The mutagenic effects of vinyl chloride have been demonstrated in* (1) metabolically activated systems AP000I2288 VI-6 cells of rats after exposure to paradichlorobenxsne at various dose levels. Xn this study, benxene and vinyl chloride were used as positive controls. The results of the vinyl chloride control showed that vinyl chloride was effective in producing chromosome damage in rat hone narrow after the multiple exposure regime. P. Carcinogenicity Evidence'has been accumulated in recent years impli cating 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. Ths first experimental data on the carcinogenic effect of vinyl chloride in rats were published by Viola et al., in 197i; preliminary results of an investi gation concerned with the oncogenic potential of vinyl chloride in experimental animals followed (Maltoni and Lefemine, 1974). These initial reports spurred a series of retrospective epidemi ologic investigations of workers in the vinyl chloride industry and supportive experimental studies in animals. Several comprehensive reviews and symposium proceedings have been published on the subject (e.g., Selikoff and Hammond, 1975; Proceedings of the Royal Sociaty of Medicine, 1976; U.S. CPA, 1975c; Kilby, 1978). AP00012289 VI-5 using Salmonella tvphlaurium (Bartsch at al., 1975; McCann t il., 1975; Elmers at al., 1976; Rannug at al., 1974; Garre at al.. 1976) davalopad by Anas at al. (1973) in which tha ganatie indicator rafers to histidina prototrophy by basa-pair substitutions* or by basa-pair insartions or dele tions; (2) Escherichia coli K12 bioaaxotrophic strain with back mutation systam arginine 4 (Grain at al.. 1975); (3) several specie* of. yaast inducing forward nutations and gana *\ convarsions at spacifie loci (Loprieno at al.* 1976* 1977); (4) in gam calls of Drosophila (Verburgt and Vogel, 1977) and (S) Chinese hamster V79 calls (Hubsman at al., 1975). Tha literature on tha mutagenic affects of vinyl chloride ware reviewed by Bartsch and Montesano (1975). Th mutagenic activity of inhalad vinyl chloride (3000, 10,000 or 30,000 ppm for 6 houra a day for 5 daya) was / assessed in infertile aale CD-I strain mice with ths dominant lethal assay (Anderson t 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 teats indicated that tha dominant lethal effect was' expressed in the CD-I mice used in these experiments. Anderson and Richardson (1976) conducted a cytogenic study investigating mutagenie effects in the bone marrow AP000I2290 VI-11 Tsbls VI-5 biM m* V|NII pps !i TmbiMI KT ST IMS US LAS LA aos OMO) aLm? SLAB a2m.7 Afltato* Wtth tram rr.A Sipt- Kdn> Xrnw- bnU mm It SL act Stis tpT Fir--<> HasB7 FteSAc VT U aLm7 * aLm7 ca4m L7 0*0) IU avow LS *> nSaos* by MutetiHi UYC to afr M.000 pis; < krM>r. 4sj%wk. Car II Mks. nu, H ad F, 17 V Tsbls VI-6 Inula Hill.* TwWIOO Mtealt arr BT LAS Aninalt with toman. 4 t Fspp Km- b Viplaw Knw Ztufati Ska rnnad but LA ELIS XU tsu SL SL CLCfc EpT hiAe KT 1 r Kaftiimawf Ml 4U 4L? U Lt LI L7 - 04 - Li L0 0.4 .7 QUN) OBO mam oust) a*M) W) 004) 004) (fiSM) B.A Kl LO JOX 0*8) 0096) ^aocort by tahatetfee t VC to tor to H rtm 4 Mv, idajVwaak. torttwdu. SpnrB-Itowtojr mi. 11 ud F. 11 *Mk old. Eanfei iur ICt wito <md to Sourest Maltoni, 1981. AP000I229I -"`frrXfr* <nM> as aa TABLE VI-7 im* T--in100 MI W US LA rr.i su ; Bto' Nt^fare- Non- ML tGymLbCail Ekfa ZpT Far*. PtomiUefte linn. Mart XT u BJ B4 ouum aou> u. 8420) LlTlf) (cvtUtimllt) Ml - U a/u - umULuu?nn a/iit) a/UA u a/iji*> a/un - IL0 ar/iao n.c ai/im ema12s.iTt? CUTIf) u ITJ - \ anuso) - - aLuTo> - - S.I (TOO) TABLE VI-8 Tljii'lwiWlTI.* WHOM X tOtJOOOnOOfjpMml *UMQtmintTm0rnmm jp N4lMtMOIM0 t Aidmilt with tenon. 41 Ttmnffltt XT IT LAS LA ELAS ELA Eto(u|t MBnLto K!T bettoal SEpfeT erFwuaiirM4*.h Mmbn> XT U B.I ` B B SU B.I 0L9T0 B 4LT IM SU SU aLLmT7 B B B B B B aatLmmTi B B LT aaauL*mmT B LT (Mn LT 0u40) M1LSB 20.0 OUMO) a1mU aIILLmOT 040) MO) (14L0T) a(MuMUmO) 84to0) auLmT (MLLOTT) 84B0) 04L0T) B (4S4.00) sur JM MJ MJ (MO) B aLLmTT * (MB B B aLmT LT (MB B B (1Bu044t) MB to B 04L0T) (MB B LT 8L4B0I ) 8a4LLm0T7) (MB (MB) 14.T 2M u m to B am 80U10) onOtJo) B to MM) DfMN bf fa-tt- u VC to to * 10.000, 0000, BOO, HO, SO. ind 10 ppm; 4 h*4ajr, dtyWMk, to 17 wdu. StnCflfr'Dnrksr mm, X tad F, tt vtdu M. toaahs itor 104 wvtka (and af aipirinito). Sources Maltoni, 1981. AP000I2292 VI-9 TABLE VI-2 Inddenoe of Tumrs in Bats and Babbits flrrwal to Vinyl Chloride by Ziti&latien (Cqputo et al., 1974) (ppn) 4 hrs/day 5 days/**: 12 Bontha # of Animals Limr Angiosarcomas Oiolanglams Img AdcnoAlveolar Carcdnenas Skin Sqmnous cell Cardnoce Acantbam Other Bats 20,000 150 10,000 200 5,000 2,000 200 200 500 150 50 Vo Treatment 200 i 200 Rabbits 10,000 40 B0 Treatment 20 31 16 12 10 s' 4* - -- 21 16 4 8 - - 6 67 7 34 8 20 2 66 3-- ---- 12 APOOO12293 li VI-10 Table VI-3 an.* Atomk wfth canon. X 1>--llIX XT BT lit LA sus Ci *1 Fan* "T- KSmL> 2rti GLCa 8EUpTn aFtoawAAadci wy 1M*nWtvWr ".T* ojx* vr *r NttmfiMt M) ALT Me BL.T M OJ XI au A* HI JU ms amSLmsT . o(IXaHMUuLm?0xi) MSI t? mu 14 uex mx (MUX Le?x i? (MX .10oX1La4T1x <M0 (MX u (MueXx a1e4x L? aex m it aex aLLeT?x auex uex aaLeeTxx eUux MutXo M1OM) (M14X MX L? (MX cUrLe.Tlx MITX SIT O1Hue1O*x) oUeoi 14 aLeTx am m aIeTx aLeTx * ex am V 14 V MaLeoTX> LT aex m w -- oLeToi 01400} - IX aLmT aex 14 wm aXeXx 1U AS 4 14 MB m aLeTx byVaean tohaliiftw to VC to air * 10,000, 0000, SS00, 100., SO, aad X NOi 4 hrrinr, i 4ayi*na)t, fer fit vttfe. %nrD*wtojr nta, M Mtf r. U-wto aU. SMlto aftar U raka (iaf Table VI-r4 Onenl I "J*. "jr Ur (MtoO tan.* T--a100 Aftfrwdl wfcK tai.y . XT IT LAS LA rt,a ELI *p- Wggta Ncofo> BL Znebal GLCa SEpdTn tonadi FalAe ULTT HT au XL? 10.0 U olux am a/Uiaw fli (MIX U am U (MU) L? au u s unix u onax a/uo) _ aUmx U 01uA1X OMJX u 44 (VIS) aix _ 10 (US) 14 a(4umUX (410.144IX am LT anil) (4LnSto> a1n140if) (4/10) Uf XLt u QUAD e ii aias> Ll MIX LI amx 1.0 MB) Sourcei Maltoni, 1981. APOOOf2294 In animal studies, Viola t al. (1971) reported the carcinogenic response of male rats (AR/IRE Wistar strain) exposed to vinyl chloride by inhalation (Table Vi-l). 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 XRB 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 et 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 Kaltonl (1981), A summary of these results are presented in Tables VI-^3 - VI-19. Vinyl APOOO12295 VI-8 chloride was shewn to cause toners in all tha animal systems tasted (i.e*, mica, rats and hamsters) both through inhalation and ingestion exposure. A clear-out dose-response relationship was shown to exist with carcinogenic effects being seen at exposures as low as 50 ppm. Newborn animals appeared to be especially sensitive to the development of hepatocarcinomas and angiosarcomas and carcinogenic effects on the embryo via the placenta were demonstrated. Table VZ-20 indicates the tumor types that have been correlated to vinyl chloride exposure in experimental animals. TABLE VI-1 Oncogenic Effects of inhaled Vinyl Chloride (Viola t aln 1971) Cone. VC (ppm) 4 hrs/day 5 days/vX 12 months t Number Rats SXin Epider moid Carci nomas Lung Adenocarci nomas a Squamous cell Carcinomas Bones Osteo chondroma 30,000 No treatment 26 25 17 6 5 AP00012296 VI-15 TABLE VI-13 flk9Hai 1 lT (mST* '.rniriii m WIT.* T--illM XT IT LAS LA Animal* with fiiww % Fort* |i Ntetoa Hm> Zvmfari SUb inmirti U w BL SL GLCt EfT PiUf JU aj - IS om At wm At OW> wLmt At (Mt) - - SM 1U AS - LI AM OM) VCii at 2 fpn;4 ftdcjWMk, Ssr B Mks. Wtarnto, M. U aid. Bash* ftr X4 TABLE Vf-14 mmSrSim 1 MLtBBtf tornM* WIKOilTMMB Mm n *VT C--mD TnmAOO tsfenab XT sr f&O MJ CAT UAt 1 At * R| sfits ' tis ms ms ms u.t U.T LAB QITMSA aSSsTLm4T aoamtasLs*oTmmmmss m tmftoui lit* Anfamk wrth tanari. t ^ , tus 1C.T (w(A17AL4WmT0t)) 04A0S) aUw a1LUmT OaSLWmT) aUsmS aLmT aaILSmmT aA/uTo) ELA Imtt ""S"T (aaaiTALASmmmT4Ott 0AA4S0t ) am 0.1 ((4TaAUmW) <aatBMuMss0t)> HaMUmSD) aassm auaIAmmsS aauMMsmsSmt asm AT wm OMI/USO) 0A0T80) fids EpT 7.1 1LmT a(AAmWS ) 0L4S0) LT (IS--O) m oIaSso) 7n* MAC (a1ULC/m8TT6) OSS) CT aLmT (ISO) -- EnMSvbt WMfatka to VC hair tt 16,000,000, IMO, HO, tSO, tad tOppMhrfer, fejnMck, forIO*kA Swin mkt, M A F. U Mk *44- BmqIu aIUt tl WMto mi * Sourest Maltoni, 1981* AP000I2297 VI-16 . TABLE VI-15 h|dnl Bl< Greapreri ST IT Lit Li KLi AataMi* Vfeh tBBflTL * /Uaih (M iimrtir Doat SUB J^T EpT MdK MBKkugwMint hilt muur I SMOOppH n "W *r* v mJT vr Malriitn-- fnirnl) M4 4M 61 B4 04 M ID.* nj Oi S4 am MU Oi * .r am 4KB 4M 4Lf <4 am 4 040) IT 040) _ 4.7 am 40 U am <4 am _ 4.7 040) 4.7 am 04 am iif 040) M.7 am J04 4*40) BM 4*m 81 am S.7 cam 14 040) IT OTO 14 am 10.0 am am 14 am 104 am tu am 104 am K4 am S4 am 14 am C.T am 14 040) m. u am 14 am SJ 0040) 04 aom 4.7 0740) 104 am 114 (440) 104 am 14.7 040) 94 (490) 0.0 090) 14.7 (S90J to.o <490) 0.0 (490) *4 114 am (MO) Tip win *f tt VC fc air at 10,030. <000, SOS, SOD, SO, aed SO ipo; 4 hrAhjr, I dajrafvaak, for SO wttkL Goldaa fcaaatan. H, 11 wib old. Hnaiti ailar 100 *ka (aid of apatenll Hjfg tlwfcwaUr GwcpLl*-7;tkBp 11,274; Creep 01.814; CrP IV, 1*4; GraapY, 224; Gray VI, SS4;G*b^V11. TABLE VI-16 IiMwMITU.1 MLOaLftc n USJB** xn ASupIt* nr oa*a (MM0 Taimoo ST ST LAS flnimila with iniiiim Fare- Sam* u| Nrpkr> Nn, Zysboi State atamaeb narr UL ELAS EL4 taw BL BL 6LC4 EpT PatAc UT AT 1*4 CJ atm aImT 4 am aum - a2m4 - 14 am 14 am 02940) A0 (490) BB4 174 124 -- -- -- U.0 aom B4 u am a1m4 - AT am - a2m4 14 74 090) <*m 0B9.07) 8.7 8J 14 - A* am am <490) MTtjac.p6opwnct<bMy>faDntitiewr nOufn,mMifMfc f<flhra,) rfVC te *Bw U ok> all ifl it <0.00.l*4riS.&nf4ccbodr'*awfat.oredtfiy,44dwwaek.fe& Soufu Ar UC woki (Si of Sourctt Maltoni, 1981. AP00012298 VI-17 TABLE VI-17 S5SL lkanlUD XT IT us Iffanafa wfck tassn. * Fora* Xu- tu SSa U BLia tfava-feraM Sfaa rtnmaA atary BL GLCa Eft ?UA< XT i Uvu o "a** "sr* Ofeaai 4MM0 H.t Bl u AT - AT ttl ms If (VMS (VM AT _ - AT (VMS (VMS (VMS 1U CJ * IAT ax - AS AO AO CV14S CVMI) (1M _ AT U AT (VMS 0140) (VMS AT AT AS CVUO) ooso) avion 0/UO> IS AT 0050) (7/lSa CxpowarSrlutiatliwCitmmhittbalafVCIaafr*aOatLA 0-A O.IB ttffrsbody wight, coatdafly. 44 SayVwatA tor S9 tb ipnifiia Piwiiy nta, M aad T, It ?wb alA BasutU attar 1SS waaka lead af irpirin--U. TABLE VI-18 JEzpcrteatfBTU.* Omp* Twnm'lDO XT XT ZjU Aafeaala witk tam. Far Sl Hapa* X*phreN#w* XjrataJ fida anr XjI SLAB TU Mm BL BL GLCa EpT PiiAt XT 1 4J5bk4 a 4X|xl ni 4SacK* rr IAS JAO LS LS 1AT SAX lit* IAS - OB) -u turn LS (MS (1/M) LS (MS) AS XAO BAS OK) m IS - OM) OK) U - AS AS (MS OSS OSS OK) Orta M AS SLT - AS OSS) E^aMft bjr Itiifii-buoaaJ Settee af VC, 4JS at fa (fin afl a ad), 4,1,1 ipnfwDairirr ntt. M tad T% 17 Mb aid. Xante after 244 vaaka (and t at twa aaott kumb er, Mljr. Sourcxs Haltonl, 1981. i APOOO12299 VI-18 TABLE VI-19 fn tin I1T1L* rzri AiiimlifMaaw.t Simla s?XT XT LAS Bap Haufau Umo tmU Stta Fmm>A Mas- LA SLAB ELI Mu SL SL GLCa EpT PaAA* l I* I l Ulai MS ns 4.0 07*) o* (mmO ns XT O/tt) amt IS 071) Tnmii bf rtrmwmfafrgfeBrfVC.<.*CU ab. ifn^i d^ii Spro-D*i*ym MtriF,!!TkifaL ItakidlvUlvMkiMtftadMM). .* ' \ Abbreviations used In tablaa* r sTo EpjtfwBww ftyfflcwi Am Ad Adi Adtama fa maUfnast tnMfafmtta* tMrT UM LA tL>AS Malignant toner* (tout If not otiianria* pdBd) `l--t`m -f'** UwrnilNansH UmMiiftrm hwMwmilMwi Nqfe8L NepfaroMafnaa ji KAmvBL WiurifciUw--> Anfiofahttte bjpgplaafa is jwr It Antfnhhftir driplaait Jo B*ar KmpmA Haoplaatfc Mthika >W.k7^ yoduIirkyptrpUafaXIftar C+t+tkrp. Difttaad hype^taik ofHirer MwfcM TathtM "lift faddeaeeaf(eta) naUgnant tad beafcataaaw*fcgf*a utbt lata) ember rf tuaon pv 100 animal* <* ardmaTmay baar *or <feu m maEcnaat ar bangs tnaer) an tht bafaa rf *"~m atiaorrtil amrmg iha arirnalr -*------ *-- **- *r~ fafaar ton abaanrtd fa tbs aaparfcMBL TW farfdms tamiw to |w, aa pamio rftba Msal* baaring tt turner iiwiifirsf. Kftmdltlk ssMala Bn vim tbt feet twaer vu ibnmil Cm ireMlmi) Sourest Maltoni, 1981* APOOO12300 VI-19 TABLE VI-20 Hiaon Presently correlated to VC Exposure (by Inhalation) on Experimental Rodents Species Anglo- sarcomas of liver Tumors of brain Timers of lung typhomas and leuKemias -s Hepatanas Anglosarcomas Nephroblastemas Sebe1' ceoqs. cuta neous- car*- ` cinemas Other cutaneous epi- thelial tutors fore-- stomach Ha*- papilloma mary ml car-- scancincmae themas He) nee Rat ^ House l Hamster 1 1 + + f 4 4 + <*) + + (+) 4 4 (+) 4- 4 (+) 4 (4) (+) 4 (4 i > Oo to UJ o VI-20 Maltoni (1981) conclude# from the available data that, vinyl Chloride may produce tumors of different types at m differsnt sites and that the incidsnes and relative distribution are greatly influenced by doss, age of the animal, and species and strain of animal used. J A recently completed study by Feron et al. (1981) examined the oral toxicity of vinyl chloride in Wistar rats* This study was carried out oyer the lifespan of the rats, and consisted of incorporating polyvinyl chloride powder containing a high contant of vinyl chloride monomer in the diet, or using gastric intubation of a 10% vinyl chlorida monomar in soya bean oil. The vinyl chloride monomer doaes (actual exposures) wers 0, 1.7, 5.0 and 14.1. mg/kg bw. through the diet or 300 9/*9 bw by gastric intubation. Ths results showsd that rats sxposed to vinyl chloride monomer at lavals of 5.0 mg/kg bw day or mora demonstrated hepatic angiosarcomas, pulmonary angiosarcomas, and at the higher levels, a few primary extrahepatic abdominal angiosarcomas. At ths lowest exposure level of 1.7 mg vinyl chloride monomer/kg bw/day, liver-call tumors and an increased incidence of foci of eellular alteration were noted. (Tables VI-21 and VI-22). AP00012302 VI-21 QOJS VI-21- Type and Inddenoo of tmtment-nlated histcpethological changes In the liver of rets exposed orally to VOI (Faroe et al. , 1981)^ Incidence of change Type of change! Treatment gnup (mg VCM/kg/itey)... Males Females s 0 1.7 5.0 14.1 300t ;0 1.7 5.0 14.1 300f Aninals killed after 26 wk Clear-cell foci No; of rats examined... 10 | -- 10 0 ---- 1 Animals killed -after 52 vAc 10 0 1 No. of rats exaadned... 9 10 9 Clear-cell foci 1 B** 0 Basophilic foci 0 00 Eosinophilic foci 0 20 Neoplastic nodule 0 l0 Hepatocellular carcinem O 10 Cystic proliferation ofbile ducts 0 0O Aniimls found dead or killed in extremis or terminally Clear-cell foci Basophilic foci Eosinophilic foci Necplastic nodule Hepatocellular cardnann Angiosarocnm examined.. .55 0 8 3 0 0 o 58 56 59 55 57 58 g** 16*** 21*** 9 4 24*** 18 21* 22** 12 0 33*** 23*** 27*** 33*** 11 8 35*** 1 1 7** 2 2a3***** 3 l 2 26** 04 0 6* 27*** 27 0 0 10 10 5** 2 *10 8** 4 5** 2 1 4* 8 0 1 o 0 o o 59 22*** 17 20* 39*** 19** 2 57 36*** 29*** 29*** 44*** 29*** 9** 54 10 19 6 2 0 29 AP00012303 TABUS VI-21 (Gentlnued) VI-22 Proliferation of atypical sinusoidal calls only Extensive necrosis Cysts Liver-cell polymorphism Centrilobular degeneration Axel haemtcpoiesis 2 4 2. 4 0 0 0 4 3 16* 0 1 4 6 4 28*** 0 0 76 23*** 21 16*** 3 42*** 36 1 '1 10** a "*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 IS 12 ^Specific hepatocellular lesions sn classified according to Squire & Levitt (1975). fThe figures of this group were not efvaluated statistically because no corresponding control group wa Included in the study* $Not examined* The initial timber of anlaals was 60/sex/group. A timber of rats could not be examined bsosuea of cannibalism or advanced autolysis* Values rafted with asteriks differ significantly frcm those of the controls according to the tihi-stjmre tests *P<0.05j **p<0.01> ***P<0.001. AP000I2304 VI-23 TABUS VI-22- Site, type and incidence of tuaours In organs other than the liver* in rate exposed orally to VCM fin over 2-5 yr (Feron et al.t 1981)______________________________________________ Inei&nce of tunoura Site1 and type of tumour Treatment group (on VCM/kq/dav)... Males lanles 0 ~T7T" 5.0 14.1 "300t 6 1.7 5.6 14.1 30frt- Effective no. of rate... No. of rate with primary tunoura... Lunge Angiosarocna Adenana Zyntoal glands * Squanouo-cell cerdncna Adenoma Abdomen Mesothelioma Angiosarocse iFibaroaaracma Osteosarcoma jsaraoma Reticulux-oeli Mteom 'Sdmnfcell tumour' UncLaasified Spleen Haamngioendothsllosarcxim Lynphcearccma Hose Squamous-cell cardnenn Brain Granular-cell nybbiastcna Oligodendroglioma Plexus papillan Glial-cell tumour Ependynona Keaodcirml tumour Pancreas Adenocarcinoma Thorax Mesothelicma Thyroid Parafollicular-cell edencna Parafollicular^cell earcdncna Pollicular-ceii afencna 55 36 0 0 0 0 3 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 1 4 1 0 58 56 59 50 49 52 55 57 44 54 0 4* 19*** 19 0 0 0 0L 1 0 0 2 0' 1 0 0 0 0` 0 0 1 78 000 003 0 0 h o31 100 000 000 11 10 01 10 00 10 00 02 100 000 00 00 001 00 I 00 000 000 0 20 00 1 0 10 00 00 00 10 00 00 000 01 000 00 12* 10 01 00 3 0 1 37 00 01 53 59 56 55 01 0 0 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 0i 0l 30 2i 00 10 00 00 00 00 00 01 00 00 00 00 00 00 00 00 00 20 00 10 AP00012J05  ^ m me m *40 o o o o 1 o o ooo o o mo eo ohoo oo o m oeo o g M gN M oo O O O O 0 4 O O *4 0 0 o m jg O f* od OOOO Of-* O O <> m o jg m J m m mo O O O m OO O O mmm m OO OO m mo OOOO Om m o moo m 7 MO m MO m o O O OO O m moo m e r CO Om m MO O O m O OO O <*> mmo O jn m tMno O OO ooOO mo O m mmo o CD m Mm m Mm m o O o oo O m moo TAGUS V I-2 2 ( S k e le ta l nuncio APOOO12306 VI-25 TAELS VI-22 (continued) Site and type of tumour Incidence of Tumours Hales Reactla* Treatment group (nq VCM/kg/dav) 0 1.7 5.0 14.1 Soot 0 1.7 5.0 14.1 300* Skull Osteens Hcocndymal tunour 10 0' 0 0 0 0 00 00 0 0 0 0 0 ,x 0 0 0 Ear region Adsnocardncna of unkncwn origin 0 0 1 0 0 0 -.0 0 0 0 Urinary bladder N unclassified epithelial tunour 0 0 1 0 00 .0 0 0 0 Preputial glands Squamous-cell carclncma 00 1 0 00 00 0 0 Mawiaiy glands . Adenom 00 0 0 00 00 2 0 \ Fibroadenooa jAdenocercincxm 00 01 0 0 0 0 21 25 12** 4** 7 2 0 3 f4 7 7 \Anaplastic cardnam 00 0 "`0 00 01 0 0 Tastes Interstitial-cell tunour 30 0 11 Uterus Adenocarcincna talignartt fihcosdenonatous tunour Leicnycne 6 31 0 10 0 01 10 0 -o 00 Cervix Mesenchymal type of tumour 2 01 0 0 Adanocarcdnom 0 1Q 0 0 Ovaries Theca-cell tunour 0 01 0 0 amall~rur>er of primary liver tianours unrelated to treatment were found In several groups. Thee tumours were one Kupffer-cell sarcoma* three reticulum-cell sarocmas# two flbroaarootma. one haarnngioendotheliam anl one mesenchimal tumour* jThe figures for this group were not evaluated statistically, because no corresponding control group was included in the study. AP000I2307 IIn several cases the neoplastic character of the lesion wag doubtful. Values narked with asteriks differ significantly fran those of the controls according to the chi-square tests *P<0.05j **P<0.01| ***p<o.ooi. VI-26 Peron at al. (1981) concluded that vinyl chloride monomer is a carcinogen when administered by the oral route, and that M the tumor response seems to shift from the exclusive development of angiosarcomas at very high levels to the exclusive induction of hepatocellular tumors st low levsls of exposure* Feron at si* have also Initiated a similar lifespan oral carcinogenicity study with vinyl chloride in rats, using three different dose levels (0*017, 0*l7 and 1*7 mg''vinyl chloride monomer/fcg bw day) and two control groups* This study is currently in prograss and the results ars not yet available* / AP00012308 VII. HUMAN HEALTH EFFECTS A. Non-carcinocenic Effects ' Vinyl chloride can produce a number of pathological consequences in humans in addition to its carcinogenic affect. These effects can be from acute or chronic exposure to vinyl chloride. Unfortunately, data regarding dose-response relation* ships in humans are Very scarce because of the virtual absence of air measurements of vinyl chloride in the work environment of vinyl chloride sianufacturing and polymerisation plants before 1975 (Mancuso, 1975). According to OSHA <39 PR 12342, April 5, 1974), eeveral 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 alone. Nicholson et al. (1975) reportsd that vinyl chloride in polymerisation reactors may often have exceeded 1000 ppm end occasionally may have approached 10,000 ppm before OSHA standards were instituted. At these levels, workers experi enced diesiness, headaches* and/or euphoria during work periods. Several instances of acute exposure have occurred in vinyl tfilorids plants. Deaths of two Canadian workers were AP00012309 VI1-2 reported by Danxiger in i960 following acuta exposures to vinyl chloride gas. Xt autopsy, there was congestion of the liver, spleen and kidneys. In another study reported by Sueiu 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 for acuta and s.ubacute cases of "occupational disease* from ** .' * * air concentrations ranging from 2,298 mg/m3 (about 900 ppm) to about 100 mg/m3 (about 40 ppm) In anothsr investigation# Spirtas et al. (1975) conducted a survey of 200 vinyl chloride workers and 89 rubber plant workers (controls) where information was sought on tha frequency of eight symptoms, including dizxinsss, loss of consciousness, headaches, etc. The vinyl chloride workers were categorised into low and high exposure groups. Because the exposure limits had bean markedly decreased a short time before the survey, the high exposure group consisted of workers who were exposed to vinyl dhloride concentrations of over 200 ppm before the standard, and 20-30 ppm subsequsntly. 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 statistically significant dose-response relationship for five of the eight symptoms (i.e., frequency of symptoms in the high exposure group * low exposure group < rubber workers), and AP00012310 VI1-3 similar but non-significant brand in two of the remaining symptom categories* Thus there appears to be a dose-response relationship between certain aeute symptoms (predominantly neurological) and level of vinyl Chloride exposure* The data also suggest that vinyl chloride levels below 50 ppm can produce health effects* * The earliest reports of hepatotoxicity in vinyl chloride workers were noted by Trlbukh*et al. (1949); however* the effects were attributed to plasticisers added in the manufaeturing'proeess. The observed concentrations of vinyl chloride ranged from 1 to 470 ppm* Since that time* impaired liver t function has been noted by other investigators (Marstellar et al., 1975; Lilis et al** 1975; Popper and Thomas, 1975; Jaeger* 1975)* * Another effect from chrpnic vinyl Chloride exposure is a condition known as acroosteolysis* Which involves bone lasions 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 numsrous other synptoms. Hany cases of acroostsolysis have been reported and characterized and most involve autoclave workers in vinyl chloride plants (Wilson et al, 1967; Dinman et al., 1971; Barrie and Adams, 1967; Lille et al.* 1975). AP00012311 V2I-4 Other long-term effects induce disturbances of the central nervous system, pulmonary insufficiency, cardiovascular manifestations, and several gastrointestinal symptoms (Hiller et al., 1975} Sueiu 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 Hammond, 1975). '* % Reproductive effects have also been noted. According to a study by Infante (Infante, 1976; Infante et al.. 1976a), the Incidence of birth defects for three small ccomunities in Ohio in which vinyl chloride polymerization plants are located were significantly higher (P<0.001) than those in i either the counties in which these communities are located or 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 csntral nervous system malformations, but no association could be found with vinyl chloride exposure. In another epidemiologic study by Infante et al. (1976b), there was a significant excess fetal loss (P<0.05) in wives whose husbands were vinyl chloride polymerization workers compared to controls (wives of polyvinyl chloride fabrication and rubber workers). The Infante studies suggest an association between vinyl AP00012312 chloride and birth defeets/fetal lots, but they are not yet supported by animal data. Cytoganic stadias have also been conducted. Picciano et al. (1977) reported no statistically significant differences in chromatid and Chromosomal aberrations or proportion of abnormal cells, in a group of 209 vinyl Chloride exposed workers. These workers were exposed for periods ranging from 1 to 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 breakage in a population of vinyl chloride exposed workers* In contrast, Ducatman et al. (1975) and Purchase et al. (1975) have reported increased incidence of chromosomal breakage among vinyl chloride exposed workers. Heath et al. C1977) examined cytoganic effects in three groups of industrial workers * PVC polymerization workers (presumed high exposure), PVC processing workers (presumed low exposure) and rubber and tire manufacture workers (presumed negligible exposure). Actual vinyl Chloride levels were not measured. Chromosome breakage in ell 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 ether agents in addition to vinyl Chloride may cause cytoganic damage in workers employed in the rubber/ plasties industry. _____________- AP00012313 VI1-6 B* Carcinogenic effect* The primary effect associated with vinyl chloride tzpoture in nan is an increased risk of cancer in several organ systems including angiosarcoma of ths liver. Hunan data have been obtained primarily from occupational exposure of workers to vinyl Chloride* Epidemiologic studies of^vinyl Chloride exposed workers have focused on cases of angiosarcoma of the liver* a type of cancer which oceurs infrequently in the general population* about 25*30 cases per year in the United States (Heath et 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 tenuous. * The first study associating vinyl chloride exposure in humans with cancsr was conducted by Creech and Johnson* 1974. Three cases of angiosarcoma in workers at a polymerization plant in Louisville, Kentucky, were described. The remaining portion of this section describes seme of the epidemiologic studies linking vinyl chloride with angiosarcoma and other types of cancer. AP00012314 VI1-7 Tabershaw and Gaffey (1974) conducted a mortality study of vinyl ehloride worker*. Mortality calculations included only those workers Who could be traced, i.e., 7,128 of 8,384 workers. These individuals were frees 33 different facilities and all had been exposed to vinyl chloride for at least 1 year. The nean 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 overall 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. Dow chemical Co. (Holder, 1974) conducted a mortality study of 594 workers in a single plant exposed to vinyl chloride AP000123)5 t Vll-b between 1942 and I960* Workers were assigned to exposure groups based on the highlit level of exposure for at least 1 month (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 excursions of 1000 ppm. Total mortality was 91 percent of expected among,*.the vinyl chloride exposed workers* No deaths n due to liver cancer were reported, and only 13 cases of neoplasms were reported as opposed to 15*4 expected* However, nine of these malignancies occurred in the high exposure group, es 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. / 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 expected (a statistically significant difference). A 900 per cent increase in cancers of the liver and biliary tract was noted (five aagioeareoaas) Excluding angiosarcoma, a 275 percent excess in numbers of cancers was observed. Two brain AP000123f6 VI1-9 tumor* (320 percent excess) and 13 lung cancers (60 percent xctia) war* observed. In addition, tha overall cancer death rate increased during the period. Nicholson et al. (1975) studied a group of 257 worker* (of whose 255 war* traced) exposed to vinyl chloride for at least 5 years subsequent to 1946. their mortality status was evaluated beginning 10 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 liver. Preliminary findings indicated e 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 (NI0SS) conducted a study which Involved 1,294 Individuals who were exposed to vinyl chloride for at least 5 yaars, and for whom at least 10 years had elapsed since initial employment. A total of 136 deaths were reported versus 126.3 sxpected (not a significant difference). A 49 percent increase over the expected number of cancer deaths was noted, a statistically significant factor. A statistically significant exeess number of deaths occurred for brain and CNS cancer, respiratory system cancer, and biliary and liver cancer (Waxweiler et al., 1976). AP000I2317 V1I-10 Ott et al. (1975) have re-examined much of the mortality data reported by Tabershav and Gaffey (1974) and have included more clearly defined exposure levels and follow-up of former company employees. The basic findings remain unchanged* no increase over expected in malignant neoplasms was found in the low exposure 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). Chiaxxe et al.(1977) have reported e crose-sectional mortality study of 4,341 employees from 17 PVC plants who died between 1964 and 1973. No angiosarcoma deaths were identified. Total cancer deaths Increased in white employees (especially due to cancer of the digestive extern) In white women employees* deaths from cancer of the breast and urinary organs were greater than expected. / In contrast* in a mortality study of 7,000 British workers 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). AP00012318 VI1-11 J In Addition, Byren et al. (19T6) traced 750 of 77x Swdih. vinyl chloride plant worker*. A four- to five- _ fold increase over expected in pancreas and liver tumors was found, and two eases were diagnosed as angiosarcoma. The numbers of other tumors did not deviate significantly from expected. i Tea cases of.hepatic angiosarcoma have been found 9 among the relatively small work force employed at a vinyl chloride polymerization 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 theee employees. The authors suggest that the cases of hepatic angiosarcoma appear to be associated with high vinyl chloride exposure levels and overtime work hours. Ho correlation was found between occurrence t of this tumor and alcdhol consumption or cigarette smoking. In workers engaged in the polymerization of vinyl chloride Who were studied by Pepper 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 the fibrotic stage tc angiosarcoma is suggested by the focal proliferation of the sinusoidal lining cells and of the AP00012319 *4.++ hepatocytes that art seen in the fibrotie stage but which becomes even acre pronounced in the initial stages of angio sarcoma development* These findings suggest that the fibrotie lesions without angiosarcomas, frequently observed in workers exposed to vinyl Chloride (Lllis et al*, 1975), might be the prestage of developing neoplastic lesions* The diagnosis of the fibrotie lesions in these workers may imply a longer*`.latency period for tumor initiation based on a lower exposure level* The aeries of changes observed in the liver appear to represent a multi-centric development of angiosarcoma and are similar to the Changes induced by Thorotrast and inorganic areenieala (Baric et al* 1976). * In the most recent update of the UIOSH register (Spirtas and Karoinaskl, 1978) a total of 64 cases of hepatic angio sarcoma have been identified worldwide among vinyl chloride exposed industrial workers A listing of ell documented cases by country is presented in Table VII-1. The number of cases per year is depicted in Figure VI1-1. Of the 64 cases, 23 have been reported in the United States* The authors reported that both the ege 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? AP00012320 V2I-13. And (3) random fluctuation* Zf the trand of increased age at diagnoais and tha longer latent period for hepatic angiosarcoma induction are indeed related to lover levels of occupational 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 hypothesised that inhalation of low levels of vinyl chloride by the general public in the vicinity of vinyl chloride/PVC manufacturing plants could be responsible for an increased risk of angiosarcoma of the liver development* t 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 cases* 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 exposure, not specifically related to occupation, might be important in the etiology of this disorder" (Brady et al., 1971). AP00012J21 The International Agency for Research on Cancer (1979) examined the available data on hunaas and concluded that ex posure to vinyl chloride results in an increased carcinogenic riak to humane. The organ systems most likely to be affected were the liver, brain, lung, and hemato and lymphopoietic systems* \ AP00012322 ms vii-i tojicwrooBB of the him In Vinyl ChlorideAVC Worker (Spirtas end Kaminski, 1978) Oorntrv Case Ho. Birth Date let VC Of PVC Exposure Diagnosis of Anqlosarccra Belgium Canada Canada Canada Canada Canada Canada Canada Canada Canada Canncfa Czechoslovakia Cfeectaetatakia Pad Rep Gncmiy Fed Rep Garnery Ped Rep Garnery Pad Rep Garnery Pad Rep Garnery Fed Rep Garnery Fed Rep Garnery Fed Rep Gernety Fed Rep Gernety Prance Franca 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' 0000-41 00-00-45 00-00-44 00-00-47 00-00-46 00-00-61 00-00-46 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 01-00-46 07-06-59 00-00-46 10-19-49 00-00-65 00-00-58 07-01-50 05-23-57 00-00-44 02-00-66 00-00-00 00-00-55 00-00-57 00-00-62 00-00-67 00-00-68 00-00-71 00-00-72 00-00-73 00-00-74 00-00-76 00-00-73 00-00-66 09-19-68 09-25-70 00-00-74 00-00-75 00-00-75 00-00-75 06-16-76 06-28-77 00-00-77 02-18-67 01-08-75 01-00-75 01-04-76 04-00-76 09-00-76 07-00-76 12-03-76 12-00-72 12-00-74 Age at Diagnosis 00 41 43 42 48 5s7i S3 53 53 61 46 40 38 39 44 43 49 58 42 47 41 43 63 55 49 30 42 49 42 71 37 Teen free 1st Exposure to Diagnosis u00 14 21 22 24 24 26 12 28 23 16 15 12 ' 13 17 2113 22 17 22 16 21 15 29 26 11 18 26 19 23 09 Total Years of Exposure 00 U 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 1229 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 Alius 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 APOOO12323 TABLE VII-1 (Continued) Country Cass Birth No. Date 1st VC Of FVC Exposure Diagnosis of Angiosarcoma Age at Diacpnsis Tsars fccn 1st Exposure to Dia^iosis Total Years of Exposure Data of Death Italy Italy Japan Norway Sweden Sweden Uwwilwi U.8.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.8.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* 08* 03* 10* 11* 12* 13* 16* 17* 10* 19* 20* 21* 22* 23* 24* 25* 01* 02* 11-13-29 03-14-20 08-01-22 12-23-15 06-23-27 06-10-10 11-16-14 10-17-23 OB-19-33 05-25-15 01-15-24 01-25-12 11-23-28 05-03-22 05-06-20 11-06-31 08-16-13 05-27-09 11-17-18 12-01-21 11-04-27 05-06-31 04-22-28 00-00-15 08-31-17 09-02-09 10-02-23 00-00-23 05-07-17 08-07-10 04-05-14 11-15-31 00-00-57 00-00-53 04-00-53 03-00-50 00-14-51. 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 05-08-50 06-23-55 09-15-54 00-00-43 00-00-55 12-00-46 07-11-47 09-00-58 00-00-39 02-00-47 00-00-53 00-00-50 12-13-72 07-10-75 08-21-74 '12-20-71 08-00-74 03-19-76 05-12-77 03-03-73 ** 05-00-70 12-19-73 06-19-67 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 04-08-73 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 18 21 31 21 13 28 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 09-28-71 12-19-73 01-07-68 04-09-64 07-24-75 03-23-68 08-29-61 03-00-75 05-10-68 03-16-70 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 04-08-73 07-12-73 AP00012324 VIXI-2 results in proliferation of a neoplasm. This change reflects a mutational event in the DMA of that cell, suggesting that the chemical carcinogen must interact directly with or otherwise alter the PHA to iatiate the Aange. In recent years, however, some eubetaaces have been ehown to be carcinogenic, but by mechanisms in Which there apparently is no direct interaction with or alteration of the DHA of the cell by the substance. Presumably, these compounds are not capable of initiating the alteration of a normal cell to neoplastic one, but can facilitate expression of a neoplastic response in latent cells. * Oa the basis of these purported differences in mechanisms, carcinogens now are often classified into two broad categoriest genotoxic and epigenetic or nongenotoxic. t The mechanisms by nhich a compound exerts its carcinogenicity rarely can be determined by the chronic testing of whole animals such as is done in the NTP bioaseay. Thus, a large number of short-term in vitro and in vivo assay aysteaa 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 remits in certain of these test sytems indicate genotoxielty. The decision as to Whether a substance is genotoxic may be made qualitatively on the baeie of several crlteriat 1) a reliable, positive demonstration of genotoxielty in appropriate prokaryotic and eukaryotic systems in vitror APOOO12325 C 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 effects, 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/ko)(70 kg) (Uncertainty factor)(2 liters/day) 4 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 health 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 derived 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 AP00012326 TABLE VXXI-1 - Basalt* of Viiyl Chloride mtagmieity Stadias A. Assay system Results References In Vitro prokaryotic and eukaryotic systems * Mstabolically actlvatad flalimnella tythlmjiiun yrtoa (Ansa; 4 Barlach at al., 1975 McCam et aIT, 1975 Snore et aT, 1976 Rennug et aT, 1974 Gazro et alT 1976 Escherichia ooli K12 faioauxotraphic strain Yeast ,1 Oam call* of Pwt^>4n. 4 \ 4 Creim et al., 1975 Loprieno at al, 1976, 1977 Verburgt and Vogel, 1977 Chinese hanetar V79 call* 4 Huberamn et al., 1975 B. OKA Hindi no Studies Msuaa tissues (brain, lung, liver, kidney, spleen, pancreas and testes) in Vitro + (Irreversible binding to RSA and OKA) BarToan, 1982 Bat livar sLcxoaenes, reconstituted cytochrcrae P-450 ayetsos and isolated hepatocytae t 4 Goangerich et al., 1981 (Irreversible binding to protein and ENA) Bat livar sdcrasanes with HADEH 4 (Alkylation Of FNA) laib and Bolt, 1977 C. Biochemical or biolooic ccnseauences of ENA danaoe Bone narrow cell* of rata (in vivo) 4 (Chroocaona Andaraon and Richardson, 1976 Bens narrow call# of Chinese hamsters (in vivo) 4 Baslar and Rehrtcrn, I960 (Chcaapscps aberrations and sistar-chrcnetidaxchanges) Cultured peripheral lynpho- + cytes in hunene (viiyl (Chransecraal Chloride exposed workers) abnormalities) Purchase et al., 1978 Purchase at aX., 1975 Ducatman at aT. , 1975 AP00012327 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.r 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 exposed 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 o 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 tissue were observed. AP00012328 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 the 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 feeding, 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 AP00012329 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 AP00012330 I IX-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 were 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 levels 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/m^ (900 ppm) produced euphoria, intoxication and narcosis, in a doseresponse relationship. In an epidemiological investigation, Spirtas et al. (1975) conducted a survey of 200 vinyl chloride workers and 89 rubber plant workers (controls). The vinyl AP00012331 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, headache 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 Non-Carcinogenic Effects Zn 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 Peron et 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. AP00012332 IX-8 Thusf 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 needed to convert from inhalation to ingestion exposure. In the Feron et, a_l. (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-observed*adverse-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 mq/kq/day) (70 kg)j<fn.o ft mg/l^X (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 number should be appropriately reduced if AP00012333 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 al. (1971) reported the carcinogenic response of male rats (AR/IRE Histar 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 except 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 (Haltoni, 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 APOOOf2334 IX-10 inhalation to vinyl chloride at concentrations ranging from 50 to 100,000 ppm for 52 weeks. Angiosarcoma of liver, zymbal gland carcinomas, skin carcinomas, mammary carcinomas and other tumors were found to occur. One ingestion study showed the occurrence of angiosarcoma of the liver, mammary carcinomas and other tumors at 50,0 mg/kg. As discussed in the "Non-Carcinogenic Effects" section, Peron et^ al^. (1981) carried out a lifespan oral toxicity study of vinyl chloride in rats, Wistar rats were exposed to 0, 1.7, 5.0 and 14.1 mg/kg bw vinyl chloride in the diet, or 300 mg/kg bw vinyl chloride by gastric intubation. The results showed that rats exposed to vinyl chloride monomer at levels of 5.0 mg/kg bw or more demonstrated hepatic angiosarcomas, pulmonary angiosarcomas, and at the higher levels, a few extrahepatic abdominal angiosarcomas. At the lowest exposure level of 1.7 mg/kg vinyl chloride, liver-cell tutors and P an increased incidence of foci of cellular alteration were noted. The author concluded that vinyl chloride is a carcinogen when administered by the oral route, and that the tumor response seems to shift from the exclusive development of angiosarcomas at very high levels to the exclusive induction of hepatocellular tumors at low levels of exposure. Epidemiological studies examining the carcinogenic effects of vinyl chloride have also been carried out. The first study associating vinyl chloride exposure in APOOOf2335 IX-11 humans with cancer was conducted by Creech and Johnson, 1974. This study described three cases of angiosarcoma of the liver in workers at a polymerization plant in Louisville, Kentucky. Since that time, a number of studies have also demonstrated this association. Monson et_ a_l. (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 expected (a statistically significant difference). A 900 percent 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. Nicholson et al^. (1975) studied a group of 257 workers (of whom 255 were traced) exposed to vinyl chloride for at least 5 years in a polymerization facility. Exposures were estimated to often exceed 10,000 ppm. Their mortality status was evalua ted beginning 10. years after start of employment until 1974. Among the 24.deaths were 3 cases of angiosarcoma of the liver. 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 AP00012336 IX-12 least 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 haezno-lymphopoietic system. Similar carcinogenic effects were first demonstrated in rats and were later confirmed in mice and hamsters. Although evidence 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". AP00012337 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 (Haltoni et a^L, 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"*), 100,000 (10**5) or 1,000,000 (10"6) respectively, per lifetime. There are several problems with the data used by CAG in risk estimation. The major problem is that inhalation data were used, and the relationship between oral and inhalation exposure toxicity is not well understood. AP00012338 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 the 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 Kuse 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 (10~5jf or 1,000,000 (10~6) 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 Health, 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 available at this time. Using the AP00012339 IX-15 NAS data, the excess cancer risk concentrations associated with 10~4, 10*"5, and 10* 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 o liver tumors in rats (Radike et al., 1977) and vinyl chloride was demonstrated to have protective effects when administered with 1,1-dichloroethylene (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, newborns and alcohol consumers may be particularly sensitive to the effects of vinyl chloride. AP00012340 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 (lO-6) people exposed, respectively, per lifetime. iii i AP00012341 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. ICI Report CTL/P/293. November 1976 (Unpublished). Anon. 1973. FDA to propose ban on use of PVC for liquor use. Food Chemical News, May 14, pp. 3-5. Bartsch, H, C. Malaveille, and R. Montesano. 1975. Human, rat and mouse liver-medicated mutagenicity of vinyl chloride in S. typhimurium strains. Int. Jour. Cancer. 15:429-437. Bartsch, H. and R. Montesano. 1975. Mutagenic and carcinogenic effects of vinyl chloride. Mutat. Res. 32:93-114. Basalaev, A.V., A.N. Vazine, and A.G. Kochetkov. 1972. On the pathogenesis of changes developing due to a long-term exposure to the effect of vinyl chloride. Gig. Tr. Prof. Zabol. 16(2):24-27 (in Russian). Basler, A. and G. Rohrborn. 1980. Vinyl chloride: An example of evaluating mutagenic effects in mammals in vivo after exposure to inhalation. Arch. Toxicol. 45:1-7. Baxter, P.J., P.P. Anthony, R.N.M. MacSween, and P.J. Schever. 1977. Angiosarcoma of the liver in Great Britian 19631973. Br. Med. Jour. 2:919-921. Becker, W.C. October 10, 1979. Letter from B.F, Goodrich, Chemical Division, to J.P. Lehman, Director, Office of Solid Waste, U.S. EPA. Comments on EPA proposed additions to hazardous waste list. 44 FR 49402, August 22, 1979. Bergman, K. 1982. Reactions of vinyl chloride with RNA and DNA of various mouse tissues in vivo. Arch. Toxicol. 49: 117-129. AP00012342 X-2 Berk, P.D., J.F. Martin, R.S. Young, J. Creech, I.G. Selikoff, H. Falk, P. Watanabe, B. Popper, ana L. Thomas. 1976. Vinyl chloride-associated liver disease. Ann. Intern. Med. 84 *717--731. Boettner, E.A., G.L. Ball, and B. Weiss. 1973. Combustion products from the incinerator of plastics. EPA Report 670/2-73-049. (PB 222 001). Bolt, H.M., H. Kappus, A. Buchter, and W. Bolt. 1976. Disposition of (lr2-14C) vinyl chloride in the rat. Arch. Toxicol. 35:153-162. Bolt, H.M., R.J. Laib, H. Kappus, and A. Buchter. 1977. Pharmacokinetics of vinyl chloride in the rat. Toxicology 7:179-188. Brady, J., F. Liberatore, P. Harper, P. Greenwald, W. Burnett, J.N.P. Davies, M. Bishop, A. Polan, and N. Vianna. 1977. Angiosarcoma of the liver: an epidemiologic survey. J. Natl. Cancer Inst. 59(5)*1383-1385. Braker, W. and A.L. Mossman. 1971. Matheson Gas Data Book, 5th Edition. East Rutherford, N.J., Matheson Gas Products, pp. 561-564. Brodzinsky,R. and Singh, H.B. 1982. Volatile organic chemicals in the atmosphere: an assessment of available data. Prepared by SRI International for Office of Research and Development, U.S. EPA, Research Triangle Park, N.C. Contract no. 68-02-3452 < Buchter, A., J.G. Filser, H. Peter, and H.M. Bolt. 1980. Pharmacokinetics of vinyl chloride in rhesus monkeys. Toxicology Letters. 6:33-36. Byren, D., G. Engholm, A. Englund, and P. Westerholm* 1976. Mortality and cancer in a group of Swedish VCK and PVC production workers. Environ. Health Perspect. 17:167-170. Caputo, A., P.L. viola, and A. Bigotti. 1974. Oncogenicity of vinyl chloride at low concentrations in rats and rabbits. IRCS 2:1582. Chiazze, L., W.E. Nichols, and 0. Wong. 1977. Mortality among employees of PVC fabricators. Jour. Occup. Med. 19(9):623628. Creech, J.L. and M.N. Johnson. 1974. Angiosarcoma of the liver in the manufacture of polyvinyl chloride. Jour. Occup, Med. 16:150-151. Danzinger, H. 1960. Accidental poisoning by vinyl chloride. Can. Med. Assoc, Jour. 82*826-830. AP000I2343 X-3 Delorme, F. and G. Theriault* 1978. Ten cases of angiosarcoma of the liver in Shawinigan, Quebec. Jour* Occup. Med. 20*339-340. Dilling, W.L,, N.B, Tefertiller, and G.J. Kallos. 1975. Evaporation rates of methylene chloride, chloroform, 1,1,1-trichloroethane, trichloroethylene, tetrachloroethylene and other chlorinated compounds in dilute aqueous solution. Environ. Sci* Technol. 9(9)*833-838. Dinman, B.D., W.A. Cook, W.M. Whitehouse, and H.J. Magnuson, 1971, Occupational acroosteolysis. Arch. Environ. Health. 22:61-73. Dressman, R.C. and E.F. HcFarren. 1978. Determination of vinyl chloride migration from polyvinyl chloride pipe into water. Am. Water Works Assoc. Jour. 70:29-30. Ducatman, A., K. Hirschhorn, and I.J. Selikoff. 1975. Vinyl chloride exposure and human chromosome aberrations. Mutat. Res. 31*163-168. Duprat, P., J.P. Fabry, D. Gradiski, and J.L. Magadur. 1977, Metabolic approach to industrial poisoning* blood kinetics and distribution of 14C-vinyl chloride monomer (V.C.M.). Acta. Pharmacol. Toxicol. Suppl. (Kbh) 41(1); 142-143. Edmonds, L.D., H. Falk and J*E. Nissim. 1975, Congenital malformations and vinyl chloride. Lancet 2:1098. Elmore, J.D., J.L. Wong, A.D. Laumbach, U.N. Streips. 1976. Vinyl chloride mutagenicity via the metabolites chlorooxirane and chloroacetaldehyde monomer hydrate. Biochem. Biophys Acta. 442*405-419. FDA. 40 FR 40529, September 3, 1975, Federal Reporting Data System. 1983. Facilities and population served by primary water supply source (FRDS07), April 19, 1983. U.S, Environmental Protection Agency, Washington, D.C. Feron, V.J., C.F.M. Hendrikson, A.J. Speek, B.P. Til and B,J. Spit. 1981. Lifespan oral toxicity study of vinyl chloride in rats. Fd. Cosmet* Toxicol. 19*317-331. Filatova, V.s. and E.S. Gronsberg. 1957. Sanitary hygienic conditions and work in the production of polychlorvinylic tar and measures of improvement* Gig* I. Sanit. 22*38-42. Fox, A,J. and P.F* Collier. 1977. Mortality experience of workers exposed to vinyl chloride monomer in the manufacture of polyvinyl chloride in Great Britian. Br. Jour* Ind* Med. AP00012344 X--4 Garro, A.J., J.B. Guttenplan, and P. Miluy. 1976. Vinyl chloride dependent mutagenesis: effects of liver extracts and free radicals* Mutat. Res. 38:81-88. Gay, B.W., P.L. Hanst, J.J. Bufalini, and R.C. Noonan. 1976. Atmospheric oxidation of chlorinated ethylenes. Environ, Science Technol. 10:58--67. Green, T. and D.E. Hathway. 1975. The biological fate in rats of vinyl chloride in relation to its oncogenicity. Chem. Biol. Interactions. 11:545-562. Greitn, H., G. Bonse, Z. Radwan, D. Reichert, and D. Henschler 1975. Mutagenicity in vitro and potential carcinogenicity of chlorinated ethylenes as a function of metabolic oxirane formation. Biochem. Pharmacol. 24:2013-2017. Groth, D.H., D.W. Lynch, W.J. Moorman, L.E. Stettler, T.R. Lewis, W.D. Wagner and C. Kommineni. 1981. Pneumoco niosis in animals exposed to poly (vinyl chloride) dust. Environmental Health Perspectives. 41:73-83. Guengerich, F.P., P. Mason, W. Stott, T. Pox, and P.G. Watanabe. 1981. Roles of 2-Haloethylene oxides and 2-haloacetaldehydes derived from vinyl bromide and vinyl chloride in irreversible binding to protein and DMA. Cancer Res. 41:4391-4398. Haley, T.S. 1975. Vinyl chlorides how many unknown problems? Jour. Toxicol. Environ. Health 1:47-73. Harris, D.K. and W.G. Adams. 1967. Acro-osteolysis occurring in men engaged in the polymerisation of vinyl chloride. Br. Med. Jour. 3:712-714. Hathway, D.E. 1977. Comparative mammalian metabolism of vinyl chloride and vinylidene chloride In relation to oncogenic potential. Environ. Health Perspect. 21:55-59. Heath, C.W., Jr., C.R. Dumont, J. Gamble, and R.J. Waxweiler. 1977, Chromosomal damage in men occupationally exposed to vinyl chloride monomer and other chemicals. Environ. Res. 14:68-72. Heath, C.W., Jr., H. Falk, and J.L. Creech, Jr. 1975. Characteristics of cases of angiosarcoma of the liver among vinyl chloride workers in the United States. Ann. N.Y. Acad. Sol. 246:231-236. Hefner, R.E., Jr., P.G. Watanabe, and P.J. Gehring. 1975a. Preliminary studies on the fate of inhaled vinyl chloride monomer in rats. Ann. N.Y. Acad. Sci. 246:135-148. AP00012345 X-5 Hefner, R.E., Jr*, P.G* Watanabe, and P.J. Gehring. 1975b. Percutaneous absorption of vinyl chloride. Toxicol. Appl. Pharmaco. 34:529-532. Hill, J.f H.P. Kollig, D.P. Parris, N.L. Wolfe, and R.G. Zepp. 1976. Dynamic behavior of vinyl chloride in aquatic ecosystems. SPA 600/3-76-001. (PB-249 302). 63 p. Hoffman, D., C. Patrianakos, K.D. Brunnemann, and G.B. Gori. 1976. Chromatographic determination of vinyl chloride in tobacco smoke. Anal. Chem. 48:47-50, Holder, B. 1974. Dow Chemical Company testimony presented at public hearings on proposed standard for occupational exposure to vinyl chloride. U.S. Dept. Labor, Washington, D.c., June 25. Huberman, E., H. Bartsch, and L. Sachs. 1975. Mutation induction in Chinese hamster V79 cells by two vinyl chloride metabolites, chloroethylene oxide and 2-chloroacetaldehyde. Xnt. Jour. Cancer. 16:639-644. International Agency for Research on Cancer. 1974. IARC monographs on the evaluation of carcinogenic risk of chemicals to man. Vol. 7. Lyon, Prance. International Agency for Research on Cancer, 1979, IARC monographs on the evaluation of carcinogenic risk of chemicals to man. Vol. 19. Lyon, France. International Commission on Radiological Protection. 1975. Report of the task group on reference man. ICRP publication 23. New York: Pergamon Press. Infante, P.F. 1976. Oncogenic and mutagenic risks in communities with polyvinyl chloride production facilities. Ann. N.Y. Acad. Sci. 271:49-57. Infante, P.F., J.K. wagoner, and R.J. Waxweiler. 1976a, Carcinogenic, mutagenic, and teratogenic risks associated with vinyl chloride, Hutat, Res. 41:131-142. Infante, P.F., J.K. Wagoner, RJ. Waxweiler, A.J. McMichael, and H. Falk. 1976b. Genetic risks of vinyl chloride. Lancet 1:734-735. Jaeger, R.J. 1975. Vinyl chloride monomer: comments on its hepatoxicity and interaction with 1,1-dichloroethylene. Ann. N.Y. Acad. Sci. 246:150-151. Jaeger, R.J., E.S. Reynolds, R.B. Conolly, M.T. Moslen, S. Szabo, S.D. Murphy. 1974, Acute hepatic injury by vinyl chloride in rats pretreated with phenobarbital. Nature 252:724-726. AP00012346 X-6 John, J.A., F.A. Smith, B.K.J, Leong, and B.A. Schwetz. 1977* The effects of maternally inhaled vinyl chloride on embryonal and fetal development in mice, rats, end rabbits, Toxicol. Appl. Pharmacol. 39:497-513. John, J.A., F.A. Smith, and B.A. Schwetz. 1981. Vinyl chloride: inhalation teratology study in mice, rats and rabbits. Environmental Health Perspectives. 41:171-179. Kappus, H., H.H. Bolt, A. Buchter, and W. Bolt, 1975. Rat liver microsomes catalyse covalent binding of 14c-vinyl chloride to macromolecules. Nature 257: 134-135. Kappus, H., H.M. Bolt, A. Buchter. and W, Bolt. 1976. Liver microsomal uptake of (*4C) vinyl chloride and transformation to protein alkylating metabolites in vitro. Toxicol. Appl. Pharmacol. 37*461-471. Killian, D.J., D.J. Picciano, and C.B. Jacobson. 1975. Industrial monitoring: a cytogenetic approach. Ann. N.Y. Acad. Sci. 269:4-11. Kramer, C.G, and J.E. Hutchler. 1972. The correlation of clinical and environmental measurements for workers exposed to vinyl chloride. Am. Ind. Hyg. Assoc. Jour. 33:19-30. Kuzmack, A.M. and R.E. McGaughy. 1975. Quantitative risk assessment for community exposure to vinyl chloride. Environ. Prot. Agency Rept. Dec. 5., Washington, D.C. Laib, R.J. and H.H. Bolt. 1977. Alkylation of RNA by vinyl chloride metabolites j^n vitro and in vivo: formation of l-N-etheno-adenosine. Toxicology"?*185-195. Lee, C.C., J.C. Bhandari, J.M. Winston, W.B. House, P.J. Peters, R.L. Dixon, and J.S. Woods. 1977. Inhalation toxicity of vinyl chloride and vinylidene chloride. Environ. Health Perspect. 21:25-32. Lee, C.C., J.C. Bhandari, J.M. Winston, W.B. House, R.L. Dixon, and J.S. Woods. 1978. Carcinogenicity of vinyl chloride and vinylidene chloride. Jour. Toxicol. Environ. Health 4:15-30. Lester, D., L.A. Greenberg, and W.R. Adams. 1963. Effects of single and repeated exposure of humans and rats to vinyl chloride. Am. Ind. Hyg. Assoc. Jour. 24:265-275. Letkiewicz, P., P. Johnston, C. Macaluso, R. Elder, W, Yu, and C. Bason. 1983. Occurrence of vinyl chloride in drinking water, food and air. Prepared by JRB Associates for Office of Drinking Water, U.S.EPA. epa No. 68-01-6388. AP00012347 X-7 Lilis, R., H. Anderson, W.J. Nicolson, S. Daum, A.S. Fischbein, and I J. Selikoff. 197S. Prevalance of disease among vinyl chloride and polyvinyl chloride Workers. _Ann. N.x. Acad. Scl. 246 122-41. Lillian, D., H.B. Singh, A* Appleby, L. Lobban, R. Arnts, R. Bumpert, R. Hague, J. Toomey, J. Kazazis, M. Antell, D. Hansen, and B. Scott. 1975. Atmospheric fates of halogenated compounds. Environ. Sci. Technol, 9:10421048. Loprieno, N., R. Barale, S. Baroneelli, C. Bauer, G. Bronzetti, A. Cammellini, G. Cercingnani, C, Corsi, G. Gervasi, C. Leporini, R. Nieri, A.M. Rossi, G. Stretti, and G. Turchi. 1976. Evaluation of the genetic effects induced by vinyl chloride monomer (VCM) under mammalian metabolic activations studies jin vitro and _in vivo. Mutat. Res. 40:85-96. Loprieno, N., R. Barale, S. Baroneelli, H. Bartsch, G. Bronzetti, A. Cammellini, C. Corsi, D* Frezza, R. Nieri, C. Leporini, D. Rosellini, and A.M. Rossi. 1977. Induction of gene mutations and gene conversions by vinyl chloride metabolites in yeast. Cancer Res. 253-257. Lu, P.Y., R.L. Metcalf, N. Plummer, and D. Handel. 1977. The environmental fate of three carcinogenss benzota)pyrene, benzidine, and vinyl chloride evaluated in laboratory model ecosystems. Arch. Environ. Contain. Toxicol. 6:129-142. Makk, L., F. Delmore, J.L. Creech, Jr., L.L. Ogden, E.H. Fadell, C.L. Songster, J. Clanton, M.N. Johnson, and W.H. Christopherson. 1976. Clinical and morphologic features of hepatic angiosarcoma in vinyl chloride workers. Cancer 37*149-163. Maltoni, C., G. Lefemine, A. Clliberti, G. Cotti and D. Carretti. 1981. Carcinogenicity bloassays of vinyl chloride monomer: a model of risk assessment on an experimental basis. Environmental Health Perspectives, 41*3-31. Maltoni, C., 1977. Vinyl chloride carcinogenicity* an experimental model for carcinogenesis studies. In: Hiatt, H.H, J.D. Watson, and J. A* Winsten (eds), Origins of Human Cancer, Book a. Cold Spring Harbor Laboratory, 119-146. Maltoni, C, Clliberti, L. Gianni, and P. Chieco. 1975. The oncogenic effects of vinyl chloride administered by oral route in the rat. Gli Ospedall della Vita 2(6):65-66. AP00012348 X-8 Maltoni, C , and G. Lefemine. 1974. Carcinogenicity bioassays of vinyl chloride. I. Research plan and early results. Environ. Res. 7*387-405. Manusco, t.f. 1975. Comments for opening of discussion on "neoplastic effects". Ann. N.Y. Acad. Sci. 246:251-254. Marsteller, H.J., W.K. Lelbach, R. Muller, and P. Gedigk. 1975. Unusual splenomegalic liver disease as evidenced by peritoneoscopy and guided liver biopsy among polyvinyl chloride production workers. Ann. N.Y. Acad. Sci. 246:95-134. Mastromatteo, E., A. K. Fisher, H. Christie, and H. Danziger. I960. Acute inhalation toxicity of vinyl chloride to laboratory animals. Amer. Ind. Hyg. Assoc. J. 21:394-398. McCann, J, , V. Simmon, D. Streitwieser, and B.N. Ames. 1975. Mutagenicity of chloroacetaldehyde, a possible metabolic product of 1,2-dichloroethane (ethylene dichloride), chloroethanol (ethylene chlorohydrin), vinyl chloride, and cyclophosphamide. Proc. Natl. Acad. Sci. 72:3190-3193. McConnell, G.D., M. Ferguson and C.R. Pearson. 1975. Chlorinated Hydrocarbons and the Environment, Endeavor 34:13. Milby, T.H. (ed.) 1978. Vinyl Chloride: An Information Resource. DHEW Pub. No. (NIH) 78-1599. Miller, A., A.S. Teirsten, M. Chuang, I.J. Selikoff, and R. Warshaw. 1975. Changes in pulmonary function in workers exposed to vinyl chloride and polyvinyl chloride. Ann. N.Y. Acad. Sci. 246:42-52. Monson, R.R., J.M. Peters, and M.N. Johnson. 1975. Proportional mortality among vinyl chloride workers. Environ. Health Perspec. 11:75-77, National Academy of Sciences. 1977. Drinking water and Health. Washington, D.C. 783-7B7. National Academy of Sciences. 1983. Drinking Water and Health, Vol. 5. National Academy Press, Washington, D.C. Nicholson, W.J., E.C. Hammond, H. Seidman, and I.J. Selikoff. 1975. Mortality experience of a cohort of vinyl chloridepolyvinyl chloride workers. Ann. N.Y. Acad. Sci. 246:225-230. AP00012349 X-9 Oster, R.H., C.J. Carr, and J.C. Rrantz, Jr. 1947. Anesthesia XXVII, Narcosis with vinyl chloride. Anesthesiology 8:359-361. Ott, H.G,, R.R. Langner, and B.B Holder, 1975. Vinyl chloride exposure in controlled industrial environments a long term mortality experience in 594 employees. Arch. Environ. Health 30:333-33. Patty, F.A., W.P. Yant, and C.P. Waite. 1930. Acute response of guinea pigs to vapors of some new commercial organic compounds. V. Vinyl chloride. Pub, Health Reports 45:1963-1971. Peoples, A.S., and C.D. Leake. 1933. The anesthetic action of vinyl chloride. Jour. Pharmacol. Exp. Therapeutics 48:284. Picciano, D.J., R.E. Flake, P.C, Gay, and D.J. Killian. 1977. Vinyl chloride cytogenetics. Jour. Occup. Med. 19:527-530. Popper, H. and L.B. Thomas. 1975. Alterations of liver and spleen among workers exposed to vinyl chloride. Ann. N.Y. Acad. Sci. 246:172-194. Proceedings of the Royal Society of Medicine. 1976. 69:275-310, Prodan, L., I. Suciu, V. Pislaru, E. Ilea, and L. Pascu. 1975. Experimental acute toxicity of vinyl chloride (monochloroethane) Ann. N.Y. Acad. Sci. 246:154-158. Purchase, I.F.H., C.R. Richardson, D. Anderson. 1975. Chromosomal and dominant lethal effects of vinyl chloride. Lancet 2(7931):410-411. Purchase, C.R. Richardson, D. Anderson, G.M. Paddle, and W.G.F. Adams. 1978. Chromosomal analyses in vinyl chloride-exposed workers. Mut. Res. 57:325-334. Radike, M. et al. 1977a. Transplacental effects of vinyl chloride in rats. Annual Report, pp.183-185. OSPHSES-00159. Center for Study of the Human Environment, Dept. Environ. Health, University of Cincinnati Medical Center. Radike, M.J. 1977b. Effect of ethanol and vinyl chloride on the induction of liver tumors: preliminary report. Environ. Health Perspect. 21:153-155. Radike,M.J., K.L. Stemitter, and E. Bringham. 1981. Effect of ethanol on vinyl chloride carcinogenesis. Environ. Health Perspectives. 41:59-63. AP00012350 1 x-io Rowe, V.K. 1975. Experience in industrial exposure control, Ann. N. Y Acad. Scl. 246:306-310. Rannug, U., A. Johansson, C. Ramel, and C.A, Wachtraeister. 1974. The mutagenicity of vinyl chloride after metabolic activation. Ambio 3:194-197. Selikoff, I.J. and E.C. Hammond (eds.) 1975. Toxicity of vinyl chloride-polyvinyl chloride. Ann. N.Y. Acad. Sci., Vol. 246. Spirtas, R. and R. Kaminski. 1978. Angiosarcoma of the liver in vinyl chloride/polyvinyl chloride workers. Update of the NIOSH Register. Jour. Occup. Ned. 20:427-429. Spirtas, R., A.J. McMichael, J. Gamble, and H. Van Ert. 1975. The association of vinyl chloride exposures with morbidity symptoms. Amer. Ind. Hyg. Assoc. J. 36:779-789. Suciu, 1., L. Prodan, E. Ilea, A. Paduraru, and L. Pascu. 1975. Clinical manifestations in vinyl chloride poisoning. Ann. N.Y. Acad. Sci. 246:53-69. Tabershaw, I.R., and W.R. Gaffey. 1974. Mortality study of workers in the manufacture of vinyl chloride and its polymers. Jour. Occup. Med. 116:509-516. Torkelson, R.R., F. Oyen, and V.K. Rowe. 1961* The toxicity of vinyl chloride as determined by repeated exposure of laboratory animals. Amer. Ind. Hyg. Assoc. J. 22:354-361. Tribukh, S.L., N.P. Tikhomirova, S.V. Levina, and L.A. Kozlov. 1949. Working conditions and measures for their sanitation in the production and utilization of vinyl chloride plastics. Gig. Sanit. 10:38-44 (in Russian) U.S. Department of Agriculture, Agricultural Research Service, Household Food Consumption Survey, 1965-1966, Food and Nutrient Intake of Individuals of the United States. U.S. Environmental Protection Agency. 1974. Preliminary assessment of the environmental problems associated with vinyl chloride and polyvinyl chloride (appendices). Report on the Activities and Findings of the Vinyl Chloride Task Force. EPA 560/4-74-001. (PB-39 110). 106 p. U.S. Environmental Protection Agency. 1975a, Preliminary assessment of suspected carcinogens in drinking water. EPA 560/4-75-003. (PB-244 415). 33p. 1 v , * ^ * AP00012351 u.s. Environmental Protection Agency. 1975b. Standard Support and Environmental Impact Statement: Emission Standard for Vinyl Chloride. EPA 600/6--75-009 (PB249 703) . 536 p. U.S. Environmental Protection Agency. 1975c. Scientific and technical assessment report on vinyl chloride and polyvinyl chloride. EPA 600/6-75-004. (PB-249 461). 116 p. U.S. Environmental Protection Agency. 1975d. National Organics Reconnaissance Survey (Office of Drinking Water), Journal of the American Water Works Association, 67, 11, 634-647, November 1975 and 67, 12, 208. U.S, Environmental Protection Agency. 1977a. The National Organic Monitoring Survey, interim Report, Office of Drinking Water. 126 p. U.S. Environmental Protection Agency. 1977b. Survey of Operating and Financial Characteristics of Community Water Systems (Temple, Barker and Sloane). U.S. Environmental Protection Agency. 1978. Compilation of data from: A Preliminary Report on the Findings of the State Ground Water Monitoring Project and a Second Preliminary Report on the Findings of the State Ground Water Monitoring Project, State of New Jersey, Department of Environmental Protection. U.s. Environmental Protection Agency. 1980a. Memo to Joseph Cotruvo from Robert McGaughy , September 17, 1980, Washington, D.C.: Carcinogen Risk for Pollutants in the Drinking Water -- Comparision of Results Obtained by the National Academy of Sciences and BPA's Water Citeria Program. U.S. Environmental Protection Agency, 1980b. The Occurrence of Volatile organics in Drinking Water (Office of Drinking Water). U.S. Environmental Protection Agency. 1980c. Survey of EPA Regional Drinking Water Representatives to Determine the Ground Water Monitoring Data Developed by State Agencies. U.S. Environmental Protection Agency. 1980d. Compilation of incidents of Drinking Water Contamination with Volatile Organic Chemicals (Office of Drinking Water). U.S. Environmental Protection Agency. 1980e. Ambient Water Quality Criteria for Vinyl Chloride (Office of Water Regulations and Standards). EPA 440/5-60-078. AP000I2352 X-12 U.S. Environmental Protection Agency. 1981a* 0*. w&unity Water Supply Survey (Office of Drinking Water). , u.s. Environmental Protection Agency. 1971b. National Organics Screening Program (SRI). Van Each, G.J. and M.J. Van Logten. 197*>, Vinyl chloride: a report of a European assessment. Fd. Cosmet. Toxicol. 13il21-124. Verburgt, F.G. and E. Vogel. 1977. Vinyl chloride mutagenesis in Drosophila melanoqaster. Mutat. Res. 48:327-33. i > f v Viola, P.L., A. Bigotti, and A. Caputo. 1971. Oncogenic response of rat skin* lungs, bones to vinyl chloride. Cancer Res. 31:516-822. Ward, A.H., S. udnoon, J. Watkins, A.E. Walker, and C.S* Drake. 1976. Immunological mechanisms in the path ogenesis of vinyl chloride disease. Br .Med. Jour. 1:936-938. Watanabe, P.G., G.R. McGowan, and P.J. Gehring. 1976a. Fate of ('*C) vinyl chloride after single oral administration in rats. Toxicol. Appl. Pharmacol. 36:339-352. Watanabe, P.G., G.R. McGowan, E.O. Madrid, and P.J. Gehring, 1976b, Fate of (*4) vinyl chloride following inhalation exposure in rats. Toxicol. Appl. Pharmacol, 37:49-59. Waxweiler, R.J., W. Stringer, J.K. Wagoner, J, Jones, H. Falk, and C. Carter. 1976. Neoplastic risk among workers exposed to vinyl chloride. Ann. N.X, Acad. Sci. 271: 40-48. Weisburger, J.H., and G.M. Williams. 1981. Carcinogen Testing: Current Problems and New Approaches. Science. 214:401-407. Wilson, R.H., W.E. McCormick, C.F. Tatum, and J.L. Creech. 1967. Occupational acroosteolysis. Report of 31 cases, Amer* Med. Assoc. J. 201:577-581. Withey, J.R. 1976. Pharmacodynamics and uptake of vinyl chloride monomer administered by various routes to rats. Jour. Toxicol. Environ. Health l:3Bl-394. Withey, J.R., and B.T, Collins. 1976. A statistical assessment of the quantitative uptake of vinyl chloride monomer from aqueous solution. Jour. Toxicol. Environ. Health 2:311-321. J * AP00012353