Document gDvNQmxg5EKqZX65O0xbEbGM3

DRAFT TECHNICAL SUPPORT DOCUMENT PR0P08ED IDENTIFICATION OF VINYL CHLORIDE AS A TOXIC AIR CONTAMINANT Part B Report State of California Air Resources Board Stationary Source Division July 1989 CMA 010334 Prepared by: California Department of Health Services Principal Editor: Norman Gravitz, Ph.D., MPH, Staff Toxicologist Reviewed by: George V. Alexeeff, Ph.D. Michael J. Lipsett, M.D. Douglas N. Cox, Ph.D. (California Public Health Foundation) Baaed in part on work submittted by: Carla C. Christensen and C. Tucker Helmes, Biological and Environmental Chemistry Department, SRI International, 333 Ravensvood Avenue, Menlo Park, California 94025, Under Contract 85-86676 (045A) and by: Deborah Grady, M.D., M.P.H. School of Medicine, University of California, San Francisco, and Allan Smith, M.D., PH.D. University of California, Berkeley CM* 010337 TABLE OF CONTENTS 1.0 EXECUTIVE SUMMARY 1.1 Vinyl Chloride Highlights 2.0 METABOLISM AND PHARMACOKINETICS 2.1 Summary 2.2 Absorption. Distribution, and Excretion 2.2.1 Inhalation Administration 2.2.2 Intragastric, Intraperitoneal, Intravenous, Dermal and Oral Administration 2.3 Metabolism 3.0 ACUTE TOXICITY 3.1 Summary 3.2 Acute Toxicity 4.0 SUBCHRONIC AND CHRONIC TOXICITY 4.1 Human 4.2 Animals 5.0 DEVELOPMENTAL AND REPRODUCTIVE EFFECTS 5.1 S.n--ary 5.2 Teratogenic Effects in Animals 5.2.1 Inhalation Studies 5.3 Reproductive Effects in Humans 1-5 2-1 2-1 2-2 2-2 2-9 2-12 3-1 3.^ 3-1 4-1 4.1 4.3 5-1 5-1 5-2 5-2 5-5 CMA 010338 i * 6.0 GENOTOXICITY 6.1 Sunnna-rv 6.2 Mutagenicitv 6.2.1 Bacterial Assays 6.2.2 Eukaryotic Systems 6.2.3 Cultured Mammalian Cell Assays 6.2.4 In Vivo Mutagenicity Assays 6.3 Chromosomal Damage 6.3.1 Dominant Lethal Tests 6.3.2 Chromosome Aberration/Sister Chromatid Exchange Studies 6.3.2.1 Experimental Studies 6.3.2.2 Human Observations 6.3.3 Micronucleus Tests 6.3.4 DMA Damage/Unscheduled DNA Synthesis (UDS) Tests 6.4 Mammalian Cell Transformation 7.0 CARCINOGENICITY 7.1 AnimalStudies 7.1.1 Suwucy 1.2 Intraperltoneal, Subcutaneous, and Transplacental Administration Pays 6-1 6-1 6-1 6-2 6-5 6-6 6-7 6-7 6-7 A 6-8 6-9 6-12 6-12 6-13 7-1 7-1 7-1 7-2 CMA 010339 ii 7.1.3 Oral Administration 7-2 7.1.3.1 Studies by Maltoni and Associates 7-2 7.1.3.2 Studies by Feron and Associates 7-3 7.1.3.3 Studies by Til and Associates 7-5 7.1.^ Inhalation Administration 7-9 7.1.4.1 S tudies in Rats 7-9 7.1.4.2 Studies in Mice 7-11 7.1.4.3 Studies on the Potential Effects of Age at Time of Exposure 7-14 7.1.4.4 Studies by Maltoni and Associates 7-20 7.2 Human Studies on the Carcinogenic Effects of Vinyl Chloride 7-31 7.2.1 Introduction 7-31 7.2.2 General Design of Epidemiologic Studies 7-31 7.2.3 Difficulties in Interpreting the Epidemiologic Evidence 7-32 7.2.4 Mortality Studies 7-35 7.2.5 Cancer Risks Associated with Exposure to Vinyl Chloride 7-47 7.2.5.1 Liver Cancer 7-47 7.2.5.2 Other Cancer* 7-50 7.2.5.2.1 Brain Cancer 7-50 7.2.5.2.2 Lung Cancer 7-51 7.2.5.2.3 Lymphoma 7-52 7.2.6 Exposure Information 7-52 7.2.7 Conclusions 7-55 iii CMA 010340 3.0 QUANTITATIVE CARCINOGENIC RISK ASSESSMENT 3.1 Introduction 3.2 Analysis of_Uata fromMaltoni et al. 3.3 Analysis of Data from Bi at al. 8-4 Analysis of Data fromDraw et al. 3.3 Human Studies 3.6 Choice of AppropriateRisk Estimates 9.0 CONCLUSIONS 9-1 ACUU TgXicitY 9-2 Subchronic and Chronic Toxicity 9.3 Pharmacokinetics 9.4 Reproductive Toxicity 9.5 Mutagenicity REFERENCES APPENDIX A: Abstracts of Maltoni et al. (1984) Bioassays APPENDIX B: Cancer Risk Assessment for Vinyl Chloride Based on Human Data APPENDIX 0& Using the Average Exposure Rate of a Cohort in Risk Assessment Analysis i & 8-1 8-1 8-3 3.5 8-6 3.7 8-8 9-1 9-1 -t 9-1 9-3 9-3 iv % CMA 01034 LIST OF TABLES 4.1 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 7.10 Subchronic and Chronic Toxicity of Vinyl Chloride Administered by Inhalation to Animals Incidence of Liver Tumors and Neoplastic Nodules in Wistar Rats Exposed Orally to Vinyl Chloride (Feron et al., 1981) Incidence of Lung Angiosarcomas, Abdominal Mesotheliomas, and Mammary Tumors in Wistar Rats Exposed Orally to Vinyl Chloride (Feron et al., 1981) Liver Tumor Incidence in Male and Female Wistar Rats Exposed to Vinyl Chloride by Oral Administration for 149 Weeks (Til et al., 1983) Tumor Incidence Following Vinyl Chloride Exposure in Female Rats, Hamsters and Mice From the Study of Drew et al. (1983) Experimental Protocol for Inhalation Studies (Maltoni et al., 1984) Tumors Correlated to Inhalation Exposure to Vinyl Chloride in Rats, Mice, and Hamsters in the BT Experiments Lowest Concentration at Which a Significant (p < 0.05) Excess of Tumors Was Reported by Maltoni and Associates in Inhalation Studies at Specific Sites in Sprague-Dawley Rats (Maltoni et al., 1984) Incidence of Liver Angiosarcomas (LAS) in Hale and Female Sprague-Dawley Rats Exposed for 52 Weeks to Vinyl Chloride (Maltoni ee al., 1984) Incidence of Mammary Gland Carcinomas in Female SpragueDWlay Rats and Swiss Mice Exposed by Inhalation to Vfxqrl Chloride (Maltoni et al., 1984) Incidence of Pulmonary Adenomas, Mammary Carcinomas, and Liver Angiosarcomas in Male and Female Swiss Mice Exposed to Vinyl Chloride by Inhalation (Experiment BT4) (Maltoni et al., 1984) Pass 4-4 7-6 7-7 7-10 7-18 7-23 7-25 7-26 7-27 7-29 7-30 V * CMA 010342 7.11 7-12 7-13 7-14 7-15 7-16 8-1 8-2 8-3 A Summary of Epidemiologic Data for Occupationally Exposed Vinyl Chloride Workers A Summary of Tumor Incidences and Standardized Mortality Ratios (SMR) for Occupationally Exposed Vinyl Chloride Workers A Summary of Epidemiologic Studies Which Examined Possible Correlations Between Occupational Vinyl Chloride Exposure and Primary Cancers of the Liver A Summary of Epidemiologic Studies Which Examined Possible Correlations Between Occupational Vinyl Chloride Exposure and Brain Cancer A Summary of Epidemiologic Studies Which Examined Possible Correlations Between Occupational Vinyl Chloride Exposure and Lung Cancer A Summary of Epidemiologic Studies Which Examined Possible Correlations Between Occupational Vinyl Chloride Exposure and Lymphoma Range of Cancer Potency Values for Vinyl Chloride Calculated from Animal Carcinogenicity Studies Range of Human Risks for Vinyl Chloride Exposure Estimated from Animal Carcinogenicity Studies Selected Human Risk Estimates for Lifetime Exposure to 1 ppb Vinyl Chloride 7-36 7-38 7-48 7-49 7-S3 7-54 8-12 8-13 8-14 * -- LIST OP FIGURES 2.1 Metabolism of Vinyl Chloride 2-14 vi GMA 010343 i iA i 1.0 Executive Summary Vinyl chloride is a short-chain halogenated hydrocarbon used predominantly in the manufacture of polyvinyl chloride and various packaging and construction products. Vinyl chloride has a very low degree of acute toxicity, with two-hour inhalation LD^Q values ranging from 27,419 ppm in mice to 236,215 ppm in rabbits and guinea pigs. Exposure to high concentrations can lead to narcosis, cardiovascular and respiratory irregularity, convulsions, cyanosis and death. Several human deaths have been attributed to occupational exposure to very high levels of vinyl chloride. Autopsies of these patients revealed congestion of the liver, spleen and kidneys. Acute toxicity symptoms are thought to occur above 100 ppm. Chronic exposure of workers to vinyl chloride has been shown to lead to "vinyl chloride disease", characterized by occupational acro-osteolysis, vasospasm of the hands similar to Raynaud's syndrome, dermatitis, circulatory and central nervous system alterations, thrombocytopenia, splenomegaly and changes in liver function. Eight symptoms commonly reported by workers exposed to vinyl chloride (including dizziness, headaches and nausea) were observed even at dose levels belov 50 ppm. Vinyl chloride has been shown to induce cancer in animals In utaro. but has not been shown to cause any other reproductive or 1-1 CMA 010344 }: ; : U in i <* developmental effects in rats, mice and rabbits. Epidemiologic studies of families of vinyl chloride workers or communities having vinyl chloride processing facilities suggested the possibility of an increased incidence of birth defects and spontaneous abortions among people at risk; however, subsequent reviews of these studies have concluded that thin__ La__ inadequate evidence to link environmental__ or paternal__ SXPQlurO__ to vinvl chloride with birth defects or spontaneous abortions in humans. The noncarcinogenic effects occur at concentrations near or above 10 ppm, which is greater chan four orders of magnitude ab ve possible general ambient levels in California (0.5 ppb). The noncarcinogenic effects also occur at concentrations greater than 3 orders of magnitude above the highest concentrations measured near landfills (10 ppb). Consequently, DHS staff do not expect noncarcinogenic__ adverse health__ effects__a__occur__from acute or chronic omoattroi to yloyl chloride in mblent, alL. Tho intemational Agency for Research on 'Cancer CIAKCK the United States Environmental ProtectionAgency (EPA) and the California --_a_ chemical for which__ thftU--il_ sufficient evidence--af carcinogenicity in both Chronic inhalation and oral exposures of rats, mice and hamsters t vinyl chloride have been associated with an increased incidence of malignant and benign tumors at several sites including the liver, lung, mammary gland and the nervous system. In humans, 1-2 CMA 010345 3 epidemiological studies of occupationally exposed workers have linked vinyl chloride exposure to development of a rare cancer, liver angiosarcoma, and have suggested a relationship between exposure and lung and brain cancers. Although pharmacokinetic studies in humans exposed to vinyl chloride are rare, limited evidence indicates chat, following Inhalation of low levels of vinyl chloride (3 to 24 ppm), up to 71% (with a mean value of 42%) of the given dose may be absorbed. Vinyl chloride absorption appears to depend on its metabolism, which is a dose-dependent, saturable process. Due to saturation*of Che enzyme systems responsible for the metabolism of vinyl chloride (cytochrome P-450 and alcohol dehydrogenase), exposur to concentrations above approximately 250 ppm will not necessarily lead to an increasing incidence of tumor development. Metabolism of vinyl chloride leads to formation of chloroethylene oxide and chloroaeetaldehyde, two reactive intermediates which undergo covalent binding to cellular macromoleeules and are thought to be responsible for the toxic effects of vinyl chloride. These and other metabolites may be further metabolized and excreted in the urine. Unmetabolized vinyl chloride is eliminated primarily in exhaled air. Vinyl chloride is mutagenic in both prokaryotic and eukaryotic test systems, with significantly greater genotoxicity seen after metabolic activation. DHS staff have found no evidence of a carcinogenic threshold level and because vinvl__ ghlPCidg--U 1-3 CMA 010346 * ____Ehl--staff recommends... .that vinvl chloride be considered as not having a threshold for carcinogenicity. Several animal carcinogenicity and human epidemiological studies of occupationally exposed workers have been analyzed for risk assessment purposes. Although actual exposure levels are not known, exposure estimates have bean used to evaluate the Waxweiler et al. (1976) study of vinyl chloride workers. Based on these estimates, DHS staff has calculated that a lifetime exposure to 0.483 ppb might result in an incremental individual cancer risk of 1 x 10(assuming liver, brain and lung cancer are all related to vinyl chloride exposure). This yields a risk estimate of 2.tx 10'Vppb. In che case that only liver cancer Is assumed to be linked to exposure, a lifetime exposure to 1.0 ppb may be expected to result in a risk of 1.0 x 10"^. Due to inadequate exposure data, follow-up time and other methodological problems, DHS staff suggest that the human risk estimates be used only for comparative purposes. Evaluation of animal experiments by the linearized multistage model yields a range of human risks spanning from 1.8 x 10'Vppb Co 3.9 x 10'Vppb, with most estimating a risk of between 1&-4 and 10-5/ppb. Evaluation of animal tumorigenicity data indicates that vinyl chloride's carcinogenic potency is dependent on sex, tumor site and age of exposure. Taking these factors into account, DHS staff believe that the human risk estimates are consistent with those obtained for laboratory animals. The staff of DHS recomsends that the animal data be used to evaluate the risks resulting from vinyl chloride exposure. Consequently, the 1-4 Cm 010347 range of risks--estimated from__ analyses of animal studies anH recommended by__ 2H3--Cor regulatory purposes lie between 3.9 y 10'6/ppb and 1.8 x 10~3/ppb. Vinyl chloride has not been detected in the ambient air of California (limit of detection >0.5 ppb) except at certain "hot spots". Air Resources Board (ARB) staff has monitored vinyl chloride emissions from the BKK hazardous waste site in Vest Covina and the Oil landfill in Monterey Park. Estimates of peak exposure concentrations for maximally exposed receptors range from 2 to 10 ppb at the BKK landfill and from 0.6 to 9 ppb at the Oil site. Air Resources Board staff has estimated that between 17,000 and 131,000 individuals may be exposed to 1 ppb at the BKK site. A lifetime exposure of 131,000 residents to 1 ppb would be associated with an upper bound estimate of 0.5 to 236 excess cancer cases. The calculations represent the upper range of plausible excess cancer risk: the actual risk, which cannot be calculated, may be insignificant. Based on the finding of vinyl chloride'induced carcinogenicity and the results of the risk assessment, DHS staff finds--that Vinyl__ chloride la an airLPollutant which may cause or contribute to an increase in mortality or an increase in serious iilnsst.__ or which may oose a present or potential Wyrd to human CMA 01034 % CMA 0103 uRftr i. vc DRAFT - - VinYi Chloride Highlights I. National and International Evaluation (Other Agencies' Evaluation) A. International Agency for Research on Cancer HARC) 1. Short-Term Testa: There__ ssUSS__ sufficient evidence of BUtagflniC--activity both with and without an exogenous metabolic, activation system. 2. Animal carcinogenicity bioassays: There exists sufficient evidence--of.animal_carclnogenlcltv bv oral administration or inhalation. 3. Human evidence: Ihltfi__ wtlti__ sufficient evidence of carcinogenicity to humans. Occupational exposure to vinyl chloride has been linked with development of angiosarcoma of the liver, and has been associated with tumors of the brain and lung and of the hematopoietic and lymphatic systems. Vlnvl chloride la grouped under IARC category 1. Mining that__ it `is causally associated with cancer in B. U.S. Environmental Protection Agency (EPA) 1. Short-Term Tests: Sufficient evidence of mutafenic activity exists both with and without__ an. 1-6 CM* 010350 b ivAf metabolic__ activation system. for both DNA damage and mutation. 2. Animal carcinogenicity bioassays: There exists sufficient evldmca---- of--animal--carcinogenicity bv administration orally or bv inhalation. 3. Hunan data: a nm.hr__ of__ epidemiological__ studies have linked vinvl chloride with angiosarcoma and other forma of neoplasms.___Sufficient--a.Yldlflfil exists to indicate that vlnvl chlnride is a human carcinogen bv inhalation. C. Conclusions: Both EFA and XARC have concluded there is ample evidence that vinyl chloride is genotoxic and is carcinogenic in both animals and humans. XI- Exposure Sources A. Air Levels 1. Ambient levels were monitored in the Los Angeles Basin area in 1983 and 1984 by the South Coast Air Quality Management District. All measurements were below their * limit of detection of 0.5 ppb. 2. Ambient levels measured in "hot spots" by ARB staff: Estimates for the maximally exposed receptors downwind from and adjacent to hazardous waste sites ranged from 010 ppb. 1-7 * Ill. Quantitative Risk Assessment A. Range of Extrapolation: Animal to human exposures in air for calculated lifetime daily exposure. 1. Experimental to ambient: Vinyl chloride has not been detected in ambient air, except at "hot spots". 2. Experimental to "hot spots": The lowest doses in the animal studies are approximately 10- to 20-fold higher than the highest residential exposures. B. Ranee of Risks: The human risks associated with a continuous, lifetime exposure to vinyl chloride have been estimated using the linearized multistage modal from both animal carcinogenicity bioassays and epidemiological studies of exposed workers. Unit risks for humans estimated from animal data range from 1.8 x 10' /ppb to 3.9 x 10 ^/ppb, depending on experimental exposure levels, tumor type observed, and sex, species, and age of animal evaluated. A unit risk of 2.1 x 10 Vppb for liver, lung, and brain cancer was derived from epidemiological studies for comparative purposes. 1-8 >10352 CHA draft tV 010353 .0 METABOLISM AND PHARMACOKINETICS draft 2.1 Summary Experimental evidence has suggested that vinyl chloride must undergo transformation to a reactive metabolite(s) by the liver to be toxic. Based on this information, the beat dose-response data would consider the amount of vinyl chloride actually absorbed and metabolized rather than the reported exposure or administered dose concentrations. Reports of the vinyl chloride metabolism in humans are sparse, but limited evidence indicates that, after inhalation exposure to low concentrations, up to 71% (average - 42%) of a given dose was absorbed (Krajewski et al., 1980). Based on this study it is assumed that 71% of an inhaled vinyl chloride exposure may be absorbed by humans at ambient concentrations. Unmetabolized vinyl chloride is eliminated primarily via the lungs. Unlike in other species, absorption of vinyl chloride at the doses tested was not concentration-dependent in humans. Data from rodent studies suggest that the absorption of vinyl chloride depends on its rate of metabolism and the expent of metabolic saturation. Studies in rats and a single experiment in monkeys indicate chat the metabolic pathways of vinyl chloride become saturated at exposure concentrations between 100 and 300 ppm. Metabolism of vinyl chloride involves the cytochrome P-450 mixedfunction oxidase system. The first step is thought to be epoxidation of the double bond to form the reactive epoxide 2-1 CMA 010354 DRAFT chloroethylene oxide, vhich may undergo a number of further reactions, including binding to cellular macromolecules. Intramolecular rearrangement of the chlorine atom may also occur, resulting in the formation of chloroacetaldehyde, another reactive intermediate. In addition, alcohol dehydrogenase has a role in vinyl chloride biotransformation, since inhibitors of this enzyme can significantly reduce the amount of vinyl chloride metabolized. Section 2.3 of this report provides a detailed discussion of vinyl chloride metabolism. Absorption. Distribution and Excretion Inhalation The pharmacokinetics of vinyl chloride following inhalation has been studied in multiple species of experimental animals. The uptake of vinyl chloride at higher doses appears to depend on its metabolism. The metabolic breakdown of vinyl chloride in rats and monkeys (and perhaps in other species) is a dose-dependent, saturable process (Buchter et al., 1980, Filser and Bolt, 1979). Substantial species differences have been observed in the rates of v$syl chloride clearance, with first-order metabolic clearance rates (in liters/hour/kg body weight) for the elimination of vinyl chloride decreasing in the order of mouse (25.6) > gerbll (12.5) > Ulster rat (11.0) > Rhesus monkey (3.55) > rabbit (2.74) > human (2.02) (Buchter et al., 1980). 2-2 CMA 010355 Results rom inhalation exposure studies in humans, monkeys, and rats using direct and indirect test methods indicate chat vinyl chloride is rapidly absorbed and mecabolized, quickly distributed throughout the body, and excreted by the kidneys. Unmetabolized vinyl chloride is expired by the lungs and, to a limited extent, expelled in the feces. Several limited studies have been conducted in humans measuring vinyl chloride absorption following inhalation exposure. Krajewski et al. (1980) observed that five male volunteers exposed to 3, 6, 12, or 24 ppm vinyl chloride for six hours by a "face only" chamber absorbed an average of 42% of the dose regardless of concentration. Large interindividual variation in the degree of vinyl chloride retention was observed, with one individual retaining 71% of the dose at the time exposure was terminated; no other individual retained greater than 45%. This indicates a possible large range of interindividual variability. Concentration of vinyl chloride in expired air, measured for 90 minutes after cessation of exposure, decreased to negligible amounts after only 30 minutes post exposure. The quantity of unmetabolized vinyl chloride exhaled was considered negligible and constituted roughly 4% of the inhalation concentration of vinyl chloride to which subjects were exposed (Krajewski et al., 1980). Thus, humans metabolized up to 96% of the absorbed vinyl chloride dose. Buchter et al. (1978) reported that humans exposed to 2.5 ppm vinyl chloride retained 26-28% of the administered dose (Krajewski et 2-3 CHA 01035* ft DRAFT al., 1980). Substantial interindividual differences were reported in this study. These differences appear due to differences in the adipose tissue mass among individuals, although this hypothesis has not been confirmed in follow-up studies (Buchcer, 1979: Buchter et al., 1978; Bolt et al., 1981). Pulmonary absorption of vinyl chloride by rats occurs rapidly. Blood levels of vinyl chloride increase with the dose. Blood concentrations quickly decline after cessation of exposure; unmetabolized vinyl chloride is exhaled (Vithey, 1976; Hefner et al., 1975a; 1975b; 1975c). % Evidence from both whole animal and "nose-only" inhalation studies in rats indicates chat the race of pulmonary uptake of vinyl chloride in a closed system is partially dependent on the extent of metabolism (Bolt et al., 1977; Hefner et al., 1975a; 1975b; Vithey, 1976). In the "nose-only" exposure system used by Hefner et al. (1975a), pretreataent of rats with either pyrazole (a non-specific inhibitor of alcohol dehydrogenase) or 95% ethanol significantly reduced both the uptake .(as calculated from the disappearance of vinyl chloride from the exposure chamber) and metabolism of vinyl olilorlde. This held true for both exposure levels. Pyra2olepretreated rats were exposed to either 65 or 1234 ppm, while ethanol-precreated rats were exposed to 56 or 1034 ppm. Several groups of investigators have presented additional data concerning the uptake, metabolism and disposition of vinyl chloride 2-4 CMA 010357 DRAFT following inhalation exposure (Bolt et al., 1976; 1977; Hefner et al., 1975a; 1975b; Buchter et al., 1977). In an investigation into 14 the disposition of C-vinyl chloride, Bolt and co-workers (1976) exposed male Wistar rats to initial concentrations of "less than 100 ppm" vinyl chloride (apparent range 1-50 ppm) in a closed system for six hours. The half-life for vinyl chloride disappearance from the chamber was about 68 minutes. From this study, the authors estimated that approximately 40% of the inspired vinyl chloride was absorbed by the lungs (Bolt et al., 1976). Pulmonary uptake of vinyl chloride by rats was completely blocked following pretreatment with the cytochrome P-450 inhibitors 6nitro-l,2,3-benzothiadiazole or 3-bromophenyl-4(5)-imidazole (Belt et al., 1976). Uptake of vinyl chloride appeared to be linked-to its metabolism, since 24 hours after pretreatment with the relatively short-lived P-450 inhibitor 3-bromophenyl-4(5)-imidazole the uptake of vinyl chloride had returned to control levels. Following exposure, the liver and kidney contained the highest levels of vinyl chloride metabolites (Bolt et al., 1976). In an attempt to determine the exact minimal concentration of vinyl chloride in air necessary .to achieve metabolic saturation. Bolt et al. (1977) exposed groups of rats to a wide range of vinyl chloride concentrations and showed chat saturation occurred at 250 ppm. First-order kinetics occurred at exposures less than 250 ppm, while zero-order kinetics predominated at higher exposures. Hefner and colleagues (1975a; 1975b) exposed male Sprague-Dawley rata to initial vinyl chloride concentrations ranging from 50 to 2-5 * CMA 010358 DRAFT 1,167 ppm in a closed nose-only inhalation system. The rate of uptake of vinyl chloride by the animals (as calculated from the rate of disappearance of vinyl chloride from the chamber atmosphere) was approximately three times greater for doses less than 103 ppm (range 30 to 105 ppm) chan for doses greater chan 220 ppm (range 220 to 1,167 ppm). After an initial equilibration period and regardless of the administered concentration, vinyl chloride disappearance from the chamber apparently followed firstorder kinetics. The half-life for atmospheric vinyl chloride at concentrations below 100 ppm was 86 minutes compared with 261 minutes for concentrations greater than 220 ppm. Hefner et al. (1975b) concluded that the predominant pathway for metabolisitffof vinyl chloride by rats exposed to 100 ppm or less is saturabl , and that this metabolism vas due primarily to alcohol dehydrogenase (based on the inhibitor studies with pyrazole and ethanol). Studies in rats and monkeys suggest that, after absorption, vinyl chloride is rapidly distributed to all tissues reached by the bloodstream (Duprat at al., 1977; Buehter et al., 1980). Lipids or lipoproteins, rather than proteins, transport vinyl chloride in the blood (Bole et al., 1977). Studios of the distribution of 14CCdbeled vinyl chloride in rats indicated that, immediately after Inhalation administration, the liver (predominant site of metabolism) and the kidneys (site of excretion of p lar metabolites) contained the highest concentrations of 14C activity, followed by lungs, spleen, and small intestine (Watanabe et al., 1976a; Bolt at al., 1976). However, C counts quickly decreased 2-6 CMA 010359 after cessation of exposure. DRAFT In one study, vinyl chloride metabolite concentrations decreased significantly in these tissues 48 hours after a single inhalation exposure (50 ppm for five hours) compared to measurements made immediately after exposure ended (Bolt et al., 1976), Watanabe and co-workers (1976a) also examined the fate of l4C-vinyl chloride following inhalation exposure in rats. Male SpragueDawley rats were exposed to 10 or 1,000 ppm vinyl chloride in whole-body metabolism cages for six hours and ware observed for an additional 72 hours. After exposure to 10 ppm vinyl chloside, urinary radioactivity accounted for 68%, expired vinyl chloridau for 2%, expired CO^ for 12%, feces for 4%, and carcass and tissues^ for 14%, respectively, of the recovered radioactivity. After exposure to 1,000 ppm, urinary radioactivity accounted for 56%, expired vinyl chloride for 12%, expired COj for 12%, feces for 4%, and carcass and tissues for 15% of the recovered radioactivity. The patterns of pulmonary elimination of unmetabolized vinyl chloride following exposure to 10 or 1,000 ppm were similar and could be described by first-order kinetics, with half-lives of 20.4 and 22.4 minutes, respectively. A corresponding biphaslc elimination of urinary radioactivity following inhalation exposure to 10 or 1,000 ppm vinyl chloride was observed; the half-lives for the initial phase were 276 and 246 minutes, respectively. The liver and skin contained the highest concentrations of radioactivity 72 hours after exposure to either dose. The authors concluded that since "the race of elimination of vinyl chloride par se from the lungs or 2-7 CNA 010360 DRAFT 14 C activity in the urine was not different in rats exposed to 10 or 1000 ppm," the dose-dependent fate (the relative amount of vinyl chloride excreted by the two different routes) was not attributable to saturation of the excretion pathways. The results are in agreement with the hypothesis that the metabolism of vinyl chloride becomes saturated at high exposure levels (Watanabe et al., 1976a). The pharmacokinetics of inhaled vinyl chloride in a closed system has also been examined in Rhesus monkeys (Buchter et al., 1980). Uptake of vinyl chloride appeared to depend on its metabolism and to be a dose-dependent, saturable process. When monkeys were exposed to concentrations up to 200-300 ppm in a closed system, vinyl chloride disappearance from the chamber followed apparent first-order kinetics. At higher exposure levels (up to 800 ppm), zero-order kinetics were observed, implying metabolic saturation. The first-order clearance rate was 3.55 liters/hour/kg. The clearance rate fell by 90% after pretreatment with the alcohol dehydrogenase inhibitor disulfiram (Buchter et al., 1980). Thus, alcohol dehydrogenase appears to have a role in vinyl chloride metabolism along with cytochrome F-430. Umr microsomal enzyme activities and macromolecular covalent binding in rats following either single or repeated exposures to vinyl chloride were compared by Watanabe et al, (1978a). One group of rats was exposed by inhalation to 5,000 ppm nonlabeled vinyl chloride 6 hours/day, 5 days/week for 7 weeks, and then exposed to 14 14 C-vinyl chloride on the last day. The fate of the C-vinyl 2-8 CMA 01031 chloride from these rats was compared with a separate group exposed 14 for a single 6 hour period to 5,000 ppm of C-vinyl chloride. The activities of aniline hydroxylase and p-nitroanisole O-demethylase were the same in rats exposed once or repeatedly or in unexposed control rats. Covalent binding to hepatic macromolecules was greater in rats repeatedly exposed as compared to those given a single exposure. Watanabe et al. (1978a) concluded that this "Increase in hepatic macromolecular binding indicates that repeated exposure augments the reaction of electrophilic metabolites with macromolecules, and this may be expected to enhance potential toxicity, including carcinogenicity". Chronic exposure (28,000 ppm, seven hours/day, five days/veek for 2, 4 or 6 weeks) was found to increase glutathione reductase activity, glutathione-S-epoxide transferase activity, glutathioneS-aralkyl transferase activities, and glutathione levels in rat liver and to depress cytochrome P-450 levels (Du et al., 1982). This suggests that a reactive metabolite of vinyl chloride can destroy cytochrome P-450 and disrupt several enzymes that may effect its chronic toxicity. 2.2.2 tntraxastric. Intraaeritoneal Intravenous. Dermal. and Oral Administration Uptake and absorption of vinyl chloride administered by intragastrie (IG), intraperitoneal (IP) and intravenous (IV) administration follows the patterns observed in inhalation studies. 2-9 CMA 0103A2 ft DRAFT I; appears from these studies chat the quantity of vinyl chloride metabolized by these routes is dependent on the quanti tv administered. Green and Hathway (1975) examined the excretion pattern of single doses of 0.25 and 450 mg/kg of radiolabeled l4C-vinyl chloride administered to rats by the IG, IP, and IV routes. More chan 904 of the administered dose was excreted within the first 24 hours. Exhalation of unmetabolized vinyl chloride is the predominant route of excretion for each route of exposure at the high dose and for the low-dose intravenous exposure. After IG administration of the high dose, more chan 90% of the dose was exhaled as unmetabolixed vinyl chloride and less chan 1% as CO^* while 5% of the administered radioactivity was found in the urine. At the low dose, urinary excretion accounted for 72% of the dose, unchanged exhaled vinyl chloride for 4% of the dose, and COj for 13% of the dose. About 100 times more vinyl chloride was metabolized at the higher dose level than at the lower dose (an 1,800-fold difference in dose). These observations suggest that the metabolism of vinyl chloride Is saturable by administration of a single dose. In another experiment, chronic IG dosing with unlabeled vinyl chloride tt 3, 30, or 300 mg/kg daily for 60 days did not affect the rate or route of elimination of a single dose of radiolabeled vinyl chloride from the body. Based on these results, the authors suggested that vinyl chloride excretion data for a single dose may also apply for chronic exposure to vinyl chloride. 2-10 CMA 0103d: DRAFT Watanab and associates (1976b) examined the excretion of Re labeled vinyl chloride following single oral doses of vinyl chloride in rats. Their results were similar to chose of Green and Hathway (1975). After administration of a single oral dose of 0.05, 1, or 100 mg/kg of 14C-vinyl chloride to male rats, urinary metabolites accounted for 68, 59, and 11%, respectively, of the administered dose while the 14CO^ in expired air accounted for 9, 13, and 3%, respectively. Pulmonary elimination of unmetabolized vinyl chloride represented only 1 to 3% at the lower dose levels, but 67% at the higher dose level. Pulmonary clearance of the 0.05 and 1 mg/kg doses was monophasic, with half-lives of 53.3 and 57.8 minutes, respectively. Clearance of the 100 mg/kg dose was biphasic, with half-lives of 14.4 and 40.8 minutes for the fast and slow phases, respectively. Absorption of vinyl chloride after oral administration has been measured in rats, both in diet studies (Feron et al., 1981) and gavage studies (Withay, 1978; Watanabe, 1976b). In these reports, almost 100% of the administered dose was absorbed, suggesting extensive gastrointestinal uptake of vinyl chloride. Maximum blood concentrations of vinyl chloride were observed within 10-20 minutes following dosing with aqueous or vegetable oil solutions (dose range 12.5-28.2 mg per rat (Withey, 1976). Green end Hathway (1975) observed absorption of 98.7% from the gastrointestinal tract following an oral dose of 450 mg/kg. 2-11 CHA 010364 DRAF Limited percutaneous absorption (0.03% of dose) following whole body exposure (excluding the head) to either 800 or 7000 ppm of vinyl chloride has been demonstrated in monkeys (Hefner et al., 1975c). The usefulness of this study is limited, however, since only one monkey was exposed at each dose level. Exposure times were limited to 2.5 hours for the 800 ppm group and 2 hours for the 7000 ppm group. The majority of the absorbed vinyl chloride was eliminated in the expired air (Hefner et al., 1975c). 2.3 Metabolism Two main routes have been proposed for the metabolism of vinyl chloride. The first involves both microsomal and nonmicrosomal enzymes and results in the conversion of vinyl chloride to 2chloroethanol and subsequent oxidation to 2-chloroacetaldahyde and monochloroacetic acid. This pathway is believed to operate at low doses ( 100 ppm) and is saturable. It leads to the production of polar metabolites, which are predominantly excreted in the urine. The initial studies of Hefner and colleagues (Hefner et al., 1975a; 1975b), discussed in Section 2.2, provide evidence for the role of alcohol dehydrogenase in the metabolism of vinyl chloride. Following exposure of Sprague-Dawley rats to low concentrations (< 200 ppm), vinyl chloride was metabolized to 2-chloroethanol, chloroacetaldahyde, and monochloroacetic acid by an alcohol dehydrogenase (ADH)-mediated pathway. Fretreatment of rats with pyrazole (an ADH inhibitor) or 95% ethanol significantly reduced 2-12 CMA 0103A5 both che uptake and metabolism of inhaled vinyl chloride (Hefner et al., 1975a). The second proposed pathway involves only microsomal enzymes and is believed to result in the formation of chloroethylene oxide, which may then spontaneously rearrange to fora 2-chloroacetaldehyde and, subsequently, monochloroacetic acid (Kilbey, 1981). The epoxide, chloroacetaldehyde, and monochloroacetic acid can then undergo conjugation with glutathione. Further metabolism of these glutathione conjugates can produce a number of compounds, some of which have been identified in the urine of animals treated with vinyl chloride (Figure 2.1). Specifically, monochloroacetic acid, S-(carboxymethyl)cysteine, N-acetyl-S-(2-hydroxyethyl) cysteine, Nacetyl-vinylcysteine, and thiodiglycolic acid have been found in the urine of rats exposed to vinyl chloride by the Inhalation and oral routes (Green and Hathvay, 1975; 1977; tfatanabe et al., 1976a; 1976b). Thiodiglycolic acid and chloroacetic acid have be n detected in the urine of workers exposed to atmospheric vinyl chloride (Muller et al., 1978; Heger et al., 1982). The generation of CO2 from vinyl chloride, has been postulated to occur through the tricarboxylic acid cycle or the one- or two-carbon pools, with <&loroacatlc acid or chloroethylene glycol as the starting intazmadiate (Voo et al., 1985). Seudies by Bolt and co-workers (1976) indicate chat the cytochrome P-450 system is involved in vinyl chloride metabolism. Their results demonstrated chat the uptake of 50 ppm vinyl chloride in a 2-13 CMA 0103dd Figure 2.1 Metabolism of Vinyl Chloride Cll2-CHCi ilxed-fonctlon% oxidases ll2C CHC l \/ vinyl chloride chloroethylcneoxide* ->ck:h2-cho aldehyde dehydrogennne chloro.n etaldehyde^ aldehyde oxidase xanthine oxidase (;ich2-cixhi l iiinnoclilurnt i'I li .n- Id 4 CSli I C-S-CIl -COOlt r\j cya-S-Oij-CHjOH <---------- - i-fk* 2 S-(2-hydroxyethyl)cysteine v H-Ac-cya-S-CMjj-CHjOH H-acetyl-S-(2-hydroxyethyl)cyatelne* S-foray1methyl- Iglutathione cys-S-CHj-CUQ <~ S-formylmetliylcyatelne S-carboxymethyl glut a th ione cy;.-S-CII -nii>U S-carboxyme thy Icy si * I ik ' (transamlnation) '---------LU 1(oxidative decarhoxylatInnj HOOC-Cllj-S-CII -(.OOII CMA 0 1 0 3 6 7 Source: IARC (1979) 1 Detected U vivo 2 Detected In vitro I CM! => c> 1 utaHi fr>nr ' `/i? - , kv./f + lliiodiglyt. o| ii .n nl* (thlodl fleet it: ,ir i i i ~n H cLosea system was completely blocked by inhibitors of cytochrome P- <*50, such as 3-bromophenyl-4(5)-imidazole or 6-nitro-1,2,3- benzothiodiazole. Pretreatment with the insecticide dichlorodiphenyl trichloroethane (DDT), an inducer of cytochrome P- 450, was effective in enhancing uptake and absorption. However, phenobarbital, another P-450 inducer, has shown no effect on vinyl chloride metabolism (Guengerich and tfatanabe, 1979), possibly due to selective induction of different cytochrome P-450 isozymes by the two compounds. Chronic ethanol treatment has been shown to potentiate the carcinogenic effect of vinyl chloride in male Sprague-Dawley rats (Radika et al., 1981). Animals were exposed by inhalation to 600 ppm vinyl chloride four hours/day, five days/week, for one year. Ingestion of 5% ethanol in water (volume/volume, v/v) $4 libitum was begun four weeks prior to vinyl chloride exposure and continued for life or until the termination of the experiment, 2.5 years after the first vinyl chloride exposure and 1.5 years after vinyl chloride exposure was terminated. The incidence of liver angiosarcoma in rats exposed to vinyl chloride and ethanol was 50% (40/80) versus 23% (18/80) in rats exposed to vinyl chloride alone and 0% (0/80) in animals created only with ethanol. Radike and associates have suggested that this potentiation of tumor formation may be due to the effect of alcohol on vinyl chlorid metabolism and a shared step in the oxidation of ethanol and vinyl chloride. The acetaldehyde product in ethanol metabolism may compete with chloroacetaldehyde for ADH. This would result in 2-15 CMA 010368 DRAFT higher levels of chloroacecaldehyde. Hovever, this metabolite may not be the ultimate carcinogen. Chloroacecaldehyde buildup may result in a decrease in epoxide-to-aldehyde conversion, leading to epoxide buildup and increased interaction with cellular macromolecules, Radiolabeled vinyl chloride has been shown to bind covalently to cellular macromoleeules in vivo and vitro (Watanabe at al. , 1978b; Woo et al., 1985; International Agency for Research on Cancer [IARC] 1979). Watanabe ec al. (1978b) exposed rats to C- vinyl chloride (range 1-5000 ppm) for six hours, and measured v covalent binding of radioactivity to hepatic macromolecules, JLMA and DMA, along with levels of hepatic glutathione. Binding, of vinyl chloride metabolites to liver macromolecules did not increase proportionately with dose, but was instead related to the total amount of vinyl chloride metabolized. Binding appeared to plateau above 500 ppm, while below 100 ppm binding was approximately proportional to the increase in exposure. Depression of hepatic glutathione occurred only at exposure levels of 100 ppm or higher. Covalent binding to RNA or DNA was not detected for any exposure grsup^ (Watanabe et al., 1978b). However, a subsequent study found 4^faemlantly bound vinyl chloride metabolites attached to proteins and nucleic acids isolated from the livers of rats exposed to either 10 or 250 ppm vinyl chloride for two hours. (Guengerich and Watanaba, 1979). Rat liver DNA isolated from the two groups of exposed animels contained 0.04 and 0.9 pg of total bound metabolitas per gram of wat liver, respectively. Pretreatment with 2-16 CMA 010349 phenobarbital had no apparent effect on metabolism or DNA-binding of metabolites, but did increase binding to protein and RNA at the 10-ppm dose level. la vitro binding of l*C-vinyl chloride to proteins and nucleic acids appeared to be dependent on the thiol content of the proteins and the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH), oxygen, and microsomal enzymes (Guengerich and Watanabe, 1979). Both chloroethylene oxide and chloroaeetaldehyde have been studied as possible reactive intermediates that could act as the "ultimate* mutagen or carcinogen formed from vinyl chloride. The epoxidsd is -| considered to be the most biologically active metabolite (Bareseh et al., 1975; Laib and Bolt, 1977). Other researchers have proposed that chloroaeetaldehyde may be a more effective alkylating agent (Woo et al., 1985). In vivo and in vitro studies by Guengerich and Watanabe (1979) suggest that the mechanism for activation and binding of vinyl chloride Involves the release of the chloride atoms as chloride ions, either in the actual activation mechanism or in rearrangment of the metabolite or adduct. However, Guengerich and Strickland (1977) have demonstrated that neither chloroethylene oxide or 2-chloroaeetaldehyde appear to her the vinyl chloride metabolite responsible for destruction the heme group of cytochrome P-450, and chat other mechanisms (or reactive metabolites) may account for this. 2-17 CMA 010370 DRAFT CMA 010371 3.0 ACUTE TOXICITY DRAF'i The toxic effaces of acuta exposur# to vinyl chloride have been reported by several investigators (Selikoff and Hammond, 1975; Torkelson and Rowe, 1981; EPA, 1984). Relevant findings are summarized below. 3.1 Summery The acute effects of vinyl chloride are similar for humans and animals: central nervous system depression (anesthesia) and cardiac, circulatory, and respiratory irregularities. Frostbite from contact of skin with liquid vinyl chloride has been reported. Repeated inhalacional exposure of humans to high concentrations of vinyl chloride has been associated with narcosis, damage to the liver, spleen, and circulatory system, and a complex of symptoms identified as occupational acro-osteolysis. With the exception of aeroosteolysis, the occurrence of these toxic symptoms has also been confirmed in experimental animals. The exact occupational exposure levels associated with these symptoms are not known, but arm thought to be above 100 ppm. 3.2 Acute Toxlcitv The doses causing 50% lethality (LD^q) in groups of animals exposed to vinyl chloride by inhalation for two hours has been reported to 3-1 * CMA 010372 DRAFT be 27,419 ppm in mice, 47,640 ppm in rats, 236,215 ppm in guinea pigs, and 263,215 ppm in rabbits, indicating a very low order of acute toxicity. Toxic symptoms following exposure included narcosis accompanied by respiratory and circulatory disturbances. Death was caused by respiratory failure. Microscopic examination of all animals indicated damage to the lungs, liver, and kidneys (Prodan et al., 1975a). Several human deaths following very high exposure (concentrations unreported) to vinyl chloride have been reported. Autopsies revealed congestion of the liver, spleen, and kidneys (Danziger, 1960, cited in Maltoni et al., 1984). Lester and co-workers (1963) estimated that the short-term (five minutes) exposure limit (STEL) of vinyl chloride to which a human could be exposed without symptoms of acute toxicity vas between 8,000 and 13,000 ppm. Suciu et al. (1975) reported that workers exposed to vinyl chloride (levels not given) experienced euphoria, intoxication, and narcosis. They also reported generalized transient contact dermatitis after dermal exposure. 3-2 CMA 010373 4.0 5UBCHROMIC AND CHRONIC TOXICITY DRAFi Several studies on the toxic effects resulting from subchronic and chronic exposure to vinyl chloride have been published (Selikoff and Hammond, 1975; Torkelson and Rowe, 1981; EPA, 1984). The relevant findings are summarized below. 4.1 Human Reports on the adverse effects of repeated occupational exposure to vinyl chloride are based mainly on the observations of workers who have been the most heavily exposed. These individuals were involved in occupations such as cleaning autoclaves and centrifuges, or engaged in drying and shifting processes. They experienced a wide range of symptoms; a vasospastic disorder in Che hands similar to Raynaud's syndrome; occupational aero* osteolysis, which Included clubbing*like swellings and loss of bone from the terminal phalanges, scleroderma-like skin changes, and dermatitis; acrocyanosis, consisting of vascular changes and impaired thermoregulation; positive cold test reactions; capillaroscopic alterations; paresthesias; and central nervous .i' system' symptoms. These clinical symptoms (classified as "vinyl chloride disease") ware accompanied by circulatory disturbances, thrombocytopenia, splenomegaly, and changes in the liver. The period of exposure before the first sign of symptoms was as short as one month to as long as three years. A year or two after removal from exposure, most of the abnormalities disappeared 4-1 CMA 010374 DRAF l (Veltman et al., 1975; Wilson et al., 1967; Harris and Adams, 1967; Lilis ec al., 1975). Several studies have reported hepatotoxicity and impaired liver function in humans resulting from exposure to vinyl chloride at concentrations ranging from 1 to 470 ppm (Marstellar and Lelbach, 1975; Lilis et al., 1975; Thomas and Popper, 1975; Suciu et al., 1975). Repeated occupational exposure to vinyl chloride has also been noted to result in impaired pulmonary function (Miller et al., 1975; Gamble et al., 1976). Interstitial pulmonary fibrosis has been reported, but these particular workers were also exp sad to polyvinyl chloride dust. It has been proposed, but not satisfactorily demonstrated, that interstitial pulmonary fibrosis may be caused by vinyl chloride-altered immune status (Lilis ec al., 1975; Hard et al., 1976). In a study of present and past workers affected with vinyl chloride disease, Ward et al. (1976) observed a range of symptoms associated with Immune system dysfunction in 19 of the 28 affected workers. From their study of occupationally exposed workers, Spircas et al. (1975) concluded that a dose-response relationship existed between exposure to vinyl chloride and certain acute (primarily neurological) symptoms. The investigators examined the frequency of eight symptoms indicative of central nervous system disturbance, peripheral neuromuscular and neurovascular disturbance, and local CHA 010375 4-2 draft ritation. VinyL chloride doses were estimated from company data describing probable exposure scenarios for different job descriptions. Exposure concentrations appeared to range from 0 to 200 ppm. They observed a statistically significant dose relationship in the occurrence of five of the eight symptoms (dizziness, nausea, headache, tingling sensation in arms and legs, and fatigue). These symptoms occurred after exposures to less than 50 ppm. These data support other observations in humans that indicate vinyl chloride can produce adverse health effects even at levels below 50 ppm (Splrtas et al., 1975). Animal * % Repeated inhalation exposure to vinyl chloride has been reported to result in osteoporosis and toxicity to the liver, kidney, spleen, lung, and testes in certain animals. The results of some of these studies are reported in Table 4.1. !>* 4-3 CMA 010374 DRAFT CMrt 0 1 0 3 7 fiSSli Guinea Rig Bat Rat Bat Rat Rat, rabbit (ABLE 4.1 SUMMON 1C MO CHROMIC TOXICITY Of VIHH CHLORIDE AOMIHI STEREO TO ANIMALS BY INHALATION Duration (Months) Observations Reference 100,000 pp. 2 hr/dey 200, 100, 7 hr/dar 100 pp. 2 hr/dey 20,000 pp. 0 hr/day 3 6 6 3 Liver, kidney, spleen toxicity. Increase in liver weights; 100 pp. HOAEL. No effects observed. Increased Man liver and spleen Might. Prodan et al., 19/5b Torkelson et al., 1961 Torkelson et al., 1961 Lester et al., 1963 5.000 pp. 7 hr/day 0.03-0.04 0/L 4 hr/day 12 6 Growth retardation; shortened blood clotting tiM; increased kidney, heart, spleen Might; increased Mortality; degenerative and hyper plastic changes In the liver. Cardiovascular disorders, changes in the bioelectric activity of the hypothale.tt, hyperadrenaIonia, osteoporosis. feron et al., 1979a,b Basalaev et al., 1972 Iat>le 4.1 continued Species Set ftSt Nice Mice PflM ^ " v> imp; 5 hr/day M. 100, 3000 ppm 0 hr/day 00/i* 1,000, 230, 50 ppm 6 hr/day o.ooo, 2,500 ppm 5 hr/dey Duration (months) to up to 12 tf> to 12 5 to 0 Observations Liver and testes lesions at exposures of 50 and 500 ppm, respectively; depression of body weight gain at dose levels. Increased kidney, liver, spleen, and heart weight; decreased testis weight in all within 0 aonths; testis damage. Deaths at high dose caused by hepatitis; at 50 ppm, lethargy, weight loss, rough coat, hepatitis. Proliferation and hypertrophy of terminal broochioiar cells at both dose levels. Reference Sokal et al., 1900 Bi et at., 1985 tee et al., 19// Suiuki 1980, 1981 DRAFT 1037S O 3 M f* f-'r- CMA 010379 DRAFT 5.0 DEVELOPMENTAL AND REPRODUCTIVE EFFECTS 5.1 Summary The developmental and reproductive toxicity of vinyl chloride has been investigated in several experimental and epidemiologic studies (Barlow and Sullivan, 1982; Bardin et al., 1982; Hemminki and Vtneis, 1985). Vinyl chloride crosses the placenta of experim ntal animals. Some data indicates it may act as a transplacental carcinogen. No teratogenic effects were observed when vinyl chloride was administered by inhalation at maternally toxic doses. A single unconfirmed report disclosed a teratogenic effect in rats after vinyl chloride exposure as low as 2.5 ppm. Evidence chat vinyl chloride causes male reproductive damage has been presented in one experimental study and in a few human case studies. Epidemiologic analysis of communities located close to polyvinyl chloride plants have suggested an association between those locations and an increased risk of birth defects, but none of the ttnUsr bmr* adequately controlled for all confounding variables, fositive correlation has been made conclusively linking vinyi caaoride exposure with harmful reproductive effects. 0J.030 5-1 leracogenic Effects in Animals DRAFT 2.1 Inhalation Studies Rata: John ct al. (1977) reported that no developmental toxicity or defects occurred when pregnant Sprague-Dawley rats were exposed to either 500 or 2500 ppm vinyl chloride for seven hours daily on days 6 through 15 of gestation, these concentrations proved toxic to the mothers, however. In a separate experiment, pregnant rats exposed to 2500 ppm vinyl chloride by inhalation and 15% ethanol in drinking water experienced greater maternal and fetal toxicity than animals exposed only to vinyl chloride, but no teratogenic response wee observed. However, fetal body measurements were lower am ng chose rats that received ethanol and vinyl chloride. These effects on fetuses were similar to those reported following administration of ethanol only (John et al., 1981). Ungvary et al. (1978) exposed groups of three pregnant CFY rats to 1500 ppm vinyl chloride continuously on days 1 through 9, 8 through 14, or 14 through 21 of gestation. An increased number of resorbed fetuses was found in the group exposed to vinyl chloride during the ftrtt 9 days (p 0.05), but no significant effects were observed in rats exposed at other stages of gestation. In a recent study reported in abstract form, Radike et al. (1988) reported that vinyl chloride was a transplacental carcinogen capable of causing perinatal oncogenesis. An increase in the 5-2 CHA 0103B* * DRAFT numbers of liver carcinomas and angiosarcomas in the offspring of pregnant rats exposed to 600 ppm for four hours/day from day 9 to day 21 of gestation was observed. Post-natal exposure of the pups to 600 ppm increased the incidence of liver tumors. Coadministration of 5% ethanol with vinyl chloride did not increase the incidence of treatment-related malignancies. A single Russian study has reported an association between vinyl chloride exposures of as low as 2.5 ppm during pregnancy and embryo lethality, teratogenicity, and fetocoxicity in rats (Hirkova et al., 1978, cited in Barlow and Sullivan, 1982). The study and^its -1 results were reported only qualitatively and ne statistical data were published. Adverse effects reported included doubling of embryo mortality, a high incidence of cerebral malformations, and fetotoxicity. B1 et al. (1985) examined the effects of vinyl chlorid on testicular seminiferous tubules . tn. rats. Groups of 75 rats were expoMd. by. inhalation, cm etches 0, 10, 100 or 3000 ppm vinyl chlAXida^fps. six bours/dey..slx dayatfweehifor three, six, nine or Japjmer--^mamths. Eight to thirty cat*, verm: sacrificed sfter ach SWMCMia' period, with remaining animals killed 18 months after Che pi*- initial exposure (i.e., six months efter terminating exposure). Incidence of seminiferous tubule damage for the control, 10, 100 and 3000 ppm group were 19, 30, 37 end 56%, respectively. Changes included cytoplssmie vacuoletIon, nuclear condensation, fusion of spermatids and spermatocytes, and epithelial necrosis and 5-3 CMd 010382 DRAFT degeneration. Seminiferous tubule damage in the two higher dose groups was significantly greater than for the control group (Bi et al., 1985). Mice: Groups of 30 to 40 pregnant CF-1 mice were exposed by inhalation to either 50 or 500 ppm vinyl chloride for seven hours/day on days 6-15 of gestation. Exposure to 500 ppm caused maternal toxicity while no maternally toxic effects were observed at 50 ppm. No developmental defects were reported in fetuses exposed to either concentration. An increased number of resorptions and decreases in litter size and fetal body weight were seen in mice exposed to 500 ppm, but these effects were considered secondary to the toxic effects of vinyl chloride in the mother (John et al., 1977; 1981). Rabbits: No teratogenic or embryotoxic effects were observed in the offspring of pregnant rabbits (15 to 20 per group) exposed by inhalation to either 500 or 2500 ppm vinyl chloride for seven hours per day on days 6-18 of gestation. The incidence of resorptions was significantly increased in rabbits exposed to 2500 ppm vinyl chloride, a dose that produced other adverse effects in the dam et al., 1977; 1981). Simultaneous administration of 15% ethanol in the drinking water and 500 ppm vinyl chloride in air resulted in increased toxicity to the mother and produced defects in the developing embryo not observed in animals exposed to vinyl chloride alone. 5-4 CMA 010383 5.3 Reproductive Effaces in Humans DRAFT Several epidemiologic studies have been conducted to assess potential reproductive and developmental effects in the families of vinyl chloride workers (reviewed in Wagoner and Infante, 1980; Clemmesen, 1982). Infante (1976) analyzed birth certificate data obtained from a group of Ohio communities, three of which contained vinyl chloride polymerization plants. Although a statistically significant increase (p < 0.01) in birth defects was observed in the towns with vinyl chloride facilities (compared with the birth defect rate for the entire State of Ohio), several other cities -i without vinyl chloride factories exhibited rates equally high Sind higher. Spontaneous abortion rates were also, elevated in wives"of vinyl chloride workers (Infante, 1976). Edmonds et al. (1975; 1978) conducted two case'Controlled studies evaluating CNS malformations among offspring of vinyl chloride workers and families living near polyvinyl chloride facilities in Painesville, IN and Kanawha County, WV. More cases than controls lived within three miles of the polyvinyl chloride plants (p < 0.02). In reviewing' these three studies, He--ink! and VLneis (1985) concluded -, * " Xi- - r*ef rheiir: was lnadaouate evidence linking environmental or chloride with birth defects in humans. Theriault et al. (1983) measured the incidence of birth defects in infants born to residents of Shawinigan, Canada between 1966 and 1979. A vinyl chloride polymerization plant had been operating in the town since 1943. Although the authors stated that soma 5-5 CHA OiO304 DRAFT descriptive data suggested an association between ambient exposure to vinyl chloride and birth defects in the exposed community, no significant increases in either still births or birth defects were observed (Theriault et al., 1983). 5-6 CMA 010385 6.0 QEPQiqxiCITY 6.1 Summary DRAFT The genocoxicity of vinyl chloride hes been reviewed by several anchors (IARC, 1979; Duverger ec el., 1981; Bertsch ec al., 1975; SRI Incernetionel, 1983; Fabricant and Legator, 1981). Vinyl chloride causes geneCie damage in many case systems, including bacteria, fungi, higher plants, and is vitro mammalian systems, as well as In vivo in Drosophila (fruit fly), rodents, and humans. Previous reviews have suggested that a metabolite of vinyl chlomtde is the major cause of the observed genocoxicity. However, vtiiyl chloride has been observed to be mutagenic in some In vitro test systems without an exogenous activation system. This particular effect may be the result of endogenous cellular metabolizing enzymes, or the molecule itself may be genotoxic. From experiments in laboratory animals vinyl chloride does not appear to cause genetic damage to. germ cells, but doe* transform mammalian cells and :?<|h^afias .j^ally-induced mamsliait cell transformation in thamgapecniElsf>y* vinyl chloride . its , reported, carcicgenieley proceeds by genotoxic Beta that support this suggestion ere summarized below. 6-2 tftrtagttiicity Vinyl chloride is mutagenic in most major short-term tests. Its activity is enhanced in the presence of exogenous or endogenous 6-1 CHft 01038A draft metabolic activation, suggesting that a metabolite may be more mutagenic than the vinyl chloride molecule itself. 6.2.1 Bacterial Assays Several studies of vinyl chloride have been conducted using the Ames' SfllaCMllft ttEBhlauriVB ( tvphlmurlum) assay (McCann et al., 1975; Bartsch and Hontesano, 1975; Bartsch et al., 1975; Garro et al, , 1976). These studies indicate that vinyl chloride apparently acts as a mutagen whose effect is significantly enhanced in the presence of liver microsomal enzyme preparations from mice, rats, j or humans, and NADPH. For example, Bartsch and Montesano (1X75) investigated tha mutagenicity of vinyl chloride in air. at concentrations of 0, 0.2, 2, or 20% in both the absence and the presence of S-9 fraction obtained from livers of uninduced or phenobarbitone-induced rata. In the absence of metabolic activation, a dose-related increase of up to 15 times background was observed in fi. ttvphiaurium strains TA1535 and G46. In the presence of S-9 from uninduced rats, the frequency of revertants was increased up to 23 times above background in strain TA1530, and up. to 16 and five tinea above background in strains TA1535 and G46, respectively. The frequency of revertants increas d to approximately 28 times above background in strain TA1530, and to 18 and six times above background in strains TA1535 and G46, respectively, when S-9 from phenobarbitone-induced rats was used. In the same study, chloroacetaldehyde, a metabolite of vinyl chloride, proved mutagenic (15 times above background) in strain 6*2 CHA 010387 * DRAFT TA1530 in the absence of exogenous metabolic activation. Chloroethylene oxide was less toxic than chloroacetaldehyde, but was also mutagenic (nine times above background) when tested without exogenous metabolic activation. The authors proposed that the increase in revertants in the absence of an exogenous metabolic activation system was either the result of nonenzymatic breakdown products of vinyl chloride or a result of compounds formed by bacterial enzymes. However, the answer to this question was not effectively resolved by this study (Bartsch and Montesano, 1975). Salmonella tvphlmurium strains TA1536, TA1537, and TA1538, i^lch are specifically reverted by frameshlft mutagens, were unaffected I by concentrations of up to 20% vinyl chloride in air, even in'the presence of liver fractions from rats or mice (Bartsch et al., 1975). Vinyl chloride in water or methanol was not mutagenic when tested in . tvnMmurium strains TA100, TA1530, TA1535 or G46, even with S-9 liver fractions from phenobarbital-induced mice. The authors hypothesized that the inactivity of vinyl chloride might have- been caused by the rapid diffusion of vinyl chloride from the solution istan the* atmosphere (Bupcachr at sfcv , 1975). have confirmed the mutagenle activity of vinyl chloride in Salmonella. Vinyl chlorida was mutagenic in . trvrthimurlum strain TA1530, both with end without activetion, after incubation in a vinyl chlorida/ethanol medium. The mutaelon rate increased when cells wsrs incubated in the presence of ultraviolet light and decreased when hydroquinone, a radical-crapping agent, 6-3 010380 DRAF was added zo che incubation medium. These results suggest that radical metabolites may be important determinants of mutagenic activity (Duverger-Van Sogaart et al., 1982). The results of other studies support this hypothesis: for example, a free-radical generating system, riboflavin irradiated with ultraviolet light, doubled the number of vinyl chloride-induced revertants in . tvphimurium strain TA1530 (Garro et al., 1976). In at least one study, the increases in vinyl chloride-Induced mutagenicity in . tvphimurium strain TA1530 observed with the addition of liver fractions obtained from untreated or PCS-induced animals were similar, although FOB would be expected to increase the mixed-function oxidase content of the liver and, consequently, the potential number of mutants (Garro at al., 1976). Vinyl chloride was mutagenic in strain TA1530 in the presence of rat or mouse liver S-9 fraction from Aroclor-induced animals. Mutagenicity was observed even in the absence of an NAOPHgenerating system. Heat-inactivation of the mixed-function oxidase system did not result in decreased mutagenicity of vinyl chloride. These result* suggest that the mutagenic activity observed with vinyl chloride in the Ames' test is not necessarily due to eipyrnsr f< activation by a mixed-function oxidase system. Vinyl chloride Induced forward and reverse mutations in Escherichia colt (. coin strain 343/113 (Mohn, 1981) and forward mutations in . colt strain K12 with, but required metabolic activation with mouse liver microsomes (Greim et al., 1975, cited in IARC, 1979). 6-4 CMA 010389 DRAFT Chloroethylene oxide ac concentrations of 2.5 mmol was more cytotoxic and mutagenic than chloroacetaldehyde at concentrations of 100 mmol when tested in . coli strain K12A (Perrard, 1985). These results are consistent with those obtained in the Salmonella f~YTh'traT"tuni assay (Bartsch et al., 1975). 6.2.2 Eukaryotic Systems Vinyl chloride induced forward mutations in the yeast Schizosaccharomveea pombe following either a host-mediated assay, in mice or in vitro after metabolic activation with mouse lver microsomes (Loprieno et al., 1976; Bartsch and Montesano, 197.5). Chloroethylene oxide was mutagenic without activation in the same system (Loprieno et al., 1976). In Saccharomvcas cerevislae strain D^, vinyl chloride (in concentrations of either 16 or 48 mM) induced gene conversion ac the adenine-2 and tryptophan-5 loci only in the presence of mouse liver microsomes (Loprieno et al., 1976). Vinyl chloride, both as a gas and as an ethanol solution, was tested for potential mutagenicity in two strains of the fungus Bfauroinora erases. There was no detectable mutagenic effect, either with or without metabolic activation. The authors suggested this was because vinyl chloride could not penetrate the conidia (spore) (Drozdowicz and Huang, 1977). 6-5 * CMA 010390 6.2.3 Cultured Mammalian Cell Assays DRAFT Vinyl chloride was tested in Che Chinese hamster ovary/hypoxanthine guanine phosphoribosyl transferase (CHO/HGPRT) system, an assay designed to detect mutations in the gene coding for the HGPRT locus. Vinyl chloride (at concentrations of 10% in air) was mutagenic only in the presence of complete S-9 mixtures from Aroclor-induced rat livers. When various cofactors used to activate the liver enzymes (for example, NADPH) were not included in this test system, vinyl chloride was inactive even at higher concentrations (Krahn, 1979). Forward mutations were induced in V79 Chinese hamster lung cells in the presence of phenobarbital-pretraated rat liver supernatant (15,000 x *) (Drevon et al., 1977, cited in IARC, 1979). Huberman et al. (1975) reported that at concentrations of 6-13 na 1 the vinyl chloride metabolites chloroethylene oxide and 2- chloroacetaldehyde caused a dose-dependent induction of 8- azaguanine (four to eight times above background) and ouabain- resistant' (up to 23 times above background) mutants in Chinese ^hamster V79 cells vitro. Both 2-chloroethanol and V*;*-xV,m'- 'ooochloroacetic acid (at concentrations of up to 2500 pmol) were found to be inactive (Huberman et al.. 1975). 6-6 01039x 6.2.4 la.Vivo Mutazenicltv Assays draft A significant increase in recessive lethal mutations in Drosonh^|fl melanoeaster was observed after exposure to 850 ppm vinyl chloride for two days. Exposure to 30 ppm for 17 days also caused an increase in recessive lethal mutations. Although vinyl chloride vas tested at concentrations ranging from 30 to 50,000 ppm, the mutation frequency rate reached a plateau at 10,000 ppm, a finding the authors attributed to saturation of metabolizing enzymes (Verburgt and Vogel, 1977). However, vinyl chloride did not cause any significant increase in dominant lethal mutations, translocations, or entire or partial sex-chromosome loss following exposure to 30,000 ppm for 2 days (Verburgt and Vogel, 1977). 6.3 Chromosomal 6.3.1 Dominant Lethal Teats Vinyl chloride failed to produce dominant lethal mutations in offspring of male CD-I mice exposed by inhalation to concentrations of 3,000, 10,000, or 30,000 ppm, six hours/day for five days, and then mated with successive pairs of untreated females over an eight-week period (Anderson et al., 1977). There was no evidence that vinyl chloride had any mutagenic effect on any maturation stage of spermatogenesis. In addition, no significant increase in the number of post-implantation early fetal deaths, no evidence of 6-7 * 010392 CHA DRAFT preimplantation egg loss, and no reduction in fertility were observed in this study (Anderson et al., 1977). Kale rats were exposed to 0, 50, 250, or 1000 ppm vinyl chloride by inhalation for six hours/day, five days/week for 11 weeks (Short et al., 1977). During the eleventh week of exposure, the rats were housed with two untreated females for seven evenings or until matings occurred in both females. Although there was a significant reduction in the number of females who became pregnant when housed with males exposed to 1000 ppm vinyl chloride, there was no significant effect on total implants/female or dead Implants/female in those females that became pregnant (Short et al., 1977). .1 No dominant lethal mutations were produced in Drosophila melanosester following exposures of up to 30,000 ppm for tw days (Verburgt and Vogel, 1977). 6.3.2 Chromosome Aberration/Sister Chromatid Exchange Studies 6.3.2.1 Experimental Studies JS. *T- 'c Stater chromatid exchanges (SCE) and aberrant metaphases ware Increased in chromosomes of bone marrow cells of Chinese hamsters exposed to either 1.25, 2.5 or 5% (v/v) vinyl chloride in air for 6, 12, or 24 hours. The greatest number of SCEs were se n after exposure to 2.5% vinyl chloride for 24 hours. The greatest number 6-8 CMA 010393 DRAFT of aberrant metaphases was observed after exposure to 5% vinyl chloride for 24 hours (Basler and Rohrborn, 1980). The mutagenic potential of vinyl chloride was evaluated in the mammalian spot test. Female C57B1/6J Han mice were mated to male Han/T mice, then exposed to 4600 ppm vinyl chloride in air for five hours on day 10 of gestation. Ho effect on litter size or coat color was seen in offspring (Peter and Ungvary, 1980). Ho significant increase in any specific genetic effect was observed in bone marrow cells obtained from male Vistar rats exposed to vinyl chloride at 1500 ppm, six hours per day for five days. There was a significant increase in total "abnormalities" (including chromatid gaps, breaks, and fragments) following this exposure scenario; no increases in any of these parameters (including total "abnormalities") were observed when vinyl chloride exposure was extended to three months (Anderson and Richardson, 1981). 6.3.2.2 Human Observations Stvmral studies of chromosomal abnormalities in the peripheral lymphocytes of workers exposed to vinyl chloride were reported in the IARC monograph (1979). Aberrations most frequently reported were fragments, dicentrics and rings, and breaks and gaps. These earlier studies were of limited value, involving small groups of workers with inadequate controls. For example, Leonard and 6-9 CMA 010394 DRAFT associates (1977) examined lymphocytes from seven men working in a vinyl chloride plant and 11 workers in a vinyl chloride polymerization plant. The incidence of such chromosome aberrations as chromatid breaks and gaps were comparable in all groups, but the degree of severity of the abnormalities observed was more severe in ten of the 11 polymerization plant workers than in the seven workers from the other vinyl chloride factory. The lack of controlled conditions greatly reduces the usefulness of this study. Vinyl chloride levels were less than 10 ppm at the time of the study, but were estimated to have been as high as 500 ppm in earlier years. Also, several of the polymerization plant workers had been given X-ray treatment on the hands, but no controls had been exposed to similar X-rays (Leonard et al., 1977). Another study of 56 workers in the polyvinyl chloride industry suggested that occupational exposure to vinyl chloride could have a measurable effect on the induction of chromosomal aberrations in cultured lymphocytes obtained from these workers (Purchase et al., 1975). Exposure levels were not measured. Workers from both the test and control groups who had been exposed to X-rays or had had prolonged drug treatment or recent viral infections were excluded from the study. However, the results from this study and their significance were not discussed (Purchase et al., 1975). Kucerova and colleagues (1979) found that the frequency of SCE and oth r chromosomal aberrations was significantly higher in workers exposed to 20-150 ppm vinyl chloride in air than in unexposed controls matched for sex and age. Chromatid and chromosome breaks were 6-10 CMA 010395 draft detected in the greatest frequency; chromatid and chromosome exchanges occurred only sporadically. Some subsequent studies have verified these findings. The majority suggest that the frequency of occurrence of aberrations decreased with decreasing occupational exposure levels. For example, polyvinyl chloride workers (N - 52) exposed to mean concentrations of 2.34 ppm vinyl chloride had significantly greater numbers of chromosome breaks and chromosomal aberrations than did unexposed controls (N - 74) (Suskov and Sazonova, 1982). However, in another study, workers exposed to low levels of vinyl chloride showed no differences from controls in the number of SCE or chromosome breaks. Significant differences had bean seen in the same population previously when occupational vinyl chloride exposures had been higher (Hansteen et al., 1978). A study of a large number of polyvinyl chloride workers suggested that vinyl chloride exposures below 15 ppm did not induce chromosomal aberrations (Pieciano et al., 1977). When lymphocyte cultures from a group of 109 workers who had worked in the plant ^exposure periods ranged from one to 332 months) were compared with multures from a control group of 295 pre-employment examinees, no significant chromosomal differences were observed. The workers had been exposed to levels of 15.2 ppm vinyl chloride before 1960, 11.4 ppm from 1960 to 1972, and 8.7 ppm between 1973 and 1974. The subjects and controls were not matched for age or for exposure to X-rays, however. 6-11 -jflb 0V % DRAFT Cytogenetic studies performed on lymphocytes isolated from 39 workers from a polyvinyl chloride plant and 16 control males demonstrated a significant increase in chromosome-breakage frequency for the exposed workers (3.41% versus 1.79%, respectively). This study was repeated for 37 of the 39 workers 2-2.5 years later, during which time the workers had only a minimal exposure to vinyl chloride. More appropriate in-plant matched controls were selected for the follow-up study. In the repeat study no difference was found in mean chromosome-breakage frequency between the workers and their controls (Hansteen et al., 1978). 6.3.3 Micronucleus.Teats In CBA male mice exposed to 5% vinyl chloride in air, nearly a four-fold increase in micronuclasted cells was observed (Jenssen and Raael, 1980). 6.3.4 DMA Damage/Unscheduled DMA Synthesis (UPS') Tests Vinyl chloride has been reported to induce unscheduled DMA synthesis in adult rat hepatocytes, but no experimental details were provided in the publication (Probst et al.t 1981). Differential killing was induced in the repair-deficient . coll strain polA* in assays using Che standard disc and liquid suspension methods (Rosenkrazu:, 1981). 6-12 CMA 010397 6.4 Mammalian Cell Transformation DRAFT Vinyl chloride, 20 to 50% in air, has been reported to transform BHK cells exposed (Styles, 1980). A clear positive transformation response was obtained in BALB/c-313 mouse cells exposed to vinyl chloride; in addition, vinyl chloride (chamber concentrations 01024 ppm) caused a dose-dependent cytotoxicity (Tu at al., 1985). An increased sensitivity to transformation by SA-7 virus was observed in primary Syrian hamster embryo (SHE) fibroblasts exposed 3 to vinyl chloride concentrations up to 194 pg/cm (75,781 ppm) (Hatch at al., 1981). - .j# Km 6-13 % CMA 010398 CMA 01039 0 carcinogenicity DRAFT 1 Animal Studies 1.1 Summary The evidence for the carcinogenicity of vinyl chloride in laboratory animals has been reviewed by Kalmaz and Kalmaz, 1984, IARC, 1979, SRI, 1983, Kuzmack and KcGaughy, 1975, and Purchase et al., 1987. Adequate experimental evidence exists to indicate that vinyl chloride is carcinogenic in mice, rats, and hamsters When given orally and by inhalation. Vinyl chloride has been found to cause tumors in a dose-related manner ae several sites, including liver, lung and mammary gland. The oncogenic response appears to be a function of the site, vinyl chloride concentration, tumor type, species of animal, and route of administration. Although some evidence of vinyl chloride-induced carcinogenesis has been observed by all routes of administration and in all species tested, important discrepancies in the protocols of many studies ha* limited their usefulness in quantitative risk assessment. Those discrepancies include the lack of appropriate control groups, insufficient exposure time, or incomplete histopathology of the animals. Studies that have been used previously in risk assessment include feeding studies (Feron et al., 1981; Til et al., 1983) and a series of inhalation studies (Maltoni et al., 1984). In th Feron studies, liver angiosarcomas and hepatocellular tumors (the 7-1 CMA 010400 % DRAFT primary sice) were produced after chronic oral administration of vinyl chloride. In the studies by Maltoni et al. (1984) a wider variety of tumor types was observed. These studies and others are reviewed below. 7.1.2 Intraoerltoneal. Subcutaneous, and Transplacental Administration Vinyl chloride has been tested in experimental animals by intraperitoneal, subcutaneous, and transplacental administration, but for various reasons all of these studies were deemed inadequate 't r for the evaluation of the carcinogenic risk of vinyl chloridi'gte. These reports and the reasons for their inadequacy are described-in Appendix A. 7.1.3 Oral Administration 7.1.3.1 Studies bv Maltoni and Associates Rats: Liver angiosarcomas and morphologic alterations of the liver mere induced in groups of 40 male and 40 female Sprague-Davley rats after gastric incubation of 0, 3.33, 16.65, or 50 mg/kg vinyl chloride in olive oil five days/week for 52 weeks. These animals were then observed for the remainder of their lives (Experiment Bill, Maltoni et al., 1984, IARC, 1979). Dose-related Increases in the incidence of several types of tumors were observed, including liver angiomas and angiosarcomas, nephroblastomas, and mammary 7-2 * CMA 0i040i tumors. DRAFT In a subsequent experiment, 0, 0.03, 0.3, or 1.0- mg/kg was administered by the same protocol, except that the dose groups contained 75 animals of each sex. Liver angiosarcomas were found in one female in 0.3 mg/kg group and two females and one male in the 1.0 mg/kg group. No such tumors were observed in controls (Experiment BT27, Maltoni et al., 1984). No statistical analyses were reported for any of these experiments. 7.1.3.2 Studlea bv Feron and Associates Vinyl chloride in soybean oil was administered by gastric intubation at a dose of 300 mg/kg once daily, five days/week for 83 weeks, to 60 male and 60 female ffistar rats; no vehicle controls were used. Of the 109 animals examined, 56 had angiosarcomas of the liver and 52 had angiosarcomas of the lung (Feron et al., 1981). Although vinyl chloride was clearly demonstrated to be carcinogenic in this study, the data are not suitable for use in quantitative risk assessment because of the lack of vehicle-treated controls. In conjunction with the above experiment, groups of 60-80 male and 60-80 female five-week old Ulster rats were fed polyvinyl chloride powder (10% of diet) with or without a high vinyl chloride monomer content (0 to 4000 ppm) in the diet for their lifetimes (Feron et al., 1981). The actual doses of vinyl chloride given to rats in the feed were 0, 1.7, 5.0, and 14.1 mg/kg/day. Access to food for controls and treated animals was limited to four hours per day; an 7-3 CMA 010402 DRAFT additional control group was fed a libitum. Gross pathology was performed on all animals that died or were killed; complete histopathology of all organs was performed on only 20 males and 20 females from the controls and 20 males and 20 females from each of the two highest dosage groups. The animals chosen for complete histopathology were those chat lived the longest before being killed. Histopathology of all other rata was restricted to the liver, zymbal glands, lungs, kidneys, spleen, pituitary, thyroid, adrenals, grossly visible tumors, and organs containing lesions suspected of bearing tumors. Statistical significance of tumor incidence was determined by the Chi-square test. Vinyl chloride caused a dose-related Increase in the death rate .In the 5.0- and 14.1-mg/kg groups; all animals receiving the highest dose were dead by week 134, with females dying earlier than males (Feron et al., 1981). In the low-dose group the mortality of male rats was comparable with chat of controls; the death rata in female rats was slightly higher than that in controls. Death of treated animals was attributed to pulmonary or hepatic insufficiency due to neoplastic or nonneoplastic lesions in these organs. . *... jJ*. wear angiosarcomas were V hepatocellular carcinomas reported in 27/59 (p < 0.001) and in 8/59 (p < 0.01) male rats receiving 14,1 mg/kg/day. Incidences of angiosarcomas and hepatocellular carcinomas were 9/59 (p < 0.01) and 29/59 (p < 0.001), respectively, in females receiving the highest dose (Table 7.1) (Feron et al. 1981). Necrosis, centrilobular degeneration and 7-4 CMA OiO DRAFT mitochondrial damage were also seen in the hepatic parenchyma of rats administered vinyl chloride. The incidence of angiosarcoma of the lung was also significantly increased in high-dose males (19/59, p < 0.001) and females (5/57, p < 0.05) (Table 7.2). Low- dose males and females showed necrotic damage of the liver and 26/58 low-dose females (p < 0.01) had neoplastic nodules of the liver (Table 7.1) (Feron et al., 1981). It is possible that underreporting of tumors at all sites occurred because of the incomplete histopathology performed and the fact that only the longest-surviving histopathology. high-dose animals were chosen for complete 7.1.3.3 Studies bv Til and Associates As a follow-up to the study of Feron and co-workers (1981), groups of 100 male and 100 female Wistar rats (except for the top-dose group, which was composed of 50 animals of each sex) were fed polyvinyl chloride (up to 1% of diet) with a high content of vinyl chloride monomer for up to 149 weeks (Til et al., 1983). Levels of vinyl chloride administered in the powder were 0, 0.017, 0.17, and 1,7 mg/kg/day for 149 weeks. Actual oral exposure to vinyl chloride monomer (calculated by measuring the evaporative loss of vinyl chloride during the four-hour feeding periods, the rate of food intake, and the level of vinyl chloride in the feces) was estimated to be 0.014, 0.13, or 1.3 mg vinyl chloride/kg/day for the low, middle, and high dose groups, respectively. Access to food was limited to four hours per day. An additional control 7-5 CMA 010404 TABLE 7.1 DRAFT INCIDENCE OF LIVER TUMORS AND NEOPLASTIC NODULES IN VISTAR RATS EXPOSED ORALLY TO VINYL CHLORIDE (Feron et al. , 1981) Tumor Tyoe/Sex Liver Angiosarcoma Male Female Hepatocellular Carcinoma Male Female Neoplastic Nodules Male Female --------------- Incidence1_________ _ .Vinyl Chloride (ma/kg/dav^ 0 1.7 5.0 14 1 0/55 0/57 0/58 0/58 6/56** 2/59 27/59**** 9/57** 0/55 0/57 1/58 4/58 2/56 19/59*** 8/59** 29/57*** 0/55 2/57 1/58 26/58** 7/56** 39/59*** 23/59**** 44/57***& Number In denominator - number of animals necropsled. 2 Values marked with asterisks differ significantly from controls according to the Chi-square test: * p < 0.05 ** p < 0,01 *** p < 0.001 7-6 CHA 010405 TABLE 7.2 DRAFT INCIDENCE OF LUNG ANGIOSARCOMAS. ABDOMINAL MESOTHELIOMAS AND MAMMARY TUMORS IN WISTAR RATS EXPOSED ORALLY TO VINYL CHLORIDE (Feron et al., 1981) Tumor Tvoe/Sex Lung Angiosarcoma Male Female Abdominal Mesotheliomas Mala Female Mammary Adenoma or Adenocarcinoma or Anaplastic carcinoma Female ______________ Incidence1_______ -Vinyl Chloride (mg/kg/dav) 0. _LJ. 5.0 14.1 0/55 0/57 0/58 0/58 4/56***2* 1/59 19/59*** 5/57* 3/55 1/57 1/58 6/58* 7/56 3/59 8/59 3/57 3/57 2/58 5/59 9/57 Number in denominator - number of animals necropsied. Values marked with asterisks differ significantly from controls according to the Chi-square test: * p < 0.05 ** p < 0.01 *** p < 0.001 0i<>40& 7-7 DRAi group, comprised of 100 rats of each sex, received food a 1lbicum and were housed in a separate room. Gross pathology was performed on all animals and was restricted to the liver, all grossly visible tumors or presumable tumors in the abdominal cavity, zymbal gland, and mammary glands. No clinical signs of toxicity attributable to vinyl chloride were observed. In the lowest- and mid-dose group, body weight and survival of treated rats ware not significantly different from those of controls. In the high-dose group, mortality was slightly Increased. I The results of this study demonstrated significant increases in^the incidences of hepatic foci of cellular alteration, neoplastic nodules, hepatocellular carcinomas, liver-cell polymorphism, .and cysts in che highest dose group. Two females and one male In this group developed liver angiosarcomas. Females, but not males, of the low- and mid-dose groups developed a higher incidence of hepatic basophilic foci of cellular alteration. No pathologic effects in other organ systems were attributed to vinyl chloride exposure (Table 7.3) (Til et al., 1983). Til and co-workers reported that a threshold of 0.17 mg vinyl chloride/kg/day for che induction of tumors in rats was obs rved. In fact, a threshold cannot be demonstrated. Vinyl chloride induced hepatocellular alterations at all concentrations tested. Histopathology of all organs was not performed on all animals; therefore, tumors not grossly observable or palpable could have CMA 010407 7-8 -4 been missed. 3ecause of che shortcomings of the study, its utility for the evaluation of carcinogenic risk is limited. Inhalation Exposure Several researchers have investigated the potential carcinogenicity of vinyl chloride administered by inhalation (Viola, 1977; Caputo et al., 1974; Keplinger et al., 1975; Lee et al., 1977; Hong et al., 1981; Suzuki, 1981; Groth et al., 1981; Drew et al., 1983; Maltoni et al., 1984). All experiments confirm the carcinogenicity of vinyl chloride, although only a few of the studies are adequate for a quantitative evaluation of carcinogenic risk. 7.1.^.1 Studies in Rats The earliest information on the experimental carcinogenicity of vinyl chloride administered by inhalation was reported by Viola (1971). Wistar rats were exposed to 30,000 ppm by inhalation (four hours/day, five days/week) for twelve months. At the end of the treatment period, che surviving animals were killed at 20-day intervals and "the most important tissues and organs examined histologically by standard methods". The primary tumors observed were located in che zymbal gland (found only in rodents), with metastases to the skin, bone, and lung. Caputo and associates (1974) exposed Wistar rats to 50-20,000 ppm vinyl chloride four hours/day, five days/week for 12 months. Liver 7-9 CMA 010408 * TABLE 7.3 DRAFT LIVER TUMOR INCIDENCE IN MALE AND FEMALE WISTAR RATS EXPOSED TO VINYL CHLORIDE BY ORAL ADMINISTRATION FOR 149 WEEKS (Til et al., 1983) __,,__Tumor Tvpe/Sex Liver Angiosarcoma Male Female Hepatocellular Carcinoma Male Female Neoplastic Nodules Male Female Vinvl Chloride (ma/ks/dav> Q 0.014 0.13 13 0/99 0/98 0/99 0/99 0/99 0/96 1/49 2/49 0/99 1/98 0/99 0/99 0/99 1/96 3/49 3/49 0/99 0/99 0/99 1/99 0/99 0/99 1/49 9/49 ; Number in denominator - number o animals nacropsied. Vinyl chloride intake data was adjusted to compensate for loss of vinyl chloride during the four-hour feeding periods. The initial levels of vinyl chloride administered in the diet were 0, 0.017, 0.17, and 1.7 mg/kg/day. 7-10 010409 CMA DRAFT angiosarcomas and skin carcinomas vere observed in animals exoosed to 500 ppm or greater and lung adenomas in those exposed to 2,000 ppm or more. Bi et al. (1985) evaluated the tumorigenic potential of vinyl chloride in rats following inhalation exposure to 0, 10, 100 or 3000 ppm (six hours/day, six days/week). The incidence of liver angiosarcomas was 0/19, 0/20, 7/19 and 17/19 for the four exposure groups, and 0/19, 0/20, 2/19 and 9/20 for lung angiosarcomas, respectively. The authors failed to discuss the specific types of tumors or their significance, focusing instead on the testicular effects of vinyl chloride (discussed in Section 5 of this document) (Bi et al., 1985). 7.1.4.2 Studies in Mice In a preliminary paper reviewed by IARC (1979), Keplinger and co workers (1975) reported results from ongoing tests on mice, rats, and hamsters. Vinyl chloride was carcinogenic in all three species; the female mouse was the most sensitive of the animals tasted-. CD1 Swiss mice were exposed to 0, 50, 200, or 2,500 ppm vinyl chloride seven hours/day, five days/week for nine months, then observed for another nine months. Primary tumors found in animals that died included liver angiosarcomas, lung adenomas, and mammary adenocarcinomas. At the time of the IARC report, histological evaluation had been carried out only on grossly visible tumors, but no final report has been published. 7-11 CMA 010410 DRAFT Consequently, ve cannot accurately quantify tumor incidence in the s tudy. Lee and co-workers (Lae et al., 1977; IARC, 1979) reported that female mice were more responsive to vinyl chloride exposure than rats. Two month-old male and female CD-I mice were exposed by inhalation to 0, 50, 250, or 1,000 ppm vinyl chloride for six hours/day, five days/week for 52 weeks (end of experiment). Vinyl chloride induced primary tumors in mice at multiple sites after exposure to 50 ppm or more. Liver cell angiosarcomas, bronchiolo alveolar adenomas, mammary ductular adenocarcinomas, and squamous and anaplastic cell carcinomas (with metastases to the lung) wire observed in treated animals. Vinyl chloride induced tumors at all dose levels, with the incidence and severity of the tumors increasing with dose. The total tumor incidence may have been underestimated because of the short duration of the study. Hong and colleagues (Hong et al., 1981), as a follow-up of the studies of Lee and associatea (Lee et al., 1977), examined the development and Incidence of vinyl chloride-related carcinogenic effects during a post-exposure follow-up period. Groups of eight Cm 28 two month-old male and female CD-I mice were exposed to 0, 50. 250, or 1,000 ppm for one, three or six months and subsequently observed for 12 months before being sacrificed. Although the. number of animals used in the experiment was inadequate for risk assessment purposes, four of sixteen female mice exposed to 50 ppm vinyl chloride for one month (and autopsied 7-12 CHA 010411 DRAFT one year later) exhibited mammary gland adenocarcinomas or carcinomas. In mice, the combined (male and female) incidences of hemangiosarcomas for the 250 and 1,000 ppm groups were significantly higher than in controls (p - 0.05). Tumor incidence was related to dose and duration of exposure. Bronchiolo-alveolar tumors were also significantly increased in the high-dose group (p - 0.05), but no clear trend for the other dose levels was observed (Hong et al., 1981). In rats, tumor incidence rates following exposure for one or three months did not differ significantly from control values. Aftei a six or ten month exposure, the combined (male and female) cumulative incidences of hemangiosarcomas, hepatocellular carcinomas, and neoplastic liver nodules in rats exposed to 250 or 1,000 ppm differed significantly from those in combined male and female control animals (statistics not reported) (Hong et al., 1981). Suzuki (1981a) exposed male CD-I mice (between 30 and 40 per group) to 1, 10, 100, 300, or 600 ppm vinyl chloride six hours/day, five days/week for four weeks. The animals were then observed for up to 41 weeks after cessation of exposures. One mouse in the 10 ppm group had a subcutaneous hemangiosarcoma in the left ear 29 weeks after exposure; one mouse in the 600 ppm group developed a hepatic hemangiosarcoma 65 weeks after exposure. In a separate study, Suzuki (1981b) exposed 27 mice to either 2500 or 6000 ppm vinyl chloride for five or six months. Additional mice were exposed to 7-13 CMA 010412 DRAFT 1. 10 or 100 ppm for four weeks, and sacrificed forty weeks after exposure. All animals were evaluated for pulmonary tumors. Twenty-six of the 27 high dose animals possessed "alveologenic" tumors. Animals in the lower dose groups exhibited a dose-related trend for pulmonary tumor formation (Suzuki, 1981b). Although this study cannot be used to quantify risk due to study design (for example, inadequate number of test animals), it did demonstrate a carcinogenic response to vinyl chloride after exposure to relatively low concentrations for short durations. 7.1.4.3 Studies on the Potential Effects of Age at Time of Sxpgw Groth et al. (1981) exposed groups of 110-128 male and female Sprague-Oawley rats to 948 ppm vinyl chloride In air seven hours/day, five days/week for 29 weeks, beginning at ages varying from six weeks to 52 weeks. Animals were sacrificed after termination of exposure. On the basis of this testing regime, those researchers concluded that vinyl chloride-induced liver angiosarcomas occurred with the greatest frequency in rats whose exposure period began at 52 weeks of age, with females more - snsceptible than males. The data and study methodology are Inadequate for making this conclusion, however. If liver angiosarcomas are expressed at a later age in the rat's life cycle, animals exposed at an early age and sacrificed early in their life cycles would not have had time to express the same tumor incidence as they would if they had lived their full lifetimes. The animals 7-14 CMA 010413 draft exposed later in their life cycles would then seem to have the highest tumor incidence. Drew et al., (1983) looked at the effect of age and exposure duration on vinyl chloride oncogenicity in females of several different species of rodents. Groups of female CD-I Swiss mice, B6C3F1 mice, Fischer 344 rats, and Golden Syrian hamsters (N - 54 for mice, N - 56 for rats and hamsters) were exposed to vinyl chloride for six hours/day, five days/week for six, 12, 18, or 24 months, beginning at eight weeks of age, and observed for their lifespans. Other groups were held until six or 12 months of age, exposed for six or 12 months, and then observed for the remainder of their lifespans. The exposures were conducted at a single dose level for each species; mice, rats and hamsters were administered 50, 100, and 200 ppm, respectively. All animals exposed to vinyl chloride at age eight weeks (the start of the experiment) exhibited decreased survival relative to controls (Drew et al., 1983). 56C3F1 mice experienced the most significant life-shortening regardless of the age at which exposure was begun. No significant decrease In survival was o.bserved in rats, hamsters, or Swiss mice initially exposed after six months of age. Other clinical signs of vinyl chloride toxicity were not evident and liver necrosis was not observed. In rats, exposure to vinyl chloride was associated with hemangiosarcomas, mammary gland adenocarcinomas and adenomas, and hepatocellular carcinomas (Table 7.4) (Drew et al., 1983). The 7-15 CMA 010414 DRftrT incidence of hemangiosarcomas was a function of the duration of exposure: the longer the exposure period the greater the incidence of hemangiosarcomas. A six-month exposure produced a low incidence of hemangiosarcomas and hepatocellular carcinomas only if begun early in life. One-year exposures produced a significant incidence of tumors, especially if begun early in life. The incidence of mammary gland adenocarcinomas and fibroadenomas was not always related to exposure duration, but the incidence was higher in rats whose exposure began at eight weeks of age. Hepatocellular carcinomas were induced in a dose-related manner In rats when exposures began at eight weeks. In hamsters, hemangiosarcomas, mammary gland carcinomas, stomach adenomas, and skin carcinomas were associated with vinyl chloride exposure (Table 7.4) (Drew et al. 1983). The highest incidence of hemangiosarcomas and stomach adenomas occurred In animals exposed early in life for only six months. The highest incidence of mammary gland carcinomas was seen in animals exposed at an early age for up to twelve months. Exposure beginning at or after eight months of age resulted in a markedly lower tumor incidence, ^possibly because the lifespana of chronically exposed hamsters were significantly reduced to the point that late-appearing tumors would i#.' not be expressed. dice, especially the B6C3F1 strain, appeared to be the species most sensitive to the carcinogenic effect* of vinyl chloride (Table 7.4) (Drew et al., 1983). Hemangiosarcomas and mammary gland carcinomas 7-16 CHf> 010415 DRAFT in both strains and lung carcinomas in Swiss mice were associated with vinyl chloride exposure. In B6C3F1 mice, exposure to vinyl chloride for six months resulted in 60-70% incidence of hemangiosarcomas, regardless of the age at exposure initiation. The incidence of mammary gland carcinomas in B6C3F1 mice was greatest when the animals were exposed early in life. Lower incidences of this tumor were seen when initial exposure occurred at a later age. In Swiss mice, exposure to vinyl chloride at an early age resulted in the highest Incidence of hemangiosarcomas, mammary gland carcinomas, and lung carcinomas, regardless of duration of exposure. Lover incidences of all tumors were observed in animals exposed later in life. The patterns of tumorigenicity produced by vinyl chloride in the study by Drew et al. (1983) are consistent with patterns reported In other Inhalation studies. However, the results reported by these investigators apparently contradict those of Groth et al. (1981). This apparent contradiction can be explained by the fact that Groth et al. reported only the incidence of hemangiosarcomas, a tumor shown in the Drew study to be a relatively late-appearing tumor that developed regardless of either the age at initial exposure or the duration of exposure. In the Groth et al. study, animals exposed at a young age were also sacrificed at a young age, thereby decreasing the probability of hemangiosareoma development relative to the older exposed animals who were allowed to live. 7-17 % CMA 010416 TABLE 7.k TUMOR INCIDENCE FOLLOWING VINYL CHLORIDE EXPOSURE IN FEMALE RATS, HAMSTERS AND MICE FROM THE STUDY OF DREW ET AL. (1983) Tumor Type Length of Exposure (Months) LDE (ppm)^ Female Fisher 344 Ret: Experimental Exposure 100 ppm Liver Hemangiosareomas control 6 12 18 24 0 4.46 8.93 13.40 17.86 Mammary Gland Adenocarcinoaa control 6 12 18 24 0 4.46 8.93 13.40 17.86 Hepatocellular Carcinoma control 6 12 18 29 0 4.46 8.93 13.40 17.86 Female B6C3F1 Mice: Experimental Exposure 30 ppm Hemangioaarcoma (all sites) control 6 12 18 0 2.23 4.46 *- Mammary Gland Carcinoma control 6 12 18 0 2.23 4.46 -- Tumor Frequency (%) 0.9 (1/112) 5.3 (4/76) 20.0 (11/55) 23.6 (13/55) 34.7 (19/55) 4.5 (5/112) 7.9 (6/76) 19.6 (11/56) 16.4 (9/55) 9.1 (5/55) . I ,f 0.9 (1/112) 4.0 (3/75) 7.1 (4/56) 14.8 (8/54) 16.4 (9/55) * 5.8 (4/69) 68.7 (46/67) 76.7 (69/90) -" 4.3 (3/69) 43.2 (29/67) 41.1 (37/90) ** 7-18 oio*17 CM* TABLE continued DRAFT Tumor Type Length of Exposure (Months) LDE (ppm)^ Female CD-I Swiss Mice: Experimental Exposure 50 ppm Tumor Frequency (%) Hemangiosarcoma (all sites) control 6 12 18 0 2.23 4.46 6.69 1.4 (1/71) 43.3 (29/67) 63.8 (30/47) 44.4 (20/45) Mammary Gland Carcinoma control 6 12 18 0 2.23 4.46 6.69 2.8 49.3 46.8 48.9 (2/71) (33/67) (22/47) (22/45) Lung Carcinoma control 6 12 18 0 2.23 4.46 6.69 12.7 27.7 31.9 24.4 (9/71) (18/65). (15/47) (11/45) v r ; Female Golden Syrian Hamster: Experimental Exposure 200 ppm Hemangiosarcoma (all sites) control 6 12 18 0 8.93 17.86 26.79 0.0 (0/143) 14.8 (13/88) 7.7 (4/52) 1.9 (2/103) Mammary Gland Carcinoma 0 6 12 18 0 8.93 17.86 26.79 0.0 (0/143) 32.2 (28/87) 59.6 (31/52) 46.1 (47/102) Skin Carcinoma 0 6 12 18 0 8.93 17.86 26.79 0 (0/133) 2.5 (2/80) 18.8 (9/47) 3.3 (3/90) 1LDE Lifetime Dally Exposure (in ppm) 7-19 CMA 010418 1.4.4 Studies bv Maltoni and. Assoc: aces draft Maltoni and co-workers performed a series of chronic inhalation studies on rats, mice, and hamsters in the Bentivoglio Laboratories (BT) or the Bologna Institute of Oncology (Maltoni et ai., 1984). The investigators studied the effects of exposure to 14 concentrations of vinyl chloride (1-30,000 ppm) in male and female rats and six concentrations of vinyl chloride in male and female mice and male hamsters. A summary of some of these experiments are included both in this section and in Appendix A. In each experiment, animals were exposed to vinyl chloride for four hours daily, five days per week for various durations, and observed.for the rest of their lives. A number of the experimental procedures were not described or were inadequately described in the report by Maltoni et al. (1984). A full necropsy was performed on each animal and the following tissues reportedly were routinely excised for histopathology: brain, zymbal glands, interscapular brown fat, salivary glands, tongue, thymus, lungs, liver, kidneys, adrenal glands, spleen, pancreas, esophagus, stomach, intestine, bladder, uterus, gonads, and any organ in which pathologic lesions were observed. Details of the experimental protocol for the BT experiments are provided in Table 7.3 (Maltoni et al., 1984). Data on nonearcinogenic toxic effects of vinyl chloride were sparsely reported in the Maltoni BT experiments. Vinyl chloride appeared to be toxic at the higher concentrations, but reportedly the high mortality at these dose levels was due to a high incidence 7-20 cm* OJ0429 DRAFT of vinyl chloride - induced tumors. The available information on survival, including Kaplan-Meier survival curves, indicates that vinyl chloride decreased survival in a dose-dependent manner. In the Maltoni experiments, exposure to vinyl chloride was associated with an increased incidence of malignant tumors at a variety of tissue sites in all of the species tested. A summary of these tumor sites is provided in Table 7.6 (Maltoni et al., 1984). A direct relationship between exposure levels and tumor incidence was apparently demonstrated, although no statistical tests for trends were performed. Results of experiments on Sprague-Datfley rats exposed to vinyl chloride for 52 weeks were statistically analyzed using the Fischer exact probability test. Correspondence analysis was also performed on the relationship of the incidence of liver angiosarcomas, zymbal gland carcinomas, nephroblastomas, and forestomach papillomas and acanthomas to vinyl chloride exposure (Tassignon, 1980, cited in Maltoni et al., 1984). The results of this analysis were not discussed by Maltoni et al. (1984). A summary of the lowest concentrations at which a statistically significant excess of tumors was observed is given in Table 7.7. Experiment BT1. Most previous risk assessments have been based on the data from experiment BT1 (Maltoni et al., 1984). In this study, 30 Sprague-Dawley rats of each sex were exposed to concentrations of vinyl chloride ranging from 50 to 10,000 ppm for four hours daily, five days per week for 52 weeks, beginning at 13 weeks of age. A positive control group received 2,500 ppm of vinyl 7-21 CMA 010420 acetate. DRAFT After treatment the animals were observed for their lifespans up to 135 weeks. Survival of both males and females decreased in a dose-related manner, especially at concentrations above 500 ppm. Vinyl chloride appeared more toxic to females than to males in this experiment. Vinyl chloride was associated with an increased incidence of liver angiosarcomas in a dose-related fashion. These results are presented in Table 7.8 (Maltoni et al., 1984). In addition to liver angiosarcomas, vinyl chloride (at concentrations above 2500 ppm) caused an Increased incidence of zymbal gland carcinomas, nephroblastomas, hepatomas, and neuroblastomas. The incidence of liver angiosarcomas was probably underestimated at the higher exposure levels due to mortality resulting from tumors at other sites. Experiment BT15. Groups of 60 male and 60 female Sprague-Dawley rats were exposed to 0, 1, 5, 10, or 25 ppm of vinyl chloride for four hours daily, five days per week for 52 weeks, beginning at 13 weeks of age (Maltoni et al., 1984). Following exp sure the animals were observed for the remainder of their lives (up to 147 weeks). Available data, including Kaplan-Meler survival curves, indicated that vinyl chloride did not affect survival at the concentrations tested. No statistical analyses of mortality and body weight data were reported. Mortality was greater in the mal control group than in the treated groups: the time at which 50* of the male control group had died was week 72, compared with week 100 in the 25-ppm vinyl chloride group. No explanation was given for this decreased survival. 7*22 QHh 010421 % Experiment Number TABLE 7.5 DRAFT EXPERIMENTAL PROTOCOL FOR INHALATION STUDIES MALTONI AND CO-WORKERS (1984) Dose (com) Exposure Duration. (weeks)1 Species/ Strain Age at Start of Exposure (weeks) Number of Animals per Dose Level'1 BT1 BT2 BT6 BT9 BT15 BT3 BT14 BT4001 BT4006 BT5 BT7 BT17 0, 50, 250, 500, 2,500, 6,000, 10,000 1, 100, 150, 200 30,000 0, 50 0, 1, 5, 10, 25 0, 50, 250, 500, 2,500, 6,000, 10,000 6,000, 10,000 0, 2,500 0, 2,500 6,000, 10,000 52 52 52 52 52 17 5 5 76 69 15 1 0, 50, 250, 500, 2,500, 6,000, 10,000 o, 1 52 52 Rat/SD 13 30 M, 30 F (30 M, 30 F) Rat/SD Rat/SD Rat/SD Rat/SD Rat/SD 13 60 M, 60 F (85 M, 100 F) 17 30 M, 30 F (no controls) 13 150 M, 150 F (50 M, 50 F) 13 60 M, 60 F (60 M, 60 F) 12 30 M, 30 F (30 M, 30 F) Rat/SD 21 (parents) 1 day (offspring) Rat/SD 13 1 day Rat/SD 1 day Rat/SD 19 (fetus) Rat/Vistar 11 6F (no controls) 21-22 M, F (no controls) 54 F (60 F) 68 M, 64 F (158 M, 149 F) 60 M, 60 F (60 M, 60 F) 30 F 13-29 M, F (no controls) 30 M (40 M) Rat/Wistar 13 120 M (130 M) 7-23 010^22 Table 7.5 continued DRAFT Experiment ..Number Dose 7 oom) BT4 0, 50, 250, 500, 2,500, 6,000. 10,000 BT8 0, 50, 250 500, 2,000, 6,000, 10,000 Exposure Duratio^i ("weeks)1 30 30 Species/ Strain Age at Start of Exposure (weeks) Number of Animals per Mouse/Swiss 11 30 M, 30 F (80 M, 70 F) Hamster/ 11 Syrian golden 30 M (62 M) ^Exposures were for four-hours daily, five days per week* 2 'Number in parentheses - number of control animals for experiment. 7-24 * CMA 010423 DRAFT TABLE 7.6 TUMORS CORRELATED TO INHALATION EXPOSURE TO VINYL CHLORIDE IN RATS, MICE, AND HAMSTERS IN THE BT EXPERIMENTS1 Tumors Liver angiosarcomas Hepatomas Encephalic neuroblastomas Lung adenomas Lymphomas/leukemias Angiosarcomas at ocher sices Zymbal gland epithelial tumors Nephroblastomas Cutaneous epithelial tumors Mammary adenocarcinomas Forescomach papillomas, acanthomas Rat 1`l9VtSS Hanufftr ++ + + (+) + + + + + <+) (+) <+> (+) ++ + (+) <+) + ^Data from Maltoni et al., 1984 + - Tumor incidence was statistically significant (p < 0.05) by the Fisher exact test. O) - Association was not statistically significant, but was considered biologically significant. 7-25 CM* 010424 TABLE 7.7 DRAFT LOWEST CONCENTRATION AT WHICH A SIGNIFICANT (p < 0.05) EXCESS OF TUMORS WAS REPORTED BY MALTONI AND ASSOCIATES1 IN INHALATION STUDIES AT SPECIFIC SITES IN SPRAGUE-DAWLEY RATS2 ---------------lUOSE Forestomach papilloma Zymbal gland carcinoma Neuroblastoma Nephroblas toma Liver angiosarcoma Mammary adenocarcinoma Vinyl Chloride Concentration (com) 30.000 (male, female) 10.000 (male, female) 10,000 (female) 250 (female) 100 (male) 200 (male) 25 (female)2 5 (female) 1Data are from Maltoni et al., 1984. 2 Significant at this dose level when specific corrected tumor incidence is used, p - 0.047. Analysis by Fisher exact probability test. 7-26 CMA 010425 TABLE 7.8 DRAFT INCIDENCE OF LIVER ANGIOSARCOMAS (LAS) IN MALE AND FEMALE SPRAGUE-DAWLEY RATS EXPOSED FOR 52 WEEKS TO VINYL CHLORIDE (Maltoni et al., 1984) Studv Experimental Dose Level (Dorn) ^ lAS-InS-idSI)?? Male Female BT1 0 0/30 0/30 50 0/30 1/30 250 1/30 2/30 500 0/30 6/30 2,500 6/30 7/30 6,000 3/30 10/30 10,000 3/30 4/30 BT2 0 0/85 0/100 100 0/60 1/60 150 1/60 5/60 200 7/60 5/60 BT6 30,000 5/30 13/30 BT9 0 0/50 0/50 50 1/150 12/150 BT15 0 0/60 0/60 1 0/60 0/60 5 0/60 0/60 10 0/60 1/60 25 1/60 4/60 LAS Incidence in Historical Controls: 1/1179 2/1202 Corrected LAS Incidence^ Male Female 0/22 0/26 1/28 0/22 6/26 3/17 3/21 0/29 1/29 2/26 6/28 7/24 10/25 4/25 0/61 0/37 1/36 7/42 0/6* 1/43, 5/46 5/44 5/22 13/24 0/29 2/70 0/38 12/110 0/25 0/48 0/43 0/42 1/41 0/44 0/55 0/47 1/46 4/40 1/364 2/541 ^Number in denominator - number of animals necropsied. 2 Number in denominator - number of animals alive when first liver angiosarcoma was observed. 7-27 CMA 010426 DRAFT the incidence of mammary gland carcinomas in created females was higher chan in controls at all concentrations of vinyl chloride exposure. However, the differences from control values were statistically significant only at concentrations above 1 ppm. the mammary gland adenocarcinoma incidence for this and the other relevant BT experiments are presented in Table 7.9 (Maltoni et al., 1984). Experiment BT4. Thirty male and 30 female Swiss mice were exposed to 0, 50, 250, 500, 2,500, 6,000, or 10,000 ppm of vinyl chloride four hours daily, five days weekly for 30 weeks, beginning at, 11 -X weeks of age (Maiconi et al., 1984). The study was terminated 81 weeks after the exposure period began. Vinyl chlorida was highly toxic to both males and females, but males appaared more sensitive than femalas to tha toxic effacts of vinyl chloride. Survival decreased in a dose-related manner, although statistical analysis apparently was not performed on the data presented. A very high incidence of lung adenomas was observed in vinyl chloride-treated male and female mice. A statistically significant increase in the incidence of liver angiosarcomas was seen in mal and female mice exposed to vinyl chloride, but a dose response was not seen in the male animals. In addition, a high incidanc of mammary gland adenocarcinomas occurred in treated female mice. These results are presented in Table 7.10 (data from Maltoni ec al., 1984). 7-28 010427 CMA TABLi 7.9 INCIDENCE OF MAMMARY GLAND CARCINOMAS IN FEMALE SPRAGUE-DAWLEY RATS AND SWISS MICE EXPOSED BY INHALATION TO VINYL CHLORIDE (Maltoni et al., 1984) S tudv No. Experimental Dose Level (Dom) 1 Tumor Incidence BT1 (Rat) 0 50 250 500 2,500 6,000 10,000 0/30 2/30 2/30 1/30 2/30 0/30 3/30 BT2 (Rat) 0 100 150 200 2/60 4/60 6/60 5/60 BT6 (Rat) 30,000 2/30 BT9 (Rat) 0 9/50 50 59/150 BT15 (Rat) 0 6/60 1 14/60 5 22/60 10 21/60 25 16/60 Tumor Incidence in Historical Controls 100/1202 BT4 (Mice) 0 50 250 500 2,500 6,000 10,000 1/80 12/30 13/30 10/30 9/30 9/30 14/30 Tumor Incidence in Historical Controls 21/554 Corrected Tuffibr Incidence 0/29 2/30 2/27 1/28 2/25 0/28 3/29 2/100 4/60 6/60 5/60 2/30 9/43 59/142 6/60 14/60 22/60 21/60 16/60 100/1202 ......................... 3.......... 1/67^ 12/301 13/291 10/281 9/3or 9/281 14/28'* 21/5543 ^Number in denominator - number of animals examined. 2 Number in denominator - number of animals alive when first malignant mammary tumor was observed (type unspecified). 3 Number in denominator - number of animals alive when first mammary tumor was observed (type unspecified). 7-29 CMA 010428 * -Vi Va> o DRAFT CMA 0 1 0 4 2 9 TABLE 7.io INCIDEMCE Of PULMONARY ADENOMAS, MAMMARY CMC I MOWS, AMD LIVER ANGIOSARCOMAS IN HAIE AMO FEMALE SUI$S NICE EXPOSED 10 VINYL CHLORIDE BY INHALATION (EXPERIMENT BT4)1 ,, jrf, --------------------------------------------- ttr ifsiftas? ---------------------------------------------Vinyl Chlorl* (bw) ~T~ 2 -1- -5ML lsas 10.000 Historical Controls Males feaalas UYsr Rnaiwtrcoims Hales feaalas 4 Males Feaalas /ra 7/67 3/27 3/30 0/62 0/62 1/10 0/26 0/74 1/67 0/27 12/30 21/29 17/29 24/29 26/29 1A/2S 22/30 23/27 24/29 20/24 26/20 9/23 9/21 6/17 0/26 6/13 10/24 2/12 11/21 1/9 9/20 0/29 13/29 1/20 10/20 0/23 9/30 0/24 9/20 0/22 14/20 34/491 27/533 0/545 0/554 1/521 22/545 'flats froa Naltoni at at., 1964. Nurtiar in danoainator * mabarof aniaals alive when first pulmonary (lung) adenoma mbs observed (II weeks). Nuaber in danoainator * nuabarof aniaals reportedly alive when first liver angiosarcoma was observed (32 weeks). Ntaber in denominator observed (16 weeks). ntaberof aniaals reportedly alive ufien first lung aaaaary tumor (type unspecified) was * ,*>* ttk Human Studies on. the Carcinogenic Effects of Vinyl Chlorine 7.2.1 Introduction In 1974, Creech and Johnson described three cases of angiosarcoma of the liver (IAS) among workers at the B.F. Goodrich Tire and Rubber Co. in Louisville, Kentucky. Because IAS is a very rare cancer (20-25 cases per year in the United States), the clustering of three cases in one vinyl chloride polymerization facility indicated an abnormally high incidence of this cancer. Based on this report, as well as data indicating that vinyl chloride*is carcinogenic In laboratory animals, multiple studies of workers exposed to this agent were conducted. By 1985, at least. 17 epidemiologic studies relating vinyl chloride exposure to the incidence of various cancers had been completed. 7.2.2 General Design of Epidemiologic Studies Host of the epidemiologic studies have been retrospective cohort designs. Groups of workers in the vinyl chloride industry were selected by reviewing employment records. Few baseline data other than age, job classification, and length of employment were obtained. The concentrations of vinyl chloride to which these workers were exposed were generally not available, since ambient levels of vinyl chloride were not routinely measured before 1975. Almost all of the investigators estimated vinyl chloride exposure 7-31 CMA 010430 % based on some combination of job classification and length of exposure. Exposure information included measured levels of vinyl chloride in only two studies (Ott et al., 1975; Buffler et al., 1979). in all reports, workers were traced to determine the number of deaths that had occurred in the defined cohort. The cause of death was based on information available from death certificates. In the studies from Sweden and Norway, national cancer registries also provided data to assess incidence of cancer (Byren et al., 1976; Heldaas et al., 1984). The expected numbers of deaths were estimated using population-based mortality statistics. Finally, a standardized mortality ratio (SMR) was calculated from Che proportion, of observed to expected deaths from each cause and the statistical significance of these ratios tested. 7.2.3 Difficulties in Interpreting the Epidemiologic Evidence There are several problems involved in the interpretation of these studies: 1. Inadequate information on worker outcome. In several of the studies reviewed, outcome data on approximately 10% of the original workers were not obtained (Duck et al., 1979). Since the tumor incidence in humans exposed to vinyl chloride is relatively low, the loss of 10% of the data base could have a 7-32 % CHA 010431 DRAFT significant effect on the observed tumor rate, and possibly allow for an underestimation of risk. 2. Inadequate exposure data. Specific exposure data did not exist in any of the studies reviewed with the exception of Ott et al. (1975) and Buffler et al. (1979). In some cases, no attempt was made to evaluate exposure. In most studies, exposure was estimated from odor levels, acute toxicity levels, job classification, or length of exposure - methods all considered unreliable for accurate exposure estimation. However, gross differences in exposure levels based on the type of job-and length of exposure may have occurred, particularly before 19.75, when very high levels of vinyl chloride were common in the industry (up to 500 ppm with rare excursions up to 4,000 ppm) (Ott et al. 1975). After 1975, ambient workplace levels were drastically reduced to an average of about 1 ppm, so that differences in dose estimated by job classification became small. 3. Inadequate follow-uo time. In this review, "follow-up time" is the tla* period between the onset of exposure and the point at which, evaluation Is completed. The average latency period for LAS among vinyl chloride workers worldwide was determined to be 22.1 years (Stafford, 1983). Several of the epidemiologic studies either do not report length of follow-up or include a large number of subjects who had recently become employed in the vinyl chloride industry and who, therefore, had very short 7-33 010**2 * DRAFT follow-up time periods. Inclusion of subjects wich shorter average follow-up time tends to obscure an exposure-response relationship. 4- USA----certificates to determine outcome. Cancer is often not listed as a cause of death on death certificates. Even when cancer is reported, the type of cancer may not be given and may not be verified. 5. Healthy worker effect. In retrospective cohort studies of mortality among occupational groups, the number of deaths ar A compared to general population races. A disproportionate number of newly hired employees demonstrating self-selection for good health, or selected for better general health through pre-employment examinations, skews the mortality experience of the worker population. Ott and co-workers (1975) have estimated that the average mortality rate for workers in the plastics industry is about 80% of population-based rates. Since observed deaths in the study cohorts are compared to estimates based on the incidence of death in the general population (not in healthy workers), the SMR becomes an #: ^ underestimate W' , epidemiologic of risk. Unfortunately, only ons of the studiee reviewed used a control group of workers not exposed to vinyl chloride (Theriault and Allard, 1981). The failure of more epidemiologic studies to uss a proper control cohort increases the difficulty in interpreting the effects of vinyl chloride on the exposed worker. 7 ,A CMA 01043 * 6. Inadequate statistical power. The term "statistical power" represents the probability of detecting an association or an excess risk if that association really exists. For example, if the power of a study to detect a specified change in risk is 80%, there is an 80% chance chat the study will show an increased risk if that risk really exists. Negative findings may have two explanations: there may actually be no increased risk, or the study may have had inadequate power to show a risk that really exists. Power depends on the level of statistic*., significance used (usually p < 0.05), the number of outcomes expected (in these studies cause-specific deaths), and the strength of the association being investigated (effect sizej^. Mortality Studies A summary of the important characteristics of individual epidemiologic studies is given in Tables 7-11 and 7-12. Each study should be evaluated keeping in mind the difficulties noted above. Soon after' the Initial case reports by Creech and Johnson (1974), . describings the identification of liver angiosarcomas in vinyl chloride workers, Monson et al. (1974) published a proportionate mortality analysis of the deaths of 161 vinyl chloride workers at two plants in the United States. A statistically significant 50% excess mortality for all cancers and an 11-fold increase in mortality from cancer of the digestive system, including five angiosarcomas of the liver (LAS), were observed. In addition, 7-35 CMA 010434 STUDY COHORT 7AK0) TABLE 7-It A SUMMARY Of EPIDEMIOLOGIC BATA FOR OCCUPAIIOKALLY EXPOSED VINYL CHLORIDE WORKERS OEATHS(O) EXPOSURE(YRS) f/U TIMES(YRS) DOSE m DEATH ALL SITES LIVER(LAS) BRAIN LUNG LYMPHOMA 1. Tabershau t Gaffay1 0,304 USA (1974) 2. Ouck at at. 2.122 U.K. (1975) 3. Nicholson at al. 257 USA (197|) 4. Ott at al. 594 USA(197S) 5. Byren at al. 771 Swedan (1976) 6. Uaxuailar at al. 1,294 USA (1976) 1250(150) 7(0.30) 352(4.70) 152(7.20) >1 10.20>20yrs >0 2(0.00) 24(9.30) >5 0(00) 79(13.30) >0 21(2.70) 50(750) 13(10) *136(10.50) >0 >5 >1 273>19yrs >10 >0 550>10yrs >10 >15 7. fox and Cot liar U K (1977) a. EEH USA (1975) 7.717 393(5.10) 409(5.30) >0 00>20yrs >0 10,173 496(4.00) 707(6.90) >1 19.30>20yrs 320>20yra 9. Buffler at at. Texes (1979) 464 0(00) 20(00) >0 >0 10. Bartaui at al. Italy (1979) 4,777 659(13.00) 62(1.30) >0.5 >0.5 11. Masuda at al. Japan (1979) 304 1(0.30) 26(0.50) >1 >1 EST 75 EST 96 EST 126 easured 09 EST EST 100 EST 75.4 EST 09 awaeured 07 EST 44 EST 110 96 231 81 'K 109 90.7 104 130 97 138 943(6) 155< 993(0) -- (3) -- - (0) 413S(2) 1155*01) 1606b -- 612a 329^ 490* 1400S(2) 54.6 112 103 77 160 156 194** 09.8 753(5) 203a 107 - (0) 206a 000*(3) 125 01 500*(0) 125 106 159 176 90.9 112 133 C37 PU CMA 0 1 0 4 3 5 TABLE 711 (con*t) STUDY COHORT F/UIX) KATHS(X) EXPOSURE(YRS) F/U TIHES(YRS) OOSE SHR 0EATH ALL SITES LIVER(LAS) BRAIN LUNG LTMPHOHA Weber, Reini, Creiser Germany (1981) production 7,021 processing 4,007 unexposed 4,910 70*4.4X) 414(5.9X> 366(9X) 4I7(6.5X) Cooper* USA (1961) Hakaaura Japan (1983) 10,173 496(4 .tt) 707(6.9X) 4,524 29(0.6X) 209(4.6X) HeIdasa et al. Norway (1964) 454 0(0X) 50(1IX) >0 >0 >0 >1 1 >1 >0 EST 95 112 1523 162 >0 EST 95 85 434* 535* >0 EST 78 65 401* 164 33.4X EST 69 104 753(B> 203* 107 ean EST 87 156 236 (3) 16.3yn 66 >i ESI 64 114 (1) ISO 214 34 77 112 1 ----- Relative Risk - - - > 1 Theriault t Allard Canada (1961) exposed 451 0(0X) 59(2.6X) >5 81X115yra EST 1.07 1.48 6.25 (10) *~ .36 uneapoaed 871 Z3K26.8X) 1. The studies ol Cooper and EEH are rsanelyses of the Tabershow and Gaffey Cohort 2. SNR subjects also in the Taberthau and Gaffey Cohort S. SMB is for "digestive aystee cancer*, not Uver cancer 4. SNR Is for *othar and unepacified cancer", LU of uhich were brain cancer 5. SHR is for cancer of CHS, not Brain DRAFT ChA 010436 F/U * Follow up ties (years) EST - Est iaated dose *p < 0.05 p < 0.01 siai TABLE 7-12 A SUMMARY OF TUMOR INCIDENCES AND STANDARDIZED MORTALITY RAIIOS (SHR) FOR OCCUPATIONALLY EXPOSED VINYL CHLORIDE WORKERS Ail CANCER LIVER CANCER BRAIN CANCER LUNG CANCER fi--e__ m 2--t___m 0___i___ SHR 0 E SHR LYMPHOMA 0__ t_ SHR Monsan at al. Tabershau 8 MI-161100 Caffay Ouck at al. at il. Ott at al. 352-467-75* 134-142.2-96 79--89.1-19 Byran at al. 41-27.9-150 79-77--110 35-36.4-96 9--3 9........ 13--16--81 8--0.7-1100 19-21.7-94 11-11.1-99 31................ 4--.97--413 5--1.2--420 17-11.78-155 13-7.9--160 25-23.9-112 16-15.5-103 2--.38--612* 3--1.8-108 5- -3.4--150 6-6.1-106 21................ Kaxueiler at al. IS year Foa t Collier 136-126.3-108 393-521'. 2-75.4 35-23.5-149* 11-16.9-184** 115-126.8-90.7 7-0.6-1155** 7-0.4-1606** 1.71140.8 3-0.9-329* 1-0.6-498* 2-3.66-54.6 12-7.7-156 ns.7-m* 46-51.2-90 4-2.5-159 3-1.7-176 9-9.0-99.9 V0j0J EEN 707-795 139-141.4-104 29-40.8-75 12-5.9 203* 45-44.3-107 11-10.4-112 uffler et al. 8--5.2--154 0 -.2........ t-0.1----- 5-1.7-289* 0--0.5........ Bertaiti at al. Naauda at al. Weber at al. 30-30.9-97 8--5.8 -118 8--1--800b 1- .6--167 1-0.8-125 0--.15-- 7-7.7- 91 1 -.8-125 4- -3--113 0--.5.......... Production 114.......... $9 Qi. . ... .11? .1.5........ 2,,1.4.b Processinp 360.......... 95 62.......... 85 31.......... 434 51..........535* 2............ 34 Control 14. Cooper 15. Weldaas 412.......... 78 707-795-80* 83- -83 139-141-104 23-20.2-110 41- -401 29-40.8-75 184 b 12-5.9-203 45-44.3-107 5--2.8--180 6............ 77 11-10.4-112 16. Theriault and Allard 20-16.4-122.2 14-5.4-259.3 0-0.6- 2-5.8-34.6 17. Nafcaaura 128-147.6-87 37-26.85-138 6-2.54-236 2-2.3-0.86 p < 0.05 p < 0.01 observed e = expected SMR^^Ltdai edited aortal it/ ratio DRA^T CMA 0 1 0 4 3 7 increases in Che proportionate mortality ratios (PMR) for brain cancer, lung cancer, and lymphoma were noted. Proportionate mortality ratios do not represent a specific measure of risk, but the consistent PMR excesses for neoplasms found in this study suggests that vinyl chloride may operate as a multisystem carcinogen. Tabershaw and Gaffey (1974) published a large cohort study of 8,384 vinyl chloride workers at 33 plants in the United States, which demonstrated a statistically significant increase in angiosarcoma of the liver and a nonsignificant positive trend correlating vinyl chloride exposure with lymphoma and cancers of the buccal cavity and pharynx, CMS (primarily brain), and lung. The SMRs for all these tumor types were greater in the high exposure groups after the cohort was stratified by high and low exposure indices (estimates based on job classification and length of exposure), but the differences in SMRs for the high* and low*exposure groups were not statistically significant. Follow*up in this study was only 85% complete. The workers for whom follow-up was incomplete wmga> mostly older workers, and Tabershaw and Gaffey (1974) suggested that these workers, who experienced a long latent period after exposure, might show a somewhat different mortality pattern from workers who were followed up. Another significant problem is that the authors reported only digestive system cancer and did not distinguish cancer of the liver from other cancers in this classification. Information on this cohort has been updated and 7-39 CMA 010438 reanalyzed by Cooper (1981). The final report included 10.173 vinyl chloride workers from 37 planes in the United States (Cooper. 1981). Follow-up had increased to 95.1% of the cohort and extended more than 20 years for 33.4% of the cohort. Statistically significant excess mortality was shown for LAS and for CNS cancers (primarily brain). Again, SMRs for lung cancar and lymphoma were elevated but not statistically significant. Duck and co-workers published an analysis of 2,122 vinyl chloride workers in Great Britain (1975). In this study, no excess of total or cause-specific mortality occurred. There were no cases of LAS, although one was recorded in the cohort after the study period ended. Only 16% of the cohort in this study was followed more than 15 years from the time of initial exposure, which undermines the reliability of the negative results of this study. Nicholson and colleagues reported on 257 workers in th United States who were exposed to vinyl chloride for at least five years and whose initial exposure occurred more than can years before the end of the study (1975); These inclusion criteria are important because this is the first study chat attampted to limit the cohort te workers who had significant vinyl chloride exposure and follow up time. Three cases of LAS were observed and the SMRs for all deaths and deaths due to cancer were elevated. Because IAS is otherwise exceedingly rare, the increased incidence of this tumor was statistically significant, but the study lacked power to detect significant increases in ocher classifications of malignancy. 7-40 CM<*> 010439 A larger cohort based on similar criteria was assembled bv Vaxweiler et ai. (1976) for the National Institute for Occupational Safety and Health (NIOSH). This study followed an adequate number of workers (1,294) for more than 10 years, with all having had more than five years of exposure. Separate analyses were also performed for those workers with more than 15 years of follow-up time. Significant excesses in the SMB. of exposed workers were found for all deaths due to cancer, liver cancer (11 cases of LAS), and CNS cancers. Standard mortality ratios for lung cancer and lymphoma were elevated, but were not significant at the p < 0.05 level. Workers with more than 15 years of follow-up time showed higher mortality rates compared to those with tan years of follow-up time. The SMR for lung cancer reached statistical significance in-the group with a 15-year follow-up. This cohort provides the strongest evidence for the association between length of time since exposure to vinyl chloride and the subsequent development of cancers of the liver, CNS, and lung (Waxweiler et al., 1976). Ott end associates completed a study of 594 Dow Chemical workers in Michigan (1975). Many of these workers were also included in the ^stwdy by Tabershaw and Gaffey (1974). The best available vinyl V c&toride exposure data are Included in this study. Automated sampling of air levels began in one plant as early as 1959. Unfortunately, a large number of workers had less than one year of vinyl chloride exposure at the time of this report. Stratifying the cohort into low, medium, and high exposure groups resulted in less than 200 subjects per group, with only 20, 18, and 22 deaths per 7-41 010440 CHA DRAFT group, respectively. ,\'o cases of LAS and no significant increase in mortality from any cause for the entire cohort were noted. However, total deaths and deaths due to cancer were significantly higher in the high vinyl chloride exposure group compared to all other dose groups. These data are insufficient to develop any human dose-response relationship. The only other study providing quantified human exposure data is by Buffler and co-workers (1979). Area sampling began after 1971 for 464 Dow Chemical vinyl chloride workers in Texas, but data on exposure levels were not available for those workers (the majority) exposed before monitoring began. No cases of LAS were obseed among these subjects. There was a ^statistically significant excpss only for lung cancer in exposed workers. The number of deaths (N - 28) in this cohort was very small, making it impossible to perform statistical assessment of many of the causes of death. Buffler and associates have published the only information on the smoking habits of vinyl chloride workers. Even after adjustment for. smoking habits, the excess of lung cancers in this group remained significant. Syren et al. (1976) and Heldaas et al. (1984) reported on Swedish and Norwegian vinyl chloride workers, respectively. Although these studies included all vinyl chloride workers in the respective countries and had the advantage of access to excellent cancer registries, the total number of workers in both studies was still quite small. Nevertheless, both studies show a significant excess 7-42 010441 CM* of LAS in exposed workers. The Swedish study indicates a significantly increased mortality for CNS cancers. Both reports also demonstrate a trend toward increased mortality due to lung cancer. Fox and Collier (1977) studied all 7,717 workers in Britain who may have been occupationally exposed to vinyl chloride between 1940 and 1974. Four cases of liver cancer were found; two of these were angiosarcomas. No ocher tumor type shoved a significant increase (statistical methods not reported). Because workers were added to this cohort as they entered the industry, the study Included a i large proportion of workers with brief exposure and short follow-up time. Approximately 75% of the subjects had been employed in the vinyl chloride industry for less than ten years and only 8% of the workers had been employed for more chan 20 years. Inadequate length of exposure and follow-up make this study's negative results of questionable validity. Bertazzi et al. (1979) examined the mortality rates among 5,441 Italian vinyl chloride workers. This study shoved a significant increase in mortality among exposed workers only for liver cancer {.three cases of LAS). Follow-up was leas than optimal (14% of the total remained untraced), and person-years at risk were calculated as if the workers unavailable to follow-up were all alive and well, which contributed to the very low SMR for all causes of death. 7-43 CMA 010-442 y.asuda and co-workers studied 304 Japanese vinyl chloride workers (1979). This cohort was too small to determine statistical significance for any cause of death. Weber. Reinl, and Greiser (1981) reported on mortality information from three cohorts of German chemical industry workers; 7,021 vinyl chloride and polyvinyl chloride production workers (usually considered a high exposure area), 4,007 polyvinyl chloride processing workers (a lover exposure area), and 4,910 chemical workers not exposed to vinyl chloride (1981). The SMRs w re determined for causes of death in each of the three groups bun, no statistical comparisons were made. A significant increase in mortality from liver cancer was observed in all three of the groups evaluated, most notably for the vinyl chloride processing workers (SMR - 1523). A significant increase in malignancies of the lymphatic and hematopoietic tissues was noted among the production workers, while a significant increase in. brain tumors was observed among the processing personnel. Analysis of the mortality experience of 4,324 Japanes vinyl chloride workers by Nakamura (1983) revealed a significant increase is' the mortality ratio for death from all cancers and from liver cancer alone (three cases of LAS). Cancer of the lung was not elevated; cancers of the CNS and lymphoma were not reported in this study. 7-44 % CMA 010443 Theriault and Allard (1981) studied Canadian vinyl chloride workers in the only cohort to employ an occupational control group for evaluation of relative risk in workers exposed to vinyl chloride. The control cohort consisted of 870 chemical workers not exposed to vinyl chloride, while the study group comprised 585 vinyl chlorideexposed workers, with 454 of these workers exposed for more than five years. Exposure levels were not quantified. Very few deaths (59 cases) occurred in the exposed group, compared with 233 in the control group. The only significantly Increased relative risk was for liver cancer (eight cases of LAS). The SMR for digestive cancer (which includes liver cancer) among workers exposed-for .i greater than five years was 259, significantly greater (P < 0&1) than for the general population. The authors suggested that -the small size of the study reduced the power of the study with respect to finding an excess of CNS cancer or lymphoma that may have been present. Theriault (1983) published an extended follow-up on this same cohort in 1983 with no significant changes in the initial findings. HeIdeas and co-workers reported a study of cancer incidence and * mortality in a cohort of 454 male workers exposed to vinyl chloride V end polyvinyl chloride between 1950 and 1969 (Heldaaa et al. 1984). This cohort was divided into three exposure groups, as estimated from job classification, and the study population followed for 27 years. The investigation demonstrated an increased incidence of malignant melanoma, and cancer of the lung, colon, and thyroid 7-45 CMA 01044-4 in the exposed cohort. This study reported cancer incidence, as well as mortality, unlike most other studies. The observation of an increased incidence of malignant melanoma is the first reported in humans (Heldaas et al., 1984), Four malignant melanomas of the skin were identified in the study population where only 0.8 were expected. Three of four cases of malignant melanomas occurred in tha high exposure group, where 0.5 cases were expected. The fourth case was in the medium exposure group with 0.18 cases expected. After the observation period, one more case was diagnosed in the medium exposure group. The authors noted one additional case of incipient malignant melanoma in the medium exposure level group that was diagnosed in 1977 but not included in the study (Heldaas et al. 1984). Dahar et al. (1988) recently published an update to the vinyl chloride mortality study of Ott et al. (1975). There was no statistically significant excess for any neoplasm or disease of interest among the exposed cohort. Rlnsky et al. (1988) evaluated the mortality rate and cause of death for a cohort of chemical workers in Vest Virginia. A statistically significant increase in liver cancer and lympho- and reticulo-sarcoma was seen among the workers. The mortality rate of the 29,319 male workers studied was similar to that of the U.S. white male population (Rlnsky et al. , 1988). Smulevich et al. (1988) reported that mortality resulting from tumors of the digestive organs, respiratory system, bone and connective tissues, brain and skin was higher in workers exposed to 7-46 CMft 010445 vinyl chloride chan for the general population (USSR) . Nro cases of Liver angiosarcoma were reported in the study cohort during the follow-up period (SmuLevich et al., 1988). 7.2.5 Cancer Risks Associated with Exposure to Vlnvl Chloride 7.2.5.1 Liver Cancer Between 1961 and 1977, 23 cases of LAS were reported among approximately 20,000 vinyl chloride workers in the United States (Lelbach and Marsteller, 1981; Spirtas and Kaminski, 1978). VThe - `if expected incidence of LAS is 0.014 cases per 100,000 per yea in the general population in the United States (Heath et al., 1975). Based on analysis of these data, the relative risk for developing LAS following vinyl chloride exposure among this country's vinyl chloride workers is 483. The epidemiologic studies also demonstrate a strong and consistent association between vinyl chloride exposure and primary cancer of the liver. All eight of the studies that assessed risk for primary .. liver cancer note a statistically significant increase in standardized mortality ratios (SMR). The average relative risk for liver cancer among vinyl chloride workers is five to six times greater than the incidence of that seen in the general population. Strong evidence suggests that exposure to vinyl chloride can cause liver cancer. All reports published to date indicate that the standardized mortality ratios of exposed workers are elevated, and 7-47 CMA 010444 TABLE 7-13 DRA A SUMMARY OF EPIDEMIOLOGIC STUDIES WHICH EXAMINED POSSIBLE CORRELATIONS BETWEEN OCCUPATIONAL VINYL CHLORIDE EXPOSURE AND PRIMARY CANCERS OF THE LIVER STUDY INCREASING INCREASING SMR RESULT DOSE1 F/U TIME2 Byren et al. Waxweiler et al. Fox & Collier Bertazzi et al. Masuda Weber et al. 3 Theriault & Allard Nakamura 413a 1155b 141a 800a 500a 1523b 6.25a 236a Significant Significant Significant Significant Significant Significant Significant Significant -- ... Yes ... ... Yes ... Yes Yes Yes ... ... ... Yes No Yes 1 - Does risk increase with higher estimated doss? 2 - F/U tins - Follow-up time (yssrs) Dos* risk lnerssss with longer latency? 3 - Reledve risk, not SMR ap < 0.05 bp < 0.01 7-48 * CMA 010447 TABLE 7-14 DRAFT A SUMMARY OF EPIDEMIOLOGIC STUDIES WHICH EXAMINED POSSIBLE CORRELATIONS BETWEEN OCCUPATIONAL VINYL CHLORIDE EXPOSURE AND BRAIN CANCER STUDY INCREASING INCREASING SUE RESULT DOSE1 m, Tins2 Byren et al. Waxweiler et al. Fox & Collier Bertazzi et al. Weber et al. 3 Cooper 612a 329* 55 125 535* 203a Significant Significant + Significant Significant -- ... Yes ... No -*- ... Yes --- . ... No ,,_ 1 - Does risk Increase with higher estimated dose? 2 - F/U Time - Follow up time (years) Does risk increase with longer latency? 3 - Cooper's data are used in the most recent reevaluation of the Tabershsw, Gaffey and EEH cohort. V* 0.05 non-significant positive trend for increased risk (p < 0.05) 7-49 * CMA 010448 DRAFJ risk of liver cancer was seen to increase with both increased dose and a longer follow-up time (Table 7-13). 2.5.2 Other Cancers The association between vinyl chloride exposure and increased risk for other cancers Is not as clear as that for liver cancer. Some evidence associates exposure to vinyl chloride with increased mortality ratios for brain cancer, lung cancer, and lymphoma. Since these cancers appear more commonly in the general population than LAS and primary liver cancer, it becomes more dificult~to show increased risk. 2.5.2.1 Brain Cancer Workers exposed to vinyl chloride appear to be at greater risk for brain cancer than do non-exposed populations. Of the six studies that assessed the risk of brain cancer, five showed a positive trend for increased risk of this cancer type following exposure to vinyl chloride, with four demonstrating statistical significance (p < 0.05) (Table 7-14). Cancer risk increased an average of four times above that expected in the general population in those studies chat exhibited a significantly increased risk. Of the two studies not showing a significant increase in risk for brain cancer, statistical power in the Bertazzi and associates study was only about 35% (Bertazzi et. 7-50 CMA 010449 al., 1979). while that of Fox and Collier (1977) vas approximately 80% (Beaumont and Breslow, 1981). In the Fox and Collier study, the number of deaths overall was low and, most importantly, a large percentage of workers in the cohort was very recently employed in the vinyl chloride industry and thus had a short follow-up time. These factors may partially explain why this study failed to detect an association between vinyl chloride exposure and brain cancer. 7.2.5.2.2 Lung Cancer remains inconclusive. Analyses of SMRs for cancer of the lung were performed in 12 studies (Table 7-15). Of these, seven studies showed an increased risk for lung cancer, but only one was statistically significant at the 5% level (Buffler et al., 1979). This increased risk persisted after adjusting for personal smoking habits (for this particular cohort). However, this cohort was small and the study vas unable to demonstrate an increased risk for any other cancer. The Vaxweiler et al. cohort (which had a follow-up period greater than 15 years) also used a small group (1976). Of all the studies that examined the risk for lung cancer, only those of Fox and Collier (1977) and Cooper (1981) have greater than 80% power to detect increased relative risks (of 1.5 or 2) for lung cancer following exposure to vinyl chloride. Both of these studies found no statistically significant increased risk for lung cancer. 7-51 CMA 010450 DRAFT Lymphoma An association between vinyl chloride exposure and lymphoma has not been established. Five studies evaluated the risk of lymphoma development among workers occupationally exposed to vinyl chloride (Table 7-16). Four of the studies showed a positive trend for lymphoma among vinyl chloride workers, but statistical significance was noted only by Weber et al. (1981). However, the statistical power in all of these studies was less chan 80% to demonstrate a relative risk of two, and less chan 40% to show a relative risk of 1.5. .2.6 Exposure Information Most of the published epidemiologic studies did not present quantified exposure data. Levels of exposure were estimated by job classification and length of employment. Only the studies by Ott and co-workers (1973) and Buffler and associates (1979) contain measured industrial hygiene data. After the workers were classified according to exposure levels, the cohorts were too small t* yield any statistically significant correlations. A dose*iW response relationship cannot be constructed based on these kinds of human data. This conclusion was also reached by the United States Environmental Protection Agency (1986). 7-52 * CHA 010451 .ABLE 7-15 DRAFT A SUMMARY OF EPIDEMIOLOGIC STUDIES WHICH EXAMINED POSSIBLE CORRELATIONS BETWEEN OCCUPATIONAL VINYL CHLORIDE EXPOSURE AND LUNG CANCER STUDY Duck et al. Ott et al. Byren et al. Waxweiler et al. Fox $ Collier Buffler et al. Bertazzi et al. Masuda et al. 3 Cooper Heldass et al. Theriault & Allard** Nakamura 103 77 168 156 90 268* 91 125 107 180 .36 86 RESULT INCREASING DOSE1 INCREASING F/U TIME2 + + Significant f H m -*... -- ... No ... ... *"Yes ... ... mmm No -- ... - ; Yes ... -- ... ... No ... '*- -^ 1 - Do** risk increase with higher estimated dose? 2 - F/U tin* - Follow-up time (years) Does risk increase with longer latency? 3 - Cooper's daca is used in ch* most recent revaluation of the Tabershaw, Gaffey and EEH cohorts. 4 - Relative risk, not SMR + - non-significant positive trend for increased risk (p < 0.05) ap < 0.05 7-53 CMtS 10452 TABLE 7-16 DRAFT A SUMMARY OF EPIDEMIOLOGIC STUDIES WHICH EXAMINED POSSIBLE CORRELATIONS BETWEEN OCCUPATIONAL VINYL CHLORIDE EXPOSURE AND LYMPHOMA STUDY Waxweiler et al. Fox & Collier Bertazzi et al. Weber et al. ,,Cooper 3 SMR 159 100 133 214a 112 RESULT INCREASING DOSE1 INCREASING F/U TIME2 3 + + Significant + -- ... ... + --* Yes ... ... ... _,,_ 1 Does risk increese with higher estimated dose? 2 - F/U time - Follow-up time (yeers) Does risk increese with longer latency? 3 - Cooper's dete ere used in the most recent reveluetion of the Tebershev, Geffey end EEH cohorts. ap < 0.05 + - non-significent positive trend for increesed risk (p < 0.05) 7-54 CMA 010453 Conclusions Epidemiologic studies of workers exposed to high levels of vinyl chloride indicate that this chemical is a human carcinogen. Strong evidence suggests that vinyl chloride causes an increased risk for angiosarcoma of the liver. Vinyl chloride appears to be associated with a moderately increased risk for brain cancer, but current epidemiologic evidence does not demonstrate a significant correlation between vinyl chloride exposure and subsequent development of lung cancer or lymphoma. Exposure data in humans are inadequate to construct a dose-response curve for any of^the cancers studied. However, exposure levels can be estimated, and appendices B and C discuss the potential human health risk.for vinyl chloride using exposure estimates for the tfaxweiler et al. <1976) study of occupationally-exposed workers. 7-55 oK>454 DRAFJ CMA 010455 3.0 QUANTITATIVE CARCINOCENIC_RI5K.ASSESSMENT DRAFT 8.I Introduction Vinyl chloride has been demonstrated to be a carcinogen in multiple species of laboratory animals, including rats, mice and hamsters. Inhalation exposure of rats to low doses of vinyl chloride (<250 ppm) led predominantly to formation of hepatocellular carcinomas, neoplastic nodules of the liver, mammary tumors and nephroblastomas, while higher exposures were associated with liver and lung angiosarcomas, neuroblastomas, and zymbal gland carcinomas. Feeding studies have confirmed these results. Vinyl chloride has also*'been identified as a human carcinogen by IARC (1979), the EFA (1984b)*, and the State of California (CDHS, 1985). Epidemiologic evidence has linked occupational exposure to vinyl chloride with the development of liver angiosarcomas in chronically exposed workers. Several aspects of vinyl chloride metabolism (reviewed in Section 2 of this document) are relevant to its carcinogenicity. First, the oncogenicity of vinyl chloride appears to be due to one or more reactive metabolites, rather than the parent molecule; and secondly, the metabolism of vinyl chloride is a saturable, dose-dependent process. The rate of formation of the carcinogenic metabolites is limited by the metabolism of the parent compound, and once the enzyme systems responsible (alcohol dehydrogenase and cytochrome P-450) become saturated, administering a larger dose of vinyl chloride may not necessarily result in a significantly greater tumor incidence. CMA 010456 8-1 D* * l\m exposure concentrations above 250 ppm may exceed :he metabolic capacity of these enzymes, and thus exposures to higher concentrations have to be evaluated with this caveat in mind. There are many inherent difficulties and uncertainties involved in using animal data to determina human risk. Because of this, risk estimates have been calculated from different species, sexes, experiments and tumor types. Several adjustments need to be made to the experimental exposure data to calculate the lifetime daily exposure (LDE) levels. Thus, for inhalation exposures, the reported dose must be multiplied by: H/24: where H is the hours of exposure per day. This converts tha exposure period to a time weighted average for 24 hours daily continuous exposure. D/7: where D is the number of days exposed per week. This converts the dosing schedule to a time- weighted average for a seven day/week continuous exposure. Le/L: where La is the length of the experiment and L is the lifespan of the animal (the longer of Le or 24 months). This converts the experimental protocol to a continuous lifetlsw exposure. The staff of DHS has used the linearized multistage computer program GL0BAL86 to calculate potential risks associated with vinyl chloride exposure. The multistage model may be expressed as: P<4> -1 - .-(-lo* W2* " + 8-2 010457 CM* ft I\r\r where ?(d) is the lifetime probability of cancer for a given dose d of carcinogen, qQ is a constant that accounts for the background incidence of cancer occurring in the absence of carcinogen, and q^, q^, ... q^ are coefficients that allow the data to be expressed to various powers of the dose of carcinogen to obtain the best fit of the model to the data. 3.2 Analysis of Data from Maltoni et al The most sensitive site, sex and species in which a significant increase in tumor formation was observed following exposure to vinyl chloride appear to be the mammary gland in female Sprague-Dawley^'rats from the Maltoni et al. BT15 experiment (Table 7-8). A statistically - significant increase in malignant mammary gland tumors was observed following a one year exposure to levels as low as 5 ppm. This experiment (BT15) has several potential problems associated with it: 1) the observed mammary tumor incidence in both treated and control animals was elevated compared to the results obtained from other Maltoni at al. vinyl chloride experiments (Table 7.8); and 2) there is no observable dose-response trend over the entire dose range of the experiment (0-25 ppm); tumor incidence at the 5 ppm dose level greater chan at the 25 ppm level. Risk estimates can be calculated by the linearized multistage model for both the entire dose range as well as for the first three doses (0, 1, and 5 ppm) where the tumor incidence increases with the dose. The 95% upper confidence interval of the cancer potency slope for mammary tumors for the entire exposure protocol in BT15 suggests a lifetime risk of 8-3 CMA 010458 DRAFT 2.i x *0 /ppb; analyzing just the 0, 1, and 5 ppm dose levels yields a risk estimate of 1.9 x 10 Vppb. However, there do not appear to be any scientifically justifiable reasons for dropping the two upper doses from the analysis; OHS staff therefore recommends that the * value of 2.4 x 10 /ppb derived from the incidence of mammary gland carcinomas in female rats for the entire exposure range from the BT15 experiment be used as an estimate of risk from vinyl chloride exposure. Risk estimates for mammary gland carcinomas for other Maltoni et al. experiments which demonstrated a significant increase in tumor formation are lower than that derived from the BT15 data (Table 8.1). Maltoni et al. also observed significant increases in the induction of liver angiosarcomas (LAS) following a one-year exposure of rats to vinyl chloride (Table 7.7). Although there is substantial variability in the different data secs, all experiments show a clear trend cowards an increased incidence of LAS, a relatively rare tumor response in laboratory animals. The incidence of LAS in control groups of the experiments evaluated herein is consistent with the low historical control value of 2/541 claimed by Maltoni et al. (1984). These turners were observed in femele rats at experimental exp sures am low as 10 ppm (1/46). Female rats were more sensitive than males to the oncogenic effects of vinyl chloride in all Maltoni et al. experiments (Table 7.7). This Increased sensitivity is reflected in the risk estimates (Table 8.1). Risk values for LAS range from 9.0 x 10' /ppb for male rats in the BT1 experiment to 7.4 x 10* /ppb for female rats from the BT15 experiment. CMA 010459 8-4 DRAFT For some of che inhalation experiments, exposures greatly exceeded the metabolic capability of the enzyme systems involved. Based on the studies of Bolt et al. (1977) and Hefner et al. (1975b), it appears that metabolic saturation is reached at vinyl chloride concentrations of approximately 250 ppm. Maltoni et al. exposed animals to doses as high as 30,000 ppm. Exposure levels in the Bt et al. study reached 3,000 ppm. Tumor incidence and risk estimates derived from the groups exposed to concentrations greater than 250 ppm may not accurately reflect the oncogenic potential of vinyl chloride. Thus, although risk estimates for the entire range of exposures from the Maltoni et al. BT1 experiment and the Bi et al. -i study have been calculated, DHS staff recommends that only that risk estimates based on exposures of less than 250 ppm be considered valid estimates of cancer risk. This choice preempts the need to adjust for saturation in the risk calculations since many experimental results using animals exposed to concentrations below 250 ppm are available. Table 8.1 gives risk estimates calculated by the linearized multistage model for IAS and other tumor types from both male and female rats for inhalation experiments done by Maltoni et al., Bi et al., and Drew et al. for the entire exposure range, as well as for exposures of less than 250 ppm. 3.3 Analysis of Data from Bl et al. Bi et al. (1985) measured liver and lung angiosarcomas in rats following an 18-month exposure to either 0, 10, 100, or 3000 ppm vinyl chloride. A significant increase in tumor induction at both 8-5 CMA 010440 * DRAFT sices was observed, especially for ehe high-dose group. The vinvl^^ chloride concencracion in che high-dose group would almost certainly have saturated the metabolizing enzymes involved. Since lung cancers have been linked to vinyl chloride in occupationally exposed workers, risk estimates for lung angiosarcomas have been estimated using the data of Bi et al. (1985). Risk estimates for liver and lung angiosarcomas for exposure scenarios of 0 to 100 ppm and 0 to 3000 ppm have been calculated, and are included in Table 8.1. Risks based on the 0 to 100 ppm exposure range are substantially greater. The risk for liver angiosarcomas calculated from the 0 to 100 ppm data was 3.6 x 10 Vppb, while che risk for lung angiosarcoma for Che same group was 1.6 x 10 -6/ppb. *% 8-4- ^nalvaia of Paw frgg-Bryf al Drew et al. evaluated the effects of age and length of exposure on vinyl chloride-induced carcinogenicity in female rats, mice and hamsters (Drew et al., 1983). Female Golden Syrian hamsters, F-344 rats, CD-I Swiss mice, and B6C3F1 mice were exposed to 200, 100, 50 and 50 ppm vinyl chloride, respectively, six hours/day, five days/week for 6, 12 and 18 months. These doses are established maKetnogenie levels of vinyl chloride for each species. The rats and hamsters also underwent exposure periods of up to 24 months. The risk assessments were based on those exposure durations demonstrating the greatest tumorigenic response in each species. Because exposure scenarios were limited to a single concentration per species, lifetime daily exposure equivalents were calculated using the 8-6 CMA 010461 different exposure lengths DR/\f as the primary variable (instead of the dose, as is more customary). Hemangiosarcoma was the most sensitive tumor type, and the most sensitive sex and species were female B6C3F1 mice. Except for female F-344 rats, the authors made no distinction between liver hemangiosarcomas and hemangiosarcomas found at other sites. Hemangiosarcomas in B6C3F1 mice yielded a risk estimate of 4.2 x 10 -4/ppb. The 95% upper confidence Interval for mammary gland carcinomas in female CD-I Swiss mice suggest a risk of 6.1 x 10 -4 /ppb. The most sensitive tumor site in female F-344 rate was the liver hemangiosarcoma, with an estimated risk value of 3.7 x 10"5/ppb; for female Syrian golden hamsters, mammary gland carcinoma was the most sensitive site, with a risk value of 5.3 x .5 10 /ppb. The risk estimates for these and the remainder of the Drew et al. study are found in Table 8.1. 3.5 Human Studies The prior review of the epidemiological studies (Section 7.2 of this document) strongly suggests a causal association between vinyl chloride and several different types of cancer, including liver, lung, and brain. Although exposure data from the occupational cohort studies were inadequate to derive a dose-response curve, other historical industrial hygiene data can be used to reconstruct a range of likely exposures from which risk estimates can be derived (Appendix B). Using this approach the exposure level associated with CMA 0104A2 8-7 DRAFT 3. one in a million risk for these carcinogenic endpoints vas^^ estimated as 0.485 ppb and Che estimated risk per ppb as 2.1 x *6 10 /ppb (Appendix B, Table D). If the assumption is made chat just liver cancer (the tumor type for which the epidemiologic evidence is strongest) is associated with vinyl chloride exposure, the risk per ppb is estimated to be 1.0 X 10 ^/ppb. In a more recent study of vinyl chloride workers, Heldaae et al. (1984) linked vinyl chloride exposure with malignant melanomas of the skin, lung cancer, colon cancer, and thyroid cancer, strengthening the association between vinyl chloride exposure and the development of human cancers. 3.6 Choice of Appropriate Risk Estimates '.9 ' Table 8.1 has identified a range of human and animal cancer potency values (q) from vinyl chloride inhalation carcinogenicity studies in laboratory animals. These potency values can be converted to risk estimates by the equation: dose x potency - risk. Therefore, 1 ppb x (3.9 x 10*6 (ppb)'1) - a risk of 3.9 x 10'6 foe a lifetime exposure to 1 ppb vinyl chloride. Human risk was estimated from rodent data as follows: <vvEstimated Human Risk - Rodent Risk <Wh)2/3/(Wr) 2/3 -1 8-8 % CMA 0104A3 where and Ijj are the inhalation rates of rodents and humans. respectively, and and W are the body weights of rodents and humans, respectively. Humans are assumed to weigh 70 kg and inhale 20 ra3/day. The inhalation rates (I) for mice and rats were estimated using the following formulas (EPA, 1985): 12/3 3 For mice: X - 0.0345 wt (kg)/0.025 (kg)j in /day For rats: I - 0.0105 wt (kg)/0.113 (kg)j 2/3 m3/day (Biology Data Book, 1974). Rodent bodyweight values for the studies of Maltoni et al. (1984) and Bi et al. (1985) were derived from data provided in the respective publications. Rodent bodyveights were not given for the Drew et al. (1983) study, and were estimated to be 300 g for rats, 30 g for mice, and 92 g for hamsters. Human risks associated with vinyl chloride exposure as estimated from the animal data range from 2.4 x 10 *6/ppb to 5.0 x 10 -3 /ppb, as shown in Table 8.2. Due to reasons previously discussed (which include 'metabolic saturation and experimental variability), the staff of DH5 believes that a more appropriate range of risks lies between 3.9 x 10 /ppb and 1.8 x 10* /ppb (Table 8.3). Using data from Maltoni and Lefemine (1975), the EPA (1984) calculated a unit risk of 6.8 X 10 6 (ppb)*-1 . This was converted to a human qj of 2.5 x 10 -2 1 - 5 -1 (mg/kg/day)* , equivalent to a q of 1.8 x 10 (ppb) The human q 's from the analysis herein range from 3.9 x 10 ^ (ppb) ^ to 1.8 x 8-9 CMA 010464 - 3 -1 .0 ,ppb) , a range which includes the EPA's potency value of 1.3 x 10*3(ppb) "l. Appendices B and C detail the calculation of human risk from estimates of occupational vinyl chloride exposure, determined to be 2.1 x 10'Vppb. Considering the potential differences in exposure duration, oncogenic sensitivity of different species, age of exposure, sex, and levels of exposure, the estimated unit risk values for the human epidemiologic data and those calculated from animal data are consistent with one another. Since many of the tumors associated with vinyl chloride exposure (particularly LAS) exhibit a long latency period, exposure at an early age would produce a greater risk. The average latency period for the development of LAS in occupationally exposed vinyl chloride workers was determined to be 22.1 years (Stafford, 1983). Drew et al. (1983) demonstrated that in rats, mice and hamsters, the highest incidence of neoplasms was observed when vinyl chloride exposure was started early in life. Exposures early in life may produce up to a 10-fold greater incidence in tumors compared to exposures late in life. The BT15 experiment by Maltoni et al. (1984) suggests that mammary gland carcinoma may be a more sensitive indicator of vinyl chloride exposure than LAS, with SfSk estimates of 6.3 x 10 -4/ppb and 1.9 x 10 -4/ppb for the tw tumor types, respectively. Also, examination of the Drew et al. data (Table 8.3) indicates that the maimsary gland is a more sensitive endpoint than LAS. Thus, it is possible that an epidemiologic study of adult males measuring the incidence of LAS may underestimate the actual risk associated with vinyl chloride exposure. Although there 8-10 CMA 010445 are significant difficulties associated with extrapolating oetween animals and humans, the animal studies have the benefit of examining both sexes for a greater proportion of their lifetimes. The human epidemiology studies have been conducted primarily in adult male vinyl chloride workers, which may not adequately estimate risks for the general population. 8-11 CMA 01046A TABLE .1. RANGE OF CANCER POTENCY VALUES FOR VINYL CHLORIDE CALCULATED FROM ANIMAL CARCINOGENICITY STUDIES Experiment Species and Sex Tumor Type Experimental Exposures (ppn) LDE . <PP") > *> q animal. (ppb) Maltonl et al. ' 17 ^ BT1 rat, male rat, female rat, female BT2 rat, female rat, female BT9 rat, male rat, female rat, female BT15 rat, male rat, female rat, female rat, female 00 1 IO B1 et al. rat, male rat, male rat, male rat, male LAS LAS LAS LAS mammary gland LAS LAS mammary gland LAS LAS mammary gland mammary gland 0-10,000 0-10,000 0-250 0-200 0-200 0-50 0-50 0-50 0-25 0-25 0-25 0-5 LAS LAS lung angiosarcoma lung angiosarcoma 0-3000 0-100 0-3000 0-100 0-595 0-595 0-14.9 0-11.9 0-11.9 0-3 0-3 0-3 0-1.5 0-1.5 0-1.5 0-0.3 0-482.1 0-16.1 0-482.1 0-16.1 9.0 x 1l00 16 2.7 x 101 1.5 x 1.5 x 10 5 1.3 2.6 x x l100 -5l 6.0 x 110014 1.6 x 2.9 x 10 5 7.4 x 10 4 2.4 1.9 x x 1100-33 8.1 x 10 5 3.6 x 10 6 2.3 x 10"-5 1.6 x 10 5 9 *0 X 0 VWO Drew et al rat, female rat, female rat, female B6C3F1 mouse, female B6C3F1 mouse, female CD-I Swiss mouse, female CD-I Swiss mouse, female CD-I Swiss mouse, female hamster, female hamster, f male hamster, female LAS mammary gland hepatocellular carcinoma hemangiosarcoma mammary gland hemangiosarcoma mammary gland lung carcinoma hemangiosarcoma skin carcinoma , mammary gland 0-100 0-100 0-100 0-50 0-50 0-50 0-50 0-50 0-200 Q?20Q 0-200 0-17.9 0-8.9 0-17.9 0-4.5 0-2.2 0-4.5 0-2.2 0-4.5 0-2.2 0-17.9 0-17.9 3.7 3.1 x x 1100'55 1.7 x 10 l 4.2 x 10_5 2.5 x 10 4 1.5 x 10 4 6.1 x 10 4 1.2 x 10 5 2.5 x 10's 2.0 5.3 x x 1100 55 ILDE - Lifetime Daily Exposure (in ppm) 2 95S^Hper Confid nee Interval 3 LAS - Liver Angiosarcoma O "n TABLE 8.2. RANGE OF HUMAN RISKS FOR VINYL CHLORIDE EXPOSURE ESTIMATED FROM ANIMAL CARCINOGENICITY STUDIES Experiment Sp|fts and Sex Estimated Height (kg) Estimated Inhalation Rate (m /day) Estimated human Risk/ppb Maltoni et al. BT1 rat, mala rat, female rat, female BT2 rat, female rat, female BT9 rat, male rat, female BT15 rat, female rat, male rat, female rat, female rat, female 00 1 w Bi et al. rat, male rat, male rat, male rat, male .425 .275 .275 .275 .275 .600 .400 .400 .600 .400 .400 .400 .300 .300 .300 .300 .254 .190 .190 .190 .190 .320 .244 .244 .320 .244 .244 .244 .201 .201 .201 .201 A 2.4 x 10 7.1 x 10 3.9 x 10 " 3.9 x 10 j! 3.4 x 10 ^ 6.8 x 10 l 1.6 x 10 ^ 4.2 x 10 j! 7.6 x 10 1.9 x 10 6.3 x 10 , 5.0 x 10 2.1 x 10'^ 9.5 x 10 * 6.0 x 10 : 4.2 x 10 CMA 0 1 0 4 6 8 Drew et al. rat, female rat, female rat, female B6C3F1 mouse, female B6C3F1 mouse, female CD-I Swiss mouse, female CD-I Swiss mouse, female CD-I Swiss mouse, female hamster, female hamster, female hamster, female .300 .300 .300 .030 .030 .030 .030 .030 .092 .092 .092 .201 .201 .201 .039 .039 .039 .039 .039 .086 .086 9.7 X 108.1 X 10~5 4.5 X 10 5 1.2 X 10 5 7.3 X 10_4 4.4 X 10 5 1.8 X 10 4 3.5 X 10-5 7.0 X 10 5 5.6 X 10-4 1.5 X 10 Se text for discussion of estimating the inhalation rat and hunan risk. po DRAFT TABLE 8.3. SELECTED HUMAN RISK ESTIMATES FOR LIFETIME EXPOSURE TO 1 PPB VINYL CHLORIDE1 Experiment Species and Sex MaiConi ec al. BT1 BT2 BT9 BT15 rac, female rac, female rac, female rat, male rac, female rac, female Mosc Sensiclve Tumor Site LAS2 LAS LAS LAS maimiiary gland LAS 95% Upper Confidence Interval (risk/ppb) 3.9 x 10* 3.9 x 10*f 1.6 x 10*3 6.8 x 10'; 6.3 x 10*, 5.0 x 10*J 3i ec al. rac, male rac, male LAS lung angiosarcoma 9.5 x 10` 4.2 x 10: Drew ec al. rac, female B6C3F1 mouse, female CD-I Swiss mouse, female hamster, female Appendices B and C human, male human, male LAS hemangiosarcoma mammary gland mammary gland liver liver, lung and brain 9.7 x 104? 1.2 x 10?4 1.8 x 10*; 1.5 x 10*4 1.0 x 10* 2.1 x 10* ^"Estimates war* salaccad. on cha basis of the most sensitive species, sex, and tumor sice for experimental exposure scenarios of less chan 250 ppm 2 LAS - Liver Angiosarcoma & 8-14 CMA 010449 9.0. INCLUSIONS DRAr 9.1 Acute Toxicity Vinyl chloride has a relatively low degree of acute toxicity in experimental animals; two-hour inhalation LD^q values are greater than 200,000 ppm in several species. Exposure to high concentrations can lead to narcosis, cardiovascular and respiratory irregularity, convulsions, cyanosis and death. Several human deaths have been attributed to occupational exposure to very high levels of vinyl chloride. Autopsies of these patients revealed congestion of the liver, spleen and kidneys. 9.2 Subchronic and Chronic Toxicity Chronic exposure of workers to vinyl chloride has been shown to lead to "vinyl chloride disease", characterized by occupational aero-osteolysis, vasospasm of the hands similar to Raynaud's syndrome, dermatitis, circulatory and central nervous system alterations, thrombocytopenia, splenomegaly and changes in liver function (Veltman et al., 1975). Spirtas et al. (1975) measured tfaa frequency of eight symptoms comtonly reported by workers exposed to vinyl chloride (including dizziness, headaches and nausea) and observed a dose-response relationship using exposure levels estimated from job classifications. These symptoms were observed even at dose levels below 50 ppm. CMA 010470 9-1 * 9.3 Pharmacokinetics DRAFT Approximately 42% (but up to 71%) of an inhaled dose of vinyl chloride was absorbed by both man and rats. Oral exposure results in more complete absorption. Radiolabeled vinyl chloride metabolites have been detected in a range of tissues, suggesting thorough distribution. Most of the metabolized vinyl chloride is excreted by the kidney, often as glutathione conjugates. Unmetabolizad vinyl chloride is eliminated primarily by pulmonary excretion. Both alcohol dehydrogenase and cytochrome P-450 are involved in the 4 metabolism of vinyl chloride. The evidence suggests that reactive metabolites may be responsible for the toxic effects of vinyl chloride, with the most likely candidates thought to be chloroethylene oxide and chloroacetaldehyda. The metabolism of vinyl chloride appears to be dose-dependent and saturable, with higher doses incompletely metabolized. It has been suggested chat saturation^ of the metabolizing enzymes occurs at exposure scenarios between 100 and 300 ppm, with 250 ppm chosen jiiiln as the concentration necessary to achieve metabolic saturation. 9*2 % CHA 010471 1 Reproductive Toxicity DRAFT No teratogenic or embryotoxic effects were observed in mice, rats or rabbits exposed to vinyl chloride at maternally toxic doses during gestation. A recent study has suggested that vinyl chloride can cross the placental barrier of exposed pregnant female rats and cause liver cancer and angiosarcoma in the offspring. Epidemiologic studies have suggested a possible increased rate of fetal deaths in women whose husbands were occupationally exposed to vinyl chloride. However, additional studies have concluded that there was no association between vinyl chloride exposure and fetal death% or birth defects. -? 9.5 Mutagenicity Vinyl chloride has been identified as a mutagen in bacteria, yeast and animal systems, both with and without addition of an exogenous metabolic activation system. Chloroacetaldehyde and chloroethylene oxide, the putative toxic metabolites of vinyl chloride, were also mutagenic. Levels of chromosomal aberrations and sister chromatid . exchanges were higher in workers exposed to vinyl chloride (20 to l50 ppm) than for unexposed control groups. Workers exposed to less than 15 ppm showed no differences in chromosome breaks or aberrations from controls. 9-3 CMA 010472 Carcinogenicity DRAFT Both experimental animal studies and epidemiological studies of worker populations have demonstrated that vinyl chloride is carcinogenic. The International Agency for Research on Cancer (IARC) reviewed the literature on vinyl chloride mutagenicity and carcinogenicity and concluded that vinyl chloride is a proven human carcinogen (IARC, 1979) and placed vinyl chloride in its carcinogenicity group 1. Substances assigned to this category have demonstrated sufficient evidence to support a causal association between exposure and cancer in humans. ^ * IARC also noted chat, "...several independent but mutually confirmatory studies have shown that exposure to vinyl chloride results in an increased carcinogenic risk in humans, involving the liver, brain, lung and hamolymphopoletic systems in man." They also noted in "two proportionate mortality studies ... there appeared to be an increased proportion of cancer of the digestive system in both sexes and possibly of the urinary system and of the breast in woman," and "there is* no evidence that there is an m^eeur* level below which no increased risk of cancer would occur 'im humans" (IARC, 1979). The Environmental Protection Agency (EPA, 1984b) has likewise reviewed the data and also concluded that vinyl chloride is a proven human carcinogen. The EPA placed vinyl chloride in its group A as a proven human carcinogen. 9-4 CMA 010473 DRAFT Although both EPA and the National Academy of Science have concluded that there were insufficient data to base a quantitative carcinogenic risk assessment from epidemiological studies, DHS staff have included a human risk assessment using an estimation of exposure made by Barnes (1976) and Paddle (1986) (see Appendices B and C). The estimated incremental lifetime risk of liver, lung, and brain tumors as a result of vinyl chloride exposure is 2.1 x 10 -6/ppb. This risk is several orders of magnitude lover than that calculated from data for female mouse liver angiosarcomas or mammary gland carcinomas (Drew et al., 1983). * The animal studies demonstrated a relationship between tuAor formation and the sex and age of the animal at first exposure. Fetuses, newborns, younger animals, and females exhibited the highest carcinogenic sensitivity (Drew et al., 1983). In the epidemiological studies of vinyl chloride workers, who were predominantly male, the average age at first exposure was 29.7 years. Thus, to protect all members of the general population, it is- more appropriate to- base risk assessment calculations on the animal inhalation studies, which were based on a more representative portion of the population actually at risk. The staff of the Department of Health Services conclude that: 1. Vlnvl chloride is mutagenic and _a proven animal and human carcinogen. 9-5 CHA 010474 2. Since vinyl chloride is genocoxic and chere is no experimental evidence chat-- chloride has a carcinogenic threshold. 1 = should not be--considered to have__ ana. Animal evidence has demonstrated that vinyl chloride is carcinogenic at a lifetime daily exposure of 0.06 ppm. Potential human residential exposures may be only from six to 60-fold lower chan chose in the animal studies. 3- Vinvl__ chloride has been demonstrated to__ cause a number of malignant tumor types in. animals. including angiosarcoma of bot^ the liver and lung, hepatocellular carcinomas, several different lung tumors.__ brain__ tumors, and other types of cancers. Vittyl A' chloride has been shown to cause liver angiosarcoma in humkns and epidemiological evidence suggests that vinyl chloride may Induce lung, breast, and brain tumors. Vinyl chloride has been demonstrated to be multislce carcinogen, and the risk analysis performed by the staff of CMS reflects this finding. (VLLntifitly.__ risk assessments of the relevant animal inhalation rans* of to 3.9 x 10 /oob occwtriwl vinyl exposure has been estimated herein to be 2.1 x lO*^/nnb (Appendices B and C). Thus, alth ugh the human risk estimate is based on a historical reconstruction of occupational exposures, it is close to the range estimated from animal studies. Vinyl chloride has noc been detected in 9-6 CMA 010475 ....i DRAFT che ambient air of California (limie of detection - 0.5 ppb). The California Air Resources Board has monitored vinyl chloride emissions from the BKK landfill in West Covina and the Oil landfill in Monterey Park. Estimates of peak exposure concentrations for maximally exposed receptors range from 2 to 10 ppb at the BKK landfill and 0.6 to 9 ppb at the Oil site. The Air Resources Board has estimated that between 17,000 and 131,000 individuals may be exposed to 1 ppb at the BKK site. A lifetime exposure of 131,000 residents to 1 ppb would be associated with an upper bound estimate of 0.5 to 236 excess cancer cases. These calculations represent an upper range at plausible excess cancer risk: the actual risk, which cannot be calculated, may be insignificant. CM* 010476 9-7 CMA 010477 REFERENCES Anderson D, Hodge MCE and Purchase IFH (1977) Dominant lethal studies with the halogenated olefins vinyl chloride and vinylidene dichloride in male CD-I mice. Environ Health Perspect 21:77-78. Anderson D and Richardson CR (1981) Issues relevant to the assessment of chemically induced chromosome damage ia vivo and their relationship to chemical mutagenesis. Mutat Res 90:261-272. Bardin CW, Taketo T, Gunsalus GL, Koide SS and Mather JP (1982) The detection of agents that have toxic effects on the testis and male reproductive tract. In: The Banbury Report. Vol. 11: Environmental Factors in Human Growth and Development, pp. 337-355. Barlow SM and Sullivan FM (eds.) (1982) Reproductive Hazards of Industrial Chemicals. Academic Press, London, pp. 566-582. Barnes AV (1976) Vinyl chloride and the production of PVC. Proc Roy Soc Med 2:278-281. Bartsch H, Malaveille C and Montesano R (1975) Human, rat and mouse Livermediated mutagenicity of vinyl chloride in . tvphimurlum strains. Int J Cancer 1^:429-437. Bartsch H and Montesano R (1975) Mutagenic and carcinogenic effects of vinyl chloride. Mutat Res 32:93-114. Basalaev AV, Vazine AN 'and Kochetkov AG (1972) On the pathogenesis of changes developing due to a long-term exposure to the effect of vinyl chloride. Gig Tr Prof Zabol 12:24-27. Cited in EPA, 1984. Basler A and Rohrborn G (1980) Vinyl chloride: an example for evaluating mutagenic effects in mamals in viyo after exposure to inhalation. Arch Toxicol 22:1-7. 0 Beaumont JJ and Breslow NE (1981) Power consideration in epidemiologic studies of vinyl chloride workers. Am J Epidemiol 114:723-734. Bertazzi PA, Villa A, Foa V, Sail B, Fabbri L, Mapp C, Mercer C, Manno M, Marchl M, Mariani F and Bottasso F (1979). An epidemiological study of vinyl chloride exposed workers in Italy. Arg Hig Rada Toksikol 30:403-409 (Supp$>. Bi W, Vang Y, Huang M and Meng D (1985) Effect of vinyl chloride on testis in rats. Ecotoxicol Environ Safety 12:281-289. Biology Data Book (1974) P. L. Altman and D. S. Dittmer, Eds. Published by the Federation of American Societies for Experimental Biology, Bethesda, MD. Volume III, p. 1741. Bolt HM, Filser JG and Buchter A (1981) Inhalation pharmacokinetics based on gas uptake studies. III. A pharmacokinetic assessment in man of "peak concentrations" of vinyl chloride. Arch Toxicol 22*213-228. R-l CMA 010478 3olt HM. Kappus H, Buchter A and Bolt W (1976) Original Investigations. Disposition of (1,2- 14 C) vinyl chloride in the rat. Arch Toxicol 35:153162. Bolt HM, Laib RJ, Kappus H and Buchter A (1977) Pharmacokinetics of vinyl chloride in the rat. Toxicol 2:179-188. Buchter A, Bolt HM, Kappus H and Bolt W (1977) Die gewebsverteilung von 1,2- 14C-vinylchlorid bei der rattc. Int Arch Oceup Environ Health 2:2732. Buchter A, Bolt HM, Filser JG, Goergens HW, Laib RJ and Bolt W (1978) Pharmakokinetlk und karzlnogenese von vinyl chloride. Arbeitsmedizinische Risikobeurteilung. Verh Dtsch Ges Arbeitsaedizln (Centner, Stuttgart) 18: 111-124. (cited in Bolt et al, 1981). Buchter A (1979) Erarbeitung elner speziellen arbeitsmedizinischen Uberwachungsuntersuchung in korrelation zur individvellen Vlnylchlorid- Exposition. Forschungsbericht des Landes Nordrhein-Westfalen. Fachgruppe Medizin, Nr. 2813, Westdeutscher Verlag, Opladen, (cited in Bolt et al., 1981). * Buchter A, Filser JG, Peter H and Bolt HM (1980) Pharmacokinetics f vinyl chloride in the Rhesus monkey. Toxicol Lett ft:33-36. s Buffler PA, Wood S. Elfler C, Suarez L and Kllian DJ (1979) M reality experience of workers in vinyl chloride monomer production plant. J Occup Med 21:195-202. Byren D, Engholm G, Englund A and Westerholm P (1976) Mortality and cancer morbidity in a group of Swedish VCM and PCV workers. Environ Health Perspect 17:167-170. California Department of Health Services (CDHS, 1985) Guidelines for Chemical Carcinogen Risk Assessments__ and Their__ Scientific Rationale. California Department of Health Services, Health and Welfare Agency, Sacramento, CA. California Health and Safety . Code (1988) Chapter 3.5: Toxic air contaminants; section 39650. la: California Air Pollution Control Laws. Calfo^mle Air Resources Board, Sacramento, CA. . Caputo ^ Viola PL and Blgottl A (1974) Oncogenicity of vinyl chloride at low concentrations in rats and rabbits. Int Res Commun 2:1582. Clemmesen J (1982) Mutagenicity and teratogenicity of vinyl chloride monomer (VCM). Epidemiologic evidence. Mutat Res 2ft:97-100. Cooper WC (1981) Epidemiologic study of vinyl chloride workers: mortality through December 31, 1972. Environ Health Perspect 1:101-106. Creech JL Jr., and Johnson MM (1974) Angiosarcoma of liver in the manufacture of polyvinyl chloride. J Occup Med 1ft:150-151. R-2 CMA 010479 I Dahar, VS, 3ond, GG, McLaren, EA, Sabel, FL, LIpps, TE and Cook, RR (1988) Update to vinyl chloride mortality study. J Occup Med 30:648-649. Danziger H (1960) Accidental poisoning by vinyl chloride: Report of two cases. Can Med Assoc J 82:828-830. Orevon C, Kuroki T and Montesano R (1977) Microsome mediated mutagenesis of a Chinese hamster cell line by various chemicals (abstract). 2nd International__ Conference__ 20__ Environmental Mutagens. Edinburgh, 1977, p. 150. Drew RT, Boorman GA, Haseman JK, McConnell EE, Busey WM and Moore JA (1983) The effect of age and exposure duration on cancer induction by a known carcinogen in rats, mica, and hamsters. Toxicol Appl Pharmacol 68:120130. Drodzdowicz BZ and Huang PC (1977) Lack of mutagenicity of vinyl chloride in two strains of Neurosnora crassa. Mutat Res 48:43-50. Du JT, Tseng MT and Tamburro CH (1982) The effect of repeated vinyl chloride exposure on rat hepatic metabolizing enzymes. Toxicol Appl Pharmacol 62:1-10. .i Duck BU, Carter JT and Coombes EJ (1975) Mortality study of workers in a polyvinyl-chloride production plant. Lancet 11:1197-1199. Duprat P, Fabry JP, Gradlski D and Magadur JL (1977) Metabolic approach to industrial poisoning: blood kinetics and distribution of 14C vinylchloride monomer (VCM). Acta Pharmacol Toxicol Suppl 41:142-143. Duverger M, Lambotte E, Malvolsin E, deMeester C, Pancelet F and Mercier M (1981) Metabolic activation and mutagenicity of vinylic monomers (vinyl chloride, styrene, acrylonitrile, butadiene). Toxicol Eur Res 2:131-140. Duverger-Van Bogaert M, Lambotte-Vandspaer M, deMeester C, Mercier M and Pancelet F (1982) Vinyl chloride and acrylonitrile: activation mechanism and mutagenicity. Toxicologie Experimentale 35-37. Edmonds, LD, Falk H and Nissim JE 01975) Congenital malformations and vinyl chlorida. Lancet 11:1098. Edmonds 1$, Anderson CE, Flynt JW Jr and James LM (1978) Congenital central nervoue system malformations and vinyl chloride monomer exposure. A community study. Teratology 17:137-142. Environmental Protection Agency (EPA) (1984a) Ambient Water Quality Criteria for Vinvl Chloride. Draft. U.S. Environmental Protection Agency. Health Effects Branch, Criteria and Standards Division. Office of Drinking Water, Washington, D.C. Environmental Protection Agency (EPA) (1984b) Health Effects Assessment for Vinyl Chloride. Office of Health and Environmental Assessm nt, Cincinnati, Ohio. R-3 CMA 010480 Environmental Protection Agency (EPA) (1985) Addendum to the Health Assessment Document for Dichloromethane (Methylene Chloride). Updated Carcinogenicity Assessment of Dichloromethane (Methylene Chloride). EPA 600-8-82/004F. Equitable Environmental Health, Inc, (EEH) (1978) Epidemiological study of vinyl chloride workers. Prepared for Manufacturing Chemists Assoc. Fabricant JD and Legator MS (1981) Mutagenicity studies of vinyl chloride. Environ. Health Perspect 41;189-193. Feron VJ, Kruysse A and Til HP (1979a) On* year time-sequence inhalation toxicity study of vinyl chloride in rata. I. Growth, mortality, hematology, clinical chemistry and organ weights. Toxicology 13:25-28 Feron VJ, Spit BJ, Ammel HR and Kroes R. (1979b) One-year time-sequence Inhalation toxicity study of vinyl chloride in rats. III. Morph logical changes In the liver. Toxicology 13:145-154. Feron VJ, Hendriksen CFM, Speck AJ, Til HP and Spit BJ (1981) Lifespan oral toxicity study of vinyl chloride in rats. Food Cosmet Toxicol 19:317-333. Filser JG and Bolt HM (1979) Pharmacokinetics of halogenated ethylened in rats. Arch Toxicol 2:123-136. - Fox AJ and Collier PF (1977) Mortality experience of workers exposed to vinyl chloride monomer in the manufacture of polyvinyl chloride in Great Britain. Br J Ind Med 3:1-10. Gamble J, Liu S, McMichael AJ and Vaxweiler RJ (1976) Effect of occupational and nonoccupatlonal factors on the respiratory system of vinyl chloride workers. J Oeeup Med 18:659-670. Garro AJ, Guttenplan JB and Mllvy P (1976) Vinyl chloride dependent mutagenesis; effects of liver extracts and free radicals. Mutat Res 14=81-88. Green T and Hathway DE (1975) The biological face in rats of vinyl chi ride In relation to its oncogenclty. Cham-Biol Interact 11:545-562. Green t and Hathway DE (1977) The chemistry and biogenesis of the Scontafttlat metabolites of vinyl chloride in rats. Chem-Biol Interact H:lMSO. Grain H, Bonse G, Radwau Z, Reichert D and Heuachler D (1975) Mutagenicity in vitro and potential carcinogenicity of chlorinated ethylenea as a function of a metabolic oxirane formation. Blochem. Pharmacol 2:2Q132017. Groth DH, Coate WB, Ulland BM and Hornung RW (1981) Effects of aging on the Induction of angiosarcoma. Environ Health Perspect 1:53-57. R-4 CMA 010481 r^ ' " IJ l'\ n i Guengerich FP and Strickland TW (1977) Metabolism of vinyl chloride: destruction of the heme of highly purified liver microsomal cytochrome P-450 by a metabolite. Mol Pharmacol 1?:993-1004. Guengerich FP and Watanabe PG (1979) Metabolism of (^CJ- and (36C1]-labeled vinyl chloride in vivo and in vitro. Biochem Pharmacol 28:589-596. Hansteen IL, Hillestad L, Thiis-Evensen E and Heldaas SS (1978) Effects of vinyl chloride in man. A cytogenetic follow-up study. Mutat Res 51:271278. Harris EA and Adams WGF (1967) Acro-osteolysis occurring in men engaged in the polymerization of vinyl chloride. Brit Med J. 2:712-714. Hatch GG, Mamay PD, Christensen CC, Casto BC, Langenbach R and Nesnow S. (1981) In vitro transformation of hamster embryo cells exposed to gas ous or volatile chlorinated hydrocarbons. Proc Am Assoc Cancer Res 2%:119 (abstract). Heath CW Jr, Falk H and Creech JL Jr (1975) Characteristics of casern of angiosarcoma of the liver among vinyl chloride workers. Ann NY Acad Sci 246:231-236. Hefner RE Jr, Watanabe PG and Gehring PJ (1975a) Preliminary studies on .the fate of inhaled vinyl chloride monomer (VCM) in rats. Environ Health Perspect 11:85-95. Hefner RE Jr, Watanabe PG and Gehring PJ (1975b) Experimental Studies. Preliminary studies of the fate of inhaled vinyl chloride monomer in rats. Ann NY Acad Sci 24$:135-148. Hefner RE Jr, Watanabe PG and Gehring PJ (1975c) Percutaneous absorption of vinyl chloride. Toxicol Appi Pharmacol' 34:529-532. Heger M, Muller G and Norpoth K (1982) Untersuchunger zur beziehung zwischen vinylchlorid (VCM) - aufnahme und metabolitenausscheidung bei 15 VCMexponierten. IZ. Messunger zur ausscheidung das VCM-metab liten thiodiglykosaure im ham. Int Arch Oceup Environ Health 187-196. Hehir SMt McNamara BP, McLaughlin J, Willigan DA, Bierbower CT and Hardisty JF (199&) Cancer induction following single and multiple exposures to a constant amount of vinyl chloride monomer. Environ Health Perspect 41:6372. Heidelberger C, Freeman AE, Pierta RJ, Sivak A, Bertram JS, Casto BC, Dunkel VC, Francis MW, Kakunaga T, Little JB and Schectman LM (1983) Cell transformation by chemical agents--a review and analysis of the literature. Mutat Res 114:283-285. Heldaas SS, Langard SL and Anderson A (1984) Incidence of cancer among vinyl chloride and polyvinyl chloride workers. Br J Ind Med 41:25-30. R-5 * CMA 010482 Hemminki K and Vineis P (1985) Extrapolation of the evidence on the teratogenicity of chemicals between humans and experimental animals: chemicals other chan drugs. Teratogen Carcinogen Mutagen 5:251-318. Hong CS, Winston JM, Thornburg LP, Lee CC and Woods JS (1981) Follow-up study on the carcinogenicity of vinyl chloride and vinylidene chloride in rats and mice: tumor incidence and mortality subsequent to exposure. J Toxicol Environ Health :909-924. Hopkins J (1979) Vinyl Chloride. Part 1: Metabolism. Food Cosmet Toxicol 12:403-412. Huberman E, Bartsch H and Sachs L (1975) Mutation induction in Chinese hamster V-79 cells by two vinyl chloride metebolites, chloroethylene oxide and 2-chloroacetaldehyde. Int J Cancer 16:639-644. Infante PF (1976) Oncogenic and mutagenic risks in communities with polyvinyl chloride production facilities. Ann Ny Acad Sci 271:49-57 International Agency for Research on Cancer (IARC) (1979) IARC Monograph* nn hS__ Evaluation of Carcinogenic Risk of Chemicals to Humana: Volume-.19, Some Monomers, Plastics and Synthetic Elastomers, and Acrolein. International Agency for Research on Cancer, Lyon, France, pp. 377-438^ * Jenssen 0 and Ramel C (1980) The micronucleue test as part of a short-(farm mutagenicity test program for the prediction of carcinogenicity evaluated by 143 agents tested. Mutat Res 75:191-202. John JA, Smith FA, Leong BKJ end Schvetz 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 and Schvetz BA (1981) Vinyl chloride: inhalation teratology study in mice, rats and rabbits. Environ Health Perspect 41:171-177. Kalmaz EE and Kalaes CD (1984) Carcinogenicity and epidemiological pr file analysis of vinyl chloride and polyvinyl chloride. Regul Toxicol Pharmacol &:13-27. Keplinggg^- ML, Good# JV, Gordon DE and Calandra JC (1975) Interim results of expoeOB* of rats, hamsters, and mice to vinyl chloride. Ann NY Acad Sci Krahn DF (1979) Utilization of the CHO/HGPRT system: metabolic activation and method for testing geses. In: Hsie, A. W., O'Neill, J. P., and McElkeny, I. K. (eds.). M--aHan Cell Mutagenesis: The Maturation of Test Systems. Benbury Report No. 2, Cold Spring Harbor Laborat ry, Cold Spring Harbor, NY, pp. 251-261. Krajevski J, Dobeckl M and Gromiec J (1980) Retention of vinyl chloride in the human lung. Br J Ind Med 37:373-374. R-6 CMA 010483 Df\ r\ r-""\ a r* h Kucerova M. Polivkova Z and Batora J (1979) Comparative evaluation of the frequency of chromosomal aberrations and the SCE numbers in peripheral lymphocytes of workers occupationally exposed to vinyl chloride monomer. Mutat Res 7:97-100. Kuzmack AM and McGaughy RE (1975) Quantitative Risk Assessment for Community Exposure to Vinyl Chloride. U.S. Environmental Protection Agency, Washington, D.C. Laib RJ and Bolt HM (1977) Formation of imidazole derivatives of nucleic acid bases (ONA and RNA) by metabolites of vinyl chloride In vivo and In vltrq- In: Proceedings__ of the 4th Meeting of the European Association for Cancer Research. Lyon, France, p. 84. Lee CC, Bhandari JC, Winston JM, House WB, Peters FJ, Dixon RL and Woods JS (1977) Inhalation toxicity of vinyl chloride and vinylidene chloride. Environ Health Perspect 21:25-32. Lee CC, Bhandari JC, Winston JM and House WB (1978) Carcinogenicity of vinyl chloride and vinylidene chloride. J Toxicol Environ Health 4:15-30. Lelbach UK and Marstaller HJ (1981) Vinyl-chloride associated disease. In: Advances in Internal Medicine and Pediatrics. Sprlnger-Verlag, Berlin.' Leonard A, Decat G, Leonard ED, Leferver MJ, Decuyper LJ and Nicaisa c (197.7) Cytogenetic investigations on lymphocytes from workers exposed to vinyl chloride. J Toxicol Environ Health 1:1135-1141. Lester D, Greenberg CA and Adams WR (1963) Effects of single and repeated exposure of humans and rats to vinyl chloride. J Am Ind Hyg Assoc 24:265275. Lills R (1981) Review of the pulmonary effects of poly (vinyl chloride) exposure. Environ Health Perspect 4^:167-169. Lilis R, Anderson H, Nicholson WJ, Daum S, Fischbein AS and Selikoff IJ (1975) Prevalence of disease among vinyl chloride and polyvinyl chloride workers. Ann NY Acad Sci 2&&:23-41. Loprieno N, Barale R, Baroneelll S, Bauer C, Bronzetti G, Camelii A, Cercianspsii G, Cars! C and Gervasi-Turckl G (1976) Evaluation of the genecivr effects induced by vinyl chloride monomer under mammalian metabmllc activation studies In vitro and la vivo. Mutat Res 40:85-96. Maltoni C and Lefemine G (1975) Carcinogenicity assays of vinyl chloride: current results. Ann NY Acad Sci 246:195-224. Maltoni C, Lefemine G, Ciliberti A, Cotti G and Caretti D (1984) Experimental Research on Vlnvl Chloride Carcinogenaala. In: Maltoni C, Mehlman MA (eds.) Archives of Research on Industrial Carcinogenesis. Vol- II. Princeton Scientific Publishers, Inc., Princeton, New Jersey. CMA 010484 R-7 * Marsteller HJ and Lelbach WK (1975) Unusual splenomegallc liver disease as evidenced by peritoneoscopy and guided liver biopsy among polyvinyl chloride production workers. Ann NY Acad Sci 246:95-134. Masuda Y (1979) Long term mortality study of vinyl chloride and polyvinyl chloride workers in a Japanese plant. Arh Hig Rada Toksikol 30:403-409 (Suppl). McCann J. Simmon V, Streitwieser D and Ames BN (1975) Mutagenicity of chioroacetaldehyde, a possible metabolic product of 1,2-dichloroethane (ethylene chloride), chloroethanol (ethylene chlorohydrin), vinyl chloride, and cyclophosphamide. Froc Natl Acad Sci USA 22:3190-3193. Miller A, Teirscein AS, Chuang M, Selikoff IJ and tfarshaw R (1975) Changes in pulmonary function in workers exposed to vinyl chloride and polyvinyl chloride. Ann NY Acad Sci 246:42-52. Mirkova E, Minailova A and Noska M. (1978) Embryonic and teratogenic action of vinyl chloride. Khigiena i Zdraveopazvana 23:440-443. Mohn GR (1981) Mutagenicity of selected chemicals in Escherichia coli test systems. Xq: de Serres, F. J., and Shelby, M. 0. (eds.) Comurtetvi Chemical Mutagenesis.--Environmental__ Science Research. Volume 24, Planum Press, New York, pp. 69-108. Monson RR, Peters JM and Johnjon MN (1974) Proportional mortality among vinyl-chloride workers. Lencetii pp. 397-398. Muller G, Norpoth K, Kuatars E, Herweg K and Versln E (1978) Determination of thlodlglycollc acid in urine specimens of- vinyl chloride xpos d workers. Int Arch Occup Environ Health 41:199-205. Nakamura J (1983) A mortality study of vinyl chloride workers in Japan. J UOEH 2:49-57 (Suppl). 4 Nicholson UJ, Hammond EC, Seldman H and Selikoff IJ (1975) Mortality experience of a cohort of vinyl chloride-polyvinyl chloride workers. Ann NY Acad Sci 225-230. Oct MG, Langner RR and Holder BB (1975) Vinyl chloride exposure in a controlled industrial environment. Arch Environ Health 30:333-339. -+X ' Paddle #(1M() Personal correspondence to A. H. Smith. Perrard MH (1985) Mutagenicity and toxicity of chloroethylane oxide and chioroacetaldehyde. Experientla 41:676-677. Peter S and Ungvary G (1980) Lack of mutagenic effect of vinyl chloride monomer in the mammalian spot test. Mutat Res 22:193*196. Picciano DJ, Flake RE, Gay PC and Kilian DJ (1977) Vinyl chloride cytogenetics. J Occup Med 19:527-530. R-8 CHA 010485 Probsc GS, McMahon RE, Hill CE, Thompson CZ, Epp JK and Neal SB (1981) Chemically-induced unscheduled DNA synthesis in primary rat hepatocyte cultures: a comparison with bacterial mutagenicity using 218 compounds. Environ Mutagen 1:11-32. Prodan L, Suciu I, Pislaru V, Ilea E and Pascu L (1975a) Experimental acute toxicity of vinyl chloride (monochloro-ethene). Ann NY Acad Sci 246:154158. Prodan L, Suciu I, Pislaru V, Ilea E and Pascu L (1975b) Experimental chronic poisoning with vinyl chloride. Ann. NY Acad. Sci 246:159-163. Purchase IFH, Richardson CR and Anderson D (1975) Chromosomal and dominant lethal effects of vinyl chloride. Lancet, August 30, 1975. Purchase IF, Stafford J and Paddle GM (1987) Vinyl chloride: an assessment of the risk of occupational exposure. Food Cham Toxicol 25:187-202. Radike MJ, Stammer KL and Bingham E (1981) Effect of ethanol on vinyl chloride carcinogenesis. Environ Health Perspect 41:59-62. Radike MJ, Warkany J, Stemmer K, and Bingham E (1988) Perinatal carcinogenesis induced by inhaled vinyl chloride. Toxicologist &;|66 (abstract 660). * Rinsky RA, Ott G, Ward E, Greenberg H, Halperin W and Leet T (1988) Study of mortality among chemical workers in the Kanawha Valley of West Virginia. Am J. Ind Hyg li:429-438. Rosenkranz HS (1981) Mutagenicity of selected chemicals in Escherichia coli DNA repair deficient assays. In: deSerres, F. J., and Shelby, M. D. (eds.), Comparative Chemical Mutagenesis. Environmental Science Research. Volume 24, Plenum Press, Nev York, pp. 5-18. Rossner P, Sram RJ, Novakova J and lamhl V (1980) Cytogenetic analysis in workers occupationally exposed to vinyl chloride. Mutat Res 73:425-427. Selikoff IJ and Hammond EC (eda.) (1975) Toxicity of vinyl chloridepolyvinyl chloride, Ann NY Acad Sci 246. Short RD* Minor JC, Winston JM and Lee CC (1977) A dominant lethal study in male rats after repeated exposures to vinyl chloride or vinylidene chloride. J Toxicol 2:965-968. Smulevich VB, Fedotova IV and Filatova VS (1988) Increasing evidence of the rise of cancer in workers exposed to vinyl chorlde. Br J Ind Med 4:9397. Sokal JA, Baranski B and Majka J (1980) Experimental studies on the chomic effects of vinyl chloride in rats. J Hyg Epidemiol Microbiol Immunol 24:285-294. R-9 CMA 010486 spengler S and Singer B (1981) Transcriptional errors and ambiguity resulting from the presence of l,N6-ethenoadenosine or 3,N^-ethenocytidine in polyribonucleotides. Nucleic Acids Res 9:365-373. Spirtas R and Kaminski R (1978) Angiosarcoma of the liver in vinyl chloride/polyvinyl chloride workers. Update of the NXOSH Register. J Occup Med 20:427-429. Spirtas R, McMichael AJ, Gamble J and VanErt M (1975) The association of vinyl chloride with morbidity symptoma. Am Ind Hyg Assoc J 779-789. Stafford J (1983) Liver angiosarcoma case registry, ICI. (cited in Maltoni et al. , 1984). Stanford Research Institute (SRI) (1983) Vinyl chloride, la: Monographs on Organic Air Pollutants. Final Report, prepared by SRI International for the National Cancer Institute, contract No. N01-CF-26004-02, pp. 375-395. Styles JA (1980) Studies on the detection of carcinogens using a mammalian cell transformation assay with liver homogenate activation, la: Norpoth KH and Gamer RC (eds.), Short Term Test Systems for Detecting Carcinogens. Springer-Verlag, New York, pp. 226-238. Sueiu I, Prodan L, Ilea E, Paduraru A and Pascu L (1975) Clinical manifestations in vinyl chloride poisoning. Ann NY Acad Sci 246:53-69. Suskov II and Sazonova LA (1982) Cytogenetic effects of epoxy, phenolformaldehyde and polyvinylchloride resins in man. Mutat Res 104:137-140. Suzuki Y (1980) Non-naoplastie effects of vinyl chloride in mouse lung. Environ Res 21:235-253. Suzuki Y (1981a) Electron microscopic observations of hepatic and subcutaneous heaengiosarcomas induced in mice exposed to vinyl chloride monomer. Am J Ind Med 2:103*117- Suzuki Y (1981b) Neoplastic and nonneoplastlc effects of vinyl chlorid in mouse lung. Environ Health Perspect 41:31-52. Tabershfm IS. sad Gaffey UR (1974) Mortality study of workers in the manufae|nnt of vinyl chloride and its polymers. J Occup Msd 509-518. Tassignftt JP (1980) Msthodologit du crsicement des dormdes de 1'etude du Profeseur Maltoni. Raport to the XX Heating of "La Club de Canc6rog6n6sa chlnioue" (Inetitut der Radium-Fondetion Curie, Peris, 1979). Publications Essestlelles, pp. 113-125. Testa B and Jaimar P (1981) Inhibitors of cytochromo P-450s and their mechanism of action. Drug Matab Rav 12-' 1-117. Theriault G and Allard P (1981) Cancer mortality of a group of Canadian workers exposed to vinyl chloride monomer. J Occup Med 23:671-676. R-10 010487 CHA Theriault G, Zcurra H and Gingras S (1983) Evaluation of the association between birth defects and exposure to ambient vinyl chloride, teratology 21:339=370. Thomas LB and Popper H (1975) Pathology of angiosarcoma of the liver among vinyl chloride-polyvinyl chloride workers. Ann NY Acad Sci 246:268-777 Til HP, Immel HR and Feron VJ (1983) Lifespan Oral Carcinogenicity Study of Vinyl Chloride. In. Rats. Prepared by the Netherlands Organization for Applied Scientific Research, Division -for Nutrition and Food Research (C1V0 Institute TNO) Report No. V 83.215/291099** Torkelson MS, Qyen, F end RowVg (19tl);Thw teglfity of vinyl chloride as determined by, repeated exposure^ of 1abesstery animals. 1 Am Ind Hyg Assoc 22:354-361. Torkelson TR and Rowe VKr (1981) Halogeneted aliphatic hydrocarbons containing chlorine bromine and iodine^ Im- Patty*s Industrial Hygiene 3rd Revised Edition, vol. 2B, Chapter 48, pp. 3433-3601. Tu. AS, Murray TA, Hatch Hi, Sivak A sad tfllman HA (1983) Is transformation of BALB/C-3T3 calls by< chlorinated ethanes end ethyls Cancer Lett 28:85-92. Ungvary G, Hudik, A, Tratui E, Lorincz ti and Felly G- (1978) Effects of vfhyl chlorida exposura alone and in combination with Trypan Blue--applied systematically during all thirds of pragnancy on the fetuses of CFy rats. Toxicology 11:45^54. .. .... or.- Veltman G, Lange CE, Jvhf .iesvtS**-* G.-gnd-*dBhe* M (1973) Clinical manifaatations and course of vinyl chloride disease. Part I. Toxicological isTmseigytlgpiff yipy1.eb^og&d**pylyvipy1 chloride. Ann NY Acad Sci 244:7-17^ . .j- looisssT .ri crai 7- *t : Verburgt FG Vogel E (1197) Vimyl chloride mutagenesis in Drosophila melanocaster. Mutat Rea 48:327-334. Viola PL, Bigotti A and Caputo A (1971) Oncogenic response of rat skin, lungs, and bonaa to vinyl chloride. Cancer Rea 21:516-522. PF (1980) A review of the Methodological approaches in i association between vinyl chloride exposure end In Infants PF, Legator MS (1980) `Proceedings of a Methodology for Assessing Reproductive Hazards in the Workm Publication No. 81-100, Washington, DC, pp. 43-49. Ward AM, Udnoon S, Vetkina J, Walker AE end Darke CS (1976) Immunological mechanisms in the pathogenesis of vinyl chloride disease. Br Med J 1:936938.14 14 Watanabe PG, McGowan GR, Madrid EO and Gehring PJ (1976a) Fata of ( C)vinyl chloride following inhalation exposure in rats. Toxicol Appl Pharmacol 21:^9-59. R-ll CMA 010488 DRAF Watanab after 352. - PG, McGowan GR and Gehring PJ (X976b) Face of (14C)vinyl chloride single oral administration in rats. Toxicol Appl Pharmacol 3^:339- Watanabe PC, Zempel JA and. Gehring PJ (1978a) Comparison of the fate f vinyl chloride following single and repeated exposure in rats. Toxicol Appl Pharmacol 44:391-399. Watanabe PC,- Zempel JA, Pegg DC andsCobtlng PJ (1978b) Hepatic meeromolecular binding following exposure-to vinyl chloride. Toxicol Appl Pharmacol 44:571-57$: - - > - .... Maxwells* RJ; Stringer W, Wegener Jte) Falt B awTarbaea J' (1976) Neoplastic risk -among workers exposed tevlnyl chloride. Ann- NY= Acad Scl 271:40. 48. Weber H, Relttl V and Greiser E (1981) German" investigation on morbidity and mortailicy of_ workers exposed to- vinyl chloride. Environ Health Perspeet 41:95-99. -- ; -- Wilson WH, McCotmiek WH and Tatum CP (1967)^ Occupational acrooateoly report of* 31 eases. J An-Mad Aasoe 201:83-8^ -- -- Withey JR (1976) Pharmacodynamics and uptake of vinyl chloride non administered" by*- varioum route* terrace. J' Toxtdd*Efcviron Health 1: 39*, Woo YT, Lai DY, Arcos JC and Argus MF (1985) Chemical Induction of Cancer. Structural Baaes and Biological Mechanisms, voliaa I1IB, Aliphatic and Polyhaloganated-Carcindgana. Adadamdc Press, tae.;pm-. 3-1Z90* ir ** ..i or.'. awu.'r'.-.j Zuccace Vi (ttrcuak-F^and^iiGkiaibi-il ^19**) Tb*1 tSTV> op fcmspitfction in vinyl chloride excretion la rats. Toxicol Let* : 213-2174 ^4 f .i ' i mflanni it~"n|"rh r**T'> M i** one jit aeg -jaJjJM. I . ><*.a o^mepoarcO 'a oiuqeG -is * " veivw* a ; OVbf.' Vi * -* Tii. i* /r?fpP&zf ^ R-12 CMA 010*89 * 'hi & T ' "A '*jc * jv .**'* *u W"~ : - !**' AggandU A Absences of Msleoni si^trHtWkr1^ A .T , . Mpssssys , ,- , ; . 6l.s i j4b *,sj_s a .JJ. ~ . *5j -*< j..'. .-)>-j *>> '. S .* A.i-.'a* ZZ J* -.0 iV'Io I "X *- ; :t%*sw *tbo4 . *.%<ajmal<rt i*3i* 4v <*i' ztsi^ .->i-m-i3 -Jgg|- sfoattaw -is***ssd insitlSib ^isaso-n .i*. . jo-o :*** iwvwis** i *i* ssjsbtj it **tci**i-- ososoib uosiailiusai *4T *-4^i ., a .0" - t ...: .:. 4s ;to to :i iasii . r -. ...tr .., _ CMA 010490 A-X Intraperitoneai Administration DRAFT Rats: groups of 30 male and 30 female 13-week-old Sprague-Dawley rats received an intraperitoneal injection of 4.25 mg vinyl chloride in oliv oil on 1, 2, 3, or 4 occasions over a two-month period and observed for the duration of their lives (145 weeks). One nephroblastoma and one subcutaneous angiosarcoma were found. No difference in survival or body weight was observed between test animal* end controls. This experiment was considered inadequate for the determination of the carcinogenic potential of vinyl chloride because of the unconventional dosing protocol, used (Experiment BT12, Maltoni et al., 1984). Subcutaneous Administration &**: In a separate studyV a gtOup of 75 male and female Sprague-Dawley rats was administered a single subcutaneous injection, of 4.5 mg vinyl chloride in 1 ml olive oil at 21 weeks of age and observed fox the remainder of their lifetime (145 weeks after injection). Body weight and survival were not significantly different between controls and treated animals. One nephroblastoma in a treated male was observed (Experiment BT13, Halt ni et Fflelent protocol prevents any assessment f the chloride from this experiment. Trnipltctptgl fareqrirt Rats: Groups of pregnant female Sprague-Dawley rats were exposed from day 12 to day 18 of gestation to 6,000 or 10,000 ppm vinyl chloride. The A`2 CMa 010492 m females and offspring were observed for their lifetimes (143 weeks after start of. experiment). Survival of the offspring was poor after week 95 of the experiment. Several animals from both groups exposed in utero had mammary tumors, zymbal gland carcinoma, leukemias and nephroblastomas; no hepatic angiosarcomas or hepatomas were reported. No results from control animals were reported, thus statistical evaluation of these results is not possible. Only a few tumors were found in the female breeders (Experiment > BT5, Halton! at al., 1984; IARC, 1979) TranwUctnul-InhaUUqn ExpMmi Rats: Groups of 12-week-old pregnant Sprague-Dawley rats were expo :o either 0 or 2,500 ppm vinyl chloride four hours/day, five days/week for seven weeks, then seven hours/day for 69 weeks, after which time all animals t . .. . *t' died. One group of offspring was first exposed trsnsplacentally from day 12 - . \,;w , i"*"1 of gestation, then exposed by inhalation after birth using the same :*, - . . . ..arsv. - r.:z . :.~3ns>e>x 7*aT; J protocol. A second group of offspring was also exposed trsnsplacentally ' . : '>'?>. MM/ ; . / : _ v; ji *;.?;> i iA. 1 3' :3 it f- . from day 12 of gestation but was exposed by inhalation four hours/day, five .. jiunsreisrti ;oe: dT io 'fxo-r c* days/week for seven weeks, then seven hours/day, five days/week for eight bib iSaev .A i^niv ` An increased incidence of zymbal gland tumors (8/54), liver angiosarcomas (27/54), hepatomas (5/54), and neuroblastomas (32/54) were reported for the C*A 010492 A- 3 breeding females exposed Co vinyl chloride, compared co 1/60, 0,60, 0/60, 1/60, respectively, in the controls. r In the male offspring exposed to vinyl chloride for 76 weeks, 9/63 had zymbal gland carcinomas, 36/63 had liver angiosarcomas, 27/63 had hepatomas. and 31/63 had neuroblastomas, compared to 2/138, 0/138, 1/158, and 0/158, - k respectively, in cha controls. In thm female offspring exposed to vinyl . -***' > 1..' . .>,> > #;car*. ayJ vl - -'TnC chloride for 76 weeks, 6/64, 28/64, 38/63, and 28/64 were reported for these ' ' ; 7.-, " 'a above tumors respectively compared to zero tumor incidence in the controls. The incidence of these same tumors in cha male offspring exposed t vinyl - _____ L'.i-jm . .... chloride for only 15 weeks was 7/59, 24/39, 42/39,, and 7/59 for the same tumors respectively,, compared to 2/138, 0/138, 1/158, anC 0/ respectively, in the controls. In female offspring exposed foe on! ..... ->ri "C t: ' weeks, the incidence was 2/60, 28/60, 43/60, sad 11/60 for the same tumors, " .... ' ;Ji.J 4W ' , J l -U" respectively, compared to a zero incidence of these tumors in c ntrols. . haeoqxe saw These studies (BT40O1, BT4006) were cited by Maltonl and colleagues <1984) - ,_rrw safe* i rti fcjr. -1 iiifca as an example of transplacentally-induced-tumorigenesis, but wee, in effect, < ij -seeqxe eeiO tad Is ' wovg bourse A an investigation of thm increased sensitivity of yomg. experimental animals iiuor1 iiol fflofeAtwteJ ** tUMdffnt 7d dohsoeg~c s.X -'--a co che toxic effeeto.of vinyl chloride. The turner incidence in breeders and -*ev\sy^ jgg| .*dSi*r ** *ct aee* ,vf offspring exposed te- vinyl chloride for 78 weeks did not appear to diffar of these parameters wee node in the report (Heltoni et al., 1984; Experiments BT4001, BT4006). i A-4 >0493 Inhalation Exposure Hamsters: Groups of 30 male Syrian golden hamsters were exposed to 0, SO, 250, 500, 2,500, 6,000, or 10,000 ppm vinyl chloride, four hours daily, five days weekly for 30 weeks, beginning at 11 weeks of age. The hamsters were then observed for their lifespan (109 weeks). Two liver angiosarcomas were observed in eha group exposed to 500 ppm vinyl chloride and one liver angiosarcoma was observed in the group exposed to 6,000 ppm. The increased incidence of forestomach epithelial tumors in hamsters exposed to 500 ppm or more of vinyl chloride appeared to be biologically significant but no statistics were reported (Experiment BT8, Maltoni et al., 1984). 'v A-5 CHA 010494 ;wo~3 i - 7 ,..tf - .xj *.,= ?! .i->j -", v* *fp. CMA 01049S DRAFT j ,5$i j ._>* :, AoDndlx B- zoi.. Cancer Risk Assessment for Vinyl*Gfelorida- Besed On Hunan Data - * . ' M ,, mJJfi * . .4. i ; .? ^ ^ l * n-: '... a.'jc : * v^w .jV -is- * r rv. f : i, :a #r: ,*(wi ^ fj. ' T** Ji, Stf3 , iM^SfCK B*1 CMA 010496 Introduction The main problem with using epidemiological data for health risk ass ssment is Che frequent lack of suitable quantitative exposure data. Exposure data from animal bioassays are, by comparison, markedly more accurate. However, a major source of potential error in using animal data for human health risk a; iment la the animal - to - human extrapolation of risk. It follows that the decision to use epidemiological data in health-based risk assessments should not be based solely on contrasting the quality of exposure dat available for humans with chat fee animal studies, but should also take into account ocher important variables such as the observed tumor type an latency period of the.tumors endec study4 In fact, the decision concerning use of human versus animal data in a health-baaed risk assessment should esko into account the main source of error from eaeh approech: cho exposure data for huaun studies end the animal-to-human extrapolation for animal studies. In the letter cas , one would hope that the error la extrapolation to humans was within one order of magnitude. Boosear.- the adjustments msds eo correct for body surface area differences (u|mm .JWtcrapoIating snlmsl bioaaaays to humans) can in itssS|M|^^HgHfof magnitude difference in estimates whan compared to estriM^^^HRPfi|(pfa simple dose par body weight extrapolation. Since other error exist, the uncertainty of animal-to-human extrapolation probably lias within one or two orders of magnitude, except in the case where there may be no effect in an animal modal but an effect In humans (or vico versa). In this case, the error would bo infinite. B-2 CHA 010497 ui\AFT Vhen human studies show a clear relationship between an outcome and an exposure', the question concerning their use in risk assessment should therefore be whether or not one can estimate exposure within one to two orders of magnitude. If sound human studies that enable exposure estimation within one to two orders of magnitude are available, then these studies should be utilized in addition to animal studies in evaluating the human health risk. In the case of vinyl chloride, there are unequivocal epidemiological data that Identify vinyl chloride as a human carcinogen. Although detailed exposure data for the relevant time periods are lacking, estimates caa|be made that should be veil within one order of magnitude of error. WhileSdie methods for estimating past "exposure"airs crude, the true ^exposure rates ^ere considered unlikely to be more then five times higher or lower than estimated."' It follows that the human data may be appropriate for vinyl . > . f Sc-, u* in !-z v..: 1- . chloride cancer risk assessment. * - Assessment ~ WySSTchlqrldf Riak ** 3* xeuiewmelr u> <ti 4id da# jo) lai" tn.' > - undartaiten'toassea* available information regarding by exposure to vinyl chloride. The results of this In Tables B-l and B-2, suggest that the cohort study reported by Waxveiler and co-workers contains the most thoroughly documented information for risk assessment purposes (tfaxwallar et al., 1976). Eleven cases of angiosarcoma of the liver were Identified aiwmg the 1,294 exposed workers. Three additional cases of biliary cancer were seen. Significant B-3 CMA 010498 * excesses of both brain cancer and lung cancer were also observed. The Waxweiler report gives SMRs for liver cancer, brain cancer, and lung cancer. It is apparent from Table B-2 that the SMRs from Waxweiler et al. are consistent with some of the other studies. The cumulative risk of liver, lung and brain cancer following vinyl chloride exposure is greatest in the Waxweiler et al. (1976) report. Thus cancer risks to vinyl chloride workers are unlikely to be substantially underestimated by a risk assessment based on this study. The results reported for the Waxweiler cohort of polyvinyl chloride. (PVC) workers involved a subset who had worked . j" f>o1r1 at least 'ol five years'bet - 1942 and 1973 and who had eoasenced work at, least -tjjenj.byoe/anrs b** efore f llh.Amum was completed. Follow-up for mortality was to the end of 1973. Ildi sv of the cohort was comprised of 1294 workers. There ijsre 136 deaths during the follow-up period o| which 33 ^wero^dua to canger^ TheSMR for biliary and liver cancer was 1133, for brain cancer, 329, and for lung cancer, 136. ;r alz rs-srv:. ' The remainder of this appendix discusses the risk of liver,.lung, and brain . - '-."its. >aT :Qh3Z. A Wi-'VTA cancer for the workers in the Waxweiler et al. (1976) oobo^J^^In additi n, assessments evaluating the risks for each cammar have been recalculated. As in many retrospactiva cohorts, individual exposurs data wero not available (Waxweiler et el., 1976). However, s-ea v,er*a. ,l rep`' o, rts hsve attempted to reconstruct the magnitude of exposure among vinyl chloride workers since B-4 CMA 010499 che 194Q's (Oct et al., 1976; Jones, 1974; Paddle, 1986). Table 3-3 summarizes proposed estimates of exposure for several countries. Most of the data available for specific United States exposure levels utilize measurements determined at a single plant operated by Dow Chemical Company (Jones, - 1974). Although.some Job class exposure* were quite high, most exposures- , war*. less .t&an proposed* international levels during commensurate time periods. However, Dow Chemical Company responded to early reports of vinyl chloride toxicity in animal studies by creating an in-house standard of 50 ppm (Ott et al., 1974; Paddle*: 1986). .This^was well below the acceptable limit during the 1960`s and early 19Z'#andproJ* not represent the average exposure et other vinyl chloride polymi plants. Dow Chemical Company had not reported any esse# efanxlea; the liver to 1985 (Forman at al., 1985). Other exposure* estimates, sucb-aa thee*v presented-by-Bernes and sumarlzed in Tables B-3ap# liirO< this sppendi*#chdP bfltCti.dassriha^ewerege exposure for.., the. tfaseilflisfsjli. ci^rprfllifmenM^^ja^tie^rnrlie^ given by -8erneSb $o Wp^fxponwrf.feg^tepvb^fathnr.he^ualifies his estimate^. 4 by^ * ft|p| renpimmmtl i epinlaBPaghroughout the during, these time., periods. Additionally. the exposure experience among cohorts with angiosarcoma of che liver should be higher when compared to exposure levels in cohorts reporting no angiosarcomas. Consequently, exposure estimates provided by Bernes ars used to quantify cumulative vinyl CMA 010500 chloride exposure for the risk assessment since the group studied by Waxweiler ec al. (1976) was presumably one of the most heavily exposed cohorts and therefore, unlikely to involve exposures lower than th se given by Barnes. Ther employment dates of th* S*xdeflatreej"al. cohort spam 1942-1973. Thus, somo work ttisSorfd#' f#tl '%dlow-; tHw *fmiuliBJw of the first time period provided by Battle*' fJanuary 1, 19499. Thee*' particular- histories were counted separately and assigned ail^ exposure-' level of 1600 ppm. This practice assumes exposure during early process days (pre-19*5) t be the same as that during the 1945-1935 #xpor# period? tttttwBg ,gr ilm Avarigt Cohtrt Biwurt Ba i . . JTH-7 Data for individual exposure estimates for the Waxweiler at al. occupational cohort^ da*' net -exiBa?* ^HBwmv*#? AppdmdixC^tM* dMunft** givM a math d fortneOperastngc average iftposdre^SM* inti* arial iitsssieht analysts used in the folieding miiBarf^^lBtllil-dMKte-S4gl*4ar6eda*efthriver occurred Between - MBwadftvfayl efcloiWa* exp sure and thU IBl tltitr Tr~inllMHrf if :MHHwr*:ranged^from five c dfc-mlf*,* 198WT<wlierd*1^ic*dtlyI Stafford (1983) has calcwj 1 period fb#~ angles ettnme of" UUP liver among vinyl chloidBkldwtda- to b* 22.1 years. The work histories for the cohort were analysed to identify-the person-time in each calendar year for the subset who had at least five years of employment and who began work (and thus vinyl chloride exposure) prior to 1964. These restrictions were incorporated to correspond to the seme restrictions used by Waxweiler and B-6 CHA 010501 co-workers (1976) in generating their SMR values. Thus, the SMR values correspond to those workers with at least five years of exposure and at y least a ten-year latency period from first exposure. The analysis herein assumes chat the average worktime cohort exposure for the period 1942 to 1964 was a time-weighted average of 647 ppm of vinyl chloride. The*plant' had'Sagun operation* in 1942. The year 1964 was chosen as an endpoint since 1969 was Che midpoint of diagnosis of liver angiosarcoma cases and since exposures in the last five years preceding b diyiy 4 *' 4 r diagnosis were probably not relevant to etiology (Smith et al., I960). It is assumed chat this exposure rate'was experienced*for eight hours per fey, rlvtt days pst week, 4$ weeks per year, and chat, outside these times,J . *" '* ` 4 '" ^ ^ O' * V --- exposure tb vinyl chloride wee the seme ss for the general population. Thus, tho average axcess exposura par day is tha average worktime exposure multiplied by^'dTJ)*"*" (5/7) "x ?&6/525 which equals 0.211. The average overall'' xposure*~ rat4'! above ""background^or vinyl chloride workers was ..cu.t.4 co t* o.ttr, Ur^rfWi4JW9#l`aaiirtiat- -a . - ildaaudi'tdd* .>3fie? 3*vu lv mei'eli. ... . Jtsynt : 4T. % nX Id' ?C sawsa aewev .a.Kuao * -fTST- relate to workplace exposures occurring over a riod of time. The SIS for liver cancer was 1155. Tha '`sf- employment fbt* thfT" cohort between 1942- and 1964 was 11.6 years and the average age at first exposure was 29.7 years. Based on the assumptions stated in Appendix C, the adjustment used to extrapolate to lifetime exposure is duration of employment/(age + duration of employment), CMA 010502 B-7 or 11.6/(29.7 + 11.6). Therefore, the average lifetime exposure estimated to resuldt.in a liver cancer SMR of 1155 is [(136 ppm)(0.281)] or 38.3 ppm. Between 1960 and 1979, 67,782 deaths from liver cancer occurred among whits males codes in the United States (International Classification of Diseases (ICD) .* " .. ' '' 'vv 'v ; a r- -~ * 155,136). The total number of death* among the same group was liver cancer. .. .,1; v * Since the workers under discussion in the ffaxveiler et al. cohort had an SMR of 1155, their l^f^time risk^of dyipj^ from liver c^pcfpwould increase above the background rate of one in ^ 270^ An SMR of 1155 laaqulvalent m a relative risk of 11.53^ (Symons and Taulbe^ 1981}^ The lifetime risv f dying from liver cancer calculated herein for workers, exposed to vinyl the added lifetime risk of live* cancer attributable to an exposure rate causing am .exposure to 38.3 ppm of vUgt ekletlde would cause a 39,(MS', in a million increase in the amittm wxii Cancer Including Ireln end tunc Cancer aa gall aa Liver The same approach can be adopted for brain cancer and lung cancer. Evidence for their relationship to vinyl chloride exposure is discussed in th next B-8 CHA <>10503 sections. In the absence of evidence to the contrary, it is assumed that the latency period is the same as for angiosarcoma of the liver. The number of deaths from brain cancer (ICD codes 191 & 192) between I960 and 1979 in the United States was 79,847 (1/229 of deaths), and for lung cancer (ICD codes 160-163, 165) 978,504 (1/18.7 of deaths/. Applying the same procedure indicated* above, the added brain cancer lifetime risk was one in 100 and, for lung cancer, was one tn-39.4,asscSing tRe raVSra^f exposure rate of 38.3 _pp_m_ . -*C'. Brain and Luna Cancer and Vinyl Chloride Exposure While it is clear that exposure to vinylcftldfida 'cause1# "angiosarcoma o e liver, the causal relationship to brain and lung cancer is not so defined. One review suggested that ttiefe- was a eons!seent relationship with brain cancer in occupational studies, but not with lung cancer (Beaumont and Breslow, 1981). ' However; ,ifrwdold ieda appropriate tS consider 'lung cancer in the risk' as*ss4ent ild*g<fc#ft8^iv>^^a^ since this is censidtent **il^V--dohife*ttWa##lr*ttl wlftfanship with lung dtacer* r senst-l^llffiidi^ektiNtfH&iW^aPlllag?' QU^hiHfffr^fcfaronced above focused*ddP athSttldkt-' pd*arBi ljHBpdiMMM? 'df- `tM4H di^ree^ of exposure KtlMs^ddhdtftf^rsafewedr' fW^Untf^iftcer findings vheh cdnsidered,rl!t conjunction with the liver cancer - by each cohort/ Sines excesses of liver cancer can be used as a surrogate indicator of exposure, this suggests that some studies not finding an excess of lung cancer may have been a result of relatively low exposures. B-9 CMA 010504 However, a more recent large study presents evidence against a relationship between lung cancer and vinyl chloride exposure (EHA, 1985). This study considered deaths between 1942 and 1982 inclusive for a cohort of 10,173 men who had worked for at least one year In joba involving exposure to vinyl chloride. The SMR for liver cancer was 841, for brain cancer was 180, but for lung cancer was only 95.8. Moat of.the liver and brain cancer excess was in two of tho 37. plants fording the.cohort. Unfortunately, lung cancer SMRs were not presented for those two plants. In spite of this, tho study provides evidence against a vinyl chloride*lung cancer association. However, without lung cancer data for the two plants with tho highest liver and brain cancer excesses, it would seen inadvisable to completely ei lung csncer from the risk assessment. Confidence Llmlte for the Lifetime Risk Estimates . Confidence . limits -fotr) the risk estimates are calculated by containing the risks, for Ogoot^ggelapme^t fon eech sipf (bJUIVWllS* observed end expected t^j^ oglculating- tfee^SISe-confidance limits of that ..x ThS:93% cenfidanee . . intarval..^ th^liysr csWf^.i*'^-2*^*5#.MtiMta0ths upper 95% tkchm excess, risk?etHimt*t*thevt|pptS limit f excess fi04) la multiplied by the.lifetime;riak^fo* the average * ms liver cancer (1/270), Therefore,. the upper 95% confidence limit for the added risk dun to vinyl chlorido exposure is 23.04 x 1/270 - 0.085 or 1/11.7. B-10 CMA 010505 rf The same calculaCion is used to estimate the upper 95% confidence limit based on liver cancer and brain cancer combined. In this case, the combined observed and expected values for liver and brain cancer (7+3)/(Q.6+0.9) results in 95% confidence interval for the SMRof (319 * 1226). Thus, the upper 95% confidence limit for the excess rials estimate is (12.26* 1)(1/270+1/229), or 1/11.0. For liver cancer, brain cancer, and lung cancer coablned, the observed to expected ratio is 22/9.2 and the 95% confidence interval fay the SMR is (149 362). Using the sane strategy, the,uppar95%.confidence limit for the estimate of added risk, is (3.62 - 1) (1/270,+ -l/22$*,*sl/l*?). or 1/6.20. Extrapolation of Risk to Low Dose Exposure, r W There are many models for extrapolating risks to low dose exposure. The ,, method-of analysis employed here giyee-only onm.exposure feint, and therefore limits the pedals*Chetc-mey he uaed*,;} 6* linear,extrapolation, of excess risk was chosan as the moat appropriate for this analysis. This approach is vary close, to *,,on*hlt drik:sxsrtppisriepeiectnpiillWkJt the one-hit modal extrapolation isyfryj close* t+i a,pultis*#iS*t**owitkclinearizacion '" e U,S. Eynrlronaentel ?r**actio<-Agen*jM*fA) Carcinogen ' ^ sf. use with, enimel data, Tkss* e simple linear $ smiH provide similar results to the more complex multistage model approach that could havo baan used with more extensive data. As indicated In the above section entitled "Lifetime Expoaura Estimations and Risk of Liver Cancer", lifetime exposure to 38.3 ppm of vinyl chloride B-ll CMA 010506 ORA is calculated to increase lifetime liver cancer risk by one in 25.6, or 39,062 la a million. The corresponding unit risk estimate for one in a million added risk is 0.98 ppb. Table B-4 gives corresponding results for the addition of brain cancer and lung cancer and the 95% confidence limits on unit risk exposures. ftaiuaptioai ladJtefitrtilntii The coitffdenee 'limits ehdt v#rS ealddlseed for-the risk estimates measure only ths uncertainty related to the SMRststistics-for workers do not measure the uncertainty"of the risk assessment^process overall, this disk assessment is based on specific assumptions which, if incorrect, affeetenths assessment by either ovttititlag or nedstiratldg^ the tree risk, Ines assumptions are listed below. t. Assumptions arm matt^cCMerniftigthe*exposure*estimitmap* This can affact che^eaadraey^efJthe^rtslt aeti^t** rt eith*r direitfbn.-J . }*>'ilftt elzvisn* kite ici -'i*** 2d ns illim^dll^ betwS>y%l*Sy^retnee ^MrtT'anV lifetime average tin*Mftsnff* - IVerieittibns*ip la batter siiftftttg^ dMng iai***i iiasas* assumption win ' Conversely,; if thi1' relationship is Better described byjPieiftlheir^dfeee, then A llnedr assumption will overstats ths risk. 3. It wss assumed that cancer risks were dependent on cumulative exp sure and not off exposure rate. A given cumulative exposure achieved as an B-12 01057 * D O i\ Z1 \\r>\ 1 adult is assumed to carry the cancer risk equal to the same cumulative exposure starting at birth. 4. It was assumed that relative risk was dependent only on cumulative exposure and not on age. S'. Based- on the pattern of excessexpoaureforthiscohort (Smith et al., 198(1), it was assumed that the dose accumulated five years prior to death was not relevant to causation of cancer. 6. The SMRs used were calculated using United States general population cancer races. tf national cancer rates were higher than local ratms, the value of the SM& is underestimated, and vice versa. 7. It is assumed that lung cancer and brain cancer are causally associated with vinyl chloride exposure and that the dose accumulated in the five years immediately prios to death we# not relevant to causation of cancer. If these cancers are net associated with exposure to vinyl chloride, then the true rlsfe ie orvereteted by including them in the analysis. the affect of a given cumulative exposure is th same Conclusions This risk assessment analysis suggests that an avaraga exposure to 38.3 ppm of vinyl chloride may result in an added lifetime cancer risk of 1/25.6 for B-13 CH* 010508 liver cancer, 1/100 for brain cancer, and 1/33.4 for lung cancer, assuming each cancer is related to vinyl chloride exposure. If one adopts a linear extrapolation approach, one would conclude that an exposure to 0.485 ppb for a lifetime night result^ ip,* capcej risk of one in a million, if all these cancers are related to exposure. In the most likely cas* that only, liver andbr^i^cajK^ajy ral^tejl to exposure, an exposure to 0.781 ppb night result in a one in a.million lifetia2**v cancer risk. ` - ~ T ^ i -j * *- an*?' . . - .'"C adl *v: a : : ...a reo-isc 3*4.: iMiutu -- t* fa hne ?uaoo*e efajrojdo I-geiv ivit -v: t -**t ttaM- <ae* e* -jetif vfKMlbennl .i: * da** MSSlaoec* '9Mi m saflMWO esena ' ana ad? ja eeda ?rl>fag* y* lIBftJWWrt* TBTdfcl i env-r , oVft* arfs Je.-f5 SnSkMO* nemo* ora t - it- B-14 * CMA 010509 TABIC B-1 Author lyrw >t !., IWt Cooper, CONQBT C|UKACTCiISTICS OF SELECTED Vim CBlOtiOC STUDIES Hunker t( | tenge of tipown duration *[ ...iBlM , 151 > 10 Tti__________________ > I Jrr 199 Ungtk ol Lon^aat follow-up 1940*a 1974 ---------------------1--------- 1940`a 1*72 .3 Nolti on Eotlow-up T7X 951 Place ot Caapany Involved Sweden 57 Plants tn United States Ouck ot at., 1975 >0 jrr > 15 yr* 1940 *' 99. *X South Vale* F> at ol., 1977 Beldaas at al.. 1904 Homan at *1., 1975*+ Micbolaen at al., 1975 . fii Ml* n. s' Tj 3L\. , it9*r mot t) 0! >0 |r 73X > 10 w, I > TO rra > 1 yr J 2J.1HL TV (not glvo*)- 1940 i 197f 1953 - 1990 1940 1970 -------------------- T 194? d * Tafaeratiau at al., 1974** lakaaura, 190 1herlavIt at al., 1901 Uaanallar at al., 1990** debar at al., 1901 Wong at at., 1904** im 35* m>1 * ii. u I* 59 ti i IXtl OflT 9021 414 10173 1330 > 1 yr * " -NH > 30 yr* 1 < > I yr > 15 yr*1 1930*9 , >1172 ------r 1950 - 19? *>** it*0 YT% a ,,3SL "*w > 3 yra yr * gS ' * f A v c. --------- .------,------p-- > 3 yro II yra .i .M*........ --r: Siyr 1 t ttk > 10 yra f " .it1 v 359 >1 yr ' pr 19*3- Hfo t* 19401* rr-^(99773 1940** 1974 l 1942 - 1902 proportional nortality study Overteppino cohort* ol Goodrich company worker* 99. IX Great Britain 99. IX 03X Louisville, Kentucky Hew York 53 Plants m United Slates Japan IX > 13 yra Canada 23X > 19 rra 99. JX 4 Plants in United States 90X West Gcnu.toy 92X United St .i 11 UHAK I ZXJ CMA 010510 -n TABLE S-2 Author lyren at at., 1976 Coopar, 1981* Duck at at., 1979 Foa at at., 1977 HaIdeas at at., 1964 Non*on ft at., 1979* miXLifc-. STAHOAM ITALIIV OAT IDS (ANO 906 COMHMHCE l*IERWALS) ' g/umm- ......... 16 KtKK VMM. CNUXtK 111DIES 1 i 5 ii9B aocMHI^HR* 40 ~ ii .~q.. > i ** 'I'*'*.)* *68 (49.9* 499.1) --mBrain (CHS) rV i 2 0.99 412 >i naplratory f29* *29.9 ^07 (72.7. 144.11 12 9.6 203 _ ' (194.4. 1904.9) (117.3, 979.3) 11 ^l^O*" n ^95.6_, lU^) *' \f > .* 4` ' i -- Ullary and Umi f * a .? its* w.it mi.*) 9 16 ` 19.9 ^09 (44.7, 194.0) 1 44 *91.29 *9.8(69.1.114.1) i * M4 {90 <99.1. V0.0> 2 9.44 34.4 (9.4, 171.7) 19 7.9 40 (97.3. 241.4) 9 1.2 479 (149.6, 673.6) dfcbolson at at., 1979 tabarahwi tt *1 , 1974* Takaaura, 190] Theriault at at., 1961 Uaawailar at al., 1976* Maher at at., 1981 > o.j im !>.>. *$*> ^'9 4ft*9tl*9 '*1 f ` lF f* . Vbil V&il >d 4* * a.* l ` Jft 1- dfeaptiw*'. . r i iu i4 m m iiix biliary 6 ll*if ! if 7 0.6 1199'*J {W4.il|||.) C, > 1 X, * ? .a 12 0.7* 1929 (674.9. 2460.7) 4 * l.l * - ' 1 0.1 ^000 (99.3, 4726.4) Yaapfcatnr 29 29**9 112 (72.6.H41.#)' 2 1 2.99 . *4 (14.**i 966*2) nfPlt.tonr 2 9.74 p4.6 ( i.O.KtaO.n raaplratory 12,. 7.7 194 (**;9| 292.9) - m-- -- 0 0.4 0 3 0.9 929 (90.0, 640.6) 2 1.23 161 (21.1, 311.0)C. Mona at at., 1986* Itwer and 6111(ary 97 9.77 641.2 (476.2. *49.6) 119) tl3%0*IO>4.2 (60.2, 110) 21 12.76 160 (129.2, 233.4f `Overlapping cohort* of Goodrich conpany uorkara. ,*j^konf I rood caaaa, irraspoctiva of Mating tha f iva-yaar aapoaura and tan-y^^latency crltarla of thla cohort study 9of^O* 90X confidence Interval CMA 010511 imOrti 11*1 0.0. tor--i 1000 wo TABLE 13 B1SI0IIIC EKKJSURE LEVEES (ppa): VINTL CHLORIDE IISA Barrata atal____ USA Kra--r 0 Hutchiar 0*1 WO la HMn bt IISA Cask at al urn Filatova A CtMibcrg Letvr c 1 Bor- Sue lu at al kuo- pary AngbelMCto Crease ( al Cltstoa ltd lirivn 4 kola bell Mt IIH* t tW'llUi <Puh.m7> inciM im |t 30-310 n*r TM|*l 13 ppa10.000 ftm (14*-peek) ECHO 1|. WO la H2 ISM - M S .1 use 1003 1040 1040 1030 031 1031 1033 1*34 1*33 (tab!00l) W--* wo* -- paaka > ppa (Pah.1*30) Sttfm: HIWII MU > HOC t 11 ppa paakar 400- W** -- 0 scrapers' Ml *!' kaada me lOilna Alleuable CmMiiilM ACC10 iMTUtt 0--1---- at ffWOTMl l--MVtol WlMlltl OSAO m OccMMtlO--I Will aad lutlk ItelllNMItM TWO to-- uelskted am-- (to ppa) kaaad m --eiphtbour toy ppa - pare par alllLea raaap--a TWHA hbllaktoeat tanod lam--aa * TVtA rap--ta4 a*a THA a aaaiapa TUB far Ikal period paaka bl|toat cent--trail-- --parted (ppa). Ik--a la llttU due--eatad-- regarding I--aty ar toratl-- of paaka raretar araa * weak ar-- ara--0 aaO rltkla tka --I akara eel--erltatl-- took alaqa KglMOHMto acrapar1 bands * altar poly--citation; uorkara entered warart ta acrapa any buildup of poly--p offtke reactor vessel walls; --aaura--ntt raprasanted this exposure pcactpitoc, centrifuge and drying ovaoa - post poiynerlsatlon work araas CM0 010512 (Ppk. 10*3) *ll* If (It- H 4 klgk M 3.3 ppa" (Pub. 1*00) A3-3I) Pfa (Pub. 1031) peak value- IIT.OM) OP* iruo. it;*) range la reac- li area: 1410 PP ~n -J TABLE 8-4 EXPOSURE LEVELS ASSOCIATED WITH ONE IN A MILLION LIFETIME CANCER RISKS Cancer Site Liver Liver and Brain Liver, Lung and Brain * . Maer Lilcelv * * 0.981 ppb * -- 0.485 ppb Upper 95% 2.82 ppb 2.17 ppb t-r A t 'l.27 mb *> ^ A * rk*c m Uwa --m ^m m * Lower 95% Llmte 0.448 ppb 0.421 ppb 0.238 ppb * 45 X. < iet . .: -t3IJi. B-18 cha 0l0St3 TABLE B-5 BARNES' EXPOSURE ESTIMATES1 Ttnw Fgrlgd 1945-1955 1955-1960 1960-1970 Mid 1973 1975 Exposure Estimate (pom> 1000 400-500 300-400 130 5 1 Barnes, 1976. <s.-jl.-a ;c.i .`is . . sz.tae..- .q : i,,iT . 'b.-io-.Ta iipjlv lai .a: :? .oaom* ;s+jM>?3amaat*2t +o*i**A. m# i Lt4gcu&& id'OTSwnwNUw'.!, joA^w-eiAia&A di ,,*K jmi* - AH20 B-19 CHA 010514 TABLE B-6: HISTORICAL EVOLUTION OF OCCUPATIONAL EXPOSURE LIMITS I, 2 Year 1934 1962 1971 1972 1974 Authority MAC 3 ACGIH3 OSHA3 OSHA OSHA Late 1974 OSHA April 1975 OSHA five for 13 ainutas Vinyl Chloride Limit (nom> 500 4 v ' ' "'e 500 500 200 50^- temporary emergency standard over an eight hour period Proposed non*detectable limit jL 1 - averaged over eight Sir ^Froa Paddle Correapondence (1986) 2 As s point of interest. Table F presents a gnwiry of historical occupational standards for vinyl chloride. 3 MAC - Mariana Allowable Concentration; ACGZH American Conference of Government Industrial Hygienists; OSHA - Occupational Safety and Health Administration B-20 CMA 010515 1 REFERENCES DRA Barnes AH' (1976) Vinyl chloride and the production of PVC. Proc Roy Soc Med fijs278-281. Beaumont JJ and Breslov NE (1981) Power considerations in epidemiologic studies of vinyl chloride workers. Am J Epidemiol 114:723-34 Cooper VC (1981) Epidemiologic study of vinyl chloride workers: mortality through December 31, 1972. Environ Health Perspect 1:101-106. Environmental Health Associates (1986) An update of an epidemiological study of vinyl chloride workers, 1942-1982. Report for Chemical Manufacturers Association, pp. 1-37. Forman D, Bennett B, Stafford J and Doll R (1985) Exposure to vinyl chloride and angiosarcoma of the liver: a report of the register of eases. Br J Ind Med 1:750-3. Jones J (1974) Worker exposure to vinyl chloride during production fabrication of vinyl chloride and polyvinyl chloride. NIOSH Report ' Contract CDC-99-74-59, pp. 2-161. Monson RR, Peters JM and Johnson MN (1974) Proportional mortality amongr vinyl chloride workers. Lancet pp.397-398. Ott MG, Langner RR and Holder BB (1975) Vinyl chloride exposure in a controlled industrial environment. Arch Environ Health 30:333-339. Paddle G (1986) Personal CoMunicatlon to A.H. Smith. Smith AH, Vaxweiler RJ and Tyroler HA (1980) Epidemiologic investigation of occupational carcinogenesis using a serially additive expected dose model. Am J Epidemiol UZ-'787-797. Symons MJ and Tsulbee JB (1981) Practical considerations for approximating relative rlsR By the standard mortality ratio. J Oeeup Med 2^:413-416. Tabershew IR and Caffey HR (1974) Mortality study of workers in the chloride and its polymers. J Oceup Med 16:509-518. j. Wagoner JKC, Falk H and Jones J (1976) Neoplastic exposed to vinyl chloride. Ann NY Acad Sci 271:40-48. B-21 CMA 010514 " ;fv j?'-' i^ oa > * ** "i - ?.'**% ti4*A rfois,^ . * . tlftltaftr ibt'lT,. "- ,~i v * >*' j. ,: .'*JT V*7 * ^ !** - c p. -*' ' : ; * i'- , C ** ? - XJO "'* . . -"7o . .."A ' *1+3*" i c t ,-.;bJ 1t .; ?'. j , *<- *." ; - ~ - - -. '* 7fT<7*T: j. is* 'j vs* ' iS A :c ri.' :'.ttO ji'SHc) A-.! a'; . . -.a. .< i2 atefc 3j* <*** svrslbi;* '0*i; TM;{ b LX **ii3****.* * wlvr zttanwnl^?** tn*i .\9?,7wrjHL IvhHtoi^A +3. *o-.qv* :oi /?*:fe**rre (i3?i> 3*dlu: j6 -- it ' -* qpnwOt .afcfwr vjJJU^Si* MWkW Mi vf Si-3 .m.v KF-wrtM & K JiittJ :_-T ''<1 *JJ iwr Altai/?:) i'-iUhr lo mrtast j-*? ',')'. tac5W V T.3%niuS L t. 1-1,' ' 1JV n~ ?^*0ir*3 CHA 010517 3C tit fil a-2* DRAFT 3 i-i? ft J U -5 4 '.l Aap#ndlx C - j - * .: *v ,; ,, $ _ ' -' mtB| Tiw Avrg* SxpoiuE*- Ram f Cohort In RMt AUtuatM- ABalyilv I v . -*^2 46:</*oq. IManmnivns <"nMa4 1 - *'.* . * !S>V U .rfoidw ,-n,nmt to *'*- -*J-i" -rfcffnt *cu i*t 2:'i**9*aafc -* - C-l CMA 010518 latigdufiCion DRAf Individual exposure data chac could be used for health risk assessment are frequently not recorded in occupational health cohort studies. However, a reasonable estimate of health risk may be found In the average exposure thae the cohort experienced in certain time periods. This appendix presents a method for using such data for risk assessment by employing certain assumptions. Objectives in Risk Assessment - - The primary objective behind health risk assessment is to contribute to It management decision-makings < including/-ragcleeiag permissible exposur levels. Workplace exposure# am# gemsmsli environmental exposures are two major areas considered. In the case of general environmental exposurer, the underlying goel Is to establish levels of exposure, which, if experienced over e lifetime, would result in level# of risk acceptable for the public. ild thus Involve lifetime exposure measurements at e exposure, the eeteblisbment of e dose-rasp nsa ^ the extrapolation of the data to low levels of exposure. Such human studies for vinyl chloride sre not available. Animal studies of this agsnt msy product rslevant information, but tha extrapolation t humans may include large potential errors. The purpose of this paper Is t present one approach to establishing exposure levels by using relevant human C-2 CMA 010519 information which, in the case of chemical exposures, usually involves occupational settings. The Model Consider a cohort of a number individuals who ere exposed at constant rates to a particular chemical. T&k races of IkpOsure differ among the individuals, but each individual has a cdnstattfc*lifeklme tsta of exposure. The model assumes a linear relationship between excess relative risk and the exposure rate: RR - 1 - bK where K& reform to relative rislf, b is a constant^ and^f is an exposture rate (lifetime). ' ' '1V" Strictly speaking, 1 la the difference la expense between the study population an# the comparison population used in calculating relative risk. " - -- negligible at of the exposed study population. Tfci%xposed study ly experiences the background population exposure. In the cattV^-d#' occupational exposures, estination of workplace exposures effectively gives an astlnate of the difference In the worker cohort exposure and that of the comparison population. C-3 * CM* O10S20 As sump cion Concerning Am The model assumes that a constant rata of exposure to the chemical over a lifetime results in a.relative risk for a particular disease outcome that does not vary by age. This implies that exposure would have a multiplicative effect on. background incidence r*tas. Such an assumption would follow tram f multistage modm^s^tuatlepvla which the exposure of concern affected particular stag*ft, wk&le tgtf background exposures predominantly affected ocher stages. Variation in Exposure Rstes The modal considers a cohort with a variety of exposure rapes, but in sll individuals sra of the ease eg*. It includea e subcohort "1" within it ai *jjier *iio sc; #1 a Tea cl beau .'sosiumpes baa - j -a.-?-; v? is3-' where is the observed number of caeem with eha disease in the subcohort and e^ is the expectsd number of cases based on some external "standard" C-4 CMA 010521 population. Hence, % bE r Now for any on* particular age group. DRAFT wh*r* e is tha expected nunber of d*aths par parson in th* dnbcohort ed n^ is tha nunber of parsons in subcohort i. Hence, 3c * . - - ^*<1 + bE^). *-''*" * Sunning ovarall exposure lavals, Zo^ - 2nj*(l + bEj) * - N* + abl*^ - - a *MbMt -ttfttfeM* (tt#*ictlar age *.-r v;. vrcr * ' . ** > C-5 CHA 010522 However, n.E E - IT Hence, SOj^ - Me + abut - Ne(X + bt) Now, Me Therefore, So. - 1 + bE S. and hone*. So. So. b- givoo an estimate of b. DRA ^ T; a '{ 9 ,,i4 r obtain: amegabwrdaafcb as:shewn in tho previous avaraga exposure race-. If ona expands the summation (S> So. SMR So. gee the familiar standardised mortality ratio. Assuming that tho SMR is not ago dependent, then tho following equati n, * (?MR-n b- E C-6 CMA 010S23 will provide an estimate of b, where E is now the average exposure rate for everyone*in the cohort. This estimate is based on the assumption that each individual experiences a constant exposure rate. It also implies that the constant exposure rate has v been experienced for a lifetime, since no distinction has been made - v- oh 'veseao. Vi'S Variation in Exposure Rates. Duration, and Asa at Exposure Host chemical risk assessments are based on occupational studies in wIBch. workers experience variation in exposure rates, variable expoSre duration, and different ages at exposure. In the ease of cancer, the risk assessment is also complicated by cancer latency. To deal with the variable exposure race, it will be assumed that the effect of exposure is related to- the average exposure rate during relevant etlologie time periods. (This assumption is analogous to the assumption that risk is- related to cumulative exposure independent of the pattern f he peake or (roughs of the exposure rate.) the assessment of exposure rste will focus on in relation to dates of diagnosis. For exampls, the iment of average exposure rste could be assessed up to s point in time 5 years before the mid-year of diagnosis of the cases. C-7 e CMA 010524 Finally, to deal with lifetime exposure risks, an adjustment will be made for the age at first exposure. A linear relationship will be assumed between risk and duration of exposure. If the average duration of exp sure up to 5 years before the mid-year of diagnosis is d, and if the average age at first exposure is a, then the calculated average rate of exposure will be corrected by multiplying by d/(d+a). (It should be noted that most carcinogen animal "bioassaye do not commence dosing until the animals are fully grown, so this correction la a conservative element in using human data). ** vi 4 A y* jjLi** CHA 010525 DRAFT TECHNICAL SUPPORT DOCUMENT PROPOSED IDENTIFICATION OF VINYL CHLORIDE AS A TOXIC AIR CONTAMINANT Part A Report i State of California Air Resources Board Stationary Source Division July 1989 CMA 01052A i '1C . / iO 4 Z\ rAni^!T^3^i ' R\A D.XOT A 2A ? A v;*3 tr.'OtiiaO to s*s?3 >60 f; 23-` w1 ; ' - .id * - PRELIMINARY DRAFT TECHNICAL SUPPORT DOCUMENT PART A PUBLIC EXPOSURE TO, SOURCES, AMO EMISSIONS OF VINYL CHLORIDE IN CALIFORNIA REPORT TO THE AIR RESOURCES BOARD ON VINYL CHLORIDE 3 Principal Author Richard Corey Contributing Authors Ton Parker Chris Nguyen Paul Allen Steve Hul Reviewed and Approved by: Joan Denton, Manager Substance Evaluation Saction Robert Barham, Chief Tdkte Air Contaminant Identification Branch Peter 0. Venturing Chief Stationary Source Division July 1989 CMA 010527 . HC ,,.. LM3 u.-! 3' -rixi 'T 301- : n xijgjW rrfi <0 1*. ^*h v , 'V : v -<!* - * *f f ' J rK ' 5 ^----' .*-.i_ii!3^< ti.---- ; . -*r.-;' .w; 'vwfldl 1 re* ' "*>fA # < -. -;** ***K*tm b* M**>rv30 1 'fit m ACKNOWLEDGMENTS The authors wish to acknowledge the valuable assistance of the following people who contributed to the preparation and review of this document: Pacita Ayala, Technical Support Division/ARB; Rich Miller, Technical Support Division/ARB; Lynn Baker, Stationary Source Division/ARB. Gary Yee, Monitoring and Laboratory Division/ARB; Barbara Fry, Stationary Source Oivision/ARB; I July 19#S (This report has been reviewed by the staff of the California Air Resources Board and approved for publication. Approval does not signify that the contents necessarily reflects the views and policies of the Air Resources Board, nor does mention of trade names or coonerclal products constitute endorsement or recoomendatlon for use.) CMA 010528 PRELIMINARY DRAFT PUBLIC EXPOSURE TO. AND SOURCES OF ATMOSPHERIC VINYL CHLORIDE IN CALIFORNIA ORAF H labULflf., CanUnta, ^ LIST OF APPENDICES ...................................................... 11 LIST OF TABLES .............................................................................................. HI LIST OF FIGURES ............................................................................................ HI I. INTRODUCTION ................................................................................. A-l - | 3 II. EXPOSURE TO VINYL CHLORIDE ........................................................ A-3 A. AMBIENT MONITORING IN CALIFORNIA...................................... A-3 B. ESTIMATING AMBIENT CONCENTRATIONS .................................... A-10 C. POPULATION EXPOSURE ............................................................. A-13 0. INDOOR EXPOSURE TO VINYL CHLORIDE ..................................... A-16 E. EXPOSURE THROUGH OTHER ROUTES ........................................... A-19 F. REFERENCES ............................................................................. A-22 HI. PRODUCTION. USES AND EMISSIONS................................................. A-24 A. PRODUCTION................................. A-24 B. CURRENT AND PROJECTED USES................................................. A-2S C. LANDFILLS: A MAJOR EMISSION SOURCE........... ....................... A-26 D. OTHER KNOWN EMISSION SOURCES............................................. A-33 E. OTHER. POTENTIAL EMISSION SOURCES ...................................... A-36 IV. IN THE ATMOSPHERE ....................... A-42 JpWSfCAi PROPERTIES ............................................................. A-42 W*ATMOSPHERIC PERSISTENCE ...................................................... A-42 C. REFERENCES.............................................................................. A-48 CMA 010529 LIST OF APPENDICES APPENDIX I - SCAQW'S ANALYTICAL METHOD FOR SAMPLING AND ANALYSIS OF ATMOSPHERIC VINYL CHLORIDE -, . APPENOIX II - DESCRIPTION OF GLEIT'S METHOD APPENDIX III - ESTIMATE OF TOTAL EXPOSURE TO VINYL CHLORIOE FROM INOOOR AIR APPENDIX IV - INFORMATION REt^T LETTEif"1ftTH ATTACHMENTS AND RESPONSES APPENDIX V - HEALTH EFFECTS REQUEST TO OKS AND LETTER OF- RESPONSE - , .a; r: ................... r-.a&HA3 -*r - * ' ic: j*Niv '-`cj-v, .98fr jAwitt/j .................................... .............................. iwmmw* ......... 2:2*1 artr-oas m mm &mmb mMr * .szrmwk* .......... :32*002 NOU20I3 SSHTO . 2338*12 40122IMS lUNiW am# ................ *.......................... 233H13P3S j ,1 -11- CM* 10S30 LIST QF TABLES AMD FIGURES TABLES Page II-l SUMMARY STATISTICS FOR THE JANUARY 1987 THROUGHDECEMBER .......... A-7 1987 MONITORING OATA FOR VINYL CHLORIDE NEAR BKK LANDFILL II-2 SUM4ARY STATISTICS FOR THE JANUARY 198$ THROUGHDECEMBER .......... A*8 1986 MONITORING DATA FOR VINYL CHLORIDE NEAR Oil LANDFILL 11-3 UPPER AND LOWER BOUND ESTIMATES OF THE ANNUAL MEAN .....................A-10 CONCENTRATIONS OF VINYL CHLORIDE AT BKK AND Oil LANDFILLS II-4 ESTIMATED EMISSION RATES OF VINYL CHLORIDE FROM BKK ..................A-12 AND Oil LANDFILLS II-5 RANGE OF CUMULATIVE POPULATION EXPOSED TO .....................................A-# VINYL CHLORIDE NEAR 8KK LANDFILL f 11-6 RANGE OF CUMULATIVE POPULATION axposed TO ................................ A-W VINYL CHLORIDE NEAR Oil II-7 ESTIMATED VINYL CHLORIDE EXPOSURE THROUGH ................................... A-20 DIFFERENT MEDIA III-l VINYL CHLORIDE LANDFILL EMISSION ESTIMATES ................................. A-30 III-2 SUMMARY OF VINYL CHLORIDE EMISSION ESTIMATES .............................. A-33 FOR OTHER SOURCES IY-1 PHYSICAL PROPERTIES OF VINYL CHLORIDE ........................ A-43 IV-2 ATMOSPHERIC LIFETIME ANO REACTION RATE CONSTANT ESTIMATES .... A-4S FOR VINYL CHLORIDE III-2 III-3 AND THE SURROUNDING AREA ......................................... A-S LANOFILL ANO THE SURROUNDING AREA................................ ........ A-6 NATIONAL VINYL CHLORIDE PRODUCTION, IMPORTS, EXPORTS................ A-25 ANO USE ANAEROBIC BREAKDOWN SEQUENCE VIA REDUCTIVE DEHALOGENATIQN .... A-28 LANDFILL GAS COLLECTION SYSTEM ..................................................... A-32 -iii- CHA 010531 *0 -' . ; if !* -::: "H / -.`4 AT AO OK!"'vrTW'v -->* "it 'wr " 4 r 4" -fyr^xu: ; "4 ; .TU V- *!* icML'" ..r * fCi < 1 c* :**9 -'^WU "5fj ;^ <ti,' '3v*'Z5 k:wj 3aj*r- iv#i ^ *"*w ^j3fluoe i3;-r: = ..........................................3<3!*cj: jyhiv w israw^ ./-r.crfw iraf 3Mm^ *1W '^laK^ ,-J? -m; u '1"- -4-t'-1 ' . ,-r '. ", - - ~V! CHA 0105 np& nn I.- `>*w TMTBOmieTTOII Part A of this report Is an evaluation of vipyl. chloride's uses, emission sources, ambient and Indoor air,concentrations, and population,exposure In California. Also Included are discussions of physical properties-and atmospheric persistence of vlayl chloride. California Health and Safety Code Section 39668 states that substance listed by the U.S. Environmental Protection Agency (EPA) as hazardous air pollutants (Section 112 of the Clean Air Act) shall be Identified as toxic air contaminants (lAC*)..by the Air Resources Board (ARB). Therefore, because the-EPA has Ufted, v,1nyX chloride as a, hazardous air pollutant, the. ARB Is directed by statute tp Identify,vinyl chloride as a TAC.................................... The ARS: is, the state 'rbspbosfble.fbr tho Identification of tacs: irLthFnp.n-^Mst,fcida ^ ^.T^oqjfqr^la Heelth and Safety Code SectfdIhII 39MVB defthOi a'TAC as "air air pelltitant which may causa or contribute to an Increase In mortality or an Increase In serious illness, or which may pose a present or potential hazard to human health." The findings of the Part A report are considered with the health effect* findings (Part B rsport) of the Department of Health Sarvices (DRlkfcm determine If e compound should be Identified as a TACte the/ .the ARB adopted an ambient air quality standard for vifflLsbleridd 10 ppb for a 24-hour avorago. Tho standard ropAVlnete#fli& limit of dotoctlon for vinyl chloride at the time it was adopted* Vinyl chloride is an extremely volatile compound that is primarily used for the production of polyvinyl chlorido (PVC). PVC is fabricated for uso In several products of which many are used by the A-l CMA 010533 * nu os\nt FT construction industry. In California, the identified sources of vinyl chloride emissions are landfills, PVC production and fabrication facilities, and sewage treatment plants. Available information indicates that landfills are the largest source category of vinyl chloride emissions In California. Vinyl chloride has been measured in the ambient air near hazardous waste and municipal waste landfills. Numerous studies have documented the presence of vinyl chloride In the landfill gas of these and other landfills, and have shown that vinyl chloride can be formed in landfills where chlorinated organic compounds have been disposed. Therefore, because disposal of such chlorinated compounds Is prevalent, the staff recomnends that all landfills (hazardous and municipal) In the state . be regarded as potential vinyl chloride emission sources. In this report; amPtent monitoring data and meteorological data are used with an atmospheric dispersion model to estimate population exposure to vinyl chloride near two California landfills. The modeling results show that people living.near these Jandfllls are exposed to elevated levels of vinyl chloride, ,'tlid restrl$s also^mply that people residing near other landfills'In the! state ly be aipostff to elevated, levels of vinyl chloride. In addition to estimating ancient air exposure, this report also evaluates indoor air exposurp to*vinyl chloride. - : , J .r .. u Based on llmftedr monitoring data. Indoor air exposure to vinyl chloride 1 S` probably not significant' fdr thp^Jcrity of the population. However, for people residing:hbaf landfHTf^ IhhaTttlon of indoor air may represent tA# most slgwlfl cant'sourcd* or flnyf chloride exposure. This Is because vinyl chloride can migrate underground from landfills and accumulate. In, no, of vinyl chlorlder* measfirA 'tkf' ftl ft h*ye bane reported to * 'Stijr: tii st;>.ftf -;s z: ,ludn:n.-. {jjpe^ee .c #joo n ;~>03*i A iveA eds 's on if **T . - < nt m s.Tr wurwMe i-J < **>' -i*' TSA s A- A-2 CHA 0105 -- II,. *1 4** exposure To viryl chloride A. AMBIENT MONITORING IN CALIFORNIA . Vinyl chloride Is frequently detected In, the ambient air of California. However, detectable levels are limited te locations near identified emission sources. Previous monitoring throughout the South Coast Air Basin (SCAB), u pert of the ARB's ambient monitoring- networ has failed- to detect vinyl chloride above the ARB's limit of detection * (LOD) of O.S ppb. In recent years, the only known emission sources in California near which vinyl chloride has been frequently detected in the ambient air are tw& landfills in the SCAB: BKK. and Operating Industries Inc., (till)-. For both of thmsoi landfills* the South Coast Air Quality Management District (SCAQMD^ has frequently measured ambient vinyl chloride concentrations above this SCAQMD's LOO of 2 ppfa* The analysis in this report estimates ambient concentrations and population exposure to vinyl chloride aeaBk&andMlbeeausa-they are^the oely landfills in the -state where vial .chiorIda has been routinely mwvitored, on a long-term bastfe*j. ;<7 ::. In response to the lack of monitoring data for other landfills. Health aqd Safety,Poda Sactioe A1I0&-5 requires haxardous and municipal 1 sndf UTi. throughout the state to, conduct monitoring for, several C0IWMlWiync1udm vinyl chloeide* As. these mqiki toeing results areii^HfiiidteertSuiF will be helpful In identifying which landfills could _____ teemit vinyl chloride and warrant further monitoring stu^HEpt'flritiget1on measures. A more detailed description of the reqjRMwta of Health and Safaty Code S^tioh 41B0&.5 Is provided on page JUft. The SCAQMD* s monitoring program for vinyl chloride at BKK and Oil has consistad of six monitoring stations. Three stations have been A-3 CA 010535 located on the southern borders of each landfill. Previous monitoring around both landfills has indicated that the southern borders are generally where the highest concentrations are detected. All samples are collected In Tedlar bags over 24-hour periods and subsequently analyzed by gas chromatography employing a flame ionization detector. Details of the SCAQMO's sampling and analysis procedures are provided in Appendix I. Topographical maps of the BKK and Oil landfills are provided respectively In Figures II-l and II-2. These figures show the approximate perimeter of the landfills, the approximate locations of the monitoring sites, and proximity of streets to the landfills. As indicated by the maps, the southern borders of MQE and Oil are adjacent to a network of streets. However, the maps do not show that the area served by these streets consist# afi *Ul$Ib-fam11y residential housing. Ambient air samples used to estimate population exposure near SICK and Oil were collected from January through December 1987 and January through December 1986, respecfftarlyC Idiots th# tdjftdlfre aitffysIs was performed, these sampling periods represented the most recent calendar Jk years of monitoring data the# war# a#fTabTe^ :FtfP BKM* 337 to 34it - M samples were taken at each of th# NMfrftbPfng shtetr of those sites, s X range of BS to 98 percent of th# samples ar# fflfrToW the TOO of 2 ppb. - OH, 128 t# 28# samples were taken s #eeh of the moeftdPfhg sites; of* those sites, 32 to 108 percent of th# Samples' ar# below<11he L08. ``i- i 3j Hie ambient vfhyF chToffd# moWitmr'fng deft fe# BKX arid Off1 are summarized In Tlb-1 ef II-l en# n-Z, respectively. 2acN stable provides the number of sample# taken a^'dedf sft#, the percent of samples below the LOT. m HtlertP Par the^blue# BefMKlih ^hheirtlmlfdtf mean concentration, and the maSlm# 2#-hdttf concd#t^VW,Wit'wa# measured. . .-.os ;s-v isooor Znoiom ?<Memf 3ae 7tee*' ' caicuw* Wfreefrcolfceifol#fr^ coi^Hcafd by ttheVfnsdMb ^Coi^hffatHonS WFelfm W* ^fNPkiAt^eiohs below the LOO must be somehow Included In the ca 1cu 1at ton ffinfgif*fte 1 r exact values are.not known. 'saje -sot tlsft rmt^atnwm >o s? eanoose'i <u = _'i_'_t_f_lc__u_l_a_t_e_ PitIons is nermef'^hgrCfMtfalf. ' DaM'thjtf'We fudged not to ? be mmmi* tkv#ttre*?Sta traneeHty. Chloride detmuggested'tha* theywere and*STe1t*f Method was applfed td the lofPMHKSr^0Me datt. The calculate# means were thin transformed becTte tbmorlglnal units. ffle1trs' method accounts for th# concentrations bafbw the LOO by Setting them equal to the *below-LO0 mein,* the mean of the portion of A-4 0i0S36 FIGURE II-l BKK LANDFILL AND THE SURROUNDING AREA A-5 * CMA 01053? FIGURE II-2 Oil LANDFILL AND THE SURROUNDING AREA DRAFT A-6 CMA 010538 DRAFT the normal distribution below the LOD. Setting the unknown concentrations to their average value seems Intuitively reasonable, and the simulations reported In Glelt's paper show that his method Is more accurate than other commonly used approximations. A detailed description of the method used to estimate the concentration of data below the LOD Is provided on Appendix II. The estimated values for rambles'below the LOD range from 1.0 ppb to L.l ppO for BKIC and from? l'.O ppb! te l.i ppd fan. Oil. As previously indicated, the specific velud fbr eaehr stabler ts shewn in Table 11 -1 for BKIC and II-2 for Oil. Because eft samples for site 1 of Oil are below the LOD, deltas method could not be used to estimate their concentration. Therefore, a value of one-half the LOD (1.0 ppb) is assumed for these samples. TABCB n-1 ' v . ' v- StMMtY STATISTICS FOfc THC JANUARY 1987 THROUGH DECEMBER 1987 MONITORING DATA FOR VINYL CHLORIDE NEAR BKK LANDFILL (Concentrations reported In parts par billion (ppb)} Station Nunbar of Semples?*' * 337> Percent of Sampled Below the LOD* ''*r1 Estimated Concentration forb Samples Below thd LOB 1.0 . Estimated Mean b Concentration j 3 *10 r Js-- I-J* -.y Max tem24dj0yS>cVntrat 1onc * 7 Station 2 337 9B-I-: 1.0 1.2 8 Station 3 34S 55 1.1 2.6 15 limit of detaction (LOO) for vinyl chloride is 2 ppb. was* used to eetlneto th*rconcentration of samples below c - California1* Ambient Air Reality Standard for vinyl chloride is 10 ppb for a 24-hour averaging period. A-7 CMA OIO539 DRAFJ The estimated mean vinyl chloride concentrations, as provided in Tables 11-1 egM II-2 rang* from 1.2 ppb to 2.6 ppb for the monitoring stations at 8KK, ant 1.0 pph ta 2.0 ppb for the monitoring, stations at Oil. For all stations, except station 3. of 8KK, the estimated annual mean concentration Is equal ta or less, than the SCAQMO' s LOO. for vinyl chloride. Tables II-l and II-2 also list the maximum 24-hour concentration of vinyl chloride, for-each monitoring station at BKK ami Oil, respectively. For BKKv the maximum 24-hcur concentration is> 16 ppb (measured at station 3); for MI: the maadmum coocentration,41\&.8> pph (mntured station 3). These concentrattione can bm compared ta ADR's amhieftb air quality standard for vinyl chioridmef IB pph for a. 24-hoi0\ averaging period. , The standard was TABLE II-2 SUMMARY STATISTICS FOR THE JANUARY 1986 THROUGH 0ECE1SER 1986 MONITORING DATA FOR VINYL CHLORIDE NEAR Oil LANDFILL - ^ - (CdMmntraClone reportadrtn parteepnr billion (ppb)) .. '< Station 1 Station 2 NmhflHL flC Smepate ... . . 264 220 Percent of Samplee Below the LOO* 10R&,' j 's.Ai.. Estmeted Concentration for* Samples Below the LOO fe A^ * Estlmeted Neem* Concentration v-1 Maximum 24 Heme. Concentration cc. jdJlh sfc.Tb -i> wj; o>: ? CXfrn! wefaA 2.0 rt*s.* 128 . 32 * 1.2 2.0 9.8 it of d#tcttQiL(J.Q01JdC vJnil chlorida_is 2 ppb. ts used to estlmete the concentration of samplas below -- . .. lentAtr Quality Standerd foewvtnyl chloride Is 10 ppb average, ere below the LOR AS CMA 010540 ^ nru adopted In 1978 In response to information which associated vinyl chloride with the development of cancer in humans. However, the standard is not necessarily health protective; it simply represented the LOD at the time it was adopted. For the monitoring periods presented in this report, BKK exceeded the state standard for vinyl chloride 11 times (all exceedances occurred at site 3) while Oil did not exceed the standard. Based on previous years of monitoring data, the number of exceedances at BKK and Oil has decreased substantially. In fact, due to the lack of exceedances of the standard, the SCAQMOi..discontinued monitoring for.vinyl chloride at Oil In early 1997. The reduction in ambient concentrations of vinyl chloride near BKK and Oil has been attributed to the Installation of gas collection and.flare systems. In an effort to represent the uncertainties associated with the estimated mean concentrations of vinyl chloride, the staff developed a statistical treatment for calculating upper and lower bound estimates of the mean concentration at each monitoring station This method takes into account factors such as sample size, variance of the data, and an estimate of the uncertainty associated with the sampling and analysis * method. Table II-3 shows the estimated mean concentration as well as. 1 the upper and lower bound estimate of the mean concentration for eactr monitoring station at BKK and 0IIr * TM The following text discusses the statistical treatment that Is used; a) After reviewing the ambient vinyl chloride monitoring data for BKK and Oil, tile staff observed that the data appear to be lognoneally distributed; Because avatlatrlesuftware analyze data that are only normally distributed, vinyl chloride monitoring data were first converted from a lognormal distribution to a normal distribution. This was done by using the logarithms of the data for the analysis. The statistical analysis system (SAS, 1992) was used to calculate .the standard error about the mean. The standard error calculatld from the logarithms of the data Is then converted back Into concentration units by taking the anti logarithms. and lower bound estimates reported for the mean dien^two standard errors. For the error associated with and analysis, ARB staff"used an overalT uncertainty or of t 20 percent to calculate the upper and lower bound of the mean. This Is In agreement with the actual error which Is estimated to be 1 ppb In the range of l ppb to SO ppb. The lower bound estimate represents two standard errors for the data with each sample concentration reduced by 20 percent. The upper bound estimate represents two standard errors for the data with each sample concentration increased by CMA 010541 20 percent. Upper and lower bound estimates for each station are shown in Table II-3. Because all values for station 1 of Oil are below the LOO. the upper and lower bound estimates represent x 20 percent of on-half the LOO. B. ESTIMATING AMBIENT CONCENTRATIONS Annual average vinyl chloride concentration* were estimated for a 4t x 41 grfd ot one square kilometer qeUs surrounding each landfill with the u*/a of the Industrial Source.CdWtOs SffBrt Term (ISCST1 Oausstan model, lo order to predictthd^amwal Meraor concentration of vfnyl chlertdein each of thir^ilf, tqw&q fmjtfirceUs. the ISCST model required the emission raves far eech'TsMfrTT it Input. Emission rates were estimated for BKK aqd 0(1 using the raneg of estimated annual mean concentrations at each of the monftaring7stat?ons. The estimated emission rates were derived by ratlolng estimated annual mean concentrations over modeTe*| concentrations for each station. UPPER AND LONER BOUND ESTIMATES OP THE*ANNUAL MEAN CONCENTRATIONS OP VINYL CHLORIDE AT BKK AND Oil LANOPILLS Upper Bound EatlmatP * - All samples are below the LOD of 2 ppb 2.1 1.4 3.4 1.2 2.8 2.6 A-10 CMA 010542 The modeled concentrations were determined by assuming a landfill emission rate of 1 gram per square meter per second (gram meter'* second-*) In conjunction with historical meteorological data. Each landfill was represented as an area source. Based on review of topographical maps as.well as Information concerning the landfills disposal history, BKK wee assumed to emit vinyl chloride from an area of approximately 1,700-^000 meters while- Oil was assumed.to emit vinyl chloride from an area of approximately 330,000 meters*. These assumed areas approximate the area where wastes have been disposed. Meteorological data for 1981 at-thd SCAQhD's Walnut and Upland stations were used for BKK and Oil, respectively.__Meteorological data from these stations were used for this study~beeause WaThuffwao* considered the most representative station for BKK where processed dale were available while Upland was considered the most representative station for Oil where processed data were available. These data were entered into the ISCST model to calculate the annual average modeled concentration at each monitoring station. Because one year of meteorological data is used, one modeled concentration is obtained for each monitoring station at BKK and Oil. For each site at BKK and OH the modeled concentration was divided Into the estimated mean concentration (from Table II-3) of Its respective monitoring station. The resulting faetoc&or ratios were, then multiplied by the assumed emission rate (1 gram meter-2 second-1) * to estimate a landfill emission rate for each monitoring; station that, * will result In an exact match between estimated and modeled f concentrations. Equation (1) illustrates the procedure that was used: . Estimated Assumed Estimated Modeled EmlSsTdh Wtb'. Emission'Ratix (Concehtratfoir/ Concentration) (1) b" The eat 1 monitoring Station at BKK arid 01 rived from the estimated mean concentration for each monitoring station and the emission rates derived from the upper and lower boumrvsttMtes of the mean concentration for each monitoring station are listed. The greatest range qf.eat Icrograms . meter,sr-~ J&MMSS meter-2 mated amission CTowde bound at mertoigft at station ^*wS^xhe^fu|t range of metssfon rate estimates mlcrograM meter** second-2 for BKK and 0.31 to 4.42 m(0tc.7ro5grtaoras3.3m2ete.r-' 2 second-2 for Oil), a range of estimated annual average vinyl chloride concentrations was derived for the 41 by 41 grid of one square kilometer A-ll CMA 010543 ORAFJ TABLE II-4 ESTIMATED EMISSION RATES OP Vim CHLORIDE from tux tm ozi-landfilis (itlcrograns meters second ) *- l. - ? ' * i Jr'* snr Landfm Station l _* Station ? Station 3 1" ' Oil Landfill Station! -* Lower Sound4 ? 1; *3` Upper Bound1 i w ' >* aati* #;m av,J k !*. JJT? 1/' J r T ' 3 r - m ' * ' anc;. l ; ; 1.38 1 <L f.t* - * r.` i; 2.30 0.7V 0.9* 'J v"i -: -.aonoo * * *- 1.8V > i -* - - 2.8V* * iJ 'T+fl , , * j ft ' s s# - . $nr xiji *** j rf r - '* C -- *. vd 31 J r.3r-j^.; $a' * *t ** ..fl (to"t5* *f >is* : - 1.29 3.32 4.48-* Station Z 0.5Z 8.74 : 1.04 Station 3 2.69 * 3.44^*5 ; 4.42 -------------------------- ------------------------------ 5ii1 ii..*.---------------------------------------------------------------- a - These Mission ratos wore dorlvod from tho loMr-bound annual moan concentration :. . UMp OiMMMSS,ar14 8 ii? 3.->6 '^MTf RttlSlfMi'' '.;*** ai *o jandneoftoj neM :a ; *4 "" "3J`. ,, M )i|UV '>)' a.--a nonm *d3 jwtI aavcM i2i~ - ij, >"T 3#s* , t if^M *: :ti* iniioltitm dan* *$ Miii'dww - * ** `fd^was d'stipw,. fronM^i* iwasr** to 1^eom*aii .alee of otirs*. approx Inatd the aroa when ^djsposad at oach landfill. However, bocausa subsurface f Mtfftll guts has boon abiarvad at BKK and QII, it Is ifMfsslons of vfnx^ chloride occur over an .area substantially greater thaa where wastes have actually been disposed. Tha ISCST iiodal usad tha range of aitlaatad Mission, rates assuming no plume rise In conjunction with historical Mtaorologlcal data to predict A-12 CHA 01054 a rang* of annual average concentrations for each of the 1681 one square kilometer cells. The annual average concentrations of vinyl chloride predicted for the one square kilometer cells within the grid centered on BKK, range from less than 0.1 ppb-to approximately 22 ppb. For Oil, the range is from less than 0.1 ppb to approximately 3.8 ppb. In order to obtain these modeling results, several assumptions are made. These assumptions may act to elevate or reduce the estimated annuel average concentrations, of vinyl* chloride predicted for the cells surrounding BKK and Oil. The primary assumptions are as follows: 1) Vinyl chloride is assumed to be emitted from an area of , approximately 1,700,000 meters* for BKK and 330,000 meters* for 01 Although these arear approximate the area where wastes have been-disposed, data are not available to demonstrate that these areas actually represent where vinyl chloride emissions occur. Emissions of vinyl chloride may occur over an area which is either larger or smaller than that assumed* . ________________ 2> Emissions of vinyl chloride are assumed to occur continuous! and uniformly over a given area of each landfill. In reallt vinyl chloride Is not likely to emanate uniformly over the surface of the landfills. However, the data required by the model to take this Into consideration are not available. If r emissions of vinyl chloride vary over the surface of the landfills, the annual concentrations estimated for some cells would be expected to be underestimated while others would be overestimated. 3) This study does not use meteorology for the same year as the vinyl chloride measurements. Because there Is not a great deal of variation In meteorological data from year to year, ',,fthe-dagree of error from using a meteorological year different than the vinyl chloride measurement year Is estimated to be less thanJM percent. Because the emission rates were derived by model calibration to He concentrations, the uncertainty Is at a minimum g^sltes. Alternatively, as the distance from each pIncreases, the uncertainty associated with the ailon Increases. EXMSURE The population exposure to vinyl chloride near BKK and Oil was estimated by using the grid celt concentrations estimated from the ISCST model In conjunction with 1985 updated census data. Estimates of the A-13 CMA 010345 emulative population exposed to various concentration levels of vinyl chlorffr near BKK and Oil landfills are shown in Tables II-S' and II-6. The im residential population estimates were determined for each l kilmeter grid cell with the concentration determined at the center of each cell by the I5CST modelv The $,681 grid Cells, with their associated populations, were sorted from high to low by concentration. The grid cell~ populations were thee sunned to detenatne the cumulative popelatloir exposed tee cartel it level a* vtnyt eMaclde. For Tables li fe and" II-6v lower bound off exposure ts eattented. Urte range of f# 3-s e '*"w --)**! - -*w*-r-1 ed? . r ~n 1 *4 ^."f^ . ' * * . ' ' : a.- ' *" v 3P.C'-' r. XW.gpt.f 'i*,o*eei.'<5-ioo * ' *" - RMIS OF CUWUWm^ POWLATIOfc EXPOSED to fmcHiarac wt mm** . '. ,J ' 4i*:j * .t - Vinyl Chloride '< ^ *... i: Concentration'' '' *''* "wi.-.- ___ CASIOftenoe of CuwulaMww Emulation Fnoad * t ?} f. .i._ . -'4 '?! -*3 ta : ' ' ;*i. -I**., i o r t x. r Uppac-Bounffc inti 3.t* Estimate.* . -'i - 3 ' ?3 i vfffr (hQfe- - rw t 154,000 ' 3 : ' . ' ' -.i: 3/ ' O.Ofr"''^ - t3 <_a;13f#0Qfcer >*'^l,970,000 3* . -* '"''tsue* 1 Hh a* add .*i: r O/fe ` * '-3. .3,.#"*& *d it fts3MgMfed Si *34,431,000 .aedenH ?sa -.avc. 1.0 17,000 - 131,000 ben **** i it v^jTeieedeB see tee tees ***t 2Jflbn sxuesed to'-eSni T^nlv 54,000 tssy nsnl #j* feafyofo^siiff * dftelwv > (mb Taslpofo-'cetee s geiae aedf teebeb-adJ 20,000 - 4? -wev iWMMsetedK *bf,f'fi tyaiv edl nsdl 4.0 .tetee Monies, esef 20,000 febem fd S>*v***b nm xedan ier*TOna *** ****$11,000 ?,1} . *dl Jesdeeone? ebiiofds f <fv t ` ,<fev*y*ie4f* es.iOeet>Tk*tee* e^7>0O9r (2HT>ni .sotted* ?*JS9"*3r'' - 0*'?"sano3 i'* 2,'58f -r~----------------------------------------- f <5i?- - ! -------------------------------- a - The exp^ure estleete Is based on e vinyl chloride anlsslon rate of 0.75 elcrogreei eeter*a sect* . b - The expoeure estleete ts based de e vinyl- chloride edfsSlon rate of 3.32 elcrogrees water"4 sec~ A-14 CMA 01054A UKH F<*\ A TABLE II-6 RANGE OF CUMULATIVE POPULATION EXPOSED TO VINYL CHLORIDE NEAR Oil Vinyl Chloride Concentration ___UbRJ__ ___ 0.01 0.05 0.10 1.0 i.r r.D5 3.0 Rfnft `.'5 9 ' - oSf\ Cu%MTitty Population Exposure 3**. 'C* Lower-Bound Upper-Bound J-Ejt1eata* Estimate0 .- . . 5' * " 272,000 - 3,111.000 33,000 - 1,073,000 1 ' <* * - v * u * ip 12.000 445,000 5,000 22,000 6,000" 12,000 vF * jau ,, . "*:*.*;r ` ifs,1 'it.ikt j 2iOoa : i?c' * 'j' -jitiv gp; *T * r 6,000 6,000 a - The exposure,estimate PF 9131 micrograms niter" sec" . *- The exWSure.Wt flatted W>t IMPlVe^UXONsrttirAf 4.42 micrograms amter'^detT^is-v'"^-iww f . 'e ^j*; -A* eGt'CAllR*3,1C* :3viJ -O ** ' ` *'T tr4 ii .-aiffliJs.. exposure represents. Uw reegpr aa*eppor-> bounds of: concentrations- predicted fer ndKAtln --r spire dllmanlpr cadlsfce~fihriII-5 shows fee1neta>ffi?t.Q0<fr1*094,6001 poapde, areaexposed? to ai* annua 1 ed at TaeetOaOOfppSeer <3ngd cdtorier from the rlawtely lf;00tr tor ttt,00* ef^these people are averager cencaetratloir of* at*' least; KOr ppb from this Table^lt-6 shows, that approximately33*000 tor 1,073,000 a exposed to an animal average concentration of at least 0.05 pptrof vinyl chloride from the Oil landfill. Additionally, Table II-6 shows that a range from 0 to 12,700 people are exposed to an annual average concentration of at least 1.0 ppfc vinyl chloride near Oil. A-15 CMA 010547 In addition to estimating the cumulative population exposure to vinyl ^Uorlde for people living near BKK and OH, the population- weightM'exposure results were calculated. The population-weighted exposure Is calculated by multiplying the estimated annual average concentration for each celT by the population represented by the cell. The exposure results for the'1611 cells are subsequently summed and divided by the total population represented by the 1681 cells. For BKK. the population-weighted exposure results show that 2,154,000 people are exposed to an annual average vinyl chloride eoncentriitloq ranging from O Jia pph to 8.34 prts_Foe^0IInt|e populat1on-we1ghtedvex$osure results show tmt**7287,0w bdejfle^att^lxposee tirair annuel averagt'vlnyl chloride concentration ranging from 0.004 ppb to 0.0$ ppb. The model was also used to estimate the annual average concentrations for the maximum exposed Individual at each landfill. For BKK, the maximum exposed Individual Is estimated to be exposed to an annual average concentration ranging from 2.3 ppb to 10.3 ppb. For 011, the maximum exposed individual Is estimated to be exposed to an annual average concentration ranging from 0.6 to 8.7 ppb. The population exposure results for BKK and 0X1 suggest that other] landfills In California that emit vinyl chloride may expose the nearby ] population to elevated concentrations. However, because monitoring dat] for other landfills Is limited, we are unable to estimate population exposure near other landfills In the State. Chapter III of this report discusses other vinyl chloride monitoring data that are available as well as existing programs Intended to provide more information concerning vinyl chloride amissions and exposure resulting from other landf 11 Is In California.______ _____ ______________________ . 304 - wtfr thgrpfhifr--m> Hm Indoor concentrations of vinyl chloride are net expects# mebe subebent 1 a 11 y greater than outdoor concentrations. Althnnabdata are limited, the above statement ft supported by the following facfbr If few Indoor to to of chloride oMI 'dccumiTate ley Inr liiiaer concentred lowerthat, may be several ad outdoor concentrations. In soot houses tev vinyl--chloride hoe bean detected at oytO Wo estimate that people living near Tendfillt-may be inhaling up to 2600 micrograms of vinyl chloride a day (see Appendix for III A-16 CHA 010548 assumptions). For those individuals, inhalation of vinyl chloride Indoors-Is expected to represent the most significant source of exposure. A more detailed discussion of indoor exposure to air contamfnants is presented in Appendix III. 1. Potential Sources of Imtaar Vloyl Chlorld* There are severe! potential sources that can contribute to elevated indoor concentrations of vieyl ciWide. These sources include landfills, polyvinyl chloride (PVC) products containing residues of vinyl chi or Ida riveter thateontaietcettdnetiOf^vtey! chloride and cigarette smoke. Per .most home*? theme tsmffsf are nek expectad to rasult in substantially elavated indaee Wt'li ethinyl chloride. However, for some hemes located near, landfills*^itaft believe that landfills may represent the most signtieaat*coiftFibutidft to indoor levels of vinyl chlortde* Vinyl Chloride Frem Landfill Coe- .Them ara at least two ways that vinyl chloride amissions from landfills may'contribute to Indoor concentratlons-ef vinyl chloride In nearby residences; l). homes that art located downwind from landfills can receive vinyl chloride through direct outdoor air Influx Into Indoor environments; and 2) landfill gases containing* vinyl chloride cap mlgrite yndprground and entor homesi through substructures. The rate ofaccumuretion.of vinyl chloride Indoors depends on several factors Including soil permeability, source strength, air exchange rata, and structure,of the home. In addition, higher indoor caecentratIons may occur because vinylchlocide Is more rapidly destroyed ip outdoor air theiModoor-airbeceyse of direct exposure tft sue^jght. ,,^ , .t ? ,, cc__ tmsw* : Mibtlc Hctertali *: * i Products. Plastic products made of PVC and other vinyl chief idp-pptpeM/jBbgudifilltout In most homes. Because vinyl chloride monomereanrmMfn fntnel*?? rasln for an estended^MpIpf af in#oedlMbyl chloride emlsslans^iapancgmpT fflMfetMngpff*fld IWf****** shift1do monomer fr^t>m<i|rtirtpptadirty|.iidyidN m-vj$ bet-viea at untmt* ? ' 'Tnl elpfe-auHRt ,iaenJr.oe r ' **** ' -?>*vrr * . CnisetjMWpf uprneeded yjoi&fhlenlclp;mnnimenahavesbeen? - iuhstiot.1elil3fejTfr.cpd dMtejtpb 1mprgyoetst menemen; stripping^ < *9*ldi Tt {anlhr ppptbttff* IdeaM * WinchI* *da *resJMt atrthertimeef sMpm*nt, weper*s high as ^______ ________ PVC resins contain about 10pp>reei4uel vinyl chf|^^^KQ^jpM|i of shipment and may lose vinyl chloride at a rata of-|flHHPdjRe#ptrper meeilr durlMRStdragu* In addition, most of the vfny&SlTbrtdb vaporize and escape during, the-high temperature processes in wfcftfc PVC resins arsmelted and made Into final products. Thus, consumer products made of.PVC resins no longer contain elevated A-17 CHa 010509 residual levels of vinyl chloride monomer and, therefore, are not expected to be an important contributor of indoor levels of vinyl chloride. ViMTflitlpit frm Mater Sources. Because activities such as using water for cooking, heating-and showering can promote rapid vaporization of vinyl chloride from water? contaminated surface or ground water may Increase indoor vinyl cM'dridd level*. / * ~ t + - In California, surface Water ft generallyfrto ef vinyl chloride (SHerrp* ns*?)In essessfng groend wafirqeelltyf the eaiffornli Department ef HoaTtN Services reported, lased en> a-Ifmtt'ef detection of 0.5 mlcrograms/litor, that one dut'ef the 8VP47 edits for large public water systame that were sampled had datattaBfd^levels *f vinyl chloride (DHS, 1986). Tha maximum concentration feend^fft^ttat well was 23 micrograms/liter with a median value of 20 mlcrograms/litor. Vinyl chloride has not bean detected In well* 4iSd-f0ftrsmll public water system* (DNS, 1987). Therefore, vinyl chlorfd#c1ft-th* water supply Is not believed to sfgnfflcantly Impact tndeor alr Cdncantratlons of vlnyL chloride.' `t . Ii>: f I ~->C. imttkm a minute maount of vinyl1 chloride has bsseen# Identified In the smoke of cigarettes (1.3 tolS-nanograms/cigarette) $ and ef ItttTi cigars (14 te 27 nanograms/elgar) (IA8C, 1988; Hoffmann, Patrlanakosand Brunnamann, 1975). The vlnyt'efrltrlde level In the malnstreelr smoke may be estimated by the tetal^ftMfgantc chloride content of thetobaeco. However, the contribution froavtobacco smoke does not appear to have a significant Impact anttlMMnddor concentration of vinyl chloride. IhdedPVMf dit*-iln b^main#4oimf fed perSb**l*1fstealing or *y*fl*ediiltrilr"*ii#11H|.-Ih`perdn*l-siltiint*;tB(ft*imp4ln(f^* equipment is carried by an Individual iliigilr ary taken wherever the Indlvldnal may be. In contrast, fixed-site air sampling refers to air saMeen6feMPtWtr4b6*t1*lk*t r*emp4Wg data ganara4%rgfpMirirmbre- NmflstWbstlmtffc BTVndlvldWl- WpPBera. ` spend'Ttewr percent of. tnadrtlmfc liethdbor la 1 air smiling*dat**re^*t*giyw*igw*d by indoor ai tw-a& -'"-.i":' -w.'ij Baseroirllmlta#personal sampling that Indoor air tzpoaurd trvinyl chloride Is apparently 1dm; In menltorlng nine subjects In New* Jersey and thrao from North Carellna for several day* an three separata occasions, all of the 138 air samples taken ware below tha LOD (Wallace at al., 1984). The LOO was reported to rang# from 0.25 ppb to 1.11 ppb (0.63 to 2.84 micrograms nter~J). A-18 CMA 010550 Flxed-SIte Sanding Data. For a study conducted in California, fixed-site monitoring stations were installed to monitor indoor and outdoor air concentration! of vinyl chloride.- Based on the analysis of 32 Indoor samples taken in eight homes during summer season for two twelve-hour sampling periods (daytime and ntghttjnie), concentrations of vinyl chloride are ell below the LOO. The samples were analyzed by two analytical methods with LODs Ringings from about 0.21 ppb to 55 ppb (0.55 and 140 micrograms meter''1) (Pwllizzari, 1989). A similar study was conducted In Baltimore where Indoor air concentrations of vinyl chloride In about 160 homes were monitored by fixed-site sampling stationer. Speed on partially analyzed results, vinyl chloride wee not detected in Indoor air environments. The LOO was reported to range frees 10.2 ppb to ISLT^ppft (28*tO PVmCcrograras meter'3) (Pellizzarl, 1987). Special Situation Air Monitor1no. In 1981^the SCAQMO collected 24-hour bag samples In the vicinity of BKK 1andfill. Over 500 air samples were taken at two outdoor sites and at four Indoor sites downwind of the landfill (SCAQMO, 1982). All of the samples (approximately 120 samples) that egualed or exceeded the state vinyl * chloride standard of 10 ppb (2b micrograms meter ), were* taken Inside the residences. The highest recorded Indoor vinyl chloride ' concentration was 50 ppb (130 mlerggrams/meter ). fbe LQfr was reports to be 2 ppb (5.2 mlerograms meter). ? * ff v.'iop In 1588. the SCAQMO collected grab-samples instdmeome residences adjacent to Oil. The sampling study was prompted by the SCAQMO1s finding of - elevated levels of vinyl chloride in amrerehenter meter boxes in homes adjacent to Olt. Indeer sampling results shew vinyl chloride concentrations ranging from t te 100 ppb (20.8-260 micrograms meter'3) (SCAQMO, 1988). Presently, Indoor concentrations!Minvl chloride In these residences are believed to be substantially lower because routine monitoring of water meter boxes taMPldMtaOd significant tapIs of landfill gases. Thimbu* beg^dRraMta to improvements in. the Oil lahdf111 gas collection system (Coy. 1987). E. EXPQStMF'MoiWI OTHEIkaftW jfifmi Jn 300tapiwM objective of this report Is to estimate exposure tire to vinyTchTofide mey alsooccur from the water- that contain reeldues lor ide. y Code specifies that the AR8 shaH-Identify tha fbn to total axposura to the contaminant from indoor concentrations, taking into account both ambient and Indoor environments (California Health and Safety Code, 1989). The Inclusion of thaso data provide a useful perspective of the overall exposure to vinyl chloride through environmental media. The estimated dally dose of vinyl chloride A-19 CHA 010551 from different environmental media are presented In Table II-7. From the table, exposure to vinyl chloride from the Indoor air of homes not 1ocatMtnear landfills, food, and water appears to be minor. However, for people living in houses located neer landfills. Indoor exposure to vinyl chloride may represent the major source of total vinyl chloride exposure. The need for total exposure assessment and some of the issues and concepts involved inr total exposure estimates are discussed in Appendix Xn. '--v ^ , ' * v w' t (t * ' V -i *t jsst ,, It "saon- ju-s-se *br mfiiv far. '*> n > t ' a r ; - s- ;.v uu,, . * estimate) nun: chloridc exposure mourn oifferewt media4 Media Reference AIR 1 am, t> Ambient Air Jnddor Afr * ^ H - > t ;-: c 10b to 71* uuagrr ^^ ' jJ / :1TtoTe H-t -j.,- ,`a.i5 ` .if - pa;:**' JOO - `*v ` * !*; , ^-v.a , . i';: . Homes not near . -'TandfiTlW* -* Airu- . tfelteee a*_al., 1984 >^.sMD'a **w flwja 9fl.,'ome .1.; <- . Names neer Tandfm#* 'ip'Wmir'iib Ml fis- "sooesi .nS cj Saessrs* emoe ; *3f e dqq 'Aii 3 eerl pH-pne* **<* i* i, .J' Tuerewfeo. < leases leeedl (d*M .HnOA^j (* --a.*- - 'eUfliJadu* d oJ eeveHed ene ampoee- i a.u *v n>shd|iIn| daHR>f ~tote* lP*m ie|p*Moifte* ***;*-> = ouMuatfEduw# WRbrfW *** iMJpyjJ0 ltms, imi?*f87 : eic* *wTao^OP^MlPiniMpI **8 ** sn*i,*ve^- FoodriecTedtnt < SiasUR* iSSSdri rtl ~e evi jsst^e r-s - m: jfi-'-asrj -t'<< jf aesameae ,n# tst* met wer#u5erffVw<^*fH-Tere prov trfed in ^ s . s.i; je $oo. r.'.s 1 .'-1 ' A-20 CHA 010552 1. Mtr Tnqastion ruDi IAFT jfte major source of drinking water for California is surface water which, because of vinyl chloride's high volatility, is not expected to have detectable levels of vinyl chloride. Ground water used for public water systems is also relatively free of vinyl chloride with concentrations typically below 0.5 ug liter'1 (DHS, 1387, 1986). Based on this Information, staff believe that exposure to vinyl chloride through drinking water is not Important under ordinary situations. 2. Feed Ingestion Vinyl chloride is not routinely monitored for in tf.5. food products. However, before 1973, vinyl chloride was found in food and beverages packaged In vinyl chloride polymer materials (IARC, 1979). kg-1 (ppm) of vinyl chloride monomer were present In alcoholic beverages packaged In this material. Vinyl chloride was also found in edible oils, butter and margarine at concentrations ranging from 0.05-14.8 mg kg . When cleaner PVC resins became available after 1975, vinyl chloride polymer containers typically contained less than 10 ppb of residual vinyl chloride monomer. In Its recent rule-making proposal, the Food and Drug Administration (FDA) estimated lifetime-averaged individual exposure.to vinyl chloride from food and beverages packaged' with vinyl chloride polymer materials would not exceed 25 nanograms p< day. A-21 CMA 010553 DRAFJ ^3* ^f. A.'.' ' fco- Jl: tt aat^zi r.3 <*'1 ' - -: :2 . *. + <1 i ..j V'- * a *''^ ^ *, .>, J,-,u.H ^VT . - -no^oai T** v'fl *' MH< ' iXU> zc- : v* .- -tnaq*8 !saa n *mv*oq ^c--o'rti t * OlO*5* REFERENCES TO CHAPTER II draft California Health and Safety Code, 1989., Section 39660.5 (d). Coy, C., 1987. Personal coamunicatlon between Richard Corey of ARB staff and Carol Coy of SCAQMO. February, 1987. OHS, 1986. California Department of Health Services. Final report on a monitoring program for organic chemical contamination of large public water systems in California. DH3, 1982. California Department of Health Services. Statue report- AB1803 small system program: Sumary of result#* FDA, 1986. Proposed uses of vinyl chloride polymers by the Food and Drug Administration-Proposed rule. Federal Register 51(22):4177-4188. Glelt, A., 1985. "Estimation for Small Normal Data Sets with Detection Limits," Environmental Science and Technology. 19:1201-1206. Hoffmann D.; Patrlanakos C.; and Brunnemann K.D., 1976. "Chromatograph!* determination of vinyl chloride In tobacco smoke," Analytical Chemistrf. 48(1):47-50. f IARC, 1979. "IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans-some monomers, plastics and synthetic elastomers and acrolein," Volume 19. International Agency for Research on Cancer, World Health Organization. IARC, 1988. "IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans-tobacco smoking". Volume 38. International Agency for Research on Cancer, World Health Organisation. Pelllzzarl, E., 1987. Personal comaunlcatlon between Steve Hul of ARB staff and Dr. E. D. Pelllzzarl of Research Triangle Institute on December, 1987. Pelllzzarl. E.P.. et al.. 1988. Development and Implementation of exposure Brndedures for toxic airpollutants In several Los Angelas Countv rch Trianole'Park. ;ute, Inc. "SAS User's Guide: Statistics 1982 Editor", Box illna. chloride In the South Coast Air Basin", Report by the South Coast Air Quality Management District. A-22 CHA 010555 SCAQM0v l985. Internal Memorandum between S. Levy and Edward Caraarena of the South Gpest Air Quality Management 01 strict on September, 1985. Sharrp, C., 198?. Personal communication between Steve Hul of ARB staff and Chris Sharrb, staff of California Department of- He*1th Services on December, 1987. . .. VttWactr L.Ai, at aK198*. "Personal, exposures te volattloorganic compounds- Direvt measurements tm breetlmcunm ates,~.brtrtttnfcmatac,. food, and exhaled breath," Environmental Research. 38(10):293-3Msr*c^ . *- ......... WHemtefv ItJf., Mi!y "ffotyfvloylt cJtTomfdfc)n0froetesta add products. Environmental Health Perspective. *U 14MMU .** yr.a m.t - i*in 'seacQa-'-H Ja beeeme-^Mtor j-j jje1 --. - . ..if: i\'. . snA - . *'" . ! , , s :.Z tOAtnu'Jb^ ..0 'V a - fv'-.'rv 1" -*0 -itiim . '1 -' . . * , '0 ~ - *i ! is, . ; : -,#^4 , ansf . - tiPIUh < .<- . - u,a 'te-j rnsoA. s.of;c.:^*jnl l -O M3 ,',0 irtpa '** .$* mmfeV ,"ffWJloms *a^*de.J-inero<t c; .isarjrwrt: .MMJesHniiniB Ottae# .tooosJ no -..i -g rvH 4v*^.eigtfad. flti.t&inmsid .anoemeA .Tffl. ,.i .r^esr^f ''a-3 3= --;*q -io efpnsHf &neeaot * .8 .3 -a o~* A-23 CMA 010550 III. PftOMJCTIQIi. USES AMD EMISSIONS Although vinyl chloride is not produced in California, several thousand tone are used each year in the State for the production of polyvinyl chloride (PVC). The PVC which is produced is primarily used# by fabricators for the production of materials used by the constructioik packaging, electrical, and transportation industries. f Based on the emission estimates for two landfills in California (BKK and Oil), landfills are the largest Identified source category of vinyl chloride emissions In the state. The Information necessary to estimate vinyl chloride emissions for the hundreds of other landfills In California Is not available. However, without monitoring data which shows otherwise, all of the state's landfills should be regarded as potential vinyl chloride emission sodreds* Qfhdirknown emission sources of vinyl chloride In the state Include PVC production and fabrication facilities, and? sewage-treatment iptantd; ~ A V -4 " - * - A. PftQOOCTIO* 15? ~sr. * in 1936r Oerlmpther first jroee? of" product tent twothousand tons were r* With acreytorted annual &3:'production of 3.8 1 chi orIdo ranfced21st on a list of-the most produced lited States In 1984 (CEM; 1985a): Figure III-l shows Imports, exports, and use of vinyl chloride from 1974 (CEM, 1989a; US DOC, 1989; and US DOC, 1985b). Ouring ___ _______ vinyl chloride production increased at an average annuel rate of 3% (CEM, 1989a). Mere recent estimates for U.S. vinyl chloride production are 4.7 million tons and 4.2 million tons for 1985 and 1986, respectively (CEN, 1987). A-24 CMA 010557 FIGURE III-l NATIONAL VINYL CHLORIDE PRODUCTION, IMPORTS, EXPORTS, AND USE Twe fsetllttes in CaMforela currently us* vinyl chloride to produce PVC. Tweothsr fsclltttes In theStatethat were, producing PVC ceeted production* one In 1902 end the other In,1989v(Personal Caenuntcettoe. 1996*. 19t>b, 1998*; odrZu1echer>.W.-*tM 1993). ,,: v, . .j cm i' B. CUMBTT 4M PMOKCTED.WSCS. f o* er-'-w'-o rv 5 'rza -s' idS azu.ie. jJsJti sol r.' ;.-fo743 1. About 99 percent of ther.vleylrclilocldetprodvcedslnithetU..S*- is used to menufecture PYC. The reminder Is either exported or used to manufacture 1.1.1-trlchloroetbane (methyl chlorofonhtttlKtfaoiNAHB, 1978; and McPhersen, d.t 1978). Sixty percent of the PVC 1* mod' for fahrlcstlegyvenlee* plastic, meterlata ueedbhettpei ceestructlon industry. - Specif 1cel lyajP9M*n*se^hrt^*/**l**^e*t** ffcl9p*> HtTipnim fMMtiil Mriiinir-rfii ntsa$ ett* usedjhr the l.furelttnlef tsmsecrtsfcVsn* reeeteUMs,, apparel. as; . i *3 -11" " liU ,-iO' -- vinyl chloride Industry fcrdomly tied to PVC ,4ita ferC*11 feral* shew the number of housing units in therciiisffitftaft Ihdustry Increased free approximately l.Q million units in 1991 to 1.8 alllloe units In 1994 (U.S.^BOC^ 197>, If this growth A-2S CMA 01053 in the construction industry continues, the PVC use by this industry is also expected to increase. Data are not available to forecast the use of PV<* in other sectors. However, the total United States demand for PVC has been forecasted to increase by approximately 1 to 5 percent annually from 1985 ta 1990 CCMR, 1985). C. LANDFILLS: A MAJOR EMISSION SOURCE .' k.Ci Landfills are estimated Oa the largest source.category of vinyl chloride emissions in California^ because landfills vary in the amount ted composition disposaljeethodf used*:fl " "* ,,, the waste emissions for the state's hundreds of TapdftU: all WndtiUd'are potential* section presents information oo tl .types andlouebes at Tandfills in California, the disposal methods employM^jtlie caused of vinyl chloride emissions from landfills, vinyl chloride emission estimates for landfills, and some methods used to con^^^Jj^ei|tssions. 1. Types of ,LiPdtilli . -v j* There are three types'of landfills ip^Califarnia: ,-ttiss t vijwt *' QKK. located-,in West Covina) whi^h accept aU iyas of wasted.f Including hazardous materials; pass.,I$ sitat^n.g. *rQparet1ng Industries Inc. (0II) locatedfn-Hoqiarey Park) which permalTy-accept * only 'non-hazardous' wastes hut can accept certain types of hazardous landfills) Sites which can acceflt lp 14*. there are fourteen Cfess I sJtM.CfefJ) facilities), 28rS--*!SJ? {Aj 1982b: wqcB,. 197A,-sen** hp <'<* *ee le- **aen*et noOfcih l; : 'c.n mm*tmmedt em**'* oi lioci y as waste practi p three t H often used jeey b f the method, s. In inVjefchod. over frequent ...a*. are used to dispose of certafn types of itqufd wastes* As the-n-a-m--e--tisp. li,,es, surface impoundments allow the wastes to be evaporated into the atmosphere. A-26 CMA 010559 Landcovering is most often used at Class III sites or municipal landfills. In landcovering, wastes are spread over the land. At the end oFeach day, the wastes are covered with approximately six Inches to 12 Inches of cover. Ultimately, the wastes are covered with a layer of cover material that Is at least four feet deep. 3. Landfill Emissions Emfsstons' ofvlnyl chloride freerfarfptfTTs mdlnly occur by two mechmlsmri If d^ert wipes rtof dfipefed wastes which contain vinyl "chTortdei .PI^YlnyT chloride fro* the bldtfegfadatton of chTorfriutid hffrelai^loes. Other minor mechanisms by which vinyl chloridd f*JjjJ fficTyde chemical reactions such aipyftlysis, surfaid fkydrofysis of trichloroethylene and other chlor1nated hydrocarbons, and off-gassing of PVC (Holton at al;, 1987). ? ' " ttfreet gmfssions. Direct maisfforif 4? vlnyt chloride can only occur at landfill sites where vinyl chloride containing wastes wereprevlously disposed. Because vinyl ch1er1dda3Betawning wastes cannot b* legally disposed In Class II or Class III landfills. Class .I landfills (e.g., 8KT) at which vinyl chloride hap Been d?s|fosd4bafe probably the m largest source of direct emissions of vthyi^chfdrldd. fWbever, bgcauiaft vinyl* chTdrfde containing wastes may have bien fTtegatfy dlsposed, Clasp* II and Class III landfills may also wnttvinyl ch Tor Ida directly, Fermat< of Vlayl Chloride. Mceuse vinyl chloride can be formed from the biodegradation of ehTefltibted"wastes, amissions of vinyl chlorldi smy ocedf from gtfyiandftTtsfte Unfading Clasp ft and Class III sites where nd'tlnyFCTlorfde^e* bedh^tjpoied: Of the three landfill disposal methods. It appeers that landcovering"and Tandfarming are most likely to produce the conditions necessary,for the.formatlon of vinyl chloride. tWaCTIIgaJc "naJ * tloo of Similar mechanism ite,< llffapns. Sub-, udder it"e*peffmentation with aettfdnes and cffforoetl i yielded carbon-13 sell as othdr biodegradation products. These ftJt other studied which evaluated the item chlorinated hydrocarbons to produce vinyl chloride (Kleopfer, 1985; laeman, et aT., 1978; Moerf et at., 1980; and Parsons at al., 198d). Figure III-2 Illustrates the "pathways by which vinyl chloride Is formed from the dohalogenatlon (chlorine removal) of A-27 CMA 010560 DRAFT FIGURE III-2 ANAEROBIC BREAKDOWN SEQUENCE VIA REDUCTIVE DEHAL06EKATT0N IMonnitxl ...C...-.C...-. TSi --*** CVc..*c yc` *.y a >* - OMHrawt . '3 'or. *j ."Jji.? D'i iiib.*:: 5 *T* s Ml. tajRlfci aSft +/ * ft; * n"' " * 4^.4 t , w, ^ - :'asnr..i.y> ''V'WJh-" qhWwt---s Clv * -c ^CJ -<a11\- CCll/Scr" ct I.u- l.t ... . *" Ct_ ... ,-, -.p t ' -Oi. ^^ j i * t ' - ; :r ^ - "Vi} . .: .. iftC'f ,1J?* ?' iwsmj *** it ft:jua >* * * **'' --r.Miwoa icn si* y - W " v - - ;mw: ** * 1 *iw A - V' (31* Slbv diniiiiio'ik .-ruc**'. M ' .'V'all-.'** u .; :; vf\t- -y-:: v ^*f*W fMfft amt n^Jtwombs in*f ' 5* 7D dsfaeif sa*e ? f **<* irrojtffc nt lftOi *o aar: 'eM^ftratfWf relative rate fcy which the * * * unequ current -VWlfWtis tha MbTrll of tven the hhlorlde #j nt *****- ** .#f r nueei ' int+ilTy restrfetetf. for dtttMatf tJhetaf*trlals I Tandf ftT* Stf'WeTT ^`TortT Clttl fTTendfllls I III iiapBiwf llWnilJl 1 Tlir heloigMieta* Waste* are coated of many of tho cfrtorliwtereaepounds which cin load E'er therfbWaatfdn of vinyl eh lorIda. Howavar, tho ftiaount of halooenated wastes previously disposed tn these fad Titles ts unknown. Therefore, without iwnttoHng data that A-21 % CMA 010561 shows otherwise, all Class I and Class II facilities (this includes open and closed facilities) should be regarded as potential vinyl chloride emlsstab sources. Industrially generated halogenated wastes were never permitted to be disposed in Class III facilities. However, many of the chlorinated compounds which can lead to the formation of vinyl chloride are used eitensively In consumer products, which after use typically end up in Class III landfills.,- The amount of chlorinated compounds remaining in consuper products and disposed In Infills Is not known. However, because of the widespread use of the** compounds In consumer products, airrtas* IirTandftUs (this irMTudWTopen, aftd clort<Tfac1 lities) should be regarded as potential vinyl chloride ^emission sources. Methods of Estiwatlna Landfill Emissions. Several models have been developed to estimate volatile organic gaseous emissions from hazardous waste landfills (Thldobeaux, 1981; Hwang, 1982; Shen, 1981; and Hartley, 1969). The models usually apply to specific landfill operations such as landfarming, surface Impoundments, etc. However, these models are difficult to use because they require a number of*in parameters such as waste composition, wind speed, and ambient condltl which are not commonly known. These models Involve the use of Tick's law (Pick's Law describes the diffusion of a spectes through a layer fluid) and may be appropriate for estimating dtract amissions of volatile compounds such as vinyl chloride. However, because the models * do not consider factors such as formation! they may not be appropriate for estimating vinyl chloride emissions where formation Is occurring. A method to estimate vinyl chloride emissions whore*formation may be occurring Is to establish monitoring stations around tanSfTlI sites to measure the ambient concentrations* ef thpkcompoiyidv of Interest. The ambient concentrations along with appropriate meteorological data can then be used In dispersion models te beck-ca leu late the emission rate The vinyl chloride emission estimates for BKK and Oil make several assumptions. These assumptions are: 1) vinyl chloride Is emitted from A-29 CMA 010502 * TABLE I1I-1 VINYL CHLORIDE LANDFILL EMISSION ESTIMATES* Source Clast I Landfills BKK, West Covina Other Sites Class It Landfills Oil, Los Angara* Other Site* Class III Landfills .... re*.-1?Source IarfralonV rnventprv weed;;; i Art*' Area y 4 4-1r9-,,z7f-- 1987 xft Area Area Area ' * -.i * n z ^ 4-tf * . ? , * , MAf' m' i Raf. ARB, 1988b ARB, 1988b * - These Mission estimate*'assum that the vinyl chloride mission rates art unifond throughout tlfCWar over the arts of the landfill that is estimated mt vlnyr&lotf<Mf. - ^ NA - Not fcallaBN1 ' "''iff*, f t tv ' ' * *1-* . *>* 1 . main pntliei >r:T ;TW. - 4- >.- c xtcoJiaat itau^.: -c -v , an art* ofca#xitfteHffi#B?l(**fPs*k BKTiWdrtffSWO deters2 Tor 811? 2) liMlir avdrfgp .felfffffi rFtdtf qfVlnyl; chloride from BKK ilkt 8Htbd*fjhRl|^eiffiaatdif*fri,F|fRj w-ff amissions of v1ftyf1ifwilPaf unIfOrtTWir^fllt tilt 1i*t are**of =ffln WWftn that is est1i|CM*^iterv1it&a|!itfd4P `AnRtooN tNfcn e**M*ftns add rtsil^stWBs WBtriiid Bit. ARB staff believe. _ fitfdrtHsf rand/lTts riererent thaMergest ttaortTdf^vittl^eRTdffat^amiNsImni tif California. IT monitoring data for BKK, ARB staff tsffhMtt a ulnyl chl^Fffil7mission rata ranging from 0.7S to 3.32 micrograms meter"4 secondr* (see'Table 11 -4). For BKJtTandffll, this, translates to estlmatad vinyl ehlorldt missions ranging from 44 and 197 tons par year. Over BKK*s history It Is net known how much vinyl chlorlda containing1 or haloganatad wastes ware disposed at the landfill. However, In 1984, BKK received approximately 136,000 tons of volatile or toxic wastes. An unknown portion of these wastes were haloganatad solvents (ARB, 1982b). For Oil, ARB staff estimated a vinyl chloride mission rate ranging from 0.31 to 4.42 micrograms meter' second' A-30 CMA 0105A3 (Tablt II-4). For the Oil landfill, this translates to estimated vinyl chloride emissions ranging from 4 and 51 tons per year. The amount of halogenated wastes disposed at Oil over its history is unknown. However, In 1982, Oil received 9,200 tons of volatile or toxic wastes. As with BKK, an unknown portion of these wastes were halogenated solvents (ARB, 1982a). "" '4 4 ;*! <**' Othtr thn for Bn and Oil; vfnyT chlorld* missions have not boon estimated- for any of tho state's landfill sites. However, based on test results from severe! Cttt*n*>ndCl4W III landfills, it, 1$ expected that many other landffTtffn Ctllf^hfa are vinyl chloride emission sources. '- Monitoring results available for several qther Tdddfllls are as follows: Flux measurements on the sunface of the Schott Canyon sanitary landfill (a former Class II landfill located In Glendale, California) showed vinyl chloride concentrations ranging from.neo-dotactible to 188 ppbv (parts- per billion by volume) at various locationfttTOdd and Proppor, 1985). In addition, tests conducted By the .SOMjMty at severs other Class II landfill sites from 1981 to 198ft confirmed the presenc of vinyl chloride In landfill surface gas or gas collection system (C 1985). -- -- To partially address the Tack of monitoring data from other landfills throughout In the state. Health and Safety Code Section 41805..5 (Aft 3825 and subsequent arnonmeonts by Aft 3374} requires the development and imp lomentat1m,ef fulfill l monitoring guidelines and the reporting of monitoring results, lee taw requicf%,the AM^to establish guidelines to monitor gas migration, gas constituency, and the ambient air at many of the hazardous and municipal waste landfills In California (ARB. 1986; AM. 19*7). The testing guidelines identTfjnwiyrChloride as one of the compounds requiring monitoring, landfill operators wort For many landfills amissions aro rseuirad to be control ltd to roduco odors as well as amissions of msthsno and toxicants. Howovor, A-31 CMA 010564 DRAFT gas control systems have been installed at some landfills as a resource recovery and/or energy conservation measure. For example, BKK transmits collected landfill gases to either one of two flare stations and/or to a five megawatt gas turbine for use as a fuel in generating electricity. Both well (vertical piping) and trench systems (horizontal piping) are used to collect landfill gases. In 1983, BKK Installed a number of wells and gas collection lines to help control gaseous emissions. Although there are stfTl potentfa1 sources of gaseous emissions such as cracks at the landfill surface, pip* connections, and valves, and burner exhaust, ambient concentrations of vinyl chtoftdb near BKK have been declining. Since installing their gas collection system. BKK has continued to expand the system by adding wetlf ami trenches. Since Installing a gas collection systam at 0I aamfdrtt Concentrations at the perimeter of the facility have continued to dec fine. Oiie to the lack of violations of the state standard for v1nylichlb/`ida (10 ppb), ambient monitoring at the perimeter of Oil was discontinued by the SCAQMD In early 1987. A well system consists of a network of wells drilled vertically into the refuse to collect the generated gases. These wells are connected to collection pipelines whire gases are withdrawn from the buried layers of waste. In general, a Vertical gas well is construcfaC by drilling a 30-Inch diameter hole 50 to 100 feet deep Into the wastes. Perforated PVC pipes are then placed Inside the hole. The space between the pipe and the hole Is backfilled with uncrushed gravel (Sanitation Districts of Los Angeles County, 1984). A typical gas control systam showing both well and trench systams is shown In Figure III-3. r1 'c -v- FI6UBE III-3 uwomtps cation** system FLAMNC STATION 0 GA CGtLECTICK TRENCHES^ - Source: Sanitation Districts of Los Angeles, 1984 A-3Z CMA 0105A5 In. th# trench system, a network of perforated pipelines is laid in trenclii* within the waste at approximately 200-foot intervals horizontally and 80-foot intervals vertically. To support the pipes and to allow the migration of the generated gases, approximately Z feet of uncrushed gravel, are packed around the pipelines:. These pipelines are then connected to, a main, collection oipe where gaser are withdrawn (Sanitation Districts of Up* AngalsffCotmtx, 1984f. ~ ` - * 3 Y ' <- j ' O . , from: .wj^dil2ft.5i ai tahnfci^iwr'Sde tde ^iiVstahs occur l^eif.tment w--o--r-ks (POlYs)-, pthy<ttchIdfide productloff.^t^f^WiJaeproduction, methyl chthrofbne production, caprdfSfctbe production,' and incomplete Incineration of chlorine containlngmsteriaf* (ffttiff, dr, 1981; ZwIaCher et air, 1980; and Lamorte, M., iffttyf fn California, the identified sources of vinyl chloride emissions that can tie quantified are PV^ production, PVC fabrication, and PQTW*. Table II1-2 provides estimates of'vinyl chloride emissions tof idenflfiedsources. Currently*.,theft are no knoMS vinyl chlqf'tdd,. athylsM dfchloride* methyl cht^oform (TCAX or caprola^li produced* fa^yitles opiratlnr in the State* ,, _ -- tt ! ,V' J*i*' 3 ' wf: <> 1 *3^ SURMRY OF VINYL CHLORIDE EMISSION ESTIMATES FOR OTHER SOURCES e-m Source Reference NA - Not Avallablo A-33 CMA 010566^ 1. Pfllwlnvl Chloride 1PVC1 Production Three PVC producers reported emitting a cumulative total of 3 tons of vinyl chloride in 1984 (Personal Conmunication, 1985a, 1985b, and 1985c). In 198Z, vinyl chloride emissions from these producers were estimated to be 1.4 tons (Zwiacher, W. et al., 1983). All three producers reported that they were in compliance with South Coast Air Quality Managment District's (SCAQMO's) Rifle 1157. This ruTe requires that vinyl chloride emissions from designated plants not cause ambient vinyT chloride levels to exceed Iff ppbv (partS'"per pmion by volume) during any 24-hour period when measured beydrid tlidpTiht's property line (Personal Conmunicatlon, 1988a, 1985b, 1985c; and AM, 1980). Rule 1163 was adopted by SCAQMO as part ed their prdgrmiitttcadetrol vinyl chloride emissions to 10 ppbv. In 1984, the PVC producers operating fh^the'State reported using closed systems, incineration, routine leak surveyed and maintenance programs as control technologies to comply witb existing standards for vinyl chloride amissions (Personal Communication, 1989a, 1985b, and 1985c). The primary control method used By thd tdb Reproducers currently operating in California Is fneindratlMF?*' (Ate facility (facility A) usas an aftarburnar with an operating tamparature of approximately 2000F while the other facility (facility B) usas a eatalyttc type incinerator. Both feeliftfid Have a monitoring systam that eontinuoesiy measures the vtnyl chloride concentration within various areas of the plant. Portable hydrocarbon (HC) detectors are used te plnpdtnt Teats detected by the area monitoring systam. These plants are also* Inspected at laasf once a yearly the SCAQMO Enforcement Division to ensure compllancewith dfstrfdf>wete* (Personal Comaunlcation, 19888). ` '*** - ' *;u jv 1 i - The SCAQMO?pafiodlca 1 ly^Cdddactft^amiTaM iiMftodlng for vinyl ch 1or 1db*need'the*twd'- PVC producers-fA",ea Ilfb*Ma. '"In addition to the SCAW rnon4trin|#Mefam, tf SCAQNPradeiPU dhe ef^the PVC producers (faWlfty* Af-to*o8ttoenh8' idb*nt*ffiPfaf'vfyl ahlorida at theperlM88ear*ll8ft mttit#M8at^|afcts***ffe*othdr PVC producer (foclllty 8)-l<Pjotriqu1itodJ>b8tl5f conduet ongoing offsit* mbfintfmen1ter leg foe v fc Jjftaridafc T^Htf la because: ilerlda^ and 2) the process that 1 s used to ilifeni li net eepedtdtfTttefeeutl'1n vinyl chloride pl^thesa associated #lth thft^othdf facility which GeneraTly, 24-hour avarage concentratIons near Mtfdff are below thelO' ppb standard. However, in October of 9CNBMT Reported concentrations as high as 28'ppb for facility A (Mellta.l989). As a result, the SCAQMO plans te conduct ambient monitoring mere frequently at thts facilitate ensure compliance with the ambient air quality standard for vinyl chloride. The SCAQMO's A-34 CMA 010587 DRAFJ monitoring results indicate that this PVC producer may contribute to the public';* exposure to vinyl chloride. Therefore, this facility should be investigated in more detail when considering control measures to reduce the public's exposure to vinyl chloride. Table 1^-2 lists the cumulative vinyl chloride amissions estimates from th* two PVC producers tit California at,less than 0.5 tons for 19ft7. This, estimate is substantially toman; than the 1914 estimate of 3 tone when three PVC producers ,we -perat left, 10 forn i a (Personal Comajfttcation* .19tfaa3**bw.l9ftftci,: ,, 'K' " : y.~.l *- * Polyvinyl chloride (PVC) can be fabricated Into several products such asPVCgtpas, pipe fittings, plastic*, etc. Seme major fabrication processes are extrusion (to shape by .foreleg through a die), calendering, molding, and bonding,> PVC conteistthavinyl chloride, monomer as a residual from the PVC product ten processes* Residual vinyl chloride (RVC) In PVC ranges from Q.Q02 ppm* (peetS-peerPi 11 ion by . weighty to 10 ppmw (U.3. EPA. 19*2). When PVC,,If jfabricated tnt%ftna products, vinyl chloride is maltied*-.*- , :j -I Thm SCAQMD Identified 33 PVC handling and 'febg{cetion facilities undec its jurisdiction with an estimated usagesof H#0Oft tons of:PVC In. 1982. The SCAQM staff assumed that all uleyirchlertde~is emitted from the fabrication processes. Using tMijaMumptien and a maalmum BVC of lft ppmw in PVC, the~$CAQMD estimated that, the*e haedlin* and.fabr 1 cat 1 on fact lines emitted aprexlmately-ft*7;tee n*yleyj;ft1elde In 19*2 (Zwlacher, 1993). This estimate represents ana*--or,jhetftfti condition becsuse the maximum RVC was used to estimate emissions, and because all emissions of organic gases are volatilisation and biodegradation. Because POTWs treat wastewater which can contain vinyl chloride and A-35 CMA 010548 halogenated compounds from industries, vinyl chloride can be volatilized duringTthe treatment processes. In addition, chlorinated hydrocarbons such as trichloroethylene and 1,2-dichloroethane could be biodegraded to vinyl chloride. Ha'ogenated hydrocarbons including vinyl chloride have seen measured at wastewater treatment plants throughout the nation, including California (U.S- EPA, 1980).- ApreMminery study oftwe wastewater traatmenli plants* one In Loe^Angeles awd^anatd--t te the Sacramento Valley, iedteeted that vinyl <>fc1omtdm ttf'presptfC.t* the anaerobic digeater^tenfce.?Caocentrat1eM.ef hdem measured (ARB 198B*. / ' These d ifester<lanksere eeatpped with -presiure/vacuum (P/V) vaUetsta eeetitbrate the teeidPtendteiitcMpiinsdurm *f the tanks. TheeePiVvalve* are potential eouece* <rf vinyl chloride emissions along.with fug ttive.ami**ion*assoctatedrwtthpipe fittings and valves. ........ ,,^Gun. -.....I In a study performed by the University of California at Davtr* (UCD), researchers used a mass' baUncftjspprmachh&fcpstimate that ^ approximately 1.7 tons of vlnylchlortoeirwene-amitted by^POTW* CaHfor-nia in 1988 (Chang at aW.c 1987). .sSpeci,f<tcathmdi between the concentration of vinyl chIodide ImvthakrPCItt brtlue affluent was assumed to be emitted to thnatmosphereu. this ap he useful in eeeassing which POTWe aanttttubo * threefc to putol However, because thin approach does, net tehm inter) acnsiint the formation or degradation of vinyl chloride within POTW*, the resulting emission estimates should only be considered rough approximetions. In response to the need for more Information concerning emissions of toxicants from POTWs, ARB is currently funding a research contract. When the research is compute, the resulting report will contain the most recent information concerning the estlawtloe of emissions of toxicants from POTWs and P07V collection 1Inee. The report will also address the efficacy of POTW odor control systems on reducing emissions of toxic compounds. A^ifdfddiidd In tho discussion on POTWs, wastawator treatment facilities are sources of vinyl chlorido emissions. At several industrial facilities such as oil refineries, chemical manufacturers. A-36 m CMA 010549 DRAFJ etc., industrial wastewater is normally treated before being discharged. Theseleastewater treatment plants are also potential sources of vinyl chloride emissions. 2. Waste Incinerators Vinyl chloride her been Identified as a combustion product in the flue gas of an incinerator burning plastics (Boettner et al., 1973). It has also been hypothesized to .form upee the combustten of PVC materials (AhVtag et at., 197*>^ PVC materials are used eitdnsively in automobile' upholstery* bumper parte and fleer matt; when these materials are incinerated, vinyl chlortdsls a lihdly pollutant in the incinerator exhaust. Hospital-waste.4Incinerators are.another potential source: of vinyl chloride emissions since much of trie hospital waste such as syringes and plastic bags are PC*contetn1ng materials. 3. Transportation and Accidental Soillag# Another potential source of emission**** the accidental spillage and/or leakage of winyh chloride that is bathf transported either by retl car, tank car, or marine vessel. "Vinyr chMridd is transported b rail, cars to the two PVC producers currently'operating in California. As far back as records are aval labId, there have been no reported accidents involving vihyT chloride in the State (OffIce Of Emergency Services, 19S8; California Highway Petrol, 19Sfy. `.i -'Hf; S ,.}W' -w * i r j : .. \i' . jsjss" > --ae.irvj ` mmk mntm 1 siauzi a '90 -!oi or i m . * r5 A-37 cma oio: REFERENCES TO CHAPTER TIT Ahling, B-; Bjorseth, A., Lunde, G., 1978. "Formation of Chlorinated Hydrocarbon During Combustion of Poljtui ktertd*," Chemosoherc. 1(10): 799806. .< 4- . Air Resources Board*(AR8), 198#; `Reepobf* dfcafafcit to* Purs Hint to California Health and Safety Code Section 40451 to Adoption of Rule 1005.1, Control of Vinyl Chloride Emissions by the South Coast Air Quality Management District," Sacramento, CA. ARB, 1982. "Suggested Control Measure t Reduce Organic Compound Emissions Associated with Volatile Organic Waste Disposal," Stationary Source Division, Sacramento, CA. ARB, 1982. "An Assessment of the Volatile and Toxic Organic Emissions! from Hazardous Waste Disposal in California,'' Stefcl entry Source Division, Sacramento, CA. ARB, 1985. Memorandum from Ken Jones to Doan Simeroth on "Source Tests for Vinyl Chloride and other VOC at Sewage Treatment Plante** dated October 1985, Engineering Evaluation Branch, Stationary Source Division, Sacramento, CA. ARB, 19:84, * Test int&uidetiQPS;Pon Aetivei SetVid Meet* Otspeaal Sites," Prepared Pursuant to CaltfowH>Mdlth-omb Safeby Cod# Smetdon 41805.5, Stationary Source Division, December 1986. , . `is: i < ^ ARB,1987&"Jlffegdeyfetlefif IliaetaiiJeabln^r^tttteltrfee.^irepered Pursuant to California Health and Safety Coda Section 41801.5, Stationary Source Division, January 19B&. a**?* fcekfai rflantd#concerning "Updated uriurfW, t NldaTI ng Support :6 , 'nri"'* of eahifonmia w;irm4MMfa. imam MBt. di et., 1878. "Survey oft Tr ihelamethane Distribution in Various Miter Supply Sources in the State of Florida,"' Fine! Report to the State of Florida, Department of Environmental Regulation, Tallahassee, FL. Boettner, E.A., at el., 1973. "Combustion Products from the Incineration of Plastics," U.S. EPA, Report No. 67-12-73-049, Cincinnati, OH. BSK & Associates, 1987. "Solid Waste Assessment - Air: City of Clovis Landfill," Job No. 87147. Fresno, CA. A-38 CMA 010571 --- r-4 h V* U ft n i Chang, D.P.Y.; Schroeder, E.D.; Corst, R.L., 1987. "Emissions of Volatile & Potentially Toxic Organic Compounds from Sewage Treatment Plants and Collection Systems,' U.C. Oavis, Department of Civil Engineering, Davis ,CA. Chemical and Engineering News. 1984. 'Addtttves Sales Buoyed by PVC Recovery,' June 18, 1984. Chemical and Engineering Hews. 19Wa. '^eduction By the U.S. Chemical Industry,' June 10, -198ft. Chemical and Engineering Hews. 1988b. 'Prodtie* Report," Jane 3, 1985. Chemical and Enoineerino News. 1987. 'Facts and Figures for the Chemical Industry,' June 8, 1987. California Highway Patrol, Operational Planning Section, Sacramento, CA| Chemical Marketlne Reporter. June 24; 1988, pp. 3, 8v 24, and 27. 1 Cline, P.V., and Vlste, O.R., 1984. 'Migration and Degradation Patterns.of Volatile Organic Compounds,* Municipal and Industrial Wasta, Annual Madison a. Waste Conference, 102(28): 14*29. *. , -i ' '- 4 V' . Coy, C., 1988. Attachments of the letter from Carol Coy of the South Coast Air Quality Manegement DlstrfcetfSeAQP) te Ralph Propper of the CARB on September 28, 1988. SCftQIV, fP'MdnW CA, - - Eljumally 8 Butter Associates (EBA), 1987. "Air Quality.Sol id Waste . Aesmedb^^Tes^evq^tBdP WIHfil 4MiMemt1JH|>dsal Site,1* Santa Rosa, CA. : .c i -.v itbi-j his i Hartley, S.S., 1989. Evaporation of Pesticides - Formulation Research, Pitys.icrV^nd^#Vl#fdaT CIem1te7 Aspe4tf; MiffiPBtfemttal Serfts. 86. pp. 1IS-134. 'IIS or* ' t>* oxlc Emissions from Land Disposal Facilities, r Vdl. 1, pp. 48-82." ,v > KleBHpPP^.; tasley, D.M.; Heas, B.B.'JV'.; DelhT, T.5. 198f. "Anaarobic Degreiertwi of Trichloroethylene In SoiT,* Environmental Science and Technology. 19(3): 277-280. Lamorte, It., 1978. 'National Emission Standards for Hazardous Air Pollutants - Inspection Manual for Vinyl Chloride," prepared for U.S. Environmental Protection Agency by Research Triangle Institute, PB 289778, Research Triangl Park, MC. A-39 CMA 010572 * DRAFT McPherson, W., at al., 1979. Hydrocarbon Processing, "Vinyl Chloride Monomer - What You Should Know," March 1979. Mo lit*. D.. 198$v, Telephone conversation between Richard Corey of ARB and Dave Molita of SCAQMO, April 1989. v'" Molto*;P.tftjHki-Tem R.T.l pytr*, J.f&l'lffll1'' of Vtttyl Chloride Formation at Landfill Sitas in Calif&M1a',"*`Prepefld'fbp the CARB under contract # A4-15A-32 and 2311206J7f B*|tyl Jje, PtC^f Nprthwest Laboratory. Richland, WA. '' * 11 Offics of Emrgncy Services* Planning, ,D/ivJis'"j "i*o' n., t Swr e' r7c4rVs*metito, CA. Parson, et al., 1984. "TransfoneatJonsYfff TtiraKfrloroethene and Trlchloroethen* In Microcosms and Srouniiwater.* Journal of the American Water Association. February 1984. >^ala of Personal Communication, 19858. Telephone*conversation between Pacita, ARB and PVC producer A, September 1988; '* Personal'tbdsbiinicatlon,' 1986b. Teliplrohik cohMlihdptibn'between Pacita Ayala of ARffand PVC producer B, September 4,1988. L Personal Coaeeunfeat ion, 1988c. Telephone^conversation between Pacita Ayala of Personnel CoweinicetIon, 19854. Telephone cowersetion betweeh Pacita Ayala ff .r.r?!"* ^ST****^ J!8e-- mn*t ** *etourte>'C CA. or,Prqjectv^vHeW^P^*ift|j,, Whittier, Sorokin i*fc=* IHFORM, w- ilmatfng Hazardous Air Emissions from Disposal Sites, August 1981, pp. 31-34. _______ Sitf9^Pf|H 19K. `Vinyl Chloride and PVC Manufacture,* Noyes Data Corporation, Perk Ridge, M.J. Thidobeaux, J.J., 1981. Estimating the Air Emissions of Chemicals from Hazardous Waste Landfills, Journal of Hazardous Materials. 1981(4): 235-244. Todd, D. and Ralph Propper, 1985. "Method to Determine Emissions and Possible Health Effects of Organic Compounds from California Landfills," California Air Resources Board, Sacramento, CA. A-40 010573 CHA ' ;* UiV U.S. Department of Comnerce (U.S. DOC) - Bureau of Census. U.S. F*nnrt<. FT410 and FT 446. Annual 1974-1984. U.S. DOC - Bureau of Census. U.S. Imports for Consumption and general Imports. FT 246, Annual 1974-1984. U.S. DOC -International Trace Commission. Construction Review. Bi-monthly Industrial report. Washington, DC. U.S. Department of Health and Human Services, 1978". "Vinyl Chloride: An Information Resource," DHEW Publication No. (NIH) 79-1599. U.S. Environmental Protection Agency (U.S. EPA), 1980. "Fate of Priority Pollutants in the Publicly Owned Treatment Works - Final Report, Volume I and II," EPA 440/1.82/303, PB83-122/88, Washington, O.C. U.S. EPA, 1982. "Vinyl Chloride - A Review of National Emission Standalds," Prepared by TRW Inc., for U.S. EPA, EPA-450/3^82-003,. NTIS no. PB-114-34, Research Triangle Park, N.C. ) | Water Resources Quality Control Board, 1987. Data retrieved from computer database consists of Information as required by the Caledron Bill (AB 2535)Jonathan Mulder. Sacramento, CA. Wood, P. R., et al., 1980. "Removieg Potential Organic Carcinogens and Precursors from Drinking Water," EPA Report, EPA-600/2-80-130a, U.S. EPA, MERL, Cine inoat 1..QH., , Zwiacher, W.; Yuhas, L.D.; Fakhoury.T.S.; Whittacker, J.L.; Grisinger, J., 1983, "`Emissions pgf Poteentially T. osic/Hazardous Air Contaminants in the South Coast Air Bating ^ _ ir1' qg.8|v1i1en,. Sout^asAsA^ Qual ity Management District, CorAngeTes, 1! **<< ' i A-41 * CMA 010S74 IV. PERSISTENCE IN THE ATMOSPHERE A. PHYSICAL PROPERTIES Thu chemical structure of vinyl chloride (chloro*thene. chloroethylene) Is CH.-CHCl. Vinyl chloride It 4 sw*et,,s*l1ing, colorless gas at ambient temperature and pressure. It polymerizes In l ight- oi* m thf presence of a catalyst* V1ny>> chloride is readily flammable and forms explosive mixtures in air. Upon combustion, it Is ' degrade* meinl* to hydrogen chloride gas, carbon monoxide, carbon dioxide and traces of phosgene. Vinyl chloride Is expected to jralatfeUm rapidly from water sys&vs. Expsrhaentai data indicate that for an Initial concentration of 1 ppm at a solution depth of 6.5 cm and a xttrrlitgrate of 200 rpm, the average evaporative helf-U/e of- vinyl chloride at a temperature of approxImetely 25 C Is 27.6 minutes (OIIHng, 1977). Another study determined that distilled weter spliced with 16 ppm vinyl chloride lost 90 percent of the vinyl chloride within Jv MtftgiflfeJl, i ?,,iSiisIkJJLltheao 1 industrial solvents, and * number oforgenic llcjufds, vinyl chloride is only slightly soluble in weter. Vinyl chloride' 1 physical properties are showjt,iif<^h1* IV-1. no tiytlr %<* m*H sen rorijm** e*4 Vn ;n#B*e**#. *>t cad^Htts ltoj*mefneit mechanism removing like troposphere .-(t9tfo Atkinoon, IStfca Estimates re0**pher1o.;lifefc1me irange from a,i**tci 5.8 days. rw,,._, provided later In this section, AR& staff believe frbpeipherlc lifetime ranging from 1.6 to 3.9 days is representative of typical atmospheric condition*. The rate at which this reaction proceeds depend* on the temperature and th* tropospheric A-42 CMA 010575 TABLE IV-1 PHYSICAL PROPERTIES OF VINYL CHLORIDE Prooertles Value Reference Soiling point, 1 Atm -13.37 C Merck Index, 1983 Molecular weight 62.5 Merck Index, 1983 Vapor Pressure, 20 C 2530 niaHg Merck Index, 1983 Sol. in water, 25 C 0.llg/lOQg H20 Kirk-Qthmer, 1980 Partition Coeff.H20/air 10C 0.02 McConnel1,G., at al.,^975 Octanol/HgO Partition Coeff. 20.7 Specific gravity, 20/4 C 0.912 ' Wfthey, 1976 KTrk-Othmer, 1980 I Flash pt, opart Iflip v' -77.rC Liq. Den*.; TJg/a*1 <*.9691 i- i-- *- Heat capacity, 27 ' S' 'r r - > " ,r-~ 1 ' > *: w?I ti ' ' i'. ii C5U 1*^1 s ?*'' *"!'> *''> iin >. h5i ;?) a-` ;.o ,,,u'< ' : - < ' . ..3f tiO : ' > f** * " **.?*V -tf { K-trk-Othmer, 1980 KfrtkMJtttaer1, 1980 CRC Handbook,, 1985 *' *< -w . V ,,i .*;V j h vinyl chlortde and^ydredyFlridTcaYi^ Thai ice of the reictlon rat* Is incorporated In the rata iction of vlnyichlonidewlth Hydroxy* radicals. The w-- eonstanf and both specie* concentrations glvas the vtffytebTorlde fs being degraded (Fin>ay*on-P1tts and The tropospheric lifetime of a compound Is an estimate of the time required for a given amount of the compound to decrease to 1/e (0.368) A-43 CHft 010574 of its original concentration (at time zero). The tropospheric lifetime (r) of vinyl chloride is related to the rate constant (k) and the hydroxyl radical concentration ([.OH]) by the equation (1): r - (k[.0H]) (1) In deriving thw above equation, it is assumed that hydroxyl radicals are at a constant or steady state concentration in the troposphere. from vinyl hge of 299 ht^for a reaction* of vinyl chloride with hydretyl radicals at 2%"K over a range of pressure where the highest.pressure employed had dot reached the limiting high oresSure regime (Howard it al., 1976]/*'Hbwever, when data obtained by Howard are extrapolated to .the high pressure limit, tbe resulting rate constant Is approximeteTy"7 x llT cm molecules second-1 (Perry et el., 1,97$), This is in good agreement with the value reported by Perry et al. Table IV-2 suakaarizes the rate constant estimates, atmospheric lifetime estlmetes, average temperature assumed, and the method used to estimate the rate constant for the reaction of vinyl chloride with hydroxyl radicals and ozone (0^). The 24-hour average hydroxyl radical concentration in the, troposphere has been estimated to range from 3 x 103 to 3 x 10 molecules cm (Hewitt & Harrison, 1985). Because hydroxyl radicals are only present during daylight, the actual range for daytime concentrations is twice the 24-hour averages given above while nighttime concentrations are essentially zaro. Daytime hydroxyl radical concentrations vWy depending on many factors including photolytic activity and the concentration of ozone- as well as other pollutants in the troposphere. Using the rate constant determined by Perry et al. for an average tropospheric temperature of 299K and a range,of hydroxyl radical concentrations ranging from 3 x IQ3 to 3 x 10 molecules cm"; the estimated tropospheric lifetime for vinyl' chloride ranges from: 0.6 days for [.OH] -Ox 10* molecules cm-3 to 5.8 days for [.OH] 3 x 10 molecules cm-3 A-44 CMA 010577 * TABLE IY-2 ATMOSPHERIC LIFETDC AND REACTION RATE CONSTANT ESTIMATES FOR VINYL CHLORIDE Ui Reactant 'tOnStfrit Tempdfature i:*' CKaWnl ^ lens*: * " " ' ' - ' '#>&* tff " -- 1 Y>V W *Tf' OH, SaS*|WMf Njt JW- SjfTIR* ; * $0. . Ga/it al., 1976 ,6.i!virn ,- t ^ ...I- 4.9 ywrl Sanbueza et al 1976 1 -lr 1 ' a - Rat* constant units art cm molacule . second' . b - The atmospheric lifetime Is defined as the time required for a given amount of the compound to decrees^ tq 1/e (0.3$^ of its original concentration, (at time zero). c - FP-RF flash photolysis, resonarfee flourestence. 5 d - Assumes a 24-hour avecage hydroxyl radical concentration ranging from 0.5 x 10 to 1 x 10 molecule cm* ,(Cup1tt, 1980). e - S-FTIR St^jcltyttep, Fourier transform Infrared absorption spectroscopy. f - As sines a 24-hpqr average Qj. cencentratlon of 1 x 1012 molecules cm*3 (Singh et al., 1971). "* g - S-UV * Static systma, ultraviolet absorption. NR- Not Reported' A-45 CMA 010578 As previously indicated, the concentration of hydroxyl radicals in the troposphere can vary considerably. However, several researchers recommend 24-hour average hydroxyl radical concentrations which are between 0.5 x 10 and 1 x 10 molecules cm (Prinn et al., 1987; Winer, 1987; Singh et al., 1983; Cupitt, 1980; Cox et al., 1976; Davis et al., 1976). 8y using this range of 24-hour average hydroxyl radical concentrations (0.5 x 10* to 1 x 10 molecules cra"J) in conjunction with the rate constants determined from Perry1s rate constant at 299K, the resulting range in atmospheric lifetimes is from-l-ft to 3.9 days. Using Howard's adjusted rate constant derived by'eatrfydfb^ifiiitto tne high pressure limit, and, the .same range of hydrdXVjlradls concentrations (0.5 x.10 to 1 x 10" molecules tfi TlC lifetime estimatef for vinyl chloride <;anp$ The initial step in the reafetjoe ef viny^ hydroxyl radicals proceeds by the addition of hydroxyl radical to the carbon- carbon deuble pood..,-Althogflt),,sub*aqMaat,stefrS7)p,eUe^Jteg<;tion mechanism are unknown* .rpact ion product* have -efa,idniiU In* 1986b). The major product .rasultlag fra*^y^o^J,,cadUni on vinyl chloride is.formyl chloride, 4$|tspg|#|4 itudydamoostrateo that the yield of foumyl chloriddrfrem.th^r^flftWiYW fdi**l* with vinyl chloride is unity (one molecule of formyl chloride for etch molecule of vinyl chloride) within the experimental error of the study (Pitts etY*l.. 1984). .l$t observed unit y 1414 of fowiyl-chloride implies a corresponding unit yield of formaldehyde and shows that tne reaction of vinyl chloride with .hydroxyl radicals proceeds by essentially 108 percent cleavage of the double bond. .Equations (2) through (6) summarize the overall-reaction scheme which seems most likely (Pitts et al., 1984), .OH * CH2-CHC1 TM~--> H0CH2CHC1 (2) 0, 0-0. WOCHjCHCT ------ - --> HOCHjCHCl (3) 5-0. a. HOCHjCHCI M0 ---------------> HOCHjCHCl M02 (4) -----------.CH-OH ... w HCOCh (S>- ^formyl chloride) - .f-'r o - " *. .CH.OH 0- ----------- > HCH0 .HO, * (formaldehyde) c K (6) A-46 CMA 010579 Under atmospheric conditions, the reaction of vinyl chloride with ozone is not expected to be important compared to its reaction with hydroxyl radicals (Atkinson, 1986a; Atkinson and Carter, 1984). Several rate constant estimates have been made for the reaction of vinyl chloride with ozone. Based on these rate constants, atmospheric lifetime estimates range from about 47 days to approximately 5 years (Zhang et al., 1983; Sanhueza et al., 1976). Table IV-Z summarizes the atmospheric lifetime and rate constant estimates along with other pertinent information for vtnyl chloride's reaction with o* Due to the variability aaong the estimated rate constants; a made no reconnendations as td the rate constant fair tilt Jbllcation of vinyl chloride with ozoneJ(Atk1ffson and Carter, iiHfv Irmore, because the reaction of -^"vltfr vfnVl chloride ;||j|jMrci ted by secondary reactions, .the rata coestants providaf,lpwP,lI#' 1t-2 should be considered W Sf dppdf bound ffteffd? ..-tJ? . 6f" A _ ' *0 ~C ' 1 ioees-. frodects iHdsdltfM'frdi^tid tdheftozoladlthav'1nyl chloride th the absence of ,^a<l!|ligeri9lr< fSni^t^thTdrite'ihd fefmlc*acid (Zhang et. al.; 199$J.Othef prddd^f'.restilillW fr^th^rllctloh of ozone wlth-vfnynewid^fde include Cartfcn Monoxide, carbdiTdloxIdi, formaIdehydd, 4Ad hydrochfdrltf'dcldTCtt ft al., r9T6; Zhang et al.. .re srj As St atwrthd dost "importahtrtmdspher 1C removal Mechanism for vinyl chloride If tt'fNityilme reaction with hydroxyl radicals. Vinyl chloride does htit aitdft in thef actlnlc ultraviolet region, hence photolysis need hot Pe considered. Reaction with nitrate radicals (.NO.) mey peril ctpttelh the atmospheric removal of vinyl chloride. However, no kinetic data for .NO. are available, and studies of .NO. reactions are not yet sufficiently advanced that lifetime est1matesJcan be made (Flnlayson-Pltis-4nd Pitts; 1986). Little is known about the formation of vinyl chloride in the atmosphere. However; under experimental condlttoms, vinyl chloride has been shown to be a photodissociation product of 1,2-dichloroethane (Yano and Tschulkaw-Roux, 1980). In the study, 1,2-dlchloroethane photodlssoclated when 4rrablated with ultraviolet light at 147 nanometers (nm^ under pressure and In the presence of NO and CF, additives. Although It wes not the purpose of the study to Identify vinyl chloride formetlen pathways, vinyl chloride was one of the photodlssoeihUon produrte. Since wavelengths of ultraviolet light below 290 nm do net rfeach the troposphere, this formation pathway is not important for vinyl chloride In the atmosphere. ' , " v. . -- A-47 010580 crth REFERENCES TQ CHAPTER IV 1J iLS <i \uins j Atkinson, R., 1986. Personal communication between Richard Corey of ARB Staff and Dr. Roger Atkinson of UCR. May, 1986. Atkinson, R., 1986. "Kinetics and Mechanisms of the Gas-Phase Reactions of the Hydroxyl Radical with Organic Compounds under Atmospheric Conditions," Chemical Reviews.. 6:69-201. Atkinson, R. and Carter, W.P.L-, 1984. "Kinetics and Phase Reactions of Ozone with Organic Compounds .under Chemical Rev-jimt,, 84:497-470. of the Gasic Conditions, Cox, R.A.; Derwent, R.G.; Eggleton, A.E.J.; LoveTock', J.E., 1976. 'Photochemical Oxidation of Halocarbons in the Troposphere,* Atmospheric EnY 1 ronmeot,, 9HU.- CRC Handbddk of Chaiftntry-alifr PTfysics', *1985. 66tfdition. Cupiti, L98C. ."Fat# .of Toxic .and-Hazardors Materials in the Air Environment," 'Environmental Protection Agency^ ERA-60073-80-084. Research Triangle Park, North Carolina, August 1980. Davis, D.D.; Machado, Conaway, 8.; Oh, Y.; Watson, R., 1976. "A Temperature Dependent Kinetics Study of the Reaction of OH with CH,C1, CH,C1,, CHClg, and CH^Br," Journal of Chemical Physics. 65(4): 1268-1269. 3 22 Dilllng, W.L., 1977. "Interphase Transfer Processes. II. Evaporation Rates of Chlororaethanes, Ethanes, Ethylene, Propenes, Propylenes from Dilute Aqeous Solutions, Comparisons with Theoretical Prediction," Environmental Science and Technology. 11(4): 408-409. Finlayson-PItts, B. J. and Pitts, Jr., J. N., 1986 " Atmospheric Chemistry: Fundamentals and Experimental Techniques," John Wiley 6 Sons Inc., 1986. Gay, B.W. et. ill., 1976. "Atmospheric Oxidation of Chlorinated Ethylenes," Environmental Science and Technology. 10(1):58-67. Hewitt, C.K. and Hanriaon. R.M., 1986. "Tropospheric Concentrations of the Hydroxyl Radical - A Review," Afmpmhoric Environment. 19(A): S45-554. Howard, C.S., 1978..'Rate Constants for the Gas-Phese Reactions of OH Radicals with Ethylene and Halogenated Ethylene Compounds," Journal of Chemical Physics. 68(11)-.4771-4777. IARC, 1979. Vinyl Chloride, Polyvinyl Chloride and Vinyl Chloride-Vinyl Acetate Copolymers. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. 19:377-438. A-48 t CMA 010581 np S H i% u a& Kirk-Othmer, 1980. Encyclopedia of Chemical Technology. 3rd Edition, Volume 23, John Wiley and Sons, Inc., New York. Lillian, D.; Singh, H.B.; Appleby, A.; Lobban, l.; Arnts, R.; Gumpert, R.; Hague, R.; Toomey, J.; Kazazis, J.; Anteil, M.; Hansen, D.; Scott, B., 1975. "Atmospheric Fates of Haloganated Compounds," Envlronmentai Science and Technology. 9(12): 1042-1048. McConnell, G.; Ferguson, D.M.; Pearson, C.R., and the Environment," Endeavour. 34 (,121): 13 Merck Index, 1983. An Encyclopedia of Chemici Edition, Merck &' C~o., Inc. ,, , . .... Perry, ; Atkinson, R.; "Pftti^.H., Jr4 OzfL^tti Constants for the Reaction of OH Radicals with CH--CHF, CH--CTCrr'art#'t1TreCH8r ovdi* the Temperature Range 299 - 428k."^Journal 8f Chemical Physics. 61(2): 458-462. . * ft - J r -f ^ ' V i, i - "-V -J ** -` ^ *r Pitts, J.N., Jr.; Atkinsop, R*; Winer, A., 1984. "Formation and Fate of Toxic ChemlOale In tallfornlrf Atmolfihere,* Ftne"! Heportr to ClTtfornia Air Resources Boer'Cootreet to.'AZ-ltf-'Sf.0' - :; 'PL- . Prlnn, R.Cunnold, 0.; Rasmussen, R.; Siamonds, P.; Alyea, F.; Crawford, A.; Fraser, P.; Roten-V R., 1987. "Atmospheric Trends In MethyTchToroform and the Global Average for*thb Hydroxyl Radical," Science. 238(133: 94S-950. Sanhueza, E.; Hlsatsune, I.C.; Heicklen, J., 1976. "Oxidation of Haloethylanes,` Ch--leal Reviews. 76(6): 801-826. Singh, 8.8, r Ludwtgf Ff L.; Johnson, W. B., 1978. ' ^Tropospheric Ozone: Concentrations and Varlabl1itles In Clean Remote Atmospheres," Atmospheric Environment. 12:2185. Singh, H.B.; Salas, L.J.; Stiles, R.E., 1983. "Selected Han-made Halogenated Chemicals in the Air and Oceanic Environment," Journal of Geophysical Research, 88(06): 3676-3683. U.S. EPA, 1974. "Preliminary Assessment of the Environmental Problem Associated with Vinyl Chloride and Pbtyvfnyi ChlorTtfb." Office of Toxic Substances, Wes84ngte*,9.l&K PA/960/C-74-(Wl. Winer, A*." 1987. FeHortai communication 1>etWeen Richard Corby of ARB staff and Arthur Winer of OCT.'October, 1983. A-49 010582 CHA % ~ DAC i :: k 1 1*1 - Withey, J. R., 1976. "Pharmacodynamics and Update of Vinyl Chloride Monomer Administered by Various Routes to Rats," Journal of Toiir.nloav and Environmental Health. 1: 381-394. Yano, T. and Tschulkaw-Roux, E-, 1980. "A Reexamination of the Photodissociation of CHjCICHjCl at 147 nm. Test for Chlorine Atom Reactions," The Journal of Physical Chemistry. 84(25):3372-3377. Zhang, J.; Hataheyana, S.; Ahemoto, H., 1983. of Ozone with Trans-1, 2-0ichloroethene and Viny\ International Journal of Chemical Kinetics. 15 of the Reaction ir." A-50 010583 CH<*> 010584 DRAFT APPENDICES June 1983 CMA 010585 APPENDIX I SCAQMD'S ANALYTICAL METHOO FOR SAMPLING AMD ANALYSIS OF ATMOSPHERIC VINYL CHLORIDE CMA 01058& -AMBIENT -AIR -SAMPLES AT LANDFILL PAKTMETER (REQUIRED BY SUBPARAGRAPH (c) (4) (D) 07 RUlk,,I150.1) 1 SAMPLING FREQUENCY ti. -*T* ' , ~fT r,, Ones per month or at less frequent inte, itarni ned by the Executive Officer. The landfill owner/opermtor TMt file a written request with the Executive Officer' IjTfcte wantsT'to sample ^ ------ - ----- , c > at intervals less frequent than nontfily. Such a recfuet be supported with previous sampling results and other" documentation. In determining if the requested s~mpTfnq frequency is appropriate, the Executive Officer will consider previous ambient air sampling results, landfill' surffacs sampling I results, landfill gas composition and other pertinent data. Hie I Executive officer will notify the landfill ownsr/opsxa'tor of his decision in writing. NUMBER 0? SAMPLES -- v ev* ^ > * ; v'- Thw number of CTibl^aiit ^in saxpl+m' rmjiilTmdi >' `-.r* dopant! iipdhLh^ * -topography ana thee, siizre ,ooTf ithe`tl-ab (.Dtimimj ---- sjegiSK-ra-vAr', ~ ~W-- --* will be sited to provide good meteorological(,<ocposure to- the , 'rf.-.Vt- -- i,y.*i- Vv-V;- predommant offsherre "(drainage land- breezeV_a3ui onshore (sea >' `-'v '*rr ***^*r breeze) wind flow patterns-'la areas, with ^grrf-ricaJ&.:s3.opggy - ' -- . -32- : : ' CMA 010587 local nightly drainage patterns will also be sampled. All sampling locations roust be approved by the Executive Officer prior to sampling. SAMPLING CONDITIONS AmbIant~ailTaaaiprrhg wlir~he conducted on days when stable (offshore" djtlTnagT''^TTd unstabW'-ixmakore-Vee- br>ag) raataorologi cal conditions are raptWerrtst'fVmfor tha mton. Preferable sampling conditions are character^iad by the following meteorological conditioner- '*z 1. Clear cool nights with wind- speeds -two (2) miles par ~ Hour or less. 2. Onshore sea breezes with wind speeds io miles per hour " *" . \U 1 " "" ' ....... M. -- II. |, or Iftff. No sampling will be conducted if the following adverse meteorological conditions exist: 1 Rain 2. Average wind speeds greater then 1*5 miles per hour for any 30 minute period. - ^ ,, -* 9 3. Instantaneous wind speeds greater than 25 alias per hour. ' ' Continuously recorded on site wind speed and direction i# measurements will characterize the aicroroeteorology of the site and serve to verify that the meteorological criteria have been i -33- CMft 010588 EQUIPMENT DESCRIPTION An ambient air sampling unit consists of a (Dupont trade name for polyvinyl fluorine)'^1 pump, stainless steel capillary tubi*i^jf$pjj rate to the bag, a bypass' valve to eorfVro'F tfife sample flow rate (and mimimize back pressure wnaie pumprf a' rotameter for flow indication to aid in setting? tife -a* -Mr-ttowr clock timer to shut off the sampler at the' `Ini? 8t the 2C^hour sampling' period. and associated tubing and connections (made of stainless steel, teflon, or borosilicate glass to minimize contamination and reactivity). The. physical layout of the sampler is shown in Figure 5 (see Appendix A). i EQUIPMENT SPECIFICATIONS A. Power -- orie^2%*1^4 marine battery v .r c > * The marine battery provides 12V DC to the pump and the clock. C , la B. Pump -- one 12V be pump _* The diaphragm is made of non-lubricated Viton (Dupont trade name for co-polymer of hexafluoropropylene and vinylidena fluoride) rubber. The maximum pump unloaded flow rate is -34- CHA 010589 % 4.5 liters per minute. c. Bag -- one 10-liter Tedlar bag with a valve i TEDLAR BAG IS ENCLOSED IN A LIGHT-SEALED CARDBOARD BOX TO PREVENT PHOTOCHEMICAL REACTIONS FROM OCCURING DURING SAMPLING AND TRANSPORTATION. The valve ie a push-poll of aluminum and stainless steel, vittlk constructed ring seal. D. Rotam' eter\ `- .\ - *_* _ . ^ .^ ... "A ,, f y--y r_, _fto-*-ijae*-nr im made, of bgrosilicete glass and has a flow range -ars#Srale is in * . milliast*^ vi$h i|^o^^aduatioi>s (labeled) every 5 nuo and -mtoesrgeAduetion* every X ma. , s^ E. Air*low^control Qfi.fice -- 316 stainless steel capillary tubing F. Bypass valve G. Fittings, tubing, and connectors -- 316 stainless steel or teflon H. Clock timer Accuracy should be better than 1%. I. wind speed and direction monitor with continuous recorder 1. wind speed, UPL assembly, range 0 - SO miles per . twyr^yitfa a threshold of 0.75 mile per hour or less. 2. Wind direction --, Vane, range 0-540 degrees with a threshold of 0.75 mile per hour or less. -35- CMA 010590 SAMPLING PROCEDURES Ambient air samples will be collected at the of the landfill over a 24-hour period beginning between iq A.M. and 11 A.M. using the above described elf-canr*-<TvM sampling units. The samplers will begpp->-ovd locations as described previously. speed_ and direction^ monitors with continuous reoKSS^Svill be installed SnsJsnoa and operated in areas approved' by the Executive Officer to "tTT '.IfHKfUr Ltr. measure wind, speed and direction throughout the entire sampling --....... . _ *" 1 ...... "j ' *mm VL ^ ..- ..... period, jyhs wind direction transmitter mist be oriented to true ' ' ' ?.. ' ' , a - north using a compass. XQU--ALIT Y- I I CONTROL i--HP--'' - ........... PROCEDURE The following quality control procedure is required for the ambient air sampling operation: A. Assign an identification number to each sampling bag. a. Clearly mark sampling locations on a landfill topographic t :-c" map which is drawn to scale. C. Document the date and time that the bag was put into operation, the sampling location, and the date and time that it was pulled from service. D. Check the clock timer. The clock tiat and the actual time should agree within + 3 minutes. rU 1f ?1 if !j. E. Check whether or not the pump is running. ;j F. Check the rotameter reading. The float (measured at the middle) should be within +3 and -6 minor graduations of the marked setting for 6.0 cubic centimeters per minute. If the 'rotameter setting exceeds the above limits adjust the bypass valve to correct the flev xefK 3" that "the flow has" Stihilited ta Make sure minutes at ViO constant flow)...Vine* tlrrsrmay-be a lag-time between the adjustiient*ana^flhT~ftwrr---------............." - G * ~Check"wfietheiTTase ti^-veive-ie-in- the open position. If T 9 Z' 77 Z'* TM T "TIT HGXX * the valve is in the closed position open the valve and and record the time on the quality control sheet. H. Remove the bag for analyses at the end of the 2 4-hour period. KP THE BAG IN A LIGHT-SEALED CONTAINER AT ALL TIMES. .. ' -*T~ -- J . ; Data for each Sample collected must be entered on a quality control sheet as shown in Figure 3 (see Appendix A}.: Prior to -------- * --f.'" * =*n' use,. the.Tedlar bags should be evacuated and filled with purified nitrogen three times to flush out the old sample. *. : J r, f. ; - Before sei?din9 the bags into the field, they should be checked - *.. - XLX " - to make sure that the vacuum has been maintained* Remove .trap , t'4 "' service any bag that has experienced any leakage. -37- ChA 010592 ANALYTICAL PROCEDURES Bag samples collected must be analyzed within 72 hours of collection, _or^^shorter period if notified foy the Executive Officer, for total organic compounds and toxic air-ontaminants using analytical methods identified in Table 1 (see Appendix A) or equivalent methods approved by the fficex. NOTE THAT ALL BAG SAMPLES MUST BE KEPT IN CONTAINERS TO AVOID PHOTOCHEMICAL REACTIONS. REPORTING OF THE RESULTS The following data must be submitted to the Director of Engineering within 4 5 days after the end of the quarterly reporting period for the -landfill or 45 days after the analytical results are available whichever Is sooner. A different submittal time may be implemented upon approval of the Executive Officer. A. Volume concentration of total organic compounds (reported as metthane and total non-methane hydroca rbons) . B. Volume concentration of toxic air contaminants identified in these guidelines. C. Barometric sea level pressure (inches of mercury) on the d. the samples were collected. If a bazroaater is not availab at the landfill site, use the National Weather Service dat. at the nearest station. CMA 010593 V / 0D. Wind speed and direction data. E. A drawn to scale landfill*-topographic nap with sampling locations clearly marked and numbered. F. Quality control data sheets. * ^4.. 4 ' .1* *LV, :.cc ar.sdr oo lie - 39 - CMA 010594 * VINYL CHLORIDE Instrument: Hewlett Packard 5700A. Gas Chromatograph Detector: Plane Ionization V ' Injection System: jTwo Carle *- are pluatoed to contain a 4 ml, 1/4" stainles steel sample loop with pre-column, back-flua and pressure balance. f valve plumbing. GC Conditions: ? s Detector Temp. - 200C - t iv " f , See Figure D Cor Oven-Temp. - *60C Analytical^olumn^ 6' x 1/4" ss, Chromesil 310, 60/80 mesh t Pre-Columnj--"'"^ " ` -6' x 1/8"; ss*. fiurapack m-octane/Porasil "l " 100/120 m'esL..:. Carrier; Gas - ...-} '* 80/100 nl/nin nitrogen Data Gatl^r|lewlatVPackar^3S8^^^grator is usad to / 111 111 imfTit r mn~en^rh'u1^irt'>r|- peak area comparis* 4 to an external; standard. Valve Timing: Timing and switching events are perCormed by tfa , integrator. 1.4 minutes aft*r injection both v are switched to the back-flush or initial posit -64- Chrt 010595 r+. S:\2" * xu a.riv ' : ' '' ;ia 9\ass*m *n( &r % * 'j 1 ?f &v 5 MAIN COLUMN *- FIGURE C: Valve Plumbir3 -65- CMA 010596 Standard: Approximately 1 ppa vinyl chloride i prepared by ScotEnvironmental Technology and certified to 2% Analysis Range: 2 ppb to 1% vinyl chloride -66- CNA 010597 CMA 010598 % LM\ AFT APPENDIX II DESCRIPTION OF GLEIT'S METHOD CMrt 010599 * 1 CA 010600 % APPENDIX II DESCRIPTION OFGLEITS METHOD Gleifs method accounts for the .concentrations thamadWWIW*11 used approximations. mm** The below-LOD mean of a normal detectidtf^LTi of the <tfebib*di<iaril^ of dsviationo - r `V 4 ,{ -;,4 . r 0::"'' .; if- (1) ,( i'-rf-A '* SGillo-'. **>1> < * r- ' to eQUffen $&! Ri3^^^9ctiytlttJte probabity:dwty function andcumula^/^dislrai^on func^papf the standard normal distribution. The -%timatBdt^n^pal^^^ Below the- tOD* reported in Table H-2 are the below-LOu means of the assumed lognormal distrfbufioaa ofttie concentrations. These betow-LOD means are computed from equation (2) in (which is net tabubNSd). ' >y - ' exp (p+f3.5 o^)* F((tf^b^/d) / F(L^iA30" "" (ZJ We now describe how Gleifs method estimates the mean andttaariance of the assumed normal distribution. The mean and variance cannct beafetimaled by merely substituting into standard formulas, if be!ow-LOD concentrations are to be set to th belcw-LOD mean. On the one hand, the mean and variance must be known in order to calculate the below-LCD mean from (1); on the cth r hand. CMA 010601 .1. the below-LOD mean must be known if it is to be used in the calculation of the mean and variance. Statistical theory, by asserting that a "best -fitting " mean and variance for the distribution exist provides a way out of this dilemma. Gleit uses a simple iterative procedure to compute these best fitting parameters. Since his procedure can be simply described in words, a written description is given, supplemented where necessary by equations written in a notation more convenient than Gleits. Starting with initial guesses u(0) and cri^O) for procedure repeatedly generates new estimates c the two-step computation described below until $ - m, ean an ?d*n'*va4.r*&i:ijrT"^` cOTv^erge_ isuv fficiently' OTjethmte. _ K-th pa` it r of estimates are , .V. , i -- lij1*** v.__ t- orr r ~rv -' - denoted by n(K)' ana The two steps are: ,_ (a)'Trie K+1 -st beloyv-LQQ meea^oQd^) .is computed by substituting p(K) and o(K) (the square root of intis equation (1J- (b) The K+1-st estimate of the mean, p(K+1), is computed in the usual way with pblQDO^) substituted for the sample values below e the LOD. The K+1 -st estimate of the variance, o^fK+l), is also I computed in the usual way, with an analogous substitution for t sample values below theLOD: the squared deviations from the mean 9 of concentrations befowfoe LOD are set equal to the average squared deviation from foe mean of the below-LOD portion of tfte distribution. Let the N sample items b#X(1),r...,X(N), and let p be foe number off sample items below foefcOD. Efcomputedby: p.(K+1) - (1/N) Z Y(J), where Y(J) - X(J) if X(J) * L and Y(J) - jibLOD(k+1) otherwise. o^K+l) is computed by: a2*K+1)- (1/N) Z D2(J), where D^J) - (X(J) - u(K+1 ))2 if X(J) ^ L, and D2(J) - o2gLQQ(K+1) otherwise. CMA 010602 n * DRAFT The quantity o2BLOD(k+1 )the average squared deviation of the beiow-LOD portion of the distribution, is computed from the following equation: o^lodOC+D- <j2(K)*[1 - Z(K)* <f(Z(K / F(2(K))) ], where Z(K) - ((L-)i (K)) / o(K)). Gleft's method neiuty always converges in a few few distinct vaM*fcove the detectioftltaM , very sfowty. Gleifs method and cfoseiy lel-ifirf bo the best available estimators of the mean when the sampto Irwfades values below the LOO, as is demonstrated by the simulations reported In Gleifs paper. r:, f i APPENDIX III ESTIMATE OF TOTAL EXPOSURE TO VIRYL CHLORIDE FROM INDOOR AIR CMA 01060A % DRAFT INDOOR AIR EXPOSURE/OTHER ROUTES OF EXPOSURE ASSESSMENT FOR VINYL CHLORIDE I. Ha*1th and Safety Cod* Section 39(60.5 directs th# Board, In Its toxic air contaminants Identification process, to assess exposures to toxic air contaminants In Indoor as *11 as outdoor environments. Indoor exposure assessment ha* become Increasingly Important as an Integral part of air exposure assessment because (ARBlfST; 198B)f" 1. people spend a predominant proportion of their time Indoors; and 2. personal and indoor air monitoring data Indicate that some p llutant concentrations are regularly higher indoors than outdoors. Indoor air exposure data, combined with outdoor air exposure data, can provide e realistic estimate of personal exposure through, the air environment. A more detailed: discussion of Indoor air exposurf Is contained In Appends A. Indoor air data can be obtained either by parsonel afr* Sampling or, tv fixed-site air sampling. In personal sampling, the sampling equipment 111 carried by an Individual and air samples are taksn wherever th Individual may be. In contrast, fixed-sit* air samplings refer to air temples tafeen at a fixed location. Personal air sampling data generally; prbyfdp a more realistic estimate of Individual exposure. Since most paoplg $pfpd80^901 of their time In indoor environments, personal' air sampling data' aft^ strongly Righted by indoor air exposure data. WhfTO th min oOJfctlve of tJI"repprt: i*r^/.esjwaur* through the air, this report*ifto presents personal StposuCe ditPtSou^otW media. The Inclusion" of^tKesi^data v1lrprpy1d|' anr1 (Hi|fuJ diri|tttfv% of the overall exposures tfcf toxic, air. Sotam1nihrH^|gik%^^i|orAi|^- Thm ne d for total exposura aisassmeht and some of the Itsues and concepts Involved In total exposure estimates are d 1 scussedjn ;^$P|g?1 g jA II. ~~ uvo? *<*J 1 > ...it vc) ;> Ing data for most organic compound!, come from th Total SiHPtfN Assessment Methodology (TEAM} studies conducted by the Environmental Protection Agency (EPA) during 1980-85 (Wallace, 1987; USEPA 1987a,b; Wallace & Clayton, 1987; Wallace at al.. 1986; Pellizzarl et al.. 1986). Although vinyl chloride was Included In th* Initial pilot study (Phase I) of the TEAM project, vinyl chloride was deleted from the subsequent main studies (Phase II and III). The deletion of vinyl chloride was due to two -1* CMA 010605 factors (Pelllzzarl, 1987). First, Tenax, the most cost-effective sampling medium which could collect a number of compounds of concern, was not suitable for vinyl chloride collection. In addition, the alternative sampling method used to collect vinyl chloride in the pilot study did not provide the required reliability for detecting low vinyl chloride concentrations. Consequently, the pilot study, provides the only available personal air sampling data for vinyl chloride. Based on*this limited Information, indoor air exposure te vinyl chloride is apparently. )ov. Jr monitoring nine subjects in New Jersty and,three froot,Worth-Carol4ne,for sevecfl dayv on three separate visits over a 6-month perlodt .fll of^tbewiBI aip*jfmplea taken were below the limit of detection (Wallace et el. 1984). The range of the limit of detection was frgni Q.6 to. 2.84 ug/mJ,. B. FIXED-SITE AIR SAMPLING , . As part'of a recant follow-up TEAfT study In California, fixed-site monitoring.stations were Installed to monitor,indoor and outdoor air concentrations of a .number of organic- compound^ (PelljzzarV Afc-AXtr 1988). Spec Tally designed stainless steel can Isters^wqre. used for collecting vliwl cMoridd afr samples from homes in t.he Los Angeles are* for two seasons. Ten homes were sampled In the Winter season and eight, of the original home w sampled IX the Summer season. Canister ajr samples wqre-collected Indoors and outdoors at, each home dprlng two, 12-hour periods. Samples, obtained In the Winter season did not provide reliable data due to technical problems. All outdoor or indoor samples, a total, of 32 samples, obtained In th* Summer Sfason inXfttW.that,v1nyl chlor1de air conpantrations were befow th limit of detection. The. samples were analyzed hyrtwd analytical methods with limits of tfetictfdit it'about 0.55 and 14* ug%, respectively*,,,^.. 4 A similar caheerrtr^fens. o sIiSl ii, wasr"atrdct'e: quoted by* . 5/ v n-T- c. SPECIAL SlfuAfT6WcAiR*y!t6iiNGfe timpre. 1r werelamgtored by fixed- ^ ch* rtd limit dnia^Joa was S Z.i i04^ v ;>.! *- -J7 Coast A^^amy'iinigemenrbtltrfk (SCAQMD J coUedWwBH^HOImples in the vicinity,of?thosBIQCulapdf111 (a Class I sitmj^j^HRHmHnrA t0^a1 of more than 50u 41r'samples were taken et two outdodr^H|uj8|rpPfer sites inside downwind.residences (5CAQMD, 1982). All the total sampled) that equaled or exceeded th state vinyl dnd^^Jiir quality standard of 10 ppb (26 ug/m ) were taken Inside the residences. Ihe'highest recorded Indoor vinyl chloride concentration was 50 ppb (130 ug/rtrj. The limit of detection was 2 ppb (5.2 ug/nr). In late 1984, the SCAQMD staff took about tan grab-samples inside the water meter boxes of residences adjacent to the Operating Industrial Tnc. -2- * CMA 010406 (Oil) landfill (SCAQMD, 1985a). Vinyl chloride with other landfill gases, had migrated to and accumulated in water meter boxes at concentrations ranging from 13 to 36000 ppb (31.2-93600 ug/mJ). In 1985, the SCA3K3 (1385b) conducted further monitoring by grab-samples Inside some of the residences and found indoor vinyl chloride air concentrations at 8 to ICO ppb (20.8-260 ug/mJ). Present Indoor concentrations of vinyl chloride In these residences near Oil landfill may be lower since recent routine monitoring of water meter boxes have not detected significant levels of landfill g$se* due to improvements of Oil's landfill gas collection systear (Coy, 1987). C. SUMMARY ; Except for houses near landfills, the vin^l chi or Itfh concentration In Indoor air appears to be low. However, this' eofttHisfirh is ^aiiiA dir the evaluation of a very limited database. In addition, the sampling.and analytical procedures for vinyl chloride Indoor air monitoring are Tits thin satisfactory as evidenced by the wide range for reported limits of detection. The limit of detection, 0.55 ug/m , reported in the latest California TEAM study appears to be the most reliable. This limit of detection will be used to estimate the upper limit exposure for house not adjacent th lthdftlIs. * For houses near landfills, the measured high indOOf rfhy'j* chloride air I concentrations may Indicate the potential Impact of nearly emission sourgms to indoor environments. A more detailed dlscussloh'of landflT'V emissions if i source of Indoor vinyl chloride Is presented In section III(C)% HI. PQTENHAt 50USCE1 QE_INBflQft YXHYi CH10RIPC' A. PLASTIC MATERIALS AND CONSUMER PROOOfiTtf- Vlnyf chloeiddhis mat been used IflPlhy cofViunmr products since 1974 when vinyl ehtoritfe wd>fafcned a* e propeTlaht5 lifthusiro1lr iir&sot' products and as an ingredient-fMrt|F end cosmetic prodbctV'(tARC; 1979). .* ;oeefo {i 1 * 6* j-inJi t* r Because of ItWertatilltyi p18stl'2?prWKcti ade of polyvinyl chi ride (PYC) and other Why* eWorld* Vdfyaar*' Witfrttbu* In eny household. Before being maddMdtm different pradUct*;' PW* pfclywMH Win- OTt;Torm of a resin that Is made by chemically linking the vinyl chloride meTfccule*. Individual vinwlygJUgf Ida mol ecu las Ire also called vinyl chloride monomer (VCM). ^dfejmHKin^fliPlen remain in the PW" raslft foT*scfti Iffladi'depending on the unreltted VOf/ Thtreforei'afl lndtrect source of vinyl may coma ffbor the releise of'unreacted VCM from these p 1 astlcIMBUcts.`' FOO examp 1 e, during 1975 to 1976, law VCft concentrations, ranglng'TrCm below'2 ppb-to 1.2 ppm, were measured In autonobile interior air space under experimental conditions (U.S.EPA, 1976; 1977). Emissions of unraactad VCM have been greatly reduced due to Improvements in monomer stripping technology (Wheeler, 1981). In the past, residual VCM -3CMA 010607 DRAF concentration* In the PVC resins at the time of shipment ranged as high as 2000 ppm. Currently, PVC resins contain about 10 ppm residual VCM at the time of shipment and may lose VCM at a rate of 20 to 50f per month during storage. In addition, most of the VCM will vaporize and escape during the high temperature processes In which PVC resins are melted and made into final products. Thus, commercial products made of PVC resins do not now contain significant residual vinyl chloride for later emission. B. VAPORIZATION FROM WATER SOURCES Water can serve as a medium to carry pollutants front outdoor to indoor environments. Once in contact with air Indoors, volatile chemicals such as vinyl chloride. ctn leave the water and enter th* air*. Human, activities such as using water for cooking, heating,or showering can prgpote rapid vaporization of vinyl chloride from water. Industrial solvent contaminated surface or ground water may, therafore,,bring, outdoor vinyl chloride Indo rs via the water supply. In California, surfaca water is generally free ef.vinyl chloride (Sharrp, 1987). In assessing ground water quality, tho-CaJIferplarDepartment of Itealth Services (CDHS, 1986) reported that only one out of the 2,347 wells for lirg public water systems was contamlnatad with, vinyl chloride-. #Th* maximum 1 concentration found In that well was 23 ug/1 with-medtam value of 20 yJl. Vinyl chloride has not baen datacted In. wills-used for-immlT public water7 systems (CDHS, 1987). ,The limit of detection-of vinyl* chloride In water is 0.5 ug/1. Based on this Information, vinyl chloride in tho water supply will have an Insignificant impact on tho^ Indoor vii^ ^lpride air concentration. C. VINYL CHLORIDE' FROM kAN|FJli Mftw "^ Homos built,on.or near landfill-containing yieyfcchtarKhe or related chlorinated hydrocarbons aaywfcavfi$hdg|r;4pdor-, a^nogcnntredbiofim of vinyl cHTorfda. Vinyl or!de.tmisti^fro* )**#-(W*op**er**<l by the vaporization of vinyl cnTorida that wat originally disposed thnra. Class I landfills that 4fa.des1grutadn|of toji* ***te KP'kikeiy t contain vinyl chtprtdg wast.nj Ie,addlt1en,.,micrnbiiptpg1p|l >jwyaffj|pp eCudilorlnatad hydrocarbons cap, pc`pdwc*; andr JsJertdib ldiiritth fHaoktsom, Halien and Pyna, 1387.)., loldo t\r<*tu y. . .**<'> ; bem u *5-ji..ns w aer >o "* ?vn' i-.'- Mpg^U^n^pp|tSi7) reported their*eve leaf ieee erover>20 Class II 1ndfilMWLi%migMtitf only fof9pup44ai. wastevtyMnety porcsnt of these n^HPp^miilitirlpnd measurable amounts- of. vinyl chloride and the concenuHHn at half of these landfills were above lOOfrppbv These high concentricens were measured by grab-sampling, an Instant filling of a two- liter evacuated flask, at ground levels or at landfill ges collection points. For five of the landfills, 24-hour bag sampling was also conducted. Only one of these five landfills produced measurable 24-hour concentrations of vinyl chloride off-site. -4* CMA 010608 There are at least two ways that vinyl chloride frcro landfills may contribute to indoor vinyl chloride concentrations of nearby residentiel houses. First, houses that are located downwind from landfills can receive vinyl chloride through direct outdoor air influx into indoor environments. Secondly, landfill gases, carrying vinyl chloride, can migrate underground and enter houses through substructures. The rate of accumulation of vinyl chlorldt Indoors depends heavily on the soil permeability, source strength, air exchange rate and structure of the house. Higher Indoor than outdoor vinyl chloride concentration may occur because vinyl, chloride is more rapidly destroyed by direct exposure to sunlight. Another contributing factor Is the trapping of migrating, subterranean Tendffll g<ir Sy the bj^sb. As discussed In Section 11(B), houses! faceted nearass I landfills had higher Indoor than outdoor air concentrations of vinyl chloride. The accumulation of high vinyl chloride concentrations in the water meter boxes Indicated that landfill gas containing vinyl chloride can migrate underground and enters nearby Indoor environments. Controlled release or combustion of landfill gas on site may slow down vinyl chloride subterranean migration. 0. OTHER FACTORS THAT MAY INFLUENCE INDOOR CPHCEKTRATIONS l A minute amount of vinyl chToride has been Identified in the smoke cigarettes (1.3-16 ng/clgarette) and of little cigars (14-27 ng/clgar) (IRC, 1985; Hoffmann, Patrianakos and Brunnemann, 1976). The vinyl chloride level in the mainstream smoke may ba determined by the. total Inorganic chloride content of the tobacco. The contribution from tiobscco smoke appears to have insignificant ingjact on the Indoor-air concentration of v.tnyl chloride. E. SUMMARY , ' '. " In general, there are very fiW, mlbor etfluton sdtS%|l^of vinyl chlorld indoors. However, houses that are situated ned^TandfllT* may accumulate vinyl chloride In the indoor environment due t^sufetarraftean gas migration and direct air Inf 1 ltration. Some of these housed may have tndddr air levels f vln^chlorine higher than the, Anient, .Air-duality The rdsiiltV fBiiISflSWf'Y Yfve IfcindrW 24-hour bag samples can be used to ast1mete,J|iejM0^JM& of Indoor air exposure te virvyl ofctarlde In houses near lafliHHHi|^iup|f 1982). The results obtained by grab-sample monltopl^QKiipYi!^.** not useful for estimating long-term Indoor exposure to vinyl IV. OF YIKXl CKLQRIOE-EXEflSURE A. WATER INGESTION The major source of drinking water for California is surface water which does not have detectable vinyl chloride concentrations. Ground water used for -5- CMA 010A09 DRAFF public water systems is also relatively free of vinyl chloride (CDHS, 1987, 1986). The detectable limit of vinyl chloride in water is 0.5 ug/1 (0.5 ppb). Based on this information, vinyl chloride exposure through drinking water Is judged to be Insignificant under ordinary situations. B. FOOD INGESTION Vinyl chloride 1$ not one of the compound's that have been monitored routinely In U.S. food and fodd products., However* before 1973, vinyl chlortde was found In food and beverages, ttvHkted In vinyl chloride polymer containers or deckadtha meterUU At tJWftine, levels as high as 20 mg/kg (0pm) of vfnyt chloride monomer were present in alcoholic beverages packaged In this materials Vinyl cblanUe,,was also found In edible oils, butter and margarine at 0.05-14.8 mg/kg." " When cleaner PVC resins became aViliable' after 1975, vinyl chloride polymer containers contained only about 10 ppb of residual vinyl chloride monomer. In its recent rule-making proposal* the Food and Drug administration (FDA) (1986) estimated vinyl chloride exposure from food and beverages packaged with vinyl chloride polymer materials* The** materials include llguor bottles', vtm* "bottles, oil bottTes, vffiyl chloride homopolymer ftl and materials made, with vinyl chlorlde-vlnylidene chloride copolymers. 1 on a conservative approach, the FDA's estimated Hfetime-anreraged indivit exposure to vtnyT chloride wouTd not efcetd s25 nanograos: per, day. V. ESTIMATES Of TOTAL. EXPOSURE FRO* INtfOOlT AIM AND QTHEtt MUTES The estimated1 datTy dose of vinyl ckforlde from different environmental media are presented in Table 1. From the Table, exposuney^ylnyl chloride In indoor air, food and water appears to be Insignificant. Hbwever, exposure to pwt,oB of u.- tilin'|iu&Ttfwy.evehmWK i'?. 'Sporf wt# ^ e. i*uaj To ww ->c . ! > s The 24- "omtdoefeFrang s from below the LOO of 2 ppb (5.2 u..g./.4) t_o_ t.h..e. m...a..x.t.m..t.i.m..."..Z. ifh..o..u. r a..v..e. r..age eoncntr.ttot tf JjTpyjW u,/m WYHJSTJS <' )3Wtf cVo *fm?f ~p> - atfforr of Vinyl cbtorfd'e indoors "fft houses not near landfil ed to be below the limit of detection (0.35 ug/nr or 1.4 ppb). tNMt are located near landfills, tha highest observed dally average measurement, 50 ppb or 130 ug/nr, is used for a conservative estimate. C. FOOD INGESTION The estimate of daily dose reported by FDA (1986) is directly used. -6- 01061 0. DRINKING WATER DRAFT The relative contribution of drinking water to daily exposures of vinyl chloride appears to be insignificant. The average concentration of vinyl chloride in drinking water is estimated to be below the limit of detection (0.5 ppb or 0.5 ug/1). E. ASSUMPTIONS Some of the assumptions used for making the dally dose estimates from different environmental media are: 1. The average person ingests t liters of drinking water per day; 2. The average person Inhales ait atterage^otf 20 cubic meters of air dally; 3. Dermal exposure is negligible; and `SJ 4. 1Q0X of the pollutant Ingested or iriheltd Is absorbed* 1 > .. JV* S -7- CMA OlOdll Tab!* 1: Estimated Doses Of Vinyl Chloride Exposure Through Different Media Media Daily-. Doit Refs. AT ft Outdoor air < 104 to 780 ug TabTe n-1 Indoor Aif Homes not near landffUr - less the# It'uj** *6-***THz*er1 at at.. 1989 Homes near rahdfWs up to Z00 ug ' 9CAQMD, 1982 FOOD Including beverages less than O.OZ5 ug WATER-DRIHKIM6 PURPOSES Surface/Sround Water less than 1 ug FDA, 1986 > CDHS, 1986; 1987 -8- CHA 010612 REFERENCES: y ARB (Air Resources Board) 1989. Staff report on reducing exposures to Indoor air pollutants in California: existing authorities and reconxnended actions. ARB (1987). Staff report on indoor air quality and personal exposurebriefing paper. COhS (Calif. Dept. or Health Services) 1987. Status'report- AS1803 small system program: Summary of results. COKS (1984). Plrfei report on a monltorfng program for organic chemical contamination of Targe public water system* in California. Coy (1987). Person*! communication between Richard COhey of ARB staff and Carol Coy of SCAQMD. February 10, 1987, FDA (Food and Drug Administration) 1988. Proposed uses of vinyl chloride polymers by the Food and Drug Adilntstratlon-Proposetf rule. : Federal Register Sl{22):4177-4188. ' ' -i { Sirman, JR, J Wesolowskf and P Jenkins (1987). '' The roT* of total exposurefin air pollution control strategies. In: indoor* Volume 3--Developing countries, guaranteeing adequate Indoor air quality, control measures, ventilation effectiveness, thermal control and comfort, policy and strategies. West Berlin, Gfrmdny, pp. 515-82(7. 2 * -* - * r * ' T fi * , " * r^ Hoffmann D, C Patrlanakos and KB lrHhnemfdfi(l9?8)? Chromatographic determination of vinyl chloride In tobecco smoke. Analytical Cham. 48(11:47- 5rt . .'-i y.,-i *1T A. - c w-t s: i'v '# j< *vf -****,. nos IARC (International Agency for Researclrl8t$d0d); 1979monographs on the evaluation of the carcinogenic risk if chemicals to humans-some monomers, plastic* and ijnitlMft1^*1itom*r*-artd'irol4lftJ' .Wlluma f8, CMC, World Health Organization. :I* * J;, : IARC 1988.' chemical Orgenl tphs On tftrtttfciatldfte*# tlirtirefnogeni* risk of ;*cco smoking. Volume 38. lAR^l World health - - "A - - . > .w;'-" MoUofti^^Bpf'Bl^SM^Sd JW-Pyn* (198?). Study of vinyl chloride formation at landfB^ftte* t(l California. Battelle, Pacific Northwest Laooratories report protored fed the CaTtfornie Air Resources Board, Contract No. A4-154- 32. Felllzzari, ED (1987). Personal communication between Steve Hul of ARB staff and Or. E. D. Pellizzari of Research Triangle Institute on 12/28/1987. Pelllzzari, E-D et al. (1986). Comparison of indoor and outdoor residential levels of volatile organic chemicals in five U.S. geographical areas. Environ. International 12:619-623. -9- CHA 010A13 GRAFT Pel 1izzari, ED et. al. (1989) Development and implementation of exposure -- assessment procedures for toxic air pollutants in several Los Angeles county, CA community. Research Triangle Institute. SCAQMO (South Coast Air Quality Management District) 1982. Vinyl chloride In the South Coast Air Basin. Report by the South Coast Air Quality Management district. SCAQMD (1985a). Letter from Edward Camarena of the South Coast Air Quality Management district to Angelo Be Homo of the Qltfor|>ia Department of Health Services on 1/5/1985. SCAQMD - (1985b). Internal Memorandum between. S* Levy *n4 Edward Camarena of the South Coast Air Quality Management district en 9/W1986. Sharrp (1987). Personal communication between Stave Hui af ARB staff and Chris Sharrp, staff of California Department of Heal the Services on 12/12/1987. Wallace, LA (1981)^ The total exposure assessmentjaethodology (TEAM) study: Summery and Analyels: Vol. I Final Report. (EPA/4Q0/6-I7/Q82a) Wallace, LA and CA Clayton (1987). Volatile organic compounds in 600 US Homes.: Major sources of personal exposure. Im Indoor Air *87, Volume 1 Volatile organic compounds, combustion gases, particles and fibers, microbiological agents. Berlin, West Sermeny, pp.183-187. Wallace, LA et al. (1984). Personal exposures te,volatile organic compounds- 1. Direct measurements In breath-zone air, drinking water, food, and exhaled breath.- Environ., Researh,35(sM)i:293-31t* ^ - . , - .v> ; ei ' Wallace, LA at aT. (1986). TEAM study: Personal exposures, indoor-outdo r relationships, and breath levels of volatile compounds In Hew Jersey. Environ, Internet ig114*349-387,., *#ta# ^o> onefA *- - -- . .-w-. ,-j; < f j re"? % cni Wheeler, All (IPXfW6e| #nd;*redttts.. Environ. Heelth Perspective :I23-Izt. s.rap Wood, JA aad JAPCA (1987)< daaerdous poHetant*te"jU*s landfills. . " }* , : .. i :. * in*-.-. '. Protection Agency) 1976. Sampling of automobile loride monomer. EPA-60Q/2-76-124. 1c emissions from automobile interiors. EPA-600/7-77- U.S. EPA (1987a). The total exposure assessment methodology (TEAM) study: Elizabeth and Bayonne,Hew Jersey, Devils Lake, Worth Dakota and Greensboro, North Carolina: Vol. II Part 1&2, Final Report. (EPA/600/6-87/002b) U.S. EPA (1987b). The total exposure assessment methodology (TEAM) study: Selected communities in northern and southern California: Vol. Ill, Final Report. (EPA/600/6-87/002C) -10- CMA 010614 APPENDIX A INCtQQR. AIR EXPOSURE DRAFT Prediction of health risk from pollutants depends upon knowledge of total personal exposure to the pollutants. For direct exposure to air pollutants, the dose of pollutant received through the respiratory system Is the baste quantity needed for risk assessment. In general*, that dose depends on: a) the pollutant concentration In the environment occupied by an Individual (exposure cancentratten); *b) thej Tength of ttme'spent .Irt Tthet environment (exposure duration); c) the rate breath Ing W Wat environment; and d) other physiological factors. Exposure through air can be estimated by using only the first two parameters, exposure concentrat'idif* exposure duration. Historically, outdoor air concentrations of an afr pollutant have been used as a surrogate for estimating personal air exposure. However, studies of indoor environments and of personal exposures to pollutants have revealed! that Indoor concentrations of some pollutants are regularly higher than outdoor concentrations of those pollutants. In addition, human time-activity pattern studies show that people spend most of thefr time fit non-outdoor T microenvironments such as in their homes, wort places,' transportation veljcles and public buildings. On tha average, people spend aff-W percent of the* time indoors. The California Legislature recognizes the importance to risk assessment of considering both Indoor air exposure and outdoor air exposure. The current statute requires the Board, when Identifying toxic at? contaminants, to assess exposures in Indoor, as well as outdoor, environments (HiSC Sec. 39660.5). This combined Indoor plus outdoor, or tdtaraiCt.exposureassessment permits more accurate public health, risk estlraates for afrbornO toxics. Indoor air exposure Information can also provide dffggtfob of many, toxic concentrations Indoors, ventilation with clean air is the only feasible method of reducing exposure. The Board must, therefore, manage outdoor concentrations of toxic air contaminants, not only to reduce significant outdoor exposures where they occur, but also to preserve a clean air supply for controlling indoor exposure to these substances. -11- CMA 010615 APPENDIX B TOTAL EXPOSURE FROM ALL MEDIA DRAFJ The concentration! of some pollutants have been measured in different environmental media such as air* water*, food* pesticides.and drugs. Ideally* these measurements can be integrated to estimate the total exposure to those pollutants through all the environmental medfa^- Total exposure data are critical ,{o setting pr.ior i t ies and. forraulat i cg cegyl|tory., act ions that can best achiey*-overall personal risklreductlqn. ^ :' While, one of the main objectives, of this repprj^is t%,dii4n*> exposure through the air medium, personal exposure data through other media are also Included. Exposure data are presented according to. thrpe basic routes of exposure which are Inhalation, ingestion* and skin absorption. <, 5" 1 '*** * X ' The combination of exposure data from all media will el la*, the determination of tha total human exposure to a toxic air contaminant through the environment. To determine the added risk.caused particular exposurdL both the shape of the dose-response curve and.the (keylbusJy. msistlng exp&ure level must be known. Although the exposure through a.particular medium.aw be small. Its addition to exposures through other media could provide a totegT dose in excess of e postulated "safe level". In add1t1on**the pathway of pollutants in.tbe environment is. dynamic and complex. Pbllutsrits emitted into the environment in oee medium can remain in that medium* transfer to ,another medium* and/tedl sparse. a. number of media. This feSuKs in different J,outes of axpgsure.,i.|pr example, s Ivents emitted as watte pqllutahts can bdcomealrborneand cause, exposure through will provide a more accurate exposure estimate for each rowca of exposure, including. &*5*iWHTlV v, ...: ' odctrnntmicpihcrti.nc^iuitum JifHrSrssif**rv. mad* ftr~t tvecalljtxptsurg. thoughr o%ip,,|dta if they are data. '^nr '' ?> -12- CHA 010A1& DRAFT APPENDIX IY INFORMATION REQUEST LETTER WITH ATTACHMENTS ANO RESPONSES CMA 010617 ) ti ; * m 5TATf O1 CAJJFC.NIA AIR RESOURCES BOARD U03 0 $T*sST PO SO* 7813 SACRAMENTO. Ca 95813 GEOBGE DEITWMEjIAn. Gm". April 4, 19B5 Dear Sir or Madam: Subject: Request for Information Regarelng Vinyl Chloride I am writing to request Information on the health effects of vinyl chloride as part of'our toxic air contaminant program* This program Is based on Health and Safety Code Sections 39650, et jeg. which require the ARB to IdentlfjT compounds as toxic air contaminants and once Identified to develop ana a<$pt control measures for such compounds* After consultation wtth the staff of th Department of Health Services (DHS), we have selected vinyl chloride as a canoidat* toxic air contaminant to be evaluated in accordaace with the provisions, of Health and Safety Code Sections 39450, et ten." Wring our evaluation of vfnyT chloride, we will consider al V avail able heel th Information., regarding this compound. Addl%1 notfyr we are soliciting information regarding possible Dialogical production ofWIstyT chloride. * 'i i. .* .. a "f *. . ` < rf-v' + 13 Vi - i Eeform the AJtl cen fermetljr identify e comfound as a toxic 1r contaminant, sevevaVsteps must be,tales* AftHMft request the^Cdpartment of health Services<o evaluate the beefth effects of candMat* 'dtajttuvtds. Second, the ARB staff most prepare repem^whtdh fneludfc Ihe health effects evaluation ana then submit the report to a Scientific Review Panel for Its review. The rcpMttnsulMrttted to the henetfc^wilT dd-medd availaWe to the public. Iftfo*me#le#.Lib1tted in responoe^tothtsreqwst will be considered in the AMifiMiihqp^p^p Panel. ATthbegft*any person majp *1 so-submit informea^gmdm^^K the Panel for Its consideration, I urge you to submit all. 1 tlme for our consideration in the development of the report WmSmlviMr. --The Panel reviews the sufficiency of the information, nethoas'^wdHttta used by the DHS in its evaluation. Last, after review by the Scientific Review Panel, the report with the written findings of the Panel will be considered by the Air Resources Board and will be the basis for any regulatory action by the Board officially to Identify a compound as a toxic air contaminant. Prior to formally requesting the DHS to prepare a health effects evaluation of vinyl chloride, we are providing, pursuant to the provisions of CMA 010618 DRAFT 2- - April 4, 1985 Section 39660(e) of the Health ana Safety Code, an opportunity to Interested parties to submit information on the health effects of vinyl chloride which he or she believes would be important in DHS's evaluation of vinyl chloride as a candidate toxic air contaminant. In March 1985, we received a reference search on vinyl chloride health effects using the MEDLINE and TOXlINE Information Services. These information services Include material available to the public in late 1984. The attached bibliography lists the references from this information search. We are requesting pertinent information on vinyl chloride health effects, including any material that may not be available to the public, that is not included in the attached bibliography. Pursuant to the provisions of the Public Records Act (Government Code Secti ns 6280 et seq.), the information you provide wlll.be a public record and subject to puBTicoisclosure, except for trade secrets which are not emission data or other information which is exempt from disclosure or-the disclosure of whfch is.prohibited by law. The information may also be released to the i Environmental Protection Agency, whieh protects trade secrets and confid#t1al information in accordance with federal Taw, and to otner public agencies# which are also required to protect such information. - To expedite the review process,* we atk that an^/informatlon which you believe should be regarded as "trade secret" be clearly marked and separated from other information. You may identify portions e# the fnfermation you submit as "trade secret" in accordance wtth<\Healthtand Safety Cede'Section 39660(e). The. claim of trade secrecy-mutt be supported upon the request of the Air Resources Board. Other information claimed to be trade secret and information otherwise claimed. Jo dbe-exemptefrom dlseleeurt may be identified as confidential in aiyweangr-with Section-1 ed 7,lalifomia Admlnistralive-Cooen- Section >918111 reeuires that the claim:of"confidentiality be afcompanied I would apprecUtetnecefcviTtg ai^rreleetnt-lrifomaaertOftjyQU wish to submit by May 19* Tljr'iftnlr expediting our`review will be: greatly appreeieM^ The Information te the attention ef: William V. Loscutoff, Chief Toxic Pollutants Branch Re: Vinyl Chloride California Air Resources Board P. 0. Box 2815 Sacramento, CA 95812 If you have any further questions regarding health effects information, please contact Mr. John Batchelder at (916) 323-1505. For any other questions, please contact Mr. Don Ames at (516) 322-8285. OlO^19 CMA 3- April 4. 1985 If you are not the person to whom this request should be addressed, pi ase forward It to the appropriate person in your organization. Also, please let us know whether you would like to continue to receive information inquiries for other candidate compounds, and if not, if there is anyone in your organization to whom such requests should be sent. Sincerely, jtfluunai/ jwurwc uif ijiwii cc: Alex Kelter, DHS Lori Johnston, DFA Wayne Morgan, President, CAPCOA Jan Bush, Executive Secretary, CAPCOA David Howekamp, EPA Region IX Assemblywoman Sally Tanner, Chairwoman, Committee on Toxic Material Senator Ralph Dills, Chairman, Committee on Governmental Organizatl Senator Art Torres, Chairman, Committee on Toxics and Public Safety Management Emil Mrak, Chairman and Scientific Review Panel Members APCs Attachment CMA 010A20 % Vinyl Chloride Rtfs ! 3 / 1 ! 5 ) E Tha pr s d i ct ah i Utf of Stomay* Frag Clin 3 & o i gas 10f:lf-4l : ir,d:scr., C and Richardson, C R, (1781) Ifion nlirtst to tha ssufsaut of -.haaically mducad chranssoaa daaago in vivo and thalr relationship to chnmtcnL -e115 anas11. Mutat Rss. TOC3 ) . 24 1-72, 3 r.-i*: ten, 0 , Richardson,. C. g.4 Porehtsa., 1. _r.. Enann, H. J. and O'Htordan, R. L. Chroecsoaa! analysis m vinyl chlorido axposad woriari: comparison of thm * *:hni;uo with tho sistar-dhtoat id aichango t oeSiniqc*. Motat Ros *: .1 **-< 5 Indiriic. K V . Hotl, 0. S. and Kaplan, N L. (1T8C) A genaral acBans for tho a ;a :f pharaacokinotics m low-dosa risk animation for chemical :; irsi ; 3 txi;;Ia--viny1 chiorida., Toxicol Appl ?Sarai:e! 33(13:154-41 :' 5:: Tha Ca: c : nogan i c i y of Vinyl Chiorida and Roiatad Compsends ris/pgso- ` Ka;::i* Announcamants S Ir.da* (CRAB II4 11 f i e?i'- Editorial- Vinyl chiorida. tha earci-cgoxie risk.. Ir dj . 2 d-5 tr. tvoiler H *' 1 ?76> Stadias on tha asttboliis of ? i nyf cSii or i do . . Environ Hoalth ? * : Ipt C t 17 pi17 -T Apialdcrf. R. and- Inf an-ta* P. F. (19 31) Ravi aw of apidanaslogie study roavlts of vinyl ehlori dt-r*1 at ad compounds Environ Saaltli Parsphct.Ulll-4- 7 Sihlsar., 1, C,, . AI anaiujar , V_ , lnf ant a F,. Va*on*r , X. K. , Las*. X. K. and Smghai,. E <1?7?) f iy l`,fcol IdtnZ ftarn)nonottieit,| ^Viay! fcxonida, einpl ehlorid , at vinylidona chlcrida. A* Id <4*1 A*S* XI* twH :A3, 11,1(1 " 10. Barbin. A . Bar tneli. lf. , Laconta, P*'' iWfc^fc'nilMi'', ' M. (lttll^St'edlana* tha miscoding propartias oI..,H4-01hanaadanina and 3,H(-ath*nacytosino, OMAroaction prodnsts of vinyl chlorido ol^|^ila.doilnt An,vitro^^pt synthosi*. . Mnclaie Acid* tos. 9(11;373- 3 A AtSC CANCER 1 EWCITY TESTS IH CHEHICAl CARCiNCSIMESiS I ARC UKT AGENCY 3 -1(0. BARTSCHv^JCV mjJMtHit. C. BARI IN, A , PLANCHE, C and MONTES AMO. 1. (1974 ) ALKYLATING AND KUTACENK METABOLITES OF HAIOCENATED OLEFINS FRODUCED BY HUMAN AND ANIMAL TISSUES PROC AM AS30C CANCER RES. 17:17. CMA 0 1 0 6 2 1 1Sartssh. H , Mt I a-.-a i 1 I a , C , Canus, A M , Ma r t a t-P ! anchn . Z , Bran, C. , Kac`af *')I lla , A , Sabadia, N. , Barbin, A Koraki 7 Cravor. C , PieeoU, C. and Mentions. E !S0' Validation and comparative sttidits cr. ISC choaicals with S *-p hirecr mm strains ar.d V79 Chinaia hansttr calls ir. th* prassnet of various cs'itclisin; s v s : ? r. * Mutat R a " i - [ ' ! -1C < ie.\, H and Mor.tastr.r R F.v.ajmu and c a r r i s 5 *r. i e *f facts of vinyl ;::df M'Jtaf R * * 3 7 'l p ? 3 - 11 ( ;;" 1" :c.?>.e: H TOM.ATIS L and MA LAVE I CL E CTSJ) 'UAL! TATI ms betjef:; m"tacek:c amc carcin- ENI-: ACTIVITIES of AMD QUANTITATIVE MEMICALS MVTACEK-NEW % is Easier, A and Rohriorn, 2 (1780) Vinyl chloride: an enaaple for evalnating^V mutagenic effects in mammals in v i v; after exposure to inhalation.. Arch Toxieel. 4111) 1-7 b IT Eecktr, C E and Coys, K J <1'84) Recent advances in occupational cases!.. J Tocicol Clin Toiicol. 22(3) 71-208 It Singhaa, l and Lane, J N (1*807 Vinyl haUdes -- carclnogenici ty. . Vt Horn Toiicol. 2 2 ( 1 ) : 3 1 - 3. 11. Belt, H. M. (117V) fhirmaeet:ntfe of vinyl chloride.. Cen Pharmacol . 1 (2>:pl- 23 3011, H M., filler, J C and Buehter, A (ffllT Inhalation pharmacokinetics bated : r, gas uptake studies 111 A ; ha rates k ;n * 11 e attettment in man of "peak concentr at ions: o vinyl ehloride . Arch Toiicol 48<<):Z13-21. Z\ BOLT, H. H. , mSEK, J. C , LAIfl, R J and OTTENVAELDER, H. <10> BINOXKC XIMZT* : chlosice and vinyl sr:m:ee-at very lcv ocses, iw. quaktitativi asp* RISK ASSESSMENT IN CHEMICAL CARCINOGENESIS ARCH TOXICOL 3VPPL. 3:12f-M2 CL Sc-lr, H K. , Laib, R J , Ktppus H and SUeMer, A. (M77) Pha rmaooft iaeS i e t vu chloride in the rat Toxicology 7C2)pl7*-H. J 23 Erar.d, E G , Beoen, L C ar.d Brand, I (1*73) Foreign-Body tnaortfeaesla bp vinyl ehicride vinyl acetate copciyaer no evidence ter chtmieal cocarcinogenesi.. J Me Cancer Inst 54 (5i p 1 2T?-42 . 24 ERAVN, P.. , 3CHCSIIEICH, J . LEGATOR, H 3 MCGREGOR, D. B. and ROHN, C. B. (tjA "UTAGENICITT Sf 3ELECTE0 CHEMICALS IN THE HOST-KEOIATEO A3 SAT, IH: COHPARATIV^F CHEMICAL MUTAGENESIS ENVIRON SCI RES. 24 333-3*2: B-J'.htsr; A , Filsarr^.C , r(t: i H* indl la 111 * ^ f JS*.' (JTtfB) Pharmacol toot ics of vi-./l chloride i%Uf .4*eJf.honk*f-A Tei.1 eei; Lett' ' . * '.l):p3S-4. rZZ, \ k I*** ; T.i : at ~ ' *pMfeflK'&r *rSL -TM 3- v- vT\*u. , 'r luJHDKtii u;l.'k v' Ai r . !* ): ni / Sn *avV -:a*v*- ?I*;'*' Itp4wicrsiammih>alsil* elfc'sgeeeiefs bwej u :cpe * jm*X d rtnyl i M : r: d Environ Hsalth Petspect f 1 :211-2B 2* 0 i emmeewSk J . (1*8 IT. International Consislion for Protection against laviions atal Mutagens and Carcinogens 1C 7EMC wopkm; paper TCI/2/7*. Mutagenicity and teratogenicity of vinyl chi: :: de monomer VCMT epidealo1ogfcaI evidence < . a * * , a A Kutst R "; t ' er. Z ; " 11 L ;'c ik J ! : . .ij - . : : Ag; : "ha-ui: : 1 WIT v--;7yy i * . *d a , I ai 1 . . 7 J - I_.; , H 3' 2- 1 r .: : :.t- .- '" : j* --j vinyl chloride tletterl. ; ; ; p3i2-3 :1 s ,, i * d i r. * h * ; * r a * c * u i i c * I t ^ -T ' ; 0*' Icnfitf.rce intervals . :-s !;:c animal ar. d^^St CMA 010622 - Tiaiuf f! = * ; *; . *: .. ini "it, " Y -r-L-- T^ K !.*T fL*> A T C?a:> 0-ca?*t i sailing i * - i s s : c : 111 i bopatjc injisurcoii. . An r-T ZZ* * ZZ Z \ ':* *! 13 ; i~-i i"A.": ?. : :-;n mvtacehicity cr selected chemicals lethal assae. ::: cc::?ahat:ve chemical mutagenesis. emvik E . 5 " S ' [*ne:iiti4s. ot *nsiifireoaa of tba liror tad hopatono in oinyj. ih I::. ft : -it'. Ann A.*, it Fit hoi (Fiiii) . 13 <11 : pi 09-14. f* ".*t i . *i , L:xti3t;-vin 2o;t;t. X.. Liabot to-Vtndopoor , W. , Soborfroid. H. , Ter.;*:*;. ~ and Mticit:, Mattpoaicilr f Tiayl chlocid* in tho Ana* taot s : t. 1 i : f * : * 1 i f i 1 *. s f-pt:`.atn*. i I loniHioa* . Mutit ?, 77(2) I75-. : Matt: *r. I . rsr.ttltl, : Xcbttfralf. M. tad Motcior, M C177V) Vinyl cMorida: i.:*L :: ;ni::-osf t-Ugoa L;: ;*od i n;* : A;ch 1st fhjtiol Elochin ? (3) :p*Z0- . . * * J fc . , . i i. Vitr.i* T. i I - E 3 ? S*Iiine cl anparimontal : : K * i 1 > !: = i i p c t . 5 1 - I 4 . tr.iit, ? ; f; i . - t :: :L tnd fftfcrm*. ?, J. dill) Air S = p Mod ti ff 134 >t o Z,ii Iti.ji. E E *nf ''al'.nirt, C . r :: ;h ; r . r.: i v i t h '.rinidun to Vinyl cftloritfo-indffcod bopitie ic hapttic porphyria . Klin Vochonschr . 7. T 3 A ^ n.**atn, C, if., MsCosnoU, ., Bnnoy, V. K. <nd A 'i"`` "> if i;o tn.f tipconr* iarttfoa in uneir induction by ^ j? * i ' :rt*. n.. mi haterlor* . . Tcit.ci Ajpl Fharaacol. <l<l1.120-30 M : Liilitt*. M , Milvjiiin, t do Moottor, C * foaeolot, r- tnd Horeior `I*:..*;;. i ;ti. i'. ; in tad aati;nici tj if ? ><iay2 ic sonoaoro Coinyl . ,it4f**o. 03#y isi t li i*. Sat*di*T.oA. To* f il E* too. 1(31:131-40 ; i: -~i r, C * i *- M. . ItaSo 11 o-Vindop* r , M , 3* Moootor- C , Jforeior, K. and .ahlacido- tad tin,-lonttr i I* *cli*ition aocHonisn and WL viTED a::: : zzziitz i a*.:h ?ha?.*:a::: * t-.i :TTi:r.'\r.ci3 h mutagenicity or :#*:th ieast as :TM:catd3 os cam ism nauntn- ' 1 3 V " " L ' H13 . .1 1 i 4. , *.i - C ir.i 3" :i p* , "Z !l :?7i) Vinyl ,`ii ih 1: : i ;~ : n i:.t mi :Mor oac* 111 dabyd and 7ips.toc.*llnlv .f.isiii U p*fticid< ;ayl ih lor ida CMA 010423 11 ; ; n o g t r. : and nutign :; 7. U : ".in ran {. 11 i ; e ( Ha loganatad w m. -w V t .......... -- rv:::s .........: " c:-:ics:3i external r".-;::-; -:7>: v;i vitkovt ve iilnsss a.`3 on vc exposed untuu f- *i ' >t E ir.i H: I . y , P; Vinyl- chlocidi dapandant : is'.rXiti ind t id U I a R* 38 <l) ;p| H ':7E 1 ' Expaaart iniicii let apidamiologict. ', i : - :r :ndc*t;!tl '.Ran deal anrironaant.. J Occap ` i - i* ~Z 3ci Publ . (22):p i-:-. : - i. rs :-c3> i-u*i&k at :J ca?: -.hlcrja* tawftd* Dltt: ` hy 1 atP.ar Cireiaegta a* 1*. d(lf):HIJ-4. . * - d ii. ** *< "1 iif i* `.St alliptlng ftc* parantal `' ; =" -: 3. . ~. v . l:af*ts. an4 c. (19*11 Thi i"; ,i *5-* i: : atad fabealToIar fraction* af Dreaophila. Li.(j ;bt :i : .r. i, i*; l-*l>.oifttt;aeana and bantoCalpyrana j w.* - ij is*:t-4 s7`i. .a.-; J. ty;?ri`*cr ;*. CAan lial Internet . -gf z i 7 -. i, 7 * ` .... : _.** wt > x 2;.T<Sis.:, 7 ; kS*iJss: ;cS. *> wtllMtl Stan?praetleal problaao jfitf; ;:ii :i< tflikatM.. J Taaieol i . 1 1".. : ` l ` 3 * * - ` i - , , . *r.il * 1 . - ij-ir.iiji-:: alr.flcbloetd* cavtlmganieityVaittaganicit y Ww ^ irai*--.' r-t'.-.-. intervention and need* for new rataarcb oi i A", -i~k: > i, yil'.ie palfej perspective.. Environ Health. lutant* and tha aptdaaiologp at canctr. r. J J , Villtgan, D A , Biarbowar, C. in Allowing aingla and naltipla :oJrii to Environ Haalth Parapact 41 43-72 r : Ar.darian, k f 19 B 4) Inudanoa of cancat aaong i t war rat* lr J Ind Had 41(11 15-33. * - i : * i. . 7 ar.d Vjimo. H _t 1 P 8 4 ) naptsductia* ? : t ; 1; r. Eiol Aa* 141,79-8' CMA 010A2-4 11 ? ?*to, R (U'7B) Carcinogime tffccts cf ihronic txgosur* `.cut substane** Environ Htalth Pn ipt:*, 22 pis*-? US PRESTON, R. J , ADLER I-D, , LEONARD, A apd IVON, M - E (Ueli MUTAGENICITY OF SELECTED CHEMICALS IN IN VIVO CYTOGENETIC ASSAYS , IN CCMPAHATZVt CHEMICAL MUTAGENESIS ENVIRON SCI RES. 24:547-422 US Praussaann, R. (IT7B) Toxicological aspects of food itfttf - carcinogenicity and mutagtnieity Arch Toiieol CSupplI (l):p47-24- 110 Fr*u*mann, R (1-774) Chnre*i earcinogtnr'in tits honor environment; problem* tad quantitative aspact > . - Otic# 1 ogy (SwlirrfxntfA . 38*21:5 31-7. IZ1 Fureha**, I f UffO) Appraiiaf of th* snrrtn ar.d short cming* of toots of eutigonic potential. 0*v Toiieol Envir:n Sc i. I.:;S-17 1ZZ P.idik*, ft J., Stommor, K L. and fiirghtn. E. (HUT I!ftet of ethanol on vinyl chloride or cinogonos Is Environ Health Ferspect. 4t:!8-d2_ 123 F.ANNUG, U ' t * 7 8 > SHORT-TERM MUTAGENICITY TESTS ON SALMLKTl LA TTPHIHUmUM. STUDIES VINYL CHLORIDE, ETHYtEN* DfCHLOR IDE AND OTHER C0KPCUN3S 8J1ATED TO THE tftMYL CHIOR INDUSTRY: ACTA UTIIV UPS AR3TR UPPSALA DIES tXS SCI J 447 31 PP 124 Eanaug, U , Goth*, R tnd V* eh tat i t r , Z A C77t> The srtaganicity o chloroefh*Ine arid*, elf loroaeefxl dehyde, Z-ehlsroetharol tnd chi *r oac* f.le acts, conceivable m*tabolit*s of vinylehlsrii* Ch*n liol lettriet. 12(3-4)251-43. 1 2 5 Ric*, J. M. (1711) Prtntttl *n c*p-A ib i l i t y to carcinogenesis by xenobiotic sub*tan deluding vinyf chloride. Environ Redftlt Jvrspvet. 4f*?T7-ls, ' ' t j*+ . * 7' ' <a t L 2 4 Richardson, C. R.. Styles, J. A. and Bdenetb, I. P. C I*IJ1 Activity of vinyl ehlor monomer in th* nous* mieronueleu* assay Mutat R*s. lll31:237-42 * '. rg ` ; . i. i 117 Rinfcus, 3 ' and Legator, H. 3. ' 1.777 ' Chemical chat act ex:tation o' 445 known or suspected cnremoynns and th*ir corralatioa with actagtaic activity in th* Salnonn Jt yphinur in* syst**''.8tne*( Ri* I *d`-P7 :RU7aff; * 5 - ' a > 4 *1 . r - . tb 12 f Robinson. J S. Thompson, J. II., lleh*t, R. and Stephen, V I. (1774) Vinyl chloride p*t* rU^isRMledtejfH^if Mfed J* Utagland) a 1 I f ", ? / , . 2 (40 37) it ? Rowan; aecupa IS 3 . *21-48. V M. and lrown. K 3 (17143 Evaluating th* us* f 1* for controlling toxic air pcllnlants. Environ Sci Hvalth 130 Sabadi*, N. ., Malav*iil, C., Camus, A. ft and Eariseh, H. U7I0I Comparison of th* hydcoiylation of b*n*o(a)pyr*n with th* metabolism of vinyl chloride, Nnitrosoaorpholin*, and N-nitro*o-N-meth*1p;partrin* tr nu-.agens by human and rat liver microsomal fractions Cancer R* (!!!) 117-24 13 1 Shubii, F i l * ? 5 I> Potential c a r c i no g *n i : : v of i::d id!::;?** tnd eont eminent s Career Rt* 33 U1 Ft 2) p347J-!I Si-*, p (l"5U Th* at 11 bo 1 : c tetivt l;:r. :( 3411) 11-8 ct. Br Mad Soil k H v 17 i 3) Fr obi tic* m dev* ':*!::'* ;r.: *:?r " `" sci'ucatisnal i?:d*nicIog/ Stngyo Ibt Dtigtks Zasih. ' Sup;i :i'~ * ': S390T0 VW3 31, J tdtychowski , R. A., 5okal, J A and Chmelnicka, J. (1784) Influence of tx^^pri mode on vinyl chloride action. Arch Tosieol 55<3>pl:l1S-i?l. 83 John, J A , Ss. i t h, F A ind Schvets, 3 A (1711) Vinyl chloride: inhalation teratology study in mice, rate and rabbit* " Environ Health Psrspoct. <1:171-7. 88 K11 nr i, E E md Kalmar, C. 0. (1788) C ar c inogen i c i t y ind op i demi o 1 og i cal prtflls analysis of vinyl chloride and polyvinyl chlorido. Regmi Toxicol Pharaac i 8S KILEEY. 8. J. U7I1) COMPARATIVE MUTAGENICITY- 10*, AFLATCIIN It AKB VINYL CHLORIDE. 1 COMPARATIVE CHEMICAL MUTAGENESIS,.. ENVIRON. SCI, All. , 14:137-412. 34 Roller, l. 0. (1781) Public health risks at aaniromnental contaminants. hoovy metal and industrial chemical,* J An Vt Mod Assoc, 174(4):ELI-7. 87 KUR0K1 , T. , ABSONDANDOLO, A, DREVQN, C., HUIIRMAN, t. and LAVAL, F. <1710) MUTACENES13 ASSAYS VITH MAMMALIAN CELLS. IK: LONG-TERM AND SHORT-TERM SCREENING ASSAYS FOR CARCINOGENS A CRITICAL APPRAISAL. IARC MONOCH SVPPL . 2:107-133. II Langauar-towoeeieka, H., Kurxbauer, H., Sycskewsfca, L.aadVecka-Marofc, TL (ltll) Vinyl chlorido d as oaso-noar olog i cal disturbances,,. Int Ah Oceop Envlr^ Psalth. 51(21.151-7. If Lassitor, D. V (if74i Recent approaches to-ths control afcareinagenie Caso study 3: vinyl chlorido-- bast avaiLablo technology.. Ann NY Acad Sei 271 :p 17 4-8. 91 Lot, C. C., Ihtndari, J. C., Vincten, J. M. , H%|ee, tf. I., Dinsn, R. L. and , S. (1771) Carcinogtniei ty of vinyl chlorido and vinylidaao chlorido.. J Tozi^F Environ Health; . 4 41) plS-l^. , fl t \- .. . . . 4* St, s. 1 ,1 . . .n 71. Li, F. p. (1977) Clinical studios of canctt etiology.. Caneor < ft Suppt) 4;. . vs* -mr' i h .coiaps. t'i ; * : i.-r, . ` : c i . w i , a I * . : s a .; * ; t e nt , n .-a -. .. 91. Litis, . U981)#SfTlW:f pnlaaatry Hl"**Slo*1r4j!t9J iMWr*.4*!* **4 ?io*1 chlorido oiposnto. Environ Health Parspact. <1:147-*. ~ * d C e ; '. , J 'OMS- E 9 '> T quo.'-" CO 73. Lloyd.;Cop 1 aa, E,,; an#, S| H#t -**? fipl4ilogica 1 stndy of tho l verktrs at a factory manufacturing polyvinylchloride. Ir ,. lad Ms ^ * rf C 94, Lotw^^^HBKpW^kS|ail7 t. and Rehagliati,, M 1 1783) Metabolism and relative earctab|ptSm|tblsn*f * ehieroothylonss a quantum ehonical structuro-act iv i ty study.. ChO IIOl tntoract. 43(l):33-44. 75 Lopriono, K. , laralo, R., Baroncolli.. 3., Rauor, C... , Bronsotti C, , Camnolltni Cercignani, G., Corsi, C Gorvasi, G., Laporini, C,. Kiori, R., Rossi, A. W., Slrotti, G and Turchi, G ( 1 7 74 ) Evaluation of ths gar.atic affects induced by !' chlorido monomer fVCM) under mammalian metabolic activation- studies in vitro and v:'."3 Mu tat R* 4C (2, p85-74 -0 IN -0 O i t, Y A G: a nolle F K e * m ? J , Eon bled, Vinyl chloride-induced hepatic angio*acroti Sr J 5urg i r, d H a o t , J . 4 ` 312-323 ( 1 784 ) C r :i i".:sj? n , H11 i a t r: m : and Kamel, C ( 1 77 7 ) Studies or. metabolic a ; : ; ; v i * ion ; -;nyj : h. : r i d e in Drosophila nelanogaster alter protreatr wi -. - phinebarbi t ; : 1 y.ch i c r i na * #d b;?h.#r.ylf Ihte Biol Interact 24 : r ? * _ $ fi m Li V I , and Smnnt, Z < 1 ? 7 8 ) Mutagenicity of W. J See 7(2) 71-75 : 1:,i Seme, 3 (1977) Metabolic activation o chlorinated ethylene*: ... .... i... i z.-. r *:ect on a 1ectroph 11 i e reactivity of the aetabol ieal ly ..;*! itch Toitcol lEerl). 39(1-2) :7-l2. C .. i .... I H 3 , ":!!*, C and Otkant, U. (1 9 8 3) tlKhuuiBf of formation and reaction; of 11ctroph11 :c ir.littiJuS ii of haloganstad olefins.. Prog Clin Biol Rt* 1321-lf! S3 . H Kensehler, 0., Eonse, G. and Groin, H. (1774) Carcinogenic potential of chlorinated ethylene* ' tentities mUciiUc ruin*-... IJtWbSci Pub! . (lJ);pi7i-3. Herr.*.-, ioc Eronchud, M. (17S4) Toiic oil syndrom* and vinyl chloride disease Hotter Lancet. 2(84081.731. Kiaeno, S , Gfcuda, H. and Suruki, T. ( 1 7 83 ) Lack of dominant lethal affects an sale CD-I met after short-tern and. lanjTttra exposure* to vinyl eh I o r ids, eoeoaer Toxicol Lett. 1 4 l 1 -2>:47-S3 71 Hdnborg, 3 (1751) The toxicology of monomers of the pelyvinyl plestie $*ri*. . Pr Cl in Bioi See. 141.77-112. 72 Kong, C 3 , Winston, J. M., Thornburg, L. P., tee, C. C. and VSoode, J.*S. <8711) Follow-up study on the careinogonic i bp of etnjl chloride nd einyiiden# chlortdo in rats and mice: tuner incidence and mortality subsequent tn exposure. J Toxicol Environ Health 7'4):701-24, ' 71 . Hopkins'. J. (17BO> V inyb.:*Jt 1 or l d*--pact 3T nfcageslcity r nan.. Food Cosnot Tonics 18 ( 2) 2 00*1 1 *, . r\; Mr . 7V. HQPHIN91-. J3 lltTHKWiNTt CILQIIM* 2 .MVTbGIMIGlTf7&KtC9 COSIEST. TOTtCQfc. I7.542-3M "it; -or? rodt-An; 73 . Hubornan. E., iartseh, H. and Sachs, L. (1773) Mutation induction in Chinos* hannton V79 eeilsrbpt twevelayb, chdssidcfnstebeiite*. ehlor oet&ycknn* snide sad 2- ehloroacetaidehpda. . Tnt J Cancer 18 : (ft: pil7-44 * 74 1AIG ( 1774+cSenme 4*i4*4hyr*l*ead. r*J at edssbstasee* initial urarm and industrial chanicaj^yJ^itggatfWM^il*. I ISC. Honsg r a p hs*S th*|*aluali*it of .the Caxcinogonic Ris of " - inftfffr 7-271-318. 77 1AXC '.t^HHPKKi^aSMoscr s , plastics and syn.that ic a las tennrs and aero lain--visy 1 chi or i d'ilP'fWtf.u i 1 o r i da and vinyl chloride-vinyl acatata copolyncrs. IAHC Monograph* oibtha Eielmation of the Careineganic Bisk of Chemical* to Hunans. 17:37. 431 N Infante, ? F (1777) Mutagenic and carcinogenic risks associated with halogenated N -0 oltt-.ns Environ Health Ferspect 21 p25l-4. O 7e-` I nf an *. . l?5i.: Cbaervations of the site-specific carcinogenicity of vinyl < do u hue a r. i Environ Health Ferspect 41 If - 4 u I n: a r.: a . r MeM:eh11 i , A wagoner Va xwe ; 2 e t , F-, J and Falk, H. (tot; Genetic r . s * f vinyl chlcridt Lanctt 1 734-733 p7 * *r.d Vaxweiler fi J -17*4.; Carcinogenic, xatiaante ' * r a t : e n : e r -. a ' r associated w i ' h vinyl chloride. Matat Hes 41 it spel no I ?! Mikirov, 1. A ind Fedotovi, I. V (1783) CMeehinifn* of the ciccinoginic of vinyl chloride (literature ttutw) 1 Gig 7r Prof libel (USSR) . U) K '7 Miltoni, C. (17 77 ) Recent finding* on the eircinogtn:city of chlorinated olefin*. Environ Heelth Perspeet 21:p1--5. 100 Miltoni , C <t??l> Prediet it* eir einogen i e i t y bioimyi in industrial oncogen**!* . , Prog lioeh** Phirnacol 14:p47-54. 101 Miltoni, C. (1774) Occupational chonictl eireinogeso* 1* : no** fact*, prioriti** ind perepeetive* I ARC Sci Fobl (TRANCE) (13) :pl27-47. 10 2 MALTONI, C. (If??) VINM. CHLOAlDt CARC IMOGENtOm rEXFERJMENTAL MODEL FOR CARCINOGENES 1 3 STUDIES. COLD SPRING HARBOR COMP GILL P RO L I TEN ATI ON . 4:117-144. , , V- 3, 103. MALTONI, C. Cl*?*) CARCINOCENICITT 0 T VINYL CHLORIDE: CURRENT RESULTS. EEPESI MENTAL EVIDENCE ADV TUMOR PREV DETECT CHARACT. ,3 214-237. 104 Miltoni, C Cilibortv-, A ind Carrttir D. <t732> Eaportaentil eontrihot 1 on* in identifying bmti potentiil circlnogen* in th* potroeheaicil industry.. Ant NT Acid Sci. 311.216 -- 4? e^Xorid*: 105 Miltoni, C ind Lefenine, C. (1775) Carcinogenicity blfi*s<ys *f viayl a- current results Ann NY Acid Sci . 244 : p 1 75-111. 104 Miltoni, C, Cofonins, G., Ciliberti, A., Gotti, 8. and Carrotti, D. <1711) Cireing*alei7y Bioisstys oi vinyl ohtotid* mmt 3 nodal of risk ia**s*nent on eeperinontil basis.. Environ Hoilth Peripoet. 41:3-18. 1D7 MOKN, G. Re (tilt) KU7M1N1C1TT OS tlSBCTER CMXMtCAEi CM XSCHSRXCXfA COLI TEST SYSTEMS, IN: COMPARATIVE CHEMICAL HUTAGtNESIS. ENVIRON SCI R*i- 14: fOI MONTESANCr: R?, 'an^tJUTSCR, H, tIT*47 NftAiINTCITT AND KETAlOLIIW OF T1KTL CHLORIDE. ADV TUMOUR PREV,DETECT CHARACT PRO^ INT STMT 5THU773). 3:341-24-3. -i.. i 3i .'itsrf* r 1 : 121.3 : n i > .. ; i. 107 l*lch#`l*of*i)A,'di'17*4):R#*Ol*ht**0-ln'-*aar*t l*nii,*a4 iMirfemeit al cincnr.. Arch Environ Hoii th . F t*C S) : 171-271. uo Niche 1V WR 'li, eh lor 14 111 ifmir UtlevlifiekiiHtiHAl HRTOtrif to uleite* and viny 44 l*pf4)^ :pt7?2*44l. <J. - v ' ir- vT ?' terger, F. K ind Soidaan, K. (17*41 Oceapational hinrda in * Frog Clin >1*1 los. 141.131-73. 112 Nich*l**V J*, Konnobergor, P. X. ind Tiri, D- ( 1334.1 Trend* in eaneor mortality mong worker* in th* *ynth*tie polymers indutry.. Prog Clin liol Ros 141:45-78. 113 0**eh, F. and- Door) r, C. (17I2> Detection of N2,3-e t hmogemino in DMA after treitaont with eh 1orsice111dehyd* in vitro. Circin*gtee* is 3(4>-443~3. CD CM 'O 4 0**r, J L (17*0; Extent of industrial erpe*ur* to epiehlorohydtin, vinyl fluoride O--4 viny: brraide ind ethylene dibromde. An Ind Hyg Assoc J 41 ( 7) 443-3. o c , ;; otter.w elder, H Kippu* K md Bolt, H. M ( 1 7 83; Covilent protom binding of vir r o chloride metabolite* during co-incutit i on of trejhly iielittd hopitocyto* md hopit i : r. ij s n 111 -oil* of r 11 * Arch Toxicol CSupplI 4 244*70. sit: *nd Ungvirv, G ^ 1 ? 8 0) Lick of nuiigeruc effect oi vinyl chloride aononoi . c - - * til* "]*' *H 11>`' 173-1 * 5 O' <N 'O o "C X u 13 4 Smith, A H V* wnlir, R J and Tyroler, H A (1480) of occupat i ona l cucinogtnuu using * additive expected dost nodtl . . Am J Epidemiol U1U) 7 37-97 135 Spirtis, H , B*b, S. , Baxter, P., Dicey, E. , Fiber, M., Talk, H., van Kaiek, G. ea Stafford, J ( 1 9 8 3 ) Angiosarcoma as i codol for comparator# carcinogen** is UettorJ. Lancet, 1(8347) 434 13s Slorotvedt Hitldaas, S., L*ng"ard, S. t. end Andersen, A. 1 1484 ) Incidence of center isong vinyl chloride and polyvinyl chloride worlceri.. British Journal of Industries Medicine 4 1 ( 1 ) : 25-30 . 137 . Styles, J. A (1977) A method for detecting carcinogenic organic chemicals using manmalian cells in culture. Br J Cancer 38 (3) :p358-43. 138. Suxuki, T. (1983) Neoplastic effect of vinyl chloride is zorse lung--lower doses and short-term exposure Environ Res 31(1):51-103. 139 Tamturro, C H. (1971) Health effects of vinyl chlorido.. Tez Rep Biol tied 44 . 37:pl3 140. TAMBURRO, C H (1971) HEPATIC ROLE IN CARCINOGENESIS AND ITS EA2Z.T DRTIAlON-THK VINYL CHLORIDE MODEL YALE J BIOL MED 31 87-10. 141 . Tamburro, C H. (1 9 84 Hay) Relationship of vinyl acnoasrs and Iivmr cancers: angiosarcoma and hepatoco11u 1 ar carcinoma Ssmin Livor Sis. 4(I>:138~84 141 Tambucro, C H and Grtenborg, R A. (1980) Identification of human tozicity and carcinogsnicity by sthylons derivatives Dev Toaicol Environ Sei. 1314-33 14 3 Tamburro, C H., Makk, L. and Poppor, H. (1984) Early hepatic histologic alterations among chomical (vinyl aonomor) workers. Kepetology. 4(3>:41J-8. 144. Th:eriauit, I., Iturra, H. end Gingras, S ( 1 983 3 Evaluatisn of the association botwoon birth detects and osposuro to ambient vinyl chloride.. Teratology. I7Cl);3i. 78 145. USE.PA (1*14) Draft Critoria Document for Vinyl Chloride.(NTIS/PB14-199538). EDA Repor t. 1Q9pp. 148 . Water Ouelity Crtterie for Vinyl Chloride (NT1S/PB81ffpeit. tfA 400/5-80-7! 49pp 147 tfngeary tt? * iedak, A., Tetrei, E. , Lorincr, M. end Folly, G. (1978) Effects of vinyl chloride esposnre elono and in combination with trypan blue--applied systomatically during all thirds of pregnancy on the fetnses of CFT rets. Toxicology 11 (1) p43-54 143 Va :n: o . H (197!) Vinyl chlorido and vinyl bemene ( s t y r *r.t)--me t abo 1 i sm, mutagenicity tnd carcinogenicity Chtm Biol Interact 2 2 (l) pi 17-24. ;< 0 Van Duuren, B t (1??5> On the possible mechanism of carcinogenic action of vinyl chloride Ann NY Acad Sci 248 p25E-87 150 Wagoner , J X ( 1 9 8 3 ) Toxicity of vinyl chloride and palylvanyl chloride), a critic, review Environ Health Perspect 52 e 1 - i is: WAGONER v c t ^ *. -- X and INFANTE, P F (197E' QUALITATIVE EXTRAPOLATION FROM LABORATOP.T *?>$ > ;rr>: **J --4r *, - - - : w--A "117 0 7 TY OR 7E~t--"CONIC I""v" % U-.. Toi C| A Cnt Duvld ttw tNicfc winhiig* MhomuV cguUlo > Mvufvtrd ft (shirr Ml* sUMos I llalyer or OAvhIu, m |*jh tiw m Hkj 1>*J Vsiyl cl# fa si vnyl pUshc frrfo iftrtiRiicao I Vn> g.ts ki i Ifvongli ewf pfixlnls S of Nnj vasl 1slwf oval ac C3 - * dU , r' ' :*m___ WTvvT *! " * ,- * - -m. TIic Law and Policy of Toxic Substances Control A Cm &Mjr f Vinyl Chloride , f , ,***$'** #+- . .. -% (1M*1'** %** J *" * > t ? '**JV P* f'*' ( ' " tf***-^^ %* ****.M ^^'lr"" i- i** /ffc* n*- /r -' * ' ft/ *-^1 V4 ~ 9 ' " v` jf,. w (* i jom* y ^-5^ *V] ?-**** *tv r rft #W'"M jm n1* * ' ft.i *|r^ <4*JftM s . ; If ^ attufigttrt Hr- tfrnlf -4 * ( I * iv* $stOC '.j^J ^f*4 ft*w**1f*v' f" * -nr ^^intt****** i.*# ** 'i' IT j H"*iP ,, ' >- "' U* ' ! '<*' ''"' '' ` si- -9% Mr * K -f -~" , vi.|pd-'< tnajl'iWJ ` ' - - Jtf W t I ***&* ?** , 1 l~J ( < OTO VHO DRAFT AC Dnvf Ui TMi (Jr WOHkC Uvtrcrtl imjnfj (nth vl thiK I It*** !* 1* II H* 1* V.r 4 I* 1 H *.fc 'VlH'Jl Hii- <ft .. .. ' tlru ti U>( *4 \ r *- li wewe e^^r haunter gi*e virNatty mi gnhlam* oft |M (tMw Height fn k ktiiwH kraMi ml rmlHinnitirtal id rnnylnm M niMc MM, Muttuihiie. be agencWV iuW^ icMeetCmificiC*Ini<<fttKIwftwK m the h$w nl tlsfc A iwnwr <if gttMaart hi rircUhm mafcdrt hi Ihe Ifcttd amertafrfty amt |*k if iihwnimi K pvkW by dir ftbwtfddfciH dM Kifthihitjf Aci> itmt tnv*J*e mmal m *fl a mumuMk n|Mh W| MjJvghi *Ni K fiKmiitM that the undb nf an falrldml fra the benefit df ft gttia^ h KcrfiiMr If dir henefk KiteJ H the |fraf'f m*ind ra the Mllfmcnf of uhtk other basic aeed The vactWke k morally utiftteqftabfe, koweveOflt b fra no mrar hnpnriwtf benefit dun fiw prinrfiina tif fhe hiMki of rat riraramjM| widely That unite imu fir mi dm alt cm eat h rate ddny; that time imiMdir w that all caa lm icr dlfftifll food packaging n wiAff,** frrikMlafly whftft ntMtHtMlal prmfum m* wnwiwd, lhe hmg term grad *4 Untie wfHtaHtt runnel ml m huglerm rffrcl nf tah regntatJun ihuotil he m tlunnrl eenmande grawdi away from Mtaitri kamduit M kiNh ami towwnh ufrt jtralorit ami ham of employment Ai the tm mdy la Pari ti dnm, the fraWnm nf drvhftng motet tmreriamty ami nf batanrinf ItcnnwatwAlt interest* have per valeft the rrgttlathai nf VC ftrladatre hi fare these ftiflkah pniHrmi KnmH hi part fnr the lad dm hi mrav than Iran years the ifrnrici hare sei omihmh ho inly two nf the mafia wwm nf ck|imnc In VC. WWh* the ilmliith ilm hare lecn fcI amt the pifnsiH that hare hern pn fra wmJ we by m> newff hnilly deficient. deft have hern iigudkam imimn M whkb the ,*grm ifs hare mailc fwtiwdy nr tngkatty inswpp'wtable ii*mhihniv ra hi which they have igmned evidence ami fafkd tn ihta iumhinim the evidence virtually ilemanrfi. In alt hhlancri, the agencies hare hrhl hack hunt imposing MandaA that wimM rrtptke any skgnifkaid finmnitk change la the regulated hxhvrlri The industries* prnltls, volume nf pttidwetiun of the regulated luhliran, and future growth pmspccit have lecn virtually Niuffnird One may ipe^lirai whether the knrfifi of VC proefac* Km ami mw we rafKiaonl rnnogh tn fuMtly tiKh cxlrrmc iklrtrmc h* the Sli Ut*r vpbra j*4pw*lt iM ra mat n Ue Arawa <m KratiR fmJ mmt lwt |wlja"t firfKaair ft upmhhO> all ihr piraunulwl wtarak) U irctrl M X iwwi hi iIhi if*f4 twfhi f ik 4*fftiU|r tt rwfciwa w awwy at Arvr fcw S*r, * , mt'm *f tJf* amt Lhwfr. iifra mh 14. m ml W, W fera lit* AMHl)r *4 iKc tuftlnftimi 4*n m iffMi m M **! whIm^ lt ck(M ml Ant Mar trt m ncf* lK 4w lKm lK< wcirlf nwnl h |wl(4n ini i*Kli rM| ttMUfr * a wmmmt *M Ulr rmKmiaaJ Km tmaMf Mt iltr h-- At MflNrKft t yiwf i, mh Or huitti tairi-- wN|f. wMi mt fl--wrU KwcarW^ tn yrnrnan^ (K< Mu*fartrM4r fiHumiin HkavK* mi (Kr awIrfK A twfuM TiJW pnak "tW|c ymutU rwifly nnw UuH mmOimK Kr* rMatimawt alili--n a********* **t Ktlttr* bM wr iMJm. rmt (lira eUUrm'l iKtUtm w Kr h-amt fholr raU ' TiiN, Htni M* M IK4 4Km HmOt Trl Wrn N ll i Ckwi H1 f I, ftO- lltw.C Sikrtw|,lf Vt%nt (lK||(HflaOi m mi)|hm4| hr n#w Orlmn Am Afttrw**4 ttmrmm* Ymtrrtt intd m id m l1 TI ______ ,----- ---- ,im ^nciMno n pwtard m mr rtiJ M>w, tm-fc * >*>** alWMti'ii whh regard tn one ra rtaae nf the many vnerrn *4 hamatt ecyaHme m VC *t: ntftn i a<.< Swniiliiww w V(mfi (MrMr irflr (WahM aKlkw rtae fiiiWtim nt derMbqi mdM am-rrialntf mti rrtpfwWaf mfettp nutflaKi tMtc wttt n thejr apptjr at hihk MlMMKra w)l>ltiir> yiwally h Mt cate tMy, thete ftiMrim mt ttMajW*a<4a* HaylaMMlaftiftt afvwy itrc+Jo" nMInc wMi tetpeu m tlte K|altMa M aim (HtfT W M atm!? Ir|hi *Mi IikIi- ymaMilMtaW-ittaMhltll tC.na Hr IwhiMiWt wliUhiitmt, leaiaJatt. mM n< h, tM tm l aaH) yn^nitri. Sdlwriiwm I uMe)tihc ckemkaTi met dmI M hiMailtt ncM vMi ikm tnlwdiiHi 1 awvtp VC't amt Hk tnttrtt ti Iwwmiw ctfMrvnc to it I. Vloyt (MiirUr '> Uutmmttkr Auacimttt fmimitiiri Uic tcatrkm^^tm ft of the rrtranf rami wirlefy mrd yholk In the tInhrJ iftatei M vr, gas. h made kora |*ctin^|HMmah aad ifriralar When fwdymrtfitd kahi yidythijrl chhwklc. a m4uI, it is fabricated ban a fdw anmtwel array *f fmdrnoi V(' was Ihst m.mdMhnril cnmmcrciaHy ht the United Iftatcs W acceded $.5 Mftbra gaatmh/* hy I'fJft, VC |nra(iKiirai The wide vathrff td aver of PVC h tntharaiy hi its whfaahdiiy The ma(nt tree of PV4' k hi cmrshaglfon fmahnls; nther "Mrs arc garlaging ami ownamn friahtcis nf aH kimh Itgutc t wntHowi/ev tic fftfitaltom of PVCht 1974. Woods, metals, glass, raho ^4asiksv jivf ralwi mate*Ms ran lahsHtate fra neatly ad of PVCs atws, tnh 1*VC is jticlnml hecame nf better performance nr lower cost M Hnwevvi, there ate mtly a few uses for whhh 10 dhect aalmhatrs esfsi #1 Sevetal idml wet nf VC gat htrlf time extant, hwt these h.tvc km dhcoatianud la the late Ihflk, VI* wax leMed ha me as an ana^lkiii. ho I Xrt yhwwv4>m^fW^^af>ftwWhe frms. I'ws ft tn. Him KKm I Wta, m ft iktathihA Hdft Ihmsi Miihiwk. W II tlftl4 IVrwrawW ftMUrdfto gf^ Mllakh I, Hft*B 1ft trcrrvMBwfc- ihM(hhH*.faiih1Kd'miihS^ MIt ttvatna.. .m 1 u l *r"wrf riMwfcrart> ffC.tPdft^t Wtla.Mi * V% ra J iihmi* as.ra. dum m.-- iv*r mm iiss ri jwmhm I hK'M ftawuinf he 41 _, - f fltkliMWIIlJ Ml tr* tm.it* f.r.tinnMewAfinmohm TttAt. tern IKimJtn tr.l m.mt VMt ~M'" wWfM mt ll*r tniftM 4ct4>wKs imB ghdbap d ttk> Vm t (MtriiufM tMrt I Ca In'* Imu tlMidr Xi)HRf iKr I ! IV Will ****'9WflT ft tt-'1 --TTOr^T------- * M '' ' T E 9 0 T 0 VW3 if i (=. F;.,i I- L. U * u*tr ` T B r CHA 0 1 0 6 3 Wv'jj, tei Tlw TC C( AC Davi ^ -I 4 fit* 4* tom III ,tten rcviAt ivuta VljkiH IhjTlVJi ( l*tf l*:i U Hh) IJi t*il l IllJSltC Amutti M*e 04 KwotQ l*oa>x 1*3 ii-jtfU |ri 14 UL~ <a: Tttgie IrflMKII ni.oMht tin I.ni I'trttm Vwti ( I'm vviHii Cihimmi* ((' !( hr**.*"*'!" PrfffrlMiAitlllli HUffllb 11 MwW | f Vto)ltMinlll |>* 11| JVC |itrirj|<tl . fanntftfblf tv\\ UHhMlWH I jW * wW<M klf failvl,Ur m|%l.*im*!-<f*t'l I I r-4t**i i **-#** !*** faiKwi mi IVC t*4y m 1lrr* WwfVC V I r\f 1* uti.KWil JllWWVt iflfchMlfHlfKO IvkikMlMftMtt wwnff PVt MkiMiifMjt4ir4MJlN(f*airAii p)*itK plttluilt JtOHM Vt icw*>*1<w.*pt. iMfimi iiwiM^uttiil *Mr< qtHh-' dvlaijrte #*!< > **Uc W *M<4 4fcvtk*r<' 'A' IrUtlAf #1 Mlp44< ** *lf -MtlnUffW fHetutll4Wm<Ju*iN<01llta<d| ... plfM. i4ll*ri (WlJtti p***!} I kn i k <4| * ct*M lag d(Wfi.<UMklv !Iiw<^jlViHawk|fwfcwi|inrp-- ifksw. oa*W*,sW**nyriJ|. Apr>*u,HVbr p**m. rt<* |<*rf MmcftmoKt t*wJ*4lW* kr. ttrb* *4* JO I l|MII (wmk V( mid#4iftn*n I Hi t'i ** 1*S Urtcitot at* V A+Mawrl ^ fiwA.kl^ <tUMWl i ^pimpirr t-. (Ml t>. Otolftr ^ 11 h wm iryikil hccMts* It upscl ctrdinc lunclioa ** IVrc ue *!ui Imllrallims 4hal VC wtti once Kvd * nrhifcianl In entiling " Unlit laic 1971, a iniill |*icnM|( n1 the VC |*iidweil wn aiul at an acrnutl funjictlinl In dime cinie4ici, ilrngi, peak-Wei, ami mhei mminner |*injncM. In 1974, *Vn VC'i caitinofenicity became gem'inlly lixwn. mil lifHH nf VC |mi|Mtled miihuiK writ Hilt no die mwtcl t* in cuiisuiiki tiamti Tbc aye i4 VC In neiiKitii Ml lime heeN jKoliilkitril11 Figure I illuiliMei ibe cycle nl VC'itieatkm, Kamlmmallmi, uk. ami idvjaisal, ami iV imnei <4 Imman eijanaie Tlicie me three imluvliki ol tennal Innm*nct. TV VC Imlnniy |*mhKei VC hum (kHhcVihIijU. IV I'Ve IniN'ffJ dir |ii iMii IV italml jda'iiir, Lwiwn In hi inw fofiii ns r^ln. 11 imhtbtf^ iimvcfK ffVl` tcvlm iiMi fiitnlj' etl |wihIuv`M rtuly lot itmsttnio wk o* (im Ihcim|>9Hm1hh fnin |*i*hui\ il nlhcr imltNiici. Il it In ihcst lime iinhutiia ilmt tin- Kmltn nc nmti hcavlljr hr VC, awl iM the Imtwn knuHi vam t-M hive i*cniMril 4hiifticle til thejee plttil*, whlhhuwl ftcrifile we ci|Niw<| in VC In iwn iiufcw w<f% rial, VC cMlulmtt c\cm\*c (mm faehkkN m live tuvnmmling aif w .SciikhI, ilmt the pnlfitteri/arinn jitoicn is imfKrlccl. imie VC iciitMitt (it lra|i|tcJ hi PVC makiirti I hi* i<shhil etcajet ftmti llte U lalet |*Mt(ftM:tkn hi (tlwkMkui plarris twt Iwyiimi, hhI In i|iicftl use ami iliKftn*l, Ai nnr mtvn llifim(h ihe |MuliHiiim eyrie nl VC awl PVC. iIk. numkt itl plftHH ami cmnfMmct incieisn, ami plants Ikiihim smaller mul nune Irfmr hnrnslve the VI' Imltisliy is aait|K>sril u( Ml vnmfutiits iH>crating itimMi, lot 1*171, Shell, Ihiw. amMliNnhich Ingcilier IkIiI Vs |atueM itf c|viiiy.* In 1*171, 71 fimtpanici operating 17 |Hants ctxiijifM Ihe PVC imluvirp. OmtJrkh is the mayor PVC fNuhicef with 15 fieficnl; Firesiiate, Cnmtut. UmwCxhitle, fliatles, Diamond Shariwmlc, and Ten necn each prnduce between five and nine percent n* Ihrit are about H.fXKJ lihiiMioA emupankt f aU tii Heynml this point imlmiries cease hlr Meniili-d primarily by iheh uu of VC an ISirr. Tjm, Krwar, A S^htiwcU. dtwuWiM* VU'tf t1 HI HOT) *1 Pirn, latvstnu IttmoT sw f\iuitii.i PM(I.U M Ml 1 |ir far i# ihrv Mionti h Awoivta We debt jniwf lotwr ouki "t is* *nf*n n UhM Vl~ cum1 Mnl^ IohmW m v** kwillk yiiiMi wtlftow witi, own 4 (tii VI' (iiifihiki nta W mt Shom lwriti evils AmStHf ,,nrf Vr? I FA f I iia* Irnof, Nfrr *U *. n 1. It AffroJkli M 11, Hwhimioum f*ivlti ini'* Ai-tvi r Pl | Mtbill Asm luttltl 40 ScsTM n ** (\MWI4(A *4 IlflMIM WUO Htl HIM Ki f'WAS -.`vj ) Has t1. rtiiSi*.; jiimiomw liw* i\ rrA HI lUWiihi Si nil iv^ ltol'49,1'*. WuiofiniMbO Kt| W fKl4 l IllMMlf S'* It* V| I11TMI VI l ^ tmlWPllHMil F4lll I HM1 Al.l -9 4 1, StHNMlh inii Tit hm u Aim nsm* h* it KmM im S is h < h*4WHh imi Ann uibi i iiMoti:* Silw ISVS| |IkuiiuIWi i#tA m ItMi s vihh |9|i Iimivd u Hirwrl SI U -< *1 ?l a; irsus uro^n ant fFp*1 TV 'I, 1 'iV i' ly' fi'nn1 ' i r-t Davit U, Mto A-i wuili(i( ratten* reguLaV nvuKrut INKhtl I I U.iMei ) if*HKh |*n I,Mr II Hf Of* Vi.yi * MT.I. vt f4.i AK I AjHUilCi Ik' y.i t*nSitl *4 Mw y > l*d I DRAFT 01063^ H Tmik MuttMil CtHttoi As ilk' above 1i)!ihv\ Indicate, ihc VC wv) PVC iikluxtfict me HtbvURllally atmcnhainl Iky imc ilv< vctfindly itrtcgiakd In PJ72, .VI perteM of VC imkluu'd * uv miM io PVC plants iwned by VC vmnptwiief, ahhmigk tills hfuic had df>ppcd from 61 pci cent In IWil if Ihe Industriei grew.** 1 k- ft Ihiif Ik* VC1 jnnI I1 VI* imJushlc* cinrtaln only a mull tMMnkr of iclaiiwly iwcUfMisI aw) Iwpabd fkms fui mate H eny 1m lha Mmirlri lo Kpeak with nw voice In iciulumy proceedings itgwding the It min uf their kt hrkfktgkal and economic capaWihies to tuntud VC eapo- vuus I k: btduvlffol martcl tituentre ifso mate* fi dif'kuk to analyse ihe ink? costs iif tntrtaof iwl to itleimiM (he iikidcixc of fksc tin on ptudtkt plkev, pwAH, wages, and oriici Inputs Mot VC plants ate open-air. ienmUiit| till tcfitwfci. Tltcjr arc located in p*HHj(a*ci1 areai k warm tittti - pfimlpttlly lihiislafta* lean, Ketiuuiy, awl (aUfotnt* ** PVC ptnu w*enclosed, M iiiltemit VC, and iky ion me kacil runtly in pojwljfcd arras. In nklitloit to Ik above slates. Hew Jersey, (Mao, and HavudwtrOi are may* PVC-producing (tact ** (My aknrt uttr Mol of and VC pidunlon is pofyincrired at Ik ike al which H is pnHtmcd Mml VC mtni he HB>o|sirtc(l letwcm VC amt PVC |i(.oKi, nuiiily by raff rartk car, etui also by tank itm t m*J binge In aJditliw, PVC (CMn must le liamito*tei between the PVC awl talwicalhm plants; lids is done primarily hy tram and IukV * VC and PVC pkoli arc highly utcihani/cd awl rnifiMy a relatively mull mmtkr of worker*. Al any one time, there are only sIhwI |,IJ0(I employees in ihe VC Irtduvhy, ami otify ahu( 5,5(10 in the PVC industry.*1 rating into KnMiU the m*ntal turnover td workers, about 50,00t> employccs are estimated In have worked In these kknliki since I9PJ m labile* thus plants are min< |Imk intensive The wimki of fabrication workers la eviinialed at MH.OUO.** these worker* ate subject to much lower eapuswes id VC Own the worker* in VC ami PVC plm*v a\ fix t|HUwe (4 the fiihrtcarion workers emne* only from escaping VC rcsithral l*H The sire of the grmrp, howevv*. gives rise to fears that even a hiw imidewe of cancer* may cluiru a large number of lives VI I usifi It S*<a. Im> INmIi I mJ I unwwws StwU^ U iht I Util* at rv^-.^rJ (1MIA %(4<Jtav l.a Vwt*1 t WuihSt -MM H!Wf* tl HJ-t| 1S****jOi thW SikM I .tlMIHK l*lf|W I *4 u * im 1.1 r\ i is ***** ha* at * j n, * < t f'S Si Mcihm mi In ##m 4| 1<ni uyvx m*K W m .`I-?* Wt I M f*t !<< Mtf***i, h^ *h*r |( a 1 O tm i I nHiMiik l>f u I ShmIjt. ***** m*l* 1), a* lit t. * W K AnUid^Wn/ ***** mi* * t*-4t 4i t^fK-wUis VC r*t*Ltlb" ** Ilk ariMltrAd Ux IwMbcl * C*Wv (wind *m *KK Mc k.N l4*| I* iIimiMi it im, t mi oiifwar ttigti imiikkf w itw udA (ifuUiiaii n 1 Pa I<4 ii*< iifM Miif it a (I (UH 4l\fH tVr--nrmt Mu*JWJ /,* I f ,*Pt* satr t at SS M,*fl DilttJ l> flittiltff 11 J Ttr VC and PVC wutteri ate re|*eseMrd primarily by three uubtni I the 1 inlleJ Muldier Wurkrrs. the United Steelworkers, and the i ill, Chemical [ and Ahsnli Worker*. On (heir own and Ihtnugh die lulutlrUl l)lo* iX'jwKiem of die Afl. flO, ihcie tuduHi were may* paiiklfunH in filing Ik VC riuttpfttioMal slawlard IV likkallnn workers are ic|*c^ sotted hy a variety of uniiHh, and unm are mil unkmisvil at all. ! | Ihe tcilutofogical and economic capabitirki of Ihe VC, KVC, atid f frkicsiidn tikktttie* fa lowar (he tekasc id VC-k plants, Inlk swfwinJ j In# ah. and ihrnugh Irdei ertriplog teshkaf in PVC have kcncnmramly m loot In the (r|drtnty attfcmc dckiKeil In aidiMMyient aeclfons llte diffietthy id |*edinjnf the fMc k(Witn|y tod economic U u> changci hi these iadwKki Is dncniied elsewhere,m but here h k useful in give some huhcadoti of their cleatly rkswnvsltatet! past and present CflpnNHlki. Without neerf for any ilgrdfiranl tcchnoloflcal brodihrougfu. k tfie fotir years time VC's carcinogeaichy became clear, (fw VC, PVC, and fabrication industries have significantly reduced their releases of VC ht ( irifauwc ik regulathint or the threat of legiilaiions, live VC and PVC imhisiiles have been shown In he able to rrtluce wml|rfti e aukune comen Hirthuts of VC" from af**ut T5t) putts per mdlWui (ppm) to aUnrt iwk hi reduce VC emissions Irtihe owtsMa by aboui 95 percent,m arid to reilikc Ihe VC rciiikil content of IihkI pucksgiog by several oolcis of mag nitmle m New |*fants Inc no ififflcwftics *ccting rlicse foweicd Icvch w' I wihcimtwc. dte*e U no sign that the limiK of cvhicM lechnologics have been retihed and ihe pniikliiy renuim that fumtaroental lahmikyicai kesbktIUgiK Urtkl OCCAM. Ik* lidwcthms have been achieved widMnil any signifktor eciHuimic hiiMQ on the companies or damage m PVC* market pnllliw and tuture growth pro\|fCits lhrouglumt the IWh and early lUTIis. PVC rrmtomp lkw grew m a staggering rale as prices declined anJ Hie mimhcr of uses iHUfisfil.14* In |V7t, ihe huskies* uwlyMi ftertirt unl*rtcmt|*cd govdi; the major ptohlem ea|iecnced at Hurt time was the tight supply of |viriHlwi-ka) raw material!.*1 KM mm*\a|-l} tapf* km v* wo MtMaMfi* 111, tjs tai Ktf fTA I IN, tmf* nrr as, m II; l-TA 5< hmo*m 4mT14hmi ai Vi non, imx* V.MIIIN MM Vr *%A mm SW Hh W U* W K*% <h* Sw liitfaM.ru mm m Wrt*. M.lta.MH, mmw as mi ! iKW W Iwl | ri--innh lnr(1 Scrty. M|W hT *!.( Itt 1, clM* Ml I, ftA H%, w. mb Himmm Smffb nmn PVC ftrhw. Cmu ft k Newt, U*r >1. c TL O Lr t lo' Tl Tt Cl A( 0,u Hv< isiVkl 'in*# -* i4y - >-h t t <fi * t*oi*,, tit 1N` i 21 Toiic Smiumcei CmNraf 111 i'tji :iul |M?V Vf iml I1 VI' rmflMiHi|tfhtH ibitflhil riuNply. nuufc tnj! life; liM lmiA in tin' hcml *4 jikrtomowt growth 11*0 shitup. fiowcver, ah> rttM *,ton'll It) *i u'mmiiim tespoflu' N> Ik im'lHhn of VCstwibai' gcitkify uinl Pit rbe iosls of i omjil)iii|e with M#b**et|ltvn*ly buposol slun- il.wih Kjrtlnt, ik stump h;t mo esliinstc iiHU's. Ill uthtMpis In ik catty DJlh fo p.ns iw littonsiimnsfin lislug utils nf IctilslutU; ami (?) tlw gettoal cuHtomk1 rocuiou wt 1074 ami 1073, nhkh was (uitMtljily st'U'iv in (lie kuhttng innvifUtlMw indutiry, a rtMjiir user of pl.Mu v,tl0 Ik slump Hut sltwi',1 o|u;illj Itj' fH ik oujirr pfcitiit* With llna Vkl *4 the ami tin* o Kttl i<4 tin- fkttivhig Huhrsrry, (ilisms i-im-uHy m\ t*Vr m iuiihuIw Mtaud up ik \hm ftml piuMaMv |iinMh iVwnll), new plains nit* king hwlh hi iin-i I aoihiiHilCif ikm.mil, without any m(patent hiMitr fitutt o**KM tool Kgufv ititth M* Mowv. h nt^vtus that Ktmicwlwi pieawt icdm'ifiM* l\\ Vl*e*ptMire ttmM In tk mamlcil of tk bukuMilah wllhoul ie miming tHk* titm'it* opei*' it. ms m v ijMHvhwi unpti 4 halite As On lotto* hiy sotviry if Vf's Nwhity niH Urnn, fkte in w> lioli Iih ik VI' bN/utl has ta'cn eliminated hy Ik meastMrv idtrady j,Ler. h fhtri tl will In' t'lmtiiMtt'tl !>' Ik mlilittOMal KKrasmes .othnWiI liy }Ik imkshtes hi In' hull tcchmdogkaHy ami ntWHiikifly within tkb i jt b ! link* H'llm iiotis me jnsidted h) tk iimtkal evitkm c Ik jnhhI *1 wlmI* ilk.1 iiklHsifii v would k seitomdy kinkucd c <*wimkally Is, however, tm|H^siUUr tn [Httlitl nliuldy 2 Ut-nUh ffifs umt Stmiuti ttf bxfutsmr Jo V/H)l 1`hUnnl* lln (oak 1`lfcov of VC are wiw known lelkf Ilian those `4 nearly arty Milter HKlitstri.il ckrtm'al V("s lartimtfvnh tly has ken wvH esialtlttktl by humati iijefk-iitr, wumal experiments, iwl other hlHirxtivy Irsti Tk iMlit'f cK|k'rtc(KC of (Kai[iilHHwl exposure has timfinintf VC's alitlhy lo uuse tamers and a hrtsi <4 lever cfleth in batmans Tk risks cxlrinl kyiunf tk workers; millfoats of oftk'i peofilc are exposeit lo VI' This subset fioti surveys Ik evitlemc of Vf* Imichy am) lltc exlenl of hitman rx|ki\tne In tk tkoikal ft Aitttr ttmi ikrtmh humim to\hhf llcfiMt 1974, svktt V(' hail not )ri Ken eortocek'ii >o lawman tamer, otkf il.m^ers of tk- tlmtiical were well known Vf is esireritcly Ilammal'kr uwl tomeirtuitHms t aw extecihrtg kl.tHMI |fNtl ate ex|4mve ll* n* (!,-<. t* fJM&h4 Hfttthirr M It V rilW f f1k'**i#Hi*JMHrb'i 1 mu 1<|^' 1 In. .Hh \f* IHk 4* II, I.IMI iMirt MktJr Sfii JwpV Vkxr^ri fit J*rt. hM ih> NtM \n( m tuts mi a tul H i Jt.rffl tw <4 tutu tuMlIhH SI^Hil Mks Nil M *< l* Mil>|. t'wi/ i XJpoiJt tlai NptMt'Mri1, I ) 1 <> a , A t wvl'l 1M"- rr >' Vi- IK 0*mtgr* I* SflH'mt uuflm li.iki! Jknl ll<Nlt Maliitf curcnk'ly high (iiiki iiliirfiiiiK 1)1 kjNHHit hi tomeitlriilNiiM greak'i Ihox X.IMI |i^mt Vf' noises one to ki'inite iNr/), tlrntfiy, itlvuiiMiinl, anti eventually iiiK'immUis Ijiwvi ilnses it4mh.il over a ivimhI if m win! sliifl iuhVc itm* |i im' lo ileep, tlieatukss shvp M* lb lore 1971 Vf* tomI'lUmilou*. of jV) ;<i h|i p^il tent i.aiumwt l.fl many |ub vmegutW* in ik VC aotl l*VC nkhtstries "* Among wtakers exposal u iksc pHHCMuiiotii fur pcthftb til tminfltt m yews a mtwk i of cffetls hml ikvn hlentifktl Many wortteix snlfcml enUrfeuteiii ami liMtisis of tk liivi anal K(bvH IM Mntt) eshHnttil IIc)ihhI\ syiktoMik.*. ilma leii/nl tty vht nlMmy ih'gi'mMhlUm in tk esio'UHlies mmI by a itthl feeling tv a frellitg t4 |*ins ami nerdlrs In Ik hatHls ami leti.,|fc hfutiy <h vtht|>iif uhuliHiM, a shin rnwIllNi nmlnirtNish>nly\il arareiltseast ihaiutN-iisril by Ik hlumLing of Ik hM hones in tk Itopers mm) Uv\ tn Alikm^h amteu wti udliKil ntw id these clfeeis iHd not always Millet the mho, Ik ellciis *vtc grtM^vtl timVr Ik Mimr "vinyl eMothk iltM-asc.*'"11 Wko Vf v ih)(m hy to cause imkci In hmoaos kcamc i lent in l*Ui, tjuvr oictliyiil evamlmriton of Vf' ami I*Vf wothets kh'Milicii iHimcrmis Nttk atul thtoim cffctls of Vf that |Hevlmisly lust gmic loHHMticil Im palicil tovital tirinlwinn and filnmix of tk Itvci ami s(ihTO woe Inuml to mint at a inUioscofMc level hmg klme rtwy woe ctinH all) i4iseriiible ,r' 11 i ^to4S, Pin sit* ikk-t, llwmMtv. a V4 t M. Jhr tliisMfi>k if Muf (tWh/r f if< hf* U'ufc Srv4H-*i, H, SM IhIm s mHV/lf Ilf | f*A MNXMIII ISO 1 | | MO Si *.p*. MUlC U 4* P' tl ft'** I/ONI JlntioHs ftuMw* tifM Mk | ta. a* at Mi H'JJfwnuri. iMf t. ju ait*clit Moots Kn ItHrci.e N4u.iH.1r tihWWf Im IVi*|MsShl SJcli mU ttv^MO IM K1 MM 4 M*k hfer.. 1 hr < mrr*m.M y < %#< +t rf*J F*i W< mwVVmI Mt4*>wrrm**t i Fit NWtrn X|V*toJk> IWfU-Jr t Su tom s lln.iihi h I IO tHJ'l |Iko:h..I|o cfkd as In tt'l, t fA MO l.i HSH o Hi OWI. luffi M<c Ml Ji 41. l 44 t|S |4i'. ^mK'Hmi, Hlithhw. IXhmi, kMoc A Hud t>*tn4r**r */ Mm our tcsHy S'Mtff MwnJvMfTfteoMif/aawaJf1 Wmi.tr* ;0SAn*.M\N\ \i M S. i J.'ltVI') IlkivNMflii'i .'irA JS JSr'iwAwfMf JhM'riicI I htK Stem A IVIiimi t *nlK*t M, nUn m 4TJ.Jr ikfJ as h*ttkrt ImU|i| 14a AkHMs N V As sw Si \ \% s'.SIH Ith J>r>ua'Mf',^rvv*o4', ttyw# war It*. l f.*, f miAvi i*f** .<( M' wit" |U ftrawr tf IHvmv. icff# a<M IIV H 1). f mlllrr NriiAi nprj h>h 11' -a t Wuh Aw i ewso .tww| AAm>l ( Mw4c JShAhhi S'Mtrri w Jiymi Nh A''ws NY At to Al NlllHl. n ` IN* IJ#mv IMdms |>Nrai 4 iumm *Mi l la -l h? hi |la WHaam I 4pr, >Mh, Awm A IMiHaer. nMaJAAnaJcirmawt haJi .hhvhf CihO f'W-mir fhvaw *Cssm>NV A* s S> i AltVIM Via 1>WI.<4I s'firi'.HHk'. * ca*n CafMMn . Ik CVitiJr JSmJaNmt ttmiro JimmmmHim 9f fa Von Mkrannfr JU J \.t Min Ass * |lMtilVN.| rv*rr*' a I hMHui. 4Jms*aami **f | No mtU two** Ntwl,#-! J t- tJnrl < Hoiir. Ann m NV to o* til |Tf (IVJ1I. Ihiiius A f'jih**( ttf tiyioMnihmi m/ It* itirr Kwoif I'arf rUcNr-JW|ftM(l (M>n4r Hi*ilm *X Asmms ,;\t 1 -i n'-if t"ry ...." fi f,;- T1-- CMA 0 1 0 6 3 4 l- -U f,- F). kmi hi if. cr.hk (A1* ** i V. f~NM i'(W* *fiw' Cv if **Wt.hr fatfctk t* ** * 'Mk DRAFT CMA 0 1 0 6 3 5 M r*tfc ii Mkrnsciifric cvmMUirtk** itfViMlfJ nihcf cliwij*t'$ i* ttvei crHs ,J* &hw ilkjMlIII Hk xaikly (4 HtHMKIlwl tlu`1 fHIRltMH UMlt htlNkf lchlv ui SlMlMT tuMt'lwl illlfMlfMklrf |4 hiHg IihmIiin.1** Tfe nifiiitfll re^Mthm ifal Ihcsr lw(v*Mc effect* eoM he iwJ m wlm ii #1 iwtieawJ rlilt irf i&vehtfrJitf tmer *] huw VC |rot|iCL'4 its can Mogeiik effete fn Ihclf tluftpjHiimiiit-nl. however, miiw 4 itvcsc effects ciMrchied <wrtt enmifh wilk ulirvJ cnscv 4 liver tfntiirtaiuNiw nr i4 taftri utntrib \ MrihMr tkiiffy vrlikh wmtris mc rf jin n-jscil rkk. fa* has the km>wk`il|!e (4 ihew HKu*ttwWcd reveauhets la a|il4ffi Imw VC mnfi nttf,**1 b flumtm itmtYfi IlHimclumf ife ittftaf nf lM, itfffr lift fr#k (4 if* Im thmkirh wintili Ik-miiii; ifatw*. nHKf uNdpMkl re|Hitfr4 nfcjJliitil*) iiii|Urtfwl ikaths iw| VC m4 HVC wt*Ler*.*M llie k4l lui il%cR stci*llly 1U1 Hwfi IInnten crtci <4 angii*UMCt*wi i4 IM liver tu4 ktfl ctwtnctf mmini AtturoH wikkt'is by July WVIH hhI kMl of 2.1 cases were Iimiwh MV A* a !mi <4miin| |*.if|inittf Hulft, A lnli*rK>lwir. )|ni|ilMli||)>tj I f*w Ikw4| ftitJw (Iini d'M#irr- A Arf+mt *m ! f^wl. }<* A*mJ\ N V lun $4i }Hl*>*l t .V Srr , % rictl *m <K 1IV iRf* m 1 Jl j&hickn umm km fa** mwwr fad *H hN. *kUmn MIimi .MtgMts-erv.*- Nta | i*vi f**o*i lews fanH*- 4 rdr aatielf *4 ***wililws /Vnwfrwr *f fUtrair, tafM i*mc 111, f rtir IfpiM**, wpr* mk MC Vcknwi. I Mgr. Nib*. Sirfa, A Ixlkl. fMpra wtf* III. fcl.11 airtki I rAnuk. fclwfarf A *K>fa(l. Hkmimti Sr4*mm*rt*lk fur* fkv**ri** I inlr*r eJ kt ***4 (ifadrd I utt Vntfi)1 ^wmk RifHaH ( ft*Jm Nim , ?4hAu*M'tlV A* mi 5Ui VMIVT'I |,? tfanfah, 1m. ittifafatcl, A WmmciUi, I0nti mf On*p+tUm*t **J Ntmmtvp** iHHutt fmititrt tmtit* AtifWt mt>*} $>*1i* i*f Vt*jt fA4*Jr mmJ ft*fcrr U airlrr*. IM I M M pa- IMMUI hfl |t *Vt1|lh| F.'l 1a fi'ii<wk^<t| a* yiM--nrt mw-IwiI Ixt wntfUtt OV|UiKt ik fMh(k ImJ tti UdwJ ifttv, hwtr Iihkmh* Kti\, iihI ifiula mIhfi tuimmliii* irfuMn iwkj4# tit ih4i#trf rU ttMtA fttmm+rmt \t*n4m4 t+* VC, xuynnmt I. irt Smi rttf t*4f uf IVM. thR 4>MIA * <* Nwk. fWrr |u% W* A)W ihttti Ht itw -A4U ( l,rH><w.WJr ul V(' 4UtntMMfnr4t SvMtr |h>|* wt HTtMlir|il*( VI mifci>cJ tlhwyir*. m mm iwl> n-fe W> IMA HUM ywv (am k wtUn'vMk)^J|4y. * 4c.Vt^lX f<l* lt kH t fk ltr` ( kM4iA.il wpMh Mk.ktt *lw I*P1 mtd 'fictm amIhmI str4| ib'tMfk t**rl !< \.m*t Ikit imttttvtid amIi<iWi fiuit t t* lkt.4 1 >!<. Itmiftl. \y<a>^\ SdMth. A IlMkl ftthmimimf ffriAtlt tjikrf rtr |*lwi*4*rijf*f<4|| *# rtp IM<fF>i|ii / Vupff M>Hi4r IHiNnrfJVr< nll1ftrrfW<fi4,4tllw* tiki n Smi vMih t*i Aumkff lnhmyt Jduh Mt.ftiHtfH * iMangY* m Mw i!iiUh|| k|ki<Mlkt !)*> 11 Huk it^wJ ikja )1k RtifiwMl v tjriiifMit mJ AiiMMtufyvk wutK h* ptnt4<4 kjp luUliNivittiijtir 4 Art M IimmI itkiM St n imHokii* ( ihl M-uu* |wti4UM, WlHlkMMt, I Ru||, Ii^ip Mir 111 HoArl uf lltcve Hiln>iyio.lkMtlti, uFlut ih) iiwmu < 41v1tiqt i(u|r> kf*( iVr < lump* a kh< uM trnl khnlt iirMtilt)1 kil m OkMti )u*i frtiMfr A<Wit IM (Vi.ufA|iuful S^fpli M*d lUallti A4wiMtUM*i. Vin^P i 'WrMik JYr*wttrif )VT(4 *.f |4 rK (|r| IkcrcMMlwf tM *% miH StmmAttJ $.* VCl If' ffVjfA PrriMtf*piM VC 11+** nmc 1. M 1'Wl fWvU(i. IW*t ' J( wnklv>hlc rtne i**lh lalti"* AHHoMjh the nujivky lit ciwi lnnilvcd wtitLm A I'Vt' (ilmilv iHhri mLci wcic tlui ><lci.l<>il ,,t llwic vnu IK uk< wuliloblc lif Iiiik lUI,"* * kasl 11 nui I ly I Vi i-iiiIh i I-I III u' nd M kM Wl va-jcs hy tF* tf4ii| F WJI,** Ahti-ni|li In aliMifuK KiMt iVse huihI-civ mc mk huge, tkir im ii( IIwi Mf!<kii>< m In Vwlmrv |(mi|n td I'VC winkcm imM iM|<s limn 4110 In J.IHKI ilinrs the ri(K'ttcrf lorklcaiC In iIk pnfntkiliiin '" Simt llw lifeltLy jKiiml like linn iKIwnn lnili*l HjimiHt ki VC >mt ilk.1 clliili'al K<|ii'iiriMtY nl Vivti raiHLi--hi* kici;ii avrfkf.ing nlnmf III friM -. nnne tiif* CM tut c|k`*h il as Ilk.- icuih n( MgN cajniMNci in Ihc |1Vh, t'Kifh, ami wly ItWK MM) ii tin: wpW)c** wikifcn** ilkil *4 limn nnginuuimM wmVcif l* ritMM ill ih* t^irmtri^km wh im (ita chmhH hi whki VC ii uwml eii In PVl'i at winkml hi mem whh tlmAml? Mgli VC rapmwn "' Ihew; wiakm |i*i4i*l4f wcie ihe awn hcnvtty tifKMcil, hi kim* *4 I <* nnHitcn- iMf |ic*ll nml iHMaincil Mi|n The (Hectic kevck hc **n hrviwn bul wr eiliHHHcil ht kite Ltnimh'd |wA ei|u*iiia u( kkuI ihntiiMkl |i(Hn mmI m iwii|e nf IFOhi hMfi|in 1 " Oher Bvci ttfknmamui vkliwi* fiecittniitlily had htwei, lei* tuMainctl tapmtwei ht Vt'.11' 1*1 VImhc nflriltd mlihMl i*tri V W * nnilri )ht fjUrJ (h-iFh*k (4i wtft W f*|4|<Wi4M *U dA.H.ClMMMMM *mS M ^V4' i, 1a*tl fdl*k.dtlnf |4jHlh U lhop ks* t* mt h'lMwtrd 4* twup 4mf vnt ||*W ipah<Mirt ttft Ut M,tTASistH<i. ASthlhtHMw \t 4* j* >1. 12$ RfftaNlfd Osnrv id AM|h>MM4MMi id lW I i( AWiH| Vm)J ddmUr ISdfMtartipjttMfi WiMllfh (Oti A 1VTA1 rtycwMiw lalwitdr dup tm h*t<d l> ItWct * <W Um* KwtiHihlkJ, ^iMitkHfw* Hhw'it Mln.lv Vkhmm, INvivmm <4 r-**rhrdl-MM. M^f-Md ItMH 1W Itdi wd kr*d WWl, NiMWWMd htalMMI* fw Kidcly N*J llc^M Ilk h 4 tSflMWAI c..h--IHUMlKW mAh M Kwtmtil, AMhtklM IHciAhl U. .1 11 14a>>\MW id SMvpdlMMPt Itilwt pinilh--dilM i. Mat I trU .Sffclan-c. N^Aawd IhiNiMc fiv IktwfAttMttid Url) ami Ihkkk, Af* l(. tttfl 41*1 IN kiHrn ffh< it fiwa llAlV, i'al. A (`(tenth, (tw Ahfk i H^Cntet 4 Am fA*if t mm mf tk* I lire Atmmmf Vtmfl tf HmA im fir 1 Wr4 .CfiMri. M Aim m>H V A* am Vi 1*1. !** Uk tilftni liftn lv Itwf >A. I VA. WiHiniiH.miiiHi SnhJ*wJ( ft* fk,wi4wi 4*r ftilkiiHfit /VifwwT %tm>4m4 fmr iW/ /tfUwIr. -Ml f rd ttr ** *12 tllfM lltirhMlltl hlKd l.M n<twinf $M. tnd fmr VC% Itrw t<w indtul cihiY-mi*^ *A iMr\ *4 MftiMatiiMH* at fik KC fa M Ik taH* m itw frnri4 fuftUitM, nhuMdaf fad fae ^HMdafa*# ixi wr nul cmk4 kf VC )Mf tl, at Ike imfaAi d fa*\ yiHM MaMkMv. ww vd far vvtv fa far ^mal faywfaitaifi W i wui) k/ nMWH.-mpMnwd VC r ifnwHi far* face t%wrt --drrd^rf far *4 far tfcrmthf 11} *CnyM mi4 I. M IhMriurMdIt favoafl VUdll.llufl.laA A fiidt. wfn wMr Ml. M i*f 111. Hktntti >ldiniir4L VfaM, A VAmN. IfakAi' f-ytrwwr nf m f'farr `>f Vimfi CAfanfa fWrfavt t Afarfav Wmifi, 2-14 Akmm i H Y Attn Sn II* V< dm | in A Ctdiri *1tviaim* Ptpatinm* mf Wmrii** htfwtntfc* Vfatl/'hi>w*Jr kf.*m***tr fa A* llwfiMW mf fktriMrt (IfawiJr fa f>W fakidW M |fa* t I'Mnv 'Im I |1*Mt HiMirr ftfuntu* to t'C *** wr (14 M* l.rwikiktiH kii Iiimh* hi Hvrwf.'td** 'fa $* aJ! * J u fi>lir 1**1 rtf t. Anitmit |iNMiM>f #Jhf ftfk*rlr*n*ti*f5t#* vtM* iMdiutgenkJiy Ms Mew urtjjftiw4 fcy (hr loulh iif eiptilmri*fl <(|| grtillltff wi \ty olMt UlwHaimy Mi, VC Ms kru *hir* 10 cause cancer In niMiiuih bmh wk Mutnl utf when ingested Ik Jir*t Id** (Ml the iIkimUhI L-awti tMU'ct came fimn Ik pnHicMinii in 1*0! u( ik icswHt of llalian capuriMicnlft x|hmmm(iI by ibe IfuftipcRM mh! AmeiicM VC ami TVC iditdiKcrv In the* KUt sart. Itdalini high imertiMium id VC | Wl.ttJfl ppm) dcvehtjArd cimcrwi tumors id llic iLk, fuo|, ami bme ,H \ uiikt lest* spoilm wed by rite findiKdi were umcludcd aivl reported In ik (km pal1011.11 Safely and tlcatlh AihaiHitHirikNi (OSIPA) in early I '>7*1 A* ImM ,, Ut the case umly at OSIIA's stumbid setting, the diriu auived ii a omrial time (k l ebiuaiy 1 Jr al OSIlA't fact finding healing ini VC, lire llitlian icu-jickri irpxld ifieir then-unpublished findings (Ml VC bad induced angHi^arionw id the liver in ia inhaling coocciUf alksi* a* low as 2.'Hi ppm tB On Ajwil IS, OSH A received reporti Inwti lesh usmlucted in IMS 1\t1wi tlu< A li-lfr*. Mortality Ao^r "f Wmrttrt tm #M Mharnfaitarr iif Vtmyt ihUmJr mJii* FtMimrn. 14 > (kruMtwmi fc|i>n. if/ mitt* Momwm*, fetrtt, A J.An>a>M Vmy* CMortdt Hauler.. Im| iwi i. A** I?. 1**4. t 1*1 ill i *di/tt NkIwh. A Wm(, MmetmUty A<m| fimfhifrtt ttf W* IaMrmtmt*, I* I fhiursih.nu Min *IJ. *? |I*?T| |Mrvla*ftr i*4 at Afurlahty Amo** faAOtMiMi l 11 IW mmIhm % auu J * atHaMf at flow t la the drwg* A**ti ha iMir oiJy Huh ficiloiltj (va uwluuurs (cmm h la iMOKatw. <1 wU k awful m (<At ik* fs>|>wtrik>n fatwa aliua wurtri i fur www pratt w>4 Ik* Mar as vwflkwat kN<K| |*iM nuy Ml f(f kjTS (lif^cf f wi umi* illulv * *nd< A ilMrtWirt s lit Mm4. OMofrar ant Mwtafraid Ktl U ('mmhmMwi AHyslaff f Ahvidr ISvJiMriua tmtUkUi. 2*1 AnwuI N At Art Sn ** M (1*7*1 <7 tofuatf. ftfcUjrltMl. , Wttwfrtrr, a f wH.. (i/attt* Mhti* mf Vtmtl CkkmtAt Tin I u*M. Apr * l*tt. at 5 J4 OihhM Murtiurd Idol Vvs aaiuaa mm al wih1*i t ry rvf < Vt'i I)* VhJe, MtasaH, A CfMu. thtfmgrmk if flat Slav. I**fi, hhJ Utmwj tm Vtayl f Akwitlr II rw i Roi Mli Ml lltllf |lwi<iMliir exit ** flu. <*ff/Nw (frimmmtt *f Matt to M | 140 fkiWftttieHUl }*4c)r and llri.Mi AAawal'U'rtam, gawr|>*ai f )t/*+*11S***4t4fmr Ji /*<<'* a* ViHft t blrntJf HlrJ Mi| 4?.M.'r|v7J |kir#Mfltf #>TM+ Frmrrfrmrf F*t*i'o*orf ito*Ja'4 f*m W\ IMrM p. Omkr i) . Illinnit nt iltiillir reuilli h mice M die lii*l level iiI(i|<iiiiic I lx n U-Inf fcsicj, JO p|>m.<" AihhwI lex leulu uiknI * Ibli |>tim until eul|r 1974. fl wh itixririf He* Hum iHjtUlM If eat of i Utile u mpfxutbnuely II mtlil|iiiv pci lllofiam ot IwiJy wcl(M |>imIucci Bvcr angkitMcuma end wber unccri."' Most (tctaly, la StfHtmlKi 1976. *c icwNs vt anmkt inund ul iuli)l*il<>n opcrimcMt UemunMHeil rtiM VC rewei liver tnfhninciinia In nit at !J p)mi, *ml ihd ll cMvet m>HHiim)r Immet | ihk ppm, the biwetltanceiHiilion ycl Ictlcil1,1 TIlC Sdfliwl t miui lu,ipuil uitpkiuHt IkM VC mw twinan cmmit mbci llwn Milkimkihim i>t Ihc liver. Ibe ctpciiiiwnn Imvc vIhiwk llvitiv.ll CaiH'Ci Wlilrwt el Humy iii <Mhcr thurttkc livci. iirMut llv hm|i, tpkcii, hrelii, mhI, k utrcmly tuned, bread.14* I'apciiiiienll ileiww Priljii| Ihc fwhiflkM of mmlCi In lun kvclci abet Him iait mkt aiut bamdeii - Iwlher umIImi iImI VC It imlmifnlc '*' In IlM animal ca|il meat Iht iuh|celi were erpnscfl In cumiatM, pridnnted duvet nl VC Die need war wired In mk)-l974 Inr fliidtet nf ibe cffeilt nl ila(k nvt ipHalic dosei, i^ilcrl nt nway bnmam' eapmme Swt b a slmly it mm ncaiing compkilkM. hul Ibe reudts we not yet availalde d A /MilitHurl Numint el rlit In ailtiillim in veveial tiumked rhmivand wirlcis In VC and i'V, ` fModiKikm ami in I'VC latHlealHin, millkins ol Amelkin have lieen, and continue ki be. exposed lu VC rktr. ahour 4 6 million [v-ifife livr iviiliin 141 ftSttA At fwiri Arotknf fmr VC. wp** atk 114. at M.IM TM rctwlis uf th< kalUn icsJl. ah* skumie<g |M iaAkitM df Iwr M|MUHsiitM M 1# j^hh, *rtr pubti>kc>f u *Mpf |*T) MAiwiA Irlralnr Cmrrinnftaittof fMiai it*vs *tf I'latffllrdii^ i'mrt/ntH* rvki } AnmiiHV A. ah Set f**|t*M| 441 Mahrwih, CihkrrM, tViquw, A CWio. f*J Ffimft Obitarm fVf ITidirM fA Viwfc Smmmdnitttmim At Via Ormte Htt tmmrn tOmrmrmte Wfft* H mf VC AdmimurrrJtfrmMf to Mf* ffriMiwy Mtpmrtf, fit i Ovrwt * Vim. f**< . Iff* lawfi>giwirrf itftiM on ft*t la uffkc uf At IrxiUff t.mrn Cktnrrffl Ml McpwwwwMai titaw Civat MwIMhh m iM Mea4ar t*f iM Tihhiwm f'lurpc+wl*'e Rrf far tM ta^OMxaik assar' wa Viayf tUarUc l JHLMtu(r.Mi iamUtnll |Mir>axf Mr ttorfat Mokuai MtaormAial M4 Sc* uatCfi ciwi I* aao I4M |4I usfra 14} (fA Serf matt * fonwa m Hr nan. tapaw aut* M.a M la aMwawt, awrutiH Imi t4 VC Irn Men 4ww if *MMM Wwm *4 ft*s klW >awrk knu ' fur mwi^nM.E jf Sr*. r| . lufflrwi. taili. lanj-rS, UmIhA, AtMiriti, C dmawSfi. Imm. ft rtf.* NkH. I.ayarik. ImcNm, A Mm, fwJkr~*Mn mf t!rmr IfoMlmir mmi lirw f'lMirniMH hf Vlmti (IMA Mai.ifcn je Vy-u, ;; SrxurN i'i MT'rt| m4 varin (iMJ iMttta MafMcakMy \ totoM ra iktw HVt (hIhIj *tl ak bduiwittaw.9(|i Sit McCaaa A *wi, rapra aaM }?, Ftmm IA'4rt tm lira, xpra m*t IT }4fc VC HrarMft. ipw aat* I, at lAf I |twraaa af Dr Tkalntr R ItaicKuai MV Ttlrf4ua UM*tk Mi Hi. Karp* Mrl-ataykAa lAmiwt Dimtawnl Itmolcir uJ MtAk, (mwmi DuAri Mttf CmMM. Frk 17, WT* T*rnf" '.Vi, 1 - llv. !' ,-HA 0 1 0 6 3 6 LantaJ. Torfc Jatshuieri Control Till TC CC AC U- ^QC^ O five mlki ol a VC or rvc iJwh1** Ik 1974, tboio 110 millhm 1**1wh of VC rtraped liK the ah surrounding fuch pUtKl '" The plant neighbor! appeal w have txcn crpnicd to mote (ha* one ppm leu than 10 petvenl til the lime.1** One ale uunpk. hnwevei, mcaimcd 33 [quit neat a pi suggesting ftml ilirte may he tlnKI temi, totalized peat eipmnrei.m la aihlilioii, VC It luund Ih the tbulge watte ami wafti elltueiK ul iheae gilaaaia. ' VC hat (teen found In sludge at levels at high if 3,00(1 ppm,1" and in water rlHoenl at high at 20 jigtati.,M Moil of ihil VC cscapci Into the alt suirounding die plants;'*' unite, however, make) In wap Into drinking walrt "* I line VC cmitilntH lit die muhlrnt all have been implicated at the caute of imiratcil talei uf ranee! am) bbth ikfetli In Ihc tmiuunding vom- UlW' munillci.1" Ainkrtwf Ufje |MMf d priuMi h cRftincA lo VC icIraMd kt hMHRMti* flint Only Mhrm iwc-lhliilof VCpnatatlinN (ipofyioailieil M (he (in when Tint J wtdkl I'alfUf >< K^fli tVI Jv lklf if iltfl I Mjf w 1 lAjit f i (JO. I Dm U i V* far si AdlHM mj Q ttwou pi ok Itrslw U It prodmed The let! Mil he shipped htlween VC amt l`VC lat links under (Heituie at a IkptUkd |1< Aboul 93 percent of ddt ll thirled In tail tank cars. and the ml In tank Huckr, tank vetteb, ami barges."* Thcte I Milk t Inay kak, punctata, nt crptude, linnetIntel In heavily popuhUcJ ate at lletweea 1971 ami 1974, there woe at kail 34 accWeiUal rckacea o( VC (unii tail lank can alone '** As VC diffuse* hum the the ol a spill i n aecktcHl, hantpiKtalion workeis, Kathy ic tide Mi, liavelkn, am) olliet hytlMiwIeit can receive ahtnl-lerm espoturet lit VC ctMccukaitom tanging (iihh a lew |taili |iei billiun (p|ih} In ihnutanch of ppm. Tratnpurlallnn wotltrif aad emetgewy pci tonneI tuch at fitemen and polke ullieet) may III If*. W*(4lrl 4U Adauawi. StMjttdfm tlMff itixUi. ti id > tt.Miniti itnnhntKi i*e ! (M **rA* et i |4t rrA Skit rill* It **> III mhical RkMwI. Uffd mmH M, M J* I* M 111 W It) Srf U 1)1 CM Tk !( (pwl. fH|M Mlf It, M ) IU U ta IH SMKt9 ft*** III S<t Wdrcn fM I* daw 14 MfM Ilf CM Tl (-*: Hapnel, lrfd mmtm II, at 1, J 'f See MH 1*4 Ilf* l*f Uau mi idkcin* KiUtatt iiCMrH la Ton Mi 1-wlilaM, *>** *rti IN Mghnl rMHMMMUi mi VC mJ rVC facMtk* TWif mi wntJtddi wfUraii fivalvUf M fflteM. (HU tccMraii fduMi b dtdimA hm iMfHMi Wd mt dm ml 1iwtpdiiMiM 1ikli iicordilatUoifl( MimJwi MMiall w M(U(Mli*Mia| ifch (<rid4. iwHiMUb^aditidllR 1Ur Hu Ml, IUC*if .Mini HMHI14) Om kcMcm, l K** Wmfm. ImliJUM, iwrotiulef iW 4,fO*pcwf4. U Hll WWk lid IMI* (a* iwp4M*i. Mth a* M.M (iKmi ml VC UCiyd Mad iflwm hr III jaMtNM tt*44 lfca figwt lor dw autioiMi Umk hk tuMl from M ialii*lr* *t* Uwy Wilioi, (IkOMkCKl tifiMCT, (VpartMM mi TfMtfW'Jka, OOhr id llu*t MrieiWi Opfihkoi, tkl , tIH WTO" {28 ()$ ; - :\m DotU 0 fkan%er he tubjetl In repeated caputiHea am). If accidentt occur hi die tnine plviec, to may teihknn and bytlamklt. llwte eipmutei nc leu oiiuineil dim thine toffeied Ity VC and l`VC wiwttn and |danl heightens, Ihh |'jl ciHteantialhiui may teach dune eapnknced hy I'VC polymeiliaiion to, Im chraneit, ihc mini heavily tipmed mmfialliimt ginup I bird. pcii(4e uecf|HtKilhi VC thmugbcuntamei laiHhols, IimhI, ami ihlnklag water. Until late 197) inly 1974, VC wat used at an acrntnl propellant In drug, ccnmelk. pettkhk. amlothcl umiutlnt |H>v*lKli ,H Tin? usei of l VC j.npelkd aetovil jumhtu tutli at a hah t|nay a ixtiichk in a iHiatl, er* kiseil space tuch H a badwoutti may have been e spitted to tlatl kirn cimcenlialioni appuiathinf 400 |guM. and prtuutt nuy have kail an average cipotare liom iH VCpnnwded piodwctt In riicH butnet ei|iiivalenl lu an average eapuunc of alnnH Id ppm In the lctlHict.'*, VC hat been dekt'led It) Ihc ik of imam fltkldy painted with mliin later painti, bin nu VC endtaliint have been delected in a limited laMiding of miter new I'VC producti or (mm awonrobtk iMcrkitt '*' VC kathet Imo fiwl ami Itcverget floor the mute than 300 tnllliim pmtmk of PVC packaging and tulier I'VC food contact materials used anmuHy.m VC alto riUerr ih Ink lug water Itom raw water snpfdki and by kachiag Irum increasingly cornu*hi I'VC pl|ic 141 One study estimates average American daily human Intake of VC Ihiough food, walci, ami ail al 34 tnicrograirtf The baranfousKir of mm-nccnpathinnl ex|*iiinct to VC Is even kit well nmktstood than the titk lu the wmken The danger liom inhaling cullfinely low cuoce Milllout ol VC, nt hum tingk nr spmadic ci|*itnici in high VC couceuiraliunt. Is unknown. Similaily, the telative tiiktid iiifcn ing and inhaling VC ate unknown '** Thus the mgcncy of ieducing in eliminating tliere souteci of cK|mtuie !r hnt*Ksildc to runt 111 Set Mil KCddfd^ Mitt Hi SH tmfrm 1*1 (l*|l. I .dktwit, IiiAmJ, A UdtM, Mrridfrtdrdf *f VMjrirUutf/r from A*n>u4 Sfmji )4* AMtklt H Y Atkk Sit M*. 1*4 t) (tlltl 1*1 Cu*mhmbUI PiaNOkM Affnci'.fMlk.d mi Tftair IwfkMjMite<. Sdn^Bnt Amly mh ml Tdik lwfcildm.dk Tail IH--V*tp1 CMmUc, Vtwlfiy Sawtctk.fahW I. u || tAr* t+Ht M4 Fwmd mmd Cnf AAwMviraiiw<b. Viw|4 HM* Mydwii i (VdMri wA* / mi*d, Mmtift *4 Bmtfimmitmg. 4f I'gJ lt| 4*,)If, 4f.)9ftlVM| (fcrrMuf(rr k mi 4IM I>mfmu4 Mtdti |wr MT 1*1 tTA SiMNi** uwTtiWNidi Htruwi. faprd H. w f H; ITA rni i mwit Ktruni h tlMtMMfWua Ctanwaam. mw CI.mM 44. ttA It1 Fatk Ar|ami. IlfM wwdc II. M 1, If. I** tM SrRHttf AMTiiTiwiki. Himi, tmf*m wwd* , mt 41 1*1 St* Wwfcd|r A Clidi A StHiMkmt Attfttmtm mf do* t^mmmlilmnir* tlptmlr uf YtUfi CUdtit Hrnmmmtrpmm Afmtmm StMmm. 1 I Itiuiid'ii) A f.Hvr i Ih > im III |l*i*l. Wfcfcdjr, n. IhdrawdJpwMlrf *wl UfM&r *4 Wwft fUrMr ttmMume* AdmmitittrJ kp Ymti+mt Nwtft M Aaf*. I J ItMwiattth 1 Imi't IlkM ID Ml fl*H| U ifct Itdowi aflkk, Ihr Mfftwt rtliwiM ifcwl la* talk, 1,1 wkwfidMi irf W m dfcc 4mdp wwaLr 14 won * kfyfkiwwagly *u*l hi iwfcdhwf * ffm |wd wlflilMMd Thtf iawdaww HfMnva mmp 4nk| cl'd*u tmHmm M hawwdw x+Jn^Umcti Wdhf % Cdfcdt, M 11* H 010637 I *C XO. b~ > Chemicals May 13, 1985 C"-3T-Ajk4l Business urm PPG Cne.-nicaii O*-* PPG Ptsce P^sourg*. Pennsytvsnis 15Z72 draft Mr. William V. Loscutoff, Chief Toxic Pollutants Branch California Air Resources Board P.0. Box 2815 Sacramento, CA 95812 Re: Vinyl Chloride Dear Sirs: Relative to your request for health information on vinyl chloride, we have no information which was not covered in the MEDLINE and TOXLINE information services. We thank you for asking for our input. Sincerely yours, Clete M. Smith Technical Service CMS/rs CMA 010638 IF.A.OIF'IO GAS GLINT C EL3CTRIC CO &IsA.2Tir 77 EEAlE STREET SR'. rsi;;c:s s:e itz es57 May 7, 1985 Mr. William V. Locustoff, Chief Toxic Pollutants Branch Re: Vinyl Chloride California Air Resources Board P.0. Box 2815 Sacramento, California 95812 Dear Mr. Loscutoff: Request for Public Health Information Regarding Vinyl Chloride Pacific Gas ana Electric company received your April 4, 1985 request for additional public health information regarding Vinyl Chloride. We have reviewed the bibliography attached to your request and concluded that we are unaware of any additional information which would be of use to you. Sincerely, CMA 010639 NiT'.-ri.' Sr-'.ir-Ctf Doicr-t C'.. '-.rr.-.i. \ *tr,in;T.on. DC l'//.-; :c: '63-tso: To: William v. Loscutoff From: David D. poniger Dte: April 10, 19S5 Subject: Vinyl Chloride The attached is in answer to your recen inquiry. n! J CHA 0106-40 PRAFT 152 Vigener, J. K , Intint*, P F. tr.d Xpfeldcrf, R. B. (i?C) Toxicity of vinyl chlorid ind polyvinyl chlorid* is s*n through epidemiologic observation*.. J Toxicol Enviio Hei1th 4<5-4>:1101-7 15 3. Vatinibe, P. G., Young, J. 3. end Gehrir.g. ?. J (17771 The importance of non-linear < dos-d*p*nd*nt) phirmicsk met i cs in hitird issestEomt. J Environ Pitho Toxicol. 1(3). 1(7-5?. 154 Viters, N. D., Cirrott, N. ., Covon*-0*S*rres, C. H., Xowird, B. E. and Stick, 9. (1993) Genetic toxicology of sea* known or suspected hen. an carcinogens. Choa Hotigans:Prin mothods their detection. 1241-3(1. 155 Vithey, J. R. ind Collins, B 7 (1774) X etitistieil issessaent of tho quantitative uptake of vinyl chloride : on igneous solution.. J Toxicol Environ Health . 2 (2) p311-21. ' 154. Iijdela, F., Croisy, A., Harbin, A , Kaliveille, C, Toma, tie, L. end Birtsch, H. C ir c inogen id t y of chloroethylene ezide, in ultimate reictivo notibolit* of vinyl chloride, and bis< chi or methyl-ether after subcutaneous administration tad in initii*ion-pronotion experiments in nisi Center Res. <0(21:352-4. CH* 0106*1 South Coast j AIR. QUALITY MANAGEMENT DISTRICT 8150 FLAIR DRIVE. EL MONTE. CA 91731 (818) 572-6200 April 22, 1535 Mr. William V. Loscutoff, Chief Toxic Pollutants Branch California Air Resources Board P.0. Box 2815 Sacramento, California 95812 Dear Mx^oseutoff: Vinyl Chloride In response to Mr. Venturis's request for information on the health effects of vinyl chloride, we are submitting several references which could be of use in your toxic air contaminant program. These references were not included in your bibliography dated March 1, 1985. Also, information regarding possible biological production of vinyl chloride may be obtained from Or. Freeman Allen of Pomona College. ._ "_ * We would like to continue to receive information inquiries for other candidate compounds and to be kept Informed of your program's progress. Very truly yours. JAA:cas Enclosure jo Anne Aplet Director of Planning CMA 010642 % Additional References on Vinyl Chloride Health Effects draft Albert, R.E. Letter to R.S. Naveen, EPA, "Comparison of Vinyl Chloride Carcinogenic Risks with Risk From Other Pollutants," Washington, D.C., June IS, 1978. Edmonds, L. "Birth Defects and Vinyl Chloride," Proc. Conference on Women and the Workplace. Washington* D.C., 1976, also Teratology 17. 137/19751. Equitable Environmental Health, Inc. "Epidemiological Study of Vinyl Chloride. Workers, Final Report." Prepared for Manufacturing Chemists Association, Washington, D.C., January, 1978. Graniger, R.G., A.E. Walker, and A.M. Ward. "Vinyl Chloride Monomer*Induced Disease: Chemical, Radiological and Immunological Aspects," Chapter II In Induced Oisease; Drug, Irradiation, Occupation, L. Preger, ed., Grune and Stratton, London, 1980. Kuzmack, A.M. and R.E. McGaughy. "Quantitative Risk Assessment for Cotnminlty Exposure to yinyl Chloride," U.S. EPA, Washington, D.C., December 5, 1975. National Academy of Science. Principles of Toxicological Interactions Associated with Multiple Chemicals. Exposures 1981, Z07 p. AD-A093 809/2 PC A10/MF A01. National Cancer Institute (1978). Vinyl Chloride - An Information Resource, 112 p. HRP-0028012/3 PC A06/MF A01. National Institute of Occupational Safety and Health (1977). A Cross-Sectional Epidemiologic Survey of Vinyl Chloride Workers. 50 p. NIOSH Pub. No. 77-177, WTJS No. PB-274. Zlskind, R.A., Smith, D.F., and Spivey, G.H. Health Effects in Children Exposed to Vinyl Chloride. Final Report to U.S. Environmental Protection Agency, SAI-d68-81-!>69, January 1981. CMA 010643 INTEROFFICE MEMORANDUM To From L. B. Tepper J- T. Barr Subject Surgical Removal of Angiosarcoma Corporate Medical Department ILawiUn. OwoUtlUn, o O-- Regulatory Response (VSUUM, OrfHHUtiM, m OlfWIlIMM) cc: G. Bays H. L. Watson The attached article is a report of an apparently successful surgical removal of an angiosarcoma from the liver of a PVC worker. It appeared at Br. J. Surg. 71 322 (1984). JTBrcsb * CM* 010644 V > co 16 April 1985 DRAFT W. v. Loscutoff Chief, Toxics Pollutant Branch CARB Box 2815 Sacramento, CA 95812 Re: Vinyl Chloride Dear Mr. Loscutoff: We are happy to provide some information relative to vinyl chloride in response to the April request of P. D. Ventairlnl. This includes: 1. A paper by me given at the APCA, New Orleans meeting. 2. A paper presented at a CMA seminar in Washington, 9 December 1983. 3. An unpublished review by me on the safety and health aspects of vinyl chloride, which contains several references not in the bibliography with the Venturinl letter. 4. A report from Br. J. Surg. 71 322 (1984) of an apparently successful liver resection on an ASL patient. 5. An article from EST J9 277 (1985) on biodegradation of TCE to VC. Note especially reference 10, Parsons, et. al., for corroborating evidence. You may want to get the Dade County report "An Investigation into the Source of Vinyl Chloride Detected at the Preston and Hialiah Water Treatment Plants" by J. C. Balter, 1983, for more details. 6. A summary of a report on a 1934 bioassay by CIVO. I hope that these are useful to you in your evaluation of this substance. JIB:csb CMA 010645 * ^.y Z-V- Short note* end cue report* v.VuO draftVinylchloride induced hepatijG 2 1 te34 nonwL, oL'ltrurannd fhowA a argte* dennee tumour ofthe rig; , __ angiosarcoma hcpstiic lobe with sresi ot nccri The **Tc hepatic na confirxnt . v#"-' presence ofan ill-datlincd filling defect in the interior pa ofit right lobe with two small defects az the level ofthe hilua. Y.A. Louagie, P. Gianello, P.J. Kestens, F. Bonbted and J.G. Haot The liter coaptncriaed tomography confirmed the iracgrinrci'i} left lobe. A selenite angiography of the celiac artery revealed a hype vascularized tumour ofthe right hepatic lobel/tnrrr/). Department of Surgery of the Alimentary Tract Louvein-en-Woluwa Medical School, and St Luc Hospital. J200 Brussels. Belgium At a ngru thoracophmcnoiaparozomy the icmour was found to t confined to the right lobe. An extended right lobectomy was the performed. The postoperative recovery was uneventful and it patient was sent homewith a monthly administration ofVtnonoir Correspondence to: Or V.A. Louagie, 20 Avenue d'Huert (bte 3). 1150 Brussels. Belgium (I mg IV)and Adriassgcin (150 mg. ro? (V) which vmdbmniaat in June 1981. Repeated coatrob up to September 1981 by fiver TM nr computerized tomography remained wntaLThc patient issriB The relationship between vinylchloride exposure end good health 38 months&ftcrthe resection. human angiosarcoma ofthe liver (ASL) received attention in 1973 when a case of this rare tumour was diagnosed at Pathology autopsy1. The resected specimen was 2050 g. On innciracopiraf examhtatto the main tumour (13-5 x S cm) was yellowish- and spongy m cor.uined cystic and 5iaemorrbn*ie zones. A second seal) Case report haemorrhagic mail was found at the inferior aspect ofthe right lot surrounded by numerals purple TMTM A 39-year old man was first seen in July 1979 wiih pahs in the right upper quadrant. The liver was palpated at the right costal margin. Oral cholecystography and barium swallow were normal and liver (unction tests were in normal limits. From 1965 to 1970 he had cleaned reactors used for the polymerization of the vinylchloride Macroscoptally. the stain tumour showed targe aras ofnextus and haemorrhagic psewdscystic s^cts {Firmer2L These spaces w* surrounded by areas ofdense vascular proliferation. The rinemii were lined with varixtJy sized irregular' szmoinatous ccfla wr hyperchromatic nuclei Elsewhere, blood-filled qTM we monomer in PVC and was thus exposed to high amounts. He was admitted 3 months later with persisting right upper quadrant pain, loss of appetite and fatigue. The liver edge was by then hard and 4 cm below the costal margin. The E5R was accele rated (80 mm/h) and alkaline phosphatases and GGTP were elevated. Cartino-embryonic antigen (CEA) and a fetoglobulin surrounded by sarcomssous cells. The sarcoma cells cpcompsrai adjacent liver cells ta bile duoules and infiltrated the pane chyma. The pathoiogjnl diagnosis of nsuhkemric angiosaieon was made. The rot of the lher was normal except for sob mederatefy enlarged portal tract*. Progressive fibrosis sepmafe hepatocytes at the margins ofthe portal tracts from adjacent hepai Figure 1 Stledne auvu'V'ophv el the im-hac unerv. TV hvpertu'i ui,m:eil luimmr is supplied hr (in anieriiir brum ii turrossi i>l the Fiuure 2 /V.i ri'i/r'/rr the muin nirrumr >k,mirte Mb Pile,I spuees surnnui*A i! he ^urntinuuus utiv 1 luemuitiKiim no * :pi;, Short not** and cxsc report* cord edit. AniNocarvo^is and anisocytosi* were frequent. A crowsection biopsy of the left lobe showed normal tissue with slight hcpaioeytie anisocaryosis. The lymph nodes taken from the liver hilum were hyperplastic. The main features ofthis tumour were iu multicentricity and the presence ofmild fibrosis. Discussion The occurrence of liver angiosarcoma in vinylchloride polymerization workers was reported in 1974***. Prolonged exposure and long interval from initial exposure is required before liver disease becomes apparent. The average interval is 12 years (range 6-29)*. Our patient was exposed for 5 years and became symptomatic 14 years later. It is a rapidly progressing fatal disease, especially in adults. The clinical features include rapid liver enlargement with haemorrhagic ascites, fast deterioration and caehexia usually with death within 6 months. The treatment is disappointing and chemotherapy and radiation of palliative value only. If the diagnosis is made early, the disease is toeaiized and there is no associated liver fibrosis or portal hypertension, resective operation might prove to be curative. However, there are few reported of successful operative removal of hepatic angiosarcoma and the longest survival has been 16 months*. ' In our case the tumour was oontined to the right lobe and ' there was no sign of the extensive fibrosis. So far the patient ' is apparently free ofdisease after 38 months. This is. to our knowledge, the longest published surv ival. References 1. Creech JL Jr. Johnson MV. Angiosarcoma of the fiver in the manolacturc of Polyvinyl Chloride. J Ckxvp Med 1974; 16s 150-1. 2. Block JB. Angiosarcoma ofthe liver following vinyl chloride exposure. JAMA 19M:2I9-.S3M. 3. Heath CW. Flak H. Creech Jg. Jr. Characteristics of axes of angiosarcoma ofthe Inner among vinyl chloride workers in the United Slates, . lee .V F. lew/Sri 1975:246:231-6. 4. Adam YG, Hwvos AGl. Hajdu SI- Malignant vascular tumours ofthe liver. A** 5tanr1972; ITS: 375-83. . Paper accepted 27 July 1983 * ! i CMA 010647 % nvroa $cL T*ch*oi. 1115. 79. 277*280 face morphology, there was ao evidence that the surface nodules were composed of any special, unique element. These particles from these particular collections seem to be quite similar to the micrometer size panicles emitted in the ash (2). It is not dear, therefore, why the collected aah shows a bimodai distribution of micrometer size partides centered around 5 Mm and submicrometer size par ticles centered around 0.5 mea. X-ray photoelectron spectroscopy (XPS) and depth profile XPS have been applied to these samples to determine surface composition. Results cf these analyses will be presented in the near future. Literature Cited (1) 'Planning Studies for Measurements ofChemical Emissions in Stack Gu*t of Coal-Fired Power Planta*. Report pte- pl fw ET|lJ>4 V*. 4by sAithere R innaana. Bmagffham AL R^tnA. (Vj.,,.k.- T,k Columbus, OH. and Roth Associate*, la*, Rocha (EA-Z892. Research Project 1776-1). March 1983. (2) Kauifcarr. N.; Uchtman, D. Environ. So. Tethruu 18, 544. (3) ValkovSd. V. "Traci Quanta in CoaT; CRC Ptur Raton, FL1983: VoL l. pp 83-177. W Diamond. Lopu-Floru. F. Proe. Symp. tf. Mate Sot. 1781, 34. (5) Rahn, K. A^- Lowenthal. D. H. Science {Washington, 1984, 223. 132. - Received for rtzdem April 23,1884. Revised manuscript rot* September 4. 984. Accepted October 30.1S84. This mar* supported by Electric router Research Institute Contract 1625-1. Anaerobic Degradation of Trichloroethylene in Soil Robert 0. Kleopfar,* Diane M. Easley, Barnard B. Haas, Jr., and Trudy Q. OaM Region VII Laboratory, U.S. Environmental Protection Aganey. Kansas City, Kansas 86115 Oavld E. Jackson* Ecology and Environment. Inc,, Kansas CKy. Kansas 66101 Charles J. Wurrey Department of Chemistry, University of Missouri Kansas Oty, Missouri 64110 d When trichloroethylene (TCE) isotoplcaily labeled with one 13C atom is used and fas chromatography/mass .spectrometry is employed to monitor the production of *l,2-diehloroethy!ene-uC] (DCE), it has been demonstrated that reductive dechlorination of TCE takas place in the soil. Microbial involvement in this process is indicated sines unsterilized soil samples yielded up to 78 ppb of labeled DCE while sterilized soil samples produced none. Isomer specificity was also found; only 1,2-DCE was produced--no i.l-DCE was observed. Introduction Since trichloroethylene (TCE) is a major industrial solvent (234000 metric toes produced annually, worldwide (J)) used for degreasing and cleaning metal parts and electronic components, it is perhaps not surprising that TCE has found iu way into the environment In fact TCE appears to be widely distributed in the aquatic environ ment(1). However, the environmental fata ofTCE has not been well documented, and considerable controversy still crista concerning its behavior in environmental matrices. Early literature references have concluded that Q and C? halo* genated hydrocarbons are not metabolized by microor ganisms (2, J). Mora recent studies, however, are split on the issue of whether TCE is biodegraded (4-7), with one research group reporting both *no appreciable anaerobic degradation* and 40% degradation of TCE in similar methanogenic cultures (8,9). la s very recent publication. Parsons et aL have dem onstrated that tetrachloroethylene (herein referred to as perchloroethylene, PCE) is reductively dechlorinated to 'Pftoi addreu: Dtpartaect of Civil Enjiawrinj. University o." Illinois, Urbans, U. 61501. kJ- TCE, dichlqroethytana (DCS!), and vinyl chlSride in Florida muck/surface water microcoams (10). Whether TCE, which was present a* a L6% impurity in the PCE study, was similarly biotranafotmed was not directly investigated but was implied by the results for PCE (10).____ Therefore, in order to detannine whether TCE itself undergoes biodegradation, ww have undertaken a study using TCE with singia atom "C isotopic labeling, soQ from a TCE spill site in Dea Moinas (II), and vary sensitive pa chromatography/mass spectrometry (GC/MS) analytical techniques. Sines DCE-^Cj co-.uld only arise via a toil or soQ-miezobwinducad reductive dechlorination ofTCE-"Ci, this expariaental method should provide concrete evidence in support of such a pathway. 'The results of our inves tigation of this problem are reported herein. Experimental Section Materials. Since any microbe* present had probably adapted to TCE. soil temples ware collected at the Das Moines site, at depths of 1-2 ("A* samples), 6-8 ("B* samples), and 15-17 ft ("C" samples), by using an 18 in. long by 2 in. o-d. split barrel sampler (11). These soQ samples were analyzed by GC/MS Cat the presence ofTCE end DCE. In spite of the TCE sludge application having been discontinued in 1979 (if), all soil samples contained 6 ppb of `native* (ualabeled) TCE. No DCE*s were found in any soil sample. (An analysis of the Dea Moines TCE siudgs itself by this laboratory and by an independent testing laborttory showed very high levels of TCE (3000 ppm), but no DCE was detected.) TCE-l5Cj was purchased from MIerck Sharp St Dohme Isotopes. Single 1SC labeling was used to produce molec ular and fragment ion peaks which did not hav* *w m/s values as the "C',r'" Or '> ' CHA 0 1 0 6 4 8 aI l A DRAFT Iil.g a--^ i i a a1 ! i i ngw* 1. Representative nn ipwi of frfcMoreethylene and 1.2 Ochtorosmyfne: (A) fcteUoroeetyfcWK OT lilrtasoeltivlww "T ; ec) U-SeMoroethyiene: (0) 1.2 <SehtorosmyfoqC,. contamination Volatile organic standards warn purchased TCE to DCE by the soybean meal Itself or any `foreign* from Supelco, Inc, and *rt diluted appropriately with microbes and to monitor adsorption of the TCE onto this methanol to contain 200 ppb of TCE and DCE. Soybean organic matter. (3) For tha 6-week samples only, vials meal was obtained commercially. containing sofle A-C. soybean meal, end water without the Methods. Five grams of soil from each depth was TCE-uCi spike wx prepared aa method hU"W placed in 5-mL amber vials which had been baked at 150 For the analyses, the contents of each vial wars trans *C for 3 h to remove any adhering volatile organic com ferred to e 25-mL vial by using organic-free water to pounds. One gram ofsoybean meal was added to each vial eliminate headspace again, sealed with a Teflon septum, to ensure anaerobic conditions, and the vials were then mixed, and allowed to settle. Fiva mimiiten of the su filled with `organic-free* distilled water (which had baan pernatant liquid waa then removed for volatile organics 2 purged with nitrogen). (Organic-free water is distilled, passed through e carbon column, and checked for organics analysis using a Fmzugin Modal OWA GC/MS and standard purge and trap mezhodnlo^ (12,1J\. Detection by using GC/MS methods.) The vials were seeled with limits for TCE and DCE by this method are estimated to TeQon septa. Semples to be sterilized were placed in an be 1 ppb. autodavt for 30 min at 15 psL Each vial was then injactad CMA 010649 with 10 Mg of TCE*13^ (2000 ppb, or Mg/kg). Duplicatas Result and Discussion of each sample were prepared. The sealed vials were AQ compounds involved in this study were identified by transferred into COj/Hj Anaerobic-Paks (SBL, Division their characteristic GC elusion rimes and mass spectaa. of Sioquest), which were then placed in an incubator at (Figure 1 shows the observed mess spectra of labeled end i 23 *C. A* much as possible, the samples were kept in the unlibeled TCE end DCE.) Both qualitative end quanti dark to avoid photoiytic degradation of the TCE. Subsets tative identifications were effected from several selected i of the vials were removed for analyses at 6.17, end 41 weeks. ion mass chromatograms for each substance: Far example the ions at the listed m/s values were used for the analyses i tt Control and method blink samples were prepared as follows: (1) Vials containing only organic-free water, both of the following compounds TCE (m/x (95.97.130.132, 134); TCE*,JC, (m/r 96,98,131.133,135); DCE <m/r SI, i with and without tha TCE-uCj spike, were prepared to 63, 97,99); DCE-"Cj (<n/z 62.64,98,100). N confusion < monitor volatilization losses and to check for cross-con resulted from peaks hiving the seme m/x values for these ! tamination throughout the procedure. (2) Vials containing only soybean meal fbeth sterilized and unste-ilizedl and substances since each compound (exclusive of its isoto- <i* p ^ t*r -* * -- e % Table I. Aaouste Lc/kg) of 12-DicUoroeihyleoe-uC| Produced by Dcxradatlo'o of Trieh!orootbyIn',1C| La UaaurilUed Soils time, w**ke oil A* o3B* on c* 8 8 7u 17 28 31 8 41 78* 27 25 'So* text for toil depth detifeationa. Results m averagae for duplicate samples; notes were 50%. *No duplicate value was obtained. for the 13C sad "C compounds were identical. This as sumption appears to be valid since we observed natural abundance C peaks in the unlabeled TCE and DCS mass spectra having 2% of the intensity of the corresponding "C peaks (theoretical value 12%). The pertinent results of this study are discussed as follows: (1) In ths water-only simples, no cross-contamination was observed at any stag* of the experiment. Therefore, no exogenous substances appear to have entered the sam ple vials. (2) The vials containing the water with the TCE-^C, spike showed considerable variability in their percent re coveries, indicating substantial and inconsistent volatil ization losses of the TCE. We were thus unable to obtain reliable quantitative data measuring the conversion ofTCE to DCE by following tbs rate of loss of TCE. Any ex periment that measures only ths loss of TCE appears to suffer from these volatilization problems and from ad sorption problems (to be discussed next). No degradation products of TCE-l3C, were observed, in these water and TCE-13Ct samples, so soil or microorganisms contained in the soil must be present to effect this conversion. (3) In the samples containing water, soybean meal (whether sterilized or not), and the TCE-llC, spike, no conversion of TCE-"Ct to DCE-"Ct was observed. Thus, these control samples eliminate the soybean meal as a potential source ofTCE degradation. However, adsorption of the TCE on the soybean meal was significant From 50 to 60% of the TCE spike was adsorbed after 6 weeks. As seen from the sterilized soil samples (where, except in one case of incomplete sterilization, no conversion of TCE to DCE occurred), another 10-15% of the TCE wee ad sorbed on the sod. Thus, adsorption losses pose another major probitm in a study like this. Experiments that monitor the Va> of, for example, TCE and attribute it solely to degradation are potentially suspect, particularly if cars is not taken to account for volatilization and ad sorption losses. (4) Tha 6-week method blanks (containing water, soQ, and soybean meal with no TCE*Ci spike) showed no generation of any substance (TCE or DCE, labeled or unlabeled) not already present in the soQ itself. (5) Conversion of TCE-13Ci to DCE-^Cj was noted in all unsterilized soils. Table I summarizes the amounts of labeled DCE produced. As seen from Table I, s general and gradual increase in the amount of DCE-13Ct produced occurs with time. (Of course, due to adsorption end vol atilization losses, the amounts of DCE-uCi actually pro duced are no doubt Larger than those reported here. Actual amounts of TCE -- DCE conversion in "real* soils may be even larger than those reported here, since the soybean meal edded to ensure anaerobiosis may well have been a more attractive energy source for the soil microbes than the TCE. Indeed, breakdown products of the soybean meal were also noted in the unsterilized sail samples.) soil samples showed thqpaesfnqp fsafgib of DCE-UC Hiis may, however, be tSe result of xn incomplete star .Ifcation since ths was only observed for one of tha longe time samples. Since conversion of TCE-UC, to DCE-^j occurre almost exclusively in unsterilized soils, mimobial partic pttion seems certain. Soma caution should be exercise in drawing this conclusion, however, since Kaufman (Jhas reported that autoclaving changes not only ths hi logical properties of the soQ but also its physiol sz chemical properties. Nevertheless, on tha bssis of oi results for TCE and those of Parsons at ah (10) far PCI it appears that the degradation of TCE to DCE m tha ac is indeed of biological origin. (7) Only U20C&Ct mm produced whenever TCE-*1^2 3 4 5 was degraded. No U-DCE-^C, (which elutes more rapid than 1,2-DCE) was found in any sample. Under our * perimental conditions, c* and trsna-1,2-DCE coeluu (and cannot be differentiated on the basis of their ma spectra). Thus, we could not identify which geometric isomer was formed, or if a mixture of the two was pr duced. (In their study of PCE biodegradation. Fanoi *t aL (JO) wars able to separate the cxe and txans isome chrematcgraphireHy. They found, that cir-1,2-DCE significantly fswad over die txans isomer.) Summary By using TCE isotopiceDy labeled with ( single C atoi we have shown that TCE b definitely dechlorinetad in t soil to 1.2-DCE. Isomer specificity eras also observed; t 1,1-DCE was detected. The TCE -- DCE degraded appears to be biological in nature, sines soil samples wfai had bean sterilized exhibited no such conversion. Since it has hems shown that microbes that have adept to degrade one member ofe homologous series have el simultaneously adapted to degrade ocher members of same series (15>, tbs possibility exists that DCE os ' Anther biotransfismed into vinyl chloride in soils. itcring date at the Dee Moines site (21} and elsewhere (It this work sad the work of Parsons et eh (JO) all strong: support this DCS -- vinyl chloride contention. Conak ering the well-known carcinogenicity of vinyl chlorid Amber research along these lines is definitely warrantet Acknowledgment* We grstafiiSy acknowledge John Geode (of Ecology a Environment. Inc.) for obtaining the soil temples and C Bailey and Angelo Caxesaa (of ths Region VH Eavirt mental Protection Agency Laboratory) for prowidi technical assistance. Registry Nw TCE. 79411-6; DCE. -un-S&O. literature Ciled CM* 010650 (1) 'Ambient Wetar Quality Criteria tor inowivwjw. U.S. Environmental Protection Agency. 19S0t SPA 4 5-80-077 OTTO cPPSl-117871). <2) Pesx*on,C. JLMcConnell.G.Proe.JLSoe.London, B 1975,139. 305-332. (3) McConnell,G.;Ferguson,B.MiPeenon,GRStdmot 1973. 34.13-18. (4) Van Dyke, R. A. Environ. Health Penpeet. 1977, 121-124. (5) Wilson, J. Enfield. C. Dunlap. W. J.; Coeby, R. Foster, D. A.; Beskin. LB.J. Environ- QuaL 1981, 501-506. (S) Tabak. H. H.; Quave, S. A^ Mashni, C. L; Banh. E. F Wear Po'.iut. Control Fed. 1951. 2,1503-1518.^ Emren. ScL Technet 1985, 13, 280-282 (8) Bouwtr, EL Ji Rittmn. B. EL; McCarty, P. L. Environ. So. Ttchrwi. 1961, 15,596-599. (9) Bouwtr, . J-; McCarty, P. L. Appl Environ. Microbiol. 1983, 45, 1280*1294. (10) Persons, F4 Wood, P. EL; DeMarco, J. J.--Am. Water Work* Artot. 1984. 76. 56-59. (11) Caofla, J. `Field Inveetigetioni of Uncontrolled Hazardous Waste Sites*, 1983, task report subsittad to the Environ* mental Protection Agency. Contract 68*01-6066. (12) Easley, D. Keopfer, R. D.; Canaan, A. \LJ. Assoc. Off. AnaL Chem. 1951. 64, 853-656. (13) Longbortoa. J. EL; L'chtenberg. J. J. "Methods for Organic Chemical Analysis of Muaidpal and Industrial Wastewater"; U.S. Environmental tetita <-82-057. Method 634. 982; EPA 600/ (14) Kaufman. D. D. In "pasdedas in Soil and Wster"; Coensi. W. D, Ed; S5SA FubEaheru Madison, WI, 1974; pp 133-202. (15) Stanier. R. Y. J. EasierioL 1947. 54,339-348. (16) Sprague. R- T. Pact, 3uekely, Srhuh and Jeiaigaaenvm; CO, private 1983L Received for mans Avgust 22,1953. Revised mttrmeeripcreceived May 7,1984. Accepted August 9,1984. Mention of product* owa manufacturer> is for idmriflection only and dote not imply endorsement by tha US, Environmental Protection Agency. Gas-Ph^so Hydrogenolysl* of Polychloroblphonyls Jeffrey A. Mahfon, Patar Muidar, and Robert Louw* Goriaaus LaboratodM, The University of Leiden. 2300 RA Leiden. The Netherlands Chlcroarcne* in an atmosphere of hydrogen are thar* aally dechlorinated to yihM HC1 and benzene as major products between 700 and 925 *C, with residence tunas of ca. 10 a. PolychJorobiphenylp (PCBs) are both dechlorinatad and split into chlorinat about twice as fast as dechlorinirioa. Themalhydro* renolysis, which occurs via radical mechanisms involving H atoms, may therefore ba coastdcremps a UMful "**rbpd for workup of (toxic) chlorinated Following studiss on thermolysis (1-3) a^d on several free-radical gas-phasa aromatic t . (4), cyanation (J), nioation (6), and oxidation (71r-we art nowengagad in tharmal convarsionsof benzeneapd de rivatives with hydrogen. Within this category, cracking* of chlorinated aranaa dasarm special at ; In general, reaction 1 is of potential mtereat as a methi Ar(R)Q + H*-- Ar(R)H + HQ (I) for dechlorination of (highly) chlorinatad industrial waste materials etc Thermolysis of chlorinated benzenes in ah excass of H* (quartz flow reactor, atmospheric pressure, residence time 5-15 s) proceeds smoothly at 750 "C and shows very high degrees of conversion (HQ ibrmstka) at ca. 900 *C (). Sooting is unimportant'evsn at 900 *C provided that tbs Hsmrtnt molar mtaka ratio is above 10. Aliphatic and oleffnlc chlorides, in gsnaral, react much faster than chlorobenzenes (5). Polychlorobiphenyls (PCBs) have found widatpread application, especially ss tranaformar oil, its use and dis posal entailing considerable environmental problems. W therefore thought it worth while to examine tha behavior of PCB in hydrocracking (eq 1). Our observations, in cluding those on appropriate model compounds reported below, confirm our expectation that PCS can be com pletely converted into HQ and non-chlorinattd organic products, mainly benzene. Hydrocracking thus constitutes an environmentally clean alternative to incineration. Representative examples with Arocior 1248 (Q * 48% wt) are outlined in Table L. That conversion of PCB is essentially complete and is illustrated by Figure 1. De chlorination of chlorobenzene (PhCl) is 97%; monochlorobiphenyls are seen in minor amounts only, biphenyl comprising ca. 0.7% on the PhG feed. This biphenyl stems from PhCl--or better, from benzene made Table L Thermolysis ( PCS la Chlerobenseaa will* Hydrogen? r. *c r, s ^ __ conversion* o4PCBS.1t FbCV-% PbOs*% Ph** ClPh**' % PhiLPbQ solar i l 7T5 U <m.X0> U u 04)10 0463 C1059 3 790 U 2* LS 13 003 (US 34 80S 63 70 IS ouo 0040 0.13 032 878 TO 0l2 0.60 <040 33 'Spiraliaed quars zabtihr Hem rtactor (35a,4 Inflow (amol/h): H* 221 a 4; PbQ. IflL3t Aroehior 1246 (049): dorsdow of run* 40-48 mine ptodnet mOwted in a map cooled with liquid N * By GLC with Ph3r a interned iteadard; total of --<'-- area from dicfalorobiphaayf on (maados tee > 27 mia. Figuzw I), fuming response to bo isd*pendent at chlorine ------ These numbers parallel theeo toe degrees at deobioriuadeo of PbQ. PbOf or PbQ) nadir the man rmrlitkiie 'Mole percent em PCS \bX0i. `Mole peremit on benntnee-oat. t--. -*rr^o-f*----vt wpera. %|c ran I. 40&36; ton t 3737.36* run 3, 'Isomer distribution %). wm ^ : ran 2.3*3843; na 3.343338. `Confirmed by GC with Tha trichlorobenzenes dearly stem from splitting of PCB secoemt .far ca. 6% of tha Aroehior feed, Chlorol i produced ria tha tame route but is ob scursdbyits is diluent. Its * can ba -- from what is about the eampodticn of tbs PCS mixture. Spt tha identified portion of Axocblor 1248, ca-half; is ~ of thn following ratios of phnyi units PluPhChPhCl^phQ%- OU)2:ltl5bOLl6. If changmt due to the small dagri of dachlormaxioa are neglected, PbQ from PCB would ` ba 1:0-3 + 016) x 6 = 4%, so aa to give a total degraa ofsplitting of about 10%. PhCl alone yields ca. 6% of HCl imder these conditions *o this mode of hydrogenolysl* ta about twics as fast as dechlo rination. \ Aa we have reported elsewherk (6, 9), methane in alst^H formed, ranging from 0.2% (run Irtp 1% (run 4) on Phu^^ feed; small amounts of C^H* and C-H and traces of C*H* are also produced. v Simultaneous splitting and dechlorination of PC3 will cause the yields of PhClj and PhQ- to pass through a maximum with increasing temperature. The same holds CHrt 0 1 0 6 5 1 THE DOW CHEMICAL C October 5, 1984 THE OOWf CENTIH MCXANO. MCKICAN 4*640 Document Control Officer Management Support Division Office of Toxic Substances (WH-557) U.S. Environmental Protection Agency 401 M Street, S.W. Washington, D.C. 20460 AIRBORNE Dear Sir/Madams Attached for your information please find a copy of a summary of a report on a Lifespan Oral Carcinogenicity Study of Vinyl Chloride in Rats which we recently received and which I discussed with David Williams on Tuesday, October 2, 1984. This study was conducted in Europe by Civo Institute* TNO and was sponsored by Verband Kunstofferzeugende Industrie E.v. (VXD. It is our understanding from VKI that the E?& will soon be receiving a copy of the final report, we do not have a copy. er Upon review of this summary, we have been unable to determine whether this study presents any substantial risk information under the EPA's Statement of Interpretation and Enforcement Policy. 43 Fed. Reg. 11110 (March 16, 1978). It appears from the minimal data presented in this summary that tfcie study is corroborative of effects already documented in the scientific literature. Sincerely# Attorney W 2030 Willard H. Dow Center 517/636-0933 Attachment occ: F. D. Hoerger, 2020 KHDC d. Schumacher, Horgen CM* 010652 * SUKMI / 1. Tha ml uteluiitleltT i( vttjl tUr* hmmc (VOt) mi tiulm la a Ufaapaa ettey (ltfjnaha) vlth fita gravy* af Ylatac rata, aaah teaalatlag af 100 uIm ate 100 fmlu, iai>ft far tha tar-teat |ti^ teteh eavyrilte >0 uln ate JO (miIii, IQ ava itel*llM(4 caryatatltg fflplwl eum<! (mj itk i high rot MMMI lata the Hit, ft* flat vaa yravlfef Wally far ?erlte af 4 CIUICV tlaa keurt, vhtratt fate u itiMtiaa (slag tka ethar 10 havra. Tka tee af till way af eral fOl OUtliaatln reaelttf la tka liUarfai ttyeevre latelai 0 (caattal), 8.011. 0,11 amt 1.3 ag TOl/kg Vtey night/ley, Aa uut tiuiil (mp aM 190 ritt/ut aaa kaanf la a ararate teeau Ufltliaal tetalLlta fteape af U ula ate 10 faaala rata, aaeh ta> CtlTlag tha aaaa umaiK aa tka vaa itMfi vara aaa4 far litaiat> aaclaar af glutathleaa latelt la tka lint after > ate II vantka. Obaat*atlaaa vara aaft af gaaaral i^atttea arttllry, gtawtk, fate latakai thravWcytt cavat. ytitknakla tlaa, ilwitklm 1avala ta tha Uwr, graaa pattalaty ate atmittfla lutalao' af tba lint aa4 af all greatly ttitkU Mawn ar rruMakU fara ta tha aMaalaal cavity, the glatea af Zratal ate tka aiiry (Latea. 2. Oaaatal haalth, hahatlaar( hafy valgbx ate fate lataba vara tat i4* taraaly affactil ky tha teat tvhataa--. 1, la tha aacate half af tha aayarlaattal ratete, vartallty la tha ten taattal gravy vaa kfghar tbea la. all atkar grmrye. TMi a aaat yrakr- ahly tua ta a high iiclfiui af cknall raeylretety tlaaeee la tha aatta aaatral grant, ta tha (ital iu|t af tea atter, tha aartellty la tha tap-faaa [ramp am* allghtly htgbar them la tha 1aver 4aaa graaya ate tha taacrvla. 4. nrakatytuam^nitkaiMl tlaa ate Unt tlituklm lavala IU at thaw Uiiaaatnilitat HSIammma laaag tba gratipe. CMA 010653 J..A diiftf Mldt lauiut af ;rtlT twaiicaua, Ilfr +* ul* vat faual ta W(t taltt anrf f<l if tka wHt* mn tkaa f.m ; t( th ithae jitutt. Ksnanf, it fnttw at lk tpM trttt tha Ltal4aaea af trail. erica t. Xleraacaait iuileitlta af :tc llwftill ftlffartMn. bapatls t/IH, fKl tf ctilultr iltatatlat tUttie 4uXt id uwttMt ft t> tr<>'iw tuW tt tfci istiMl trvt. Xtnmf, U^tilt nlwtt fatal U Ht uli al tva ftttltt tf tU ttylat itw*. >ktrui mm tuck ciaaurt tt iicMtttrN U *mj t/ tkt tckct trtwf*. ** aaakar it citwli Wtrtu fact t< itUtlii dtcfcttw U tta Uwt uu dtt tmtulccUr tliiitictcdy ttcwcuk U ftatUta tf tbt !<*< I rou-y u cn;ttU ca cntnlt. U Otitite, U Itultt Ms mTU ulit, tk> liditiiu if Uc|h;dt tut if nllttir dtinttw la the liver <tt iHtluictllT t:iit`.ur.tli Mtlut la hath tfaa - tof tin ilWin tiu| ikti la tka mwil atw. 7. tkm i aa ifttnci it VOt-fttCUi ittictiii tkt ImUmm of ik 4e*tel uiiUclttMi tr tkt 1771 tail ImMiim if imiq (leal it* mmi a Zpetti |1m1 tutnr vat facial. t. Xt v* malultl tktc ttsltr cka cMltint if eke ftteaeat of*rtitiit - Ta at a IimI af 1,3 <Ac Mir mt|tit/<cr liteti Mitlml! ini mmiiltittc ckcstit 1 Ik* Ur it rati, VQC at a lawl af 0.13 <At kelr Mal|fct/lT ay lad ta vara ftaala rata kitrtii !wl af uUultf dtiTttlti ti_ai Uttt, ~ 7Q a* lavaLa af 0.01* ay 0.13 ag/kt bttr *f revel* la aa lacttiMk luUaui af kttiiktlla tut at cal Talar ilttncin tt tbt Liver af fcatala rata, * M3 t( *Qt/k* fcaty Mlfkt/tif ta a *ia;iiiMimauwia-itti laval* vltk taaaaat ta the laluetlta af twa--r tt rata. CM* 010*54  <).: -a f. tick mlMttM fcataC a* ch ttwlu ( lk< rriMM tu atuCy C ul| lid (((MU tti initui at tk UmW mUJ tfrllr4 aaa i 1mn( uultltUr ( liwu ( tU urctwtulc tttltm ( TQf U cwurtm wick tact, Mlutu Out tha uk<( rlak / * UUI7 uitea aral lailT letaka at 0.1 pt VCK jar yaraaa hc Cay eaa ka practically U|l*cliC. CHlS 010655 4 RISK MANAGEMENT OF EXISTING CHEMICALS Proceedings of a Seminar Conducted December 8-9. 1S33; Washington. D.C. Sponsored by: & CMh 010A5A Chemical Manufacturers Association avels for subIn each ease, npUes a regulaacceptable to ial carcinogens, id EPA have all 'Ulion ought not values represent phthalate esters, not be regulated. .*o be subjected to significant'popuilcs t regulatory , "Review of Data 'ormaldehyde and .1982. ;ologv and Pharma- CHAPTER 10 11 f ;U VINYL CHLORIDE AND TSCA John T. Barr Air Products and Chemicals, Inc.1' INTRODUCTION The well-known regulatory history of vinyl chloride and its role ss s bellwether of current regulatory philosophy makes it a useful paradigm for examining the relationship of existing laws and Che Toxic Substances Control Act (TSCA) for control of chronic hazards. To this end, we will first review some of the highlights of its regulatory history, and then engage in some speculation as to the response these events might elicit today under TSCA. INDUSTRIAL AND COMMERCIAL USE OP VINYL CHLORIDE Vinyl chloride became of industrial Importance about fifty yean ago, approximately a hundred yean after its discovery, when Semons discovered that its polymer could be converted into useful articles by plastization with phthalate esters. Commercial develop ment began first in Europe and then in this country in the late 1/ Air Products and Chemicals, Inc., 1983. 129' CMA 010657 t i t m f : l' * i` j It thirties, largely using existing rubber processing equipment, for it was rubber which it Initially replaced in the market. For the same reason, the use of polyvinyl chloride (PVC) was sequestered by the government during the war years, and it was not until the early fifties that widespread consumer applications developed. PVC is now a mature product, and its growth rate falls in step with the Gross National Product, Presently, about sSr billion pounds are used annually in this country, and about four times that in the world. Some of the broader toxicological attributes cl vinyl chloride (VC) were recognized in the thirties. It was knows to be an anes thetic, but problems with cardiac arrythmia prevented its use in that application.^' As pathological techniques improved, industry scien tists recommended in the early sixties that exposure be limited to 50 ppm. because of temporary liver enlargement in animals at that level,*' but the American Conference of Governmental and Indus trial Hygienists considered this overly conservetin and accepted instead the 500 ppm recommendation of Harrard scientists.'*/ Tills was the value adopted by the Occupational Safety and Health Administration (OSRA) in its formative day*. Also in the early sixties, the European industry recognized among Its workers a disease termed aeroosteolysis, AOL, which is a degenerative disease of the bone tufts, particularly in the fingers, that is accompanied by Raynaud's phenomenon.5^ An extensive cpfr- 2/ W. F. ven Oettigin, The Halogenaied Hydrocarbons, Their Toxicity and Potential Dangers," Public Health Service Publication No. 414 (Washington, D.C.: U.S. Department of Health, Education and Welfare, 1955). 3/ T. R. Torkelson, F. Overs, and V. K. Ecrve, "The Toxicity of VC as Determined by Repeated Exposures of Laboratory Animals," American Industrial Hvgiene Association Jemal. XXII (1961), p, Z5T. 4/ American Conference of Governmental and Industrial Hygien ists, "Documentation of the Threshold Limit Value, 1963" (Cincin nati, OH, 1963). 5/ S. Sueiu, J. Drejman, and M. Valaskai, "Study of Diseases Caused by Vinyl Chloride." Medical Intern- XV (1953), p. 967. i CMA 010658 % \G CHEMICALS rocessing equipment, for it the market. For the same VC) was sequestered by the it was not until the early nations developed. PVC is rate falls in step with the t six billion pounds are used mes that in the world, attributes of vinyl chloride was known to be an anesi?e prevented its use in that s improved, industry scienhat exposure be limited to gement in animals at that r Governmental and Indusconservative and scented Harvard scientists.4^ This tional Safety and Health ys. -pean industry recognized steolysis, AOL, which is a artieularly in the fingers, enon.5' An extensive epi ted Hydrocarbons, Their ieslth Service Publication lent of Health, Education :o*.ve, ."The Toxicity of VC of Laboratory Animals," Journal. XXII (1961), p. al and Industrial Hygien"it Value, 1963" (Cincin- :ai, "Study of Diseases XV (1963), p. 967. DRAFT yhttl chloride / in demiological survey here and in Europe found about a hundred possi ble cases which were associated closely with manual cleaning of reactor walls between polymerization batches, but neither the pre cise etiological agent nor the disease mechanism was identified-1^ An attempt was made to reproduce this disease in rats by the medical department of one of the European producers. An exact duplication of the human disease was not seen, but many ot the rata developed tumors at numerous sites. The reporting of this fincRng by Viola7' in 1970 evoked little interest in the regulatory community, possibly because of the very high doses rased, several thousand ppm, which were frankly toxic to the animals, and the fact that the tumors were largely metastatic from the ZymbeZ gland, an organ not present in humans. Nevertheless, both the European and domestic producers formed consortia to perform bioassays at lower concentrations and also began epidemiological surveys of their employees. -r Preliminary results of the European bioassay became available first in early 1973, and showed tumor development at much Lower concentrations in organs which do have human counterparts- This result was transmitted to regulatory officials that summer, and industry screening of employee records was intensified.8^ This re sulted in the recognition that winter by an industry medical director of a cluster of three rare liver tumors termed angiosarcoma, ASL, la the employees of one facility.9' The reporting of this fact to 6/ V. A. Cook, et aL, "Industrial Hygiene Evaluation of Thermal Degradation Products from PVC Fetus in Meat-wrapping Opera tions," Arch, Environ. Health. XXII (1971), p. 74-. Also, B. D. Diman, et all, "Occupational Acroosteolysis I, An Epidemiological Study,* ibid., p. 61. <. 7/ P. L. Viola, "Pathology of Vinyl Chloride,* Medicine d 1 , Ltvoro. LXI(1970), p. 174. 8/ A. W. Barnes, TCI Ends Its Silence cn Vinyl Chloride,* Chemical Engineering News. (July 8, 1974), p. 21. 9/ J. L. Creech and M. N. Johnson, "Angiosarcoma in Workers Ex posed to Vinyl Chloride as Predicted for Studies in gats." Journal of Occupational Medicine. XVI (1974), p. 150. CMA 010659 * ___ *'.5CAs*E?S:*gi"ESi',sls: *es I-^.- tr&n&gS. ~^;\~ ^;c^`v^%.v^r^r*-' - .*- *- "-.':-r:ZZr'-^-.~Z c> -->. :*-\r-"Mr "T draft 132 / RISK MANAGEMENT OF EXISTING CHEMICALS government officials led to the current regulatory status of vinyl chloride. It also led to a virtual explosion of research on the chrooi toxicity of VC. The body of scientific literature on the oncogenicity of vinyl chloride is as large es that for any other substance. It is recognized that VC is a classical procarcinogen. Metabolism by the mixed function oxidase in the Ever converts it to the ultimate car* cinogen, an epoxide. Detoxification of this intermediate by the suifhydryl group of glutathione or ether proteins removes the toxic potential.10' Both of those mechanisms are saturable.11' An over* load of the metabolic step asstres that the vinyl chloride will pass through the Ever end some will be metabolized in other organs* An overload of the detoxification step allows escape of the toxicant into the sinusoidal passages of the Ever where Interaction with th chromosomal protein causes ASL to develop. An overload of both mechanisms can lead to tumor development outside of the Ever, as is seen in mice and rats at very high doses. Despite the lazge data base, however, information on the precise mechanism of these vari ous steps still is lacking. We do not even imdestand why some per sons respond with AOL and some with ASL, but none with both diseases. REGULATORY STANDARDS OSHA proceeded promptly in early 1S74 to set an emergency temporary Emit of 50 ppm for worker exposure, and later that year reduced the Emit to one ppm, the current figure. Industry was given a grace period during which respirators could be used to meet this requirement, but now that level must be met by engineering prae- 10/ W. K. Lelbaeh and H. J. &usteer, "Advance in Internal Medicine and Pediatrics " Saringw-Verlsg. XLV3 (New York, 1981). 11/ R. Hefner, P. Watanabe, and ?. Gahrlnr, "Percutaneous Ab sorption of Vinyl Chloride Gas in Rhesus Monkey," Toxicology and ApoEed Pharmacology. XXXIV (19751, p. 559. 12/ OSHA Standard for Vinyl Chloric-, 2S C??. 1910.1017. CMA 010660 CHEMICALS /1 jguiatory status of vinyl The Environmental Protection Agency CEPA) promulgated a research on the chronic lture on the oncogenicity iy other substance. It is >gen. Metabolism by the s it to the ultimate carhis intermediate by the )teins removes the toxic ! saturable. ^ An over' vinyl chloride will pass zed in other organs. An escape of the toxicant ere interaction with the p. An overload of both outside of the liver, as Despite the large data >echanism Of these varir derstand why some per* ;L, but none with both to set an emergency ure. and later that year ure. Industry was given id be used to meet this st by engineering prae- combined engineering and works practice standard In 1S7S which has resulted in ambient concentrations in the fractional ppb range near producing or using facilities.18' In the meanwhile, the Food and Drug Administration (FDA) and Consumer Product Safety Commission (CPSC3 established prohibi tions on the use of VC in aerosol or other censumar applications, a practice which had been discontinued in 1973. The Bureau of Alcohol, Tobacco and Firearms of the Treascy Department CBATF) had already banned the use of PYC liquor botCos fa 1973 because of concern for taste effects from migratica of residual VC Into fh contents. In 1975 the FDA proposed reeoectica of the generally regarded as safe (GRAS) status of rigid FVC packaging under the Delaney clause, also because of migration concerns, but that proposal never has been promulgated, end 13m FDA has stated that it is considering withdrawal of the 'proposal and recommending to 8ATF the reauthorization of plastic liquor bottles hi light f the current very low residual monomer levels ha fabricated FVC erticles. Other regulations have followed as new statutes and rales have come into play. The Department of Transportation (DOT) and the Coast Guard regulate the transportation of VC, of coarse, and VC tM listed is a priority pollutant and hazardous waste tinder various water and solid waste rules, and has a reportable quantity of one pound under Superfund. Did the existing laws operate satisfactorily at the tin of discovery of the chronic hazards of VCt It appears that they did. A leading medical authority who was deeply fcvehrad hi the worker health evaluation in 1974 has termed VC a "r._ :*s story.*1 Reevmluation of the risk to employees under tha c~ i ppm standard by a * conservative nonthreshold extrapolation Bieths::^ yields a lifetime i i estimate of less than IQ-8, a risk level which is not thought to be of concern. The comparable risk estimate for the general populace is I "Advance in Internal -VH (New York, 1981). i ng, "Percutaneous Ab>nkey," Toxicology and *R 1910.1017. 13/ EPA Standard for Vinyl Chloride, 40 CPS $1.60. 14/ P. J. Gehring, P. G. Watanabe, and C. K. Park, "Risk of Angio sarcoma in Workers Exposed to Vinyl Chloride as Predicted for Stud ies in Rats," Toxicology and Applied Pharmacology," XLEX (1979), p. 15. % cLBAFT 134 / RISK MANAGEMENT OP EXISTING several orders of magnitude lower. EPA has stated on several occasions that it believes that vinyl chloride is regulated adequately. RISK ASSESSMENT Risk assessment has been a popular avocation among those interested in VC, and more than a dozen have been performed.*3' These can be divided generally fnto two classes: those which rely solely on animal data; and thosa which attempt to incorporate the human experience. Those in the first class yield similar results, end show the normal spread of estimates from the various mathematical models in common use. These range from l,50ff to 10"3 ppb for a lifetime risk of NT6, or. eight orders of magnitudes It Is necessary to eliminate the high-dose data points, that is, those over 2,500 ppm from the Maltoni data*6/ in order to get reasonable fits to most .models, because these doses show broad systemic toxicity. The lower doses, 500 ppm and below, as a group fall into a general pattern on a legprobit plot, but individual two or three dose experiments show tre mendous differences in slope when plotted separately. The popular multihit model predicts a lifetime risk of IQ"3 at fractional ppb levels. The human factor was accounted for in two ways. The EPA used some preliminary employee epidemiological data to confirm its animal-based extrapolation.*7' Unfortunately, the human data were 15/ J. T. Barr, "Risk Assessment for Vinyl Chloride in Perspec tive," (Paper 82-9.2 presented at the 75th Annual Meeting of the Air Pollution Control Association, New- Orleans. LA, 1982), Lines ?(^ 25. 16/ C. Maltoni, et aL, "Vinyl Chloride Carcinogenicity Bioassays (BT Project)," (Paper presented et "Le Club de Cencerogenesc Chemique," Institute Curie, Paris, November 10, 1979). 17/ A. M. Kusmaek and R. E. MeGcughy, "Quantitative Risk Assessment for Community Exposure to Vinyl Chloride," (Washing ton, D.C.: U.S. Environmental Protection Agency, December 5, 1975). CMA 010A62  o2j stated on several .e regulated adequately. .o'ai-tion among those 1 ii been performed.*5' : ;:^si those which rely ar.'jt to incorporate the and show the TiA-ht.metical models in 3 j-j-h for a lifetime risk " i iassary to eliminate 'ai Z,500 ppm from the 2 fits tn host models, '.Icit'-. Th#lower doses, oners! pattern cn a log; imeftts show tref'psrasely. The popular 10"- at fractional ppb in tw ways. The EPA ;ic&i data to confirm its !y; the human data were :?l Chloride in PerspecAnnual Meeting of the :ss, La, 1982), Lines 20- ircinqgenicity Bioassays ~lub da Cancerogenese 10, 1S751. hy, "Quantitative Risk :yl Chloride," (Washing- Agency, December 5, sclected from those locations known to have ASL cases, while other facility data were omitted. They also were in error on the past exposures by more than an order of magnitude. This resulted in an estimate of 20 cases per year from the estimated 1974 ambient concentrations for the population within five miles of production and processing facilities. The EPA seldom bothers to check its estimates against avail able data, so it sometimes comes up with results such as that made for arsenic a few yean ago that would have predicted 18 million cases of skin cancer a year is this country if it had bees applied to Agency data on the average arsenic concentrations in drinking water. Similarly, a survey of all known ASL cases in this country for the ten years before 1974 showed no cases associated with residency near such plants,*' rather than the 200 predicted cases. It is rea sonable to assume that if any cases had developed since that time, the publicity associated with it would have brought them to light. Thug we have 110 million-person years of negative history for nearby residents. This places an upper limit on risk of less than 10"' per ppm-yr. Two studies applied pharmacokinetics in an attempt to obtain relevant human data. Gehring and coworkers estimated a lifetime risk of 10" at one ppm from the probit model, based on e biotransformation of rat data. The unconstrained linear model predicted no risk at less than 99 ppm.*9' Anderson, Hoel and Kaplan carried this procedure one step further, and applied it to bound metabolic products, rather than to the total amount metabolized. Their results gave a lifetime risk of 10'7 at less than one ppm, with the probit model, or at less than tw ppm with the linearized multistep model.7/ 18/ H. Popper, et aL, "Development of Hepatic Angiosarcoma in Man Induced by Vinyl Chloride, Thorotrast, and Arsenic." American Journal of Pathology. XCH (1978). p. 349. -- 19/ P. J. Gehring, P. G. Watanabe, and C. N. Park, Toxicology and Applied Pharmacology. XUX (1979), p. 15. 20/ M. 17. Anderson, >. G. Hoel, and K. L. Kaplan. "A General Scheme for the Incorporation of Pharmacokinetics in Low-dose Risk Estimation for Chemical Carcinogens, ibid.. LV (1980), p. 154. CMA 010663 136 / RISK MANAGEMENT OP EE53TNG CHEMICALS Thus we see thet risk is In the eye of the estimator, but H Is clear that estimates incorporating ha-man data reflect th human experience for VC far better than do tthe direct application f ani mal data. There was understandable uncertainty on the pert of both the regulators and industry in 1974. This nms the first commodity chem ical to be regulated under the relatively new statutory situation as the result of new information. Nevertheless, both the regulatory agencies and industry acted promptly tea reduce exposures and emis sions to an acceptable level. The current count of occupational ASL cases is about 100 worldwide, with 30 of these in this coumtry.2^ All these cases had their first exposure in 1964 or earlier, .end there appears to b room for optimism that the steps taken in tthe mid-sixties because f the AOL information will have prevented! any significant nuo\pr of casas developing from exposures commencing after that date. Cer tainly it is reasonable to expect that tihere have been no new cases initiated after the early seventies. Had TSCA been in place in the anO-abcties, would it ha-e made any difference in the course of eventsS? It appears unlikely that it would. Certainly the AOL discovery would have resulted in a series of 8(e) notices to TSCA. The probable outcome of that would have been either a recommendation from the Interagency Testing1 Com mittee (ITC) for more tests, or a Section 4 testing requirement. It is possible that, because of its commercial importance, VC could have been placed on the rTC list before the AOL- data became available. Additional data could have been called! for under Sections 8(a) and (d). The result of all this most likely would have been e negotiated testing rule, under which industry would ha ve initiated a series of studlei which would have culminated in a bioassay, and the car cinogenicity of VC would have been discovered in due time. Yet, this is precisely what did happen in the absence of TSCA, except that the preliminaries were omitted, and the bioassay was performed concurrently with the screening tests* Thus it is possible that th 21/ J. Stafford, personal cemruurdziticn, Liver Angiosarcoma Cases, April IS, 1983. CMA 010664 * a CHEMICALS of the estimator, but it is n tiata reflect the human direct application of ani- ty on the part of both the the first commodity ehemnew statutory situation as $3 ess, both the regulatory iduce exposures and emls- ASL cases is about 100 y.*^ All these cases had there appears to be room md-slxties because of the iy significant number of ing after that data. Car* st have been no new eases xties, would it have made t appears unlikely that it have resulted in a series come of that would have iteragency Testing Cont esting requirement. It is portance, VC could have L data became available. - under Sections 8(a) and ! have been a negotiated rve initiated a series of bi assay, and the carered in du time. Yet, isence of TSCA, except bioassay was performed s it is possible that the * Liver Angiosarcoma VBfYL CHLORIDE / 1ST final critical data were obtained earlier than would have occurred under present conditions. Bear In mind that most of today's powerful testing method* were not available twenty years ago. That fact would not have been changed by legislative fiat, and any decision made at that time had to be made in light of the available knowledge, j If the data of Viola suddenly became available today Instead, I would there be any significant difference la the outcome, or the | timing of that outcome? Probably so, but only because of the vastly I more powerful scientific tools which we have available to us now. Neither the speed of agency motion nor the rate at which Industrial I facilities can be built or modified has increased. If anything, tbw . latter has slowed, given the multiplicity of permits and approvals I now required. Overall, it is possible that if today we knew nothing more about VC than was known In 1970, wa would arrive at a reguI lated stats a few months earlier than was achieved In 1974, but | scientific progress, and not legislative or regulatory advancement, I should get the credit. I What if VC were to become a new product today? Would it run 1 the same course in which it would be 40 years before there was fall I recognition of its chronic potential? Certainly not. Again, however, the reason is due more to scientific progress rather than statutory | development. One change might be apparent. If VC were the subject of a | Premanufacture Notification (PMN) today, rather than being the I model to which all other aliphatic olefins are compared for struc- ture-ectivity analysis, .it would be judged by the others In its family. This comparison would be less dogmatla than the reverse is now. Ethylene and vinylidene chloride are not animal carcinogens the relevance to humans of the carcinogenicity of high doses of trichloroethylene (TCE) is equivocal and controversial* and vfnyl acetate has only a preliminary "non-negative" report. Thus, tills class of substances would have lost its leader for structure activity * comparison, and a decision as to the need for further testing from that analysis would not bt clear-cut, based on analogous compounds^ Neither would a full minimum premanufacture data (MPD) set be of any great assistance. VC responds poorly to the classical invitro tests, and only recently has it become possible to obtain repro ducible positive results in many of these. If the position were taken CMA 010665 -JR AFT 140 / BISK MANAGEMENT OF EXISTING "little lists" for the executioners apparently is too great to be resisted,2^ as Lester Lave pointed out recently. We believe that EPA can best obey its statutory mandate by developing a more efficient system for establishing priorities, and by implementing more effectively its Section 9 procedures. BIBLIOGRAPHY American Conference of Governmental and Industrial Hygienists. "Documentation of the Threshold Limit Value, 1963." Cincinnati* OH, 1963. Anderson* M. W.; Hoel, D. G.; and Kaplan, N. L. "A General Scheme for the Incorporation of Pharmacokinetics in Low-dose Risk Estimation for Chemical Carcinogens." Ttodcology and Applied Pharmacology." VoL LV (1980), 154. * Barnes, A. W. "ICI Ends its Silence on Vinyl Chloride." Chemical Engineering News. (July 8, 1974), 21. Barr, J. T. "Risk Assessment for Vinyl Chloride in Perspective." Paper 82-9.2, 75th Annual Meeting of the Air Pollution Control Association, New Orleans, LA (1982). Barr, J. T. "Establishing Regulatory Priorities." Toxic Substance Journal. VoL TV (1983), 290. " Cook, W. A. "Industrial Hygiene Evaluation of Thermal Degradation Products from PVC Fetus in Meat-wrapping Operations." Arch. Environ. Health. VoL XXE (1971), 74. Creech, J. L., and Johnson, M. N. "Angiosarcoma of Liver in Manu facture of PVC." Journal of Occupational Medicine XVI (1974). 150. j ' * i | ] J j ! ' 26/ Lester Lave, "The High Cost of Regulating Low Risks," Wall Street Journal. August 19, 1983. % y is too great to be re ly. 15 statutory mandate by Wishing priorities, and by procedures. d Industrial Hygienists, slue, 1963." Cincinnati, . L. "A General Scheme ics in Low-dose Risk lexicology -and Applied yl Chloride.'* Chemical iloride in Perspective.* Air Pollution Control Ities." Toxic Substance >f Thermal Degradation jg Operations." Arch. :oma of Liver in Manudicire XVI (1374), 150. iting Low Risks," WaU Diman, B. D., et aL "Occupational Acroosteolysis I, An Epid miologieal Study." Arch. Environ. Haalth. VoL XXH (1971), 61. Environmental Protection Agency. "The Cost of Clean Air and Clean Water." Annual Report to Congress, Senate Document 96-38, December, 1979. Gehring, P. J., Wstanabe, P. G., and Park, C. N. "Risk of Angio sarcoma in Workers Exposed to Vinyl Chloride as Predicted for Studies in Rats." Toxicology and Applied Pharmacology. VoL XLDC (1979), 15. Hefner, R.; Watanibe, P.; and Gehring, P. "Percutaneous Absorption of Vinyl Chloride Gas in Rhesus Monkesy." Toxicology and Applied Pharmacology. VoL XXXIV (1975), 529. Kusmaek, A. M., End McGoughy, R. E. "Quantitative Ride Assess ment for Community Exposure to Vinyl Chloride." O.S. Environ mental Protection Agency, Washington, D.C.; December 5,1975. Lave, L. "The High Cost of Regulating Low IRisks." Wall Street JounUl. August 19, 1983. Lelbach, W, K., and Marstellcr, H. J. "Advance in Internal Medicine and Pediatrics." New York: Springer-Verlag, VolL XLVH (1981). Maltoni, C., et aL, "Vinyl Chloridt Carcinogenicity Bioassays (BT Project)." Paper presented at "Le Club de Canccrogcnese Chemique," Institute Cirie, Paris, November 10, 1979. National Research Council. "Regulating Pesticides." Environmental Studies Board, Committee on National Resources, Washington, D.C., 1980. Popper, H., et aL Development cf Hepatic Angiosarcoma In Man Induced by Vinyl Chloride, Thorotrast, and Arsenic." American Journal of Patholcrv, VoL XCH (1978), 349. Stafford, J. Personal communication, Liver Angiosarcoma Cases, April 15, 1933. CMA 010667 142 / RISK MANAGEMENT OF EXISTING CHEMI Suciu, S.; Drejman, J.; and Valaskai, M. "Study of Diseases Caused by Vinyl Chloride." Medical Intern. Vol* XV (1963), 967. Torkelson, T. R.; Oyers, F.; and Rowe, Y. K. "The Toxicity of VC as Determined by Repeated Exposures of Laboratory Animals." Amer ican Industrial Hvgienc Association Jomrwi[. voL KSR (1961), 354. Viola, P. L. "Pathology of Vinyl Chloridta.** Medicina del Lavoro. VoL LXI (1970), 174. Von Oettigin, W. F. "The Halogenated Hydrocarbons, their Toxicity and Potential Dangers." Public Health Service Publication No. 414. U.S. Department of Health, Education and Welfare, Washington, D.C., 1955. . - CMA 010668 U-- 82-9.2 Risk Assessment for Vinyl Chloride in Perspective * 0 John T. Barr Air Products and Chemicals* Inc. Allentown* Pennsylvania 1 For Presonlalion at the 75th Annual Meeting of the Air Pollution Control Association New Orleans, Louisiana Juno 20- 25,1962 V] l 6990X 0 VW0 roiluclton combination of circumstances which found ttw carcinogenic haiard vinyl chloride (VC) being discovered at about the tamo Mao a* the ence or risk analysis was undergoing rapid development, and tho at commercial Interest and long history of use of the substance has ailed In a body of literature and pharmacological data greater than can expect to have for nosl substances, it 1s therefore Instruce to review the aany risk aticisatnls which have bee* prepared for against the available biological Infarnallan to determine If we can luate the extrapolation nethods used, and to discuss the current ulatfoni for VC In light of this conparison. ards of Vinyl Chloride Is necessary to decide first which of the haiards presented by VC uld be the basis for the risk estimation. The substance presents acute haiards nf frostbite from exposure to the liquid, of anes* ila *1 concentrations over 8.000 ppm and suffocatlen at higher centrallons (von Oelllnger, I95S). It alto forms explosive mixtures air above 3.75 volume percent, and so the efforts to control the sical safely of operations generally preclude exposure to acutoly lc concentrations. >* control efforts, were reinforced In tho mld-1968's where It was overcil (SueIn, 1963) that workers who had been exposed to very i levels of VC developed "vinyl chloride disease," the primary ffHtallon of which was acroasteolysls (MU), a degenerative dI seat* the bone tufts In the hands, and non nrtly gf Uii foot and luabar Ion. although crippling to some degree, this disease ts not fatal, It at least partially reversible If exposure It ellmineled (Cranlger, *r and Hard, 1980). >st ten years later It was found that some ef the barkers having tar exposure also were developing angiosarcoma of the I Ivor (ail), pldly fetal disease. Oddly enough, there |f only one possible of a worker developing both Ml and ASl (Stafford, I9AI) among UQ-plut cates af AOt and 90*010$ cases of ASL now known worldwide, iough both art diseases of the vascular system. Several largo kmlelogy studies were conducted on workers exposed to VC (flaxter fox, 197b; Chi ana, 1900; buck. Carter and Coombu, 1979; Equitable ronmental Health, 1978; fox and Collier, 1977; FrenUel-Beyme. IU, and 1 belts, 1978; Theriault and Allard, 1901), and ASl was only fatal dlteata found consistently to ho In excess In these CMA 010670 s * i *> ' v h t persons. Animal studies have shown an excess of tumors at other sites, but the lowest exposures at which these occur are considerably higher than that for ASL. Far example, Haltonl (1979) reported the following data: Site Concentration For Significant Elevation Forestomach papillomas: neuroblastomas: Zymbat gland carcinomas: nephroblastomas: Liver anglasarcoma male: female: Hammary adenocarcinoma: 30,008 ppm 10,000 ppm 10,000 ppm 2!i0 ppm 700 p))*, SO mg/kg SO ppm, 16.7 ag/kg S ppm The low concentration for onset nf mamaary tumors was of concern when a preliminary study of fabrication employees reported an excess of breast lumOrs (Chlaiie, et al., 1979) but a follow-up case-controlled study (Chlaue, 1900) found no association between the cases and VC exposure. The largest study of VC-PVC workers In the United States reported slight excesses of brain and lung tunors (Equitable Environ mental Health, 1978), but this was not seen in the other studies referenced above. The excess of brain tumors was small, and not doseor exposure-related. ' The overall excess of lung tumors resulted from an excess In one plant only, and reexamination of those cases also showed no association with VC exposure (Waxweller, 1978). Vinyl chloride has been found to b active In several jn vitro muta- geneltc tests with bacteria and yeasts (Hopkins, 1979) and llappcars to cause chromosome abnormalities In exposed workers, but these changes are reversible when exposure ts reduced (llansleene, 1978) and several studies ef neighborhoods around PVC plants have Tailed to show a supportable association with birth defects (Edmonds, 197S, 1976). It is not a teratogen In rodents (Johns, 1977). Therefore It appears reatanable to assume that If there Is any signif icant chronic risk other than ASL, It Is considerably smaller than that for ML, and that an adequate risk assessment can be based en only the liver tuneri, NOTE TO EDITORS Under the now lodtral copyright Uw, publication right* to this paper or* retained by the aulbor(t). --n in-- 1 view of HUt AnnnwnU 1. Sthneldtraun, I1K One of the first attempts U nil I lie animat data U estimate risks at very low Hpuum mi that of Schnatdaraun, Mantel and drown (1973). they used prellaliury Neltenf recalls to coapare the estimates obtained Iron three pot*Idle mathematical models. IMW assurance level of a "tare" date at a 11 fttlee risk of 10 was estimated Iron aeveral extrapolation models at fallawi: log froblt (dope = I) Logit (dope MS) logit (slope 2.3. one-hit> 7J ppb 119 apb 2.1 ppb She authors discussed the recagatied dllMcalttes of extending these rat data to humans and of providing anInal experiments that could answer satisfactorily the question of hunan risk at very low doses. 2. Muinack and HcGaughy, 1979 Ihe (PA was the llrst group to attoopt a hunan risk asseswant for vinyl chloride (Kunacfc and HcCaughy, 1979). this planeerlag effort altcopied to use both anInal and hunan data, and U show cooperative results Iron hath the linear and log-prablt models. It concluded that there was an Individual risk af 71 x 19 u per p|M ol 11 feline exposure U VC by the linear extrapolation nethod, ami that the tog-probtl results were one-tenth to enc-hundredth ef that. Ihls effort Is subject la several serious criticises. Ihe exposure data used for hunan experience was that free a group with less than average exposure, while the AM. rate was chasan from only those plants which did report cases, and Ignored the renalnder of the population. Ibus, their Incidence rale af 7.5X coapares ta an actual figure af about I.U, Ihty used it their prtoary method s linear extrapalatlax ef pgt data, which often has bean seen to avoroitlaato the actual rotes by at least two orders ef nagnltude, and they assuned the total CMCtr r*lf I* ho twice that found for AH. This sane estlnate was used by l|g (fA (1979) to estimate tho concentration of VC In drinking water which would product various levels ef risk. Unit attlaslas era, ef caursa, subject ta tha isae crtltctias. Hislicl (197S) challenged the estlnate af kutaack and HcGaughy (1979) when it was used by Ullsan la Ustlaeay befare the OSHA hearing on Its generic cancer policy. Nlshet stated that his calculations showed the risk ta be 10*30 tines grsster, by tbs sane calculation nethod. Wilson (1971) suggested severe) flaws CMA 010671 a *J a 'va < * 70 In the Hlsbct procedure, Including the fact that he chose for hit extrapolation one point at 19 ppa froa Haltonl experiment BI-19, and that this point Is not In good egreeaenl with the whole body of data, further, ho chose to use total cancer Incidence In the rats, Including those at lymbal glands, which have no counterpart In buaans. Both Wilson end Kuinack and HcCaughy had used a factor of two Hoes ASl to account for possible cancer at other sites. Wilton did achnowledgo a aatbeaatlcal error which node hit results half the proper nuaber. Albert (197B) applied this sane general procedure to other poten tially carcinogenic air pollutants In the United States and calculated the expected annual cancer deaths as follows: Arsenic Beniena Cadmium Coke evens VC (after regulation) 15.0 77.9 29.2 H9.S 1.0 9. Cebring, 1979 Gahrtng, el at., (1979) applied an expartaentally derived bio* transformation correction (Gehrlng, ol al., 1979) to rat data and cstlaalcd the Incidence In buaans al two different exposures by aeans of four different extrapolation models. Their estimates at 900 and 200 ppm IWA bracket the observed experience for hunanr when derived from the preblt and the unconstrained linear models. The linear*lhreuglt-ro and one-hit models consistently ever- estinsted tha Incidence. Although net considered by the authors, tho llnoar and problt nodeIs natch rather closely the total U.S. experience ef occupational ASL at an assumed 1,000 ppm exposure. Tho linear modal predicts no Incidence below 99 ppg-ln humans. The preblt model predicts a human risk of 1.3 x 10 " at I ppm. Thus, a mechanism far adjusting for the difference In metabolism between animals and humans appear* le be useful. A Unite11an ef the Gehrlng procedure is that It uses partial MaUenl data, and toil* tho retultl against the CHA spIdeeIclogy study. That study was net the "end of the experiment"; It slopped at tha end ef 1973, and several deaths have occurred since then. Neither did It cover the entire population, but only the employees f U* plants Hitch Ml certain crltarla for Oats retention and length ef operation, the Stafford (I9SI) data does cover the entire population and extends tha history for Sevan years. The site of the population Is not known, but e reasonable estlnate, bend on normal worker turnover raUs and Uta number of plants net Included In the CM study. Is certainly not lass than 73,000. This would give a gross Incidence of about 0.IX. Of those, the nuaber actually exposed to substantial exposures would be about 29-19 per plant at any one tins. Multiplication by IS plants, and a factor of three far the turnover during this period, would glvo about 2,000 highly expattd persons, for an effective loci- 0 di-nct of Just over IX. Personal experience would Indicate that, for Hi* period prior to 1964, when all of the first exposures of Ihe fatal 26 cases had occurred, the average exposures of this highly exposed group certainly was In excess of 1,000 ppn for the working day. Hallont (1979) found a IX Incidence at about I-10 ppn In rats. Calculation of the dose equivalent to a IX Incidence In rats gives 0 ppn by tbi linear Method and 2.5 ppn Iron the log-probil equation for the contained HaItenI Inhalation experinents. litis crude end subjective estiaate would then say that nan Is about 100 tines es resistant as the ret to VC Inhale- lion. e figure generally In egreenent with ether cstlaatei (NCM, 1929). Food Safety Council 1910, 1980 Ihe Food Safely Council has recoauwnded (fSC, 1918) the use of the game nulll-hlt node I because of Its flexibility In handling dose response data of varying curvlllnearlty at lew dotes. It has calculated (F9C, 1980) the nextnun likely and lower 92.SB Unit doses for substances at various risk levels end with dlffeient Models. Far VC. at 18 * risk, these results are es follows {based an early Heltenl date): One-hil Anailagc-Dell Welbutl HullI-hit 2.0 x tol| Pi 2.0 x le., PI** 2.1 x 10 * 1.9 x 10 Tor this substance, the goodness ef fit of the Vflbull node) (0.96) was superior to that of the oultl-hlt (0.J2). Neither ef the other two Models gave acceptable fits, litis was In pert breamr of Ih* concave shapr of the curve, which Included all of the high doses In the dose response data. Onw, 19/9 ft Onw llralh Tran performed a relative risk est loot lex far several t'.HxpuuiHh (t auger, rt at., 19/1) wiilih urns Id*red prune* Ia expo* mi*, the consequence ef exposure, the physical flait of Uil substanrr during processing, and the current exposure standards. Ibis resulted In a value of 400 for VC I* a "closed systeM but will) employees In the vicinity." Ihe sane procedure assigned baiard rating values to tone oilier substances es fellows; btmtne, 10; phosgene, 410; hydrogen sulfide, I; arsine, 9,208; and bls-chloranelhvl ether, 69,200. In a belch operation with occasional Manual handling, the haierd rating for VC locreastd to 9,208 by this Method. Ilchlr, 1980 llvlilr, el at., (1980) conducted e aeries of tests far the ContuMar Printed Safely Commission, a part of which consisted of exposing rats and nice ta a series of short, high exposures, rather than CMA 010672 . > 1 * it (he usual extended low dosage. They Included one-hour exposures lo rets and nice at 90, 900, 9,000, and 90,000 ppn, 10 and 40 hour exposures at 900 ppn, and 49 and 100 one-hour exposure) at 90 ppn. ftfter lifeline observation they found no effects on rats, or their offspring, nor on nice exposed to less than 900 ppM. those exposed to over 900 ppn developed pulnonary adenonas, but they also had suffered Iron pneumonitis. i Ihey cons Itiered the published data on anlna) exposures and concluded that there was a lifeline dose below which no oncogenic response Is seen, ihfs was esttaaled to be 9,000 ppn-hri for otco and greater than 90,000 ppn for rats, regardless of whether the dost was administered over a short or long period. This concept of equality of effectiveness for all nodes of exposure does not have general acceptance and would not appear to be correct, based on our present understanding of carcinogenesis. Dose-rale effects are, ef course, well known. However, the degree -to which this can<bt extended to all types of effects Is not known. Those authors also used the Crump-Guess node) (Crunp, Guess and Deal, 1922) to evaluate their data on Mouse pulnonary cancer, and estlnated that exposure to 9,000 ppn VC doubles the probability of cancer, while-90,000 ppn increased the risk nine-fold. In view of the fact that pneunonltls was present In all anfoals exposed above 900 ppn. It Is questionable If this was a direct oncogenic response, or the result of an nongenet1c event because of severe lung daaaqe. HaIton1 (1929) also reports an increase In lung tuners In alee, but not in rats or haosters. Thus, the significance of this finding lo risk In hunans Is questionable. 2. Anderson, 1980 Anderson, et al., (1980) extended the work of Gehrtng, et !.. (1921 and 1929) to Incorporate the amount of nelaboltc products Iron VC which actually was hound to the DIM of exposed rats, (Gehrtng and Blau, 1922) rather than the total anount Metabolised. assigned various values In Iftp psrflwelrrs In a HIcharMt* aill etjujllan depicting III* kinetics of the Metabolic process, and compared the results froa extrapolation to low doses by log-protalt and aullf-Ml Models. They found that the two extrap olation node Is responded quite differently to these variations at very low dnses, and that U was not possible lo select one model at the store appropriate froa lisa high-dost data. Use of the values af Gehrtng for the primary parameter!.gave estimates of the dote equivalent lo IIfeline risks of ID of less than I ppn for the problt model and lets than 2 ppm (or the Multistage model, a correspondence which the authors pointed out was better then the precision of Intartpecles cooperIsons. EPA, 1980 The final version of the water quality criteria document far VC (1M, 1980) used a different approach for risk ettlnatlan. The slope of the Incidence of all tumors at the loweet date* of Haltonl experiment BT-I wat adjetted for the fraction of exposure, the equivalent feeding level to give the eaM hlaod concentration of VC as by Inhalation (tee WI they and Collin*, I1K), and the ratio of the surface area of huaant vs. ratt, to produce an estimate that a lifeline risk of I*'' would he canted by drinking 1 I/day of water containing 20 g/l. There t* tone confusion In the aatheaatlcs given In the report, and the attunpllont on which the adjusiaenlt are node are far fron having general acceptance, although generally following HAS reccomndatlent. It appoort that this procedure overtlalet the rltk by several orders af nagnllude. HAS, 1900 Ihe National Acadeay af Science (191?) calculated the upper 9SX confidence Unit-lor rltk Iron drinking water containing vinyl chloride Iron the probabilistic nuHIttago node) and earjy Haltonl rat data. They report (M{, I960) a lifetime rltk af 10 * at being equivalent to 3.0010 3 ng/kg/day. Far a TO kg person consuming 1 l/day, this would calculate ta an acceptable level ef I g/l. The difference between the [FA and HAS nunbert cones Iron the different curve-fitting Methods for the anInal data. Gaylor and Kodell (1900) applied linear 'InterpolatIan" to the iMt early Hallonl data used by the Food Safely Council (I9?t) to arrive at a predicted mmIsmo risk of 10 . The ippor 9T.SX confidence linlt ef the anInal data wat token os on* point on tho Interpolatlve line, and tero Incidence at taro onpoture as tho other, jkis produced o lower 91.St confidence limit dotage of 1.1 10 1 ppa for a Itlotlnc risk of 10 * in rots. Ibefr appltcatlon or tho ArnUgge-Oell Multistage nodal gavo S.l g.lt ' ppn at the dosage at 10 m llltiioe risk coapared ta 2 * TO * by the food Safely Ceuncll. the difference Is due to ellernellve osswap tions on the value of tho exponentlei dose tern. , Crunp and Suets (I9M) reviewed sane of the earlier risk eillnales for vinyl chloride In drinking water, and recalculated the risks, using the ana-hit and nultlslag* nodeIt. they arrived at an upper 9SX confidence Unit of llfejiao risk for drinking water containing I g/l tf VC ol 4 e It *, based an eerly Haltonl Inhalation data. Using the assuoptlan that a 1,0 Incidence af ASt In workers had resulted fran a lifeline egoeturt ef It (/kg, they obtained nexlnun likelihood risk of II * fron g,34 g/l by both the nultlslage and linear nedels, with !U lower ceefldence Units or the saoo risk at 0.24 g/l. Thtto two nodeIs reduce te e linear lorn when used at very law dotes end with the estuapOen of no threshold value. 1-9.> q CHrt 010673 i These authors cite [PA data on the occurrence of VC In public ' water somites which by their nethods yield a 11 felloe risk of 1.1 m IS ", or 12 deaths per year fron this cause In the United [tales. Mane of these hat been observed, despite tho accumula tion of IS years' data on ASL deaths (Popper, 19)0). 12. Scott (I9BI) ascribed the decreased incidence af tuners In rat* at tho higher doses to s cell killing process, and adopted the Welbull Model to account for this. Application of tho nodel to toot early Haltonl data produced a curve which lit the data fron SO-10,000 ppa. Ho did net ottcapt to extrapolate to doses beyond Iht experimental rang*. 13. Carlhorg, 1901, alsa applied the Welbull node) to 31 bioassay reports on s variety of anInal carcinogens. Ik concluded that the one-hit nodel was not appropriate and that carcinogens could bo divided Into categories according to the shape of the curve, * concave or convex.. He found that the early Haltonl data on VC loll Into the foraer category. Application of Ms parameter estlnates to those data, assuming no spontaneous Incidence of ASt, gives 2.9 x 10 ppn for a. Illaitmp risk ol 10 * for rats. Later calculations Including all of tho published Haltonl datadid net change tho results significantly (personal conaunlcattea). He found tho Welbull ships paraaeler to ho approximately 0.3, which Is assumed to be the lumber of stages for lunar Initiation. Tbi* I* consistent with tho finding by Cellring (19)7) of a saturablo nelabeltc path which produces the proxlnate carcinogen. It alsn suggests that the number of "stages" Is the number of finiterate steps before the rate-limiting step. There may he other stages following, but they are not rate controlling. Actually, there appears to bo at laast twa saturable Mechanisms Involved li the pbamaceh incites af VC, the netaboltsn to the ultlnate care I r.ogea and the dolanIfkalian by tulfhydryl groups. 14. One further evaluation of bunon risk can be made from the experi ence of porsono residing near VC-PYC plants. The EPA estimated (Nunack and Hcfiaugby. II)*) Util five nil linn person* lived within five miles of these plants, and were exposed to an annual average concentration of IT ppb. Ihc prasent distribution of plants was genarotly wall-established by 1999, thus wo have 22 ysars of history, or aheuh tl* million person-years. About five or six of these plants, with 1-2 million neighbors, go bock another 20 yoare, but these date ere net fine enough far Inclusion. Tho fact that no case af ASL has bean confirmed at arising fron thess ambient exposures placet the upper hound of risk at lets than 2.7 a 10 per ppu-yr. It li believed that the exposure data were overestimated by EPA, and thus this result way ha too low, hut It Is In tho tamo general range as that arrlvsd at by Cehrtag (19)9) and Andersen (19*0) after making corrections for pharmaenklootlet. f*tending this crude cildilallim, these five ail lion persons are now supposed by (PA to be eposed to 0.1 ppb (probably high ' figure), which would predict no aore than 0.000) deaths per year, or one per 1,100 year* In that whole population due to VC exposure. But It also aust be recognlied that with approximately 10 cases per year of ASl In the general population, there can be expected froa a purely statistical basis tlpl there should be one case every two years or so among this group of | all lie* plant neigh bors. I he result* of these estimates discussed above art ceapartd In fable 1, liter rdiversion to a uniform 10 * lifetime risk. Estimates S, (Dow 1919) and 11 (Scntl, 1981) were net In a fora to permit this ceaporlson. tt OSIU, (I'JOO), for references to a few other estimates that wart tal considered here. It can be seen that the results fp)l Into two major categories, these -Men project that the risk of 10 * occurs ol exposures of greater than I ppm, and those which find that risk In the ppb range, the situates which yield the higher allowable exposures ara based on uiinan data (Nos. 1, 1 and 14) or uso a log-probit extrapolation modal (Ho. 1. second estimate), or predict a threshold (Ha. I). The rrastnder generally are based on tbo linear, non-threshold model, and Mke no biological correction. The result Is a difference of 1 or 4 jrders of magnitude, the estimate* which yield the higher allowable exposures are In bolter agreement with human experience than ara these <>f the other group. Additional Data All of the extrapolations reported here have used far the original utionl data from Ms experiment Il-l. it* ha* now reported (Haltool. 1919) three other comparable Inhalation experiments on the tame strain >1 rats, and one on another strain. In addition to two Ingestion Uudies. Ihe results of these experiments ara shewn In Figure I, on o iog-problt scale. It can be seen that they ail follow a similar lattern, but that there arc large varlattans In slope between the /arlous data groups. Table III contains the log-prebit equation* . alculaird from some of llit Individual experiments, and various groups if experiments. Excellent fits are obtained for tingle enperiaenl, is would bo expected Iron the small number of data points, hut adequate 'Its are obtained for the group as a whole. Inclusion of the historic onlrol data on ASL (Q.OTX spontaneous Incidence) did not affect the >lt substantially, except lar the very low data data. Inclusion of .he 0,0 (originl as a data paint did give significantly poorer fits, ihe combined onparlHnts Indicate that a 11 Inline risk of 10 * for at* Is obtained from a dose In the 1*2 ppb rang*. plmllar variation It teen with the other mathematical expressions, .uch at linear er exponential equations. 1-9.1 4 CMA 010674 10 * a ,t a. ' v a * Aeoulatory Status The current regulatory status of vinyl chloride Is summarlied In Table II, Ihe first regulatory action on VC was taken In I9f) when the bureau of Tax, Alcohol and Firearms prohibited the use of rigid fVC ss liquor containers. This was based on tl being present as an adulterant, and not on any consideration of risk. Ihe Consumer Product Safety Commission (CISC), the Food and Drug Adoletstraiten, (FOA), and tho IPA all acted to ban the use ol VC as an aerosol propellant thus establishing a lero risk position. Ihe TIM proposed (fOA, 1915) to withdraw the prior sanction status of rigid PVC as a food package component because of the concern for residual VC that might migrate. Tiie TDA has taken no further action on this proposal, and now Is considering a "constituent" policy which would permit a lifetime exposure at seme (cceptable risk level. This risk has been proposed recently to he 10 * lifetime for the gluttonous consumer. As was discussed above, the EPA required a best available technology approach which reduces the average exposure to those within 5 miles of a plant to about 0.2 ppb, by EPA estimates. 051IA established a rule in 1974 which set 1 ppm for 8 hours as the maximum permissible exposure, and also set 0.5 ppm as an action level below which most features ol the regulation did not apply. These were chosen .as feasible levels, and not necessarily "safe" doses (OSIIA, 1914; EPA, 1916). The EPA has established an exposure to the general population only O.IX of that allowed in the workplace. The CPSC has required iera exposure, and the FDA has considered that approach. Depending on which method ol estimation Ute FDA may choose. Us allowable exposure could he either greater or less than those currently set by EPA and OSIIA. It has been estimated that the maximum amount of VC Ingested by the average European, who uses much more plastic packaging than we. Is left than g/day, (CEF1C, 1916) which would be In the order of e 10 * or 10 " lifetime risk by even the most conservative models. There have been various estimates made of the cost-effectiveness or the Federal regulation far vinyl chloride. Crabao and Vaupel (1901) estimated that the OSHA rule cost 17-5 million per life saved, and 1490 thousand par life-year saved over the option of leaving the exposure Holt at 90 ppm, Lukcn and Miller (1901) state that the tepuled value of l life fro* the OSIIA standard It $4 nil)Ion. Horrcll (1982) uses ao annual cost of F20 million and an annual benefit ef 0.1 life saved to derive e cosl/benefll of 4200 million per life for the OSIIA rule, Itie [PA Mi reported (EPA, 1979) Uul Ihe cait of coopt, nee with Its VC standard was 4296 million through July 2, 1981, and will bo an additional 4410 million during the next five years, all In 1927 dollars. If tho EPA estUule of up to 20 dealths per year were correct, this would be a cost of 44.7 nil Hon per life. Itowover, as discussed here, there Is no ovtdenco that any lives have been saved by this rule. There ara maw difficulties In abtatnlng accurate estimates of this type, and serious prebleos In determining the proper value la bo isfgned U a life, nevertheless, IM doubtful nature ef the clalns 4 r iy tlgnificinl benefit Iron (Iww rule* suggests that at bast, >fi rrgultl(M( ire euciiinty easily to society, therefore, we * >1.1 attempt to laprove both our date base end our mtlheds lor Inter* etlng awl applying the dote. ntusslon >et can be learned Iron this exercise other than the already -cognised (act that various extrapolation Models can yield very Hfrrent results? In this case, at least, there are several paints licit are worth consIderlag. 1. Vinyl chloride Is no exception to the rule that Inman data always ust be Incorporated whenever possible. The epidemic el occupa tional ly induced ASL which wes leered In WM Ms not Mterlollied, probably duo to llte steps Ibst were taken In the early lMO's to rrduce exposure because nl the discovery el MU. He Instances el Ail Iron exposure to VC In the general papuletlen have hcan substantiated. The overpredietten el occupational cases ms due to the underesttnation ol worker exposure and everrelUnco on raw anloal data without proper phaneacokinetlc adjustment. We ere not now able to extrapolalo rellehly hetween slut Ior species and certainly not Iron rodents to humml, without ouch additional data. 2. Ihe regulations lor vinyl chloride were net based primarily an scientific data, but an toeleecenapfc and political decisions. Ihls is no surprise {Crandall and lava. I9>l), hut is a (act which should Ite acknowledged openly, along with the understanding that this position will continue to penal lie good science. 3. Hathroatleal extrapolation nodcls are net adequate In thensalves lor predictions ol risks ouch beyond the experimental range, no alter how good the III is tn the data In In* observed range. Ihe variability el relatively sate 11 taperloanlaI groups adds to the error range, thus, kfeastays Intended far quantitative risk assessment appilealions should be at ai lew desas as pessibla, and as Urge as possible, end should be Interpreted very cau tiously. 4. Tin current stale el the art Is such that quantitative risk assessments may be useful ler determining relative risks Iron sinlUrly acting carclnagans, but ere not suitable ler acretiIhe-beard application U ell mechanisms ol carclnoganesls, Ihls Is not to say that we should abandon efferli et developing more effective risk asseisasnt netbeds. We nest, however, recognise the problm Inherent In blind application nl Mtheoallcal oodels without proper assessment nl (he available hlechenlcel kata, nr an understanding of bow applicable the experimental data are U CMA 010&75 II * a l p k Wa have available to us at least at nuch data regarding vinyl chloride . as wa have for any other substance, and wa still have difficulty in deriving a suitable expression lor risk Iron a purely mathematical or statistical basis. Only whan human relevance Is considered can we arrive at a prediction that approximates actual experience. 2 The regulators are faced with a tremendously difficult tssk when they are presented with e few pieces el enlnal data which suggest the need ler concern end potential regulation. We must develop a suitable program to obtain and use as nuch ralovanl data as possible to assure that rational regulations aro possible. Ihe vinyl chloride experiencecu help us understand the kind el data uhleb era needed. 3MS-AI tmm 0 "fl 11-9.I it.rrt, R. f. . teller to R. S. Navren. IPA, "Comparison of vinyl .lortde carcinogenic risks with risk Iron oilier pollutants", iihtnylon, OC, 16 June ll/l. idenon, H. W.. et it., Iw. tool. Pham. iS, ISI (ISM). later, F. J., and A. J. foe, lancet, 1)11 21). irlborg, F. M., 11 Cornel. Toe. J9 KS (1901). IIC Cowitllee lor the loetclly of Vinyl Chloride, 'Vinyl Chloride Icily and the use of PVC for Packaging Foodstuffs," Brussels, Feb. 1)6. ilane, l., 1 Octup. Hed. 22 (10) G77 (1900). iletie, L., Jr., W. . Nichols, and 0. Wong, JL Occup. Hed.. 19 623 1971). randall, R. W.. and l. lave, "The Scientific Basis of Health and jfety Regulations," Brookings Institution, Washington, 1981. ruap, k. S., and II. A. Guess, "Drinking Water and Cancer", 1)81-118167, Oeceober, ISM. rump, k. S.. II. A. Guess, and K. 1. Beal, Biometrics. 33 4370451 1977). uck, B. W,, J. 1. Carter, and C. 3. Coenbes, lancet 197S II, 1197. .Imonds. t.. "Birth Delects and Vinyl Chloride", Proc. Conference on .wen and the Workplace. Washington, OC, 1976, also leraloloaf. 1Z137 i97s>:-------------- dnonds, l. 0., II. Falk and J. C. Hiss In, The lancet 1975 1090. nvlionmwtal Protection Agency, Standard for Vinyl Chloride, 41 $&. eg. 46,560 (19/6). nvlrotwcnlal Protection Agency "Vinyl Chloride, Anhlent Water Quality rllerIa", PB-291446. Washington, OC, 1979. nvironoental Protection Agency "Ambient Water Ovality Crltgrl# for Inyl Chloride," IPA 440/9-00*070, October, 190(1. nv I momenta I Protection Agency "The Cost of Cloan Air and Clean aier". Annual Report to the Congress, Oeceober, 1979b. Senate ocuoenl Ho. 96-30. I). S. fiovernuent Printing Office, Washington, OC. CKA 010676 u Equitable tnvironoental Health, Inc., "Epidemiological Study of Vinyl . Chloride Workers, final Report". Prepared for Hanulacturlng Cheatsis Assoc., Washington, OC, January, 1970. food and Drug Administration, Notice of proposed rulemaking, SO Fed. Beg.. 40,529 (1975). ------ Food Safety Council Final Report "Proposed System for Food Safety Assessment , Washington, OC, June, 1900. Food Safety Council, Scientific Committee "Proposed System for Food Safety AsseswKnt." food and Cosmet. Ton. 16 Suppl. 2 December 1970. Iok, A. J., and P. F. Collier, Or. X jnT Hcd^ 14 ) (1977). frentiel-leyme, R., T. Schmitt, and A. H. lhless. Arb. Soclalmed. Prevent., 13 210 (1970). ----------------------- Gaylor, 0. W., and R. L. Kodell. R. L., J. Environ. Pathol. Ion. 4 30S (1900). ---------------------------------------- Behring. P. J., and G. E. tin, J. Environ. Pathol. Toxicol. 1 163 (1977). ---------------------- ----------------------- Gehrlng, P. J., P. G. Watanaba, and C. N. Park. Ton. and tool. Pharm. 4915(1979). ------------ ------------------- Gehrlng, P. J., at el., Ton. AppI. Pharmacol. 44 501 (1970). Graham, J. 0., and J. W. Vaupol, Bisk Analysis l 09 (1901). Granlgar, R. G., A. E. Walker, and A. H. Ward "Vinyl Chloride Hononer-Induced Disease; Clinical. Radiological and Imounologlcal Aspects." Chapter 11 In "Induced Olsease; Drug, Irradiation, Occupation", L. Preger, td., Grune and Stratton, London, 1900. Ilanstoeno, l.-L., el al., NuU As*. 70 211 (1978). Ilehir, R. H.. at al.. "Toxicology, Carcinogenicity and Reproductive FfFfflt pf Single and Hultlpla fxpofvret l Vinyl Chloride In Bali end Mlct", Pri-Bubilcillon drill, fob. f, 1)00, II.$. Contuoer Product lately CoaolttUa, Washington, DC, Mopklna, J., IjL Cosnet, Tokltol.. 642 (1979). John, J. A., (t kl., Tor and AppI. Pharmacol. 39 497 (1977). Kutnack, A. H., and R. I. HcGaughy, "QuantItstfvt Risk-Assessment For Cnomuntly Exposure u Vinyl Chloride", W.S. IPA, Washington, PC, Otccmber 6, 1975. ' langtr, B. B., S. K, Norwood, G. E. Sochi, and II. R. Hoyla, An. Ind. I>yg. Assn. X, (12) 1039 (1979). ----------- It II., end S. C. Hlllrr, J. Mr Pol. Control >noc. Jl 1154 I. C. , fi. lefenlne, A. ClltbcrM, 6. CoUt, and 6. Carroltt, Chloride Cere Ioogenic I ty OioiiMyi, (B T Project) * on >rnlil Model for Bisk I dent If leal loo and Mmiont In menial imI Occupational Carcinogenesis? Prssenled it "to dull erogenese CMilqw*, Institute Curio, Pori*, Now. IB, ISIS. <1 Acadtny of Science, "OrInking Wotor end He*Ilb*. Nation*I / Press. 19;;. I Acadeoy of Science, "Drinking Water and Health^, Vol. 3, p. .lonal Acadcny Press, 1960. >1 Cancer Advisory Board. "The leUtion of Bloassay 601a to th# ent of the Bisk of Carcinogens lor llunant under Conditions of i)inre*. Subcoamlllee on Cnvtronnental Carcinogenesis, Draft of Itliuj data Iron Heselson and Buttoll, 19)9. I.C.I., Post-bearing statenent to OSHA docket B9B, Septonbor '0. tonal Safely and Health AdnlnfStratton, Standard for Eaposur* J Chloride, 19 fed^ Bet^ 35,696 (19)4). . II. et al., A*^ JL Pathol. 91 349 (19)6). tcman, H. A., H. Mantel, and C. C. Brown, Ann. HV Acad. Scl.. ' (ISIS). 6. N., Bull. Halbeanllcal Biology. In press, 1961. <1, J., private communication (1961). J. , J. Ore)nan, and N. Valaskal, Me^ Intern, IS 96) (1961). It, C., and P. Allard, X Ottup, Ned.. JJ (16) 6)1 (1961). tlngen, W. f., Public Health Service Publication No. 414, li.t. rnt of Health, Education and Welfare, Washington, K, I9SS. er, I., tl at., "An (pldenlologUtl Invest3f A Exceii near Bisk In a Synthetic Chenicsls Plant*, Presented at the nth International Congress Inr Occupations! Nsslth, Dubrovnik, Sept., 19)8. r. "Response to coneents of 1. C. Blshti," fost'hosrlng rscord cfcet 696, I9)S. J. I., end B. 1. Collins, jK Toil Envlr, HialUi, 2 HI (ISJI). CMA 010677 A FIGURE 1 GRAPHICAL REPRESENTATION OF TABLE 111 LOG'PROBIT PLOT 1 ttc;nn INt-'iLAt I or 1 c BT I C BTO *= BM* -c IHGCSTIO IMI B imi -m C3 -O ""Tt CLRAlFT TABLE I SUMMARY OF UANTITATIVE RISK ASSESSMENTS FOR VC SUMATE MO. AUTHOR ME SPECIE* EXPOSURE P0A 10* LIFETIME RISK COMMENTS 1 SCIINEUERMAN, 1*15 RAT 11*1991 Ip* LOQfRQWT LOGIT SLOPE * 3.4S LOGIT SLOPE 2.3, MIIT 7 KUSMACK A MeCAUGHV, RAT. HUMAN 14 H* I97S 140-1400pp* LINEAR THROUGH ZERO LOG-PROOIT 3 GEHHWG. 1*16 RAT, HUMAN > 1 wpm BtOTRANSfORMAL DATA ANO LINEAR OR LOG-PROOIT 4 FOOO SAFETY COUNCIL, IBM RAT *I**R* WEI0ULL G IIEHIR, 19*0 RAT, MOUSE THRESHOLDS SEEN IN BOTH SPECIES 7 ANDERSON. 19*0 RAT, HUMAN >1*P* DMA BINOINQ t (FA, 19*0 RAT 4 jiG/DAY FOOO OR WATER NAS, 1**0 RAT 3 X 10 s MG/KG/DAY WATER 10. GAYLOfl A KOOELL, 1*90 RAT 07 wA Mn* UPPER 0T.BK CONFIDENCE LIMIT OF LINEAR MODEL ARMI1 AGE DOLL MOOEL 11 CRUMP* GUESS. 1900 HUMAN RAT O.TffG/DAY 01 piO/DAY APPLYING WORKS R DATA TO WATEn, UPPER on CONFIDENCE LIMITS 13 CAflLBORO, INI HAT I.l X10 pfto WIE0ULL 14 THIS PATER HUMAN > 1 P*9I NEGATIVE EPIOiMIOLOOY UJ Q CC O -J X o - .J > z > UJ O _] to CQ < H Z) H< h- (O > gCC D a LU x ea rs >oo > o ui o < x. a >- ,Hz aX. Oto O_j aU<:i H_l I> aX. Q < V to K OCC UfMI CD <1n-- UI oo < cUoz--ci a 0o*t2c Z X UoI H U1 _l (0 <_j < > < 1CUm--OJ -j UI >U--1I U-JI to Uu<J. 1tI--Uo 5 -oJ UJ >UJ -I O UI -i _J Ui o m cc o 3 a 3 i/i h* O n> a o tc a. DC ui S D to Z oo zs oz o < o < a. Q O O U. OO 5S JaQO. IN o > <C 5 Ga a. in o 5 D 5 X< g-j O a H z o O ui Z a UI Z z < CC O iu "J to O X o tc acl. CO Z Eg Cal Ho o m m OO < - < > o Z Ui O< IL H C<D otCooL L<aL < aU<J. tXo O TABLE ill EQUATIONS FOR CURVES FITTED TO VARIOUS AND COMBINED MALTONI EXPERIMENTS EXPERIMENT ST-1 PLUS CONTROLS ST-2 PLUSCONTROLS 8T-1S PLUSCONTROLS ALL INHALATION STUDIES (4) PLUS CONTROLS ALL INGESTION STUDIES (21 PLUS CONTROLS ALL STUOIE5 (8) PLUS CONTROLS ALL STUDIES; LOW DOSES ONLY PLUS CONTROLS LINEAR v* * b a br LOG PROSIT Pm IN DOSE b a br CONCENTRATION AT Iff6 RISK. (L0G-PRO3IT). bom 025 027 3.05 1.53 5.5 528 025 0.27 1.75 1.74 029 029 328 2.47 -ass -1.13 0.97 0.97 1.0 0.88 -1.05 ' 1.0 020 OSS 3.07 0J1 2JO 0.91 0.15 0.95 020 0.95 3.10 0.73 3.41 0.72 i.cn 0J7 0.79 0.35 1.80 0.89 0.27 0.30 027 0.51 0.17 2.78 OJS 148 2J8 322 3L0S 3l53 2.71 0J9 1J 1J 0.82 OJS 0J2 0.75 0.49 J0> 23 03* OLOD2 QlQOS OlOOI 0.42 0.0002 J ft-l* 010^79 CM* APPENDIX V HEALTH EFFECTS REQUEST-TO DHS AND LETTER OF RESPONSE 010*8 % Memorandum To Kenneth Kizer, Director Department of Health Services 714 P Street Dei* t Svbj*ekt June 17, 1985 Evaluation of vinyl chloride I am writing \o request formally that tha Department evaluate the health effects of vinyl chloride as a candidate toxic air contaminant in accordance with Assembly Bill 1807 (Tanner). According to Health and Safety Code Sections 39660-62, your Department has ninety days to submit a written evaluation and recommendations on the health effects of vinyl chloride to the Air Resources Board and may request a thirty day extension. Attached for your staff's consideration in evaluating vinyl chloride are: Attachment I - a suggested list of topics that we believe should be included in your vinyl chloride evaluation and recommendations; Attachment II - a list of references on vinyl chloride health effects which were presented in an ARB letter of public inquiry; Attachment III - additional references and comments received from the public in response to the inquiry letter; and Attachment iv - ambient vinyl chloride concentration data and emission data which should be used to estimate the range of cist t California residents as required in Health and safety code Section 39660(c). My staff is available for consultation in conducting this health effects evaluation, we look forward to continuing to work closely with you and your staff in carrying out this legislative mandate. If you have any further questions regarding this matter, please contact me at 445-4383. Attachments cc: Jananne Sharpless Alex Kelter, w/attachments Raymond Neutra, w/attachments Peter D. Venturini Assemblywomen Sally Tanner Claire Berryhill Emil Hrak, chairman and Members of the Scientific Review panel Senator Ralph Dills Senator Art Torres John Holmes AR3 CMA 010681 ACTAC .v a SUMMARY 0? AK3ISNT VINYL CHLORIDE CONCENTRATIONS Vinyl chloride has been produced in one Industrial facility and used by four facilities in California}, all of them ia the South Coast Air Basin (SCAB). In May 1978, the Air Resources Board (ARB) adopted an ambient air quality standard for vinyl chloride of 10 ppb, 24-hour average. Subsequent ambient monitoring in the SCAB found the 10 ppb standard to be exceeded frequently in the vicinity of these facilities from 1979-1981. However, sine 1982 the recent monitoring data fer VC near these vinyl chloride facilities has shown all values ic be below 10 ppb, without a determination of the actual value.' These reductions in ambient concentrations are likely due to the closure of the production facility in 1982 and implementation of regulations by the South Coast Air Quality Management District (SCAQKD) designed to reduce vinyl chloride emissions. vinyl chloride has beer. detected in the community near t-hjQ bkk Class l landfill in Nest. Covin a. In 1983, the Department of Health Services (DKS), AR3, and ch e South Coast Air Quality Management District issued a reper c detailing ambient concentrations (report attached). As the report indicates, the average vinyl chloride concentrations varied with location. The worst cas residential location, Station A, h ad mean 24-hour VC concentrations of 7.1-7.3 ppb, with a maximum rea ding of about 39 ppb. Data for this report were collected over th ree months (July 19-October 15, 1982), with 24-hour samples taken five days per week. A newly discovered potential source of vinyl chloride emissions into the air is that of sewage treatment facilities, aa EPA contractor recently made some estimates of vinyl chloride emissions, as well as other volatile aromatic compounds, from the "Top 20" sewage treatment plants, nationwide. (Please see Appendix D of Versar Memorandum, Attachment IVC.) in this document, the Hyperion facility, which is located in the SCAB, was calculated to release 171 metric tons/year of vinyl chloride. ARB staff m del <3 this emission estimate (assumptions on Attachment IVB) and predicted 8 ppb above any background as an annual average vinyl chloride concentration. The 24-hour maximum VC concentration prediction is * 23 ppb above background. ARB and S CASED plan to confirm these estimates with source and ambient vinyl chloride testing at the Hyperion facility in the summer of 1935. CMA 010&82 Surmiary of the Health Effects ot Vinyl Chloride HEALTH EFFECTS The health effects of vinyl chloride have ceen reviewed by several sources. Two good reviews are by the International Agency for Research on Cancer (IARC, 1979) and the U.S. Department of Health, Education and Welfare (U.S. HEW, 1978). A. Carcinogenicity 1. Humans - Epidemiological studies have shown that vinyl chloride causes angiosarcoma'of the liver in humans. Strong evidence also exists that vinyl chloride may cause cancer of the central nervous system, especially glioblastoma multiforne. Evidence also exists that vinyl chloride induces cancers of the lung and lymphatic system but this evidence is weaker. (IARC, 1979; U.S. HEW, 1978) 2. Animals - Vinyl chloride has been shown to be carcinogenic in several animal species after oral and inhalation administration. Liver angiosarcomas were observed in mice, rats and hamsters exposed to vinyl chloride. Other tumors seen were mammary adenocarcinomas, lung adenomas, Zymbal gland tumors and angiosarcomas at sites other than the liver. Doses in the inhalation experiments ranged from 50 to 10,000 ppm. A significant Increase in some tumors (angiosarcomas) was seen at the low dose (50 ppm) level. (IARC, 1979; U.S. HEW, 1978) CMA 010683 % B. Mutagenesis Vinyl chloriae is mutagenic in several test systems. Vinyl chlorid has been found to be mutagenic in several strains of bacteria, insects and nannalian cells. Chromosomal aberrations have been induced in workers exposed to vinyl chloride. (IARC, 1982) C. Teratogenicity Evidence that vinyl chloride causes teratogenic effects in humans or animals is equivocal. Vinyl chloride has been implicated In causing increased fetal deaths in the wives of vinyl chloride exposed worker's and birth defects in children of workers. Evidence Is inconclusive. (IARC, 1979) D. Pharmacokinetics The metabolism of vinyl chloride has been reviewed by several authors (IARC, 1979). Absorbec vinyl chloride is eliminated preaominantly via metabolism and exretion of metabolites into the urine. A small amount is excreted via the expired air as unchanged vinyl chloride. As the concentration of vinyl chloride to which an animal Is exposed is raised, a larger percentage of the absorbed dose Is eliminated as unchanged vinyl chloride In the expired air. The initial product of saetabollsm Is believed to be chloroethylene oxide. Vinyl chloride, in the presence of a microsomal enzyme fraction, binds to RNA in vitro and to RNA and DNA In vivo, Cnloroethylene oxide is believec to be involved in the covalent CMA 010684 * MFTbinding to kNA and DMA. Since an abundance of animal phalraictfki data exists, it may be possible to incorporate it into the aose-response assessment. (IARC, 1979) E. Acute and Chronic Effects (non-carcinogenlc) Acute exposure to vinyl chloride causes narcosis, cardiac irregularites and liver and kidney toxicity. These effects are seen at relatively high doses. Liver toxicity is evident as centrilcbular degeneration, hepatic fibrosis and necrosis. Degeneration of bone, nerves and connective tissue is seen after chronic exposure. Acroosteolysls, a degeneration of the bones in the fingers, occurs in workers. Disturbances in liver, kidney and pulmonary function also occur after chronic exposure. .11. THRESHOLD The U.S. EPA proposed a National Emission Standard for vinyl chloride in 1975, which was promulgated in 1976. The proposal for the emission standard states that there is no known threshold for vinyl chloride's toxic effects. (Federal Register, 1975) III. DOSE-RESPONSE ASSESSMENT The U.S. EPA's Carcinogen Assessment Group has performed a risk assessment of vinyl chloride's carcinogenic effects (U.S. EPA, 1975). The potency slope for vinyl chloride, derived from an animal inhalation study, is 1.75 x 10"^(mg/kg/day)"\ CMA 010685