Document jevZaNVwJbzX8dmB8bBNpJDZ

1 TR-540-162 FINAL DRAFT FOR THE DRINKING WATER CRITERIA DOCUMENT ON VINYL CHLORIDE January 1985 rreparec Under Program No. 13C2 for Contract 68-01-6750 Work Assignment 01 by ICAIR Life Systems, Inc. Cleveland, OH 44122 for Criteria and Standards Division Office of Drinking Water U.S. Environmental Protection Agency Washington, DC 20460 067l19 SI* r * TR-540-162 FINAL DRAFT FOR THE DRINKING WATER CRITERIA DOCUMENT ON VINYL CHLORIDE January 1985 rreparea Under Program No. 1302 for Contract 68-01-6750 Work Assignment 01 by ICAIR Life Systems, Inc. Cleveland, OH 44122 for Criteria and Standards Division Office of Drinking Water D.S. Environmental Protection Agency Weshington, DC 20460 J J ] ,, ni SL 06712 i-t DISCLAIMER This document is a preliminary draft. It has not been eleased by the Office Drinking Water , U.S. Environmental Protection Agency (E?A), and should not this stage be construed to represent Agency policy, It is being circulated for cevents on i ts technical merit. SL 067121 TABLE OF CONTENTS LIST OF FIGURES......................................................................................................................... PACE ii LIST OF TABLES......................................................................................................................... iii I. SUMMARY......................................................................................................................... 1-1 II. INTRODUCTION '........................................................................................................ II-l III. PHYSICAL AND CHEMICALPROPERTIES................................................................. ril-l IV. ' PHARMACOKINETICS.................................................................................................... IV-l A. Absorption and Distribution .............................................................. B. Metabolism....................................................................................................... C. Excretion....................................................................................................... IV-I IV-5 TV-6 V. HUMAN EXPOSURE....................................................................................................... V-l A. Exposure Estimation ................................................................................. V-l 1. Water....................................................................................................... 2. Diet....................................................................................................... 3. Air........................................................................................................... V-2 V-4 V-6 B. Summary............................................................................................................ V--8 VI. HEALTH EFFECTS INANIMALS ................................................................................... VI-1 A. Acute/Subchronic/Chronic Effects ...................................................... VI-1 B. Teratogenicity.............................................................................................. VI-3 C. Mutagenicity................................................................................................... VI-* D. Carcinogenicity.......................................................................................... VI-38 VII. HUMAN HEALTH EFFECTS ....................................................................................... VII-I A. Non-Carcinogenic Effects ........................................................................ VIX-l B. Carcinogenic Effects ................................................................................. VII-5 VIII. MECHANIAMS OF TOXICITY..................................................................................... VIII-1 IX. QUANTIFICATION OFTOXICOLOGICAL EFFECTS FOR VINYL CHLORIDE . . IX-I A. Non-Carcinogenic Effects ........................................................................ IX-4 B. Quantification of Non-Carcinogenic Effects ................................ IX-8 C. Carcinogenic Effects ................................................................................. IX-10 D. Quantification of CarcinogenicEffects ........................................... IX-13 X. REFERENCES................................................................................................................ Z~1 APPENDIX 1 Unit Risk Assessment for Vinyl Chloride ........................................ Al-1 i SL 067122 LIST 0? FIGURES FIGURE IX--1 VII-1 Locations of Vinyl Chloride and Polyvinyl Chloride Plants ir. the United States......................................... .... .................................................. Number of Cases of Vinyl Chloriae/PVC Related Angiosarcomas Reported to KIOSK by Year of Diagnosis (Representing Only 63 of the 64 Cases Knovn to NIOSH Since Information on Diagnosis is Missing for One Case.................................................................................. H PAGE II-2 VI ii SL 067123 LIST OF TABLES TABLE IV-1 IV-2 IV-3 IV-A IV- 5 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 PAGE Percentage of the Administered .C Activity per Gram of Tissue After Administration of (iuC) Vinyl Chloride by Gavage to Male.Sprague-Dawley Rats ........................................................ Percentage of c Activity ^gr Gram Tissue 72 Hours Following an Inhalation Exposure to l C) Vinyl Chloride for 6 Hours in Male Sprague-Oavley Rats ........................................................ Percentage of Administered C Activity Recovered Following a |Jngle Oral Dose of Vinyl Chloride...................................................... C-Containing Urinary Metabolites from Male Sprague-Davley Rats Given Vinyl Chloride by Gavage ...................................................... Excretion of Radioactivity in Rats, Given a Single Dose of r C) Vinyl Chloride...................................................................................... Total Estimated Cumulative Population (in Thousands) Exposed ro Vinyl Chloride in Drinking Water Exceeding the Indicated Concentration ........................................................................................................ Estimated Drinking Water Intake cf Vinyl Chloride ........................ Estimated Respiratory Intake of Vinyl Chloride ............................. Estimated Intake of Vinyl Chloride from the Environment by Adult Males in ug/kg/day (X 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 ... .............................................................................................................. Experiment BT11...................................................................................................... Experiment ... .............................................................................................................. Experiment BT12..................................................................................................... Experiment BT13..................................................................................................... Tumors Presently Correlated to VC Exposure (by Inhalation) on Experimental Rodents ...................................................................................... Type and Incidence of Treatment-Related Histopethological Changes in the Liver of Rats Exposed Orally to VCM.................. 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-11 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 contlnued- 111 SL 067124 List cf Tables - continued TABLE PAGE VI-22 "1-23 VI- 24 VII- l VIII- 1 Site, Type and Incidence of Tuners ir. Organs Other than the Liver in Rats Exposed Orally to VCM for Over 2 tc 5 Years . . Type and Incidence of Kisrepathclegical Changes in the Liver.......................................................................................................................... Type and Incidence of Tuners of the Mansary Glands and Incidences of Abdominal Mesothelinas .................................................. Angiosarcooa of the Liver in Vinyl Chloride/PVC Worker . . . Results of Vinyl Chloride Mutagenicity Studies............................. VI-32 VI-3? VI-42 VII-I VIII- iv SL 067125 I. 'summary Almost seven billion pounds of vinyl chloride are produced in the United States annually. Most emissions into the environment originate from manufacturing plants vhich 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 vacer. Three national surveys have demonstrated the presence cf 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, vhich 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 art excreted primarily In the urine. At high doses (e.g., 100 mg/kg), most of the solvent is expired as vinyl chloride. Acute and chronic exposure to vinyl chloride can result in toxicity in experimental animals and humans. In animals, an inhalation exposure of 1-1 SL 067126 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, Vir.yl chloride does not appear to be teratogenic in rats or rabbits, but insuf ficient 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 narure can be demonstrated at exposure levels below 50 ppm. Seme plant workers may have been exposed to concentrations exceeding 1,000 ppm and occasionally approaching 10,000 ppm before OSHA standards were instituted in 1974, At these levels, workers manifested dizziness, headaches and/or euphoria. Long-term exposure to these levels in vinyl 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 humar.s are very scarce because there were few air measurements of vinyl chloride ir. the work environment before 1974. Vinyl chloride It e proves carcinogen in mice, hamsters end rets. Animals sCudlas have shows that vinyl chloride produces cumors of different types tt different sites, end thet the incidence and relative distribution f these tumors ere influenced by dose, age of the animal end speeles end strain of animal used. Angiosarcomas of the liver were found in all animals studied. 1-2 SL 067127 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 that 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 bw/dey. Human data have been obtained primarily from workers exposed to vinyl chloride. A number of epidemiologic studies have linked vinyl chloride with angiosarcoma and ocher 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 6- cases 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 la insufficient data available for calculation of one-day health advisories but Che 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 el. (1975). An adjusted ADI of 0.046 mg/L for chronic noncarcinogenic effects was calculated using the 1-3 SL 067128 liver lesion data in the lifetime carcinogenicity study ir. rats by Til et ai. (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 oost 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 NAS and EPA'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 nor-threshclc multi-stage model was utilized, the range of vinyl chloride ccncentraticr.s were computed that would nominally increase the risk of one excess cancer per million (10^), per hundred thousand (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 952 confidence limit, that consuming two liters per day with a vinyl chloride concentration of 100 ug/L, 10 ug/L or 1 ug/L would increase the risk of one excess cancer per 10,000, 100,000 or 1,000,000 people exposed over e lifetime, respectively. Using the revised CAG approach and the multistage model, it was estimated, at the 952 confidence limit, that consuming two liters of water per day with a vinyl chloride concentration of 200 ug/L, 1-4 SL 067129 20 ug/L or 2 ug/L would increase the risk, of one excess cancer per 10,000, 100,000 or 1,000,000 people exposed, over a 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. (1973) in which rats were exposed to vinyl chloride by gavage, while the CAG used the same Maltoni et al. (1973) study, but based its estimate upon the Increased incidence of total tumors in rats exposed to vinyl chloride through inhalation. The CAG has recalculated the cancer risk with the method described above and the Fercr. et al. (19S1) data to estimate an increased risk of one 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/t, 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 SL 067130 II. INTRODUCTION Vinyl chloride has been used for over 40 years in the production cf polyvinyl chloride (PVC) , the most widely used material in the mar.ufacture cf plastics in the world. About 25*.' cf the estimated IS billion pounds cf vinyl chloride produced worldwide in 1972 was manufactured in the United State (5erk et al., 1976). 3etween 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 upcr. products and components fabricated from polyvinyl chloride (USEPA 1974). Tct the location of vinyl chloride and PVC manufacturing and processing plants in the United States in 1978, refer to Figure II--1. Vinyl chloride is not known to occur in nature (NAS 1977). The compound is synthesized as chlorinated olefinic hydrocarbon monomer from petrochemical feedstock and chlorine. In 1975, vinyl chloride emissions in the United States were found to originate from three major sources: (1) 17 plants where vinyl chloride was commercially 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 SL 067131 Figure 11"1 Locations of Vinyl Chloride and Polyvinyl Chloride Plants In the United States II-2 Vinyl Chloride Plan Location *Polyvinyl Chloride Plan Location Source: SRI SL 067132 ..J L_JJ III. PHYSICAL AND CHEMICAL PROPERTIES The structure of vinyl chloride is: H2C - CHC1 Molecular Weight - 62.5 Vinyl chloride is highly flammable (limits of inflammability: 4.00Z to 21.70Z) 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*0. 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 mere 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 ves added to distilled water in beakers and the concentration determined with time (USEPA 1974). The data indicate that if first order kinetics are assumed, the volatilization half-life in quiescent water (unstirred) is 290 minutes, and in continually stirred water it is 25.8 minutee. Dilling et el. (1975) found similar values for volatilization from stirred water. As Dilling et al., noted, prediction* of vinyl chloride loss from water at relatively high concentrations (e.g., 1 mg/L) mty not reflect the situation at very low concentrations. III-l SL 067134 in the manufacture of electrical vire insulation and cables, piping, industrial and household equipment, medical supplied, food packaging materials and building and construction products. FVC and vinyl chloride copolymers are distributed and processed in a variety cf forms, including dry resins, plastisol (dispersions ir. plasticizers) , crganoscl (dispersions in plasticizers plus volatile solvent), and latex (a colloidal dispersion in water used to coat paper, fabric or leather). II-3 SL 067133 t1 Volatilization appears to be the most significant process in the loss of vinyl chloride from the aquatic environment (Hill et ai. 1976). Once in the atmosphere, vinyl chloride undergoes rapid photochemical oxidation (Gay et al, 1976) , Lillian et al. 1975). r III-2 SL 067135 IV, PHARMACOKINETICS A. Absorption and Distribution An investigation by Duprat et al, (197") indicated chat 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 C 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 chat vinyl chloride is rapidly absorbed from the gastrointestinal tract following gastric intubation of aqueous solutions containing up to 2.C mg/mL vinyl chloride. Vinyl chloride uptake by this route was extremely rapid; peak concentrations were found less than ten minutes after the dose was administered. In a study by Watanabe et al. (1976a), rats were given single oral doses (gavage) of 0.05, 1 or 100 mg/kg of 14C-vinyl chloride dissolved in com oil, and the routes and rates of elimination of 14C activity were followed for 72 hours. The percentage of the dose expired as vinyl chloride was 1Z, 2Z and 672, 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 IV-1 SL 067136 found in muscle, lung or fat (Table IV-l). The invescigacors concluded Chet the fate of vinyl chloride following oral administration is a dose-dependent saturable process, with the saturaticr. of the vinyl chloride-metabolizing enzymes occurring at a concentration between 1 and IOC 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 and the routes and rates of elimination of 1>* C activity were followed for 72 hours after termination of exposure. The animals were sacrificed after 72 hours and samples of tissues collected for analysis of 1 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 1C ppm and 1.C0C ppm in this study. 14 Bolt et al. (1976) also studied the tissue disposition of C-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 *4C-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 brein. Forty-eight hours efter 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 IV-2 SL 067137 Table IV-1 Percentage of the Administered l4C Activity per Gram of Tissue After Administration of (i4C) Vinyl Chloride by Gavage to Male Sprague-Dawley Rats4 Tissue 0.05 Dose (mg/kg)b 1.0 Liver Skin Carcass Plasma Muscle Lung Fat 0.172l0.025C 0.07010.023 0.02710.007 0.041C0.004 0.02810.003 0.05010.003 0.03010.004 0.18210.005 0.07610.010 0.046i0.002 0.05310.007 0.03110.003 0.061r0.003 0.04510.008 ^Remaining in the body after 72 hr. "Vinyl chloride dissolved in com oil. ^Mean i S, five rats per dose. Not detectable above background. Adaoted from Natanabe et al. 1576a. 100 0.02910.002 0.01010.002 0.007*0.001 NDd 0.00610.001 o.omo.ooi 0.00610.001 IV-3 SL 067138 14 able IV-2 Percentage of C Ag tivity per Gram Tissue 72 Hours Following an Inhalation Exposure to ( C) Vinyl Chloride for 6 Hours in Male Sprague-Davley Rats Tissue Liver Skin Carcass Plasma Muscle Lung Fat Kidney _Percentage C act.ivi. ty Exposure concentration 10 ppm 1,000 ppm 0.1390.009* (0.35)(b) 0.141:0.009C 0.072:0.004 (0.18) 0.073:0.004 0.048:0.004 (0.12) 0.049:0.004 0.051:0.001 (0.13) 0.052:0.001 0.052:0.005 (0.13) 0.053:0.005 0.065:0.007 (0.16) 0.066:0.007 0.026:0.006 (0.07) 0.026:0.006 0.079:0.003 (0.20) 0.080:0.003 0.145:0.008* (9.63) 0.165:0.009C 0.115:0.010 (7.64) 0.131:0.011 0.049:0.004 (3.26) 0.056:0.005 NDd 0.038:0.003 (2.52) 0.043:0.003 0.046:0.001 (3.06) 0.052:0.001 NDd 0.057:0.005 (3.79) 0.065:0.006 aExpressed as percentage of total 14 C activity per gram of tissue. Uncorreeted for expired VC: dpn per % tissue Total dpm recovered t SE from four rats nflerogrem equivalents vinyl chloride.ger gram of tissue. eExpraaeed as percentage metabolized C activity per gram tissue. Corrected for expired VC: dpm per gram of tissue__________ Total dpmrecovered - dpm of expired VC Mean t SE from rats. "Hot detectable, detection limit for plasma and fat vas 3 ug/g of tissue (3 ppm). Adapted from Watanabe ct al. 1976b. IV-4 SL 067139 on percent ebsorption from the gastrointestinal tract, the risk calculations in this document vill assume a 1002 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 net (Bartsch and Mcntesano 1975). exposure to vinyl chloride leads to the reduction of nen-protein sulfhydryl levels in rat liver, suggesting that the metabolites of vinyl chloride conjugate vit'n glutathione and/or cysteine (Hefner et al. 1975a). Kathvav (1977) reported in vitro depurination of calf thymus INA by chioroacetaidehyde 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 bloeransformatloa schemes--one involving alcohol dehydrogenase (Scheme I) end the other Involving the mixed function oxidase system (Scheme II). These are Indicated below: Scheme I: ClHC-CHj----- C1H2C-CH20H----- >C1H2C-CH0----- >C1H2C-C00H Scheme II: C1H-CH2----- >[H2c2cHC1]----- >C1H2C-CH0----- >C1H2C-C00H IV-5 SL 067140 Evidence for biodegradation involving the alcohol dehydrogenase pathway includes data which demonstrates that pretreatment of rats with either ethanol or pyrazole (an inhibitor of alcohol dehydrogenase) inhi s the metabolism of vinyl chloride (Hefner et al. 1975a). There is also ample evidence that the mixed function cxicase (MFC) system is involved in the metabolism of vinyl chloride. Precreatment of rats with phenobarbital, which induces the MFC system, also enhanced liver toxicity of vinyl chloride (Jaeger ec al. 197). Rat liver aicresomes catalyzed the covalert binding of vinyl chloride metabolites 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 ir.tra-ceilular macromolecules (Laib and Bolt 1977). Several pathways may be involved in vinyl chloride metabolism, the predominant one depending on dose. Hefner et al. (1975) performed an inhalation study in which rats were exposed to vinyl chloride concentrations ranging from 50.5 to 1,167.0 ppm for 12-monchs time. The rate of metabolism, as determined by measuring the declining level of vinyl chloride in the chamber atmosphere, was thrac 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 lower concentrations, probably involving alcohol dehydrogenase, is saturable between 105 and 220 ppm. This group also found evidence that oxidases in the mierosomes may be Involved in metabolism at high level exposures. TV-6 SL 067141 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 grcup calculated that saturation of the vinyl chloride-metabolizing enzymes of the rat occurs at 250 ppm. C. Excretion Excretion of 1^ C activity within 72 hours following a single oral dose of 14 C-labeled vinyl chloride (C.05, 1.0 or IOC ng/kg) is shown in Table IV-3 (Vatanabe et al. 1976a). As the dose 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 to determine the decline of vinyl chloride in the gas phase of the system. The results showed that the metabolic elimination of vinyl chloride in Rhesus monkeys is a dose-dependent, saturable process, as it is in rats. Elimination was shown to obey a first-order law of kinetics at air concentrations below 17-7 SL 067142 Table IV-3 Percentage of Administered 14 C Activity Recovered Following a Single Oral Dose of Vinyl Chloride4 0.05 Dose (ng/'kg) 1.0 100 Expired: As VC As C02 Urine Feces Carcass and tissues Cage washC Total recovery 1.43=0.13b 8.96r0.59 68.34=0.54 2.25=0.52 10.13=1.92 0 91.25=2.47 2.13=0.22 13.26=0.47 59.30=2.75 2.20=0.39 11.10=0.47 0.84=0.45 88.831.98 66.64=0.67 2.52=0.13 10.84=0.95 0.47=0.06 1.83=0.14 0 82.30=0.43 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 = Sc five rats per dcse. cDistilled water wash of metabolism cage at termination of the study. Adapted from Vatanabe et al. 1976a. IV-8 067143 Si* 14 Table IV-4 C-Containing Urinary Metabolites from Male Sprague-Davley Rats Given Vinyl Chloride by Gavage Compound (A) N-acetyl-S-(2-hydroxyethy1cysteine) (B) Thiodiglycolic acid (C) Unidentified Total Dose (mg/kg) 0.05(4)b 1.0(5) 100(3) 30.4=2.0C 36.2=3.9 29.1=2.0 25.6*1.9 38.612.9 94.6 23.7=1.1 34.5=4.6 94.6 25.4=0.9 36.6=2.0 91.1 ^Metabolites vere separated and quantitated by high pressure liquid chromatography. Values are expressed as percentage of total urinary radioactivity. D( ) * Number of animals per dose. cMean t SE Adapted from Watanabe et al. 1976a. IV-9 SL 0671^4 200 to 300 ppm, and at high concentrations the maximal velocity of metabolic elimination of vinyl chloride was about half that cf rats when related to kg body weight. 1L Green and Hathvay (1975) measured the excretion of * C-vinyl chloride administered to rats by intragastric, intravenous (femoral vein), or intraperitoneal routes. Two doses were used: 0.23 ag/kg and i5Q ag/kg. The results are shown in Table IV-5. During the first 24 hours after treatment, more than 9C2 was excreted from the animals irrespective route. Significant differences were noted, however, in the manner cf excretion for the 0.25 ng/kg cose, "cr the intragastric route, 71.51 was excreted in the urine, whereas 992 was exhaled from the lungs when vinyl chloride was administered intravenously. For the intraperitoneal route, 43.22 was exhaled while 41.52 was excreted in the urine. At the higher cose (450 mg/kg), over 902 was exhaled as vinyl chloride in both intragastric and intraperitoneal administered rats. The intragastric values are consistent with the values reported in the oral studies performed by Vatanabe et al. (1976a) (see Table IV-3). Withey and Collins (1976) developed e 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 dally liquid Intake contained 20 ppm vinyl chloride, then the area genarated 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. IV-10 SL 067145 I V - 11 Table IV-5 sxcamoit or nAOKMcrivtir in bah, omw* siw-.u oost cm |"C)vinvl oiuonirr 4 nil wen each doted l.|. with 2)0 /ig of |M('|vinyl chloride per kg in corn oil solution, and another 4 rati were each doted ilmllarlf with 4JO mg of (>4CMn]rt chloride per kg. 4 tell were each inicctcd in the femoral vein with 2JO ;>g of C'CJvinyl chloride per kg in 7V-(i*-hydroayeibyl7 ladamide. - Four rati were each Injected l.p. with 2J0 /<g of |MC|vinyl chloride per kg In M[/l-hydrotyelhyl) Iactamide, and another 4 animal) were each Injected similarly with 4JO mg of l"C|vinyl chloride. Site #/ Time KadtoaeiirUy excreted (7, oftbit}* Inlrafllrlc friaMair Urine farm ytnyl CO, chloride Inlraweneui f.thaftA air t'inyl CO, chloride Urine Inlraperllonent force1 Exhaled ate yin) 1 CO, rhloride Urine farm HOpg/kg 0-24 J.7 1.2 12 6 1 1 It J ) JO 2* > 2 ) 99.0 0.1 0.1 0.J 0.1 4)1 4.6 10.) 3t.l 41 J 4 1 1.6 24-41 0.9 11 1.6 0.7 16 0.2 41-12 A t 0.2 Total J.1 1.2 U.J 1 1 ) 7J.I | 4.2 4.6+ JO 99.0 0 6 0.1 0.J 0.1 4J.2 4.6 11.0 i12 43.1 J.7 I t 4J0 mg/kg 0-24 24-41 4*12 Total 91.9 2.J 0.6 0.1 fi t 2.J 0.7 4.J | 2 1 0.4 o a 0.1 A1 J.4 | 2 2 01 96.2 4.1 0 7 96.2 4.| 0 7 2.J 7 0.9 0.1 0.1 2.6 0.9 0.1 * Values shown arc Ihe meant S.D. of thoce meant. Adapted fro* Green rind llatliwny (1975). SL 067146 v. human exposure Humans cay be exposed tc vinyl chloride in drinking water, food and air. Detailed infcreation 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. 1963). 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.. Exposure Estimation This analysis is limited to drinking water, food and air, since these media are considered tc be general sources common to all individuals. Some individuals may be exposed to vinyl chloride from sources other than the three considered here, notablv in occupational settings and from the use of consumer products containing vinyl chloride. Ever, 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 end travels, whet one cats end physiologic characteristics related to age, sex end health status can ell profoundly affect dally exposure end intake. Individuals living in the same neighborhood or even in the same household can experience vastly different exposure patterns. Unfortunately, date and methods to estimate exposure of identifiable population subgroups from all sources simultaneously have not yet been V-l SL 067147 developed. To che 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. Water Cumulative estimates of che U.S. populations exposed to various vinyl chloride levels in drinking water from public drinking water systems are presented in Table V-l. The values in che table were obtained using Federal Reporting Data Systems data on populations served by primary water supply systems (FRCS 1983) and the estimated number of these water systems that contain a given level of vinyl chloride. An estimated 1.922.C0C individuals (0.92 of the population cf 214,419,000 using public water supplies) are exposed to levels of vinyl chloride in drinking water 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 (652) obtain water from surface water supplies. All exposure to vinyl chloride in drinking water at levels above 5 Ug/L is expected to be from groundwater sources. No deta vers obtained on regional variations in the concentration f vinyl chloride in drinking water. The highest concentrations ars expectsd to occur near sites of polyvinyl chloride production. V-2 SL 067148 Table V-l Total Estimated Cumulative Population (in Thousands) Exposed to Vinyl Chloride in Drinking Water Exceeding the Indicated Concentration Systeia type hkMber of 1i people served In U.S. Cumulative population (thousands) exposed to concentrations (ug/1) of: (thousands) "TO >5 >lo >20 >30 >40 >50 >60 >70 Groundwater Surface water Total (X of total) 73,473 140,946 214,419 (loot) 1,063 059 1,922 (0.M) 591 0 591 (O.JX) 110 0 HO (0.11) 110 no 00 11B . 118 (0.1%) (0.1X) lie 0 lie 1 (0. IX) US 0 110 (0. IX) no 0 tie (0.IX) 0 0 0 (0.0X) Ui SL 067149 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 ug/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 of the population is exposed. An explanation of the derivation of these values is presented in Appendix C. Population concentration estimates for vinyl chloride in drinking water were 1.1 x 10-7 -g/L x persons Chest case), 1.5 x 10-7 ug/L x persons (mean best case), 2.3 x 108e ug/L x persons (mean worst case), and 2.3 x 10-8 ug/L * persons (worst case). Assuming a consumption rate of 2 liters of water/day, population-exposure values of 2.2 x 10/ ug/day x persons (best case), 3.C x 10' ug/day x persons (mean best case), 4.6 x 10 8 ug/day x persons (mean worst case), and g 4.6 x 10 ug/day x persons (worst case) were derived. 2. Diet No data wera obtained on levels of vinyl chloride found in foods in tha United States. Therefore, no estimates of the daily intake of vinyl chloride from the U.S. diet could be made. ' V-4 SL 067150 Table V-2 Estinated Drinking Water Intake of Vinyl Chloride Exposure level (ug/L) ^1.0 >5.0 >10 >50 >70 Persons using supplies exposed to ir.cio ated levels 2 of total Population population 1,522,000 591,000 118,000 118,000 0 0.92 0.32 0.12 0.12 C. 02 Assumptions: 70-kg nan, 2 liters of uater/day. OV o A Intake (.g/kg/day) ^0.028 >1 ,L >2.0 V-5 SL 067151 3. Air Exposure to vinyl chloride in the atmosphere varies from one location to another. The highest level of vinyl chloride reported in the atmosphere was 33 2,100,000 ng/m (2,100 ug/m ) (Lillian et al. 1975 cited in 3rodzinsky and Singh 1982). High levels, averaging greater chan 15,000 ng/o^ (15 'jg/m^), have been detected in ocher areas. Normal levels, hovever, are somewhat lowep. Bordzinsky and Singh (1982) calculated a median air level of 0.0 ng/m^ (0.0 ug/m^) in each of three types of areas: rural/remote, urban/suburban and source dominated. The monitoring data available are not sufficient to determine regional variations in exposure levels for vinyl chloride. The daily respiratory intake of vinyl chloride from air was estimated using the assumptions presented in Table V-3 and median and maximum levels for vinyl chloride reported above. The estimates in Table V-3 indicate that the daily vinyl chloride intake from air for adults in rural/remote, urban/suburban, and source dominated areas is 0.0 ug/kg/day. In contrast, the intake calculated using the maximum vinyl chloride level reported is 690 ug/kg/day; few, if any, persons ar believed to be exposed at that level. The values presented do net account for variances in individual exposure or uncertainties in the assumptions used to estimate exposure. V-6 SL 067152 Table V-3 Estimated Respiratory Intake of Vinyl Chloride 3 Exposure (ug/m ) Rural/remote (O.C) Urban/suburban (0.0) Source dominated (0.0) Maximum (2,100) Intake (ug/kg/day) 0.0 690 3 Assumptions: 70-kg man, 23 m of air inhaled/day (ICRP 1975) V-7 SL 067153 B. Suimarv Table V-4 presents a general viev of the total amount of vinyl chloride received by an adult male from air ar.c 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 cf concentrations for the tvc 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 that would be exposed to vinyl chloride at any of the combined exposure levels. The data presented represent possible exposures based cn the occurrence data and the estimated intakes. The relative source contribution data are based on estimated intake and do not account for a possible differential absorption rate for vinyl chloride by route of exposure. The relative dose received may vary from the relative intake. In addition, the relative effects of the chemical on the body may vary by different routes of exposure. Brodzinsky and Singh (1982) calculated a median urban/suburban air level of vinyl chloride of 0 ug/m^ based on air monitoring data. Assuming an air V-8 SL 067154 Table V-4 Estimated locate of Vinyl Chloride from the Environment by Adult Males In ug/kg/day (" from Drinking Water) Concentration in air ~ Aural/remote Uroan/suourban Source dominated Concentration In v________________ / drinking water s'' " Maximum (ug/1)(0.0 ug/nr)(2.100 ug/m3) o 0.0 .(--) 690 (OX) 1.0* s.o5 * 10* 0.028 (10CX) 0.14 (100X) 0.29 (lOOt) 690 (<0.01I) 690 (0.02X) 690 (0.04%) so*1 1.4 (100%) 690 (0.2%) 70* 2.0 (10CX) 690 (0.3%) Intake from each source ^see Sections 5.1-5.3): Water: 1.0 ug/1: S.O 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/oay 1.4 ug/kg/day 2.0 ug/kg/day Air: 0.0 ug/rn^: 2.100 ug/nr: 0.0 ug/kg/day 690 ug/kg/day Food: Not included al,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 (0.3* of population using public water supplies). c118,000 Individuals using public drinking water systems are estimated to be exposed to levels > 10 ug/1 (0.IX of population using public water supplies). d118,000 Individuals using public drinking water systems are estimated to be exposed to levels > 50 ug/1 (0.1X of population using public water supplies). eNo individuals using public drinking water systems are estimated to be exposed to levels > 70 ug/1. V-9 SL 067155 level of 0 ug/m\ drinking water would be the predominant source of vinyl chloride exposure at all 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 SL 067156 VI. HEALTH EFFECTS IN ANIMALS A. Acute/Subchronic/Chronic Effects Acute toxicity tests with vinyl chloride were performed by Fatty 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 ir. 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. I960, Kaley 19~5, Frodan 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 Vlstar 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 (?<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 067157 higher tine* it was their opinion chat 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 che basis of appearance, mortality, growth, hematological examination and ocher 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 189 days) appeared to be normal in appearance, mortality and growth, and the increase in weight of the rat livers did not occur at this concentration. Basalaev et al. (1972) administered gaseous vinyl chloride to rats and rabbits at a concentration of 0.03 to 0.04 mg/L for four hours/day for six months. Cardiovascular disorders, changes in the bioelectric activity of the hypothalamus, hyperadrenalinemia, 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, hepacotoxicity was measured by the elevation of serum alanine-a-ketoglutarate transaminase (ART). When fasted rats were exposed to 0.022 (V/V), 1,1-DCE, serum ART activity was elevated about 50-fold, two hours after the termination of a four-hour inhalation exposure. No elevation was observed when 0.12 vinyl chloride was administered alone. When the two VI-2 SL 067158 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 repented by Kramer and Mutchier (19~2). 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 or. days 6 to 18. 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. No teratogenic effects were noted in the fetuses of mice exposed to 50 ppm, but a significantly greater Incidence of unfused sternebrae end delayed ossification of sternebrae (no. 5) and bones of the skull were observed among litters of slice exposed to 500 ppm compared to unexpoeed controls. Embryotoxic effects were not generally noted, but some decrease in fetal body weight and crown-rump length was observed in rats and slice. VI-3 SL 067159 Radik* (1977) did not observe gross (nonaicroscopic) abnormalities in the offspring of rats exposed for four hours dally on days 9 to 21 of gescacion 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 whit* 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 fecal 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 (i.e., ehloroethylene oxide, 2-chloroacetaldehyde). The mutagenic effects of vinyl chloride have been demonstrated in: (1) metabollcally activated systems using Salmonella typhimurium (Bartsch et al. 1975, McCann et al. 1975, Elmore et al. 1976, Rannug et al. 1974, Garro et al. 1976) developed by Ames et al. (1973) in VI-4 SL 067160 which th genetic indicator refers to histidine prototrophy by base-pair substitution*, or by base-pair insertions or deletions; (2) Escherichia coll K12 bioauxotrophie strain with back nutation system arginine + (Greia et al. 1975); (3) several species of yeast inducing forward mutations and gene conversions at specific loci (Loprieno et al. 1976, 1977); (4) germ cells f 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 Hontesano (1975). L The mutagenic actlvly 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 , r post-implantation fetal deaths, pre-implantation egg losses and reduction in r fertility. Positive control tests Indicated that the dominant lethal effect was expressed in the CD-I mice used in these experiments. r~ Anderson and Richardson (1976) conducted a cytogenic study investigating mutagenic effects in the bone marrow cells of rats after exposure to paradlchlorobcnzene 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 L damage In ret bone marrow after the multiple exposure regime. L VI-5 SL 067161 b. 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 (Maltoni 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 Wistar strain) exposed to vinyl chloride by inhalation (Table VI-1), Skin tumors were first noted at approximately ten months; tumors in the lungs end bone were observed at about 11 months. Caputo St cl. (1974) exposed male and female rats (A and IRE Wistar strain) by inhalation to various concentrations of vinyl chloride. Carcinomas end sarcomas were observed in ell groups except those exposed to 50 ppm (Table VI-2). The date indicate that a dose response relationship exists VI-6 SL 067162 Table VI-1 Oncogenic Effects of Inhaled Vinyl Chloride Cone. VC (ppm) 4 hours/day 5 days/veek 12 months 30,000 So treatment Number rats 26 25 Skin epidermoid carcinomas 17 __ Lung adenocarcinomas and squamous cell carcinomas 6 Bones Osteo chondromas 5 Adapted fret: Vic la et al. 1971;. VI-7 SL 067163 Table VI-2 Incidence of Tumors in Rats and Rabbles Exposed eo Vinyl Chloride by Inhalation (ppm) 4 hours/day 5 days/veek 12 months Number of animals Liver angiosarcomas cholangiomas Lung adeno-alveolar carcinomas Skin squa mous 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 t-ooJ 2,000 10 8 6 6 500 150 4-- 3-- 50 200 -- -- -- -- No treatment 200 Rabbits "" 10,000 40 -- 6 12 -- No 20 -- " " treatment Adapted from Caputo ct al. (1974). VI-8 SL 067164 L. me exposure* between 50 and 20.000 ppm. Tumors appeared between 8 end 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 f" River Breeding Lab) confirmed the carcinogenicity of vinyl chloride at concentrations as low as 50 ppm (Lee et al. 1977, 1978). Liver anglosarc mas !I .. as well as other forms of cancers were found in both species. u An extensive examination of vinyl chloride in experimental animals was conducted by Maltonl (1981). A summary of these results arc presented in Tables VI-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. Kaltaml (1981) concluded that vinyl chloride may produce tumors of c different types at different sites and that the incidence and relative E distribution are greatly influenced by dose, age of the animal, and species and strain of animal used. p L VI-9 SL 067165 Table VI-3 ( Tumom'lOO Experiment BT1. Animal* with tuman. % Fere- Mam Group and Hepa Nephro- Neuro- Zymbol Shin atomaeh mary conccnlrallon MT BT LAS LA ELAS ELA toma* BL BL CIC* EpT Pad Ac MT i 10,000 ppm II 0000 ppm III 2500 ppm IV 600 ppm V 250 ppm VJ vr No treatment (control) #1? 00.0 63.3 61.1 300 16.0 133 23.3 303 200 13 3 250 36.7 433 11.7 11/60) 220 03/69) 21.1 03/60) 100 (6/60) 61 (3/69) IT 0/60) 3.4 12*59) - - IT 0 69) - __ 60 (360) 51 (-V591 50 (3 601 17 (160) .1 4 (259) 17 (1/60) - 50 13 60) 68 (159) 11 1260) 11 0 60) - 3.3 (2/60) 31 <1581 IT 0 GO) 1.7 (I'591 17 (260) 83 (560) 17 (159) - 83 (5*0) 85 (5/591 10 0 (6*0) too 1660) 85 15/591 IT O0| 11.7 <1*01 6.1 13*9) 61 (1*0) _ _ - - 26.1 06*0) 11.9 (1*9) 3.3 (2*0) 6.7 14*01 60 (3*0) 3.4 (2*9) 1.1 0*0) IT 0*01 3.4 (2*9) 1.7 0*0) _ 1.7 0*8) 1.1 0*9) 1.7 0*0) 60 (2*0) 3.3 (2*0) 17 (1*0) 3.4 (2*9) 3.3 (2*0) `Expo*urc by inhalation la VC In air at 10.000. 6000. 2500. 500. 250. and 50 ppm: 4 hr/day. 6 daya/wceh, for 62 weeh*. Sprague-Dawkey rmla, M and F, 13 wttki old. ResuKx after 135 neeha tend of experiment!. Adapted Iron HaltonI, 1981 SL 067166 f r~\ r~". r > * vx-n Table VI-4 Eaperlmcnl IIT2.* Group and concentration 1 200 ppm 11 160 ppm II 100 ppm IV No treatment (control) Tumora/100 HT err LAS Animili oith litmon, *6 Fore Mam Ilepa- Nrphro- Nruro- Zymbal Skin stomach mary LA ELAS EI.A tonu* ML nL Gl.Ca EpT r*Ae MT 30.0 30.0 31.? .? 20.0 Z7.6 too 33 (12/120) (4/120) 00 (6/119) 0.8 08 (1/120) (1/120) 08 (1/120) - - 08 (1/120) 08 (I/I 19) - 25 5 B (3/120) (7/120) - 92 (11/119) - 83 (10/120) - - 31 (4/120) 34 (VI19) 08 (1/120) 42 (5/1201 34 (VI19) 0.8 (1/120) - IT (2/119) 3.3 (VI20) 60 (6/120) 50 (VI19) 3.3 (V120) 10.? 31.0 - - 11 - - - - It II 16 10 (2/185) (2/1B5) (2/185) (3/185) (2/185) Eapoaur* by Inhalation I* VC in air >1 200, 150, 100 ppm; 4 hi/day. 5 d*y*'ueek, foe 52 necks. SprayueDawiry raU, H and F, 11 week* U. Hewitt* after 143 week* (end of eapenmeni). Adapted front Haltoni, 1901 SL 067167 V I-1 2 ) Table VI-5 Eirtilminl BT6.* Group and concentration Tumora/100 antmala MT BT LAS Animals with tumors, % Fore- Hamllrpa- Nephre- Nturo- Zymbal Skin stomach miry l*A ELAS FLA tomas BL Bl. Cl.Ca EpT PaAAc MT I 30,000 ppm 100.0 60.0 300 IT 1.7 60 IT - 17 U.) 1.7 10.3 33 08/60) (1/601 (1/601 (3/60) (MO) (1/60) (36/60) (1/60) (11/60) (MO) `Eapoeure bjr Inhalation t VC In nir at 30,000 ppm; 4 hr/day, 6 daya/week, lor H weeks. SprsfueDawtey rata. It and F, IT weeks eld. Results after 66 weeks {end af eaperimeni). 067168 Adapted from Haltonl, 1901 t l - - .... - i . I-., I .J L_I r-' r * *i i V I-1 3 Table VI-6 Eiptrimrnl BTf.* Croup and MKtalnlioa Aniwilt Hh turnon, T_____________________________________________________________ TWnen/IOQ mJimIi Forr- Mim- """""llf[u Nrphrtt- Nruro- Zymbil Shin ilwntth mart MT BT LAS LA ELAS ELA lom** III, PL Cl Ca EpT PaAAt MT | Hm II KilRiMMl (Mini) 44.3 41.1 4 A 2 7 3.1 3 7 - (14294) 111291) (9291101201) 0.3 (1/291) - 3.1 1.0 0 4 21 1 (92941 (3/294) (1/294) (2/2941 231 24.0 - - - - - - - - - 1.0 10 2 IWO) (10/08) *tipawt Of Inhalation to VC In air at 50 ppm; 4 hr'day. 3 dtyi'anh, far 32 wtclu. SprajfutDawley rata, M and F, 13 weeka old. ladu aJUr 143 wttki (and of caperimeni). Adapted froa Hnltonl, 1981 oenf-9 si- V I-1 4 Table VI-7 Eiprrlmenl OTIS.* Croup end conteM ration Tumora/100 HT BT LAS Animal* with tumor*. % Fore- MemHepa Nrpliro- Nruro- Zymbal syn atomarh mary LA ELAS ELA toma* BL BL Gl.Ca EpT Fail Ac HT 1 SShm* II 10 ppm III Ippm IV Ippm v Ha treatment (cantroll 3.1 68 3 42 OR 2 6 - 08 (6/1201 (1/120) (3/1201 (1/120) 1.1 63.3 0 8 - 1.7 26 - - (I/II9P (2/119) (3/119) iil 66.0 - - - - - - 22.6 44 2 - - -- -- 23.3 37.6 08 (1/120) _ _ 33 (4/120) 1.7 _ (2/119) 0.8 08 (1/119) (1/119) 0.8 0.8 (1/1 IB) (1/118) 1.7 (2/120) __ 16.0 (17/120) 17 6 (21/119) 18 6 (22/119) 12.1 (16/1)8) 68 (1/120) `CipMure by Inhalation U VC In air at 25, 10. S. I ppm; 4 Hr/day. S daya/week, for 12 week*. Spragut DawIry ml*. M and F, 13 nil *U fteaull* after 147 areeka (end of eapenment). Adapted fro* Haltonl, 1981 Li l Sb 067170 j L___ J i___ I J :__ J ____ i :..jJ Table VI-8 Eaptrlmenl BT3. Cioup lad raneent ration Tnmoea/100 --daub NT BT LAS Animals m ilh (umnrs. %________________________________________________________________ Fore- Mam flrpa- Nephro- Nrtiro- Zymbai Skin alomarh marjr LA EI.AS El.A lomu 0). BL Cl Ca EpT TaAAc MT 1 10,000 ppm II 0000 ppm III 2600 ppm IV 600 ppm V 260 ppm VI 60 ppm VII Ni treatment (control) 46.0 61.) 41.7 U.0 21.7 113 14.7 20.0 26.0 36.0 ISO 26.0 26.0 20.0 - 1.1 (H60) 17 (1160) 1.7 (1*0) ** * - - 1 7 17 1.7 16 6 16 6 86 1 7 1 7 (1168) (1160) (1168) (9168) (9/68) (6/68) (1168) (1168) " - 13 1.7 1.7 20.0 ISO 8.3 33 1.7 tznot (l0) (1160) (1260) (91G0) (6160) (2160) (1160) " " 33 3 3 83 117 33 * 6 7 (2160) (2160) (6160) (7100) I21G0) (4160) - * 1.7 - * 60 (1160) (3/C0) 1.7 (1/59) 1.7 (11691 - 10 2 - 17 (6169) (1169) " 6.1 1.7 (3169) (11691 1 7 1 1 6.2 IT 1.1 (USA) (1160) (3168) (11681 (1168) " 06 (11190) ~- 10 0 6 (21190) (111901 26 (61190) `Cipnaitre bjr Inhalation U VC in air at 10.000, 0000, 2600. &00, 260, and 60 ppm; 4 hr/day, 6 daya/wrdk, (or IT week* aMrDiwl(j rata, M and F, 12 week* old Reaulln after 166 wwlu (end of experiment). Adapted Iron Halton! 1981 SL 067171 V I - 16 Table VI-9 Group and concentration Tiamoea'lOO animala NT BT LAS EiH'lownl DTIf * Animal* with lumora, *1 Fore- Mam Ilepa Nrphrs- Nruro- Zymbal Skin atsmack nun LA ELAS ELA lomaa IIL BL Cl.Co LpT Pa* Ac SIT 1 11,000 ppm 11 6000 ppm III 10.000 ppm IV 6000 ppm V 10,000 ppm VI 6000 ppm VII No treatment (control) 33.3 30.0 36 0 300 41.7 31.3 16 6 41 7 46 0 46 0 39 2 46.0 606 on - 0 6 06 _ _ 7.6 * 26 114 (11116) (1116) (1)116) <9il8> (3)118) 113)1), - 06 - 1 7 - 00 00 7 6 - 1 7 101 (1/1201 (2/120) IDI20I (DI20I (9'120) (2)120) (13)120, 00 1 7 - 06 - - - 16 26 26 134 (1)119) (2)119) (DII9) 19)119) (3)119) (3/119) lltltli 26 - 1 7 - - (3)110) U'118) 42 3.4 17 01 (S'! IB) 14)118) (2)118) (11)111, 0.0 1.7 - 08 - 00 08 61 00 08 141 (DM9) (2)1191 (DM91 (DM9) (DM91 18)119) (DII9) (DM9) I20)| Hi 00 1 7 06 - 1 7 06 - 76 06 10 4 (DI20) (2)120) (DI20) 12)120) (1/(20) (9)1201 (DIM) (12'12ft 41 0 .. _ 0.4 (D2Z7) _ 09 22 76 (2227) (6/227) (I7(2n `Eipoaurt by Injtililwn ta VC in ur *t 10,000. 6000, ppm: 4 kr/day, 6 day* * cek. (or & efks lyroup* I and 11) or I Kr day. | daya)*eck, for ZS weeka (yroupa 111 and IV)or 4 hr/day, oner weekly, (or 26 weeka (yroupa V end VI) (100hr). Sprayue-Dawlry rail M and F, 11 weeka old. Reaulla after 164 weeka (end el experiment). Adapted Iron Maltoni, 1901 l l t Ob'1 .i i_.J . .1 - - J X. REFERENCES American Public Health Association. 1975. Population residing near plants producing vinyl chloride. Ames BN, Durstor. Up, Yamasaki Z, lea 72. 15*'. Carcir.cger.s are mutagens: a simple test system combining iver homogenates for activation and bacteria for detection. Proc. Natl. Acac. Sci. 8:2281-2265, Anderson D, Hodge MCE, Purchase IFK. 1976. Vinyl chloride: dominant lethal studies in male CD-I mice. Mutat. Res. 40:359-370. Anderson D, Richardson CR. 1976. Faradichlorobenzene: Cytogenic study in the rat. ICI Report CTL/P/293. November 1976 (Unpublished). Anderson D, Richardson CR, Purchase IFK, Evans, HJ, O'Riordan ML. 1981. Chromosomal analysis in vinyl chloride exposed vorkers: Comparisons of the standard technique with the sister chromatic exchange technique. Mutat. Res. .63:137-144. Andersen 0, Richardson CR, Weight 7K, Purchase IFH, Adams WGF. 1980. Chromosomal analyses in vinyl chloride exposed workers. Results from analysis 18 and 42 months after an initial sampling. Mutat. Res. 79:151-162. Aron. 1973. FDA to propose ban on use of PVC for liquor use. Food Chemical News, May 14, pp. 3-5. Hartsch H, Malaveiile C, Montesano R. 1975. Human, rat and mouse livermedicated mutagenicity of vinyl chloride in S_. typhimurium strains. Int. J. Cancer. 15:429-437. Bartsch H, Montesano R. 1975. Mutagenic and carcinogenic effects of vinyl chloride. Mutat. Res. 32:93-114. Basalaev AV, Vazine AN, Kochetkov AG. 1972. On the pathogenesis of changes developing due to a long-term exposure to the effect of vinyl chlorde. Gig. Tr. Prof. 2abol. 16(2):24-27 (in Russian). Sesler A, Rohrborn G. 1980. Vinyl chloride: An example of evaluating mutagenic effects in mammals in vivo after exposure to inhalation. Arch. Toxicol. 45:1-7. Baxter PJ, Atotbony PP, MacSween RNM, Schevar PJ. 1977. Angiosarcoma of th# liver in Great Britian 1963-1973. Br. Med. J. 2:919-921. Becker WC. 1979. Letter from B.F. Goodrich, Chemical Division, to J.P. Lehman, Director, Office of Solid Waste, USEPA. Comments on EPA proposed additions to hazardous vaste list. 44 FR 49402, Auguat 22, 1979. Bergman K. 1982. Reactions of vinyl chloride with RNA and DNA of various mouse tissues in vivo. Arch. Toxicol. 49:117-129. X-l 061V>3 Berk PD. Martin JF, Young RS. Creech J. Selikoff IG, Falk H, Wacanabe F, Popper H, Thomas L. 1976. Vinyl chloride-associated liver disease. Ann. Intern. Med. 84r717--731. Boettner EA, Ball GL, Weiss B. 1973. Combustion products fror. the incinerator of plastics. EPA Report 670/2-73-049. (PB 222 001). Bolt HM, Kappus H, Buchter A, Bolt W. 1976. Disposition of (1,2-`4C) vinyl chloride in the rat. Arch. Toxicol. 35:153-162. Bolt HM. Laib RJ, Kappus H, Buchter A. 1977. Pharmacokinetics of vinyl chloride in the rat. Toxicol. 7:179-188. Brady J, Liberatore F, Harper P, Greenwald P. Burnett V, Davies JNP, Bishop K, Polan A, Vienna N. 1977. Angiosarcoma of the liver: an epidemiologic survey. J. Natl. Cancer Inst. 59(5):1383-1385. Braker. W. and A.L. Mossnan. 1971. Mathescn Gas Data Book, 5th Edition. East Rutherford, N.J., Mat'neson Gas Products, pp. 561-564. Brodzinsky R, Singh HB. 1982. Volatile organic chemicals in the atmosphere: an assessment of available data. Prepared by SRI International for Office of Research and Development, USEPA, Research Triangle Park, N.C. Contract no. 68-02-3452. Buchter A, Filser JG, Peter H, Bolt HM. I960. Pharmacokinetics of vinyl chloride in rhesus monkeys. Toxicol. Letters. 6:33-36. Byren D, Engholm G, Englund A, Westerholm ?. 1976. Mortality and cancer in a group of Swedish VCM and PVC production workers. Environ. Health Perspec. 17:167-170. Caputo A, Viola PL, Bigotti A. 1974. Oncogenicity of vinyl chloride at low concentrations in rats and rabbits. IRC5 2:1582. Chiazze L, Nichols WE, Wong O. 1977. Mortality among employees of PVC fabricators. J. Occup. Med. 19(9) 1623--628- Chiazze L Jr, Wong 0, Nichols WE, Ference LD. 1980. Breast cancer mortality among PVC fabricators. J. Occup. Med. 22:677-679. Creech JL, Johnson MN. 1974, Angiosarcoma of the liver in the manufacture of polyvinyl chloride. J. Occup. Med. 16:150-151. Danzinger H. 1960. Accidental poisoning by vinyl chloride. Can. Med. Assoc. J. 82:828-830. Dslorma F, Theriault G. 1978. Ten cases of angiosarcoma of the liver in Shsvlnigan, Quebec. J. Occup. Med. 20:338-340. X-2 06^ Dilling WL, Tefertiller NB, Kallos GJ. 1975. Evaporation rates of methylene chloride, chloroform, 1,1,1-trichloroethane, trichloroethylene, tetrachloroethylene and other chlorinated compounds in dilute aqueous solution. Environ. Sci. Teehnol. 9(9):833-838. Dinman BD, Cook WA, Whitehouse WM, Magnuson HJ. 1971. Occupational acroosteolysis. Arch. Environ. Health. 22:61-73. Dressman RC, McFarren EF. 1978. Determination of vinyl chloride migration from polyvinyl chloride pipe into water. Am. Water Works Assoc. J. 70:29-30. Dueatman A, Hirschhom K, Selikoff IJ. 1975. Vinyl chloride exposure and human chromosome aberrations, Mutat. Res. 31:163-168. Duprat P, Fabry JP, Gradiskl D. Kagadur JL. 1977. Metabolic approach to industrial poisoning: blood kinetics and distribution of c-vinyl chloride monomer (V.C.M.). Acta. Pharmacol. Toxicol. Suppl. (Kbh) 41(1):142-143. Edmonds LD, Falk H, Nissim JE. 1975. Congenital malformations and vinyl chloride. Lancet 2:1098. Elmore JD, Wong JL, Laumbach AD, Strelps UK. 1976. Vinyl chloride mutagenicity via the metabolites chlorooxlrane and chloroacetaldehyde monomer hydrate. Blochem. Blophys. Acta. 442:405-419, Falk H, Herbert J, Crowley S, Ishak KG, Thomas LB, Popper H, Caldwell GC. 1981. Epidemiology of hepatic angiosarcoma in the United States: 1964-1974. Environ. Health Perspec. 41:107-113. FDA. 40 FR 40529, September 3, 1975. Federal Reporting Data System. 1983. Faclities and population served by primary water supply source (FRDS07), April 19, 1983. U.S. Environmental Protection Agency, Washington, D.C. Feron VJ, Hendrikson CFM, Speak AJ, Til HP, Spit BJ. 1981. Lifespan oral toxicity study of vinyl chloride in rats. Fd. Cosmet. Toxicol. 19:317-331. Feron VJ, Speak AJ, Willem* MX, van Battum D, de Groot AP. 1975. Obaervations on the oral administration and toxicity of vinyl chloride in rats. Fd. Cosmet. Toxicol. 13:633-638. Filatova VS, Gronsberg ES. 1957. Sanitary hygienic conditions and work in the production of polyehlorvinyllc tar and measures of improvement. Gig. X. Sanit. 22:38-42. Fox AJ, Collier PF. 1977. Mortality experience of worker* exposed to vinyl chloride monomer In the manufacture of polyvinyl chloride in Great Brltlan. Br. J. Ind. Med. X-3 SL 067175 Garro AJ, Guttenplan JB, Miluy P. 1976. Vinyl chloride dependent mutagenesis: effects of liver extracts and free radicals. Mutat. Res. 38:81-88. Gay BV, Hanst PL, Bufallnl JJ, Noonan RC. 1976. Atmospheric oxidation of chlorinated ethylencs. Environ. Science Technol, 10:58-67. Green I, Hathvay DE. 1975. The biological fate in rats of vinyl chloride In relation to its oncogenicity. Chem. Biol. Interactions. 11:545-562. Greta H, Bonse G, Radvan Z, Reichert D, Henschler D. 1975. Mutagenicity in vitro and potential carcinogenicity of chlorinated ethylcnes as a function of metabolic oxlrane formation. Biochem. Pharmacol. 24:2013-2017. Groth DH, Lynch DV, Moorman VJ, Stettler LE, Levis TR, Vagner VO, Kommineni C. 1981. Pneumoconiosis in animals exposed to poly (vinyl chloride) dust. Environ. Health Ferspec. 41:73-83. Guengerich FP, Mason P, Stott V, Pox T, Vatanabc PG. 1981. Roles of 2-haloethylene oxides and 2-haloacetaldehydes derived from vinyl bromide and vinyl chloride in irreversible binding to protein and DNA. Cancer Res. 41:4391-4398. Haley TS. 1975. Vinyl chloride: hov many unknovn problems? J. Toxicol. Environ. Health 1:47-73. Hansteen I-L, Hlllestad L, Thlls-Evensen E, Storevedt Heldoos S. 1978. Effects of vinyl chloride in man a cytogenetic follov-up study. Mutat. Res. 51:271-278. Harris DK, Adams VG. 1967. Acro-osteolysis occurring in men engaged in the polymerization of vinyl chloride. Br. Med. J. 3:712-714. Hatch M, Kline J, Stein 2. 1981. Power considerations in studies of reproductive effects of vinyl chloride and some structural analogs. Environ. Health Perspec. 41:195-201. Hathvay DE. 1977. Comparative mammalian metabolism of vinyl chloride and vinylidene chloride in relation to oncogenic potential. Environ. Health Perspect. 21:55-59. Heath CV, Jr, Dumont CR, Gamble J, Vaxveiler RJ. 1977. Chromosomal damage in men occupationally exposed to vinyl chloride monomer and other chemicals. Environ. Res. 14:68-72. Heath CV, Jr, Palk H, Creech JL, Jr. 1975. Characteristics of eases of anglosarcosu of the liver among vinyl chloride workers in the United States. Ann. N.T. Acad. Scl. 246:231-236. Hefner R, Jr, Vatanabe PG, Gehring PJ. 1975a. fate of Inhaled vinyl chloride monomer in rats. 246:135-148. Preliminary studies on the Ann. NT. Acad. Sci. X-4 SL 067176 Hefner RE, Jr, Watanabe PG, Gehring PJ. 1975b, Percutaneous absorption of vinyl chloride. Toxicol. Appl. Pharmaco. 34:529-532. Hill J, Kollig HP, Parris DF, Wolfe NL, Zepp RG. 1976. Dynamic behavior of vinyl chloride in aquatic ecosystems. EPA 600/3-76-001. (PB-249 302). 63 pp. Hoffman D, Patrianakos C, Brunnemann KD, Gori GB. 1976. Chromatographic determinaton of vinyl chloride in tobacco smoke. Anal. Chem. 48:47-50. Holder B. 1974. Dov Chemical Company testimony presented at public hearings on proposed standard for occupational exposure to vinyl chloride. U.S. Dept. Labor, Washington, D.C., June 25. Huberman E, Bartsch H, Sachs L. 1975. Mutation induction in Chinese hamster V79 cells by two vinyl chloride metabolites, chloroethylene oxide and 2-chloroacetaldehyde. Int. J. Cancer. 16:639-644. International Agency for Research on Cancer. 1974. IARC monographs on the evaluation of carcinogenic risk of chemicals to man. Vol. 7, Lyon, France. International Agency for Research on Cancer. 1979. 1ARC monographs on the evaluation of carcinogenic risk of chemicals to man. Vol. 19. Lyon, France. International Commission on Radiological Protection. 1975. Report of the task group on reference man. ICRP publication 23. New York:Pergamon Press. Infante PF. 1976. Oncogenic and mutagenic risks in communities with polyvinyl chloride production facilities. Ann. N.Y. Acad. Sci. 271:49-57. Infante PF, Wagoner JK, Waxweiler RJ. 1976a. Carcinogenic, mutagenic, and teratogenic risks associated with vinyl chloride. Mutat. Res. 41:131-142. Infante PF, Wagoner JK, Waxweiler RJ, McMichael AJ, Falk H. 1976b. Genetic risks of vinyl chloride. Lancet 1:734-735. Jaeger RJ. 1975. Vinyl chlorde monomer: comments on its hepatoxlcty and Interaction with 1,1-dichloroethylene. Ann. N.Y. Acad. Sel. 246:150-151. Jaeger RJ, Reynolds ES, Conolly RB, Moslen MX, Szabo S, Murphy SD. 1974. Acute hepatic Injury by vinyl chloride in rats pretreated with phenobarbital. Nature 252:724-726. John JA, Smith FA, Leong BKJ, Schwetz BA. 1977. The effects of maternally Inhaled vinyl chloride on embryonal and fetal development in mice, rats, and rabbits. Toxicol. Appl. Pharmacol. 39:497-513. John JA, Smith FA, Schwetz BA, 1981. Vinyl chloride: inhalation teratology study in mice, rats and rabbits. Environ. Health Perspectives 41:171-179. Kappus H, Bolt HM, Buchter A, Bolt W. 1975. Rat liver mlcrosomes catalyse covalent binding of C-vlnyl chloride to macromolecules. Nature 257: 134-135. X-5 SL 067177 Kappus H, Bolt HM, Buchtar A, Bolt U. 1976. Liver microsomal uptake of (UC) vinyl chloride and transformation to protein alkylating metabolites in vitro. Toxicol. Appl. Pharmacol. 37:461-471. Killian VJ, Picciano UJ, Jacobson CB. 1973. Industrial monitoring: a cytogenetic approach. Ann. N.Y. Acad. Sci. 269:4-11. Kramer CC., Mutchler JE. 1972. The correlation of clinical and environmental measurements for workers exposed to vinyl chloride. Am. lnd. Hyg. Assoc. J. 33:19-30. Kuzmack AM, McGaughy RE, 1975. Quantitative risk assessment for community exposure to vinyl chloride. Environ. Prot. Agency Rept., Dec. 5., Washington, D.C. Laib RJ, Bolt HM. 1977. Alkylation of RNA by vinyl chloride metabolites in vitro and in vivo: formation of l-N'-etheno-adenosine. Toxicology 8:185-195. Lee CC, Bhandari JC, Winston JM, House WB, Dixon RL, Woods JS. 1978. Carcinogenicity of vinyl chloride and vlnylidene chloride. J. Toxicol. Environ. Health 4:15-30. Lee CC, Bhandari JC, Winston JM, House WB, Peters PJ, Dixon RL, Woods JS. 1977. Inhalation toxicity of vinyl chloride and vlnylidene chloride. Environ. Health Perspect. 21:25-32. Lester D, Greenberg LA, Adams WR. 1963. Effects of single and repeated exposure of humans and rats to vinyl chloride. Am. Ind. Hyg. Assoc. J. 24:265-275. Letkiewicz F, Johnston P, Macaluso C, Elder R, Yu W, Bason C. 1983. Occurrence of vinyl chloride in drinking water, food and air. Prepared by JRB Associates for Office of Drinking Water, USEFA, EPA No. 68-01-6388. Lilia R. Anderson H, Nicolaon WJ, Daum S, Fischbein AS, Selikoff IJ. 1975. Prevalence of disease among vinyl chloride and polyvinyl chloride vorkers. Ann. N.Y. Acad. Sci. 246:22-41. Lillian D, Singh HB, Appleby A, Lobban L, Amts R, Bumpert R, Hague R, Toomey J, Kazazls J, Antall M, Hansen D, Scott B. 1975. Atmospheric fates of halogenated compounds. Environ. Sci. Technol. 9:1042-1048. Loprieno N, Barale R, Baroncelli S, Bartsch H, Bronzetti G, Cammellini A, Corsi C, Frezza D, Nieri R, Leporini C, Rosellini D, Rossi AM. 1977. Induction of gene mutations and gene conversions by vinyl chloride metabolites in yeast. Cancer Res. 253-257. Loprieno N, Barale R, Baroncelli S, Bauer C, Bronzetti G, Cammellini A, Cerclngnani G, Coral C, Gervasl G, Leporini C, Nieri R, Rossi AM, Stretti G, Turchi G. 1976. Evaluation of the genetic effects induced by vinyl chloride monomer (VCM) under mammalian metabolic activation: studies in vitro and in vivo. Mutat. Res. 40:85-96. X-6 s, 067H Lu PY, Metcalf RL, Pluwer N, Handel D. 1977. The environmental fate of three carcinogens: benzo(a)pyrene, benzidine, and vinyl chloride evaluated in lahoratorv model ecosystem*. Arch. Environ. Contar. Toxicol. 6:129-14?. Makk L, Delmore F, Creech Jl., Jr, Ogden LI., Fadell F.~ , Songster Cl., Clantcr J, Johnson MK, Christopherson WM. 1976. Clinical and morphologic features of hepatic angiosarcoma in vinyl chloride workers. Cancer 37:149-163. Maltoni C. 1977. Vinyl chloride carcinogencity: an experimental model for carcinogenesis studies. In: Hiatt HH, JD Watson, JA Winsten (eds.). Origins of Human Cancer, Book A. Cold Spring Harbor Laboratory, 119-146. Maltoni C, Ciliberti, Gianni L, Chieco P. 1975. Tbe oncogenic effects of vinyl chloride administered by oral route in the rat. Gil Ospedali della Vita 2(6):65-66. Maltoni C, Lefemine G. 1974. Carcinogenicity bioassays of vinyl chloride. 1. Research plan and early results. Environ. Res. 7:387-405. Maltoni C, Lefemine G, Ciliberti A, Cottl G, Carretti D. 1981. Carcinogenicity bioassays of vinyl chloride monomer: a model of risk assessment on an experimental basis. Environ. Haalth Perspec. 41:3-31. Hanusco TF. 1975. Comments for opening of discussion oh "neoplastic affects." Ann. N.Y. Acad. Sci. 246:251-254. Marsteller HJ. Lelbach UK, Muller R, Gedigk P. 1975. Unusual splenomegalic liver disease as evidenced by peritoneoscopy and guided liver biopsy among polyvinyl chloride production workers. Ann. N.Y. Acad. Sci. 246:95-134. Mastrocatteo E, Fisher AM, Christie H. Danziger H. 1960. Acute inhalation toxicity of vinyl chloride to laboratory animals. Amer. Xnd. Hyg. Assoc. J. 21:394-398. McCann J, Simmon V, Streitvleser D, Ames BN. 1975. Mutagenicity of chloroacetsldehyda, a possible metabolic product of 1,2-dichloroathane (ethylene dichloride), chloroethanol (ethylene chlorohydrin), vinyl chloride, and cyclophosphamide. Proc. Natl. Acad. Sci. 72:3190-3193. McConnell GD, Ferguson M, Pearson CR. 1975. Chlorinated hydrocarbons and the environment. Endeavor 34:13. Milby TH (ad.). 1978. Vinyl chloride: an information resource. DHEW Pub. No. (N1H) 78-1599. Miller A, Teirsten AS, Chuang M, Selikoff IJ, Warshaw R. 1975. Change! in pulmonary function in workers exposed to vinyl chloride and polyvinyl chloride. Ann. N.Y. Acad. Sci. 246:42-52. Monson RR, Peters JM, Johnson MN. 1975. Proportional mortality among vinyl chloride workers. Environ. Health Perspec. 11:75-77. X-7 Si S>J?9 National Acadaay of Sciences. 1977. Drinking Water and Health. Washington, DC. 783-787. National Academy of Sciences. 1483. Drinking Water and Health, Vo 1.5. National Academy Press, Washington, DC. Nevberne, PM. 1982. Assessment of the hepatocarcinogenic potential of chemicals: response of the liver, In: Plaa, 0 and W. R. Hewitt (eds.). Toxicology of the liver. Raven Press. New York, 266-267. Nicholson WJ, Hammond EC, Seldman H, Selikoff It. 1975. Mortalty experience of a cohort of vinyl chloride-polyvinyl chloride workers. Ann. N.Y. Acad. Scl. 246:225-230. Oster RH, Carr CJ, Krantz JC, Jr. 1947. Anesthesia XXVII. Narcosis with vinyl chloride. Anesthesiology 8:359-361. Ott MG, tangner RR, Holder BB. 1975. Vinyl chloride exposure in controlled industrial environment: a long-term mortality experience in 594 employees. Arch. Environ. Health 30:333-339. Patty FA, Yant UP, Waite CP. 1930. Acute response of guinea pigs to vapors of some new commercial organic compounds. V. Vinyl chloride. Pub. Health Reports 45:1963-1971. Peoples AS, teake CD. 1933. The anesthetic action of vinyl chloride. J. Pharmacol. Exp. Therapeutics 48:284. Picciano DJ, Flake RE, Gay PC, Killian DJ. 1977. Vinyl chloride cytogenetics. J. Occup. Med. 19:527-530. Popper H, Thomas LB. 1975. Alteration; f liver and spleen among workers exposed to vinyl chloride. Ann. N.Y. A. . Sci. 246:172-194. Proceedings of the Royal Society of Medicine. 1976. 69:275-310. Prodan L, Suciu I, Pialaru V, Ilea E, Paseu L. toxicity of vinyl chloride (monochloroethane). 246:154-158. 1975. Experimental acuta Ann. N.Y. Acad. Sci. Purchaaa 1FH. Richardson CR, Anderson D. 1975. Chromosomal and dominant lethal affects of vinyl chloride. Lancet 2(7931) *.410-411. Purchase IFH, Richardson CR, Anderson D, Paddle GM, Adams WGF. 1978. Chromosomal analyses in vinyl chloride--exposed workers. Mut. Raa 57:325--334 Radiks M. 1977. Transplacental affects of vinyl chloride in rats. Annual Report, pp. 183-185. USPHS-ES-00159. Center for Study of the Human Environment, Dept. Environ. Health, University of Cincinnati Medical Center. X-8 SL 067180 Radlke MJ, Steamier KL, Brown PG, Larson , Bingham E. 1977. Effect of ethanol and vinyl chloride on the Induction of liver tumors: preliminary report. Environ. Health Perr.pect. 21:153-155. Kadike MJI, Stenr.er KL, Binphar F. 19Pj. LI feet of ethanol on viryl chloride carcinogenesis. Environ. Health Perspec. 41:59-63. Rove VK. 1975- Experience in industrial exposure control. Ann. N.Y. Acad. Sci. 246:306-310. Rannug U. Johansson, A. Ramel C., Uachtmelster CA. 1974. The mutagenicity of vinyl chloride after metabolic activation. Ambio 3:194-197. Selikcff IJ, Hammond EC, eds. 1975. Toxicty of vinyl chloride-polyvinyl chloride. Anr.. N.Y. Acad. Sci., Vol. 246. Spirtas R, Kaminski R. 1976. Angiosarcoma of the liver in vinyl chloride/polyvinyl chloride workers. Update of the NIOSH Reglater. J. Occup. Med. 20:427-429. Spirtas R, McMichael AJ, Gamble J, Van Ert M. 1975. The association of vinyl chloride exposures with morbidity symptoms. Amer. Ind. Hyg. Assoc. J. 36:779-789. Suclu 1, Prodsn L, Ilea E, Paduraru A, Pascu L. 1975. Clinical manifestations in vinyl chloride poisoning. Ann. N.Y. Acad. Sci. 246:53-69. Tabershav IR, Gaffey VR, 1974. Mortality study of workers in the manufacture of vinyl chloride and its polymers. J. Occup. Med. 116:509-518. Til HP, Imoel HR, Feron VJ. 1983. Lifespan oral carcinogenicity study of vinyl chloride in rats. Final report. Civo Institutes TNO. Report No. V 83.285/291099. Torkelson RR, Oyen F, Rowe VK, 1961. The toxicity of vinyl chloride as determined by repeated exposure of laboratory animals. Amer. Ind. Byg. Assoc. J. 22:354-361. Tribukh SL, Tikhomirovs NP, Ltvins SV, Kotlov LA. 1949. Working conditions and measures for their sanitation in the production and utilization of vinyl chloride plastics. Gig. Sanit. 10:38-44 (in Russian). U.S. Department of Agriculture, Agricultural Research Service, Household Food Consumption Survey, 1965--1966, Food and Nutrient Intake of Individuals of the United States. U.S. Environmental Protection Agency. 1974. Preliminary assessment of the environmental problems associated with vinyl chloride and polyvinyl chloride (appendices). Report on the Activities and Findings of the Vinyl Chloride Task Force. EPA 560/4-74-001, (PB-39 110). 67 pp. X-9 SL 067181 U.S. Environmental Protection Agency. 1975s. Preliminary assessment of suspected carcinogens In drinking voter. 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 Coanunlty Water Systems (Temple, Barker and Sloans). 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 -- Cooparislon of Results Obtained by the National Academy of Sciences and EPA's 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 Agencies. U,S. Environmental Protecton Agency. 1980d. Compilation of Incidents of Drinking Vatar Contamination with Volatile Organic Chemicals (Office of Drinking Water). U.S. Environmental Protection Agency. 1980a. Ambient Water Quality Criteria for Vinyl Chloride (Office of Water Regulations and Standards). EPA 440/5-80-078. U.S. Environmental Protection Agency. 1981a. Cotmnunity Water Supply Survey (Office of Drinking Water). X-10 SL 067182 U.s. Environmental Protection Agency. 1981b. National Organics Screening Prograr fSRl). Van tsch 01, Van Lop ter. M.l. !Q'b. Vi:\I chloride: a report cf a Lv.r're assessment. Fd. Cosmft. Toxicol, lj: 101 -- 124. Verburgt FG, Vogel E. 1977. Vinyl chloride mutagenesis in Drosophila nclanogaster. Mutat. Res. 48:327-323 . Viola PL, Bigotti A, Caputo A. 1971. Oncogenic response of rat sk.ln, lungs, bones to vinyl chloride. Cancer Res. 31:516-522. Ward AW, Udnoon S, Watkins J, Walker AE, Drake CS. 1976. Immunological mechanisms tr. the pathogenesis of vinyl chloride disease. Br. Ked. J. 1:936-938. Watanabe PG, McGowan GR, Gehring PJ. 1976a. Fate of ( 14 C) vinyl chloride after single oral administration in rats. Toxicol. Appl. Pharmacol. 36:339-352. Watanabe PG, HcGovan GR, Madrid EO, Gehring PJ. chloride following Inhalation exposure in rata. 37:49-59. 1976b. Fate of ( 14 C) vinyl Toxicol. Appl. Pharmacol. Waxweiler RJ, Stringer W, Wagoner JK, Jones J, Falk H, Carter C. 1976. Neoplastic risk among worker exposed to vinyl chloride. Ann. N.Y. Acad. Scl. 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. Withey JR. 1976. Pharmacodynamics and uptake of vinyl chloride monomer administered by various routes to rsts. J. Toxicol. Environ. Health 1:381-394. W'ithey JR, Collins BT. i976. A statistical assessment of the quantitative uptake of vinyl chloride monomer froc aqueous solution. J. Toxicol. Environ. Health 2:311-321. X-ll SL 067183 I V I-1 7 Table VI-10 Croup and rente nUaUon Tumor*/100 animats MT BT Eaprrimrnl UTS * ________________________________Animal* Hh lumnrs, *) LAS Hepa Nrphro Neuro- 7.vmbal I.A ELAS F.LA tomas 1)1. III. Cl Ca Skin r.pT Fore- Mam si oinarh marj f*a*Ar MT 1 10,000 ppm II 0000 ppm III 14,000 ppm IV (000 ppm 6.1 0.1 29.6 Ilf 367 23.3 22 2 46 9 - -- _ 69 (3/511 3.1 - - 11/321 33 11/30) - __ 98 IVSI) 94 (3/32) 31 (1-321 20 (1/51) 3.1 (1/32) 20 (I'M) 62 (232) `Exposure by Uulitlonlt VC in air at 10,000. am) 0000 ppm ol brerders; 4 hf'ilay for I airk (from 12th lo IHtti day of pregnanrtl Sprague-Dowky rail, M and F, 19 eeka olil (breeders). Breeders (groups I and tl) and offsprings (group* III and IV) Result; afUi 143 neck* (end of experiment). Adapted from Mnltoni, 1981 SL 067184 V I-18 Table VI-11 Croup and cawcentrmlian 1 10,000 ppra (breeders) 11 0000 ppm (breeders) 111 10,000 ppm (newborn) IV 6000 ppm (newborn) TmrmVIPft NT BT F.iptriimnl IIT1I.* ______________________________ Animals wiih tumors, % LAS Heps- Nrphru- Neuro- 7.ymhal LA ELAS El.A lomas 0L RL Cl.Ca For*- Mam Skin stomach mirv EpT PaAAc JIT 10.1 06.1 100.0 00.6 34 1 (16/44) - 68 45.4 (3/44) (20/441 100.3 68.1 406 2 4 24 24 41.6 (11/42) (1/421 (1/42) (1/42) (20/421 - - 23 2 3 _ (1/441 (1/44) _ 4.8 4.8 (2/42) (2/42) 24 (1/42) `Eaposur* by Inhalation ( VC in air at 10.000 and 0000 pjwn, 4 hr.day, 5 day a/week. for 5 wreks (Irom 1 day In & week* of ayrt Spraguc-Dawley rala, M and F, 21 weeka old (breeders) ((roups I and 111 and newborn ((roups III and IV). Results after IZ4 oeeki (end of caperimenU. Adapted fron Haltoni, 1981 i SL 067185 L.____1 -__ J J , i) _) V I - 19 Table VI --12 . Experiment HT7.* Croup and ranreatralian 1 I0.0U) ppm II 1000 pfM 111 1500 ppm IV 100 ppm V tWppm VI Wppm VII Ka treatment Mrdl TumoiVlUO animala MT BT W0 too M.3 200 K.7 13.1 NO 10 0 13.3 ir. 7 1*7 6 7 IV0 15 0 LAS Animal* trHh tumor*. 1 1 ore Hepa Nrphro- Nrurtr Zymbel Skin lomacti LA l.l.AS ELA toma* ni. bl Cl.Ca EpT r*At 2!> 0 18271 II 5 (3 .*6| 12 0 <3 "251 10 7 <3th) :i; II I'll - 77 12701 * 30 11/28) * * 38 112fi> 40 (125) ~ 37 <1771 - 38 076) - " 37 (1/27) - 77 12761 40 <1751 - 37 41/771 7.7 12261 - 7.1 (2/2H) ' 36 II7R) 11 1 <3771 38 (1761 40 (ITS) - 7.1 <277) 77 (2761 " - - ' - " 40 075) - 37 077) " " 2 r, (1/38) '---- `Eipmure kv inkilation to VC in air al iO.INKl. (nio. 2500.500. 250. and Ml ppm, 4 hntli>. 5 d\ a/rck. (orilvnln Wialar nil, M, II neek* aid NttulU after IU neek* lend of ri|rrimrn() Adapted fro Maltonl, 1981 SL 067186 Table VI-13 Eaprrimtnl UT11.* Group and roortMralMO Animals with lunmra, 9 FoirIlepa- Nrphro Nruro- Zvmbal Skin (omark MT 8T LAS LA ELAS ELA Inmaa BL BL Cl.Ca EpT Pat At 1 Ippm II Ka litatmot (nalidl 24.2 292 20.0 IB* 1 0 30 SO ID IIWI (399) (SW) <1/991 - --- 20 (299) " 32 - II <3941 (194) 'CipaiiHt by InkaUlfon ( VC in air at I ppm; 4 hriday, 6di)Vrtk, for S2 week*. Wislar rala. M, 13 ks old. Resuha after 134 artki lend d riperimeail. V I- 20 Adapted fro* Haltoni, 1901 :11 SL 067187 J C___ i I -- j i__*--J V I-2 1 Table VI-14 Croup and cwwrntratMn 1 10,000 ppm II 0000 ppm III BOO ppm IV 00 ppm V ISO ppm VI W ppm Vlt Ka lifalmrnt (rooirol) TimmnVIOO animali HT BT MO 98.3 K.l 100.0 U.) 00.0 HI 103.3 0.1 08.3 a> 23.3 14.1 14.1 I.AS 11 8 < 10-Mll 21 1 (13*0| 21 1 116-59) 2.1 3 (14/60) 30 0 (18*0) 11 (I'M) - Kipfrimvnl IIT4." Animats with lumora, ^ LA HI 1 ir.'W,) II 1 (1/00) 8S (6*!)) 83 (s*m IB.3 (11/00) 11 (1*01 - I.I.AS 1B d/r>M 1.1 (1*0) 13 S <8*9) II 1 (l/M) SO (3*0) 11 (1/00) 01 ll/IMD LI.A Mammary Limp T Ca 11 O'.Vfi) SO . (3*0) 11 (1/59) SO (3*0) SO (3*0) 83 (S/SO) R2 1 (46-561 18 3 (41*0) 61 8 (40/59) B3.3 I.'|0*0| 68 3 141*0) 10 0 (6*0) 2.1 2 (I3V.I 13 3 (AMI) 13 S (A'.V) 13 3 (8*0) 200 02*01 200 (12/00) 01 (1/150) 100 IIS'ISO) 01 (l/ISO) Skin r.pT tlnmach I'ai Ar 11 (4*6) II 1 (7*0) 68 (4/S9) 33 (2*0) n (1*0) - 1.8 (l/f>6) 11 0*0) 1.7 (I/S9) - 1.7 (1*0) 1.7 (1*0) 13 (2/ISO) - 'Eipwun by Inhahlftm U VC in Mr *1 10,(MW. 6000. ZMM). $00. 250. and $0 ppm, 4 kr/dat, $ data/nrrk. for 30 nrrka. Skim mice, M and f, || ucka ld. ReaatU alUr SI ka (tnd of e*pnnwn(|. Adapted from Hnltonl, 1981 0b7l88 7 1 -2 2 Table Vl-15 Eaperiment I1T6 * Croup and concentration Turnon/100 Animal:) with tumor*. % anlmala Acoualic rorr Ilrpa- Chulan- (*hnl< Duct Skin McU- atamackLeidn MT BT LAS LA ELA tomaa ([to-Ca poniu EpT EpT nomas Pa6 Ac mar* 1 13,000 ppm 11 3000 ppm III 2600 ppm IV 603 ppm V ISO ppm VI SO ppm VII \i< treatment (central) 60.0 40.3 43.3 63.3 30.0 603 20 0 13 3 63.3 103.3 63.3 43 3 40 0 46.1 33 (1/301 _ 61 12/30) - - :i .1 II 301 3.3 1130) 61 <2.301 - - - 67 U-Vft _ - 33 (I :ti :i 3 <1/303 - _ 33 (130) - - - - 67 <230) 61 <2301 _ - - - 13 3 <130) 16.1 (S30I 26.1 <sao> 200 (630) 200 <6/301 23 3 (7/30) 33 <1301 6.7 <230) 33 (130) 10.0 (330) - - 23.3 (130) 1.1 (130) 10.0 (330) 233 (130) 10.0 (330) 300 (930) 33 (130) 6.1 (230) 11 (130) - - 3.3 (130) 3.3 (130) 21.3 (1030) 23.3 (1030) 66.1 (1730) 300 (930) 13 3 (430) 10.0 (330) It) (Mb t (6 3b Ml nm 161 iti (60b 201 (60b - - - _ .16 1 - SO _ 60 ill 122001 (3/60) (3/60) (66b `Eipotun by inhalation to VC in air at 10,000. 6000. ZMC. j0. 2TtO. and .VO ppm; 4 hrfday, S daya/week, for 30 week! GoUn kamatera, U, 11 anb old. Rcaulta after 109 weeks tend of eapenmrntt kLatency lime In weeka; Croup I, 16 1; Croup II. 27.2; Croup 1(1. 30 H. Croup IV. 19 0; Croup V, 22.6; Croup VI, 3S.3, Group VII 36.6. Adapted ftoo Halton!, 1981 SL 067189 j 1--J _J t . . J c__i ( (--- 1 1 li V I-2 3 Table VI--16 Esperimenl 1ITII.* Group and concentration 1 66.05 ngAf II 15.56 mg/kg HI l.D mg/fcg IV Ollee oil (cantrsl) TumoaVlOO MT BT l.AS Animals with tumors, 1 lore Mam llrpa- Nrphro Nruro- Zymbal Skin alomarh man LA F.LAS ELA lomas 1IL 111. til Ca EpT Tad Ac MT *5.7 MO 15.6 36 0 17.6 26.0 21.2 (1740) 12 5 <1(0801 37 (340) 25 (24> - 25 ivm\ 25 (2/80) i2 (1401 25 - 1 2 12 25 50 (2 MO) (14)0) (14)0) 1240) (440) 3 7 25 - 1.2 75 tawti (240) (140) 1640) "` 37 (3401 13.7 22 6 ---- '' 1.2 12 " 6.0 U>80) 1140) <4001 `Eapeaure by Ingestion (stomach tube) of VC in olive oil at SO 00. 16.65and 3.33 my/kg bndv * tight. once duly. 4 5 daya/week. (w U week*. Sprague-Dawtey raU, H and F, 13 weeks old Result* alter 135 weeks tend of rapenmcnl). Adapted fro* Hnltonl, 1981 sb 067190 Table VI-17 Eaperimrni BT17.* Group and concentration Tureon/100 animals HT BT LAS Animals nh tumors, % Fore Mam llrpa- Nrphro- Neuro- Zymhal Skin stomarb mary LA LLAS LLA tomaa III. RL GICa EpT PaOAr MT 1 1.0 M|/kg II 0.9 o|A( 111 0.09 ma/kf IV Olive o0 (control) 24 7 19.9 10.0 96.9 200 91 3 20 (31149) 0.7 (1/148) _ 07 (1/148) 07 (1/149) - 07 (1/149) 07 (I/I 48) - 16.0 28.7 - - - - - 3 3 _ 2.0 80 (6/149) (3/149) (12/1411 - 07 13 2.7 (1/148) (2/148) (i/itn 0.7 0 7 93 (1/IS0) (1/160) (14/160) 0.7 _ 13 47 (l/ISO) (2/160) (7/160) 'Eipooure by irifeitlon (alonurh tube) or VC in olive oi) at 1 0. 0 3, 0.03 m*/Vy body urirhl. once daily, 4-kdayo/wrek, for 69 necks Sprague Da*ley rata, H and F, 10 weeks old. He suits after 136 wecka (end of eaperiment). V I-2 4 Adapted from Haltoni, 1901 SL 067191 lJ *< JJJJ (--- 1 [ -- ri -) V I-2 5 Table VL-18 Eaperlmrnl BTII* Crwp and dote 1 I IS mg * 4 II 4.8 mg* S III 4.16 mg *8 IV i.l&nf *1 v Oh** all teantrol) Tli/nor&lOO animal* MT BT ia.a 1*7 18.1 11.7 18 3 80.0 .o ___________________________________Animal* with tumor*. 1 LAS Hep*- Wrphro- Neurn Z vmbal LA r.i.As r.i.A toma* IIL III. Cl Ca Shin F.pT Fnie- Mam Komarh mirv Pa* Ar MT 1.8 1 8 (1/661 (1/66) J f - - - - _ * IS IS M .'all (1/63) (1/63) hi - a. _ - 18 6.1 (1/561 (1/66) (3/66) - 1A - - 1A 3 6 36 (1/551 (l/MO (Z/M) (2/66) si 11.7 3.6 (2/W) 'CifoWT by InttapcHtoneal litjtdlon of VC, 4,25 my in oil!f oil (I ml), 4, 3, 2 limn, il two month interval* or oner only Syrigvc Donley nil, H and F, 17 week* old. Hrsulu after 144 wrrha lend of eapenmenl) Adapted Iron Maltont, 1901 SL 067192 Table VI-19 Gnupurf 4m i 4mg 11 ObteaU (contrail TMnm/lOO MT DT LAS ito 17.3 11.1 267 Experiment I1T13.' Ammalt vrilh lumor*. *1 Fwe- Mam Hepa Nrphre Nruro- Zymbal Skin tlomath miry LA ELAS ELA toma* fll. UL Gl Ca EpT PaA Ac MT 1.3 (1/75) -- -- "" 4 <1 13-76) 1.3 11/751 13 (1/75) 13 11/75) tipiww by aubcuUneaua Injection of VC, (25 mg, in olive oil (I mil, tingle dose. Sprague-Dawley raU. M and F. 21 neekaold. Imb alter 141 areeka (end af experiment) V I - 26 Adapted from Haltonl, 1981 SL 067193 t l. I _ .J \___. ._] . .___ J (------- ( VI-27 Table Vl-20 Tumors Presently Correlotcd to VC KKpnr.it re (by ) nlio lot inn) on Expc * Anpo- Sr ha Olher f MTCflmU rrmis nil a- rorrslo and an- cue* nroua msrh pa- **** Tumor* Tumor* LjrmpKo- jpomu Ntphra- imms tpith Mam- pillomax ummu of of mu and llrpa- of other Maslo- earn that mart car and aran Mela Sprat* sf liter brain hinp Irukrcmas lamas Silt* MBA nomas lumnrs rinomas Ihomas nomas lUt 4 4 444 Name 4 4 UtMucr 4 (* ( + ) 4 1<> 4 4 to 4 (4 1 m 4 < t SL 067194 Adopted from Hoi tool, 1981 A recently completed study by Feron et al. (1981) examined the oral toxicity of vinyl chloride in Wlatar 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 10Z VCM in soybean oil. The VCM doses (actual exposures) were 0, 1.7, 5.0 and 14.1 mg/kg bv through the diet or 300 mg/kg bv by gastric intubation. The results showed that rats exposed to VCM at levels of 5.0 mg/kg bw 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 bv/day, liver-cell tumors and an increased incidence of foci of cellular alteration were noted (Tables VI-21 and VI-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 bw 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 Vlstar rats, each consisting of 100 males and 100 females, except for the top-dose group which comprised 50 males and 50 females. VCM was administered by incorporating FVC powder with a high VCM content into the diet. The diet was provided daily for a period of four VI-29 SL 067196 Table VI-21 Type end Incidence of Treatment-Relnted Itlstopathological Changes In the Liver of Rats Exposed Orally to VCH V I-30 Type of thangel Treatment. (mg VCM/kg^day)... Incidence of Change Halee Fcmnlee 0 1.7 5.0 14.1 300j 0 1.7 5.0 14.1 300f Aniimla killed after 26 k Clear-cell foci No. of rata examined.. . 10 0 1-- ---- 10 1 Animale killed -after 52 wk 9 1 10 -- 0-- No. of rate examined.. . 9 _ 10 9 9-- Clear-oell fod Basqpttilic fod Eoeinophllic fbd 1 ---- 0 ---- 0 ---- 8** 0 00 20 0-- 0 -- 0 *-- Neqplaetic nodule 0 ---- 10 0-- Hepatocellular cardnora 0 ---- 10 0-- eyetic proliferation of bile ducta o ---- 00 0-- Animate found dead or killed in extreede or terminally No. of ratee examined. ..55 Clear-cell fod 0 Daecphlllc fod 8 Eoaincphllic foci 3 Neqplaetic nodule 0 Hepatocellular oardnema 0 Angicaaroaaa 0 50 56 59 55 57 58 9** 16*** 21*** 9 4 24*** 18 21* 22** 12 23*** 27*** 33*** 11 0 33*** 8 35*** I 7** 23*** 3 2 26** 12 8** 1 0 4 0 6* 27*** 27 0 0 -- 10 10 -- 5** 2 -- 10 8 -- 8** 0 -- 41 -- 5** -- 20 -- 10 -- 4* 0 59 22*** 17 20* 39*** 19** 2 57 36** 28 * 29*** 44*** 29* 9** 54 IP 19 6 2 0 29 SL 067197 ; l .. L i i - L -J t l__J CU u t-----J - ;__ J ;. 4* Tabic VI-21 - continued Proliferation of atypical sinusoidal ceils only Extensive necrosis Cysts Livec*cell polymorphism Centrilbbular degeneration Fbaal haexatqpoiesla 2 0 4 7 646 34 7 4 4B 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 1 1 2 3 1 IB 0 10 10** 8 1 3 1 6 12 ^Specific Hepatocellular leelone wtra classified according to Squire fc Levitt (1975). fltw figures o( this group were not evaluated statistically because no corresponding control greup tea included in the study. iNot examined. THs initial rnuber of animals was 60/sex/group. A nuaber of rats could not be cnasdned because of csmUbaiime advanced autolysls. Values miked with asterlXs differ alryilficanfcly frem those of the controls according to ths dh l-square test* *P<0.05| **P>.01 ***P<0.001. Adapted from Feron et al. 1981. SL 067198 T-hl. VI-22 Site. Type end Incidence of Timore in Orgen. Other then the Liver In Rate Table vwz gloved Orally to VCM for Over 2 to 5 Teare ""' Site ami tvna of tuwour "* Traataant group (an VCM/kg/day).. ~1 5 ________ Incidence of tunoura Malea 0 1.1 5.0 14.1 30b| d T7T" hwalaa 14.1 "35 Effective no. oi rata... No. g rata with prlmiy tunoura Lunga Angioearocaa Mencau tynbal glanda 55 58 56 59 55 57 56 59 57 54 30 50 49 52 44 54 56 55 57 47 0 0 4* 19*** 19 0 0 1 5* 23 0 0 0 ft. 10 00 00 0 0 2 0- 1 0 0 0 0 1 0 0 0 0* 0 0 0 0 0 1 Heoothalloaa Anglawocaa Irlberoaarooaa Oataoaaroam fcaroaa* Reticuftisa-call aaroom *SchMann-oaIi twour' Unclaeaifled Spleen HaanangloandotheUaearoam Squoeoue-cell oardnom Brain Granular-cell ayoblaatcna Ol igodendroglioaa Plexue papillcna Glial-cell tuMour Epend^aoaa Meaodunaal tuaour Pancreaa Adenouardnoaa Thorax Heaotheliaae Thyroid Parafol Lloulap-cel 1 adaaoaa Parafollicular-cell cardncma I 'ien-- 3 1 7 8 1 1 6* 3 3 . 0 0 0 0 0 10 00 2 1 0 0 0 3 01 20 0 0 0 00 10 00 I0 0 0 3 1 00 0 1 0 0 0 1 0 0 10 00 0 0 0 0 0 0 00 10 0 0 0 0 0 0 02 00 0 0 0 1 0 0 00 00 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 1 0 0 0 0 0 c 1 1 0 0 00 1 0 0 0 1 0 0 0 00 00 0 0 0 0 0 0 00 1 0 0 0 0 0 2 0 10 00 0 0 0 0 0 1 00 00 0 0 0 0 1 0 00 00 0 0 0 0 0 0 01 21 0 0 1 0 0 0 00 00 0 0 4 1 n i -_J 12* 0 Li") 10 1 n 3 3 7 10 3 2 C 0 00 0 0 A0 0 1n !! J "Jo < r,.f [ n-: f " -r MU VI-22 (ooritlnMd) site Ml) typa of (la VCH/kg/day) Males Incidence of Turbure Peonies 0 1.7 5.0 14.1 300t 0 1.7 5.0 14.1 300* Cortical edenum HiMoJumocyiniB 18 25 17 10 9 26 3P 20 17 14 11 21 B 4 62 12 0 2 Pituitary 12 25** 6 10 1 2** O 14 0 03 16 10 O2 5* 3 00 Blood Leukeeda 10 1 1 31 21 0 1 H<I Hwrt Endocardial disease* 20 2 2 1 1 00 0 1 teMMI^lOMdCthaliOMtODMI 10 0 0 0 0 Q. 0 0 0 Kidtaya Neptirbblastam 10 0 1 00 00 0 0 Clear-cell tumor 00 0 0 00 00 1 0 llfBlime tunour 00 1 0 00 00 0 0 Uhclaeeified epithelial tu 0O 0 0 o1 00 0 0 Dpwa Fibrosaroion Reticulue~cel1 eareem 0. 1 00 0 0 O 0o 00 0 10 11 0 :0 00 Hooonterlc lyoph nodes Reticulue-cell earocea 00 0 0 10 00 0 0 Skin Oquuoue-cell cardram 23 3 1 00 00 1 0 Sttxutie tuoour 21 1 1 13 31 00 01 1 0 01 10 0 0 00 0 0 01 00 0 0 Skeletal le 00 0 1 1 1 00 0 0 SL 067200 TABLE VI-22 (oontiiued) V I-34 n^7?01 Site and type of tusour Treetsent group (eg VCH/kg/dey) 0 Hales Incidence of 1 eanlee 1.7 5.0 14.1 300* 0 1.7 5.0 14.1 300* Skull Oeteosn Heaandysil tumour I 00 000 0 00 00 0 0 0 00 X 0 0 0 Ear region AdsnooarcincM of tsiuiown origin 0 0 1 0 00 00 0 0 Urinary bladder Unclassified epithelial tusour 0 0 1 0 00 00 0 0 Preputial glands Stfnaoua call cardname 00 1 0 00 00 0 0 Hasnnry glands Adsnom Manooardnam Anaplastic oardnosn 00 00 0l 00 0 0 0 0 o 00 00 2 0 0 0 21 25 12** 4** 7 2 0 3 i4 7 7 0 00 0 1 0 0 Testes Interstitial-cel 1 tusour 30 0 II Uterus Adsnooarcima Msiimant fibcoadenonatous tusour Lsiosycse 6 3I 1 0 o I0 0 0 0 01 0 0 Cervix Hesenchyeel type of tuiour Admooercincse 2 01 0 0 0 10 0 0 Ovaries Theca-os11 tusour 0 01 0 U Mil tutor ot primary livtr tisnaurs unrelated to treatment were found in several groups, 0 one Kupffer-celI sarcoma, three reticulum-cell earaame, two fibressraaens, one hawngioendathellow d Me mand^nl tumour. t*lhe figures for thia group were net evaluated statistically, because no corresponding control group was Incl^d in the study. Iln several case* tbs neoplastic character of the lesion was doubtful. Values marked with asterlks diff r significantl OSij **P<0,* ***P<O.Opl, those of the controls according to the chi-square taeti 1 1 L- -J -J ' . J j . 'i 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 067202 sh ocher groups. Moreover, in females of che cop-dose group the incidence of hepatic cysts vas 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 che cop-dose group as compared to the control group. One mid-dose female had a hepatocellular carcinoma and neoplastic nodules were found in one lov-dose female and in one mid-dose female. A control female ves diagnosed vlth hepatocellular carcinoma. A hepatic angiosarcoma vas found in ona male and tvo females of che cop-dose group, but r.o such tumors were encountered in any of the other groups. The number of animals bearing foci of cellular alteration in che liver was also statistically significantly increased In females of the mid-dose group as compared to controls. In addition, in females but not ir. males, the incidence of basophilic foci of cellular alteration in the liver vas statistically significantly higher in both the lov- and the mid-dose group chan in che control group. Details of che hiscopachological examination of liver are in Table VI-23. ~ ) "! 1 j I ~J ^ ~ There was no evidence of VCW-feeding affecting the incidence of abdominal mesotheliomas or the type and incidence of mammary gland tumors (Table VI-24). Ho Zymbal gland tumor was found. VI-36 SL 067203 r; '' |----- ' ' i------ r"-"" f " r Table Vl-23 Type and incidence rtf IlistopathologicaJ Changes in tlie IJvrr TyM ( changea'* Ihanbor of aalools tinliuf Inc Hence of change# Hales fenalea *CH/k| b.w.. fdmj VCH/kg b.w., /d*f 0 0.011 T? TT O.lf i.r 0 0 o.ou TT tt ion 66 100 O.lf T6 i./ * AT 0 1. foci of cellular alteration o. clear cell foci 1 anc or a few 11 several If 0 k. basophilic foci 1 one or a few 4 If aeeeral 0 c. alrtf cell foci one or a few 0 4. eosinophilic loci I one or a few I 6 0 f 0 1 1 6 16** 0 1* J * 00 ;f f1 4 0n n6 00 06 00 1 1 I)*** 1 0 0 6*** 0 fo* fh** 10f 4 0 6 4 n* 0 0 i 10* * f Total Huaber of focibearing snloala If If 16 If 15 10 s IT If i* Ml J n Ijaaa i** IT ff n* if*** f* SL 067204 Tfible Vl-23 - continued Type ( chanpea 2. HioplutJc nodule* , one k. a lew J. Hepatocellular carclnoaa 0 0 0 0 t, Anploaarcoae 0 1. Llwrr-cell polyaorphlaa a. allpfct k. aodcrate it 4 1 1. Trowleant elnueotdal cella a. eltpM 1 k. aoderate/narked 1 1. Cyata a, one k. a lew c. tnf 1 4 0 B. kite duct proliferation a. ellpM k. noderale Co ieverr 1) 9 1 1nc1 deuce of c he n re Ha lea fftilea 1 VCM/hp b.u,. /day 0.01? 0.1? 1 ./ 0* 0 VCH/kp k.v../day 0.01? 0.1? 1. ? 0 00 1 00 1 0 0 1 00 O 00 1* 0 1 0 00 1 00 0 1 9aa 0 0 i0 1 i0 0 i0 11 16 19 11** 46 41 4 ; 10* 1 14 11 1 i 1n1 1 1 i 0i 4 0 1 i 1. 0 i a 49 n la a ii* i) 4 9* * i 1 ia 1 i0 0 i 00 i i 4 i 4 i ii ii 0 0 00 i 4 4 ii II ? i** 9 14*** i 16 Ji 14 ii** i? 11 9 a ) i** 11 6 0 0 0i i 1 >6 IB 1 4* 10 1 1* 1 14 V I-3 8 SL l J L. j L .J ._____ I f l II V I-3 9 Table VI-23 - continued Type of change* 0 9. Cholaagloftbroala a. alight 11 b. madecote 1 10. Fertpartal flbraal* a. alight b. moderate 1 1 11. fertpart a I/centratabalar Infiltrate* af nanonuclear cell* a. alight b. moderate c. 11. Fact af OF.S-cel 1* accaalaaally accompanied 14 1 0 by a lew necratIc hepatacytea a. an* ar a few b. aeveral 11. Slight haemalopal atIc activity 10 i 1 Incidence of change! Male# Tern# VCH/hg b.w,. /day g VCM/hg b.w,,/dy 0.011 0.1/ 1.1 00 0.,017 0 .1/ 1.7 19* io* 11 14 11 1/ 4 0* 1 1 4 1 4 0 1 1 110 0 0 0 0 0 0 1 0 r* 0 Cl 0 1* 0* 1 0 10 a J 1 1 i 1 1 4 1 i 000 0 1 0 0 1 i 000 0 0 0 0 11 1/ 01 00 i 11 J9 /a 41 11* 14* 01 4 l i 0 ) 01 1 0 1 00 SL 067206 Table VI-23 - continued Tvpr of 14. Slagle cell aecroela a. alight It. Focal necroala a. alight I. node rate 11, Centrolobular llver-cell degrh* rat ion |7. One or a lew foci of degenerated hepalocple* If. Pelloala-1Ike chanpea 10. Soall gramtlooa 11. VacuolliatIon of hepatocytea aalnljr a. periportal 1 alight III arvere _______________________________ intldenro of thangea Halt*_________________________________tfllln VCH/kg h.v./day g VQI/kg b.v./dap 0 0.(11) 0.17 1.7 0 0 0.017 0.17 1.7 h 0 i i 1 0 4 l 1 1)** 5* * i i 0 00 i J 4 1 i n j* g 1 4* 4 4 6 4 l i i i 00 3 1 1 0 l i 0 0 10 ) 0 1 0 i i 1 ) 1 0 1 1 1 ft 0 i 0 7 } 0 1 1 0 ft 0 i 0 i 000 0 1 0 0 0 l 0 101 1 0 ft 0 (1 0 0 00 1 0 0 00 1 A ii* ] 4 14 71 If 4* 0 1 s* 0 0 1 1 4 ft 1 n 1 i 00 0 0 0 ft ft V I-4 0 SL 067207 i ; i ! ; L .. . , J L _J 1--J _J } L) fr f r ~i 1r Table VI-23 - continued Type of changed b. dllfuae t alight 11 Moderate 111 e*ere c. cantrolobolar 1 alight Incidence of change* Halve Feu It a a VCH/kg b.v. /dap LVCH/kg b.w ./dy 0 o.oi; o.j; 1.) 0 0 0 .011 0.1) 1 .) 0 1 0 1 00 0 0 000 1 0 1 0n j 0 000 0 l 0 0O 1 0 00 1 0 i 0 00 0 0 000 Specific hepatocellwlar lnlim* vee claaalflrd according to Siulrf and l.evltt (Ibli). F t O.Oi; * F <0.01; ** t <0,001, according to the Flaher*' enact teat (one tailed). Adapted fro Til et al. I9R3. V I-4 1 SL 6720fi Tnblc Vl-W Type and Incidence of Tumora of the Hnmmnry filandn nnd Incidences of Ahdonlnal Menothollonao Sit* and tjrp* l tuanur* Inclrtrnrr of ti Hale* Fra* l*a a vat/ba b *'- /<f*t aa VOt/ht b.w./dap 0 0.011 0.11 1.1 0 0 O.Olf 0.11 1.1 0 Nuabtr of anlaal* *aaala*d 99 99 99 49 100 90 100 9b 4R *98 Haaaarr aland* - Ko of tuMtir-b*rf<ta nlBl* 1. Adaiwa* i. lln|ll b. li 1. Intraductal papMJoa* }. Flbroadeaea* a. alngl* b. too c. aultfple 9A 00 00 00 01 00 00 1 0 1 41 M* 18* ii 10** 0 0 04 4 1 91 0 0 01 1 1 o0 0 0 00 0 0 10 0 0 0 19 10* 19 0 0 01 1 1 0 0 0) 1 1 |4 11** 14 11 V I-4 2 SL 067209 I______ J 1__ I r [------1 t;i f I"- 1i Table VI-24 - continued Stta r4 typa of tUMHO *. Fibrosa a, llD|lt b, two c, nltlflt 5. Adenocarclnoaa a. tingle b. two Incident* of tuooura ___________Malta___________________ __________ fcwlci___________ a| *CM/l| h.w./doy_________ _____ >1 *Q</1| b.w./day 0 o.on o.n i.i o 0___ o.m i 0.11 1.1 0 *6 00 00 1 0 1|4 I 11 I 0 00 0 0 no 0 0 0|0 0 o o 0i 1o o o 0 10 0 0 00 0 1 I0 1 0I bbdottr. I. Heaothtllooa 0 1 0 0 11 1 I * f < O.M; 1 < 0.01; ** r ( 0.001, according to t hr flahrra' enact teat (one tallrdl V I-4 3 Adapted fro* Til et al. 19ai. SL 067210 VII. HUMAH HEALTH EFFECTS A. Kon-Carclnogcnic Effects Vinyl chloride can produce a number of pathological consequences in humans in addition to its carcinogenic effect. These effects can be caused by 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 made before 1975 (Kancuso 1975). According to OSHA (3? Federal Register 12342, April 5, 1974), several facilities revealed vinyl chloride concentrations for some job classifications as high as 229 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. Nicholscr. 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 vere instituted. Ac 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 workers following acute exposures to vinyl chloride gas vere reported by Danziger in 1960. At autopsy, there was congestion of the liver, spleen and kidneys. In mother study reported by Suciu et al. (1975), exposure of workers to high . .ncentrations of vinyl VI I-i SL 067211 chloride produced euphoria, intoxication and narcosis. In this study, the investigators found a dose-response relationship for acute and subacute cases of "occupational disease" from air concentrations ranging fro 2,25? mg/m (about 900 ppm) to about 100 mg/m0 (about 40 ppm). In another investigation, Spirtas et al. (19~5) 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 (l.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 067212 plasticizer! 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 et 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 (Wilson et al. 1967, Dinman 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. 19~5, Suciu et al. 1975), these and other vinyl chloride-induced health effects are reviewed in the New fork Academy of Sciences report "Toxicity of Vinyl Chloride-Polyvinyl Chloride" (Sclikoff and Hammond 1975). Reproductive effects have also been noted. According to a study by Infanta (Infante 1976, Infant* et al. 1976a), the incidence of birth defects fcr three small communities in Ohio in vhich vinyl chloride polymerization plants are located was significantly higher (?<0.001) than that in either the counties in vhich these communities are located or the State of Ohio. Significant excesses were observed for clubfoot and defects of the central VII-3 SL 067213 nervous system, upper alimentary tract and genital organs. A follow-up study by Edmonds t 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 (?<0.G5) 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 and 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. Cycogenic 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 s lack of evidence f r 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 067214 Hansteen et al. (1978) and Anderson et 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 cytogenic effects in three groups of industrial workers: PVC polymerization workers (presumed high exposure), PVC processing workers (presumed low exposure) and rubber and tire manufacture workers (presumed negligible exposure). Actual vinyl chloride levels were not measured. Chromosome breakage in all three groups was 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 esneer 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 VII-5 SL 067215 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 tc vir.yi chloride and the development of this tuner. 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 polymerize!ion plant in Louisville, Kentucky, were described. The remaining portion cf this section describes some of the epidemiologic studies linking vinyl chloride with angiosarcoma and other types of cancer. Tabershav and Gaffey (19741 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 tc 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.ef, 75 percent of the expected rate compared to the general male U.5. 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 067216 4* expected in a comparable population) for malignant neoplasms increased with increasing exposure level and/or longer duration. In the group identified as the high exposure group, there were increases In liver cancer (primarily angiosarcoma), respiratory system cancer and brain cancer. These differences were not statistically significant. Dow Chemical Co. (Holder 1971) 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 tc 300 ppm TVa). Also included in the high group were workers normally exposed to 25 to 200 ppm 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. No 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. Mongos t al. (1975) conducted a proportional mortality study of workers from two vinyl chloride plants who died between 1947 and 1973, Death certificates were obtained for 142 of 161 workers (882) 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 VII-7 SL 067217 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 brain 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 to 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 death* was notad, a statistically significant factor. A statistically significant axcesa number of deaths occurred for brain and CMS caneer, respira tory system cancer, and biliary and liver cancer (Waxveiler et al. 1976). Ott et al. (1975) reexamined much of the mortality date reported by Tabershaw and Gaffey (1974) and included more clearly defined exposure levels VII-8 SL 067218 and follow-up of former company employees. The basic findings remain unchanged; no increase over expected in malignant neoplasms was found in the low exposure group (TWA from 10 to 100 ppm) and an increase in deaths due to malignant neoplasms was observed in the high exposure group (TWA of greater than 200 ppm). Chiazze et al. (1977) reported a cross-sectional mortality study of 4,341 employees from 17 PVC plants who died between 1964 and 1973. The exposed employee population was compared with the entire U.S. population, specific fer color and sex and adjusted for age. No 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 PVC fabricators, as an extension of their 1977 study, Chiazze et al. (1980) found no statistically significant relative risks for breast cancer in ?VC fabricators and concluded that very large increases in risk for breast car.cer 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 end 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 VII-9 067219 sb > , r r*- L ii L. f r i'__ ri i liver tumors was found, and two cases were diagnosed as angiosarcoma. The numbers of other tumors did not deviate significantly from expected. Ter. 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 rc be diagnosed in a single plant (Makk et al, 1976). As a result, Delcrme 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. lr workers engaged in the polymerization of vinyl chloride who were studied by Popper and Thomas (1975), the characteristic hepatic fibrosis was present ir. all cases of angiosarcoma. Although the relation of fibrotic lesions to the development of angiosarcoma requires further study, a transition from the fibrotic stage tc angiosarcoma is suggested by the focal proliferation of the sinusoidal lining cells and of the hepatocytes that are seen in the fibrotic stage, but which becomes even more pronounced in the initial stages of angiosarcoma development. These findings suggest thst the fibrotic lesions without angiosarcomes, 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 e longer latency period for tumor initiation based on a lower exposure level. The series of changes observed in the liver appear to vn-io SL 067220 represent a multi-centric development of angiosarcoma and are similar to the changes induced by Thorotrast and inorganic arsenicals (Berk et al. 1976). In the most recent update of the NIOSH register (Spirtas and Kaminaski 1978) a total of 64 cases of hepatic angiosarcoma have been identified worldwide among vinyl chloride-exposed industrial workers. A listing of all documented cases by country is presented in Table VII-1. The number of cases per year is depicted in Figure VII-1. Of the 64 cases, 23 have been reported in the United States. The authors reported that both the age at diagnosis and the latency period for cancer induction appear to be increasing. They 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 lover levels of occupational exposure, then the latent period for cancer induction as a result of these low levels of exposure may be longer than previously anticipated, i.e., it would be many years before the ultimate outcome of these exposures will be known. It has bean hypothesized that inhalation of low levels of vinyl chloride by the general public in the vicinity of vinyl chlorlde/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 York (excluding New York City). Exposures to arsenic, vinyl chloride or thorium dioxide were suggested as significant factors in the etiology of these tumors. VII-11 SI- 067221 V ii t: i^ Table VI1-1 Ang loss re emit of the Uver in Vinyl Clilorl!e/PVC Worker SL 067222 1 *9 *3 SB V I I - 12 Country Caae No. Birth Date lat VC of PVC Exposure Diagnoeia of Angioaarocna Canada Canada Canada Canada Canada Canada Canada Canada Canada Canada CtechoaUr/akla Crechca lerrakia Fed Rep Gorman/ fal Rap Onmany Fed Rap Onmaty Fad Rap Oansaiy Fad Rap Onmany Fad Rap Osnaiy Fed Rap Goman/ Fed Rap Genaany Fed Rep Oemany France Franca France Franca France Franca Franca Franca Great Britain Great Britain 01 00-00-00 00-00-00 01* 12-15-13 . 00-00-44 02* 03-06-14 I 00-00-43 ` 03* 08-26-19 < 00-00-41 04* 04-05-19 00-00-45 05* 05-07-11 :k 00-00-44 06* 12-15-19 ... 00-00-47 07* 11-09-19 - .00-00-46 08 05-13-20 : 00-00-6I 09 07-19-21 ' 00-00-46 10 05-16-15 . 00-00-53 01* 00-00-28 00-00-57 02* 00-00-26 00-00-51 01* 06-04-30 10-01-56 02* 07-26-31 10-14-57 04 09-04-30 04-16-57 05* 01-01-32 12-16-62 07* 09-29-26 04-15-54 08* 10-19-17 i 04-19-54 09* 12-13-34 . 12-02-59 10* 07-25-29 . 10-10-55 11* 12-29-36 , 01-02-61 01* 04-15-24 01-00-46 02 06-03-11 .. 07-06-59 03* 00-00-19 00-00-46 04* 01-27-27 10-19-49 05* 01-29-38 00-00-65 06* 04-14-34 ' 00-00-58 07 00-00-27 07-01-50 08* 04-01-34 05-23-57 01* 04-20-01 ", 00-00-44 03 06-02-37 V 02-00-66 00-00-00 00-00-55 00-00-57 00-00-62 00-00-67 00-00-68 00-00-71 00-00-72 00-00-73 00-00-74 00-00-76 00-00-73 00-00-66 09-19-60 09-25-70 00-00-74 00-00-75 00-00-75 00-00-75 06-16-76 06-28-77 00-00-77 02-18-67 01-08-75 01-00-75 01-04-76 04-00-76 09-00-76 07-00-76 12-03-76 12-00-72 12-00-74 Rtja at Diagnoala Years from lat Exposure to Dlagnals 00 -00 41 t. JM 43 - 14 42 *** . 21 40 22 57 24 51 24 53 26 53 12 53 28 61 - 23 46 16 40 15 30 12 39 : 13 44 17 43 13 49 21 50 22 42 17 47 22 41 16 43 21 63 15 55 29 49 26 38 11 42 18 49 26 42 19 71 20 37 09 Total Yeare of Exposure 00 11 14 20 22 05 23 25 05 26 14 16 15 12 12 17 12 12 21 15 22 10 19 12 29 26 10 17 23 19 22 04 Date of Daeth 06-29-76 09-02-55 12-21-55 02-22-62 01-21-68 07-05-68 04-10-71 12-24-72 06-12-73 09-04-74 04-00-77 00-00-74 00-00-66 01-25-69 12-14-71 11-25-74 01-09-75 11-13-75 12-25-75 Mlve 06-28-77 03-07-77 02-19-67 01-24-75 06-29-75 01-04-76 05-13-76 09-12-76 07-02-76 01-30-77 12-00-72 12-24-74 Table VI-1 - continued Country Caae Birth No. Date lat VC Of PVC Exposure Diagnosis of Angiosarcom Age at Dtagneia Yean Crae lat Exposure to Diagnosis * Total Yean of Italy Italy Japan Homey Sweden Sweden Sweden U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.S.A. U.8.A. U.S.A. U.S.A. U.6.A. U.S.A. U.S.A. U.8.A. U.S.A. U.S.A. U.S.A.' U.S.A. U.S.A. U.S.A. U.S.A. U.6.A. U.S.A. U.S.A. Yu9oelavla Yugoelavla 02* 03* 01 01* 01* 03* 04* 01* 02* 03* 04* 05* 06* 07* 00* 09* 10* 11* 12* 13* 16* 17* 10* 19* 20* 21* 22* 23* 24* 25* 01* 02* 11-13-29 00-00-57 12-13-72 03-14-20 00-00-53 07-10-75 00-01-22 04-00-53 08-21-74 12-23-15 03-00-50 . *12-20-71 06-23-27 00-14-51. 00-00-74 06-10-10 05-00-47 03-19-76 11-16-14 00-00-46 05-12-77 10-17-23 12-09-48 03-03-73 08-19-33 11-15-55 ** 05-00-70 05-25-15 11-28-45 12-19-73 01-15-24 07-06-52 00-19-67 01-25-12 06-19-44 04-09-64 11-23-28 01-17-62 02-00-74 05-03-22 08-27-44 00-00-60 05-06-20 10-07-46 00-00-61 11-08-31 05-20-45 03-01-74 08-16-13 06-12-51 05-00-68 ' 05-27-09 10-14-46 03-00-70 11-17-18 09-13-49 05-02-69 12-01-21 12-11-42 05-00-74 11-04-27 05-08-50 00-00-69 05-06-31 06-23-55 10-11-74 04-22-20 09-15-54 00-00-75 00-00-15 00-0043 06-19-75 00-31-17 00-00-55 01-30-76 09-02-09 12-00-46 00-00-77 10-02-23 07-11-47 01-00-76 00-00-23 09-00-50 04-06-73 05-07-17 00-00-39 05-27-77 08-07-10 02-00-47 03-10-77 04-05-14 00-00-53 04-00-73 11-15-31 00-00-50 07-12-73 Total Reported Casea 64 i rnfii Sniff HR Atilt K<IW * iir.i 1 k SL 0672, y t 43 55 52 56 43 65 62 49 37 58 43 52 46 45 41 43 55 61 50 52 41 43 46 60 58 67 52 50 60 67 59 42 L . ij L..J 15 22 22 22 19 31 ..*24 14 28 15 20 12 24 -15 29 17 23 20 32 19 19 21 32 21 30 29 15 30 30 20 23 ; ' r. ,->> . 06 21 22 21 18 21 31 21 13 20 15 20 12 17 13 24 17 23 19 26 04 19 : 11 22 10 21 20 14 26 20 20 10 Date of Death 12-00-72 07-10-75 10-26-75 01-06-72 10-20-70 03-19-76 05-12-77 03-03-73 09-28-71 12-19-73 01-07-68 04-09-64 07-24-75 03-23-68 08-29-61 03-00-75 05-10-66 ,03-16-70 05-02-69 07-06-74 03-27-69 Alive 11-02-75 064)6-76 01-30-77 01-02-77 12-06-16 04-06-73 05-27-77 03-10-77 04-08-73 07-12-73 L_. )<  f> > 94 - Figure VII-1 Number of Cases of Vinyl Chloride/PVC Related Angiosarcomas Reported NIOSH by Year of Diagnosis (Representing only 63 of the 64 Cases Knovr to NIOSH Since Information cn Diagnosis is Kissing for One Case Adapted from Spirtas and Kaminski 1978. VII-14 SL 067224 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 Batched controls. This may lend some support to the idea that "indirect modes of exposure, not specifically related to occupation, might be important in the etiology of this disorder" (Brady et al. 1971). 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 vith 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 PVC polymerization workers. IARC (1579) 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 SL 067225 VIII. MECHANISMS OF TOXICITY The mechanisms by which vinyl chloride causes non-carcinoger.ic injury are unknown. It is theorized that the toxicity of this compound is attributable to its enzymatic oxidation to reactive polar metabolites, possible chloroethylene oxide or chloroacetaldehyde (see Pharmacokinetics section). Ward et al. (1976) 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 which 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 ir. 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 oechaniso{s) by which 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 vith or VI11-1 SL 067226 * 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: genotoxic and epigenetic or nongenotoxic. The mechanism by which a compound causes its carcinogenic effect can 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 in 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 (Velsburger and Williams 1981). No single test system appears capable of identifying all carcinogens that are genotoxic. Therefor*, a number of scientists have proposed testing batteries such that the results from each test within th* battery, when evaluated in conjunction with th* others, will enable researchers to determine VIII-2 SL 067227 the mechanism of carcinogenicity of a particular compound. Vinyl chloride has not been systematically studied in any specific battery of tests, but has been evaluated in a number of test systems that have been proposed for inclusion ir. one or more batteries. Table vni-1 summarizes some of the mutagenicity studies on vinyl chloride which have demonstrated the chemical's genotoxic potential. The studies have beer, divided according to the three criteria for genotoxieity (Weisburger and Williams 1981) outlined above. Considering all of the data or. vinyl chloride, it is probable that vinyl chloride exerts its carcinogenicity through genotoxic mechanisms. VIII-3 SL 067228 Tabic V1I1-1 Result* of Vinyl Chloride Mutagenicity Studies * A. Asaey SVetMa HtfsrsMM In Vitro proltarvotie and edsrwtic iytw * HstjM,l<illy activated fialsrnalla tvthiniirijn yet* (Anas) 1+ BertsA at ml*, 1975 MoCann at *17, 1975 ZteiatkT, 1976 tamugat 1974 Gaxro at alT 1976. Itodherichis aali K12 etrmln + Grain at al., 1975 Tzatwiiut. .* * Gam cal la of Dio* tMIli v + Lcprieno at al, 1976, 1977 Varturgt and Vbgal, 1977 CMmm hastar V79 calls + Btiaamn at al., 1975 B. EKA Binding Studies tbiM tissues (brain, lung, liver, kidney, spleen, pancreas and teatas) in vitro + (Irreversible binding to WX and ENA) Bargnan, 1982 Rat liver mcroeone*, reconstituted cytoArar* P-450 system and isolated hnatocytas , + GuengeriA et al., 1981 (Irreversible binding to [retain and E*3A) Rat liver Bdorcaanas with StDPS (AUcylatim of raoO I*ib and Bolt, 1977 C. BlodMtniml cr biologic ameeougee of ENA denege Bene snrrcw cells at rats (in vivo) Anderson and Ridiardson, 1576 Bone narrow calls of Qiinaaa toasters (in vivo? Basler and Rehrtaom, 1960 Cultured peripheral lynpho- cytes in tosians (vinyl (Chiuiueotal Aloriito `YTM* workers) alxunraliti' PurAase et el., 1978 Purchase et al., 1975 Ducatnan et ml., 1975 VIII-A SL 067229  i> > APPENDIX 1 vn:t risk assessment to? :nyi The dare usee cc estimate a unit risk for oral exposure to vinyl chloride are based cr. the Percn ec al. (158:) study. The statistically significant increases reported for liver and lung tumors were considered biologically significant. Per the liver tuners, neoplastic ncdules were considered a progression toward hepatocellular carcinonas, 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 -2 1.3 x 1C for the males and from 5.8 x 1C to 1.3 for the females. The -1 -1 value of q* based on males was 3.C x 10 * for liver tumors and 2.9 x 10 based on all tumors combined. For the females the value of q* based cn liver tumors was 1.9 and for all tumors combined was 2.3. mg/kg/day. All units of q*A are per Before proceeding with the unit risk estimates an explanation of the total tumor counts in Tables 1 and 2 is necessary. Por the liver all animals with 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 ware not allowed to exceed one less than the number examined. The Al-1 SL 067230 Tabic 1 Type and Incidence of Statist leally Significant Treatment-Releated Changes in the Liver and Lung of Hale Wlstar Rats Exposed to VCH in the Diet. Values of q* and Concentration from Multistage Extrapolation Model Included A l-2 Treatment group (ng/kg/day) 0 1.7 5.0 14.1 Number of rata examinedC 55 58 56 59 Liver Neoplastic nodules 0 1 7 23 Hepatocellular carcinomas 0 1 2 8 Angiosarcomas d Total liver tumors 0 0 6 27 0 2 13 50 Lon* AngloBarcomas e Total animal with tumors 0 0 4 19 0 2 17 56 95X lower-limit concentrating < - associated with risk (ug/L) fmg/kg/day) io~4 io"5 I0~6 2.1 x io-1 8.8 x .o'2 1.3 x 10-1 3.0 x 10-` 1.1 x I0_l 2.9 x 10_I 16.7 39.8 27.0 11.7 1.7 4.0 2.7 1.2 0.2 0.4 0.3 0. 1 31.8 12.1 3.2 0. 3 1.2 0. 1 *Human equivalent q* " qj (a) (W /W ) iinn ((amg/kg/day)"1, "Concentration in ug/L (-35,000/q*) Infl-R). ^Eound dead or killed in extremis or terminally, sum of neoplastic nodules and liver angiosarcomas. Total must be at leaBt lean than total examiner r . t SL 067231 L. i Table 2 Type and Incidence of Statistically Significant Treatment-Related Changes in the Liver and Lung of Female Ulster Rats Exposed to VCH in the Diet. Values of q| and Concentration from Multistage Extrapolation Model Included Number of rate examined Liver Neoplastic nodules Hepatocellular carcinomas Angiosarcomas Total liver tumors*1 Lung Angiosarcomas Total animal with tumors Treatment group (mg/kg/day) 0 1.7 5.0 14. I 57 58 59 57 2 26 39 4A 0 A 19 29 002 9 2 26 A1 53 00 1 5 2 26 42 56 q* (mg/k1 g/day) -1 951 lover-limit concentrating associated with risk (ug/L) in'* JO"5 JO"6 1.3 5.0 x I0~1 8.8 x I0~2 1.9 5.8 x I0~2 2.3 2.7 70.0 39.8 1.8 0.3 0.7 A. 0 0.2 0.03 0.07 0. A 0.02 60. 3 J.5 6.0 0.2 0.6 0.02 *Human equivalent q* - q* (a) (W /W ) in (mg/kg/day) ^Concentration in pg/L - (-35,000/q)ln(l-R). *TFound dead or killed in extremis or terminally. aSu of neoplastic nodules nnd liver angiosarcomas. *Total must be at least less than total examined. SL 067232 *f result of this latter restriction was to raise the value of qf 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^)*^. The human weight (V, ) was assumed to be 70 kg; the male rats were estimated to weight 350 g and h 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 the male rats, and 0, 0.24, 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 95X upper limit on the largest linear term (Table 2) was: q* - 2.3 (mg/kg/day) To derive an estimate of the 95Z lower level of concentration, d, corresponding to a 95Z upper level of risk, 8, the following equation is used: where d is the lower limit on dose in mg/kg/day. To solve for d in ug/L, we use the transformation1 1 mg/kg/day x (70 kg/2 L) * 1,000 ug/mg 35,000 ug/L Al-4 SL 067233 4, f * 4' * * iOOr Duration of experiment, 8 The weight curves of the rats receiving 0, 1.7, 5.0 or 14.1 mg VCK/kg body weight/day from the 102 PVC diets fed for four hours each day all lie within the shaded area. Adapted from Feron et al. 1981. Figure 1 Average Body Weight* of the Extra Controls Fed the ft 102-PVC Diet Ad Libitum (-) and of the Rats Given 300 mg VCM/kg Body Weight in Oil by Cavage* Al-5 Si 6?234 4. r If v ICC R - 10 5 then d - (-35,000/q*) In (1-10-5) (ug/L). For chc highest value of q* - 2.3 (mg/kg/day) * (Table 2), setting R 10~^ yields a value of d 0,15 ug/L. Setting 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 the potency of vinyl chloride by the diet versus the inhalation routes. A previous memo ve sent you estimated the 95X upper limit of potency for VCM as q* 1.7 x 10 -2 (mg/kg/day) -1 based on an inhalation study shoving angiosarcomas and other tumors In rats. ThaC potency estimate vas derived for water quality criterion purposes. In chat document an inhalation to 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 breathing 20 m^/day would have yielded a 1 ppm inhaled 0.76 mg/kg/day relationship and a q* 5.2 x 10-2 mg/kg/day, still 44 times less than the estimate from the diet study. In summary, the VCM potency estimates are reported in Table 3. Al-6 SL 067235 Table 3 VCM Potency Estimates Route Potency q*(mg/kg/day) 1 95X lower Halt concentration associated with risk (ug/L) io"4 IO"5 io'6 Oral Based on diet study Based on Inhalation study Inhalation Based on Inhalation study 2.3 1.7 * 10~2 5.2 * 10-2 1.5 20* 0 67.3 0.15 20.0 0.015 2.0 6.7 0.7 Al-7 SL 067236