Document DvLMmxweMe57Qrxbpwj9Rdkz5

draft f- 'C 'j *4 DRAFT CRITERIA DOCUMENT FOR VINYL CHLORIDE FEBRUARY 1984 HEALTH EFFECTS BRANCH CRITERIA AND STANDARDS DIVISION OFFICE OF DRINKING WATER U.S. ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460 CMA 007112 TABLE OF CONTENTS Z*21 I. II. III. IV. V. VI. VII. VIII. IX. X. XI. SUMMARY 1-1 INTRODUCTION II-l PHYSICAL AND CHEMICAL PROPERTIES III-l PHARMACOKINETICS IV-1 A. Absorption IV-1 B. Metabolism IV-5 C. Excretion IV-8 HUMAN EXPOSURE* V-l HEALTH EFFECTS IN ANIMALS VI-1 A. Acute/Chronic Effects VI-1 B. Teratogenicity VI-3 C. Mutagenicity VI-4 D. Carcinogenicity VI-6 HUMAN HEALTH EFFECTS VII-1 A. Non-Carcinogenic effects VII-1 B. Carcinogenic effects VII-6 MECHANISM OF TOXICITY VIII-1 RISK ASSESSMENT IX-1 QUANTIFICATION OF TOXICOLOGICAL EFFECTS X-1 REFERENCES XI-1 Prepared by the science and Technology Branch CMA 007113 EPA's Carcinogen Assessment Group (CAG) have recently recalculated their excess carcinogenic risk estimates resulting from lifetime exposure to vinyl chloride through the drinking water. CAG based their preliminary revised risk estimates (1984) on the Feron et al.(1981) study. The total number of tumors, considering tumors of the lung and liver, in rats exposed through the diet were used to calculate the excess cancer risk. They calculated that consuming 2 liters of water per day having a vinyl chloride concentration of 1.5 ug/1, 0.15 ug/1 and 0.015 ug/1 would increase the risk of one excess cancer per 10,000 (10-4), 100,000 (10"5) or 1,000,000 (10"6) people exposed, respectively, per lifetime. CMA 007114 I. SUMMARY Almost 7 billion pounds of vinyl chloride are produc d' in the United States 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. Thts source contributes approximately 1 ppb to the diet. Vinyl chloride has also been found in drinking water. Three national surveys of drinking water have demonstrated the presence of vinyl chloride at very low levels (ug/1 range) in a small number of supplies. Upon ingestion, vinyl chloride is rapidly absorbed from the gastrointestinal tract and is distributed to the liver and 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 chloroacetaldehyde or chloroethylene oxide. Several of these suspected meta bolites are mutagenic, while vinyl chloride itself is not, accord ing to available information. At low doses (e.g., 1 mg/kg) the metabolites of vinyl choride are primarily excreted in the urine. CMrt 0071X5 At high doses (e.g., 100 mg/kg), most of the solvent is expir d 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 edema of the lungs and hyperemia of the kidneys and liver. Test animals exposed to an inspired air concentration below 100 ppm exhibit no pronounced adverse health effects. Vinyl chloride does not appear to be terato genic in rats or rabbits, and insufficient data exists to evaluate the teratogenicity of vinyl chloride in humans. Studies on humans working ih vinyl chloride plants sug gest that systemic toxic effects that are noncarcinogenic in nature can be demonstrated at exposure levels below 50 ppm. Some plant workers may have been exposed to concentra tions exceeding 1000 ppm and occasionally approaching 10,000 ppm before OSHA standards were instituted in 1974. At these levels, workers manifested dizziness, headaches, and/or euphoria. Long-term exposure to these levels in vinyl chlor ide plants have resulted in a number of diseases (i.e., acroosteolysis, pulmonary insufficiency), cardiovascular and gastrointestinal manifestations, and disturbances of the central nervous system. Unfortunately, data regarding CMA 007116 1-3 dose-respons relati nships in humans are v ry scarce b cause 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 tumors of different types at different sites, and that the incidence and relative distribution are influenced by \ dose, age of the animal, 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 chlorid exposures to have a carcinogenic effect to be 50 ppm. A recent ly completed ingestion study demonstrated the occurrence of h pat ic angiosarcomas and pulmonary angiosarcomas in rats at levels of 5.0 mg/kg bw/day or more, and the increased incidence of foci of cellular alteration and liver cell tumors at the lowest exposure level of 1.7 mg/kg/ bw/day. Human data have been primarily obtained from workers 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 CMA 007117 1-4 type of cancer (25 - 30 cases/year in the United States), and it is reasonable to infer a causal relationship between exposure to vinyl chloride and the development of this tumor. Through 1977, a total of 64 cases of liver angiosarcoma hav been identified worldwide among vinyl chloride-exposed indus trial workers. Although rare, the carcinogenicity of vinyl chloride to humans is unambiguous. ** * \ The International Agency for Research on Cancer (XARC) analyzed the available data and concluded that exposure to vinyl chloride results in an increased carcinogenic risk to humans. The organs most likely to be affected were the liver, brain, lung and hemato-and lymphopoietic systems. The National Academy of Sciences (1983) also examined the data and concluded that vinyl chloride is an established carcinogen in humans and animals with older animals and females appearing to be more susceptible. The National Academy of Science (NAS) and EPA's Carcin ogen Assessment Group (CAG) have calculated projected incre mental excess cancer risks associated with the consumption of a specific chemical via drinking water by mathematical extrapolation from high-dose anisul studies. Using the risk estimates generated by the NAS (1977-1979) where the linear non-threshold multi-stage model was utilized, the range of vinyl chloride concentrations were computed that would nomi- CMA 0071IS 1-5 / nally increase the risk of one excess cancer per million (106), per hundred thousand (lO^), or per ten thousand (104) people over a 70-year lifetime assuming daily consumption at the stated exposure level. From the HAS model it is estimated at the 95% confidence limit that consuming two liters per day over a lifetime having a vinyl chloride concentration of 100 ug/1, 10 ug/1 or 1 ug/ would increase the risk of one excess cancer per 10,000, 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 . vinyl chloride concentration of 200 ug/1, 20 ug/1 or 2 ug/1 would increase the risk of one excess cancer per 10,000, 100,000 or 1,000,000 people exposed respectively. The numerical differences observed after utilizing the NAS and CAG risk estimates are due to the selection of data for use t 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) study but based its estimate upon the increased incidence of total tumors in rats exposed to vinyl chloride through inhalation. CMA 007119 II. INTRODUCTION Vinyl chloride has been used for over 40 years in the production of polyvinyl chloride (PVC), the most widely used material 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 t* chloride production in the United States rose 14% annually, reaching a production level of nearly 7 billion pounds in 1978 (U.S. Int. Trade Comm.). This increase in vinyl 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 1978, refer to Figure II-l.) 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 from three major sources* (1) 17 plants where vinyl chloride was commercially synthesised (about 11 percent); (2) 41 PVC plants where the vinyl chloride monomer was used in the production of PVC CMA 007120 FIGURE II-l Locations of Vinyl Chloride and Polyvinyl Chloride Plants in the United States (Milby, 1978) i VW3 >Vinyl Chloride Plant Location 'Polyvinyl Chloride Plant Location o o N1 SOURCEt SRI. w PUERTO RICO II-2 r sins 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 and polyvinyl chloride are used in the manufacture of electrical wire insulation and cables, piping, industrial and household equipment, medical supplies, food packaging materials and building and construction products. Polyvinyl chloride and vinyl chloride copolymers are distributed and processed in a variety of forms, including dry resins, plastisol (dispersions in plasti cisers), organosol (dispersions in plasticisers plus volatil solvent), and later (a colloidal dispersion in water used to coat paper, fabric or leather). Cii* 007122 III. PHYSICAL AND CHEMICAL PROPERTIES The structure of vinyl chloride is as follows: H2C * CHC1 Molecular Weight * 62.5 Vinyl chloride is highly flammable (limits of inflamma bility: 4.00-21.70%) and in sufficient concentrations (at least 1200-2000 ppm) has a sweet, pleasant odor. The compound has a boiling point of -13.3*C. Thus, at standard temperature i* * \ and pressure, vinyl chloride exists as a gas. Vinyl chloride is only sparingly soluble in water (0.11 g/100 g water at 28*0), but is soluble in alcohol and very soluble in ether and carton tetrachloride. The specific gravity of the chemical is 0.91; thus it would tend to rise to the surface of water. The vapor density of vinyl chloride is slightly more than twice that of air (CRC Handbook of Chemistry and Physics. 1978-1979; Braker and Mossman. 1971). t The above information indicates that vinyl chloride is volatile and readily passes from water into the gas phase under most laboratory and environmental conditions. This was confirmed in experiments where 16 mg/1 vinyl chloride was added to distilled water in beakers and the concentration determined with time (U.S. SPA. 1974). The data indicate that if first order kinetics are assumed, the volatilization half-life in quiescent water (unstirred) is 290 minutes and CMA 007123 in continually stirred water is 25.fi minutes. Billing, et al. (1975) found similar values for the stirred water. As Billing, et al., note, predictions of vinyl chloride loss from water at relatively high concentrations (e.g., 1 mg/l) may not reflect the situation at very low concentrations. Volatilisation appears to be the most significant process in the loss of vinyl chloride from the aquatic environment (Hill, et al. ,t;1976).. Once in the atmosphere, vinyl chloride undergoes rapid photochemical oxidation (Gay, et al.,1976? Lillian et al., 1975). CMA 007124 IV. PHARMACOKINETICS A. Absorption and Distribution An investigation by Duprat et al. (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 vinyl chlo- ride for 5 minutes, and then the distribution of radioactive i* f - . v vinyl chloride in the various body organs was determined. After 10 minutes exposure, radioactivity was found in the liver, bile duct, digestive lumen, and kidneys. With increas ing time (up to 3 hours), 1*C activity was detected in the urinary system, salivary and lacrimal glands, skin and thymus. Using male Wistar rats, Withey (1976) determined that vinyl chloride is rapidly absorbed from the gastrointestinal tract following gastric intubation of aqueous 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 were given single oral doses (gavage) of 0.05, 1, or 100 mg/kg of 1*C- vinyl chloride dissolved in corn oil, and the 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 CMA 00712 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 aj.. , 1976b), rats were exposed to 10 or 1000 ppm -^C-vinyl chloride for 6 hours and the routes and rates of elimination of *4C 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 ^4C 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 <rt al_. (1976) studied the tissue disposition of ^4C-vinyl chloride in rats. Immediately after exposure by inhalation of 50 ppm vinyl chloride for 5 CMA 007126 TABLE IV-1 Pare ntag of the Administ rad Activity par Gram of Tissue Aftar Administration of, (**C) Vinyl Chloride by Gavage to Male Sprague-Dawley Rats* (Watanabe at al., 1976a) Tissue 0,05 Dose (mq/kg)d 1.0 100 Liver Skin Carcass Plasma Muscle Lung Pat 0 .172 + 0.025b 0 .070 + 0.023 t *, 0 1*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 HDC 0.006 + 0.001 0.011 + 0.001 0.006 + 0.001 a Remaining in the body after 72 hr. b Mean + SE, five rats per dose c Mot detectable above background 6 Vinyl chloride dissolved in corn oil CMA 007127 IV-4 TABLE IV-2 Percentage of 1*C Activity per Gram Tissue 72 hr Following an Inhalation Exposure to (1*0 Vinyl Chloride For 6 hr in sale Sprague-Davley Rats (Watanabe et al^, 1976b) Percentage 1*C activity Tissue Liver Skin Carcass Plasma Muscle Lung Fat Kidney Exposure concentration 10 ppa 1000 ppm 0.139 + 0.009* (0 *35)c 0 *141 + 0.009b 0.145 + 0.008* (9.63)c 0.165 + 0.009b 0.072 + 0.004 (0.18) 0.073 + 0.004 0.115 + 0.010 (7.64) 0.131 + 0.011 0.048 + 0.004 (0.12) 0.049 7 0.004 0.051 + 0.001 (0.13) 0.052 + 0.001 0.049 + 0.004 (3.26) 0.056 7 0.005 ND<* 0.052 + 0.005 (0.13) 0.053 + 0.005 0.038 + 0.003 (2.52) 0.043 7 0.003 0.065 + 0.007 (0.16) 0.066 + 0.007 t 0.026 + 0.006 (0.07) . 0.026 + 0.006 0.046 + 0.001 (3.06) 0.052 7 0.001 NDd 0.079 + 0.003 (0.20) 0.080 7 0.003 0.057 + 0.005 (3.79) 0.065 7 0.006 * Expressed as percentage of total 1*C activity per gram of tissue. Oncorrected for expired VC: dpm per q tissue total dpm recovered Mean + SE from four rats. b Expressed as percentage metabolized **C activity per gram tissue. Corrected for expired VC: dpm per q of tissue Total dpm recovered minus dpm of expired VC Mean + SE from rats. c Microgram equivalents vinyl chloride per gram of tissue, d Not detectable, detection limit for plasma and fat was 3 ug/g of tissu (3ppm) CMA 007128 IV-5 hours in a closed system, the percentage incorporated as 14Cradioactivity per g tissue was highest for kidney (2.13) and liver (1.86). The percent of incorporated activity was 0.73 for the spleen and 0.17 for the brain* 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 dhloride occurs primarily in the liver by microsomal enzymes. There is strong evidence that the toxicity of this compound is attributable to its enzymatic oxidation to reactive polar metabolites. Several of these suspected metabolites are strongly mutagenic, while vinyl chloride itself is not (Bartsch and Montesano, 1975). Exposure to vinyl dhloride leads to the reduction f non-protein sulfhydryl levels in rat liver, suggesting that the metabolites of vinyl chloride conjugate with glutathione and/or cysteine (Hefner et al., 1975a). Hathway (1977) reported in vitro depurination of calf thymus DNA by chloroacetaldehyde identical to that observed in hepatocyte CMA 007129 IV-6 DNA following administrati n of vinyl chlorid to rata in vivo. This auggaata that vinyl chloride metabolitea may interact with aome purine and pyrimidine reaidues of DNA, providing a poeBible explanation for the oncogenic propertiea associated with vinyl chloride. In a review of the literature. Bartach and Montesano (1975) report two possible biotransformation schemes - one * involving alcohol dehydrogenase (Scheme I) and the other involving the mixed function oxidase system (Scheme II). These are indicated below: scheme I* Scheme II* C1HC-CH2------>C1H2C-CH20H------>C1H2C-CH0-->C1H2C-C00H o C1H*CH2*--> [H2C-CHCI]------>C1H2C-CH0------->C1H2C-C00H Evidence for biodegradation involving the alcohol dehydrogenase pathway includes data which demonstrates that pretreatnwnt of rats with either ethanol or pyrazole (an inhibitor of alcohol dehydrogenase) irihibits the metabolism of vinyl chloride (Hefner et al., 1975a). There is also ample evidence that the mixed function oxidase (MFC) system is involved in the metabolism of vinyl chloride. Pretreatment of rats with phenobarbetal, which which induces the MFO system, also enhances liver toxicity of vinyl chloride (Jaeger et al., 1974). Rat liver microsomes catalyse the covalent binding of vinyl chloride metabolitea to CMA 007130 IV-7 prot in and nucl ic acids (Kappus __t al., 1975; 1976); chloroethylene oxide, Which is thought to be formed by the MFO syst m, may be the primary microsomal metabolite capable of alkylating these intra-cellular macromolecules (Laib and Bolt, 1977). Several pathways may be involved in vinyl chloride metab olism, the predominant one depending on dose. Hefner et al. (1975) performed an inhalation study in Which rats were 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 and 220 ppm. This group also found evidence that oxidases in the microsomes may be involved in metabolism at high level exposures. In another study. Bolt et al. (1977) subjected rats to an inspired concentration of ^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-metabolizing enzymes of the rat is achieved at 250 ppm. CMA 007131 IV-8 C. Excretion Excretion of 14C activity within 72 hours following a single oral dose of labeled vinyl chloride (0.05, 1.0, or 100 mg/kg) is shown in Table IV-3 (Watanabe et al., 1976a). As the dose increases, a markedly greater proportion of vinyl ^lloride is expired unmetabolized, 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. Buchter et al. (1980) examined the metabolic elimination of vinyl chloride in Rhesus monkeys. Rhesus monkeys were placed in a closed exposure system into Which vinyl chloride was 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 chloride in Rhesus monkeys is a dose-dependent, saturable process, as in rats. Elimination was shown to obey a first-order law CMA 007132 TABLE IV-3 Percentage of Administered Activity Recovered Following a Single Oral Doee of Vinyl Chloridea (Watanabe et al.f 1976a) Doee (mg/Teg) * * 01.05 v 1.,0 Expired: As VC As C2 Urine Feces 1.43 + o.iab 8.96 i 0.59 68.34 + 0.54 2.13 + 0.22 13.26 + 0.47 59.30 + 2.75 2.39 + 0.52 2.20 + 0.39 Carcass and tissues Cage washc Total recovery 10.13 + 1.93 11.10 + 0.47 0 0.84 + 0.45 , 91.25 + 2.47 88.83 + 1.98 100 66.64 + 0.67 2.52 + .i3 10.84 *95 0.47 + 0.06 1.83 + 0.14 0 82.30 + 0.43 a Percentage of dose excreted over 72 hr. Only the 14c activity associated with the expired VC can be attributed to VC per se. b Mean + SE five rats per dose. c Distilled water wash of metabolism cage at termination of the study. 007 IV-10 TABLE IV-4 l^C-cox&taining Urinary Metabolites from Male Sprague-Dawley Rata Given Vinyl Chloride by Gavage* (Watanabe et al.f 1976a) Compound vDose (mg/kg) 0.05(4)b 1.0(5) 100(5) A) N-aeety1-S-(2- hydroxyethyleysteine) 30.4 + 2.0C B) Thiodiglycolic acid 25.6 + 1.9 C) Unidentified 38.6 + 2.9 Total 94.6 36.2 + 3.9 23.7 + 1.1 34.5 + 4.6 94.6 29.1 + 2.0 25.4 + 0.9 36.6 + 2.0 91.1 * Metabolites were separated and quantitated by high pressure liquid chromatography. Values are expressed as percentage of total urinary radioactivity. b ( ) * Number of animals per dose c Mean + SE CMA 007134 IV-II below 200-300 ppm, and at high cone ntrations th maximal velocity of metabolic elimination'of vinyl chloride was about half that of rats when related to kg body weight. Green and Bathway (1975) measured the excretion of 14Cvinyl chloride administered to rats by intragastric, intravenous (femoral vein), or intraperitoneal routes. Two doses were ueedj 0.25 mgA^ and 450 mg/kg. The results are shown in Table XV-5. During the first 24 hours after treatment, more than 90 percent was excreted from the animals for all three routes. Significant differences were noted, however, in the manner of excretion for the 0.25 mg/kg dose. For the intragastric route, 71.5% was excreted in the urine, whereas 99% was exhaled from the lungs when vinyl chloride was administered intravenously. For the Intraperitoneal route, 43.2% was exhaled while 41.5% was excreted in the urine. At the higher dose (450 mg/kg), over 90% was exhaled as vinyl chloride in both intragastric and intraperitoneal administered rats. The intragastric values are consistent with the values reported in the oral studies performed by Watanabe et al^., (1976a) (see Table IV-3). Withey and Collins (1976) have developed a statistical model for use in equating oral dose levels of vinyl chloride to inhalation exposure levels in rats, using blood level CMA 007135 IV-12 TABLE IV-5 (Green and Hathway, 1975) OP RADIOACTIVITY IN RATS, GIVEN A SINGLE DOSE OF (^ClVINYL CHLORIDE re each doaed l.g. with 250ug of (1*CJvinyl chloride per kg in corn oil solution, and another 4 rats were each ilarly with 450 tag of |14cjvinyl chloride per kg* 4 rata were each injected in the tenoral vein with 250 ug of 1 chloride per kg in N-(B-hydrcwyethyl)lacUuide. Four rats were each injected l.p. with 250 ug of (Hclvinyl per kg in N-(B-hydroxyethyl) lactanide, and another 4 aniaals were each injected similarly with 450 ag of (Me) ride. Tine (h) Radioactivity excreted (% of does)* ___________________________________________ \ Intraoastric Exhaled air Urine Ffeaes Vinyl GOj chloride Intravenous Exhaled air Urine Feces Vinyl chloride 002 Intraperitoneal Exhaled air Vinyl 002 chloride Urine Feces r 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 Sr 0.T 1.6 0.2 48-72 0.3 0.2 Tbtal 3.7 --+ 1.2 13.5 + 1.3 75.1 + 4.2. 4.6 + 3.0 99.0 + 0.8 0.1 -0.5 0.1 43.2 + 4.6 11.0 + 1.2 43.1 w+* 5.7 1.8 f 0-24 91.9 + 2.5 24-48 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+4.10.7 96.2 + 4.1 0.7 2.5 + 0.9 0.1 0.1 2.6 + 0.9 0.1 shown are the means + S*D. of those 7 l3 6 oic: IV-13 time curves. The authors c ncluded that "if th 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. CMA 007137 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" (Letklewicz et al. 1983). This section summarizes the pertinent information presented in that document in order to assess the relative source contribution from drinking water, food, and air. Exposure Estimation This analysis is limited to drinking water, food, and air, since these media are considered to be general sources conmon to all individuals. Some individuals may be exposed to vinyl chloride from sources other than the three considered here, notably in occupational settings and from the use of consumer products containing vinyl chloride. Even in limiting the analysis to these three sources, it must be recognized that individual exposure will vary widely based on many personal choices and several factors over which there is little control. Where one lives, works, and travels, what one eats, and physiologic characteristics related to age, sex, and health status can all profoundly affect daily exposure and intake. Individuals living in the same neighborhood or even in the same household can experience vastly different exposure patterns. Unfortunately, data and methods to estimate exposure of identifiable population subgroups from all sources simultaneously have not yet been developed. To the extent possible, estimates are provided of the number of individuals exposed to each medium at various vinyl chloride concentrations. The 70-kg male is used for estimating intake. a. Water Cumulative estimates of the U.S. populations exposed to various vinyl chloride levels in drinking water from public drinking water systems are presented in Table V-I. The values in the table were obtained using Federal Reporting Data Systems data on populations served by primary water supply systems (FRDS 19E3) and the estimated number of these water systems that I 0?138 I Table V-l. 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. (thousands) Cumulative population (thousands) exposed to concentratl ons (ug/1) of: M.O >5 >10 >20 >30 >40 >50 >60 >70 Groundwater Surface water Total (X of total) 73,473 140,946 214,419 (100X) 1,063 859 1,922 (0.9X) 591 118 118 118 118 00 000 591 118 118 > 118 118 (0.3X) (0.W) (0.1*) (0.1X) (0.1X) 118 0 118 (0.1*) 118 0 118 (0.1*) 0 0 (0.0*) vwo contain a given level of vinyl chloride. An estimated 1,922,000 individuals (0.9% of the population of 214,419,000 using public water supplies) are exposed to levels of vinyl chloride in drinking water at or above 1.0 ug/1, while 591,000 individuals (0.3%) are exposed to levels above 5 ug/1. It is estimated that 118,000 individuals are exposed to levels greater than 60 ug/1. Of the approximately 1.3 million people exposed to levels ranging from 1.0to 5 ug/1, 0.9 million (65%) obtain water from surface water supplies. All exposure to vinyl chloride in drinking water at levels above 5 ug/1 is expected to be from groundwater sources. No data were obtained on regional variations in the concentration of vinyl chloride in drinking water. The highest concentrations are expected to occur near sites of polyvinyl chloride production. Daily intake levels of vinyl chloride from drinking water were estimated using various exposure levels and the assumptions presented in Table IV--II. The data in the table suggest that the majority of the persons using public drinking water supplies would be exposed to intake levels below 0.028 ug/kg/day. Table V-II. Estimated Drinking Water Intake of Vinyl Chloride Exposure level (ug/1) 2.1-0 >5.0 >10 >50 >70 Persons using supplies exposed to indicated levels % of Total Population population 1,922,000 0.9% 591,000 0.3% 118,000 0.1% 118,000 0.1% 0 0.0% Assumptions: 70-kg man, 2 liters of water/day. Intake (ug/kg/day) 20.028 >0.14 >0.29 >1.4 >2.0 An indication of the overall exposure of the total population to vinyl chloride can be obtained through the calculation of population-concentration values. These values are a summation of the individual levels of vinyl chloride to which each member of the population is exposed. An explanation of the derivation of these values is presented in Appendix C. Population- concentration estimates for vinyl chloride in drinking water were 1.1 x IQ7 ug/1 x persons (best case), 1.5 x 107 ug/1 x persons (mean best case), 2.3 x 108 ug/1 x persons (mean worst case), and 2.3 x 108 ug/1 x persons (worst case). Assuming a consumption rate of 2 liters of water/day, population-exposure values of 2.2 x 107 ug/day x persons (best case), 3.0 x 107 ug/day x persons (mean best case), 4.6 x 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 daily intake of vinyl chloride from the U.S. diet could be made. c. Ai r 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/m8 (2,100 ug/m8) (Lillian et al. 1975 cited in Brodzinsky and Singh 1982). High levels, averaging greater than 15,000 ng/m^ (15 ug/m8), have been detected in other areas. Normal levels, however, are somewhat lower. Brodzinsky and Singh (1982) calculated a median air level of 0.0 ng/m8 (0.0 ug/m8) in each of three types of areas: rural/remote, urban/suburban, and source dominated. The monitoring data available are not sufficient to determine regional variations in exposure levels for vinyl chloride. The daily respiratory Intake of vinyl chloride from air was estimated using the assumptions presented in Table IV-III and the median and maximum levels for vinyl chloride reported above. The estimates in Table IV-III indicate that the daily vinyl chloride Intake from air for adults in rural/remote, urban/suburban, and source dominated areas is 0.0 ug/kg/day. In contrast, the intake calculated using the maximum vinyl chloride level reported is 690 ug/kc/day; few if any persons are believed to be exposed at that level. The va'-jes presented do not account for variances in individual exposure or uncertainties in the assumptions used to estimate exposure. 4 CMA 007141 Table V-III. Estimated Respiratory Intake of Vinyl Chloride 3 Exposure (ug/nr) Intake (ug/kg/day) Rural/remote (0.0) Urban/suburban (0.0) ""l ) Source dominated (0.0) ^ Maximum (2,100) 0.0 690 Assumptions: 70-kg man, 23 m^ of air inhaled/day (ICRP 1975). SUMMARY Table V-IV presents a general view of the total amount of vinyl chloride received by an adult male from air and drinking water. Two separate exposure levels in air and six exposure levels in drinking water are shown in the table. Since no data were obtained on levels of vinyl chloride in foods in the United States, the contribution of vinyl chloride in the diet to total vinyl chloride exposure could not be assessed. The data presented have been selected, from an infinite number of possible combinations of concentrations for the two sources. The actual exposures encountered would represent some finite subset of this infinite series of combinations. Whether exposure occurs at any specific combination of levels is not known; nor is it possible to determine the number of persons that would be exposed to vinyl chloride at any of the combined exposure levels. The data presented represent possible exposures based on the occurrence data and the estimated intakes. The relative source contribution data are based on estimated intake and do not account for a possible differential absorption rate for vinyl chloride by route of exposure. The relative dose received may vary from the relative intake. In addition, the relative effects of the chemical on the body may vary by different routes of exposure. Brodzinsky and Singh (1982) calculated a median urban/suburban air level of vinyl chloride of 0 ug/m^ based on air monitoring data. Assuming an air level of 0 ug/m^, d-inking water would be the predominant source of vinyl chloride exposure all drinking water levels above 0 ug/1. An accurate 5 CMA 007142 Table V-IV. Estimated Intake of Vinyl Chloride from the Environment by Adult Males in ug/kg/day (% from Drinking Water) Concentration in drinking water (ug/l_) 0 Rural/remote V Concentration in ai r Urban/suburban Source dominated (0.0 ug/m ) Maximum (2,100 uq/m3) 0.0 (-) 690 (0%) 1.0a 0.028 (100%) 690 (<0.01%) 5.0b 0.14 (100%) 690 (0.02%) 10c 0.29 (100%) 690 (0.04%) 50d 1.4 (100%) 690 (0.2%) 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 Ai r: 0.0 ug/m3: 0.0 ug/kg/day 2,100 ug/m. 690 ug/kg/day Food: Not included al,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). b591,000 individuals using public drinking water systems are estimated to be exposed to levels > 5.0 ug/1 (0.3% of population using public water supplies). c118,000 individuals using public drinking water systems are estimated to be exposed to levels > 10 ug/1 (0.1% of population using public water supplies). d118,000 individuals using public drinking water systems are estimated to be exposed to levels > 50 ug/1 (0.1% of population using public water supplies). eNo individuals using public drinking water systems are estimated to be exposed to levels > 70 ug/1. 6 CMA 007143 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 CMA 007144 VI. HEALTH EFFECTS IN ANIMALS A. Acute/Chronic Effects Acute toxicity tests with vinyl chloride were carried out toy 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 concentretions resulted in ataxia and narcosis* Pathological findings at necropsy were congestion and edema of the lungs and hypere mia of the Xidneys 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, cats, dogs (Peoples and Leake, 1933; Lester et al., 1963; Mastroraatteo et al., 1960; Haley, 1975; Prodan et al., 1975). In animal studies, LC50's at 2 hours ranged from 117,500 ppm / for mice to 230,800 ppm for rabbits. Marsteller et al. (1975) reviewed and 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 CMA 00714 VI-2 light increase in the liver weight was observed. Rats, guinea pigs, rabbits, and dogs exposed 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 mg/l for 4 hours/day for $ months. CardiWascular disorders, changes in the bioelectric activity of the hypothalamus, hyperadrenalinemia, osteoporosis and resorption of bone tissue were observed. Jaeger (1975) conducted experiments with rats to determine the interaction between vinylidene chloride (1,1DCE) and vinyl chloride. In this study, hepatotoxicity was measured by the elevation of serum alanine-c<-ketoglutarate t transaminase (AKT). When fasted rats were exposed to 0.02% (V/V), 1,1-DCE, serum AKT activity was elevated about 50fold, two hours after the termination of a 4-hour inhalation exposure. No elevation was observed when 0.11 vinyl chloride was administered 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 the production of vinyl copolymers, and exposure to both agents in the workplace was reported by Kramer and Mutchler (1972). CMA 007146 VI-3 B. Teratogenicity John et al. (1977) examined the effects of vinyl chloride inhalation on the fetuses of mice, rats, and rabbits. The pregnant animals were exposed 7 hours daily to concentrations of 50 or 500 ppm for mice and 500 or 2500 ppm for rats and rabbits* Mice and rats were exposed on days 6 to 15 of gestation, and rabbits on days 6 to 18. ** t* * > Bo teratogenic effects were observed at 2500 ppm in rats and rabbits, except that a greater incidence of dilated ureters were noted in rats. Indeed, vinyl chloride exposure at this level actually decreased the incidence of certain skeletal anomalies in rats compared to controls (e.g., delayed ossification of the bones of the skull, and unfused centers of ossification of the skull and sternebrae). Mice were the most sensitive to vinyl chloride. No teratogenic j 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 were observed among litters of mice xposed to 500 ppm compared to unexposed controls. Enbryotoxic effects were not generally noted, but some decrease in fetal body weight and crown-run^ length was observed in rats and mice. CMA 007147 Radike at al. (1977a) did not observe gross (nonmicroscopic) abnormalities in the offspring of rats xpoaed 4 hours daily on the 9th to the 21st day of gestation by inha lation of 600 or 6000 ppm vinyl chloride. A small increase in the incidence of minor skeletal abnormalities, including wavy ribs, extra 14th ribs and delayed calcification of small bones, were observed in the offspring of the exposed animals. However, the investigators concluded that such a small incidence' is difficult tJb 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 chloride did not cause any significant embryonal or fetal toxicity and was not teratogenic / in any of the three species tested. (John et al., 1981). C. Mutagenicity Vinyl chloride is mutagenic in a number of biological systems. The mutagenic action of vinyl chloride appears to he 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) metabelically activated systems CMA 007148 VI-5 using Salmon 11a typhimurimn (Bartsch et al., 1975; McCann t al., 1975; Elmore et al., 1976; Rannug et al., 1974; Garro et al., 1976) developed by Ames et al. (1973) in which the genetic indicator refers to histidine prototrophy by base-pair substitutions, or by base-pair insertions or dele tions; (2) Escherichia coli K12 biauxotrophic strain with back mutation system arginine + (Greim et al., 1975); (3) several specie* of. yeast inducing forward mutations and gene conversions at specific loci (Loprieno et al., 1976, 1977); (4) in germ cells of Drosophila (Verburgt and Vogel, 1977) and (5) Chinese hamster V79 cells (Huberman et al., 1975). The literature on the mutagenic effects of vinyl chloride were reviewed by Bartsch and Montesano (1975). The mutagenic activity of inhaled vinyl chloride (3000, 10,000 or 30,000 ppm for 6 hours a day for 5 days) was assessed in infertile male CD-I strain mice with the dominant lethal assay (Anderson et al ., 1976). At these concentrations, vinyl chloride was not mutagenic as judged by scoring of post-implantation fetal deaths, pre-implantation egg losses and reduction in fertility. Positive control tests indicated that the dominant lethal effect was expressed in the CD-I mice used in these experiments. Anderson and Richardson (1976) conducted a cytogenic study investigating mutagenic effects in the bone marrow CMA 007149 VI-6 cells of rats after exposur t paradichlorobenzene at various dose levels. In this study, benzene 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 bone marrow after the multiple exposure regime. D. 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. The 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 compre hensive reviews and symposium proceedings have been published on the subject (e.g., Selikoff and Hammond, 1975; Proceedings of the Royal Society of Medicine, 1976; U.S. EPA, 1975c; Milby, 1978). CMA 007150 VI- / In animal atudi s* Viola _t al. (1971) r port d the carcinog nic response of mal rats (AR/IRE Wistar strain) exposed to vinyl chloride by inhalation (Table VI-1). Skin tumors were first noted at approximately 10 months; tumors in the lungs and bones were observed at about 11 months. Caputo et al. (1974) exposed male and female rats (A and IRE Winstar strain) by inhalation to various concentrations of vinyl chloride * Carcinomas and sarcomas were observed ' in all groups except those Exposed to 50 ppm (Table VI-2). As can be observed* a dose response relationship exists between exposure of 50 to 20*000 ppm. Tumors appeared between 8 and 13 months from the beginning of the inhalation treatment. These investigations also exposed rabbits by inhalation to 10*000 ppm vinyl chloride for 15 months (Table VI-2) and reported the occurrence of lung and skin carcinomas. Recent inhalation studies with albino CD-I mice and CD rats (Charles River Breeding Lab) confirm the carcinogenicity of vinyl chloride at concentrations as low as 50 ppm (Lee 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 Maltoni (1981). A summary of these results are presented in Tables VI-3 - VI-19. Vinyl CMA 007151 VI-8 chlorid was shown to cause tumors in all the animal systems tested (i.e., mice, rats and hamsters) both through inhalation and ingestion exposure. A clear-cut dose-response relationship was shown to exist, with carcinogenic effects being seen at xposures 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 VI-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 et al.r 1971) Cone. VC (ppm) 4 hrs/day, 5 days/wk 12 months t Number Rats Skin Epider moid Carci nomas Lung Adenocarci nomas & Squamous cell Carcinomas Bones Ost ochondroma 30,000 No treatment 26 25 17 -- 6 - 5 - CMA 007152 VI-9 TABLE VI-2 Incidence of Tutor* in Rat* and Rabbits Exposed to Vinyl Chloride by Iztialation (Caputo et al., 1974) (FP") 4 hr*/day 5 dbys/wk 12 nnnths * Of Aninels Liver Angiosarcoma Qtolangiams Lung Alveolar Skin Sqiami Cell Cardnona Awxtham Other 20,000 10,000 5,000 2,000 500 50 No Treatment 10,000 NO Treatment Rat* 150 200 200 200 150 200 200 Rabbits 40 20 31 16 12 ID 4 - -- 21 67 7 16 34 8 4 20 2 8 66 - 3- -- 6 12 - CMA 007153 0 VI-10 Tabl VI-3 BTL* w ith tmnort. * FnKoto* Km- tjabti SUn mtUM* nary Bt GLC* EpT FbAAc XT U.T am U CMD) CMO) IT (MO) U 1L7 *.7 am am aw) LO am & u u u lt u ii il* *.4 lt CLT IM Q3im am XL? . OMII US . IM vaU,,mn u (*_Um_ am u m Kom am U LT ' M - ff"!"? u HT (Mm (mw am am U am u u am - am IM am too as am L7 am am IT am am am M LT am am .7 LT (mo) aao) . 14 am) LT aim am LT (mo) U am LT am L4 am u am Table VI--4 JSSSL i T. mJT mjr For*- Mia- XT BT UB LI BUS Nwhre- New Eynba) Skin eowrh bit BL BL CLCa EpT PaAAc XT mo 2L7 mo is IS U SJ 02020) (4020) OOSD) mo mo 10 0019) -- OOU) aioi SLY Si is is u 0020) 0020) oaosn T5 n - tt (4010) cum (4/120) 14 14 LT 10 (4019) (4019) 0019) 019) is is U 11 OOSD) (1090) (4020) (4020) 117 2LS - - LI LI LI Li LO (SOB) OOSS) OOB) 0W*5) Tn____im iflBM:4toMw.*0w^Bi*12rBBwta.Sasa-Dwteym.Madr.U bwObOIB--toOtorl4Bwfci<e>da(itf(nn Source: Maltoni, 1981* CttA 007154 VI-11 Tabl VI-5 EqvMITi1 ..TiZtITw Awimali with tsnon. % TtoenrtM Ten- )Un XT ST LAS LA ELAS ELA Hapa- NofaaNwa Zymbal tmm BL BL GLCa ads EpT FaAAc la l X9|P 100.0 10.0 SOLO L7 LT SO LT - LT MJ LT 111 M ooen am am am am am omo> am dlAO) Obo) "Espon* by Mialatiw ta VC bi rir at 10,000 ppm; 4 May, 1 dayWwk, for S2 nkk Spngttabtvfcy m, X and F, 17 wwb an Baauha after 68 wb (and atecptrtoimtX Table VI-6 lira* Aaimala with canon. % Bnoatia Ten- Xam- 1 -- "" Bcpn*Kepton- Nam- Zynbal SUn ammidi airy XT ST LAS LA ELAS ELA tanaa BL BL GLCa EpT FaAAc XT Aj.t *1 y a_i t.7 .! B.7 - U Q4/94) (|/94) 994) (HAM) 994) - LI L0 0.4 11.7 994) 994) 994) (0/94) 9.0 BLO ' LO 1CL2 9W) now) m,fTr-~ >yfcAktiMtaVChaii`Bi0Ben:4 today. 6daWmk.fcrOwaahi.Spn>Dtwitr na. XaadF, U wehaotd. Baafciaftai142iakitadXu)iMiO Source: Maltoni, 1981. CMA 007155 TABLE VI-7 1 r r r *9* fj u SLAB SU U 01- ti van wan m SLT MB wMan - IwSan wAa*rn Pm- MhbNotm-NwmZp^al Min Kanacfa wary BL BL GLCa EpT FaAAc XT wan IS Maim LT ouJt) u own anw U OJ aoin oais) U.0 07/1X0) 17.6 01/119) 1S.9 aann 12.7 (IMIS) ^^Mt9jtotatattoBtaVCtoitoaa*^kA^W TABLE VI-8 to VC to a* at 10.000, 0000. MOO. **. M0. J*jM InnhlMl nu, M md F. U wmk W- *** Seurca: Maltoni, 1981- 0071^6 CM* VI-13 TABLE VI-9 ^opa^ EwMltlM Awimaia with onson. % HT BT LAS LA SLAS ELA Fart- Mam Zymfcal SUa mary GLCa EpT PiAAc MX 1 n MOO ppm nr tiinftwaa IV MOOapm it MUM i_ VI "v" 949 840 au * L1 U LT 0J a OJ u TJ It 11.0 0/111) 0019) 0019) 8011) 8018) 01118) 449 u * LT - u aj TJ L7 148 0090) Qfin 0090) 0090) 8090) 8090) (19090) 840 u LT 0l8 * TJ Li 45 144 0/119) 8/119) 0019) Will) 8019) 8019) 00019) 949 u am LT * * * 49 44 L7 9J will) 8011) Will) (4019) 8018) (11018) 4L M LT IS - OJ OJ 47 OJ 48 148 0/119) 8019) 0019) 0019) 0019) (1019) 0019) 0019) 80019) iu U L7 OJ LT OJ -- TJ OJ 140 o/uo) aoao) 0090) 8090) 0090) WUO) 0090) (19090) (mMaO 141 4L0 04am am w OKI) 49 49 TJ 8297) <M2T) 07/227) ty kt-1*t--1 Is VC la a4r at 10,000, MOO, ppm; 4 hr/dsy, 5 d^wik, for I waste (gmopa I and II) or l hr/dsy. 4 dteWwaak, ftr S watte (gnaps m and IV) r 4 te^day. asm waaklp, fcr S waste (pwpa V ad VI) (100 hr). Spmctts-Oawtej nu, M sad r, IS waate aid. BasulU aAa 154 waste (ad af aKparim^X TABLE VI-10 Source: Maltoni, 1981. CHA 007157 VI-14 TABLE VI-11 fuir^i* im1 Aaiwb wilt tawwi, % Fart- Ki b*' Krtw Kw Zyntaal Skin mtrj nr xt LAS LA SLAB ELA tmm BL BL GLC EpT FaAAc XT I IKDyp **!"* MLT tAT OiiiiS m IT Mat n t S4.1 * *' *' OMO * u 4A4 CMS CMMS MU *U i it U U <TA OWB QMS (VOD (US QMS U LI (IMS (1M4) U il OMS ct<s 14 (US Wy--t-hfatoluteWknifB mam--rfmnttnMn.dkrMnv-kdw/--k-fcfw--la (ftnm 1 dT to t kinfwl SfnrM-t>BW7 nU, M A F, fl wwka U Ontdm) (fraopn I 4 II) and asvban (|Mpi 111 nd IV). Result* after 124 w* TABLE VI-12 Sourett Maltoni, 1981. CMA 007158 i T Tf"T-- VI-15 TABLE VI-13 f ij---------- VbmAII) ' Animals with tumors. * "M-B--r- IWll.nBLw--i IlTofa.nMlp Zpmbal Ekm Fan- X? IT LAS LA ELAS ELA ms BL BL GLCa EpT FsAAe Ml M4 - 14 to to (MO) am OM) h i i to OW CM 114 14 " LI 004) ami ljr"-4fc.*hy k WB..iln Witarwja.il 11--haaM RasoiUtfUr U4 * TABLE Vf-14 l 10400 ppm n 0000 ppm "mrsr vr Tamors/lOO1 MT IT 10.0 El it? 100.0 its its El El M.7 M.T LAS 174 oow n.7 OMO) m (MW B4 OOW to aim L? aw n* Anfanab wtthl Fas* LA . rtt it? (Ml) n.7 aw 14 aw 14 aw 114 01W L7 ow 14 (MS) L7 (MO) 114 aw 1L7 aw to aw L? aw otn?m ELA LangT Ca 7.1 (4W to (MO) L? OW) to aw to (MO) 14 aw B.1 MAW TU (CEO) CM MAW) El (BOW) El MMO) 10.0 urn El aiw El CMO) 1S.A <*W) El OW MlO OMO) ELO aim t? M4 M a/iM qvuo) onso) EpT FaAAc 7.1 (4W 11.7 aw) u MW) 14 (MO) L7 CMO) - 14 am 1.7 aw u aw) - L7 aw L7 (MO) (t1l4U) Sourest Maltoni, 1981. CMA 007159 VI-16 TABLE VI-15 1 3080n0 ppa in "Tr "T hr M.U LAS li Bi AO UI 88 AS A3 LT 030) 830) U U 4L3 MU O30T 0A3T0) 030) T?88 B30) 88 AT a 030) AS Ml AJ 038) - AO 40.0 - - - 88 48.7 - - - - __to VC to air at 10.000, 0000.3800. ___ r*- Daet Bfa Mala* atamaeh Lenka** EpT EpT aama. PnAAr AT 830) AT 830) - M (430) 87 830) 87 830) 810 8S3M0) 88380) (130) OAT (830) A3 0A3T0) 830) AS 030) IAS 830) -- - 88 (T3380) (130) 10S 88380) (7103.00) 883.00) 830) AO 830) U 030) IT 030) U a3o> u 030) u (1/SO) IU 0030) B.3 0030' .7 0730) 10.0 (S/30) 18.3 (430) 10.0 (MO) (8/10) 10.0 <30) 8.0 (*30) 1.0 Ui (MO) (MO) , Ml 80 m 4 today. 8 dayi/waak, to 30 Gotten *V. * (kp V, 88; (tonp VI. 88; Gnmp VII. TABLE VI-16 I AOOaf/kt E ]A8af3t Oh>4 ITU.* MT BT LAS LA ELAS ELI 8.7 80 88 AT 0730) 830) AS 830) AS 830) 88 1T8 118 OMO) 80 80 AS 18 830) 030) 87 81 u *** For*- Mam ts- Nm* SL Zrtnbal GLCa Skis EpT otaraacli mary FaAAc MT AS 18 18 A8 AO 830) 030) 030) 830) (430) AT 830) AS 830) 18 7.8 030) (430) AT ` 030) 18 18 to /A/M) Sourest Maltoni, 1981. 007160 Ctl* VI-17 TABLE VI-17 IBT.' AiriMh wtth oasan. * fort- Mm- 1 Ui _ n IV r n ui u au u AT wm ttJ AT AT (1/1483 O/MB 1A0 1A* LT AT 0/M AT (MU) ' b,fan***h.)rfvct.^ Spm^Dwkr nta. M a0 F. 10 aaato alt ** aAar 186 mb <aad MnpataMrtl. u . to AO 04*) 0/140) (11/141) - AT t AT (1/148) 0/141) (4/148) _ AT AT A8 0/180) 0/180) (14/150) AT 0/180) L8 AT 0080) 0/150) i duly, 4-5 djrV*JL, (or 59 wttb TABLE VI-18 im* hmwioo awhmI. rt{ji Qnnorv % It- Man* Nrpfcro- Nrav- Zyaba) Bds aorrarii mtry Sr MT BT LAS LA XLAS ELA mm BL BL GLGa EpT FaAAc MT I 1A8 8A0 - Mb n 4S*C<I ni 4Sa>t nr uwii V OlnttA kjmD 1AT SAS - - Lt on) 1LT' 1BJ . - u am 14 (1*4) SAO AS ta - - - u am o*6) AS SLT - Cipavt hr fpM<DTtey mtrtpts ma, M air.nwISatoaaflVt Cla,a4o1t8o at Si alto afl 0 al), A A * tAaa, altar 144 aaaka CO af a|ia*ad twa aatt 1.8 0*6) 14 0*3) A6 0*8) 14 0*6) to 0*8) A8 0*6) A6 0*8) A6 0*6) at Cy. Source: Melton!, 1981, CMA 007161 VI-18 TABLE VI-19 tniri^wr 1TU. s- Tmn/100 Antonia arttfa onan. Far* Nib- a: "SrMT NT LAS U ELAS ELA Maura Zymtel Son BL GLCa EpT FaAJU 1 um n na M.0 1T4 - * * u SET - - - 14 am 14 am 14 OW * 4.0 (A7S) 14 (V7S) byabeoaiMoa taiMtwp VC, 4Ji !. aii** fl (1 at), a|W tat. SfnfiM-OMrtey nu, M tad r, 21 Mk aid. Abbreviations uaed in tablaa* T Twer Ci Cvaena IpT Eptthriiw H Pwfflew At Acanfhama MTT Malignant tamon (total if not etherwiae (pacified) VT Benign Uaaor* OoUl V not otAenria* paoA*d) US Um miimanrana U liter angkMe EUS Exae-Orar angiaaaTitaa. EU *!* ancham Npfcro-BL NtphroMaanwa Kobb-BL NwwMiai--i A dnglnhiirir h/piTT^* in E--At Aacwbtoif dysplaita is M*w Keep. Md. Neopiaaticuedalearflaar Nad. hyp. Nodular hyparplaija at Iter D& hyp. Diftieedliypeiylaaiaafliov Marked Very aarkad Source: Maltoni, 1981. CMA 007162 VI-19 TABLE VI-20 Tunors Presently correlated to VC Exposure (by inhalation) on Experimental Rodents ________________________________(Haltoni, 1981)______________________________________ Species Angio sarcomas of liver Tunora of brain Timors of lung Lym phomas and leu kemias Hepa tomas Angio sarcomas Nephro blastomas Seba^' OBOUS . cuts neous car- ' cinemas Other cuta neous epi thelial tumors Pore-- stomach paplllcmas mary and car acan cinomas thomas Me) non Rat ^ Mouse 1 Hamster 1 + + + f 4- + (+) + + (+> + (+1 4- (+) 4 (+) (+) 4- (4 c m 007163 VI-20 Maltoni (1981) concludes from the availabl data that vinyl chloride may produce tumors of different types at different sites and that the incidence and relative distribution are greatly influenced by dose, age of the animal, and species and strain of animal used. y A recently completed study by Feron et al. (1981) examined the oral toxicity of vinyl chloride in Wistar rats. This study was carried out over the lifespan of the rats, and c ns isted of incorporating polyvinyl chloride powder containing ' a high content of vinyl chloride monomer in the diet, or using gastric intubation of a 10% vinyl chloride monomer in soyab an oil. The vinyl chloride monomer doses (actual exposures) w re 0, 1.7, 5.0 and 14.1.mg/kg bw.through the diet or 300 mg/kg bw by gastric intubation. The results showed that rats xposed to vinyl chloride monomer at levels of 5.0 mg/kg bw day or more demonstrated hepatic angiosarcomas, pulmonary angiosarcomas, and at the higher levels, a few primary extrahepatic abdominal angiosarcomas. At the lowest exposure level of 1.7 mg vinyl chloride monomer/kg bw/day, liver-cell tumors and an increased incidence of foci of cellular alteration were noted. (Tables VI-21 and VI-22). CMA 007164 VI-21 THUS VI-21- Type and Incidence of treatment-related hiatapethological changes in the liver of rats exposed orally to VCM (Perm et al. , 1981)__________________________________________________ Incidence of change Type of diangel Treatment group (mg VCM/kg/day) Males Females 0 1.7 5.0 14.1 300f 0 1.7 5.0 14.1 300| Aniimle killed after 26 wk Ho. of rats examined... 10 Clear-cell fod 0 t 1 Ho. of rats examined... Clear-cell fod Basophilic fod Eosinophilic fod Heoplastic nodule Hepatocellular cardnona Cystic proliferation of bile ducts 9 1 0 0 0 0 0 -- 10 --1 1-after 52 tdc 9 10 1" 0 -- -- ,,| 10 9 9-- -- 8** 0 0-- -- 00 0-- -- 20 0-- -- 10 0-- -- 10 0-- -- 00 0-- killed in extrends or terminally Ho. of rates examined...55 Clearcell fod 0 Basophilic: fod B Eosinophilic foci 3 Neoplastic nodule 0 Hepatocellular carcinoma o Angiosarcoma 0 58 56 59 55 57 58 9* 16*** 21*** 9 4 24*** 18 21* 22** 12 0 33*** 23* 27*** 33*** 11 8 35*** 1 7** 23*** 3 2 26** 12 8** 1 0 4 0 6* 27*** 27 0 0 -- 10 10 -- 5** 2 -- -- --' -- -- -- -- 10 8** 4 5** 2 1 4* 8 0 1 0 0 0 0 59 22*** 17 20* 39*** 19** 2 57 36*** 28 ** 29*** 44*** 29*** 9** 54 10 19 6 2 0 29 CMA 0 0 7 1 6 5 TABLE VI-21 (Continued) VI-22 Proliferation of atypical sinusoidal cells only Extensive necrosis Cysts Livsr-cell polymDrphisn Centrllobular degeneration Focal haemtepoiesis 2 04 7 6 ''4 6 34 7 4 48 23*** 21 ..5 6 19*** 27** 24 2- 34 16*** 3 9 30*** 41*** 49*** 3 4 16* 28*** 42*** 36 34 51* 38 41 41 0 00 1 112 3 1 18 0 10 10** 8 1 3 1 6 12 'Specific hepatocellular leelone were classified according to Squire fc Levitt (1975). tThe figures of this group were not evaluated statistically because no corresponding control group was included in the study. fNot examined. The initial timber of enirais was 60/sex/group. A timber of rats could net be examined because of dmUslisn or advanced autolysis. Values racked with asteriks differ significantly frem those of the controls according to the Chi-square testt *P<0.05| **P<0.01| ***P<0.001. CMA 0 0 7 1 6 6 VI-23 TABLE VI-22- Site, type and incidence of tumours in organs other than the liver* in rats exposed orally to VCW foi crsmr 2-5 yr(Feron et al., 1961) _____________________________________________________________________________ Incidence of turnouts Site and type of tumour Treatment group (mg VCM/kg/day)... Males Pennies 0 5.0 14.1 300t 6 1.1 5.6 14.1 300+ Effective no. of rate... Ho. of rats with primary tumours... Lungs Angiosarcoma Adenoma Zynbal glands Squamouu-cell cardncma Adenoma Abdomen Mesothelioma Angiosarcoma | Fibarosarooma Osteosarcoma Isarooma Reticulun-oell aarcom 'Schwann-cell tumour' Unclassified Spleen HaemangioendothBlioearccnci Lynphcearooma Nose Squairous-cell cardnom Drain Granular-cell nyoblastoma Oligodendroglioma Plexus papilloma Glial-cell tumour Ependymoma Mesodermal tumour Pancreas Adenocarcinoma Thorax Mesothelioma Thyroid Parafollicular-cell adenoma Parafollicular-cell cardnom twi nf.ilaiwol 1 nHprmf) 55 38 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 50 49 0 4* 00 02 00 17 00 00 00 03 10 00 00 10 00 00 10 00 00 02 00 01 00 00 12* 10 01 00 59 55 57 52 44 54 19*** 19 0. 1 0 0 0- 1 0 0 00 8 11 0 10 3 01 T) 1 0 1 00 0 10 0 00 0 02 0 00 0 00 1 00 0 00 0 00 0 00 0 10 1 00 0 00 0 01 0 00 3 37 0 00 1 01 58 59 56 55 01 00 00 00 6* 3 00 20 00 01 00 10 00 00 00 00 10 00 10 00 00 00 21 00 10 3 00 00 57 54 57 47 5* 23 00 01 01 30 21 00 10 00 O' 0 00 00 o0 01 00 00 00 00 00 00 00 00 00 20 00 10 CM6 0 0 7 1 6 7 VI-24 TULB VI-22 (continued) Site and type of Treatment group tumour__________(mg VCHAq/day) Incidence of Tumours ______________Males_______________ __________Feml< 0 1*7 5.0 14.1 300* 0 1.7 5.0 Adrenals Cortical adenoma IB Phaeochrcnocytcma 11 Pituitary Adenoma 12 CarcLncna 1 Blood Leukemia 1 Heart Endocardial disease* 2 Haanangioendothelioearcona 1 Kiduys Nephroblastoma 1 Clear-cell tisoour 0 Lipomatoue tumour 0 unclassified epithelial tumour 0 Ttymua Fibrosarcoma 0 Reticulum-call sarcona 0 Mesenteric lynph nodes Reticulum-cell sarccm 0 Skin Squamous-cell cardnare 2 Subcutis Fibroma 2 Fribrosarucma 0 Mesenchyiml tumour 0 Skeletal nuncle Khabdanyauarocma 0 25 17 21 8 25** 0 6 1 01 02 00 00 00 01 00 10 00 00 33 11 11 00 00 10 9 26 4 62 2** 0 14 0 03 1 31 2 11 0 00 1 00 0 00 0 00 0 01 0 00 0 10 0 10 1 00 1 13 0 01 0 01 1 11 30 20 12 16 10 02 21 00 0- 0 00 00 00 00 00 11 00 00 31 10 00 00 14.1 17 0 5* 0 0 0 0 0 1 0 0 0 0 0 1 0 0 0 0 O O O O O O O O O O O O f- t- uo 300t 14 2 0 CMA 0 0 7 1 6 8 VI-25 TABLE VI-22 (continued) Bite and type of Treatmnt groqp tumour__________(an VCM/kg/day) Incidence of TVmoura ______________Halee_______________ __________Panelee 0 1.7 5.0 14.1 300* 0 1.7 5.0 14.1 300* Skull Osteoma Meeendtyiml tumour 1 00 0 00 0 00 00 0 0 0 0 0 -10 0 0 Ear region Adenocarcinoma of wknown origin 0 Urinary bladder 01 *N 0 0 0 -.0 0 0 0 Unclassified epithelial tumour 0 0 1 0 00 00 0 0 Preputial glands Squamous-cell carednone 00 1 0 00 00 0 0 Maniary glands . Adenoma \ Fibroadencma .Adenocarcinoma ! Anaplastic carcinoma 00 00 01 00 0 0 0 0 0 0 0 00 2 0 0 0 21 25 12** 4** 7 2 0 3 54 7 7 0 0 0 01 0 0 Tastes Interstitial-cell tumour 30 0 11 % Uterus Adenocarcinoma Malicpant fibroadenomatous tumour Leiomyoma 63 1 0 10 0 01 10 0 :0 00 Cervix Mesenchymal type of tunour Adenocarclncna 2 01 0 0 0 10 0 0 Ovaries ,Theca-cell tu*1"*1**_____________________________________________________0 ^ t) 1 00 $A Bmall runtoer of prinary liver tumours unrelated to treatment were found in several groepe. These tumours were one Kupffer-cell sarcoma, three reticulum-cell sarcomas, two fibroearocmas, one haanengloendcthelicma and one mesenchyiml tumour. tThe figures for this group were not evaluated statistically, because no corresponding control group was included in the study. In several cases the neoplastic character of the lesion was doubtful. CMA 0 0 7 1 6 9 Values narked with aateriks differ significantly frcm those of the controls according to the chi-square testi *P<0.05> **P<0.01r ***P<0.001. VI-2 6 Feron et al. (1981) concluded that vinyl chloride monomer 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. Feron et al. have also initiated a similar lifespan oral carcinogenicity study with vinyl chloride in rats, using three different dose levels (0.017, 0*17 and 1.7 mg'*vinyl chloride monomer/hg bw day) and two control groups. This study is currently in progress and the results are not yet available. / CHA 007170 vil. HUMAN HEALTH EFFECTS A. Non-Carcinoqenic Effects ' Vinyl chloride can produce a number of pathological consaquancas in humans in addition to its carcinogenic effect. These affects can be front acuta 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 manufacturing and polymerization plants before 1975 (Mancuso, 1975). According to OSHA (39 FR 12342, April 5, 1974), several facilities revealed vinyl chloride concentrations for some job classifications as high as 229 ppm. Rowe (1975) commented that before 1960, a few jobs resulted in exposures in the range of 100 to 385 ppm, but these measurements could be high because the method of quanti fication measured total halogens rather than vinyl chloride alone. Nicholson et al. (1975) reported that vinyl chloride in polymerization reactors may often have exceeded 1000 ppm and occasionally may have approached 10,000 ppm before OSHA standards were instituted. At these levels, workers experi enced dizziness, headaches and/or euphoria during work periods. Several instances of acute exposure have occurred in vinyl chloride plants. Deaths of two Canadian workers were CMA 007171 VI1-2 reported by Danziger in I960 following acute exposures to vinyl chloride gas. At autopsy, there was congestion of the liver, spleen and kidneys. In another study reported by Suciu et al. (1975exposure of workers to high concentrations of vinyl chloride produced euphoria. Intoxication and narcosis. In this study, the investigators found a dose-response relationship for acute and s.ubacute cases of "occupational disease" from * ^ air concentrations ranging from 2,298 eg/a3 (about 900 ppm) to about 100 mg/m3 (about 40 ppm). In another investigation, Spirtas et al. (1975) conducted a survey of 200 vinyl chloride workers and 89 rubber plant workers (controls) where information was sought on the frequency of eight symptoms, including dizziness, loss of consciousness, headaches, etc. The vinyl chloride workers were categorized into low and high exposure groups. Because the exposure limits had been markedly decreased a short time before the survey, the high exposure group consisted of workers who were exposed to vinyl dhloride concentrations of over 200 ppm before the standard, and 20-30 ppm subsequently. The low exposure group consisted of workers who were exposed to 0-50 ppm before the standard and 0-10 ppm subsequent to it. Examination of the differences among the three groups indicated a statistically significant dose-response relationship for five of the eight symptoms (i.e., frequency of symptoms in the high exposure group < low exposure group < rubber workers), and CMA 007172 VI1-3 a similar but non-significant trend in two of the remaining symptom categories. Thus there appears to be a dose-response relationship between certain acute 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 Tribukh'et al. (1949); however, the effects were attributed to plasticizers added in the manufac turing process. The observed concentrations of vinyl chloride ranged from 1 to 470 ppm. Since that time, impaired liver function has been noted by other investigators (Marstellar et al., 1975; Lilis et al., 1975; Popper and Thomas, 1975; Jaeger, 1975). 1 Another effect from chronic vinyl chloride exposure is a condition known as acroosteolysis, which involves bone lesions in the distal phalanges of the hands and feet and scleroderma-like skin lesions. Also associated with this condition are Raynaud's syndrome, pseudoclubbing of fingers, and numerous other synptoms. Many cases of acroosteolysis have been reported and characterized and most involve autoclav workers in vinyl chloride plants (Wilson et al., 1967; Dinman et al., 1971; Harris and Adams, 1967; Lilis et al., 1975). CMA 007173 VI1-4 Other long-term effects Induce disturbances of the central nervous system, pulmonary insufficiency, cardiovascular manifestations, and several gastrointestinal symptoms (Miller et al., 1975; Suciu et al., 1975). These and other vinyl chloride-induced health effects are reviewed in the New York Academy of Sciences report "Toxicity of Vinyl Chloride-Polyvinyl Chloride" (Selikoff and Hammond, 1975). * *4 * .* i 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 communities in Ohio in Which vinyl chloride polymerisation plants are located were significantly higher (P<0.001) than those in either the counties in which these communities are located 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 central 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 CMA 00717A VII-5 chloride and birth d feet*/fetal 1 ss* but they are not yet supported by animal data* Cytogenic studies 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. Thesg 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. (1977) examined cytogenic 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 all three groups was signi ficantly greater than in non-industrial controls* and overall breakage levels were simlar in all three groups. The authors concluded that other agents in addition to vinyl chloride may cause cytogenic damage in workers employed in the rubber/ plastics industry. _-- CMA 007175 VII-6 B. Carcinogenic Effects The primary effect associated with vinyl chloride exposure in man is an increased risk of cancer in several organ systems including angiosarcoma of the liver* Human 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 occurs 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 evidenc linking vinyl chloride to other types of cancers is more tenuous. 1 The first study associating vinyl chloride exposure in humans with cancer was conducted by Creech and Johnson, 1974. Three cases of angiosarcoma in workers at a polymerization plant in Louisville, Kentucky, were described. The remaining portion of this section describes some of the epidemiologic studies linking vinyl chloride with angiosarcoma and other types of cancer. CM6 007176 VI1-7 Tabershaw and Gaffey (1974) conducted a mortality study of vinyl chloride workers. Mortality calculations included only those workers Who could be traced, i.e., 7,128 of 8,384 workers. These individuals were from 33 different facilities and all had been exposed to vinyl chloride for at least 1 year. The mean employment duration for the group of workers under study was 80 months. Among the workers, there were 854 with exposijres 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. Standarized 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 th 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 CMA 007177 Vii-O between 1942 and 1960. Workers wdre assign d to exposure groups based on the highest 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 c&loride exposed workers. No deaths A 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, as compared to 5.1 expected (the author stated that due to the small number of deaths, this difference was not tested for significance). Eight of these malignancies were in workers with 15 or more years of exposure. 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 angiosarcomas). Excluding angiosarcoma, a 275 percent excess in numbers of cancers was observed. Two brain 007178 CHft VII-9 tumors (320 percent excess) and 13 lung cancers (60 percent excess) were observed. In addition, the overall cancer death rate increased during the period. Nicholson at al. (1975) studied a group of 257 workers (of whom 255 were 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 a 25 percent increase in deaths over the expected number and a 131 percent increase in all cancer deaths, although neither of these increases was statistically significant. The National Institute for Occupational Safety and Health (NIOSH) conducted a study which involved 1.294 individuals who were exposed to vinyl chloride for at least 5 years, and 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 difference). A 49 percent increase over the expected nusiber of cancer deaths was noted, a statistically significant factor. A statistically significant excess number of deaths occurred for brain and CNS cancer, respiratory syst m cancer, and biliary and liver cancer (Waxweiler et al., 1976). 007179 VII-10 Ott et al. (1975) have re-examined much of the mortality data reported toy Taberahaw 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 increas in deaths due to malignant neoplasms was observed in the high exposure group. (TWA of greater than 200 ppm). Chiazxe et al.(1977) have reported a cross-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 sytem). 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). CMA 007180 VII-11 I In addition, Byren et al. (1976) tracad 750 of 771 Swedish vinyl chloride plant workers. A four- to five fold increase over expected in pancreas and liver tumors was found, and two cases were diagnosed as angiosarcoma. The numbers of other tumors did not deviate significantly from expected. Ten cases of. hepatic angiosarcoma have been found 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 these employees. The authors suggest that the cases of hepatic angiosarcoma appear to be associated with high vinyl chloride exposure levels and overtime work hours. No correlation was found between occurrence / of this tumor and alcohol consumption or cigarette smoking. In workers engaged in the polymerization of vinyl chlorid Who were studied by Popper and Thomas (1975), the characteristic hepatic fibrosis was present in all cases of angiosarcoma. Although the relation of fibrotic lesions to the development of angiosarcomas requires further study, a transition from the fibrotic stage to angiosarcoma is suggested by the focal proliferation of the sinusoidal lining cells and of the ChA 007181 hepatocyt s that ara s an in the fibrotic stage but which becomes even more pronounced in the initial stages of angio sarcoma development. These findings suggest that the fibrotic lesions without angiosarcomas, frequently observed in workers exposed to vinyl chloride (Lilis et al., 1975), might be the prestage of developing neoplastic lesions. The diagnosis of the fibrotic lesions in these workers may imply a longerlatency period for tumor initiation based on a lower exposure level. The series of dhanges observed in the liver appear to represent a multi-centric development of angiosarcoma and are similar to the Changes induced by Thorotrast and inorganic arsenicals (Berk et al., 1976). In the most recent update of the NIOSH register (Spirtas and Kaminaski, 1978) a total of 64 cases of hepatic angio sarcoma have been identified worldwide among vinyl chloride exposed industrial workers. A listing of all documented cases by country is presented in Table VII-1. The number of cases per year is depicted in Figure VII-1. Of the 64 cases, 23 have been reported in the United States. The authors reported that both the age at diagnosis and the latency period for cancer induction appear to be increasing. They suggest three explanations for these phenomenat (1) early eases may have heavier exposures; (2) the initial cases represented more biologically susceptible individuals; CtfA 0071S2 VI1-13 and (3) random fluctuation. If the trend of increased age at diagnosis and the longer latent period for hepatic angiosarcoma induction are indeed related to lower 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 hypothesized 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. Brady et al. (1977) examined annual rates of hepatic angio sarcoma from 1970 through 1975 in residents of the State of Mew York (excluding New York City). Exposures to arsenic, t 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 bhloride 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). CMA 007183 VI1-14 Th International Agency for Research on Cancer (1979) examined the available data on humans and concluded that ex posure to vinyl chloride results in an increased carcinogenic risk to humans. The organ systems most liXely to be affected were the liver, brain, lung, and hemato and lymphopoietic systems. \ CMA 007184 TABLE Vll-1 Angiosarocna of the Liver in Vinyl Chloride/PVC Worker (Spirtas and Famineki, 1978) Oowtrv Cam No. Birth Date 1st VC of PVC Exposure Diagnosis of Angiosarcoma Belgium Canada Canada Canada Canada Canada Canada Canada Canada Canada Canada Chechoslovakia (ihechoslo/akia Fed Rep Germany Red Rep Germny Fed Rep Germny Fed Rep Germny Fed Rep Germny Fed Rep Germany Fed Rep Germany Fed Rep Germany Fed Rep Germny France France France France France France France France Great Britain Great Britain 01 01* 02* 03* 04* 05* 06* 07* 08 09 10 01* 02* 01* 02* 04 05* 07* 08* 09* 10* 11* 01* 02 03* 04* 05* 06* 07 08* 01* 03 00-00-00 12-15-13 03-06-14 08-26-19 04-05-19 05-07-11 12-15-19 11-09-19 05-13-20 07-19-21 05-16-15 00-00-28 00-00-26 06-04-30 07-26-31 09-04-30 01-01-32 09-29-26 10-19-17 12-13-34 07-25-29 12-29-36 04-15-24 06-03-11 00-00-19 01-27-27 01-29-38 04--14--34 00-00-27 04-01-34 04-20-01 06-02-37 00-00-00 00-00-44 00-00-43' 00-00-41 00-00-45 00-00-44 00-00-47 00-00-46 00-00-61 00-00-46 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 00-00-60 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 0000-75 0000-75 06-16-76 06-28-77 0000-77 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 57 51 53 53 53 61 46 40 38 39 44 43 49 58 42 47 41 43 63 55 49 38 42 49 42 71 37 Years fran 1st Exposure to Diagnosis 00 n 14 21 22 24 24 26 12 28 23 16 15 12 13 17 13 21 22 17 22 16 21 15 29 26 11 18 26 19 28 09 Total Years of Exposure Date of Death 00 06-29-76 11 09-02-55 14 12-21-55 20 03-22-62 22 01-21-68 05 07-05-68 23 04-10-71 25 12-24-72 05 06-12-73 26 09-04-74 14 04-00-77 16 00-00-74 15 00-00-66 12 l 01-25-69 12 12-14-71 17 11-25-74 12 01-09-75 12 11-13-75 21 12-25-75 15 Alive 22 06-28-77 10 03-07-77 19 02-19-67 12 01-24-75 29 06-29-75 26 01-04-76 10 05-13-76 17 09-12-76 23 07-02-76 19 01-30-77 22 12-00-72 04 12-24-74 CMA 0 0 7 1 8 5 CMA 0 0 7 1 8 6 TABLE VII-1 (Continued) Country Case Birth No. Date 1st VC of PVC Exposure Diagnosis of Angiosarcoma Age at Diagnosis Years firan 1st Exposure to Diagxjeis Total Years of Exposure Italy Italy Japan Norway Sweden Sweden Sweden U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. Yugoelavia Yugoslavia 02* 03* 01 01* 01* 03* 04* 01* 02* 03* 04* 05* 06* 07* 08* 09* 10* 11* 12* 13* 16* 17* 18* 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 00-19-33 05-25-15 01-15-24 01-25-12 11-23-28 05-03-22 05-06-20 11-08-31 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 08-14-51. 05-00-47 00-00-46 12-09-48 11-15-55 11-28-45 07-06-52 06-19-44 01-17-62 08-27-44 10-07-46 05-28-45 06-12-51 10-14-46 09-13-49 12-11-42 05-08-50 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 08-19-67 04-09-64 02-00-74 00-00-68 00-00-61 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 50 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 10 Data of Death 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 05-10-60 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 Figure VII-1 Number of cases of vinyl chloride/PVC related angiosarcomas reported to NIOSB by year of diagnosis (representing only 63 of the 64 cases known to NIOSH since information on diagnosis is missing for one case) (Spirtas and Kaminski, 1978). teas of msewosa CMA 007187 VIII. MECHANISMS OF TOXICITY The mechanisms of non~carcinogenic injury of vinyl chloride are not Known. It is theorised that the toxicity of this compound is attributable to its enzymatic oxidation to reactive polar metabolites, possibly chloroethylene oxide or chloroacetaldehyde (see Pharmacokinetics section). Hard et al. (1976) hypothesised that an immunological mechanism is responsible for the non-carcinogenic pathological effects of vinyl chloride exposure. According to this model, , a metabolite of vinyl Chloride binds to plasma protein, producing an antibody response. The antigen and resulting immunoglobulin interact to produce a soluble complex which causes vascular occlusion, platelet aggregation, and other adverse effects which explain the observed symptoms of the disease. An investigation of workers with "vinyl chloride disease" showed the presence of circulating immune complexes in 19 of 28 patients. Abnormalities were also detected in some workers exposed to vinyl chloride who had few or no overt clinical signs. Over the past several decades, scientists have conducted a great deal of research in an effort to establish the aechanism(s) by Which chemical substances exert their carcinogenicity. The somatic cell mutation theory of carcinogenicity suggests that for a carcinogenic response to occur, an irreversible change must occur in the cell which 007188 VII1-2 results in proliferation of a neoplasm. This chang r fleets a mutational event in the DMA of that cell# suggesting that the chemical carcinogen must interact directly with or otherwise alter the DNA to intiate the change. In recent years# however# some substances have been shown to be carcinogenic, but by mechanisms in which there apparently is no direct interaction with or alteration of the DNA of the cell by the substance* Presumably# these compounds are not capable of ... ' initiating the alteration of a normal cell to a neoplastic one# but can facilitate expression of a neoplastic response in latent cells. On the basis of these purported differences in mechanisms# carcinogens now are often classified into two broad categoriesi genotoxic and epigenetic or nongenotoxic. The mechanisms by Which a compound exerts its carcinogenicity rarely can be determined by the chronic testing of whole animals such as is done in the NTP bioassay. Thus# a large number of short-term in vitro and in vivo assay systems have been developed for the purpose of elucidating mechanisms. Since most of the in vitro testing systems measure mutational events# and many carcinogens are mutagens# it is suggested that positive results in certain of these test sytems indicate genotoxicity* The decision as to whether a substance is genotoxic may be made qualitatively on the basis of several criteria! 1) a reliable# positive demonstration of genotoxicity in appropriate prokaryotic and eukaryotic systems in vitro? CHA 007189 VIII-3 2) studies on binding to DNA and 3) avid nc of biochemical or biologic consequences of DNA damage (Weisburger and Williams, 1981). No single test system appears capable of detecting all carcinogens that are genotoxic. Therefore, a number of scientists have proposed testing batteries such that results from each test within the battery When evaluated as a whole, will allow one to make a conclusion about the mechanism of carcinogenicity of a particular 'compound. Vinyl chloride has * not been systematically studied in any specific battery of tests, but has been evaluated in a number of test systems that have been proposed for inclusion in one or more batteries. Table VIII-1 summarises some of the mutagenicity studies on vinyl chloride which have demonstrated the chemical to have genotoxic potential. The studies have been divided according to the three criteria for genotoxicity (Weisburger and Williams, 1981) outlined above. When considering all of the data on vinyl chloride, it is probable that vinyl chloride exerts its carcinogenicity through genotoxic mechanisms. CMA 007190 1ABLE VXII-1 - Results of Vinyl Chloride Mutagenicity Studies A. Assay system Results References In Vitro prokaryotic and eukaryotic systems' Matabolically activated tvphiimrlun systvn (Ames; + Bartedi et al., 1975 McCann et al., 1975 Elmore et al, 1976 Ranxag et al, 1974 Garro et alT 1976 Escherichia coli KL2 bioaurotrcphic strain + Greim et al., 1975 Yeast Germ cells cf Diueutiiilia \ + Loprieno et al, 1976, 1977 Verburgt and Vtogal, 1977 Chinese hamster V79 cells + Hbbexnan et al., 1975 B. ENA Binding Studies Mouse tissues (brain, lung, liver, kidney, spleen, pancreas and tastes) in vitro + (Irreversible binding to R9A end DMA) Bergnan, 1982 Rat liver ndczoscmes, reconstituted cytochrone P-450 systmns and isolated hepatocytes t + Guengeridi et al., (Irreversible binding to protein end ENA) 1981 Rat liver ndcrcsanes with NADER + (Alkylation cf IRA) Ialb and Bolt, 1977 C. Biodiendcal or biologic consequences of ENA danage Bone narrow cells of rats (in vivo) + (ChranoscmB damage) Anderson and Ridiardeon, 1976 Bane narrow cells of Qiinese hamsters (in vivo) + Beeler and Rdhrbcm, I960 aberrations and eister-cdiranatidexchanges) Cultured peripheral lynphocytes in hisians (viryl cdilaride exposed workers) + (Chronoeaial abnornalities) Purchase et al., 1978 Purchase et al., 1975 Ducatman et aT., 1975 007191 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 mg/kq)(70 kq) (Uncertainty factor)(2 liters/day) The 70 kg adult consuming 2 liters of water per day is used as the basis for the calculations. A "no-observed-adverse-effectlevel" 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 acceptabl 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 CMA 007192 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 CMA 0071V3 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 CMA 007194 IX-4 might be set. In most cases, data exist only for animals; thus, uncertainty exists when the data are extrapolated to humans. When estimating risk rate levels, several other areas of uncertainty exist such as the effect of age, sex, species and target organ of the test animals used in the experiment, as well as the exposure mode and dosing rates. Additional uncertainty exists when there is exposure to more than one contaminant due to the lack of information about possible additive, synergistic or antagonistic interactions. A. Non-Carcinoqenic Effects Vinyl chloride has been shown to have non-carcinogenic effects in animals and humans. Acute and chronic toxicity studies have shown the major effects to be congestion and edema of the lungs and hyperemia of the kidneys and liver. Other non-carcinogenic effects have been noted, includeing disturbances of the central nervous system, pulmonary insufficency, cardiovascular manifestations, gastrointestinal symptoms and acroosteolysis. Acute toxicity tests with vinyl chloride were carried out by Patty et^ al. ( 1930). Single exposure of guinea pigs to vinyl chloride gas, 10 percent in air (100,000 ppm), resulted in narcosis and death within 30 to 60 minutes. Inhalation of lower concentrations resulted in ataxia and narcosis. Pathological findings at necropsy were 007*95 IX-5 congestion and edema of the lungs and hyperemia of the kidneys and liver. Mastrometto et a_l. (1960) exposed mice, rats and guinea pigs in an inhalation chamber to 10, 20 or 30 per cent vinyl chloride in air for 1-30 minutes. The principal pathological changes observed were pulmonary edema and hemorrhages, and congestion of the liver and kidneys. In a chronic inhalation exposure study (Torkelsen et al., 1961), rats, rabbits, guinea pigs and dogs were exposed repeatedly for up to six months to 50, 100, 200 or 500 ppm vinyl chloride in air. Detectable changes occurred at all but the lowest concentration. Rats 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 of the livers of male and female rats. Rats, guinea pigs, rabbits and dogs exposed to 50 ppm (7 hours/day for 6 months) appeared to be normal in appearance, mortality and growth, and the increase in weight of the rat livers did not occur at this concentration. At higher doses, pathological changes were increasingly more pronounced. Basalaev et^ a_l. (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. 00719& IX-6 Feron et a_l. (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 e_t jrl. ( 1975) examined exposure of workers to vinyl chloride at high concentrations. Air concentrations ranging from 100 mg/m3 (40 ppm) to 2,298 mg/m3 (900 ppm) produced euphoria, intoxication and narcosis, in a doseresponse relationship. In an epidemiological investigation, Spirtas et_ aJL. (1975) conducted a survey of 200 vinyl chlorid workers and 89 rubber plant workers (controls). The vinyl CMA 007197 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-Carcinoqenic Effects In the calculation of an adjusted ADI, a chronic study in which animals or humans are exposed to the chemical at various dose levels with a no-observed-effect-level or a minimal-effect-level being identified is used. Ideally, the study should use the oral route of exposure. For vinyl chloride, the toxicological studies which fit some of the above criteria are the Feron t 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. CMA 007198 IX-8 Thus, a minimal-effect-level of 100 ppm could be used for the derivation of the an adjusted ADI. However, a major limitation of this study is that inhalation exposure was used, which presents problems in terms of conversion factors needed to convert from inhalation to ingestion exposure. In the Peron t 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-observedadverse-effect-level from this study, as effects were seen at every dose level. However, 1.7 mg/kg/day may be used as a minimal-effect-level for the purpose of calculating an adjusted ADI, using an appropriate safety factor to account for the fact that the no-observed-adverse-effect-level is below this value. Using this study, the calculations are as follows: (1.7 mg/kg/day)(70 kg) = 0.06 mg/1 (1000)(2 1/day) Where: 1.7 mg/kg * Minimal-effect-level from Feron et^ al. (1981) study 70 kg = Average body weight of adult human 1000 = Uncertainty factor; animal study where no-observed-adverse-effect-level was not identified 2 liter = water consumption per day for an adult human Thus, the adjusted ADI for vinyl chloride using non-carcinogenic data and 100 percent exposure from drinking water would be 0.06 mg/1. This number should be appropriately reduced if CMA 007199 IX-9 there is shown to be significant vinyl chloride exposure from other sources, such as food and air. C. Carcinogenic Effects Vinyl chloride has been shown to have carcinogenic effects in animals and humans. Viola et a_l. (1971) reported the carcinogenic response of male rats (AR/IRE Wistar strain) exposed to vinyl chloride by inhalation. Rats exposed to 30,000 ppm vinyl chloride for 4 hours/ day, 5 days/week for 12 months, demonstrated an increased incidence of skin carcinomas, lung adenocarcinomas and bone osteochondroma over controls. Caputo et^ al^. ( 1974) exposed male and female rats (A and IRE Wistar strain) by inhalation to 0, 50, 500, 2,000, 5,000, 10,000 and 20,000 ppm vinyl chloride. Liver angiosarcomas, lung adenocarcinomas and skin squamous cell carcinomas were observed in all groups 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 (Maltoni, 1981). Vinyl chloride was shown to cause tumors in all the animal systems tested (mice, rats and hamsters) both through inhalation and ingestion exposure. In one study, Sprague-Dawley rats were exposed by 0072 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, Feron 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 tumors and 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 CMA 007201 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^ 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 (S8%) 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 CMA 007202 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 haemo-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". CMA 007203 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 fur vinyl chloride and it would be advantageous to use such data in the risk assessment procedure. However, the human studies available do not provide dose-response data that is needed for the calculation of the risk values, and thus human data were not used for the risk assessment. EPA's Carcinogen Assessment Group (CAG) and the National Academy of Sciences (NAS) have used the linear multistage model to calculate the projected excess cancer risk resulting from lifetime exposure to vinyl chloride through the drinking water. The CAG numbers were calculated assuming consumption of 2 liters of drinking water and 6.5 grams fish and shellfish per day, and were published in the Ambient Water Quality Criteria Document for Vinyl Chloride, U.S. EPA 440/5-80-078. For vinyl chloride, CAG used the incidence of total tumors in rats exposed through inhalation (Maltoni et 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"4), 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 exposur toxicity is not well understood. CMA 007204 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 use this study because it was felt that the limited gavage data were still superior to completed inhalation studies for assessing risk by the oral route. The NAS have calculated that consuming 2 liters of water per day over a lifetime at a vinyl chloride concentration of 100 ug/1, 10 ug/1 or 1 ug/1 would increase the risk of one excess cancer per 10,000 (10"4), 100,000 (10"5), or 1,000,000 (10"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 CMA 007205 IX-15 NAS data, the excess cancer risk concentrations associated with 10-4, 10"5, and 10~6 excess risk rates are 100 ug/1, 10 ug/1, and 1 ug/1, respectively. The World Health Organization has not calculated an action level for vinyl chloride. An EPA Health Advisory number for vinyl chloride also has not been calculated. Vinyl chloride has also been demonstrated to have interactions with other chemicals. Ingestion of ethanol was shown to increase the incidence of liver tumors in rats (Radike et a_l., 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. 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