Document 10dM6mYKzEg3XgEZo3mqyjnEE

TR-540-162 FINAL DRAFT FOR THE DRINKING WATER CRITERIA DOCUMENT ON VINYL CHLORIDE January 1985 rreparec Under Program No. 1302 for Contract 68-01-6750 Work Assignment 01 by XCAIR Life Systeas, Inc. Cleveland, OB 44122 for Criteria and Standards Division Office of Drinking Water U.S. Environmental Protection Agency Washington, DC 20460 SL l089eo TR-540-162 FINAL DRAFT FOR THE DRINKING WATER CRITERIA DOCUMENT ON VINYL CHLORIDE January 1985 rrepareo Under Program No. 1302 for Contract 68-01-6750 Work Assignment 01 by ICAXR Life Systems, Inc. Cleveland, OH 44122 for Criteria and Standards Division Office of Drinking Water U.S. Environmental Protection Agency Washington, DC 20460 SL 108961 1 J 1 J 3 3 J 3 DISCLAIMER This document is preliminary draft. It has not been released by the Office of Drinking Water, U.S. Environmental Protection Agency (EPA), end should not at this stage be construed to represent Agency policy. It is being circulated for comments on its technical merit. SL 108962 TABLE OF CONTENTS LIST OF FIGURES....................................................................................................................... LIST OF TABLES...................................................................................................................... I. SUMMARY....................................................................................................................... II. INTRODUCTION ..................................................................................................... III. PHYSICAL AND CHEMICALPROPERTIES ................................................................ IV. PHARMACOKINETICS................................................................................................ A. Absorption and Distribution ............................................................. B. Metabolism..................................................................................................... C. Excretion..................................................................................................... V. HUMAN EXPOSURE..................................................................................................... A. Exposure Estimation ............................................................................... PAGE ii Hi 1-1 n-1 ril-l tv-1 IV-1 XV-5 rV-g v-l V-l VI. VII. VIII. IX. 1. Water..................................................................................................... V-2 2. Diet..................................................................................................... V-4 3. Air......................................................................................................... V-6 B. Summary........................................................................................................... V-8 HEALTH EFFECTS INANIMALS ................................................................................. VI-1 A. Acute/Subchronic/Chronic Effects .................................................... VI-1 B. Teratogenicity............................................................................................ VI-3 C. Mutagenicity................................................................................................ VI-4 D. Carcinogenicity....................................................................................... Vl-36 HUMAN HEALTH EFFECTS........................................................................................ VII-1 A. Non-Carcinogenlc Effects ...................................................................... VII-1 B. Carcinogenic Effects ............................................................................... VII-5 HECHANIAMS OF TOXICITY ................................................................................... VIII-1 QUANTIFICATION OFTOXICOLOGICAL EFFECTS FOR VINYL CHLORIDE . . IX-I A. Non-Carcinogenlc Effects .... .................................................... IX-4 B. Quantification of Non-Carcinogenlc Effects ............................... IX- C. Carcinogenic Effects ............................................................................... IX-XO D. Quantification of Carcinogenic Effects ....................................... IX-13 X. REFERENCES.............................................................................................................. APPENDIX 1 Unit Risk Assessment for Vinyl Chloride ....................................... X-l Al-2 SL 108963 i LIST OF FIGURES FIGURE II--1 VII-1 Locations of Vinyl Chloride and Polyvinyl Chloride Plants in the United States........................................ .................................................... Number of Cases of Vinyl Chloride/PVC Related Angiosarcomas Reported to NIOSH by Year of Diagnosis (Representing Only 63 of the 64 Cases Knovn to NIOSH Since Information on Diagnosis is Kissing for One Case................................................................................ PAGE II-2 VII-14 SL 108964 ii LIST OF TABLES TABLE IV-1 IV-2 IV-3 IV-4 IV- S V- l V-2 V-3 V- 4 VI- 1 VI-2 VI-3 VI-4 VI-5 VI-6 VI-7 VI-8 VI-9 VI-10 VI-11 VI-12 VI-13 VI-14 VI-15 VI-16 VI-17 VI-18 VI-19 VI-20 VI-21 Percentage of the Administered 14.C Activity per Gram of Tissue After Administration of (L C) Vinyl Chloride by Gavage to Male.Sprague-DawleyRats ........................................................ Percentage of C Activity pgr Gram Tissue 72 Hours Following an Inhalation Exposure to (1AC) Vinyl Chloride for 6 Hours in Male Sprague-Dawley Rats .................................................................... Percentage of Administered c Activity Recovered Following a ^ngle Oral Dose of VinylChloride....................................................... C-Containing Urinary Metabolites from Male Sprague-Dawley Rats Given Vinyl Chloride by Gavage ..................................................... Excretion of Radioactivity in Rats, Given a Single Dose of ( C) Vinyl Chloride.................................................................................... Total Estimated Cumulative Population (in Thousands) Exposed to Vinyl Chloride in Drinking Water Exceeding the Indicated Concentration ...................................................................................................... Estimated Drinking Water Intake of Vinyl Chloride ........................ Estimated Respiratory Intake of Vinyl Chloride ............................ Estimated Intake of Vinyl Chloride from the Environment by Adult Males in ug/kg/day (2 from Drinking Water)...................... Oncogenic Effects of Inhaled Vinyl Chloride ................................. . Incidence of Tumors in Rats and Rabbits Exposed to Vinyl Chloride by Inhalation ................................................................................ Experiment BT1.................................................................................................. Experiment BT2.................................................................................................. Experiment BT6................................................................................................... Experiment BT9.................................................................................................. Experiment BT15................................................................................................... Experiment BT3.................................................................................................. Experiment BT10................................................................................................... Experiment BT5................................................................................................... Experiment BT14................................................................................................... Experiment BT7................................................................................................... Experiment BT17................................................................................................... Experiment BT4................................................................................................... Experiment BT8................................................................................................... Experiment BT11................................................................................................... Experiment BT27................................................................................................... Experiment BT12................................................................................................... Experiment BT13................................................................................................... Tumors Presently Correlated to VC Exposure (by Inhalation) on Experimental Rodents .................................................................................... Type and Incidence of Treatment-Related Histopathological Changes in the Liver of Rats Exposed Orally to VCM.................. PACE iv-3 IV-4 IV-8 IV-9 IV-11 V-3 V-5 V-7 V-9 VI-7 VI-8 VI-10 VI-U VI-12 VI-13 VI-14 VI-15 VI-16 VI-17 VI-18 VI-19 VI-20 VI-21 VI-22 VI-23 VI-24 VI-25 VI-26 VI-27 VI-30 continued- SL 108965 iii List of Tables - continued TABLE PAGE VI-22 VI-23 VI- 24 VII- I VIII- 1 Site, Type and Incidence of Tumors in Organs Other than the Liver in Rats Exposed Orally to VCM for Over 2 to 5 Years . . Type and Incidence of Histopathological Changes in the Liver....................................................................................................................... Type and Incidence of Tumors of the Manaery Glands and Incidences of Abdominal Kesothelinas ................................................. Angiosarcoma of the Liver in Vinyl Chloride/PVC Worker . . . Results of Vinyl Chloride Mutagenicity Studies ............................ VI-32 VI-37 VI-42 VII-12 VIII-4 SL 108966 I. SUMMARY Almost seven billion pounds of vinyl chloride are produced in the Unit d States annually. Most eaissions into the environment originate from manufacturing plants which use the compound for the production of polyvinyl chloride resins. The predominant route of exposure to the public living near these plants is through inhalation, while the principal source of vinyl chloride exposure for most Americans is probably from polyvinyl chloride food containers. This source contributes approximately 1 ppb vinyl chloride to the diet. Vinyl chloride has also been found in drinking water. Three national surveys have demonstrated the presence of vinyl chloride at very low levels (ug/L range) in a small number of drinking water 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 metabolites are mutagenic, but vinyl chloride Itself is not mutagenic, according to available information. At low doses (e.g., 1 mg/kg) of vinyl chloride the metabolites are excreted primarily in the urine. At high doses (e.g., 100 mg/kg), most of the solvent is expired es vinyl chloride. Acute end chronic exposure to vinyl chloride can result in toxicity in experimental animals and humans. In animals, an inhalation exposure of SI. 108967 1-1 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 air concentration below 100 ppm exhibit no pronounced adverse health effects. Vinyl chloride does not appear to be teratogenic in rats or rabbits, but insufficient data exist to evaluate the teratogenicity of vinyl chloride in humans. Studies on humans working in vinyl chloride plants suggest that systemic toxic effects that are noncarcincger.ic in nature can be demonstrated at exposure levels below 50 ppm. Some plant workers may have been exposed to concentrations exceeding 1,000 ppm and occasionally approaching 10,000 ppm before OSHA standards wert instituted in 1974. At these levels, workers manifested dizziness, headaches and/or euphoria. Long-term exposure to these levels in vinyl chloride plants have resulted in numerous toxic effects (i.e., acroosteolysis, pulmonary insufficiency, cardiovascular and gastrointestinal manifestations and disturbances of the central nervous system). Unfortunately, data on dose-response relationships in humans are very scarce because there were few air measurements of visyl chloride in the work environment before 1974. Vinyl chloride is a proves carcinogen In mice, hamsters end rats. Animals studies have shown that vinyl chloride produces tumors of different types at different sites, and that the incidence end relative distribution of these tumors are influenced by dose, age of the enimel end species and strain of animal used. Angiosarcomas of the liver were found is all animals studied, SL 108968 1-2 whereas some types of tumors, such as brain tumors, hepatomas and lung tumors, were observed In onlyone species of animal. A dose-response relationship was observed in most experiments. Inhalation studies have shown chat 50 ppm is the lowest vinyl chloride exposure which has a carcinogenic effect. A recently completed ingestion study demonstrated the occurrence of hepatic 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 bv/day. Human data have been obtained primarily 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 type of cancer (25 to 30 cases/year in the United States), and it is, therefore, reasonable to infer a causal relationship between exposure to vinyl chloride and the development of this tumor. Through 1977, a total of 64 cases s of liver angiosarcoma have been identified worldwide among vinyl chloride-exposed industrial workers. Although rare, the carcinogenicity of vinyl chloride to humans is unambiguous. There is insufficient data available for calculation of one-day health advisories but the ten-day health advisories can be used as conservative estimates of one-day health advisories. Ten-day health advisories of 9.0 mg/L for an adult and 2.6 mg/L for a child were developed using the subchronic toxicity data in the study by Feron et al. (1975). An adjusted ADI of 0.046 mg/L for chronic noncarcinogenic effects was calculated using the SL 108969 1-3 liver lesion data in the lifetime carcinogenicity study in rats by Til et al. (1983). The International Agency for Research on Cancer (IARC) analyzed the available data and concluded that exposure to vinyl chloride results in an increased carcinogenic risk to humans. The organs most likely to be affected are the liver, brain, lung and hemato- and lymphopoietic systems. The National Academy of Sciences (NAS) (1983) also examined the data an concluded that vinyl chloride is an established carcinogen in humans and animals, with older animals and females appearing to be more susceptible. The KAS and EFA's Carcinogenic Assessment Group (CAG) have calculated projected incremental excess cancer risks associated with the consumption of a specific chemical via drinking water by mathematical extrapolation from high-dose animal studies. Using the risk estimates generated by the NAS (1977 to 1979), in which the linear non-threshold multi-stage model was utilized, the range of vinyl chloride concentrations were computed that would nominally increase the risk of one excess cancer per million (10^), per hundred thousand 5A (10 ) or per ten thousand (10 ) people over a 70-vear lifetime assuming daily consumption at the stated exposure level. From the NAS model it is estimated, at the 95Z confidence limit, that consuming two liters per day vith a vinyl chloride concentration of 100 pg/L, 10 pg/L or 1 pg/L would Increase the risk of one excess cancer per 10,000, 100,000 or 1,000,000 people exposed over a lifetime, respectively. Using the revised CAG approach and the multistage model, it was estimated, at the 95% confidence limit, that consuming two liters of water per day vith a vinyl chloride concentration of 200 Pg/L, 1-4 SI* 108970 20 ug/L or 2 ug/L would Inert*** th* risk of one excess cancer per 10,000, 100,000 or 1,000,000 people exposed, over * lifetime respectively. The numerical differences between the NAS and CAG risk estimates are due to the selection of data for use in the model. The NAS based its calculations on an ingestion study by Maltoni et al. (1975) in which rats were exposed to vinyl chloride by gavage, while the CAG used the same Maltoni et al. (1975) study, but based its estimate upon the increased Incidence of total tumors in rats exposed to vinyl chloride through inhalation. The CAG has recalculated th# cancer risk with th* method described above and the Feron et al. (1981) data to estimate an increased risk of on* excess cancer per 10,000, 100,000 or 1,000,000 people exposed over a lifetime to a vinyl chloride concentration of 1.5, 0.15 or 0.015 ug/L, respectively. The CAG calculation based on the Feron et al. (1981) data is under reassessment to take into account new data by Til et al. (1983). 1-5 Si. 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 in the world. About 252 of the estimated 18 billion pounds of vinyl chloride produced worldwide in 1972 was manufactured in the United State (Berk et al., 1976). Between 1968 and 1973, vinyl chloride production in the United States rose 142 annually, reaching a production level of nearly seven billion pounds in 1978 (U.S. International Trade Commission). 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 (USEPA 1974). For the location of vinyl chloride and PVC manufacturing and processing plants in the United States in 1978, refer to Figure II-l. Vinyl chloride is not known to occur in nature (NAS 1977). The compound is synthesized as chlorinated oleflnic 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 synthesized (about 11 percent); (2) 41 PVC plants where the vinyl chloride monomer was used in the production of PVC resins for various industrial purposes (about 85 percent); (3) about 8,000 PVC fabricating plants (USEPA 1975b). Vinyl chloride and PVC are used as raw materials in the rubber, paper, glass and automotive industries. In addition, vinyl chloride and PVC are used II-l 108972 tn Figure II-I Locations of Vinyl Chloride and Polyvinyl Chloride Plants In the United States tL 68x lc che manufacture of eleccrical wire insulation and cables, piping, industrial and household equipment, medical supplied, food packaging materials and building and construction products. PVC and vinyl chloride copolymers are distributed and processed in a variety of forms, including dry resins, plastisol (dispersions in plasticizers), organosol (dispersions in plasticizers plus volatile solvent), and latex (a colloidal dispersion in water used to coat paper, fabric or leather). II-3 1089T4 Si* III. PHYSICAL AND CHEMICAL PROPERTIES The structure of vinyl chloride is: H2C - CHC1 Molecular Weight - 62.5 Vinyl chloride is highly fleasable (limits of inflammability: 4.002 to 21.702) and in sufficient concentrations (at least 1,200 to 2,000 ppm) has a sweet, pleasant odor. The compound has a boiling point of -13.3*C. Thus, at standard temperature and pressure, vinyl chloride is a gas. Vinyl chloride is only sparingly soluble in water (0.11 g/100 g water at 28*C), but is soluble in alcohol and very soluble in ether and carbon tetrachloride. The specific gravity of the chemical is 0.91. The vapor density of vinyl chloride is slightly more than twice that of air (CRC Handbook of Chemistry and Physics 1978 to 1979, Braker and Mossman 1971). The above information indicates that vinyl chloride is volatile and readily passes from water into the gas phase under most laboratory and environmental conditions. This was confirmed in experiments where 16 mg/L vinyl chloride was added to distilled water in beakers and the concentration determined with time (USEPA 1974). The data indicate that if first order kinetics arc assumed, the volatilization half-life in quiescent water (unstirred) is 290 minutes, and in continually stirred water it is 25.8 minutes. Dilling et al. (1975) found similar values for volatilization from stirred water. As Dilling et al., noted, 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. III-l SL 108975 Volatilization appears to be the cost significant process in the loss of vinyl chloride from the aquatic environment (Hill et al. 1976). Once in the atmosphere, vinyl chloride undergoes rapid photochemical oxidation (Gay et al. 1976), Lillian et al. 1975). III-2 SL 108976 IV. PHARMACOKINETICS A. Absorption and Distribution An investigation by Duprat et al. (1977) indicated 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 iAC vinyl chloride for five minutes, and then the distribution of radioactive vinyl chloride in the various body organs was determined. At ten minutes following treatment, radioactivity was found in the liver, bile duct, digestive lumen 14 and kidneys. With increasing time (up to three hours), 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 chan ten minutes after the dose was administered. In a study by Watanabe et al. (1976a), rats were given single oral doses 14 (gavage) of 0.05, 1 or 100 mg/kg of C-vinyl chloride dissolved in com oil, and the routes and rates of elimination of 14 C activity were followed for 72 hours. The percentage of the dose expired as vinyl chloride was 1Z, 2Z and 67X, respectively. The disposition of vinyl chloride to 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 SL 108977 IV-1 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 (Watanabe et al. 1976b), rats were exposed to 10 or 1,000 ppm 14 C-vinyl chloride for six hours end the routes and rates of elimination of 14 C activity were followed for 72 hours after termination of exposure. The animals were sacrificed after 72 hours and 14 samples of tissues collected for analysis of C activity. Table IV-2 indicates that, as in the gavage study, the liver retained the greatest percentage of vinyl chloride (or metabolites) at the dose levels studied. In contrast to the gavage experiment, however, no saturation of vinyl chloride metabolism was discernable between 10 ppm and 1,000 ppm in this study. Bolt et al. (1976) also studied the tissue disposition of 14C-vinyl chloride in rats. Immediately after exposure by inhalation of 50 ppm vinyl chloride for five hours in a closed system, the percentage of incorporated ^C-radioactivity per g tissue was highest for kidney (2.13) and liver (1.86). The percent of incorporated activity was 0.73 for the spleen and 0.17 for the brain. Forty-eight hours after the beginning of exposure, labeled material could still be detected in these tissues. The percentage absorption of vinyl chloride from the human gastro intestinal tract has not been established. Because of the lack of data TV-2 108978 SL Table IV-1 Percentage of the Administered C Activity per Grim of Tissue After Administration of ( c) Vinyl Chloride by Gavage to Male Sprague-Davley Ratsa Tissue Liver Skin Carcass Plasma Muscle Lung Fat 0.05 0.17220.025C 0.07020.023 0.02720.007 0.04120.004 0.02820.003 0.05020.003 0.03020.004 Dose (mR/kg)b 1.0 0.18220.005 0.07620.010 0.04620.002 0.05320.007 0.03120.003 0.06120.003 0.04520.008 ^Remaining in the body after ?2 hr. vinyl chloride dissolved in com oil. ^Mean 2 SE, five rats per dose. Kot detectable above background. Adapted from Watanabe et al. 1976a. 100 0.029*0.002 0.01020.002 0.007r0.001 NDd 0.00620.001 0.011*0.001 0.00620.001 rv-3 Table IV-2 Percentage of 14 C ^gtivity per Gran Tissue 72 Hours Following an Inhalation Exposure to (A C) Vinyl Chloride for 6 Hours in Male Sprague-Davley Rats Tissue _Percentage 14C. act.ivi. ty Exposure concentration 10 ppm 1,000 ppm Liver 0.139=0.009* (0.35)(b) 0.141*0.009C 0.145=0.008 (9.63) 0.165=0.009C r Skin 0.072=0.004 (0.18) 0.115=0.010 (7.64) C.07310.004 0.131=0.011 Carcass Plasma 0.046=0.004 (0.12) 0.049=0.004 0.051=0.001 (0.13) 0.052=0.001 0.049=0.004 (3.26) 0.056=0.005 NDd Muscle 0.052=0.005 (0.13) 0.053=0.005 0.038=0.003 (2.52) 0.043=0.003 Lung Fat 0.065=0.007 (0.16) 0.066=0.007 0.026=0.006 (0.07) 0.026=0.006 0.046=0.001 (3.06) 0.052=0.001 KDd Kidney 0.079=0.003 (0.20) 0.080=0.003 0.057=0.005 (3.79) 0.065=0.006 aExpressed as percentage of total 14 C activity per graft of tissue. Uncorrected for expired VC: dpm per g tissue Total dpm recovered Mean = SE from four rats L nicrograa equivalents vinyl chloride^ger gram of tissue. cExpressed as percentage metabolised C activity per gram f" tissue. Corrected for expired VC: dpm per gram of tissue Total dpmrecovered - dpm of expired VC Mean = SE from rats. `itat detectable, detection limit for plasma and fat was 3 ug/g of tissue (3 ppm). Adapted from Wetanabe et al. 1976b. IV-4 SL 108980 on percent absorption from the gastrointestinal tract, tha risk calculations in this document vill assume a 100Z absorption factor. B. Metabolism Metabolism of vinyl chloride occurs primarily by microsomal enzymes in the liver. 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, but vinyl chloride itself is not (Bartsch and Montesano 1975). Exposure to vinyl chloride leads to the reduction of nen-proteir. sulfhydryl levels in rat liver, suggesting that the metabolites of vinyl chloride conjugate vith glutathione and/or cysteine (Hefner at al. 1975a). Hathvay (1977) reported in vitro depurination of calf thymus DNA by chloroacetalaehyde identical to that observed in hepatocyte DNA following administration of vinyl chloride to rats in vivo. This suggests that vinyl chloride metabolites may interact with some purine and pyrimidine residues of DNA, providing a possible explanation for the oncogenic properties associated with vinyl chloride. In a review of the literature, Bartsch and Montesano (1975) report two possible biotransformatlon schemes--one involving alcohol dehydrogenase (Scheme I) and the other involving the mixed function oxidase system (Scheme II). These are Indicated below: Scheme I: C1HC-CH2----->C1H2C-CH20H----- >C1H2C-CH0----- >C1H2C-C00H Scheme II: C1H-CH2----- >[H2c2cHC1J----- >C1H2C-CH0----- >C1H2C-C00H 17-5 Si* Evidence for biodegradacion involving the alcohol dehydrogenase pathway includes data which demonstrates that pretreatment of rats with either ethanol or pyrazole (an inhibitor of alcohol dehydrogenase) inhibits the metabolism of vinyl chloride (Hefner et al. 1975a). There is also ample evidence that the mixed function oxidase (MFO) system is involved in the metabolism of vinyl chloride. Pretreataent of rats with phenobarbital, which induces the MFC system, also enhanced liver toxicity of vinyl chloride (Jaeger et al. 1974). Rat liver microsomes catalysed the covalert binding of vinyl chloride metabclites to protein and nucleic acids (Kappus et al. 1975. 1976). Chlorcethylene oxide, which is thought to be formed by the MFO system, 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 metabolism, the predominant one depending on dose. Hefner et el. (1975) performed an inhalation study in which rats were exposed to vinyl chloride concentrations ranging from 50.5 to 1,167.0 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 1,167 ppm. This indicated that the predominant pathway at the lover 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. TV-6 108982 Sli In another study, Bolt et al. (1977) subjected rats to an inspired concentration of 14 C-vinyl chloride ranging from 200 to 1,200 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 occurs at 250 ppm. C. Excretion Excretion of 14 C activity within 72 hours folloving a single oral dose of ^C-labeled vinyl chloride (C.05, 1.0 cr 100 mg/kg) is shown in Table XV-3 (Watanabe et al. 1976a). As the dcse increased, a markedly greater proportion of vinyl chloride was expired unmetabolized, while the percentage of metabolite in the urine decreased substantially. Again, saturation kinetics are suggested. The table also indicates that metabolites of vinyl chloride were predominantly excreted via the urine. Administration of vinyl chloride by inhalation produced almost identical results (Vatanable et al. 1976b). Two major metabolites in the urine were 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 injected, and air samples were taken t 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 it is in rats. Elimination was shown to obey a first-order law of kinetics at air concentrations below 108983 IV-7 Table IV-3 Percentage of Administered 14 C Activity Recovered Following a Single Oral Dose of Vinyl Chloride 0.05 Dose (mg/kg) 1.0 100 Expired: As VC As C02 Urine Feces Carcass and tissues c Cage wash Total recovery 1.43*0.13b 8.96i0.59 68.34i0.54 2.3910.52 10.13*1.93 0 91.2512.47 2.1310.22 13.2610.47 59.3012.75 2.2010.39 11.1010.47 0.84*0.45 88.831.96 66.64*0.67 2.5210.13 10.8410.95 0.4710.06 1.6310.14 0 82.3010.43 aPercentage of dose excreted over 72 hours. Only the 14 C activity associated with the expired VC can be attributed to VC per se. Mean i SE five rats per dose. cDistilled water wash of metabolism cage at termination of the study. Adapted from Watanabe et al. 1976a. IV-8 SL 108984 14 Table IV-4 C-Containing Urinary Metabolites froa Male Sprague-Davley Rats Given Virvi Chloride by Gavage8 Coapound (A) N-acetyl-S-(2-hydroxyethylcysteine) (B) Thlodiglycollc acid (C) Unidentified total Dose (ng/kg) 0.05(4)b 1.0(5) 100(5) 30.4l2.0c 36.213.9 29.112.0 25.6*1.9 38,612.9 94.6 23.711.1 34.514.6 94.6 25.410.9 36.612.0 91.1 Metabolites vere separated and quantitated by high pressure liquid chrenatography. Values are expressed as percentage of total urinary Radioactivity. ( ) Nutber of anioals per dose. cMean l SE Adapted froa Watanabe et al. 1976a. 200 to 300 ppm, and at high concentrations the maximal velocity of metabolic elimination of vinyl chloride was about half that of rats when related to kg body weight. Green and Hathvay (1975) measured the excretion of 14 C-vinyl chloride administered to rats by intragastric> intravenous (femoral vein), or intraperitoneal routes. Two doses were used: 0.25 mg/kg and 450 mg/kg. The results are shown in Table XV-5. During the first 24 hours after treatment, more than 9C was excreted from the animals irrespective route. Significant differences were noted, however, in the manner of excretion for the 0.25 og/kg cose. For the intragastric route, 71.5TM was excreted in the urine, whereas 99a was exhaled from the lungs when vinyl chloride was administered intravenously. For the intraperitoneal route, 43.2X was exhaled while 41.5% was excreted in the urine. At the higher dose (450 mg/kg), over 90S was exhaled as vinyl chloride in both intragastric and intraperitoneal administered rats. The intragastric values ere consistent with the values reported in the oral studies performed by Vatanabe et si. (1976a) (see Table IV-3). Withey and Collins (1976) developed a statistical model for use in equating oral dose levels of vinyl chloride to Inhalation exposure levels in rats, using blood level time curves. The authors concluded that "if the total daily liquid intake contained 20 ppm vinyl chloride, then the area generated under the blood level time curve, for rats, would be equivalent to an inhalation exposure of about 2 ppm for 24 hours." Thus, according to this model, inhalation exposure is ten times more efficient than oral exposure. 17-10 SI, X089&6 tfl c1 o CO U) CP TT-A I Table IV-S mniw or MixiMcnviTy in ah, own nmu oom or ['*C|viNn numm 4 nil wen each doted l.|. with 1)0 /<* of |"C|vinyl chloride per k| in corn oil toliillon, and another 4 nit were each dmed similarly arllh 4)0 mg of ("CJvinyl chloride per k|. 4 rail were each injected in the femoral vein with 1)0 yt of (MC|vinyl chloride per k| in Af-(/Miydryelhyt) taclamide. - Four rati were each li^ecled l.p. with 1)0 />| of |'*C|vinyl chloride per l| In AF-|/l-hydro*yethyl| laclamide, and another 4 animali were each Injected tlmilarly with 4)0 mo of |'*C|*inyt chloride. Shetf dbir Time m AmRaartlriif txtrrtrA (%afdnirf IntrataUrlt Inlraxenam Exhaled air Urine Farm F.xhatrd air Wny# tkbrMe d COt Finyf CI7t rhtorfrfr M0 ,./* 0-14 14-41 41-71 Total 3.7 1.1 12.6 I t 71.) 1: )0 l.h 2 ) 0.7 J.1 1.6 0 1 0.2 1.7 1.1 IJ.) I.J 7VI L 4.1 4.6 V J.O 97.0 -t 0 * 0.1 77.0 01 0.1 4)0 mi/ha 0-14 14-41 4H-72 Total *1.7 1.) 0.6 0.1 *1.7 1.) 0.7 4.) t 2..1 0.4 OH 0.1 01 ).4 | 2.1 0.7 Vrittf Intraperlmaral Farm Exhaled air Vinyl COt rhfarhir tfriar Farm 0.) 0.1 47.2 4.6 10.) 2.1 41.) 4.1 1.6 0.7 1.6 0.2 0.5 0.1 43.2 4.6 110 J 1.2 411 ).7 l.l 96.2 4.1 0 7 2.) >0.7 0.1 0.1 96.2 4.1 0.7 2.6 0.9 0.1 * Valuci ihown arc Ihe mean* S. O. of those meant. Adapted from Creen and llatbway (1975). V. HUMAN EXPOSURE Humans nay be exposed to vinyl chloride in drinking water, food and air. Detailed infcmation concerning the occurrence of and exposure to vinyl chloride in the environment is presented in another document entitled "Occurrence of Vinyl Chloride in Drinking Water, Food, and Air" (Letkievicz 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. A. Exnosure Estimation This analysis is limited to drinking water, food and air, since these media are considered to be general sources common to all Individuals. Some individuals may be exposed to vinyl chloride from sources other than the three considered here, notably in occupational settings and from the use of consumer products containing vinyl chloride. Even in limiting the analysis to these three sources, it must be recognized that individual exposure will vary widely based on many personal choices and several factors over which there is little control. Where one lives, works and travels, what one eats and physiologic characteristics related to age, sex and health status can all profoundly affect dally exposure and Intake. Individuals living in the same neighborhood or even in the same household can experience vastly different exposure patterns. Unfortunately, data and methods to estimate exposure of identifiable population subgroups from all sources simultaneously have not yet been V-l SL 108988 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. 1. Vater Cumulative estimates of the O.S. populations exposed to various vinyl chloride levels in drinking water from public drinking vater systems are presented in Table V-l. The values in the table were obtained using Federal Reporting Data Systems data on populations served by primary vater supply systems (FRDS 1983) and the estimated number of these vater systems that contain a given level of vinyl chloride. An estimated 1,922,00C individuals (0.92 of the population of 214,419,000 using public vater supplies) are exposed to levels of vinyl chloride in drinking vater at or above 1,0 ug/L, while 591,000 individuals (0.32) are exposed to levels above 5 ug/L. It is estimated that 118,000 individuals are exposed to levels greater than 60 ug/L. Of the approximately 1.3 million people exposed to levels ranging from 1.0 to 5 ug/L, 0.9 million (65Z) obtain vater from surface vater supplies. All exposure to vinyl chloride in drinking vater at levels above 5 ug/L is expected to be from groundwater sources. Ho data were obtained on regional variations in the concentration of vinyl chloride in drinking vater. The highest concentrations are expected to occur near sites of polyvinyl chloride production. SL 108989 V-2 f~ i ; t- ' -- r -i r~ 1 r i -- Table V-1 Total Estimated Cumulative Population (In Thousands) Exposed to Vinyl Chloride In Drinking Water Exceeding the Indicated Concentration System type Number of '\ people served In U.S. Cumulative population (thousands) exposed to concentrations (ug/1) of: (thousands) "TO >5 >10 >20 >30 >40 >50 >60 >70 Grnnndwater Surface water Total (% of total) 73,473 140,946 214,419 (loot) 1,063 059 1,922 (0.9%) 591 110 110 no no no 00 000 0 591 lie 110 < 110 lie 1 no (0.3%) (0.1%) (0.1%) (0.1%) (0.1%) (o.i%) lie 0 no (0.1*) 0 0 0 (0.0%) ui C* o C\P0 vO o Daily intake levels of vinyl chloride from drinking water were estimated using various exposure levels and the assumptions presented in Table V-2. 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 vg/kg/day. 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 cf the population is exposed. An explanation of the derivation of these values is presented in Appendix Population concentration estimates for vinyl chloride in drinking water were 1.1 x 10 ^ yg/L x persons (best case). 1.5 x 10~^ yg/L x persons (mean best 8 *.g case), 2.3 x 10 yg/L x persons (mean worst case), and 2.3 x 10 yg/L x persons (worst case). Assuming a consumption rate of 2 liters of water/day, population-exposure values of 2.2 x 10^ yg/day x persons (best case), 3.C x 10^ yg/day x persons g (mean besc case), 4.6 x 10 ug/day x persons (mean worst case), and g 4.6 x 10 yg/day x persons (worst case) were derived. 2. 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. SI* 108991 ' V-4 Table V-2 Estimated Drinking Water Intake of Vinyl Chloride Exposure level .(ug/L) M.O >5.0 >10 >50 >70 Persons using supplies exposed to indicated levels 2 of total Population population 1,922,000 591,000 118,000 118,000 0 0.92 0.32 0.12 0.12 0.02 Assumptions: 70-kg man, 2 liters of vater/day. Intake (ug/kg/day) ^0.028 >0.14 >0.29 >1.4 >2.0 SL 108992 V-5 3. Air Exposure to vinyl chloride in the ataosphere varies from one location to another. The highest level of vinyl chloride reported in the ataosphere was 2,100,000 ng/m^ (2,100 yg/m^) (Lillian et al. 1975 cited in Brodzinsky and Singh 1982). High levels, averaging greater than 15,000 ng/a (15 ug/a ), have been detected in other areas. Normal levels, hovever, are somewhat lover. Bordzinsky and Singh (1982) calculated a median air level of 0.0 ng/m (0.0 yg/m^) in each of three types of areas: rural/reaote, 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 V-3 and median and maximum levels for vinyl chloride reported above. The estimates in Table V-3 indicate chat 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 vg/kg/dey; few, if any, persons are believed to be exposed et that level. The values presented do net account for variances in individual exposure or uncertainties in the assumptions used to estimate exposure. SL 108993 V-6 Table V-3 Estimated Respiratory Intake of Vinyl Chloride 3 Exposure (ug/m ) Rural/remote (0.0) Orban/suburban (0.0) Source dominated (0.0) Kaximum (2,100) Intake (ug/kg/day) 0.0 690 3 Assumptions: 70-kg man, 23 a of air inhaled/day (ICRP 1975). SL 108994 V-7 B. Summary Table V-4 presents a general viev 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 ar.y specific combination of levels is not known; nor is it possible to determine the number of persons thet 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 3 of vinyl chloride of 0 vg/m based on air monitoring data. Assuming as air SL 108995 V-8 Table V-4 Estimated Intake of Vinyl Chloride from the Environment by Adult Males in ug/kg/day (2 from Drinking Water) Concentration In drinking water (ug/1) Rural/remote ^ Concentration in air ~ Urban/suburban Source dominated (0.0 ug/m3) Maximum (2,100 ug/m3) 0 0.0 (~) 690 (05) 1.0* 0.028 (1005) 690 (<0.01X) 5. oh 0.14 (1005) 690 (0.025) 10= 0.29 (1005) 690 (0.045) 50* 1.4 (1005) 690 (0.25) 70" 2.0 (1005) 690 (0.35) Intake from each source fsee Sections S.l-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: 2,100 ug/m 0.0 ug/kg/day 690 ug/kg/day Food: Not included *1,922,000 individuals using public drinking water systems are estimated to be exposed to levels 2 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 (0.35 of population using public water supplies). c118,000 Individuals using public drinking water systems are estimated to be exposed to levels > 10 ug/1 (0.15 of population using public water supplies). d118,000 individuals using public drinking water systems are estimated to be exposed to levels > 50 ug/1 (0.15 of population using public water supplies). eNo individuals using public drinking water systems are estimated to be exposed to levels > 70 ug/1. SL V-9 level of 0 yg/m\ drinking water would be the predominant source of vinyl chloride exposure at ell drinking water levels above 0 ug/l. An accurate assessment of the number of individuals for which drinking water is the predominant 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. V-10 VI. HEALTH EFFECTS IK ANIMALS A. Acute/Subchronic/Chronic Effects Acute toxicity tests with vinyl chloride were performed by Patty et al. (1930) of the Bureau of Mines, Department of Commerce. Single exposures 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 lover concentrations resulted in ataxia and narcosis. Pathological findings at necropsy were congestion and edema of the lungs and hyperemia of the kidneys and liver. A number of investigators have made similar observations when examining the acute inhalation effects of vinyl chloride in mice, rats, guinea pigs, rabbit, cats and dogs (Peoples and Leake 1933, Lester et al. 1963, Mastromatteo et al. 1960, Haley 1975, Prodan et al. 1975). In animal studies, LC^q's at two hours ranged from 117,500 ppm for mice to 230,800 ppm for rabbits. Feron et al. (1975) reported a subchronic toxicity study in which vinyl chloride monomer (VCM) dissolved in soybean oil was administered by gavage to male and female Wlstar rats, initially weighing 44 g, at doses of 0 (controls), 30, 100 and 300 mg/kg once daily, 6 days per week for 13 weeks. Several hematological, biochemical and organ weight values were significantly (P<0.05 or better) different in both mid- and high-dose animals compared to controls. The authors conservatively placed the no-effect level in this study at 30 mg/kg. However, they also estimated that the no-effect level may be VI-1 SL 108998 higher since it was their opinion that the effects observed with the higher doses were of doubtful toxicological significance. 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 (two hours/day for six months) were Judged normal on the basis of appearance, mortality, growth, hematological examination and other factors. A slight increase in the liver weight was observed. Rats, guinea pigs, rabbits and dogs exposed to 50 ppm (7 hours/day, 130 times in 185 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 to 0.04 mg/L for four hours/day for six months. Cardiovascular disorders, changes in the bioelectric activity of the hypothalamus, hyperadrenelinemia, osteoporosis and resorption of bene tissue were observed. Jaeger (1975) conducted experiments with rats to determine the interaction between vinylidene chloride (1,1,-DCE) and vinyl chloride. In this study, hepatotoxicity was measured by the elevation of serum alanlne-a-kctoglutarate transaminase (ART). When fasted rats were exposed to 0.02Z (V/V), 1,1-DCE, scrum AF.T activity was elavated about 50-fold, two hours aftar the termination of a four-hour Inhalation exposure. No elevation was observed when 0.1Z vinyl chloride was administered alone. When the two SL 108999 VI-2 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). 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 seven hours daily to concentrations of 50 or 500 ppm for mice and 500 or 2,500 ppm for rats and rabbits. Mice and rats were exposed on days 6 to 15 of gestation, and rabbits on days 6 to 16. No teratogenic effects were observed at 2,500 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. Ko teratogenic effects were noted in the fetuses of mice exposed to 50 ppm, but a significantly greater incidence of unfused sternebrae and delayed ossification of sternebrae (no. 5) and bones of the skull were observed among litters of mice exposed to 500 ppm compared to unexposed controls. Embryotoxic effects were not generally noted, but some decrease in fetal body weight and crown-rump length was observed in rats and mice. Vl-3 SL 109000 Redike (1977) did not observe gross (nonmicroscopic) abnormalities in the offspring of rats exposed for four hours daily on days 9 to 21 of gestation by inhalation of 600 or 6,000 ppm vinyl chloride. A small increase in the incidence of minor skeletal abnormalities, including vavy ribs, extra 14th ribs and delayed calcification of small bones, were observed in the offspring of the exposed animals. The investigators concluded that such a small Incidence is difficult to distinguish from a sporadic occurrence, and, therefore, these abnormalities should be considered skeletal variants and not malformations. Groups of pregnant CF-1 mice, Sprague-Davley rats and New Zealand white rabbits were exposed to doses of vinyl chloride ranging from 50 to 2,500 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 be dependent upon its metabolic conversion to chemically reactive metabolites (l.e., chloroethylene oxide, 2-chloroacetaldehyde). The mutagenic effects of vinyl chloride have been demonstrated in: (1) metabolieally activated systems using Salmonella typhimurium (Bartsch et al. 1975, McCann et al. 1975, Elmore et al. 1976, Kannug et al. 1974, Garro et al. 1976) developed by Ames et al. (1973) in SL 109001 VI-4 which the genetic Indicator refers to histidine prototrophy by base-pair substitutions, or by base-pair insertions or deletions; (2) Escherichia coll K12 bioauxotrophlc strain with back nutation system arginine + (Greim at al. 1975); (3) several species of yeast inducing forward nutations and gene conversions at specific loci (Loprleno et al. 1976, 1977); (4) 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 was reviewed by Bartsch and Montesano (1975). The mutagenic actlviy of Inhaled vinyl chloride (3,000, 10,000 or 30,000 ppm for 6 hours a day for 5 days) was assessed in fertile 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 cells of rats after exposure to paradlchlorobenzene 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. VI-5 SL 109002 D. Carcinogenicity Evidence has been accumulated in recent years implicating vinyl chloride as a human and animal carcinogen. The first four cases of human liver angiosarcoma in workers employed by a vinyl chloride plant were reported by Creech and Johnson in 1974. The first experimental data on the carcinogenic effect of vinyl chloride in rats were published by Viola et al. in 1971, Subsequently, preliminary results of an investigation concerned with the oncogenic potential of vinyl chloride in experimental animals were reported (Kaltoni and Lefemine 1974). These initial reports spurred a series of retrospective epidemiologic investigations of workers in the vinyl chloride industry and supportive experimental studies in animals. Several comprehensive reviews and symposium proceedings have been published on the subject (e.g., Selikoff and Hammond 1975, Proceedings of the Royal Society of Medicine 1976, USEPA 1975c, Milby 1978). Viola et al. (1971) conducted animals studies and reported the carcinogenic response of male rats (AR/IRE Vistar strain) exposed to vinyl chloride by inhalation (Table VI-1), Skin tumors were first noted at approximately ten months; tumors in the lungs and bone vara observed at about 11 months. Caputo at al. (1974) exposed male and female rats (A and IRE Viatar atrain) by inhalation to various concentrations of vinyl chloride. Carcinomas and sarcomas vert observed in all groups except those exposed to 50 ppm (Table VI-2). The data Indicate that a dose response relationship exists Si IO9003 VI-6 Tabic VI-1 Oncogenic Effects of Inhaled Vinyl Chloride Cone. VC (ppm) 4 hours/day 5 days/week 12 months 30,000 No treatment Number rats 26 25 Skin epidermoid carcinomas 17 ---- Lung adenocarcinomas and squamous cell carcinomas 6 Bones Osteo chondromas 5 -- Adapted frcs Viola et al. IS'1). VI-7 SL 109004 Table VI-2 Incidence of Tumors in Rats and Rabbits Exposed to Vinyl Chloride by Inhalation (ppm) 4 hours/day 5 days/week 12 months Number of animals Liver angiosarcomas cholangiomas Lung adeno-alvcolar carcinomas Skin s<uamous cell carcinoma acanthoma Other Rats 20,000 150 31 21 67 7 10,000 200 16 16 34 8 5,000 200 12 4 20 2 2,000 200 10 8 66 500 150 4-- 3-- 50 200 -- -- --** No treatment 200 Rabbits -- ---- " 10,000 40 -- 6 12 -- No 20 -- -- " -- treatment Adapted from Caputo et al, (1974). VI-8 at exposure! between 50 and 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) confirmed the carcinogenicity of vinyl chloride at concentrations as low as 50 ppm (Lee at al. 1977, 1978). Liver angiosarcomas as well as other forms of cancers were found in both species. An extensive examination of vinyl chloride in experimental animals was conducted by Haltoni (1981). A summary of these results arc presented in Tables Vl-3 to VI-19. Vinyl chloride caused tumors in all the animal species tested (l.e., mice, rats and hamsters) both through inhalation and Ingestion exposure. A clear-cut dose-response relationship was demonstrated, with carcinogenic effects occurring at exposures as low as 50 ppm. Newborn animals appeared to be especially sensitive to the development of hepatocarclnomas and angiosarcomas and carcinogenic effects on the embryo via the placenta were demonstrated. Table VI-20 indicates the tumor types that were correlated to vinyl chloride exposure in experimental animals. Haltoni (1981) concluded 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. VI-9 SL 109006 Table VI--3 Eaperlment BTI.* ______________________________Animalr wiih tunwn. % Fare* Mam Group and Hepa- Neptiro- Neuro- Zyntba) Skin Umaefc mary concentration MT BT LAS LA ELAS ELA Inmaa BL BL GI.Cn EpT PaAAc MT 1 10,000 ppm 11 0000 ppm III tGOOppm IV &00 ppm V *50 ppm VI "vr No treatment (control) IT 00.0 0.3 11.1 30.0 U.0 13.3 23.3 11.1 - so SO 1.7 8.3 11.7 207 60 * 6.0 (1*0) (3 00) 13 60) 1160) (5*0) (1*01 (10*0) (3*0) (2*0) 38.3 220 3.4 5.1 0.3 1.1 05 6.1 11.9 3.4 1.1 (13*01 (2*91 (3*9) (4*9) (1*91 15*91 (3*9) (1*9) (2*9) (1*9) 20.0 21.1 - *0 :i:l .13 10.0 6.7 3.3 1.1 03 (13*0) (3 501 12601 (200) 16*0) 14*0) (2*0) (1*0) (2*0) 133 10.0 - 11 1.1 03 10.0 07 1.1 17 (0*0) (l0> It 60) 1*60) 16601 (4*0) (1*01 (1*0) 25.0 5.1 l.l 3 4 - 17 05 _ 3.4 3.4 (3*9) 11*9) (2591 (159) (5*9) (2*9) (2*9) 36.7 1.7 - 11 3.3 _ 1.7 1.7 1.7 3.3 (1*0) 11*0) (2*0) 11*01 (1*0) U*0) (2*0) 433 3 4 _ (2501 1.1 (1*8) Expoaure by inhalation to VC In air at l.000. MOO. 2500. MO. ZSO. and so ppm: 4 hr/day, | dayaArreek, far 62 week* Sprague-Dawtey rata. H and F, 13 wecka ok) Scsulta after 135 necka tend of experiment). jr L0060T Adapted frnat Haltonl, 1981 i * ra ' r-^1 pr^t ty * r 11 SL 109008 Table Vl-4 Eipcrlmcnt HTl.* Gnwfi ftnd CMCtMnlien i 200 ppm II ISO ppm III 100 ppm IV Na treatment (control} TumoraHOO MT BT LAS Annual* wHh tumors, % Fstt- Mam Hepa Nrphro- Ncnro- Zymbal Skin stomach mary LA ELAS ELA toma* 8L BL Ol. Ca EpT PaSAc MT K.I 11.7 21.7 250 27.5 10.0 3.3 (12/120) (VI20) 5.0 (VI 1) 0.0 41 (1/120) (1/120) OS (1/1201 _ - OS (1/120) 0.B ivint - 25 SB (3/120) (7/1201 - 02 (1If110) - S3 (10/120) 33 (4/120) 3.4 (V110) OS (1/120) 4.2 (5/120) 34 (VI10) OS (1/120) - 1.7 (2/110) 3.3 (VI20) 5.0 (V120) so mm 3.3 (V120) IU 21.6 - 1.1 - - - - l.l II I.S 1.0 (2/185) (2/I8S) (2/185) (3/185) (2/185) `Expoave by MtalaUwi ta VC in air *1 200.150. 100 ppm; 4 hr/day. S daysarch, far 52 weeks. Sprague-Bawley rata, M and F, 13 Mb aid. HualU after 143 weeka lend at experiment). Adapted from Haltonl, 1981 SL 109009 J Table VI-5 Eiptilmtiil flTt.* Graft and concentration Twnora'IOO animals MT BT LAS Animals with tumors. % Fare* MmHeps- Nephi*- Neuro- Zjrmbal SUe stomach miry LA ELAS ELA lOVMS BL BL Cl.Ca EpT PsftAc MT 1 30,000 ppm am100.0 (0.0 30.0 1.7 1.7 6.0 1.7 (MKOt (1*0) (1/SO) (MO) 1.7 60.3 1.7 18.1 3.3 (MO) (36/00) (MO) (11/60) CKO) -Eapsstire bjr Miabtten t* VC In air at 30,000 ppm; t hr/dajr. S dajrs/week, far 63 weeks. Sprague-Dawley rl, M and F, 17 weeks Id. ResulU after M weeks (end of experiment) Adapted frem Haltonl, 1981 L LU L_J LLJ r > i--n r r --i 1 I a i-- o> in ? lrO* vO o Vo* Table VI-6 Eaprrimrnt BT9." Group and (MMHtraimn Animal* mlb tumor*. 7 ltonoro/100 Fore- Mini- llepo- Nrphro- Neuro- Zymbal Skin atomaeh roarv NT BT LAS LA ELAS ELA lamn* UL BL CICa EpT P*A At MT "Jr K* treatment iMtnll 44.1 41.1 4* 27 3.) 3.7 (14794) (6791) (97911 (117911 0.1 24.0 0.3 - 3 1 1.9 9 4 21 1 (1/291) (9094) (3094) (1/294) (62094) 1.9 10.2 (106) 0908) *t ipniMT by InbnloUonto VC b air l SO ppm; 4 krnliy,} diyvneek, far SI ntlu. S^rifw lliwky till, M and F, IS week* oM. hidti dbr 142 week* (end of nperiiMri). Adapted fro* Haltonl, 1901 tco* o\O> V-* Table VI-7 Eiprrlmcnl BTI5.* Giwp and MMitflliN Animate aith lemon. % TtommVIOO MT BT LAS LA ELAS ELA !? Fere- Mam Nephro- Neuro- Zymbal Skin atemach mary BL BL Gl.Ca EpT PaAAc MT i Sapm ll Nppm III lapm IV Iff" v Na treatment (mnlmll 3.1 68 3 4.2 0.8 26 08 3.3 (6/120) (1/1201 (3/120) (1/120) (4/120) 1.7 63.3 OB - 1.7 26 . -- 1.7 16.0 (17/120) * 17.0 (I/I19) 86.8 66 0 (2/119) 0/119) (2/119) 0.8 08 (21/119) 186 as 44.2 (1/119) (1/119) 0.8 0.8 (22/119) 12.7 (1/118) (1/118) (15/118) n.i 37.6 * 0.8 (1/120) -- 1.7 (2/120) _ 6.8 (7/120) 'Eipmti by Inhalation to VC in air at 25, 10. 6. I ppm; 4 hr/day, i dajra/areek, lor U areeka. Sprague-Dairtey nil, M and F. 13 ki aid. Rcanlla after UT weeka (end of experiment). V I-1 4 Adapted frow Haltonl, 1981 r~ f , Si to H o VD O to Table VI--8 Eipttliwni BT3.* Craap and emeemration 1 M.000 ppm 11 000 ppm III BOOppm IV BOOppm V BO ppm VI BO ppm VII No treatment (nntnl) Tnmoti'lOO MT BT 45.0 20.0 U.l 2S.4 41.1 2S.0 ISO B0 21.1 B.0 IM 26.0 14.1 20.0 Animal? with tumor?, % LAS - 1.1 (1/601 1.1 (1/60) 1.1 (1/601 - - LA _ - - - 1.1 U69) 17 (168) _ El.AS EI.A 1.1 (I/SB) - 3.3 <2/60) - . - 1.1 (169) - 17 (I/SB) OS (1/1901 Fore- Mam Hepa Nephew Newro- Zymbal Skin alontach mary tomas DL BL CICa EpT raAAc MT 1.1 (1/58) 1.1 (i/eoi 33 (2/60) - _ 1.7 (I/SB) 1.1 (1/60) 33 (2/60) 102 1669) 5.2 <3681 _ 15.6 (9681 20.0 (1260) 83 (660) _ - - ISS (96B) ISO I960) 111 (7/60) 1.7 (1/60) 1.7 (169) _ 8.6 (S68) 8.3 (660) 33 (26*0) 17 <1661 _. 1.0 0.6 (2/190) (1/190) 1.7 (168) 33 (260) _ 6.1 (369) l7 068) 1.1 (160) 6.7 (460) 6.0 (360) 1.7 (169) 1.7 068) 2.6 (6/190) "Eaprawe by Wuhlia to VC in air at 10.000. GOTO. 2500, SOD, 250, and SO ppm; 4 hr/day, 6 dijntatM, far 11 week*. SpnptDiwItj rata, M and F, 12 weeks old. RewK* after ISO week* (end of experiment). Adapted from Halt nl, 1981 SL 109013 Table VI-9 Group and concentration IWnoro'100 MT BT LAS Eift'lmnl DTI* * Animal* with (amor*. V Fare- Nam llrpa- Nrpkre- Neurn- Zyrnbal Skin rtsmack mar* LA ELAS ELA tonua RL BL Cl.C* LpT Pa* At NT 1 33.3 41.7 0.9 _ 09 09 _ 14 26 III 19,000 ppm I I/I It) (1 1191 (l.'IIH) (9/119) (3/119) 413.11). II 39.9 46.0 - 09 - 17 - 09 09 75 - 1.7 tea a *o--i> (000 ppm 111 19,009 ppm IV (1/120) (2/1291 (1/120) (1/120) (9/120) (2/120) |13/) 36.9 46.9 09 IT - 99 _ - _ 7.6 2.5 2.6 in (i/I 191 (2/1191 (I/I 191 I9/II9I 13/119) (3/1191 IIAiin 30.9 39.Z 2.6 - 17 - _ - 4 2 3.1 1.7 *i WOO ppm (3/119) (2 IIS) (&/II9) (VI19) (2/1191 (|l/IUt V 41.T 46.9 0.9 1.7 - 99 - 09 0.9 6.7 9.9 0.9 161 19,009 ppm (l/ll9) (2/1191 <1/1191 (1/119) 11/119) (ft/l 191 (|/| 19) (I/II9I <26/|)ft VI 33.3 60.9 09 17 09 - ) 7 0.9 7.5 0.9 ill C000 ppm (1/120) (2/120) (1/1201 (2/120) (1/120) (9/120) tl/120) <1212* VII No treatment (contrail ICC 41 0 94 (1/227) 0.9 2.2 7* (22271 (5/227) 117/227) "Eipoaar* bp inhalation ( VC in air at 10,000. 6000. ppm; 4 kr/day, 6 davmrek. far 5 tfki (gmnp* I and 111 ar 1 hr day. t dey*/*eek. far IS areek* (group* III and |V>ar 4 hrMay, ante weekly, far 25 weeks (group* V and VIM 100 hr). Spngue-Daclrjrm. M aid F, IS week* aid. Results after IM week* (end of caperunent). 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SL 109021 X-8 Rad Ike MJ, Sterner KL, Brown PG, Lareon E, Bingham E. 1977. Effect of ethanol and vinyl chloride on the induction of liver tumors: preliminary report. Environ. Health Perrpect. 21:153-155. Kadike MJ, Stemner KL, Binphar F. l^M. Lllect of ethanol on vinyl chloride carcinogenesis. Environ. Health Perspec. A1:59--63. Rove VK. 1975. Experience in industrial exposure control. Ann. N.Y. Acad. Sci. 246:306-310. Rannug U. Johansson, A. Ramel C., Uachtmeiater CA. 1974. The mutagenicity of vinyl chloride after metabolic activation. Ambio 3:194-197. Selikoff IJ, Hammond EC, eds. 1975. Toxicty of vinyl chloride-polyvinyl chloride. Ann. N.Y. Acad. Sci., Vol. 246. Spirtas R, Kaminski R. 1978. Angiosarcoma of the liver in vinyl chloride/polyvinyl chloride workers. Update of the N10SH Register. J. Qccup. Med. 20:427-429.' Spirtas R, McMlchael AJ, Gamble J, Van Ert M. 1975. The association of vinyl chloride exposures with morbidity eymptoms. Amer. Ind. Hyg. Assoc. J. 36:779-789. Suclu 1, Frodan L, Ilea E, Paduraru A, Paacu L. 1975. Clinical manifestations in vinyl chloride poisoning. Ann. N.Y. Acad. Sci. 246:53-69. Tabershav IR, Gaffey UR. 1974. Mortality study of workers in the manufacture of vinyl chloride and its polymers. J. Occup. Med. 116:509-518. Til HP, Immel HR, Feron VJ. 1983. Lifespan oral carcinogenicity study of vinyl chloride in rats. Final report. Clvo Institutes TNO. Report No. V 83.285/291099. Torkelson RR, Oyen F, Rove VK, 1961. The toxicity of vinyl chloride as determined by repeated exposure of laboratory animals. Amer. Ind. Hyg. Assoc. J. 22:354-361. Trlbukh SL, Tikhomirova NP, Levina SV, Kozlov LA. 1949. Vorking conditions and measures for their eenitation in the production and utilization of vinyl chloride plastics. Gig. Sanlt. 10:38-44 (in Russian). U.S. Department of Agriculture, Agricultural Research Service, Household Food Consumption Survey, 1965-1966, Food and Nutrient Intake of Individuals of the United Stetea. U.S. Environmental Protection Agency. 1974. Preliminary assessment of the environmental problems associated with vinyl chloride and polyvinyl chloride (appendices). Report on the Activities and Findings of the Vinyl Chloride Task Force. EPA 560/4-74-001, (PB-39 110). 67 pp. X-9 SL 109022 U.S. Environmental Protection Agency. 1975a. Preliminary asaessment of suspected carcinogens In drinking water. EPA 560/4-75-003. (PB-244 415). PP 33. U.S. Environmental Protection Agency. 1975b. Standard Support and Environmental Impact Statement: Emission Standard for Vinyl Chloride. 600/6-75-009. (PB-249 703). p. 536. EPA U.S. Environmental Protection Agency. 1975c. Scientific and technical assessment report on vinyl chloride and polyvinyl chloride. EPA 600/6-75-004. (PB-249 461). p. 116. U.S. Environmental Protection Agency. 1975d. National Organics Reconnaissance Survey (Office of Drinking Water), Journal of the American Water Works Assocation, 67, 11, 634-647, November 1975 and 67, 12, 208. U.S. Environmental Protection Agency. 1977a. The National Organic Monitoring Survey. Interim Report, Office of Drinking Water, p. 126. U.S. Environmental Protection Agency. 1977b. Survey of Operating and Financial Characteristics of Covunlty Water Systems (Temple, Barker and Sloane). U.S. Environmental Protection Agency. 1978. Compilation of data from: A Preliminary Report on the Findings of the State Ground Water Monitoring Project and a Second Preliminary Report on the Findings of the State Ground Water Monitoring Project, State of New Jersey, Department of Environmental Protection. U.S. Environmental Protection Agency. 1980a. Memo to Joseph Cotruvo from Robert McGaughy, September 17, 1980, Washington, D.C.: Carcinogen Risk for Pollutants in the Drinking Water -- Comparlslon of Results Obtained by the National Academy of Sciences and EPA'a Water Criteria Program. U.S. Environmental Protection Agency. 1980b. The Occurrence of Volatile Organics in Drinking Water (Office of Drinking Water). U.S. Environmental Protection Agency. 1980c. Survey of EPA Regional Drinking Water Representatives to Determine the Ground Water Monitoring Data Developed by State Agenciea. U,S. Environmental Protecton Agency. 1980d. Compilation of Incidents of Drinking Water Contamination with Volatile Organic Chemicals (Office of Drinking Water). U.S. Environmental Protection Agency. 1980e. Ambient Water Quality Criteria f r Vinyl Chloride (Office of Water Regulations and Standards). EPA 440/5-80-078. U.S. Environmental Protection Agency. 1981a. Conmmnity Water Supply Survey (Office of Drinking Water). slj x09023 X-10 U,S. Environmental Protection Agency. 1981b. National Organics Screening Program fSRI). Vati Lsch GJ, Van l.opten HI. 19/5. Vi:y] chloride: a report of a Lurrpea'" assessment. Fd. Gosmet. Toxicol. 13:111-124. Verburgt FG, Vogel E. 1977. Vinyl chloride mutagenesis in Drosophila raelanogaster. Mutat. Res. 48:327-333. Viola PL, Bigotti A, Caputo A. 1971. Oncogenic response of rat akin, lungs, bones to vinyl chloride. Cancer Res. 31:516-522. Ward AM, Udnoon S, Watkins J, Walker A, Drake CS. 1976. Immunological mechanisms in the pathogenesis of vir.yl chloride disease, Br. Ked. J. 1:936-938. 14 Watanabe PG, McGowan GR, Gehring PJ. 1976a. Fate of ( C) vinyl chloride after single oral administration in rata. Toxicol. Appl. Pharmacol. 36:339-352. Watanabe PG, McGowan GR, Madrid EO, Gehring PJ. chloride following inhalation exposure in rats. 37:49-59. 1976b. Fate of (**C) vinyl Toxicol. Appl. Pharmacol. Waxweller RJ, Stringer W, Wagoner JK, Jones J, Falk R, Carter C. 1976. Neoplastic risk among worker exposed to vinyl chloride, Ann. N.Y. Acad. Sci. 271:40-48. Weisburger JH, Williams GM. 1981. Carcinogen testing: current problems and new approaches. Sci. 214:401-407. Wilson RH, McCormick WE, Tatum CF, Creech JL. 1967. Occupational acroosteolysis. Report of 31 cases. Amer. Med. Assoc. J. 201:577-581. Wlthey JR. 1976. Pharmacodynamics and uptake of vinyl chloride monomer administered by various routes to rats. J. Toxicol. Environ. Haalth 1:381-394. Vithey JR, Collins BT. 1976. A statistical assessment of the quantitative uptake of vinyl chloride monomer from aqueous solution. J. Toxicol. Environ. Health 2:311-321. X-ll SL 109024 Ir ,) --i 1 VI-17 Table VI-10 __________________________ Group and Tumora/100 anirnal* MT BT LAS Caperlmrnl HT5 * Animals with tumors, 1 Fore- Mata Hepa Nrphro- Nruro- Zymbal Skin stomark mary LA ELAS ELA toma* BL BL til.Ca EpT PaA At MT i 10,000 ppm II 0000 ppm III 10,000 ppm IV 0000 ppm 0.1 0.1 29.0 21.9 10.1 23.3 22.2 40.9 - 33 _ _ 11/301 S.9 99 2.0 20 I3/&I) (S/SII (l/Sl) (lll 3.1 - - - 9 4 3 1 3.1 0.2 (1/32) (302) II321 (1/32) 1232) *Eiporarc 0jr Wulttlon la VC in air at 10,000. and 0000 pimrfbmdm; 4 hr'day for I arrl (from 12th ( INth day of pregtianrr) Sprague-Dawley rata, M and F, 19 areeka oM (breeders). Breeders (groups I and 111 and offspring* (group* III and IV) Rnaks after 143 necks (rad of tapartment). Adapted Iron Haltoni, 1981 si* l0 9 2 SL 109026 Table VI-11 GrapanJ (MKCfltfltllll IWn/ICO MT BT LAS Eaperimeiri IITIJ.* Aniiritb with tumors, % Fore hisat Hepa Hephro- Nrunv Zymbal Skin stomach inary LA ELAS ELA tomas BL IIL (JICa EpT PaAAc MT i 10,000 ppm 16.? 66.7 3 (breeders) I 11 COOOppn (breeders) * III 10,000 ppm (newborn) 100.0 66.6 34.1 flB/44) 6.0 45 4 (3/44) (20/44) ` 23 23 (1/441 (1/44) * IV 6000 ppm (newborn) 109.2 Ml 40.5 2 4 24 2 4 47.6 (IT/421 (1/42) (1/42) (1/42) (20/421 4.0 4.0 (2/42) (2/42) 24 (1/42) 'EipoWR by Inhalation to VC in air at 10,000 and 0000 ppm, 4 hr.day. 5 daya/werk, for S week* (from 1 day ( 5 weeks of ipl Sprafiie-Dawlcy rail, H and F, 21 weeks eld (breeders) ((roups I and lit and newborn ((roups III and IV). Results after 124 seeks (end of eaperimenl). Adapted froa Maiton!, 1901 i. L_ II Table V1-I2 . Faperintent BIT' Cmy and NKMlnliM TumwVlW inimala NT BT LAS Animal* triih tumor*. 1 Hepa Nephro- Nrum- Zymbal ForeSkin atomach LA ELAS ELA toma* CL BL Gl.Ca EpT TaiAc 1 Ml 10.0 200 - - - - 37 It 1 7.4 _ mow ppm 10271 (127) (327) (227) ii 53.3 200 II 5 7 7 38 38 7.7 7.7 3.8 7.7 < *000 ppm (3 361 12201 (1201 (126) (226) (226) (1201 (226) M I III tiOOppaa IV K.l 13 3 12 0 4O 40 40 <3-251 <1251 (1251 (125) M0 10.0 10.7 30 _ 7.1 40 (125) mppm (328) <1/2*1 (2281 V 13.3 tr. 7 37 37 37 _ 37 St ppm VI II 271 (1271 (1271 111 (.1 ' " " _ 36 (127) Mppm (128) VII Ka treatment tram rail 15 0 ISO - - 26 (1/381 *Ei|*arr by inhalation la VC in air at lo.omi. flttW. 2500.500.250. and SO pw; 4 hr'day. 5 day a/week, for 52 week*. Wialar rata. M. II d U. fteauHa after 165 week* lend of eapenmenl) SL 109027 Adapted Iron Haltoni, 1901 vo* vOD CP Table VI-13 Eipertmetri BTI1.a Croop and tonnM ration 1 Ippiu II Ki treatment (control) TtHuon/100 MT IT Ml 292 29.0 18.6 LAS * LA 1.0 (1/991 ELAS Animals *Kk tumors. V Hepa Nrphro- Neuro- Zvmhal ELA tomas BL RL Cl.Co 'ForeSkin stomach EpT Pa* Ac 3 0 6.0 10 (3/99) (699) (199) - 20 (299) - ---- 3.2 - 1.1 (394) (194) *Eponr by inkibliw to VC in air al I ppm; 4 Mar, 6 dijVimh, for U vttki. Wistar rats. M, 13 n ocks otd. Results after 134 nrrki lend of fipcrimentl. V I-20 Adapted frost Maltonl, 1981 L__. L_ !___ ! CJJ [ r--- i F'" ' n i a to Ul C* \Or* vOD vD Table VI-14 Group and MMMIlliN 1 10,000 ppm It (000 Pf III BOO ppm IV HO ppm V ISO ppm VI Hppm vil K* Irealmtut (ratrtnl) TutnorVlOO animals MT 8T Ml K.7 98.3 1000 W.I 90.8 Ml 103.3 0.1 Z8.3 90.3 23.3 ll.T 14.1 LAS 17 8 (low.) 21.7 03*00) 21.1 OO'SS) 233 (14*60) 30.0 08*00) 17 (1*60) Eiptrhntnt I1TL* Animals ilh minors, )1 LA 10 7 (6'56) II 7 (7/00) 8.5 (5*53) 83 (5*00) 18.3 (11*00) 1.7 (1*00) _ F.LAS 1.8 0*56) 1.7 (1*00) 13.5 (R/59) II 7 (7*00) 50 (3*00) 1.7 (1*00) 0.7 (insoi1 CLA Mammary Lung T Ca 7.1 (4*;*) so (3*00) 1.7 (1*59) 5.0 (3*00) 50 (3*00) 83 (5*501 82 1 (4Ol50) 78 3 (47*00) 57.8 140*59) 83.3 (50*0Of 083 (41*60) too (6*60) 23 2 (13501 13 3 (8*00) 13 5 (8*591 13 3 (800) 200 (12*60) 200 (12*00) 07 (1*150) too (15150) 07 (1/150) Skin EpT Forealomach Fair Ar 7.1 44*1561 11.7 (7*60) 68 (4*59) 3.3 (2*60) 1.7 (1*60) - - 1.8 11*56) 1.7 (1*60) 1.7 (1*59) - 1.7 (1*60) 1.7 (1*60) 1.3 (2*150) - *4 F, II week* U. RcmIU after SI **ka <trd of tpenmrn(). i I 1 li I I Adapted Croat Hnltonl, 1981 SL 109030 Table VI-15 Ci^riiwM MTU.* Croup ond twuntirllw Tanmn'IITtt animali XT BT __________________________________ Animals wilh tumora, % Atmnlit Hepa- Choisn- Chnlan- Duct LAS LA CLA IMIU pio-Ca piomu EpT Shin EpT Fore- Mela- atamachLnhw PadAc auMs 1 Ml 731 . 1.3 6 7 6 7 13.3 33 23.3 3.3 33.3 HI 11,000 ppm II 301 1230) (I'M) (4730) (1730) (TOO) (1730) (10730) (6* * II 40.0 .l 3.3 31 - 33 6.7 16.7 6.7 3.1 0.7 33.3 Ml 000 ppm (1730) (1/10) 1170 1210) (6/301 (2730) (1730) (2/30) (10730) (6Mi a Ni> N III 2600 ppm IV 600 ppm 43.1 1031 - 67 - CIO) ill Ml 67 - 1.1 (zno> 11 K _ - 26.7 13 10.0 1.3 66.7 Ml (6001 (1730) (aim (1730) (I7TMI me _ 20.0 10.0 23.3 300 in 1600) (3/30) (7/30) - (0730) (I7M V M0 41.3 - - 13 - - 20.0 - 10.0 3.3 13.3 Ml 11.701 (6/301 (3730) (1730) (4730) HOP VI HI 40.0 - - - . _ 23.3 - 30.0 3.3 10.0 Ml Mppm - VTHI] Tfe (Kilmenl 20.0 40.7 _ (77301 (M0) (1730) (MO) mu --, .16.7 6.9 _ 6.9 n.i (csnlrall (2260) (3700) (ICO) we *Eipowc Iqr inhalatian Ui VC in air *1 I0.U. 6000. 2500. 500 250. and 50 ppm: 4 hr/day, 5 dajra/wceh, Ibr M week*. G*Mn hametere, X, 11 weeha old. Results aftrr 109 reks (end of raprnmrM t. Latency Urn* h weeks: Croup I, 16.7; Croup II. 27 2; Group III. Croup IV. 19 0; Croup V, Z2.6; Croup VI, 36.1, Croup VU Adapted Iron Haltonl, 1981 L __J i ti Table VI-16 Esperimenl HTII * Croup ant) cwncewtrslio* 1 tOq n|A| II 10.05 **( III 3.33 mf/Vf IV OOresB (mini) Tnmom/100 animal* MT BT LAS Animal* with tumors, % Fore Msro Heps Nephnt Nruro- Zjrmbtl Skin stomarh man LA CLAS ELA lomu ul m. <;tca EpT FitAt MT SAT 36.0 21.2 3.7 2.5 2.5 - 2 5 (17/00) <3* <2/001 <2/001 <2 Hi so.e 17.6 12.6 - _ - _ 3.7 <1M) aooi iso 26.0 - - 26 12 _ <2/001 <10 1.2 <1/001 2.5 <2001 _ 12 <l/00) 25 <2/001 1.2 11/80) 60 <1 76 <M) 3.7 <3/80| 13.7 22.6 __* -_ 1.2 1.2 <1/00) 11/80) SO <4/80| `Exposure by Ingestion (stomach lube) of VC in olive oil it 50 00.16 65 am) 3.33 fnr'k* IkkIv wn*ht. otter duty. 4 5 (isyvwerh, for St Efn|w-Dtwlt)f reU, M and F, 13 weeks old Results ifler )3( weeks (end of experiment). V I-2 3 si) 109 3 Adapted from Mnltonlt 1981 SL 109032 Table VI-17 Experiment BTII * Group and concentration Ammols with tumors. % Fore- Mam llepo- Nrphra- Neuns- Zymbal Skin atomach mary MT BT LAS LA ELAS ELA tomoo 11L fIL GI.Co EpT P* Ac MT 1 LOmg/k* II O.Smf/kg III 0.03 mgAg IV OVveofl (controll 24.7 35 3 2.0 _ 07 (3/149) (1/149) 3 3 no 0.7 0.7 - <1/148) (1/146) 18.0 31.3 07 II/I49I 07 (1/148) U.O 28.7 - - - - 33 2.0 SO (5/149) (3/149) <12/14* 8.7 1.3 2.7 (1/148) <2/148) (4/1W 0.7 0.7 9.3 (1/150) (1/150) (14/1H) 0.7 _ 1.3 4.7 (1/150) (2/150) <7/1501 'Eipolure by bigeotlon (stomach tube)of VC in #* oil ol 1.0,0.3,0.03 mft/Vy body wr^hl, once doily, 44di]^tek,ferUoMb Sprague-Donley rata, M and F, 10 week* old. Hrsuits oiler 136 weeks (end of experiment). Adapted fr m Maltonl, 1981 i (------J T i 1 [1 1 t 1. i n M KJ U . Table VI-18 Ep*rlmtni BT1I* CrMfind foe IWtwVlOO MT BT ____________________ LAS LA CLAS Animal* oilh tumor*. a llepa- Nrphro- Nruro- Zvmbal F.LA toma* HL RL Cl Co Fore- Mam Shin atomaeh mare F.pT PaiAr MT i 4.Bmf *4 II III IV IttMgK) v (Nne of temtral) it.a 11.1 ll.T sot III 3S.0 .> ai.T |J 1 II (1/M) (I/M) 1* 1.9 <1 .VII lh ---_ (l/UI <1/S3| 1.8 (.1 (1/sfi) _ 1A _ (I/M) (3/M) 1 B as as (1/55) (1/ST.I (2*$> (2/wi Uft (2/MI Cipoaorr by ttraperitoneal lafccUs* t VC, 4. my in olive otl it ml). 4. 3. 2 times. al two month intenale or oner only Spnfae-Dawley rata. M and F. 17 week* oW ReaulU after 144 week* lend of epenmen) |. tKA? V-* o o lA )jJ Adapted from Maltonl, 1981 Table VI-19 Experiment BTU. Grsopmd TwmoiVlOO HT BT LAS Animals with tumor*. % Fore Mam Hepa- Nrphro- Neuro- Zymbal Skin stomach mary LA ELAS ELA tornas DL BL fil.Ca EpT PaftAc MT 1 . ay II Oftrcoa (control) K.I 17.3 13.1 26.7 " 1.3 - " to (l/<5| (3.75) 1.3 (105) 1.3 (1/751 - - 13 (1/75) tipnn by mbiUimt hjotiim of VC, 4.25 mu, in olive oil (I ml), unfit dose. Sprafuc-Hawley rat*. N and F. 21 weeks old. Indu after 145 weeks (end of experiment). Adapted Cron Haltoni, 1901 Table VI-20 Taaoro Presently Correlated to VC Exposure (by Inhalation) on Experimental Rodents s Anpe- Sch* Other * aarromu from ml*- ForrMcv and an- cuts* nrnua nwh pa Aafio- IWm IVmm Lpnpho- giamaa Nephro mm epilh- Mint- pillomas **** of Ipon f btr brain of mu and llrpa- al other blasto hmc leukemias tornaa titer ma* cirriMimas rhal nun w- and acan- Mela lumnr* tinomu Ummu nomas lx 4 4 4 4 *> 4 4 4+ 4 <> 4 < 4 * |4 (4) |4> 4 <+ VI-27 SL 109035 Adnptcd Iron Haltonl, 1981 Abbreviation** o*d in table** T ft ftt Pt Ait KT IT LAS Kan-BL IT Mtb. D&bjp. *4* Kww^he-- Ac>oMfte h/popeai fct lhw Xi>b>*>tiTk i/nilMii kfrar KaopUaie Mdala tfhe KttteUr Tiy^lirii rfihaPtgu--dhyyiTpliiii rflnf Kafarf V7hW TVaadMouul--lifMiw i haags fimi wm agaa tie uul ante rf tanas pa 100 until (a na) mar kmt m Uu aa aafipast m Waife taaa) m the baa tt >te tet hMrd uaj^ik tw>l. >ftn. v*m tht Bat all barky ewr *aii4aA.Cnfcm4 bTuTaaaak in ta tte Am lar * ilmnw) (to pa--laid Adapted from Maltoni, 1981 VI-28 A recently completed study by Feron ct *1. (1981) examined the oral toxicity of vinyl chloride in Ulster rats. This study was carried out over the lifespan of the rats, and consisted of incorporating FVC powder containing a high content of vinyl chloride monomer (VCM) in the diet, or using gastric intubation of a 10J VCM in soybean oil. The VCM doses (actual exposures) vere 0, 1.7, 5.0 and 14.1 mg/kg bw through the diet or 300 mg/kg bv by gastric Intubation. The results shoved that rats exposed to VCM at levels of 5.0 mg/kg bv day or more demonstrated hepatic angiosarcomas, pulmonary angiosarcomas, and at the higher levels, a few primary extrahepatlc 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 vere noted (Tables VX-21 and VX-22). Feron et al. (1981) concluded that VCM 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 VCM/kg bv day) and two control groups. Til et al. (1983) examined the oral carcinogenicity of VCM in a lifespan study (149 weeks) with five groups of Ulster rats, each consisting of 100 Mies and 100 females, except for the top-dose group which comprised 50 males and 50 females. VCM was administered by Incorporating PVC powder with a high VCM content into the diet. The diet was provided dally for a period of four VI-29 SL 109037 Table VI--21 Type *nd Incidence of TrestMent-Relntcd Histopxthological Changes In the Liver of Rats Exposed Orally to VCMi change* (mg VCH/kq/day). . 0 1.7 5.0 14.1 300t 0 1.7 5.0 14.1 300, Animals killed after 26 vk Ho. of rate examined.. . 10 1-- 10 9 10 Clear-cell Cod 0 ---- 1 1 0-- -- 3 Animals killed -after 52 wk i S No. of rata examined.. . 9 ernes 10 9 Clear-cell fod 1 ---- 8** 0 9 0-- -- Basophilic foci Eosinophilic Cod Neoplaatic nodule Hepatocellular cardnona Cyetic proliferation of bile ducta 0 ---- 0 ---- 0 ---- 0 ---- 0 ---- 00 20 10 10 00 0 0 0-- 0-- 0-- -- -- -- -- -- Animale found dead or killed In extremis ar terminally 10 10 5** 2 10 B** 4 5** 2 1 4* 0 0 1 0 0 0 0 No. of rates examined.. .55 Clear-cell fbd 0 Beeophilic fod 0 Eosinophilic fbd 3 Neoplastic nodule 0 Hepatocellular cardnona 0 Angiosarcoma 0 50 56 59 55 57 58 59 57 54 9** 16*** 21*** 9 4 24*** 22*** 36*** ur 10 21* 22** 12 0 33*** 17 20*** 19 23*** 27*** 33*** 11 8 35*** 20* 29*** 6 1 7** 23*** 3 2 26** 39*** 44* 2 12 8** 1 0 4 19** 29*** 0 0 6* 27*** 27 0 0 2 9** 29 i l_- i____; l__ J J) Table VI-21 - continued Proliferation oi atypical ainuaoidal cells only Extensive necrosis Cysts iiiveccell polynorphiest Centrilobular degeneration Fbcal haewatcpoieels 2 0 4 7 646 347 4 4e 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 lesions were classified according to Squire a Levitt (1975). fTha figures of this group were not evaluated statistically beoaues no uorresponding control grcup Me included in the study. Wot examined. The initial timber of aninala wan 60/eex/group. h nueber of rats could not be eeamlnsd baosuss of damibalisni advanced autolyeis. Values mdcd with asteriks differ si^iificantly fron those of the controls acoording to the chi-square test* *P<0.05| **IK0.01| ***P<0.001. CQ t-* Adapted froa Fsron et al. 19HI. 109039 Ttbit VI-22 Sit*. Type end Incidence of Timor* In Organa Other than the Liver In Rata Exposed Orally to VCM for Over 2 to 5 Year* Sit* and type of tuncur (iqVCR/kq/dBy).., inddonra of1 twaura Males tamli 0 ~r~ 5.0 1-4.1 1B5| 6 "XT" 5.6 l4.i "15 Effective no. of rats... No. of rat* tilth prixory tuaour*... Lung* Angiosarocna hdenonu Zynbal gland* *- Squasojo-cell oardnum Menaau Mxfcmen Meaotheliona Anglosanxaa |ribaro*anx*a rSarocnn Reticultan-onl 1 trccwi `Schwann-cell tiamr* Unclassified Spleen Haensmgioandatheliasaroaan Lysphcsaroan* Nose Squanous cell cnrdncm Drain Granular-cell nyoblaetona Ol igodendrogllcnu Plexus papillcna Glial-cell tuncur Epend)an Mesoderm1 tisnour Pancreas Adenooarcinona thorax Mesotheliana thyroid Parafo) Licuiar-cel 1 atlmcsa Parafollicular-cell cnrcdncm P~' Mcu'" c 1 ' 'lenr-- 55 58 56 59 55 57 58 59 36 50 49 52 44 54 56 55 0 0 4* 19*** 19 0 0 1 0 0 0 o. 1 0 0 0 0 0 2 0 1 0 0 0 0 0 0 0* 0 0 0 0 3 1 7S 11 6* 3 0 000 10 00 0 00 3 01 20 0 0 0 'b 10 00 0 031 00 01 0 100 10 00 0 000 00 10 0 000 02 00 0 100 00 0 .0 0 000 00 00 0 00 1 00 00 1 1 00 00 i0 1 000 00 00 0 000 00 10 0 0 20 10 00 0 00 1 00 00 0 010 00 00 0 000 01 21 1 000 00 00 4 12* 10 J EL^J 10 1 3 0 3 7 10 00 0 n .._J -J 3 0 57 54 57 47 5* 23 00 01 01 3 i0 21 00 10 00 00 00 00 00 01 0 c 00 00 00 o0 00 00 00 00 2c 00 1NU VI-32 taoritliwed) Site and typo of tumour (m VCH/kq/day) Halee Incldtnce of Ttnpure Females 0 1.7 5.0 14.1 300* 0 1.7 5.0 14.1 300* Blood Leukemia Haart Bdocardtal dlnsw* Ha<maiiglomiotliellosaraa Kldwyt Hephroblaetoma Clear-cell tunour Lipomatoue tunour Unclnsolfled epithelial tu Retlculua-cell met-- Heoontorlc lynph nodes Reticulum-cell saruema Skin Squamous call cardnom Sidicutls Fibroma Frlbrosaruoaa Skeletal nuncio IB 25 17 n 21 ' e 12 25** 6 i0 1 l0 1 20 10 2 0 10 00 00 0o 0 0 1 0 0. 1 00 0 0 00 0 23 3 21 01 00 1 1 0 00 0 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 Q. 0 00 O0 00 00 00 11 00 00 31 10 00 00 17 14 02 5* 3 00 01 01 00 00 10 00 00 0 :0 00 00 10 00 00 00 00 SL 109041 1MU VI-22 (continued) Sits and typa of Ing VOVkg/<fay) Male Incidence of lUwun 1.7 5.0 14.1 $00* 1.7 5.0 14.1 300* SL 109042 Skull 1 00 OO0 0 00 00 0 0 0 0O X 0 o o Ear region Mmooudim of urttnown origin 0 0 0 o0 00 0 0 Urinary bLaMar Unclassified epithelial tunour 0 o 1 0 00 o0 0 o Preputial 9landa cardnona 00 1 0 00 00 0 o gland* <MI Anaplaatic cardncso 00 O0 01 00 0 0 0 o o 00 00 2 0 0 o 21 25 12** 4** 7 2 0 3 S4 7 7 o o0 o1 0 o Interstitial-cell tunur 3 Uterus Menooarcinan Maligiant flbcoadencwntoue tumour 6 31 1 0 O 10 0 0 O 01 0 o Cervix Hesenchywal type of tuaour Adenocarcinoma 2 01 0 o 0 1o o o Ovariea .Theon-pell tuaour 0 01 0 O email naber ot primary liver tisnoure unrelated to treatment were found in several graupe. Thee# one KupEfer-cell sarocma, three reticulum-cel 1 saracens, two fibraeaiuusaa* one tuMMangioendctheliann and mesenchysnl tunour. fTha figures for this group were not evaluated statistically, because no corresponding control group in the study. included I In several, anas the neoplastic character of the lesion was doubtful* Values narked with aster Iks differ significantly from those of the controls according to the dil-epue teeti 05*, **v<o,TM* ***p<n.opi. 1\ ' - - L_ ' I-------i t! i________J .J . ' i___J t consecutive hours* and food was withdrawn during the other 20 hours. Oral VCM exposure levels were 0 (control), 0.014, 0.13 and 1.3 mg VCM/kg bw/day. An extra control group of 100 rats/sex was housed in a separate room. Additional groups of 10 male and 10 female rats, each receiving the same treatment as the main groups, were used for determinations of glutathione levels in the liver after 9 and 18 months. Observations were made of general appearance, mortality, growth, food intake, thrombocyte count, prothrombin time, glutathione levels in the liver, gross pathology and microscopic pathology of the liver and of all grossly visible tumors or presumable tumors in the abdominal cavity, Zymbal gland and the mammary glands. General health, behavior, body weight and food Intake were not adversely affected by the test substance. In the second half of the experimental period, mortality in the extra control group was higher than in all other groups. This was most probably due to a high incidence of chronic respiratory disease in the extra control group. In the final stage of the study, the mortality in the top-dose group was slightly higher than in the lower dose groups and the controls. Thrombocyte count, prothrombin time and liver glutathione levels did not show treatment-related differences among the groups. A clearly higher Incidence of grossly visible, tumorous, liver nodules was found in both males and females of the top-dose group than in any of the VI-35 109043 SL other groups. Moreover, in females of the top-dose group the incidence of hepatic cysts was considerably higher than in controls. Microscopic examination of the liver revealed increased incidences of liver-cell polymorphism, hepatic cysts, foci of cellular alteration, neoplastic nodules and hepatocellular carcinomas in the top-dose group as compared to the control group. One mid-dose female had a hepatocellular carcinoma and neoplastic nodules were found in one low-dose female and in one mid-dose female. A control female was diagnosed with hepatocellular carcinoma. A heparic angiosarcoma was found in one male and two females of the top-dose group, but no such tumors were encountered in any of the other groups. The number of animals bearing foci of cellular alteration in the liver was also statistically significantly increased in females of the mid-dose group as compared to controls. In addition, in females but not in males, the incidence of basophilic foci of cellular alteration in the liver was statistically significantly higher in both the low- and the mid-dose group than in the control group. Details of the histopathological examination of liver are in Table VI-23. There was no evidence of VCM-feeding affecting the incidence of abdominal mesotheliomas or the type and incidence of mammary gland tumors (Table VI-24). No Zymbal gland tumor was found. VI-36 SL 109044 Table VI-23 Type and Incidence of llistopatholnglcal Changes In the Liver ch#ng# Hwnber of mImIi eualiiH Incident* of thun^vi Ha lee Fensles *> VCM/kg b.w,. /dap g VCK/ha b.w.,/rixf 0 0.011 0.11 1.1 0 0 0.011 0.11 1.1 99 W 99 4* 100 9ft 100 9ft *9 o 09 F1 of cellular alteration a. clear call foci I one or a few 11 II several 0 b. baaophlllc fact 1 one or a few 4 II oeveral 0 c. il>ff cel 1 foci I one or a few 0 4. eoolnophllIc foci 1 one or a few 1 ft 0 1 0 1 1 1ft** 0 1* 1 ft* 0O 7I 11 54 n0 n9 00 n ft 00 5 1 I)*** 1 0 0 ft*** 0 10* 7ft* 1 01 ft 4 M 4 0 0 0 in*** 1 Total Nunber of focibearing anloala 11 II 1ft 11 15 10 15 5 19 11 14 Ml 1 I** 19 11 11* 31*** V I-3 7 CO o VO o Table Vl-23 - continued SL 109046 Type of change* _________________________________ Incidence of change* Hale* Feoalea ag VCH/hg b.w./day g VCH/hg b.w./day 2, Nfoplaitlc nodule* 0 0.01; 0.1? i.; O * 0 0.01? o.l? -------1---.?v----- 0 a one 00 0 1 00 1 1 **** 0 h. a tea 0 0- 0 200 0 0 i0 ], Nepatocellwlar caretnow* 0 0 0 1* 0 1 0 1 i0 *. Angloaarcoaa 0 0 0 1 00 0 0 20 1. L(*er-ce!l polyworphlaw a. alight II 21 16 19 12** 46 41 49 21 19 3 i b. mferiti 4 4 2 I0* 1 14 11 e 11* 11 u> 1 1 1 102 1 4 9* 1 00 1. Frowlaent alnoeoldal cell* a. alight I 1 1 01 4 9 1 I1 1. 0 1 a i 16 i 20 t. Cyata . one 1 0 1 0A 1 2 h. a few 4 4 ) 4 1 11 II c. m*of 0 0 0 00 1 4 I. Hit fact proliferation 4 11 12 ? 9 |4**a 1 a. alight b. noderate c severe 1? 26 11 14 21** 2? 21 9 9 6 1 I** 11 6 I 0 0 01 1 2 16 18 14* 10 2 1* I 14 J - f , r- - r r \ r- V I-3 9 CO e* V-* o VD O Table Vl-23 - continued Type ( changea 9. CholongfofIbroaia a. alight J1 1. aodrrate 7 10. Periportal (Ibroaia a. alight b. Moderate 1 1 11. Ferlportal/eentcolobwlar laflltratea af Mononuclear cella a. alight I* b. oodetate 1 e. aeaere 0 17. Foci of OF.S-eel la occaaloaallp accoopanled bp a few necrotIc hepatocptea a. one or a few III b. aeveral $ 11. SI I phi harnatopolet Ic actleltp 7 Inc Utntf of thangra Ha Ira frnaira g 9CH/hg b.w./dap tCH/kg b.w./dap 0.017 0.17 1.7 0.017 0.17 1.7 --1~ IP* 70* * * 71 lb II 17 11 7 I0 71 00 0 o 00 0 n 00 7** 0* 10 7J 7 7 1 00 0 0 I 00 0 0 II 77 0] 17 19 70 7 17* 71* 1t 1 1 0 1 Table VI-23 - continued V I-4 0 T*pe of change* Inc Idenee of changea t-* Ha la a renalta o VO VQt/hg b.v../day -- VCH/hg b. ./dap o 0 0.011 0.11 1.1 0 0 o.on 0.11 1.1 0 CO t 1*. Slagle coll oocroola a. alight 1 J 1 0 4 1 3 I3 5* 9* 11 0 00 1 3 4 i1 1). Focal nocroalo a. alight 11 J* 1 4* 4 4 b b 3 b. aoftratt 1 1 1 003 1 1 0 3 1 0 0 10 3 0 1 0 1 lb. Centrolohulor llvcr-cclt degeneration 1 3 3 103 1 1 0 0 11. One or a lev foci of 1 0 1* 3 0 1 1 0 n 0 IS. Karoorrhaj1c arcaa 19. Felloala-llhe change a 10. Snail gramtloon 1 0 0 0I 10 00 0 o' 0 10 1 00 1 0 1 00 t 0 n0 0 0 00 . 11. Vacuolltatlon of a. periportal I alight If CMl#rai* III aevere 3 11* J 4 14 11 19 4* f) 1 3* 0 0 1 1 4 ft 1 0 1 1 00 0 0 0P p Table VI-23 -- continued Type ot changer k. illlaae I oll|ht 11 oderote c. ctotralakolar 1 alight Incidence of chon* e* Nolee Feaeleo M VCH/ko t>. . /day 1 ven/ha b... May 0 0.01) 0.1) 1.) 0 0 0.01) 0,1) I.) 0 1 0 1 00 0 0 000 1 0 I 00 1 0 000 0 1 0 00 t 0 00 ) 0 1 0 00 0 0 0 00 ** Specific hepatocellular Ifilma were clanlllrf atcafflng t Sfalra anil l*IU (1FIS), p (0,0); * F <0.01; * F <0.001, accarftni to IK Flaheea* nact teat (a tolled). Adapted fro* Til et nl. 19B3. SL 109049 tr> 109050 Table VI-24 Type and Incidence of Tutaorn of the Mnnmnry Glands find Incidences of Abdonlnal Hoaothellomnn Sit* Hi tyft* Iwmirt Imllewt ol tawun Hale* FcmIh Iwbtr ol anlaal* iihIm! 0 a vCH/ka b../itr VOt/ki b../! 0.017 0.17 |.7 0 0 0.017 0.17 1.7 4* 100 so 100 34 4ft 0 Ibmri tUnlt - Ho of t moor-baaring hImIi 5 fl ] 0 3M 7I** 2B* 71 70** * t V I-4 2 a. alngla fc. IlC 1. latraguctal Malllwaa ). ribiaileiiMi a. alnglt b. two e. Multiple 00 00 00 01 00 00 0 b 0* 4 I 52 0 0 01 1 1 00 0 o 00 0 0 10 0 0 0 15 Iff** 15 14 11** 0 0 02 3 2 74 0 0 o3 1 1 11 ' rTJ r r- Table VI-24 - continued Sd* aM tyge of t *. Mbrowa Incident* of tuoourt Halo* rcwalea VCH/hf b.v./dajr VCH/lti b.v./dar 0 o.on 0.U 1.2 0 0 0.011 0.11 1.1* 0 i. olngle k. two c. wait 1 pie 1. UtiMKirt 1 nmi t6 00 00 2 0 .1 1 * 1 22 1 0 00 0 0 ft 0 0 0 01 0 0 00 a. ala|l 01 0 0 01 0 i 10 b. two 10 0 0 0 ft 0 1 01 <M(t>I- AMowr. 1. Htaathelliaa 01 2 0 0) 2 2 11 * f < O.M[ P < 0.01; ** t < 0.001, according to the Maher a* enact teat (onr tailed) Adapted from Til et al. 1981. SXj 1 0 9 0 5 1 VII. HUMAN HEALTH EFFECTS A. Kcn-Carcinogcnic Effects Vinyl chloride can produce a number of pathological consequences in humans in addition to its carcinogenic effect. These effects can be caused bv acute or chronic exposure to vinyl chloride. Unfortunately, data regarding dose-response relationships in humans are very scarce because fev air measurements of vinyl chloride in the work environmental of vinyl chloride manufacturing and polymerization plants were cade before 1975 (Kancuso 1975). According to OSHA (39 Federal Register 12342, April 5, 1974), several facilities revealed vinyl chloride concentrations for some job classifications as high as 225 ppm. Rove (1975) commented that before 1960, a fev jobs resulted in exposures in the range of 100 to 385 ppm, but these measurements may be high because the method of quantification measured total halogens rather than vinyl chloride alone. Nicholson et al. (1975) reported that vinyl chloride in polymerization reactors may often have exceeded 1,000 ppm and occasionally may have approached 10,000 ppm before OSHA standards were instituted. At these levels, workers experienced dizziness, headaches and/or euphoria during work periods. Several Instances of acute exposure have occurred in vinyl chloride plants. Deaths of two Canadian vorkers following acute exposures to vinyl chloride gas were reported by Dan2lger in 1960. At autopsy, there was congestion of the liver, spleen and kidneys. In another study reported by Suciu et al. (1975), exposure of vorkers to high concentrations of vinyl 109052 VI I-1 chloride produced euphoria, intoxication and narcosis. In this study, the investigators found a dose-response relationship for acute and subacute cases 3 of "occupational disease" from air concentrations ranging from 2,296 ag/m 3 (about 900 ppm) to about 100 mg/m (about 40 ppm). In another investigation, Spirtas et al. (1975) conducted a survey of 200 vinyl chloride workers and 89 rubber plant workers (controls) in which information was sought on the frequency of eight symptoms, including dizziness, loss of consciousness, headaches, etc. The vinyl chloride workers were categoriec into low and high exposure groups. Because the exposure limits had been markedly decreased a short timp before the survey, the high exposure group consisted of workers who were exposed to vinyl chloride concentrations of over 200 ppm before the standard, and 20 to 30 ppm subsequently. The low exposure group consisted of workers who were exposed to 0 to 50 ppm before the standard and 0 to 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 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 VII-2 SL 109053 plasticizers added in the manufacturing 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 ct al. 1975, Popper and Thomas 1975, Jaeger 1975). 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 symptoms. Many cases of acroosteolysis have been reported and character ized and most involve autoclave workers in vinyl chloride plants (Vils.on et al. 1967, Dlnman et al 1971, Harris and Adams 1967, Lilis et al. 1975). Other long-term effects induced by vinyl chloride are 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 Kev York Academy of Sciences report "Toxicity of Vinyl Chloride-Polyvinyl Chloride" (Selikoff and Hammond 1975). Reproductive effects have also been noted. According to a study by Infante (Infante 1976, Infante et al. 1976a), the incidence of birth defects for thTee small communities in Ohio in which vinyl chloride polymerization plants are located was significantly higher (P<0.001) than that in either the counties in which these communities are located or the State of Ohio. Significant excesses were observed for clubfoot and defects of the central Sb 109054 VII-3 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 less (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 chloride and birth defects/fetal loss, but they are not yet supported by animal data. Hatch et al. (1981) examined the statistical analysis (chi-square) used in the Infante (1976a, 1976b) work anc concluded that the difference in fetal loss reported as statistically significant by Infante (1976a, 1976b) was not statistically significant. Hatch et al. (1981) also concluded that the statistical test used was of rather low power, and that a negative finding with this analysis does not rule out a possible moderate effect. Cytogenic studies have also been conducted. Picciano et al. (1977) reported no statistically significant differences in chromatid and chromosome aberrations or proportion of abnormal cells, in a group of 209 vinyl chloride exposed workers. These workers were exposed for periods ranging from 1 to 332 months to time-weighted average (TWA) levels of vinyl chloride ranging from 0.13 to 15.2 ppm. Killian et al. (1975) 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) reported an increased incidence of chromosome breakage among vinyl chloride exposed workers. VII-4 SL 109055 Htnsteen et *1, (1978) and Anderson at al. (1981, 1980) showed that chromosome aberration frequencies in cultured lymphocytes from workers exposed to vinyl chloride returned to levels in the normal control range after a period without exposure to vinyl chloride or after a reduction in vinyl chloride exposure levels. Heath et al. (1977) examined cytogenlc effects in three groups of industrial workers: PVC polymerisation 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 significantly greater than in non-industrial controls, and overall breakage levels were similar 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. 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 SL l09056 VII-5 in the general population, about 25-30 cases per year in the United States (Heath et al. 1975). Because of its rare occurrence, it is possible to infer a causal relationship between exposure to vinyl chloride and the development of this tumor. The epidemiologic evidence linking vinyl chloride to other types of cancers is more tenuous. The first study associating vinyl chloride exposure in humans with 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. Tabershav 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 difference facilities and all had been exposed to vinyl chloride for at least one year. The mean employment duration for the group of workers under study was 80 months. Among the workers, there were 854 with exposures of 20 years or longer and 1,640 exposed 15 or more years. The overall mortality rate among vinyl chloride workers was found to be lower, i.e., 75 percent of the expected rate compared to the general male U.S. population. The favorable overall mortality rate is a phenomenon commonly observed in working populations. Standardized mortality ratios (the ratio of the number of observed deaths In the study population to the number of deaths VII-6 SL 109057 a expected In t comparable population) for malignant neoplasms Increased with Increasing exposure level and/or longer duration. In the group Identified as the high exposure group, there were increases In liver cancer (primarily angiosarcoma), respiratory system cancer and brain cancer. These differences were not statistically significant. d ^ Dow Chemical Co. (Holder 1974) conducted a mortality study of 594 workers exposed to vinyl chloride in a single plant between 1942 and 1960. Workers were assigned to exposure groups based or. the highest level of exposure for at least one month (low group - TVA less than 25 ppm vinyl chloride, intermediate - 25 to 200 ppm TVA, high - 200 to 300 ppm TVA). Also included in the high group were workers normally exposed to 25 to 200 pps TVA who were also frequently exposed to excursions of 1,000 ppm. Total mortality was 91 percent of expected among the vinyl chloride exposed workers. Ho deaths due to liver cancer were reported, and only 13 cases of neoplasms were reported as opposed to 15.4 expected. 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 vorkers from two vinyl chloride plants who died between 1947 and 1973. Death certificates were obtained for 142 of 161 vorkers (88%) who died within this time period. Deaths attributable to cancer were 50 percent higher than expected (a statistically significant difference). A 900 percent increase in 3 k 1 j 1 '] j . ji VII-7 cancers of the liver and biliary tract was noted (five angiosarcomas). Excluding angiosarcoma, a 275 percent excess in the number of cancers was observed. Two brair. 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 et al. (1975) studied a group of 257 workers (of whom 255 were traced) exposed ro vinyl chloride for at least five years subsequent to 1946. Their mortality status was evaluated beginning ten years after the 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. Prelimi nary* 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 five years, and for whom at least ten years had elapsed since initial employment. A total of 136 deaths was reported versus 126.3 expected (not a significant difference). A 49 percent increase over the expected number of cancer deaths was noted, a statistically significant factor. A statistically significant excess number of deaths occurred for brain and CNS cancer, respira tory system cancer, and biliary and liver cancer (Waxweiler et al. 1976). Ott et al. (1975) reexamined much of the mortality data reported by Tabershaw and Gaffey (1974) and included more clearly defined exposure levels VII-8 SL 109059 and follow-up of former company employees. The basic findings remain uncharged; no Increase over expected in malignant neoplasms was found in the low exposure group (TWA from 10 to 100 ppm) and an Increase in deaths due to malignant neoplasms was observed in the high exposure group (TWA of greater than 200 ppm). Chlazze et al. (1977) reported a cross-sectional mortality study of 4,341 employees from 17 FVC plants who died between 1964 and 1973. The exposed employee population was compared with the entire U.S. population, specific for color and sex and adjusted for age. Ho angiosarcoma deaths were identified. Total cancer deaths increased in white employees (especially due to cancer of the digestive system). In white women employees, deaths from cancer of the breast and urinary organs were greater than expected. In a follow-up casecontrol analysis of breast cancer deaths among FVC fabricators, as an extension of their 1977 study, Chlazze et al. (1980) found no statistically significant relative risks for breast cancer in FVC fabricators and concluded that very large Increases in risk for breast cancer did not exist among these workers. 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 as angiosarcoma. Both cases were in men exposed to high levels of vinyl chloride (Fox and Collier 1977). In addition, Byren et al. (1976) traced 750 of 771 Swedish vinyl chloride plant workers. A four- to five-fold increase over expected in pancreas and X09060 SL VII-9 liver tumors vas found, and tvo cases were diagnosed as angiosarcoma. The numbers of other tumors did not deviate significantly from expected. Ten cases of hepatic angiosarcoma were 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 (Kakk et al. 1976). As a result, Delorme and Theriault (1978) retrieved more detailed information on these employees. The authors suggest that the cases of hepatic angiosarcoma appear tc 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 chloride who were studied by Popper and Thomas (1975), the characteristic hepatic fibrosis was present in ell cases of angiosarcoma. Although the relation of fibrotic lesions to the development of angiosarcoma 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 hepatocytes that are seen in the fibrotic stage, but which becomes even more pronounced In the initial stages of angiosarcoma development. These findings suggest that the fibrotic lesions without angiosarcomas, frequently observed in workers to 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 longer latency period for tumor initiation based on a lower exposure level. The series of changes observed in the liver appear to VI1-10 SL 109061 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 Raoinsski 1978) a total of 64 cases of hepatic angiosarcoma have been identified worldwide among vinyl chloride-exposed industrial workers. A listing of all documented cases by country is presented in Table VII-]. The number of cases per year is depicted in Figure VI1-1. Of the 64 cases, 23 have been reported in the United States. The authors reported that both the age at diagnosis and the latency period for cancer induction appear to be increasing. They suggested three explanations for these phenomena; (1) early cases may have heavier exposures, (2) the initial cases represented more biologically susceptible individuals 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 developing angiosarcoma of the liver. Brady et al. (1977) examined annual rates of hepatic angiosarcoma from 1970 through 1975 in residents of the State of New Tork (excluding New York City). Exposures to arsenic, vinyl chloride or thorium dioxide were suggested as significant factors in the etiology of these tumors. VII-U 6^ " f ~ s;r c r f ' r~ --; - - n ' r j ,, ' * ' Table VII--| Angiosarcoma of the Liver in Vinyl Cli 1 orIdc/PVC Worker ODuntry Caee No. Birth Data lat VC of PVC Exposure Dlacpwala of Angiosarcoma Age at Diagnosis Years firm lat Exposure to Magnesia Total Yaara of Expoaurs Data of Death Belglim 01 00-00-00 . 00-00-00 00-00-00 Canada 01* 12-15-13 00-00-44 00-00-55 Canada 02* 03-06-14 00-00-43 00-00-57 Canada 03* 00-26-19 < 00-00-41 00-00-62 Canada 04* 04-05-19 00-00-45 00-00-67 Canada 05* 05-07-11 .w 00-00-44 00-00-68 Canada 06* 12-15-19 00-00-47 00-00-71 Canada 07* 11-09-19 ,00-00-46 00-00-72 Canada 00 05-13-20 : 00-00-61 00-00-73 <3 Canada 09 07-19-21 ' 00-00-46 00-00-74 H M Canada 10 05-16-15 . 00-00-53 00-00-76 1 --* Ciedxab'akU 01* 00-00-20 00-00-57 00-00-73 K> Creches lcrraida 02* 00-00-26 00-00-51 00-00-66 l*ed Dap Gonniy 01* 06-04-30 10-01-56 09-19-68 Fed Rap Gnrmiy 02* 07-26-31 10-14-57 09-25-70 Pad Rap Garnery 04 09-04-30 04-16-57 00-00-74 Fad Rap Gamanp 05* 01-01-32 12-16-62 004)0-75 Pad Rap Garnery 07* 09-29-26 04-15-54 004)0-75 Pad Rap Qanaiy 00* 10-19-17 > 04-19-54 00-00-75 Fad Rap Garmary 09* 12-13-34 : 12-02-59 06-16-76 Pad Rap Garnery 10* 07-25-29. 10-10-55 06-28-77 Pad Rep Garnery 11* 12-29-36 . 01-02-61 004)0-77 Franca 01* 04-15-24 01-00-46 02-10-67 Franca 02 06-03-11 ., 07-06-59 01-00-75 Franca 03* 00-00-19 00-00-46 014)0-75 Franca Co tl Franca Franca 04* 01-27-27 10-19-49 05* 01-29-30 00-00-65 06* 04-14-34 * 00-00-50 01-04-76 044)0-76 094)0-76 o Franca 07 00-00-27 07-01-50 074)0-76 VD o France 00* 04-01-34 05-23-57 12-03-76 Cu Great Britain Great Britain 01* 04-20-01 , 00-00-44 03 06-02-37 02-00-66 124)0-72 124)0-74 00 '. 00 41 v 43 14 42 , 21 40 22 57 24 51 24 53 26 53 12 53 20 61 23 46 16 40 15 30 12 39 13 44 17 43 13 49 21 58 22 42 17 47 22 41 16 43 21 63 15 55 29 49 26 30 11 42 10 49 26 42 19 71 28 37 09 00 06-29-76 11 09-02-55 14 12-21-55 20 03-22-62 22 01-21-60 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 0000-66 12 . 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 06-20-77 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 Trtbjc VI-1 - continued Country Casa Birth No. Data lat VC of PVC Exposure Diagnosia of Angiosarcoma Age at Diagnosis Years ftna 1st Exposure to Diagnosis e Total Years of Exposure IMt of Death tCrO1 Italy f-j o Italy ID O Japan CJ> Norway 02* 11-12-29 00-00-57 03* 02-14-20 00-00-53 01 08-01-22 04-06-53 01* 12-22-15 03-06-50 12-13-72 07-10-75 08-21-74 *12-20-71 43 55 52 56 9wedsn 01* 06-22-27 08-14-51 06-06-74 43 Sweden 03* 06-10-10 05-06-47 03-19-76 65 Oweden 04* 11-16-14 00-00-46 05-12-77 62 U.S.A. 01* 10-17-23 12-09-48 03-03-73 49 U.S.A. 02* 08-19-33 11-15-55 * 05-00-70 37 U.S.A. 03* 05-25-15 11-28-45 12-19-73 58 U.S.A. 04* 01-15-24 07-06-52 08-19-67 43 U.S.A. 05* 01-25-12 06-19-44 04-09-64 52 U.S.A. 06* 11-23-28 01-17-62 02-06-74 46 U.S.A. 07* 05-02-22 08-27-44 0600-66 45 V II-1 3 U.S.A. 08* 05-06-20 1607-46 06-00-61 41 U.S.A. 09* 11-06-31 05-28-45 03-01-74 43 U.S.A. 10* 06-16-13 06-12-51 05-00-68 ** 55 U.S.A. 11* 05-27-09 10-14-46 03-06-70 61 U.S.A. 12* 11-17-16 09-13-49 05-02-69 50 U.S.A. 13* 12-01-21 12-11-42 05-06-74 52 U.S.A. 16* 11-04-27 05-08-50 0606-69 41 U.S.A. 17* 05-06-31 06-23-55 10-11-74 43 U.S.A. * 18* 04-22-28 09-15-54 06-06-75 46 U.S.A. 19* 00-00-15 0600-43 06-19-75 60 U.S.A. 20* 06-31-17 0600-55 01-36-76 50 U.S.A. 21* 09-02-09 12-00-46 0600-77 67 U.S.A. 22* 10-02-23 07-11-47 01-06-76 52 U.S.A. 23* 00-06-23 0906-58 04-06-73 50 U.S.A. 24* 05-07-17 0600-39 05-27-77 60 U.S.A. 25* 08-07-10 02-00-47 03-10-77 67 Yugoslavia 01* 04-05-14 00-00-53 04-06-73 59 Yugoslavia 02* 11-15-31 0600-50 07-12-73 42 15 22 22 22 19 29 31 .-24 14 / 28 15 20 12 24 29 17 23 20 32 19 19 21 32 21 30 29 15 38 30 20 23 06 21 22 21 18 21 31 21 13 28 15 20 12 17 15 24 17 23 19 26 04 19 : 11 22 18 21 28 14 26 20 20 18 12-00-73 07-10-75 10-24-75 01- 04-72 10- 20-70 02- 19-76 05-12-77 02-02-73 09-20-71 12-19-73 01- 07-60 04- 09-64 07-24-75 02- 23-68 00- 29-61 02- 00-75 05- 10-68 03- 16-70 05-02-69 07-04-74 02- 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- 06-73 07-12-73 Total Reported Cases 64 ur>rf Vrrnn Spirtnn (mu Kamcrm*) L__ L. . -J r V i. V Vf* * l  Figure VII-1 Number of Cases of Vinyl Chloride/PVC Related Angiosarcomas Reported tc KIOSK by Year of Diagnosis (Representing only 63 of the 64 Cases Known to NIOSH Since Information on Diagnosis is Kissing for One Case 0--- a I ft** or L r' L Adapted from Spirtas and Kaminski 1978. u VII-14 sll 10965 Direct exposure to these agents could not be demonstrated in 19 of the 26 study cases. Five of the 19 patients lived closer to vinyl chloride plants than did their matched controls. This may lend some support to the Idea that "indirect modes of exposure, not specifically related to occupation, might be important in the etiology of this disorder" (Bradv et al. 1971). Falk et al. (1981) described a nationwide survey of hepatic angiosarcoma in the United States from 1964 to 1974 which identified 168 cases. Of these, 42 cases were associated with known etiologic factors including exposure to vinyl chloride, use of thorotrast, exposure to inorganic arsenic and treatment with androgenic-anabolic steriods. The remaining cases were of uncertain etiology. The authors concluded that hepatic angiosarcoma most often affects males, peaks in the sixth and seventh decades of life, and appears to occur more often in industrial areas of the Northeast and Midwest. These authors also noted a high relative risk for FVC polymerization workers. IARC (1979) examined the available data on humans and concluded that exposure to vinyl chloride results in an increased carcinogenic risk to humans. The organ systems most likely to be affected were the liver, brain, lung and hemato- and lymphopoietic systems. VII-15 VIII. MECHANISMS OF TOXICITY The mechanisms by which vinyl chloride causes non-carcinogenic injury are unknown. 1c is theorized that the toxicity of this compound is attributable to its enzymatic oxidation to reactive polar metabolites, possible chloroethylene oxide or chloroacetaldehyae (see Pharmacokinetics section). Ward et al. (2976) hypothesized 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 vhich causes vascular occlusion, platelet aggregation and other adverse effects vhich explain the observed symptoms of the disease. An investigation of workers with "vinyl chloride disease" shoved 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 undertaken considerable research in an effort to establish the mechanism(s) by vhich chemical substances cause their carcinogenic effects. The somatic cell mutation theory of carcinogenicity suggests that for a carcinogenic response to occur, an irreversible change must occur in the cell which results in proliferation of a neoplasm. This change reflects a mutational event in the DNA of that cell, suggesting that the chemical carcinogen must interact directly with or VIII-1 otherwise alter the DNA to initiate the change. In recent years, however, some substances have been shown to be carcinogenic, but by mechanisms with no apparent 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 neoplastic response in latent cells. Carcinogens now are often classified into two broad categories: genotoxlc and epigenetic or nongenotoxic. The mechanism by which a compound causes its carcinogenic effect car. rarely be determined by the chronic testing of whole animals, as 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 ir. vitro testing systems measure mutational events, and many carcinogens are mutagens, it is suggested that positive results in certain of these test systems 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, (2) studies on binding to DNA and (3) evidence of biochemical or biologic consequences of DNA damage (Ueisburger and Williams 1981). No single test system appears capable of identifying all carcinogens that are genotoxic. Therefore, a number of scientists have proposed testing batteries such that the results from each test within the battery, when evaluated in conjunction with the others, will enable researchers to determine 10968 Si* VIII-2 the mechanist: 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 summarizes some of the mutagenicity studies on vinyl chloride vhich have demonstrated the chemical's genotoxic potential. The studies have been divided according to the three criteria for genotoxicity (Weisburger and Williams 1981) outlined above. Considering all of the data on vinyl chloride, it is probable that vinyl chloride exerts its carcinogenicity through genotoxic mechanisms. VIII-3 Table Vlll-1 Result* f Vinyl Chloride Mutagenicity Studies A. A--y ryitMB Aouita **< MatAdUeally activated - galgnall* yrtan (AoeeV ' BstfiariAla coll Rd 4 at ad., 2975 taI7, 1975 at IT, 1976 it H, 1974 rT 1976 Grain at al., 1975 Yxaawasct. . * Gaos calls cf Dimauthi 11s ^ 4 lopriaro at al, 1976, 1977 Vartourgt and Vogel, 1977 Chinese bvtttf V79 calls 4 BAesmn at al., 1975 B. IKA Binding Btudiaa Msuee tlsauas (brain, lung, li^mr, kiAey, aplaea, janaaaa aid teatea) In vitro 4 (Irra^rsitole binding to WX and SOO ' Bergnan, 1982 Bat liver nicicscnes, reconstituted cytmiuona P-450 syataa aid iaolatad h^atocytae , 4 GuengerlA at al., 1981 (Irreversible binding to pertain and DKA) Bat liver udcicacnsa with KK3EH 4 (Alkylation cf K90 Laib and Bolt, 1977 C. BjoAmlcal or biologic ocnaaqumcas of IHA daemga Bona narrow calls of rats (in viva) Andaxaon and Bichaxdsan, 1976 Bona anrrw cells cf Qrinaaa hanatars (in vivo? and Bdhrbacn, 1980 Cultured peripheral lynpho- + cyt.es in lumne (vinyl (Oiratoacnnl dilaride exposed workers) alxormlities) PurAaae at al., 1978 PurAaae at al., 1975 Ducatnan et aT., 1975 SL 109070 VIII-4 APPENDIX 1 UNIT RISK ASSESSMENT FOR VINYL CHLORIDE The data used to estimate a unit risk for oral exposure to vinyl chloride are based on the Feron et al, (1981) study. The statistically significant increases reported for liver and lung tumors were considered biologically significant. For the liver tumors, neoplastic nodules were considered a progression toward hepatocellular carcinomas, and these are included in the analysis in Tables 1 anc 2. Extrapolations using the linearized multistage -2 model show values of q* for the individual tumors ranging from 8.8 x 10 to 1.3 x 10-1 for the males sr.d from 5.8 x 10-2 to 1.3 for the females. The value of q* based on males was 5.0 x 10 * for liver tumors and 2.9 x 10 * based on all tumors combined. For the females the value of q^ based on liver tumors was 1.9 and for all tumors combined was 2.3. All units of are per ng/kg/day. Before proceeding with the unit risk estimates an explanation of the total tumor counts in Tables 1 and 2 is necessary. For the liver all animals vlth hepatocellular carcinomas were assumed to also have the neoplastic nodules. Thus, only the neoplastic nodules and liver angiosarcomas were added to derive the total liver tumors. Otherwise, the totals would have exceeded the number of animals examined. Also, in adding the lung and liver tumors, the totals were not allowed to exceed one less than the number examined. The Al-1 Si l09 *1 SL 109072 Table 1 Type and Incidence of ScadsCically SlgniflcanC TreaCmenC-iteleaCed Changes In Che Liver and Lung of Male WlsCar Rats Exposed Co VCM in Che DleC. Values of q* and ConcenCradon from MuldsCage RxCrapolaClon Model Included c Number of rata examined Liver Neoplastic nodules Hepatocellular carcinomas Angiosarcomas Total liver tumors** Lung Angiosarcomas Total animal with tumors Treatment group (ag/kg/day) 0 1.7 5.0 14.1 55 58 56 59 0 1 7 23 0 1 28 0 0 6 27 0 2 13 50 0 0 4 19 0 2 17 58 95Z lower-limit concentration q* assoc laced wlch risk (ug/L) * _I (mg/kg/day) io"4 io"5 io"6 2.1 x 10"1 -2 8.8 x 10 1.3 x 10"1 3.0 x 10_l 1.1 x 10-1 2.9 x 10-1 16.7 39.8 27.0 11.7 1.7 0.2 4.0 0.4 2.7 0.3 1.2 0.1 31.8 12.1 3.2 0.3 1.2 0.1 ?Hu*an equivalenC q* q* (a) (W /W ) In (mg/kg/day) concentration In ug/L " (-35,000/qS) ln(l-R). ^Pound dead or killed In extremis or terminally. aSum of neoplastic nodules and liver angiosarcomas. Total must be at least less than total examined. r l------ r ni Table 2 Type and Incidence of Statistically Significant Treatment-Related Changes in the Liver and Lung of Female Wlstar Rats Exposed to VCM in the Diet. Values of qf and Concentration from Multistage Extrapolation Model Included c Number of rats examined Liver Neoplastic nodules Hepatocellular carcinomas Angiosarcomas Total liver tumors*^ Lung Angiosarcomas e Total animal with tumors Treatment group (mg/kg/day)_____ 0 1.7 5.0 14.1 57 58 59 57 2 26 39 44 0 4 19 29 00 29 2 26 41 53 00 1 5 2 26 42 56 95X lower-limit concentrating q* associated with risk (ug/L) (mg/k1 g/day) "I .O'* io-5 IO'* 1.3 5.0 x 10"1 8.8 x 10-2 1.9 5.8 x 10~2 2.3 2.7 70.0 J9.8 1.8 0.3 0.7 4.0 0.2 0.03 0.07 0.4 0.02 60.3 1.5 6.0 0.2 0.6 0.02 Co .Human equivalent qi " q* (a) (W. /W ) in (mg/kg/day) ^ "Concentration in ug/L " {-35,00D/qfl)ln(I-R). ^ jFound dead or killed In extremis or terminally, vo Sum of neoplastic nodules and liver angiosarcomas. 'j Total must be at least less than total examined. Co 4 result of this letter restriction was to raise the value of q* slightly due to Increased variance. In fitting the response data in Tables 1 and 2 with the human equivalent dosages, the human equivalent dosages were derived by dividing the corresponding animal dosages by (W^/W^) 1/3 The human weight (W^) was assumed to be 70 kg; the stale rats were estimated to weight 350 g and the female rats were estimated to weigh 200 g (Figure 1). Thus, the corres ponding human equivalent dosages were 0, 0.29, 0.85, and 2.41 mg/kg/day based on che male rats, and 0, 0.2**, 0.71 and 2 mg/kg/day based on the female rats. When the response and human equivalent dose data were fit to the linearized multistage model, the 95Z upper limit on the largest linear term (Table 2) was: q* 2.3 (mg/kg/day) 1 J ~i J To derive an estimate of the 95X lower level of concentration, d, corresponding to a 95Z upper level of risk, R, the following equation Is used: vhere d Is the lover limit on dose in mg/kg/day. To solve for d in ug/L, we use the transformation 1 mg/kg/day * (70 kg/2 L) * 1,000 ug/mg 35,000 ug/L 10901* Si* *1-4 *06 Duration of experiment, wk * The weight curves of the rats receiving 0, 1.7, 5.0 or 14.1 ng VCM/kg body weight/day from the 102 PVC diets fed for four hours each da'y all lie within the shaded area. Adapted from Feron et al. 1981. Figure 1 Average Body Weights of the Extra Controls Fed the 102-PVC Diet Ad Libitum (-) and of the Rats Given 300 mg VCM/kg Body Weight in Oil by Gavage Al-5 SL 10907s If vc sec R 10 ^ Chen d - (-35,000/q*) In (1-10-5) (ug/L). For Che hlghesc value of q* 2.3 (mg/kg/day)~* (Table 2), seCClng R - 10~5 yields a value of d - 0.15 ug/L. SeCClng R 10~* or 10"^ yields values of d - 1.5 ug/L and d - 0.015 ug/L. respectively. For comparison purposes only ve compare Che pocency of vinyl chloride by Che diec versus Che inhalaClon routes. A previous memo ve senC you esclmaCed che 95Z upper limic of poCency for VCM is q* 1.7 x 10-2 (mg/kg/day) -1 based on an inhalaClon scudy shoving angiosarcomas and ocher tumors in racs. That potency esdmace vas derived for vaCer quality criterion purposes. In that document an InhalaClon co Ingestion by gavage relationship of 1 ppm inhaled * 2.28 mg/kg/day Ingested vas derived for 200 g rats based on VCM uptake study. Without that adjustment for route differences, a direct transformation based on a 70 kg human breaching 20 m /day vould have yielded a 1 ppm Inhaled * _2 0.76 mg/kg/day relationship and a q* 5.2 x 10 mg/kg/day, still 44 times less Chan the estimate from Che diet study. In summary, the VCM potency estimates are reported in Table 3. Al-6 i i Table 3 VCM Potency Estimates Route Potency q*(og/kg/day) 1 95X lower Halt concentration associated with risk (ua/L) 10`4 10-5 IQ"6 Oral Based on f diet study 2.3 1.5 0.15 0.015 Based on Inhalation study 1.7 x I0-2 20* 0 20.0 2.0 Inhalation Based on Inhalation study 5.2 x 10-2 67.3 6.7 0.7 4 L r .L ! <1 L Al-7 SL 109077