Document xj9p2y6DLYb8V7aEXJqKzLMx6

HAZARD EVALUATION AND RISK ASSESSMENT FOR VINYL CHLORIDE Working Draft John T. Barr Air Products and Chemicals, Inc. Allentown, PA November, 1980 AP00020940 I. INTRODUCTION .............................. II. ENVIRONMENTAL EFFECTS................... III. ANIMAL METABOLISM....................... IV. ACUTE TOXICITY ............................... A. Plants and Lower Organisms B. Animals C. Humans V. CHRONIC TOXICITY ....................... A. Animals B. Humans VI.MUTAGENICITY ................................... VII. REPRODUCTIVE EFFECTS ................ A. Chromosomal Damage B. Birth Defects C. Summary VIII. CARCINOGENICITY............................ A. Animal B. Human. . .............................. IX. HAZARD EVALUATION....................... X. RISK ASSESSMENT........................... A. Previous Risk Assessments B. Further Calculations . . . Tables Figures References Page 1 u7 ? ? i* YfH ti u 4rf' '7 n n 4SZf AP00020941 List of Tables 1. Physical Properties of Vinyl Chloride i. Angiosarcoma Cases in the VC/PVC Industry by Country 3. Angiosarcoma Cases in the U.5. by Company 4. Chronalogy of U.S. Deaths from Angiosarcoma 5. Listing of Fully-Reported Maltonl Experiments 6. LAS Incidence, (%) in Rats, Inhalation 7. LAS Incidence In Rats, Ingestion 8. Equations for Curves Fitted to Various Single and Combined Maltoni Experiments 3. LAS Incidence in Wistar Rats, Ingestion AP00020942 t I. INTRODUCTION AND BACKGROUND Vinyl chloride (VC) is a classical carcinogen, in that it exhibits dose response effects in humans and several species of mammals, shows binding to DNA, and is mutagenic with activation in bacteria. Its industrial importance has led to one of the larger bodies of scientific data available on toxicity and metabolism, and several attempts at risk asssessments have been made. There have been a number of reviews of the literature on specific aspects of vinyl chloride, but none that has attempted a complete view of all of its toxic aspects so that their relative hazards can be evaluated. That is the purpose of this effort. A. Occurrence and Use Vinyl chloride was first prepared about 1833 (Herrle, 1963). Its industrial use dates from the late 1930s after it was discovered that mastication of polyvinyl chloride with certain esters yields a gel structure with elastomeric properties (Semon, 1933, Brous and Semon, 1935). Production and use of vinyl chloride, primarily for conversion to polyvinyl chloride polymers, has grown steadily at rates of 6*8% annually until the present manufacturing capacity in the United States Is about 8 billion pounds per year. (C&EN, J98D, Cameron, Lundeen and McCulley 1980), and the worldwide capacity is about four times that. There are minor uses of the material as a manufacturing intermediate for other chlorinated products. It was used as a propellant in aerosol containers until the early 1970s, when this application was withdrawn by the suppliers, and later officially banned (FDA, 1974, CPSC, 1974). Consideration has been given to the use of VC as an anesthetic, but it was considered unsatisfactory because of possible cardiac effects (Peoples and Leake, 1933, Oster, et al., 1947). It now appears that vinyl chloride may have been a minor constituent of the environment from natural causes. Hoffman and coworkers (1976) reported finding vinyl chloride in cigarette smoke, and therefore by inference in the combustion products of other chlorinecontaining organic matter, such as from forest fires. B. Health Concerns Vinyl chloride has been recognized for several decades as an anesthetic, and as being toxic to the liver of mammals. (See later sections for a fuller discussion of these points.) During the early 1960s a health problem was recognized in polymerization reactor cleaners termed acroosteolysls (ADI) (Dinman, 1971). Industry efforts to reproduce this effect In rodents were partially successful (Viola, TS70) and also disclosed that very high exposures of about 3% for 72 months led to cancers of the skin, bones, and lungs (Viola, 1971). More extensive studies sponsored by a European producer group led to the finding in .1973 that angiosarcoma of the liver (ASL) and tumors at other sites were developed at lower concen- AP00020943 i tratlons and longer exposures (Torgelson, 1974) and late In 1973 this same rare disease was discovered In polymerization workers (Creech and Johnson, 1974). There have now been a total of 81 cases of ASL reported worldwide and 24 cases In the U.S. (Stafford, 1980). Concern for this usually fatal disease has prompted an enormous amount of animal experimentation and human epidemiology relating to vinyl chloride health effects, and this will be summarized in the following sections. AP00020944 s II. ENVIRONMENTAL EFFECTS As the physical properties In Table I Indicate, vinyl chloride has low water solubility, and Is easily lost to the atmosphere from streams and discharges (Hill, et a!., 1976). It Is photochemically reactive, with a half-life In sunlight of about six hours (EPA, 1975). The reaction rates are slightly less than those of ethylene (Cox, Eggleton, and Sandalls, 1974, Cay, Noonan and Bufalini, 1976) in the reaction with NO , and considerably less in the reactions with ozone. It does not appear to be absorbed by microorganisms, as shown by tests with five mixed bacteria populations, three mixed fungal populations, two axenlc bacterial cultures, and one algae. The mixed bacteria did not degrade the VC, nor was It toxic to the bacteria at concentrations up to 900 mg/1 (Hill, 1976). It does not bioaccumulate In the food chain (Lu, et al., 1977). Brown, et al., (1977) reported on the acute toxicity of VC to northern pike, but the data are inadequate for evaluation of the results. The EPA has reported (EPA, 1975) finding VC in the water supplies of some cities .in.the.ppb.ranQe. The concentration was .higher .in .the finished than in the raw water, indicating that it may be produced In the chlorination step. It 1$ also present in the discharge of some VC handling plants in the low ppm range (EPA, 1974). The EPA has since Imposed stripping requirements on industrial effluents (EPA, 1976). The EPA has conducted three ambient monitoring programs around VC handling plants (EPA, 1975). The first, In 1974, found measurable quantities et distances up to 0.5 km from e PVC plant. The third program failed to find significant quantities at the fence line of five large fabricating plants. The results of the second program have not been released, but analysis of the data has shown (Air Products, 1976) that the average concentration In early 1975 at the plant tested was about 40 ppb at 500 meters for the plant center, 10 ppb at 1 km, and 2 ppb at 2 km. The EPA has calculated (EPA, 1975b) an average exposure of 17 ppb to persons residing within five miles of a typical PVC plant, using emission data and modeling techniques which were strongly disputed by Industry. The estimated 95% reduction of emissions by the current standard (EPA, 1976) presumably gives a current exposure to those within five miles of 0.4 ppb. The generally accepted field monitoring method for VC has a lower sensitivity of 10 ppb (EPA, 1976), so that these estimates cannot be verified. Grulnard, Taft, and Wiberg (1976) calculated that the steady state, worldwide ambient concentration in 1973 was about 0.0014 ppb (3.6 nanograms/nr). Hoffman, et al., (1976) found VC In tobacco smoke and speculated that it might be present in combustion gases from all chloride-contaminated materials, and therefore ubiquitous. Current industry estimates are that emissions have been reduced about two orders of magnitude from VC handling plants and three orders of magnitude In the residual VC In products, and thus In the emissions from fabrication operations. AP00020945 i Y The combustion of vinyl chloride produces stoichiometric amounts of hydrogen chloride. Heating of the polymer does not cause it to revert to the monomer, except in negligible amounts at temperatures well above the normal processing temperature (Wakeman and Johnson, 1978). The use of PVC for liquor bottles was stopped In 1973 when low concen trations of VC were found in the contents. The FOA still permits the use of rigid PVC as packaging for foods, and the use Is much more widespread In Europe than In the U.S. There, a limit of 50 ppb of VC in the foodstuff is imposed (Council of Europe, 7979). Both Feron et al., (1975) and Witney and Collins (1976) have shown that the retention of VC in drinking water by rats is inefficient. The latter author calculated that 20 ppm in total drinking water (45^Rj/day) would produce VC levels In the blood equal to a constant exposure to 2 ppm In the air. Hefner, et al., (1974) have shown that skin absorption in monkeys is only 0.1% as rapid as absorption through the lungs. AP00020946 ANIMAL METABOLISM Clapp and coworkers (Clapp, 1969) identified cystitne derivatives In the urine of rats treated with vinyl chloride (VC) or vinyl acetate, and postulated that intermediates were formed in the metabolism of these compounds which were reactive with glutathione. Vazln and Plokhova (1969) reported an increase In adrenaline derivatives in the blood of chinchilla rabbits exposed to VC. Hefner and coworkers (Hefner, 1975) proposed a saturable metabolic pathway in rats via alcohol dehydrogenase which gives rise to chloro* ethylene oxide or chloroaeetaldehyde as the first active intermediate, and which is the primary metabolic route at concentrations below 100 ppm. The final excretion products appeared to be the result of binding with glutathione and/or cysteine at the sulfhydryl group. Higher concentrations, or the addition of alcohol, result in an alternate pathway via chloroethanol. Gothe, et al. (1974) found support for this primary metabolic route by trapping metabolic products from rat liver homogenates exposed to VC. (See also Muller, Norpath, and Ouzanski, 1978. ) Van-Duuren (T-975)-aVso postulated -that -the-epoxide route was active. Kappus et al. (1976) reported that the addition of glutathione reduces the binding of VC-products to protein in rat liver mlcrosomes, and jaeger (1975) found that chronic exposure to VC reduced the glutathione concentration In the liver of rats, and that pretreatment of the rats with phenobarbitol, an alcohol metabolism suppressor, Increased the liver toxicity of VC (Jaeger, 1974). Watanabe, et al., (1976) found, however, that the suppression of hepatic nonprotein sulfhydryl was not seen at exposures below 50 ppm. Bolt, et al., 0975) found that the presence of NAOPH was required for binding of VC metabolites to protein in either rat or human liver microsomes. These workers also found (Bolt, 1976) that respiratory uptake of VC by rats was completely blocked by cytochrome P-450 inhibitors. Green and Hathaway (1975) isolated and identified the cystiene-containing metabolic products of VC, but postulated a free-radical initiated direct addition of VC to the -SH group, rather than an epoxide intermediate. However, these workers concluded later that the epoxide route was compatible with experimental data. (Green and Hathaway, 1977, 1978, Hathaway, 1977.) Guengerich and Strictland (1977) disputed both the epoxide and free-radical mechanisms in a study which found that both NADPH and cytochrome P-450, together with molecular oxygen, were necessary for the metabolism of VC, and proposed a mixed-function oxidation route. Buehter and coworkers (1978) concluded that rodents and humans have similar metabolic pathways, but that the human metabolic rate is much lower than that for rodents. The postulated metabolic intermediate chloroethylene oxide has been shown to cause tumors In nice at the site of injection or after phorbol-promoted skin application while the other intermediate chloroaeetaldehyde did not (Zajdela, et al., 1980) AP00020947 (* 6 The metabolic rate for VC In rats has been found to be 1000 times as fast as that of vlnylldene fluoride, which Is a much weaker Inducer than VC of pre-neoplastic hepatic foci in newborn rats (Stockle, et al.f 1979). Metabolites of VC have a different binding affinity for rat microsomal protein than do those of trichloroethylene, a related compound for which the demonstration of carcinomicity 1* dubious (Saib, 1979). Vinylidene chloride appears to be metabolized by a very different pathway (Hathaway, 1977), although see also Watonabe, et al., (1980) who feels that rate is Important. Styrene is also postulated to metabolize via a reactlva oxide Intermediate (Vainio, 1978) but it has not proven carcinogenic to rodents; thus, rate of metabolism, and not route, may be a key to the carcinogenicity of similar substances. Gehring (1977) has reviewed several studies of his coworkers and concluded that there is a dose-dependence for the fate of inhaled VC, with a threshold for the ability of the test animal to provide sufficient sulfhydryl groups to prevent covalent binding to protein. They, and several other workers (Green and Hathaway, 1975, Wlthey, 1976, and Buchter, et al., 1978) found that an equilibrium 1$ established very quickly between the VC content of the blood and the ambient concentration, and that the expiration levels drop very quickly after cessation of exposure In both humans and animals. This indicates that there is little or no storage of VC In the body. In summary, it appears that vinyl chloride is metabolized in most mammals tested by a mixed-function oxidase route. The metabolic intermediates are excreted after reaction with the sulfhydryl groups of glutathione or similar substances. Excess depletion of the available sulfhydryl groups In the microsomes may lead to conjugation with protein, which if it occurs in the chromosomes, can lead to genotoxic effects. AP00020948 7 IV. ACUTE TOXICITY A. Plants and tower Organisms There are few published data on the effect of VC on flora. Hill, et al. (1976) reported that VC does not appear to be absorbed by bacteria, fungi, or algae, nor was the VC degraded by the bacteria. Ho toxic effects were seen. Heck and Pines (1962) found no effect on several plant species from seven days' exposure at 10 ppm, with moderate damage at 100 and 1000 ppm, an effect very similar to that of ethylene. The EPA states (1975) that vegetational damage around VC-handling plants has not been documented. See Section VI for further discussion of effects on lower organisms. B. Animals The principal acute dangers from VC are anesthesia, which can cause death from respiratory paralysis, reversible liver damage, and cardiac arrhythmia. A summary of the early literature was prepared by von Oettinger in 1955,. and an exerpt is reproduced below: 'tike other chlorinated hydrocarbons, vinyl chloride has narcotic properties. According to Peoples and Leake (1933) the narcotic range for mice is between 3.5 and 5 mM per liter of air. Concentrations of 7 mM per liter of air will cause narcosis in rabbits and dogs after 1 minute, and the recovery Is prompt and not followed by untoward effects even after prolonged exposure. Schaumann (1934) determined the vinyl chloride level In the blood of cats anesthetized with 10 to 13 vol. percent as 15 to 17 mg. percent. Oster, Carr, Krantz, Jr., and Sauerwald (1947) used vinyl chloride stabilized with 0.5 percent of p-tert-butyl-catechol for narcosis of dogs, starting with concentrations of 50 vol. percent and reducing the concentration gradually to 7 vol. percent. They found that the induction was rapid, but that "crowing" continued even during deep anesthesia and that there was profuse salivation. During narcosis the relaxation of the abdominal muscles was good but the legs remained rigid showing, throughout the anesthesia, Incoordlnated movements. The recovery was rapid but associated with violent excitation. As to the effect of vinyl chloride on the circulation, Schaumann (1934) studied its effects in the Starling heart-lung preparation of cats judging-the action by the effect on the intra-aurieular pressure. He found that similar effects were produced by . 1.3 percent of solaesthln (dlchloroethylene), 3 vol. percent of ether, and 18 vol. percent of vinyl chloride. Higher concen trations (20 vol. percent) of vinyl chloride caused a more or less marked relative insufficiency and even 25 to 30 vol. percent were unable to produce complete cardiac failure. Oster, Carr, Krantz, Jr., and Sauerwald (1947) studied the circulatory response in dogs anesthetized with 10 vol. percent AP00020949 / of vinyl chloride. They noted a moderate fall of the blood pressure and definite evidence of cardiac Irregularities as indicated by intermittent tachycardia, extraventricular systoles and vagal beats. Electrocardiographic studies revealed marked changes of the cardiac rhythm such as tachycardia followed by bradycardia, Inversion of the R spike, and in one instance incipient ventricular fibrillation. All records showed abnormalities of the QRS interval varying from sinus arrhythmia and transitory extreme left axis deviation to very serious conditions such as auricular-ventricular block, ventricular tachycardia, ventricular multiform extrasystoles, and inversion of the T wave with elevated ST segment in lead II. As the anesthesia progressed towards respiratory failure most of the QRS abnormalities disappeared but the R amplitude was generally reduced. As to the toxicity of vinyl chloride, Patty, Yant, and Waite (1930) studied this in guinea pigs. They found that exposure to 20 to 40 vol. percent kills the animals In a very short time, that concentrations of 10 vol. percent are dangerous to life with exposures for 30 to SO minutes, and that 0.5 vol. percent is the maximum allowable concentration for several hours' exposure without causino acute disturbances of severe nature. Animals exposed in this way showed some edema of the lungs and hyperemia of liver and kidneys. They considered vinyl chloride less harmful than chloroform or carbon tetra chloride and of a similar order of toxicity as ethyl chloride. Schaumann (1938) found that mice and rats tolerate repeated light narcosis for 4 hours daily on 5 to 8 consecutive days and for 1 hour daily for 4 weeks without showing kidney or liver Injuries. Dogs which had been narcotized for 3 hours with 10 vol. percent on 7 occasions in the course of several weeks showed no considerable changes In kidney and liver. Higher concentrations (20 vol.' percent) caused in dogs marked salivation, respiratory arrest, and vomiting after narcosis. Peoples and Leake (1933) determined the lethal range for mice with 10 minutes1 exposure as 10 to 12 mM per liter, and Schaumann (1934) determined the vinyl chloride level In the blood at the time of cardiac arrest as < 40 mg. percent and at the time of respiratory arrest as 27 to 30 mg. percent, the same value for chloroform being 6Q to 70 mg. percent." Mastromatteo, et al., (1960) exposed mice, rats, and guinea pigs to 10, 20, 30, and 40% VC in air for 30 minutes and found 1 of 5 mice died at 20%, all mice and rats and one guinea pig died at 30%, and . 2 of 5 guinea pigs died at 40%. Deaths were due to narcosis and some pulmonary edema was reported. Prodan (1975) studied the two-hour lethal dose of VC in mice, rabbits, guinea pigs and rats, and found a rather sharp boundary between lethal and non-lethal doses for this time period. Sensitivity to VC was found to be: rabbits, guinea pigs < rats < mice. Surviving animals exhibited general congestion of all Internal organs. Pulmonary edema, marmorated liver, and kidney tumefaction were observed. AP00020950 9 Torgelson, Ogen, and Rowe (1961) found that repeated 7-hour exposures to 100 ppm for six months resulted In Increase In rat liver weights, but no observable effect In guinea pigs, rabbits or dogs. Similar exposure to 200 ppm resulted in mlcropathologlcal changes in rabbit livers and weight increases in rat livers. Exposure to 500 ppm for 4.5 months caused micropathological changes in rat livers. There was no observable effect from 50 ppm at six months in either species, nor from daily 100 and 200 ppm doses for one hour, but longer daily exposure times caused slight Increases in liver weights. They then suggested that a 50 ppm time-weighted average (TWA) be used as a limit for human exposure. Lester, Greenberg, and Adams (1963) proposed a 500 ppm TWA as the result of their work at much higher concentrations, and this was accepted by the American Conference of Governmental and Industrial Hygiene first as a TWA, then as a ceiling concentration (ACGIH, 1963). This was adopted by the Occupational Safety and Health Administration In Hay, 1971 as a formal regulation. The ACGIH recommended a reduction to 200 ppm TWA in its Third Edition in 1971. Rowe and Torgelson (1977) have since commented: "Had our recommendations based upon relatively simple toxicology been followed then, the difficulties of today may never have occurred." Oster, et a!., (1947) and Carr, et al., (1949) reported that the anesthetic level in dogs was 8-12%, with serious cardiac arrhythmias and the development of sensitization. Feron, et al., (1975) administered VC in soya oil to rats by gavage for 13 weeks. They reported a no-effect level for liver damage of at least 30 mg/kg, and doubtful toxic effects at ICO and 300 cng/kg. Over 92% of the administered VC was expired in four hours after treatment. One part of a bioassay (Hehir, 1980) on rodents conducted for the Consumer Product Safety Commission consisted of high, short exposures to VC in the air. These included one-hour exposures to rats and mice at 50, 500, 5000, and 50,000 ppm, 10 and 40 one-hour exposures at 500 ppm, and 49 and 100 exposures at 50 ppm. There were no external signs of toxic response during the exposure period except for the mice at 50,000 ppm, during which time the males exhibited hyperventilation, twitching, atoxia, and tremors, and the females showed hyperactivity, atoxia, and respiratory difficulty. During the lifetime holding period following exposure, all mice exposed to 500 ppm or more showed high levels of pneumonitis. Hale rats exposed at 50,000 ppm developed bronchopneumonia at a higher rate than did other groups. Mortality of two strains of mice exposed at 50,000 ppm, and one strain exposed at 50 ppm was higher than the controls. Rats showed sublethal cytoplasmic liver damage from which they recovered. Jaeger, et al., (1974) also exposed rats to 50,000 ppm VC, for up to five consecutive days at six hr/day. Those animals not pretreated with phenobarbitone showed no abnormality, while pretreated rats did have acute biochemical and histological changes after the first AP00020951 treatment. Subsequent treatments caused no further effects, which led the author to hypothesize that the first treatment caused the development of some protection against further damage. C. Humans Humans appear to respond to the acute effects of VC much as do the lower mammals. The odor threshold of VC is about 1200-2000 ppm (Union Carbide, 1974). Deaths have been reported (see, for example, Damziger, I960) of workers exposed to unknown, but high occupational concentrations, and there are numerous anecdotal reports of workers suffering temporary- loss of consciousness in the industry. (Spiritas, et al., 1975, Cole, 1975, Klein, 1976). Schauman (1936) reports that the human narcotic range Is 7*10% with 12% being dangerous. Lester, 1963, reported the range as 8*10%. There are no immediate effects of exposure in the 50-500 ppm range (Baretta, 1969). Dublin and Vane (1935) give confusion, Intoxication, burning of the soles of the feet, and subsequent headaches as the results of exposure. AP00020952 V. CHRONIC TOXICITY A. Animals Few animal studies extending more than six months have been reported apart from bioassays for carcinogenicity. Viola's attempt (1970) to reproduce AQL in rats used exposure of 25 rats at 3% for four hrs/day, five days/week for 12 months. He reported that the animals were slightly soporific, and began to show a decrease in weight and reaction to external stimuli. Half of the animals died of cardio respiratory complications and two of hematoperitoneum. Most showed pathological involvement of the brain, liver, kidney and thyroid. Six showed pathological alterations of the skeleton{ bone metaplasia and changes in*the cartilage. There were, In addition, tumors at various sites. Basalaev, et al., (1972) reported a study with rats and rabbits in which they claimed to have reproduced AOl in these species at 0.03-0.04 mg/1. Few details were given, and these results have not been duplicated. Feron and Krees (1979) exposed rats to 5,000 ppm, 7 hr/day, 5 day/week for up to one year and found tubular nephrosis, focal degeneration of the myocardium, and spleen damage, in addition to various primary tumors. B. Humans An article which has been cited frequently as supplying an early warning of the toxicity of VC is that by Tribukh (1949) which discusses health conditions in a PVC processing plant in Russia. The author actually does not ascribe the health problems to any specific material, but mentions diphenyl chloride, hydrogen chloride, and other toxic materials as being present. No measurements were made for VC, but it is extremely unlikely that any significant quantities could have been present in the workplace. Several articles appeared before 1974 describing what has come to be called "VC poisoning" or "VC disease", although the latter has become more closely associated with AOL than gastro-neural problems. Many of these are not particularly useful because there are no exposure data and there often Is known exposure to other recognized toxic materials. It does appear, however, in light of subsequent information, that the exposures must have been quite high for these symptoms to have appeared so quickly. Suciu (1975) reported a decrease in symptoms as the exposure was reduced. Some of these reports are listed briefly below; Filatova, et al., (1958) reported spastic angioneurosls in workers that had been exposed to 20-315 ppra VC in a PVC process. Gabor, et al., (1962) observed a decrease In catalase and an Increase In peroxidase activities and glutathione levels for VC and other exposures. AP00020953 it Gabor, et al., (1964) reported that PVC workers had a decrease of albumin and increase of beta- and gamma- globulins and other blood serum changes. Grlgorescu and Toba (1966) found chloroacetic acid in the urine of VC-exposed workers and changes in the alpha/gamma globulin ratio. Antonyuzhenko (1968) found that early clinical signs were reversible, but that the majority of "poisoning" manifestations were progressive. Smirnova and Granik (1970) reported residual central nervous system effects in persons exposed to a variety of chemicals, Including VC in some instances. Kudryantseva (1970) found that severe cases had cardiac disturbances, including changes in rhythm, conductance, and polarization. Juhe and Lange (1972) found liver disfunction in 2 of 7 patients with serious A01, another with respiratory disease, and three with scleradoma. Several subsequent papers by the same group reported similar findings. (Stein, Juhe, Lange and Viltoman, 1973, Juhe, et al., 1973, Lange, et al., 1974). Kramer and Mutchler (1972) made a statistical analysis of the difference between a group who had been exposed to VC for up to 25 years work history at up to 300 ppm versus other ehemical workers, and found minor changes In certain blood chemistry and liver functions. Portal fibrosis and portal hypertension, frequently combined with spleenomegaly, are found in both workers with ASL and other workers with extensive history of high VC exposure (5uciu, et al., 1967, Marsteller, et al., 1973, Falk, et al., 1974, Thomas, et al., 1975, Waxweil.er,. 1977)... Abnormal sinusoidal lining cell-development also1$ frequently associated with these symptoms. It has been postulated that these are early stages of ASL, but there have not been enough observations to confirm this hypothesis. Taylor (1977) has suggested the use of grey-scale ultrasound as a diagnostic tool for measuring portal vein Involvement. Voltman (1975), Lillis (1975), and Lange (1975) discussed this problem, and added thrombocytopenia and esophogeal variances to the list of sypmtoms. Neither Waxweiler, et al., (1977), nor Gamble, et al., (1976), found any indication of loss of respiratory function associated with VC exposure although Mapp, et al., (1978) and Miller (1975) did believe that there were some functional lung disorders in PVC workers which could not be explained totally by smoking, age, dust exposure, or bronchitis. A recent review (Joint Conference, 1980) of data relating to the respiratory functionality of VC/PVC workers supplied no significant data associating VC exposure with lung abnormalities. AP00020954 A second area of concern for humans exposed to VC over long periods Is a degenerative disease of the bone tufts, accompanied by Raynouds syndrome, and, frequently, sderadotna. Suciu (1963) first reported this disease, then Cordier (1966). These were followed by Harris and Adams (1967), Wilson, et al., (1967), and Basalaev (1970). One Industry-sponsored survey (Oirman, 1971) identified 25 definitive cases and 16 suspect cases In the U.S. No certain eiteological agent was found, but the cases were clearly associated with hand cleaning of reactors, (Cook, 1971), where there is a combination of physical joint Insult and VC exposure. The disease is most often seen in the hands and fingers, but occasionally in the feet or back (Harris, 1967). Dodson (1971) could find no obvious medical reason for predeliction to the disease in the four cases which he studied. Maricq (1976) found a strong association of capillary abnormalities In the hands with workers suffering from ADI. Lillis (1975) reported that an abnormal Allen test for circulatory efficiency was found in many affected workers, as well as many other organic symptoms related to the liver and circulatory systems. This disease is seen occasionally In patients not exposed to VC, Cheney (1965), Wilson (1967) Meyerson (1972), but there is no question that VC exposure is responsible for the cases seen in the industry. It appears to be a result of circulatory deficiencies brought on by VC exposure, possibly aggravated by physical insult. Bretza and Goldman (1979) have discussed non-occupational cases of scleradona and AOL. Thus, these are two major areas of concern In the noncarclnogenlc chronic effects of VC exposure: AOL and liver damage. These two problems are sometimes associated in workers with long histories of high exposure. Various liver symptoms have been considered precursors In the progression to ASL, but it is curious that, although there are roughly the same number of AOL and ASL cases recorded, no person has yet been confirmed as suffering from both diseases. Knowledge of the exact exposures of these cases would be of great assistance in evaluating the concern for exposures experienced at present, but there have been no definitive estimates made. Suciu (1975) reported values associated with clinical symptoms that appear to be far too low, in light of Industry experiences since 1974. A CEFIC publication (1976) has estimated the average exposure for all European PVC workers in the 1945-1960 era as "up to and beyond 1000 ppn", and there is no reason to believe that the U.S. conditions were much different, but even this is an average for all workers, and the symptoms, AOL, chronic liver damage, and ASL, are more closely associated with reactor entry and cleaning than with other jobs. The National Toxicology Program (1980) quotes IARC data which also cites very high potential exposures, and Fishbein (1979) quotes several other sources. The EPA requires (EPA, 1976) all PVC processes to displace the vapor from reactors with water before opening for entry. This is based on a study (EPA, 1975, pages 4-71) which showed that this reduced the residual content of the reactor vapor to 9,000 ppm. AP00020955 H This Is a new procedure, which had not been In general use before 1975. It had been the practice of some companies to force air through an opened reactor before entry, but this was generally an unmonltored procedure, and coupled with the anecdotal reports of anesthesia of workers (Spiritas, 1975, Cole, 1975, Klein, 1975) supports the conclusion that reactor cleaners certainly were exposed to recurring concentrations In the several thousand ppm range. This fact must be considered In any attempt to evaluate the hazard to workers at the present tine, or to the population at large. AP00020956 VI. MUTAGENICITY Vinyl chloride has been shown to cause various types of chromosomal changes in single-celled life forms. This is generally termed "mutagenesis", and is in common use as a screening test for possible carcinogenicity, and bears no necessary relationship to its ability to cause herldable changes in higher forms of life. That subject will be considered In the next section. Hopkins (1979) has published a review of the mutagenicity data on VC. Although it.is clear that VC is mutagenic in several strains of Salmonella where activated by rat liver cells (Rannung, et al., 1974, Bantsch, 1975, Grein, et al., 1975), some studies have shown it to be effective without activation (McCann, et al., 1975, Andrews, et al., 1976) and some have not (Rannung, 1974, Bartsch, 1975, Elmore, 1976). This may be explained by the direct metabolism of VC by the bacteria microsomes; Kappus, et al . (1975) found that rat liver nicrosonies are effective in this, and thus bacteria may be also. Garro, et al., (1976) suggested a free radical mechanism for the activity of the rat liver fraction, but Bartsch and Montesano (1975) and Kappus, et al., (1975) favored the mixed-function oxidase as the mediator. Both of the suspected metabolic intermediates for VC, ehloroethylene oxide and chloroacetaldehyde, are also mutaaenic to Salmonella (Halavielle. 1975, Rannung, 1976). ---------------- These metabolites also were effective in transforming Bacillus subtillls (Elmore, et al., 1976) and Chinese hampster cells in vitro (Huberman. at al., 1975). Laumbach, et al. (1978) studied the effect of VC and its metabolites on Salmonella and 5^ subtilIlls strains, and concluded that recombination repair is the mechanism for correcting VC-metabolite damage. Mouse-liver microsomes were necessary for VC to have an effect on various Sacchoromvces varieties (Soprieno, et al., 1976) while ehloroethylene oxide was active directly (Soprieno, et al., 1977). Chloroacetaldehyde was only weakly active and ehloroethanol was inactive, the mouse-mediated assay with Sacchoromyces was positive with VC, also (Soprieno, 1976). Mattern, et al., (1977) were not successful In obtaining positive results In Salmonella with urine from either exposed men or rats, even in the presence of Arochlor-treated rat liver cell preparation and glucuronidase. Therefore, the final metabolites do not appear active in this test. Drozdowicz and Huang (1977) did not find VC, with or without S-9 rat liver fraction, to cause 8 detectable change In two species of Neurosoora crassa. " Verburgt and Vogel (1977) found only recessive lethal effects with VC in Drosophila. Magnus son and Romel (1978) found that pretreatment of the Drosophila with barbiturate enhanced the activity of VC, but did not eliminate the threshold limit on activity seen by them and Verburgt. They agreed with Bartsch and Montesano (1975) that the mixed-function oxidase system was employed in the activation of VC. AP00020957 It The EPA has announced (J. Commerce, 1980) that a hybrid spiderwort changes the color of Its blooms in the presence of VC and may thus be useful as a detection device for VC emissions. In summary, the conversion of VC Into metabolites serves to affect chromosomal damage on several varieties of bacteria and plants. Repair mechanism deficiency is believed to be the cause of transmittable hereditary defects. AP00020958 VII. REPRODUCTIVE EFFECTS A. Chromosomal Damage Fleig (1976) has reviewed the literature on chromosomal damage to humans exposed to VC and concluded that damage is seen only in those persons exhibiting "VC Illness," that is, overt clinical symptoms ascribed to high exposures. The first reports discussed here are based on small cohorts, presumably selected for some special interest in this type of test. Not all studies had controls, and neither radiography, age, other occupational exposures nor smoking were accounted for In some studies. Positive results, that is, an apparent excess of chromosomal abnormalities versus controls (in most cases), were found by Oucetman, et al. (1975) in 11 U.S. workers, Funes-Cravioto et al., (1975) in 7 workers in Sweden compared to 3 controls, Puchase, et al., (1975) in 56 British workers, and Fleig 0977) in 20 German workers suffering from severe clinical symptoms. It Is possible that the severe breaks found by Leonard, et al., (1977).may be due to X-ray treatments, and those found by Kucerova (1979) to smoking or the use of alcohol. Hansteen et al., (1978) restudied 37 of 39 Norwegian workers after 2.5 years with only minimal VC exposure and found that the originally reported excess of abnormalities was not seen. No excess of abnormalities was reported by Fleig and Thiess (1974) for 10 German workers, by Picciano, et al., (1977) on 203 workers with up to 30 years exposure but probably less than average exposure, and by Lange, Swinger, and Veltman (1975) on 20 German workers with some symptoms. Milan et al., (1975) found changes only in those workers directly involved in the polymerization process. Fleig and Thiess (1978) reported chromosome aberrations In Chinese hamster bone marrow cells after exposure to high VC concentrations. Johnson, et al., (1976) did not find such an effect in the bone marrow cells of rats exposed at lower concentrations, but sufficient to cause a significant incidence of AOL-like symptoms. Picciano, et al., (1977) concluded that any cytogenic observations were probably related to length and degree of exposure, and that any genetic risks were avoidable by adequate control of exposure. Basler and Rohrborn (1980) found that this was true for the bone marrow calles of Chinese hampsters exposed to high levels of VC in vivo. B. -Birth Defects Purchase, et al., (1975) evaluated the significance of their findings of chromosomal damage to possible genetic risks by performing a dominant lethal study (Anderson, et al., 1976) in male mice, which were mated with two untreated females for 8 successive weeks after exposure to 3-30,000 ppm of VC per 6 hrs/day for 5 days. There was no Increase in the number of early deaths per implantation, and they concluded that any expression of harm to the chromosomes of somatic cells was not carried over to stem cells. Short, et al., AP00020959 ti (1979) performed a similar experiment with longer exposures to lower concentrations, and also found no effect on reproduction or survival. Hehir, at al., (1980) included an F.-generation study in their program. Parent rats were exposed to 50 or 500 ppm VC one hr/day, 5 days/week for 10 weeks before mating and the subsequent three generations were examined for litter size, percent stillborn, growth, viability, and reproductive anomalies. No effect of F0 generation exposure was seen. A study by John, et *1., (1977) found no excess fetal wastage in mice, rats or rabbits at VC exposures sufficient to cause maternal toxicity. The authors also found that VC, either alone or In combination with ethanol, was not teratogenic when dans were exposed on days 6-15 at 50-2500 ppm VC. The combination of alcohol and VC did cause higher incidences of some skeletal variations. Similarly, Hehir, et al., (1980) reported no changes In the offspring of exposed parents. Mirkova, et al., (1978) reported skeletal ossification effects, increased embryo resorption and other effects in rats, at exposures considerably below those used by other workers, but adequate details of the study are not available for thorough evaluation of the report. One portion of the Kaltoni (1977) program was an examination of the second generation rats whose dams were exposed. Experiment BT-5 found 2ymba1 gland carcinomas, angiosarcomas at sites other than the liver, and subcutaneous tumors fn the adult offspring of dams . exposed to 6,000 and 10,000 ppm VC from the 12th to the 18th day of pregnancy. There were no specific controls for these experiments, and relatively little detail Is reported. There Is no mention of other effects- to the offspring. The' total number of tumors, both' in the exposed and offspring, art substantially less than for the controls used in his other experiments. There was no ASL in either. Infante (1976) has reported finding an.excess of congenital birth malformations In three communities in Ohio that are near VC processing plants. The Center for Disease Control performed a follow-up study and stated (CDC, 1975) that "it could not establish any association between cases and vinyl chloride exposure." (Subsequently, it has reported [CDC, 1979] that the recent trend in birth defects in the U.S. has been downward.) Edmonds (1976) has discussed the methodology of the follow-up study which was of the case-control type, and stated that no relationship was found between the cases and their parents* employment or place of residence relative to the VC plants. The CDC performed two other birth-defect studies in areas possibly associated with vinyl chloride. In one (Edmonds, et al., 1975) the hospital records for a city in Pennsylvania where a PVC plant is located were reviewed, and no increase In birth defects was seen. In another (CDC, 1976) hospital records for Kanawha County, West Virginia were reviewed for 1970-74 and all cases of birth defects were AP00020960 compared for residence and employment by case-control methodology. The study concluded that "no relationship between Infants with malformations and parents1 exposure to VC could be established.11 Theriault and Goulet (197?) reported a comparison of two cities in Canada, and found an increase in birth defects in the city which contained a VC processing plant. The Increase was spread over a wide variety of types of defects, and only raw statistics were used. There was no attempt to compare exposures of the parents, nor were there controls for any other environmental factors. Thus, the significance of this finding cannot be evaluated. Infante, et al., (1976) have reported an Increase In fetal wastage among the wives of workers in a PVC plant. This study has been criticized by Paddle (1976), MacMahon, (1977) and by Downes, Stallone, and Frankowski (1977), on the grounds of Improper data gathering techniques, Incorrect' statistical treatment, and Incomplete reporting. Also, the statistical significance of the reported excess of fetal wastage of exposed workers' wives disappears if those women subject to chronic spontaneous abortion are omitted. Hass and Sehattenfeld (1979) concluded that the inferences .by Infante could not be sustained by the data. Hatch (1980) explored the statistical power of various studies on reproductive effects. She found that the Ohio birth defect study (Infante, 1976) was deficient in power, but that the negative CDC recheck (CDC, 1975, Edmonds, 1976) of this report had adequate power to detect a significant effect, as did the CDC (1976) study in West Virginia, which also was negative. Similarly, the worker study (Infante, et al., 1976) on abortions and miscarriages had design deficiencies that prevented its results from being accurate. C. Summary In summary, VC does not appear to be teratogenic, nor to cause excess fetal wastage in animals or humans. It can cause chromosome damage in somatic cells, but apparently not in stem cells. It may be a transplacental carcinogen at high exposures in rats, but the data are not conclusive. AP00020961 Za VIII. CARCINOGENICITY A. Animal Viola (1970, 1971) was the first to report the carcinogenicity of VC, as the result of an attempt to reproduce AOL in rats. (See Sections I and IV above.) His experiments were at such high exposures that life-shortening of the animals was evident, so a second series of experiments by Maltoni (1977) was sponsored. Several other studies by industrial and governmental groups were also undertaken at about the same period. Caputo, et al., (1974) exposed rats to 50-20,000 ppm of VC for 4 hrs/day, 5 days/wk for 12 months, and found ASL and skin carcinomas in those exposed at 500 ppm and above, and lung adenocarcinomas in those exposed to 2,000 ppm and above. Rabbits exposed to 10,000 ppm VC for 15 months had lung and skin tumors. Keplinger, et al., (1975) reported the preliminary results of tests with mica, rats, and hamsters which confirmed the carcinogenicity of VC. However, the study contained procedural flaws which precludes Its use In quantitative risk assessment. It has been shown (Radike, et al., 1977, Radike, 1980) that a combination of VC and ethanol enhances the number of malignant and benign tumors In rats over that found in with VC alone, or ethanol alone. Feron, et al., (1978, 1979) administered VC to rats which was absorbed into PVC so as to constitute dosages of 1.7, 5.0 and 14.1 mg/kg/day, and by gavage In soya oil at 300 mg/kg/day. This assured a 24 hr/day exposure as the VC desorbed (Feron, et al., 1975). An Increase in tumors was found at all levels of dosage, with ASL being elevated at 5.0 mg/kg and above,- andother livertumors being found at 1.7 mg/kg. Fibrosis was not seen as a precursor to tumors. There was some decrease in the incidence of normal age-related tumors as the dose increased, and there was a decrease in the latency period for ASL as the dose increased. No brain or primary lung tumors were seen. Lee, et al., (1978) reported that mice were much more responsive to VC exposure than were rats, finding tumors at many sites In mice at 50 ppm and above, but only primary ASL in rats at 250 and 1,000 ppm. Feron and Krees (1979) found tumors at multiple sites in rats at 5,000 ppm exposure for one year. Maltoni found (Maltoni, 1977) that day-old rats were more susceptible to exposure to VC than normal voung adults. He also found that Wistar rats and hamsters were less responsive than the Sprague-Dawley rats used in the bulk of his experiments, and confirmed that mice were more susceptible. Stockel et al., (1979) theorized that the relatively higher rate of metabolism of VC compared to other AP00020962 halogenated olefins was responsible for Its greater carcinogenicity In newborn rats. Groth (1980) reported that the time-to-tumor decreased and the incidence of ASL increased in rats exposed at 946 ppm VC as the age at the beginning of exposure Increased. Maltonl summarized (1979) his extensive series of experiments with rats exposed to VC by Inhalation and gavage by stating that tumors at various sites followed different dose response curves. The lowest doses at which statistically significant elevations of various tumors were seen were: Forestomach papillomas: Neuroblastomas: Zymbal gland carcinomas: Nephroblastomas: Liver angiosarcoma male: female: Hammary adenocarcinoma: 30.000 ppm 10.000 ppm 10,000 ppm 250 ppm 200 ppm, 50 mg/kg 50 ppm, 16.7 mg/kg 5 ppm The finding of an 'increase in mammary adenoma at very low exposures led to concern for female workers, particularly When a study of fabricator employees found an excess of breast cancer among females (Chiazze, Nichols, and Wong, 1977). However, a case-control follow-up (Chiazze, 1980) found no relationship to VC exposure In those workers. In any case, the very high and variable incidence of such tumors in the controls, about which Maltonl has often commented in his oral presentations, makes It very difficult to support a conclusion that the test animals did respond at such doses. Much emphasis has been placed on the fact that LAS is a rare tumor, and Maitoni found none among his 465 controls. He did report four cases among 4,200 historical controls in his colony, for an incidence of 0.952%. (Summing his seven lifetime experiments yields a total of 881 Sprague-Oewley controls for a total of 2,534 exposed animals, so some groups may have served as controls for more than one experiment.) a, It is interesting to note that in Sprague-Ctfwley rats from a different colony (FDA, 1980) a crude Incidence of 12/573, or 2.1% was reported in the five control groups, with an adjusted incidence, after allowing for competing risks, of 7.15%. The actual incidences recorded were 0-4.9% in the 65-70 animal groups, with males running about 50% higher than females. Thus, the spontaneous incidence of LAS appears to vary considerably among colonies In this strain. These experiments will be discussed in more detail In Section XB. In summary, VC exposure can cause tumors at several different sites In various species of rodents. The dose response Is quite different for the different sites and species. Age at time of exposure can also affect the sensitivity of the animal. One experiment indicates that VC may be a transplacental carcinogen, also. AP00020963 z^ 8. Human Carcinogenicity The first connection between VC and cancer in humans was made in 1973 when physicians at the Louisville, KY plant of B. F. Goodrich, Inc. recognized the association between three deaths of workers from ASl (Creech and Johnson, 1974). A review of company records (Block, 1974) revealed several other cases at that site. This tumor Is rare. A review (Popper, at al., >978) of a>> cases reported in the United States for the period from 1964 to 1974 revealed 167 cases, of which 19 were ascribed at that time to VC exposure, 26 to Thorotrast given medically, and 9 to arsenic in Fowler's solution, also used medically. The remainder were of unknown etiology, with no connection to VC. For a time, NIOSH published (see, for example, NIOSH, 1974) a summary of VC-related cases, but this task now has been taken over by John Stafford of ICI, England (Stafford, 1980). His most recent compilation shows a total of 24 cases in the U.S., one of which is alive, and 81 world-wide. A summary of the number of eases by countries, and of the U.S. cases by company and by date of death, are given in Tables 2-4, respectively. The average latency period in the U.S. has been 23.2 years, but with a mode of about 1/ years. There is an unusual clustering of cases In relatively few plants. All of the U.S. cases, and almost all of the cases In the rest of the world, are closely associated with the job of reactor cleaning, which was once done manually at the end of the polymerization cycle. It may be speculated that differing work programs and job progression has had some effect here. Ten cases of ASL have been reported in one plant in Canada, the last in 1976, with no new cases since that time (Delorme and Theriault, 1978). These cases are completely typical, both as to the clustering and the medical symptoms. It Is also worthy of note that there Is, at roost, one case of both AOL and ASL in the same person (Stafford, 1980) although both of these diseases are associated with VC exposure as a reactor cleaner. An industry-sponsored epidemiological survey of workers in the VC/PVC industry covered 8,384 men (Tabershaw and Gaffey, 1974) with at least one year exposure before 1973. The expected excess of ASL was found. There were also suggestions of an excess of cancers in the brain, respiratory, and at unknown sites, and of lymphoma. This study was expanded to 10,173 workers (Equitable Environmental Health, 1978, Cooper, 1980), where the excess of brain and respiratory cancers continued to be seen without, however, an association between the brain cancer and exposure. Plans art being made for a follow-up study of this cohort to determine the status of the workers as of the end of 1979. Several studies have been conducted on smaller groups of workers which are also subsets of the larger study discussed above. Honson, Peters and Johnson (1974) found an excess of brain and lung cancers as well in the Goodrich plant which developed the most ASL cases in AP00020964 the United States. Waxweiler, et al., (1976) studied 1,151 workers who had at least five years exposure In four older PVC plants, and found an excess of brain, respiratory, and lymphatic cancer, as well as the known cases of ASL. A later study (Waxweiler, et al., 1978) expressed the opinion that it was not VC exposure that was responsible for the excess of respiratory cancer, and speculated that it nay be due to PVC-dust (see also Waxweiler, 1980). However, preliminary results-on a study of subsequent lung cancer cases in that sane plant (Greenberg, 1980) do not show an association with PVC dust. Ott, Langner, and Holder (1975) studied 594 workers at one location and found no excess of cancer deaths in workers who had been exposed to less than 200 ppm VC in their work. There was an excess of malignancies among workers with extended experience In what was rated as a high exposure group. There were no ASl cases In this cohort. Nicholson, et al., (1975) reported a study on 257 workers employed for at least five years since 1946 in a PVC plant, and found an excess of deaths from cancer, nine as opposed to 3.9 expected. Much of the excess can be explained, by three cases of ASL; there el so were two lymphatic cancers and one brain cancer. Among the other 15 deaths was one from bleeding esophageal varicles, which is thought to be associated with liver damage from VC exposure, and a possible precursor to ASL. The statistical significance of these excess cases was not reported. Duck, Carter, and Coombes (1975) found no excess of mortality, Including cancer, in British workers for 1948-1973, while following 2,120 workers. Wagoner, Infante, and Saracci (1976) criticized the mathematical treatment of the data and stated that there was an excess mortality in the longer-exposed group. Duck and Carter (1976) then made corrections to the numerical results, but did not change the conclusion. Berry and Rossiter (1976) criticized both the original calculations and the changes proposed by Wagoner and Infante, as did Fox (1976) but neither found any evidence of excess mortality in the group. Fox and Collier (1977) studied 7,000 men who had worked with VC In Great Britain between 1940 and 1974 and found no evidence that cancers other than that of the liver are associated with VC exposure. Frentzel-Beyme, Schmit2, and Thiess (1978) reported on 1,618 VC-PVC workers in Germany, and could not confirm the U.S. reports that tumors at other sites than the liver were in excess, and suggested that this may be because of the consistently low exposures at the plant studied. A paper by Relnl, et al., (1978) reported excess deaths in German workers, but the authors have since found calculation errors in the processing of the data. Workers who fabricated PVC were of interest as a group whose exposure to VC was significantly less than the workers in the VC/PVC Industry, but much higher than any expected exposure to the general population. Chia2ze, Nichols, and Wong (1977) studied 4,341 deaths from employees of 17 PVC fabricators, and found no ASL. There was an excess of AP00020965 deaths from Intestinal cancer fn both sexes, and breast and urinary system cancer in females, using proportionate mortality ratios based on an external standard. A case-study follow-up on the breast cancer deaths showed (Chiazze, 1980) no relationship to VC exposure. ' Baxter and Fox (1976) found very similar results in a study of 707 deaths of male fabrication workers in Great Britain. There was no axcess of lung or brain cancers in either cohort. Several studies have been made of the general population using ASL as the marker disease In an effort to detect an association with possible environmental exposure to VC. There was no association with living near a VC handling plant In the general U.$. survey conducted by the Center for Disease Control (Popper, et al., 1978). Brady, et al., (1977) surveyed 26 ASL deaths In New York State between 1970 and 1975, and found five who lived nearer VC handling plants than did their matched controls, but could not establish a direct connection with the disease to exposure. Ten cases of ASL in Wisconsin were examined for possible connection with VC exposure, and none was found (Fiechtner, et al., 1976). Baxter, et al., (1977) found no relationship between distance of residence from VC emitters and the 47 cases of ASL in the general population of Great Britain reported in 1963-1973. Saric, et al., (1976) studied the deaths during the years 1968-1971 in an area surrounding a PVC plant that had been in operation since 1949 and in which three workers had died of ASL. No relationship was found for liver or lung/bronchial cancer and place of residence. A similar study for communities near a Swedish plant which had operated since 1945 and had found four ASL cases showed (Blinder and Parshager, 1978) no unexpected elevation of fetal mortality, deaths from all cancers, or cancer of the liver or lungs during the years 1961-1974. Pancreatic cancer in males was elevated in the age group over 60. All ASL cases in Holland since 1950 (27 cases) were studied, and none had any traceable contact with.VC (Qa1erup,.et.al.1976),. . Iturra (1976) observed an excess of cancer deaths In a city In Canada with a PVC plant as compared to a similar nearby city. This difference was principally found In males aged 20-64, which is not indicative of a general pollution effect. The author drew no conclusion as to why the condition existed. The Environmental Protection Agency has stated (Kusmack and McGaughy, 1975, Marcus, 1976) that It has been unable to establish a link between living near VC handling plants and ASL. It awarded a contract in 1978 (Contract 68-02-2986 to Science Application Incorporated) to examine the present health of a cohort which was exposed to VC as children, but no results have been published. The disease ASL is difficult to diagnose'(Heath, Falk and Creech, 1975), is almost invariably fatal within a short time, and presents a variety of symptoms including portal fibrosis and hypertension with splenomegaly and varicies, proliferation of the sinusoidal lining, megalocytosia, and thrombocytopenia (Thomas and Popper, 1975, Sedligk, Muller and Bechtelsheimar, 1975). Metastasis is frequently involved. These symptoms are very similar to those seen In the mouse (Schaffner, 1978) and rat (Feron, et al., 1979). No really adequate early warning tests have been devised (Waxweiler, Falk, et al., 1977, Tamburro, 1980), although the oammaglutamyl transpepsidase test is promising, along with ICG clearance and SCOT. Maltonl (1960b) has reported an ongoing study which will attempt to relate sputum cytology findings to possible lung pathology. In summary, VC is clearly a human carcinogen, causing ASl In a small percentage of highly exposed workers. There is suggestive evidence that it may be a weak general carcinogen, perhaps through an Immunosuppressive mechanism, but more data are required to confirm this suspicion. AP00020967 zc IX. HAZARD EVALUATION The hazards to humans from exposure to vinyl chloride may be summarized as follows: Acute 1. Frostbite from skin contact with liquid VC. 2. Fire and explosion from Ignition of spills above 3,5% concentration 3. Anesthesia and cardiac arrythmia from exposure to concentrations around 1%. These hazards are abated by conventional safety practices in equipment design and operating procedures which are beyond the scope of this discussion. The potential seriousness of the effect of these hazards should not be overlooked in the concern for chronic effects. Chronic 1. Damage to liver, spleen, and circulatory system. 2. AOL and associated symptoms. 3. ASL, and possibly cancer at other sites. No precise threshold for time or concentration can be given for the onset of these effects. Apparently they are not seen at lifetime occupational exposure of a few hundred ppm, and possibly higher. It also is apparent that a direct extrapolation of animal experience cannot be made. A whole generation of the entire industry experienced exposures at least an order of magnitude above those which elicited chronic response in rats, and harmful effects were seen in only a few of the higher exposed members of the group. The number of persons exposed to substantial concentrations in the VC-PVC Industry certainly Is well above 20,000 and about 0.1% of that'number have developed either AOL'or ASL.' IT humans were as sensitive to VC as are rats, the expected number of cases would be above 10% (NCAB, 1979, Reitz, et al., 1979). That is an unacceptable hazard to permit to continue, and substantial steps have been taken to abate the risks, but It is of importance to understand the degree of abatement which has been achieved by these steps, and to determine if it has been adequate, and if a significant risk exists for the non-occupationally exposed population. The metabolism of vinyl chloride seems to be carried out in the microsomes of the liver cells by a mixed oxidase function process which is thought to proceed via an epoxide Intermediate. This intermediate Is detoxified by interaction with sulfhydryl groups of amino acids. If the intermediate is generated in quantities too large for detoxification, or if there is a depletion of sulfhydryl groups by competing reactions, or for some other reason, then some of the active intermediate may escape the microsome, and eventually, some of it may attack the genetic material of the chromosomes. It is conceivable that, in the case of massive doses, some of the reactive intermediate could escape the liver cells, and attack other cells at AP00020968 remote sites. If this damaged chromosome Is not repaired by the various mechanisms available for that purpose, and If the resulting altered chromosome is a viable entity, then subsequent replication may produce a cancerous cell, which could lead to a tumor. Consideration of this sequence of events leads to the conclusion that the dose response to very low levels of VC could not be linear, with the several consecutive steps and competing reactions that are involved (Reitz, et ah, 1979, Watanabe, et al., 1980). Of the various conventional extrapolation models, it would appear that the linear quadratic, multi-hit model may be more appropriate than the others. It may also be that a unique model must be devised for each substance, and that no general model will be adequate. Bioassays of sufficient sensitivity have not been performed to answer this question. Scientists of the EPA Cancer Advisory Group have stated (Albert, 1980) that their use of the linear extrapolation method in risk assessment is not intended to represent biological processes, but merely to assure that the risk assessment result is the maximum likely probability of harm. Another question of interest is whether a single massive dose or a series of smaller doses is likely to be more harmful. Development of cancer from single doses is a familiar event to experimentalists, and should not be confused with the "one-hit11 theory, or the no-threshold concept. It would appear that a limit Is placed on the rate of formation of the active Intermediate by the amount of enzyme available, and by the rapid exhalation of surplus VC In the body. However, if enzyme availability were the limiting factor, then suppression of that enzyme by a competing substrate should lessen the toxic effect of VC, and it is seen that alcohol and phenobarbitol, which are thought to utilize the same metabolic route, actually enhance its toxicity. Thus, It may be that the detoxi fication is the limiting step, as was found by Leumback et al., (1978) for bacteria. This would lead to the conclusion that both high doses and chronic exposure are harmful, although the latter would be more effective for equal dosage because of the inability of the body to store VC In excess of the metabolic capacity. No long-term effect of a single high dose was seen In the CPSC study, (Hehir, 1980) which leads to the further conclusion that the repair capacity of the target is important, and that so long as that procedure can be effective, the mode of application of the dose is not of primary Importance. It is known that humans have more competent repair systems than do shorter-lived rodents (Hart and Setlaw* 1974) which may account in part for their relative longevity. There have been no new cases of AOL reported In recent years, and the current medical surveillance on workers is such that chronic organ damage is being prevented. Concern for exposure to single doses high enough to cause acute or chronic effects is unnecessary in the general population, and very unlikely in workers under present conditions. AP00020969 t.; Therefore, we conclude that the only reasonable possibility of harm to humans today Is from long-term exposure to low doses, and the remainder of the discussion will be devoted to evaluating that risk. In regard to tumors at sites other than the liver, the Maltoni data (1977, 1979) show that rats do develop tumors at other sites, but that the observed no-effect level is considerably above that for LAS (see data in Section VII above). Human epidemiology may show a suggestive increase in brain and lung tumors at past high exposures; the data are inconclusive. But, if present, the risk is at least an order of magnitude less than that for AOL. Therefore, the risks for AOL will be taken as representing all potential risks for tumors from VC exposure. In summary, the risk for development of AOL is thought to be the most likely chronic hazard facing the working or general population from exposure at the present time, if, indeed, there is any risk. Other chronic hazards are low in comparison. A consideration of the metabolic data suggests that the Immune and repair mechanism may be the limiting factor in controlling the onset of the disease, and that the dose response curve at very low exposures is unlikely to be linear. AP00020970 RISK ASSESSMENT Any effort at risk assessment assumes a probabalistic relationship between dose and effect; no other approach is possible. However, it must be remembered that the probability distribution for the observed population may not be the same as that of the population of interest. We have as our patterns selected strains of laboratory animals and adult white males. These may well not be representative of the general population. A. Previous Risk Assessments 1. Schneidennan, 1975 One of the first attempts to utilize animal data to estimate risks at very low exposures was that of Schneiderman, Mantel1 and Brown (1975). They used early Maltoni results to compare the estimates obtained from three possible mathematical models. Thgg99% assurance level of a "safe1 dose at a lifetime risk of 10 D was as follows: Log Probit (.slope = 1) Logit (slope = 3.45) Logit (slope = 2.3, one-hit) .73.ppb 119 ppb 2.1 ppb The authors discussed the recognized difficulties of extending these rat data to humans and of providing animal experiments that could answer satisfactorily the question of risk at very low doses. 2. Kusmack and McGaughy, 1975 The EPA was the first group to attempt a human risk assessment for vinyl chloride (Kusmack and McGaughy, 1975). This pioneering effort attempted to use both animal and human data, and to show comparative results from both the linear and log-probit modeH. It concluded that there was an individual risk of 71 x 10 0 per ppm of lifetime exposure to VC by the linear method, and that the log-probit results were one-tenth to one-hundredth of that. This effort is subject to several serious criticisms. The exposure data used for human experience was that from a group with less than average exposure, while the ASL rate was chosen from only those plants which did report cases, and ignored the remainder of the population. Thus, their Incidence rate of 7.5% compares to an actual figure of about 0.1%. They used as their primary method a linear extrapolation of rat data, which has been seen to overestimate the human rates by two orders of magnitude above that which actually exists, and they assumed the total cancer rate to be twice that found for ASL. This same estimate was used by the EPA (1979) to estimate the concentration of VC in drinking water which would produce various levels of risk. These estimates are, of course, equally Inaccurate. AP00020971 Nlsbet challenged (Nlsbet, 1978) the estimate of Kusmack end McGaughy (1975) when It was used by Wilson In testimony before the OSHA hearing on Its generic cancer policy. Nlsbet stated that his calculations showed the risk to be 10*30 times greater, by the same calculation method. Wilson (1979) suggested several flaws In the Nisbet procedure, Including the fact that he chose for his extrapolation one point at 25 ppm from Maltonl experiment BT-/S and that this point is not in good agreement with the whole body of data. Further, he chose to use total cancer incidence in the rats, including those at zy?h? glands, which have no counterplace in humans. Both Wilson and Kusmack and McGaughy had used a factor of two times LAS to account for possible cancer at other sites. Wilson did acknowledge a mathematical error which made his results half the proper number. Albert (1978) applied this same general procedure to other potentially carcinogenic air pollutants In the United States and calculated the expected annual cancer deaths as follows*. Arsenic Benzene Cadmium Coke 4*fens VC afcfter regulation 15.6 77.8 26.2 149.5 1.0 3. Gehring, 1979 Gehring, et al., (1979) applied an experimentally derived biotransformation correction to rat data and estimated the Incidence in humans at two different exposures by means of four different extrapolation models. They found that the estimates at 500 and 200 ppm TWA bracketed the observed (Cooper, 1980) experience for humans when derived from the probit and the unconstrained linear models, and that the linear-through-zero and one-hit models consistently over estimated the incidence. Although not considered by the authors, the linear and probit models match rather closely the total U.S. experience of ASL at the 500 ppm exposure. The linear model predicts no incidence below 99 ppm In humans. The probit model predicts a human risk of 1.5 x 10" at 1 ppm. Thus*, a mechanism for adjusting for the difference In metabolism between animals and humans is shown to be useful. 4. Food Safety Council 1978, 1980 The Food Safety Council has recommended (FSC, 1978) the use of the gamma multi-hit model because of Its flexibility in handling dose response data of varying curvealinity at low doses. It has calculated (FSC, 1980) the maximum likely and lower 97.5% limit doses for substances at various risk levels and with different models. For VC, at 10 risk, these results are as follows (based on early Maltoni data): AP00020972 -*I One-hit Arini tage-Doll Weibull Multi-hit For this substance, the goodness of fit of the Weibull model (0.56) was superior to that of the multi-hit (0.32). Neither of the other two models gave acceptable fits. This was in part because of the concave shape of the high doses in the dose response data used. It has been stated by OSHA (1980) that the wide range of values obtained from various models is an indication of the unsuitability of the concept. In reality, it is the result of improper manipulation of the data, which data may not always be satisfactory for the intended purpose. However, subjective use of data can, and does, sometime affect the results. The Food Safety Council recommends (FSC, 1980) that appropriate biological and other considerations be used in the choice of models. 5. Hehlr, 1980 Hehir, et al., (1980) considered the published data on animal exposures and concluded that there was a lifetime dose below which no oncogenic response Is seen. This was estimated to be 5,000 ppm-hrs for mice and greater than 50,000 ppm for rats, regardless of whether the dose was administered over a short or long period. This concept of equality of effectiveness for all modes of exposure does not have general acceptance, and would not appear to be correct, based on the earlier discussion of this point. Oose-rate effects are, of course, well known. See, e.g., Laskin, et al., (1980). However, the degree to which this can be extended is not known. See Section XB for further discussion. These authors also used the Crump-Griess model (Crump, Griess and Deal, 1977) to evaluate their data on mouse pulmonary cancer, and estimated that exposure to 5,000 ppm VC doubles the probability of cancer, while 50,000 ppm Increased the risk nine-fold. In view of the fact that pneumonitis was present in all animals exposed above 500 ppm, it is questionable if this was a direct oncogenic response, or the result of an epigenetic event because of severe lung damage. Maltoni (1977) also reports an Increase in lung tumors in mice, but not in rats or hamsters. Thus, the significance of this finding to risk in humans is questionable. In summary, prior risk assessments, most of them based on the same early Maltoni experiment, have given a wide range of calculated risks depending on the model used end the treatment of the data. A reasonable fit with experience was obtained when suitably biotransformed rat data were fitted by the probit model. AP00020973 B. Further Calculations Almost all of the risk assessments to date have been based on experiment BT-1 of Maltonl (Maltoni, 1977). Final results have new been reported (Maltonl, 1979) for several more bioassay programs. Those of interest here are listed in Table 5. Among these are four more experiments In which rat data comparable to BT-1 were obtained, containing results from one-year inhalation exposures with the animals held for a normal lifetime, BT-2,7,9 and 15. In addition, there are two ingestion studies with comparable time periods, BT-11 and 27. The exposures and percent incidence of LAS for the rats in these two series are given in Tables 6 and 7. The inhalation data have been converted from ppm to g/kg/yr by the CEFIC method (CEFIC, 1976) in order that they may be combined with the Ingestion data. All of these experiments are with Sprague-Dawley rats except 0T-7, which used the Wlstar strain. The data of Tables 6 and 7 are displayed in a log dose v$ percentage of Incidence plot on log-probit paper in Figure 1. Points for exposures above 2,500 ppm were excluded because the high rate of competing causes of death actually give a decrease In incidence at those exposures. It can be seen that the grouped data general! follow a similar trend, and thus the combined points should permit a more reliable application of mathematical extrapolation models. However, this graph also Illustrates the problems Involved in extrapolation from a single experiment. The slopes of BT-1, the first Inhalation experiment, and also the one with the greatest number of points, and experiments BT-11 and 27, the two ingestion experiments, generally are similar. Experiments BT-15, and especially BT-2, both done at lower exposures and with fewer points, have substantially different slopes. BT-9 has only a single point, but is in general concordance with the remaining experiments. Confidence ranges were not calculated for the Individuals points. This may reduce the disparity between experiments to some degree, but It will not eliminate the problem entirely. (See Wilson (1978). Equations were fitted to these results, using the Hewlett-Packard HP-67 calculator and the manufacturers program SD-Q3A (Hewlett-Packard, 1977). Linear curves were not constrained to pass through 0,0. Zero results were Included when there was no|Lobserved incidence at finite exposures, but very small values, approximately 10 , were used rather than zero with the logarithmic and expotential programs to avoid machine error. These result are presented In Table 6. Various combinations of studies were used for the calculations. The vertical line in Figure 1 Is the historical control incidence of 0.09, and when that point (0 exposure, 0.09% incidence) was used in the calculations, the experiment column contains the notation "plus controls". It can be seen that the results of several individual experiments fit various types of curves with high reliability. For example, AP00020974 2 8T-1 yields r valves of 0.95-0.99 for linear, power, and log-probit curves, and BT-2 does also for linear, logarithmic, and power curves. Inclusion of the historical controls usually lower the goodness of fit, although not always to a significant degree. The combination of the inhalation studies is an exception. However, no confidence should be placed in good fits for three-point curves (BT-2); these fits are to be expected. The apparent difference In slopes that Is seen in Figure 1 is reflected here in the greatly different values for the calculated constants from experiment to experiment. The combined Ingestion experiments, BT-11 and 27, were tested with the origin as an Included point for the linear equation. This reduced significantly the goodness of fit. The intuitive (and mathematical?) conclusion is that a poorer goodness of fit with more data points is more reliable than a higher degree of fit for fewer points, if the data are independent and of equal degree of precision. Thus, 'It appears appropriate to use the equation derived from the combined experiments for further discussion. BT-1, the combined ingestion studies, the combined Inhalation studies, and the combined injestlon and inhalation studies, with and without the controls all showed a positive X*1ntereept. That is, the date extrapolates to predict a no-observed-effect exposure, as was reported by Maltoni. The Inhalation experiments BT-2, 7, and 15 do not predict this. Some of the Maltoni experiments employed variable lengths of exposure times. In BT-3, the animals were exposed for 17 weeks, rather than the 52 weeks of experiment BT-1, which used the same exposure levels. After 155 weeks, only one animal each in three of the higher exposure groups (500, 2,500, and 6,00 ppm) had developed LAS, wtvik a total of 33 animals in these three exposure groups did so In BT-1, with 52 weeks of exposure. In BT-5, pregnant dams were . exposed to 6,000 or 10,000 ppm, 4 hr/day for one week. There were no cases of ASL in the dams or offspring. These results were confirmed by the work of Hehir (1980). See Section VIII A, above. Similarly, the CIV0 Ingestion studies (Feron, 1978, 1979) extended for.a lifetime feeding, and gave 24-hour exposure to VC, rather than the 52 weeks at 4 hr/day used by Maltoni, and resulted in a higher incidence of LAS at equal daily dose rates. See Table 9. CIV0 used Wlstar rats, while Maltoni performed this experiment with the S-D strain. However, the two strains do not appear to be greatly different In their response to VC (see Table 6). Thus, the extended exposure time, and the more uniform daily exposure, produced a higher yield of LAS. AP00020975 Therefore, it can be concluded that equal doses, if sufficient to produce cancer, are more effective In a series of small doses than as fewer high doses, and that the use of total ppm-hrs by Hehir is not appropriate over the entire range of possible exposures. The inability of the body to retain or metabolize large doses, and organ damage from continued Insult, appears to be some of the causes of this effect. This Is reassuring, in that ft lessens the concern for harmful results from one or a few high exposures, but emphasizes the need for concern over extended exposures great enough to elicit chronic organ response. The major difficulty with the Gerlg procedure is that it tests the results against the CMA epidemiology study. That study was not the "end of the experiment?" it stopped at the end of 1973, and several deaths have occurred since then. Neither did it cover the entire population, but only the employees of those plants which met certain criteria for data retention and length of operation. The Stafford (1930) data does caver the entire population and extends the history for seven years. The size of the population is not known, but a reasonable estimate, based on normal worker turnover rates and the number of plants not included in the CMA study, is certainly not less than 25,000. This would give a gross incidence of about 0.1%. Of these, the number actually exposed to substantial exposures would be about 25-30 per plant at any one time. Multiplication by 25 plants, and a factor of three for the turnover during this period, would give about 2,000 highly exposed persons, for an effective incidence of just over 1%. Personal experience would indicate that, for the period prior to 1962, when all of the first exposures of the fatal 45 cases had occurred, the average exposures of this highly exposed group certainly was in excess of 1,000 ppm for the working day. Reference to Figure 1 and Tables 6 and 7 indicate that Maltoni found a 1% incidence-at about 1-10-ppm.Calculation of the dose equivalent to a 1% Incidence in rats gives 1.9 ppm by the linear equations in Table 8, and 2 ppm from the log-problt equation for the combined inhalation experiments. This crude and subjective estimate would then say that man is about 100 times as resistant as the rat to VC inhalation, a figure generally In agreement with other estimates. Attempts to calculate the incidence for rats (or man) at low doses by the linear extrapolation method fail because the derived equations predict a no-effect dose of about 1 ppm. * AP00020976 TABLE 1 Selected Physical Properties of Vinyl Chloride Formula Weight Heat of Formation, 25C, gas Kcal/mol Free Energy of FormationBTU/lb. Oensity, liquid, g/ml 32F, 0C 50F, 10C 68F, 20C S6F, 30C 104F, 40C 62.50 7.5 -3310 0.9471 0.9293 0.9109 0.8918 0.8721 Refractive Index, 1.398 Freezing Point, C/F Boiling Point, 760 mm C/F -153.7/-244.7 -13.37/7.9 Liquid Viscosity, absolute, CP 32*F 50 F 68F 86F 0.225 .. 0.207 0.193 0.181 Heat of Fusion, cal/g Heat of Vaporization 9 57F, BTU/lb. 18.14 158.4 Specific Heat Liquid, 25C K ceVkg Vapor 25C constant pressure, Kcal/Kg-mol Vapor, constant volume . 0.38 12.83 10.64 Heat of Polymerization, BTU/lb -720 Explosive Limits in Air Lower, wt, % vcl.% Upper wt.% vol.% 8.3 3.5 37.8 22 Flash Point, open cup Autoignition temperature -78C 472*C Critical Temperature K Critical Pressure, atm Critical Oensity g/cc 431.4 52.7 0.370 Vapor cloud explosion yield, lbs. to yield the equivalent of 1 ton of TNT 24,305 AP00020977 8Z60Z000dV l L *0 %Z %i XS'O 921 m 9282 081 SU 8fr S 92 81 % `DA U* a#}** j-o ^i-Uq^LOS snoua6ov>* ui*e 0*1 W 5'0 eanssaud *** Xq % *Do0 *JWl uj. rtqmqmos DoOS DeO `qi/M8 *^*H qua^n j.ouj/l*ox `uo^snqiuoo jo laaH (p,}uo:>) i 3i8vi OoO^ OoOS Do0 DoOl DoO DeOla^sd `aanssauj joda^ TABLE 2 Angiosarcoma Cases In the VC/PVC Industry by Country as of January. 1980 United States West Germany France Canada United Kingdom Sweden Yugoslavia Italy Czechoslovakia Japan Norway Belgium 24 15 13 10 4 4 3 2 2 2 1 J. Total 81 AP00020979 TABLE 3 Angiosarcoma Cases In the U.S. by Company as of January, 1930 Goodrich, Louisville Onion Carbide, S. Charleston Goodyear, Niagara 3 Others 10 6 4 _4 Total 24 AP00020980 TABLE 4 Chronology of U.S. Deaths From Anoiosarcoma Deaths Year of First Exposure 1961 1 1946 1962 0 1963 0 1964 1 1944 1965 0 1966 0 1967 0 - 1968 -3 .1944, .195.1 , -1952 1969 2 1949, 1950 1970 1 1946 1971 1972 1 1955 0 1973 2 1945, 1948 1974 1 1942 1975 4 1945, 1947, 1954, 1962 1976 4 1943, 1947, 1955, 1958 1977 1 1946 1978 1979 2 1941, 1944 0 1980 (as of October) _0 Total 23 One Case Living (First Exposure 1955) Data From Stafford (1980) AP00020981 TABLE 5 Listing of Fully-Reported Maltoni Experiments Experiment Route Exposure Length of Range of No. of FerTod Term7wks Experimental^ Poses, ppm Animals1 Remarks RATS 1 Inhalation 4 hr/5 day 52 135 50-10,000 60 2 Inhalation 4 hr/5 day 52 143 100-200 120 3 Inhalation 4 hr/5 day 17 135 50-10,000 60 5 Inhalation 4 hr. 1 143 6,000-10,000 30 Fj study 6 Inhalation 4 hr/5 day 52 68 30,000 60 7 Inhalation 4 hr/5 day 52 136 50-10,000 30 Wistar rats (all others 5-D) 9 Inhalation 4 hr/5 day 52 142 50 294 10 Inhalation 4 hr/5 day 5 136 6,000-10,000 120 11 Ingestion once,4-5 days 52 14 Inhalation 4 hr/S day 52 136 104 3.3-50 mg/kg 80 6,000-10,000 45 Day-old rats 15 Inhalation 4 hr/5 day 52 147 1-25 120 27 Ingestion once,4-5 day .59 136 0.03rl.Q m/kg 150 MICE 4 Inhalation 4 hr/5 day 30 81 50-10,000 60 HAMPSTERS 8 Inhalation 4 hr/5 day 30 109 *Num&er of animals at each dose level, usually counted as the number alive at time of first tumor, about equally male and female. AP00020982 TABLE 6 LAS Incidence (X) In Rats, Inhalation 52 Weefcs Exposure. Lifetime Study* Exposure ppm 10,000 6,000 2,500 500 250 200 150 100 50 25 10 5 1 Equivalent dose, mg. Ag./yr. Experiment No. 300 180 75 15 7.5 6.0 4.6 3.0 1.5 0.8 0.3 0.15 0.03 1 12 22 22 10 5 1.7 2 10 5 0.8 7* 27 6.6 10 13 3.3 0 9 2.7 15 4.2 0.8 0 0 *Wistar Rats, All Others S-D. AP00020983 fr860Z000dV --C*DH CD ? tCn* ^ to *&D<> N> Ul rv> bn rss rs> O LAS Incidence In Rats, Ingestion S860Z000dV VC It ft. o 5 i/i S -1 w l CD o -o CO CO co a CO c p co v NJ a O cn D M CP --si -il -- *Q--0 ---in--no <-- a--ai. sat S rsttf in *o *D 10 3 c o ns O rr 3--I** CPI --Awl mn o SI --c r-** --a in e i* ki y> M SJW _i. u X -"S 0 <s e < u 3 r+ B 1 -V --VO --JI co u> -0 o<a3_1. 0--3c* 0 3r* O cn m A I ---- CO I A t ecn "9 ns e e+ X re * 3 i no i i i A no co co cn o ini c9o) cnI --< no cn S S cn O O ---- r* ano a --i CaO r> at < ll r; (S r-o A A *o -- (SO U* op a o nCoO w co Aa *nsoJ 0x*) ^3rae> O cn CD S3 no p CAO CO oo JS e a> ft> o &5 qOCO a cn -- CO no VO P IAS} co a po I --n 0")<O8J sa < a ut CO A sj o no O r* If 2.S n VAO tav aa CO oo Aa -O x ru x rv o 3 ia o p oo so fS5 no aA --o aa 3e mr* cwi p co --< Kt II I-DJ a 3 IQ cn $ < n O < I no CO o-- cao o CO aa aa csoo no IS) A CO cn o 10 s i c9n) a a a O* i- - O aa Aa -0 CO r" aj n -o o -- p *| + -4 09 a ao co er ^ O-i 3 TABLE 8 TABLE 9 A. LAS Incidence in Mister Rats, Ingestion Lifetiie Exposure, Lifetime Study Oose ag/kg/day g/kg/yr 300 14.1 5.0 1.7 0 110 5.2 1.8 0.6 0 Incidence ASL, % 58 31 7.1 0 0 AP00020986 Z860Z000dV 0 (J W U 0 I j U u i t i J<j N U IJ.JU O M I 'JU I HO td J b J .IU U | H lN L tllU l't REFERENCES Air Products and Chemicals, Inc., "Comments on the Proposed Standard for Vinyl Chloride", letter to D. R. Goodwin, EPA, 23 September 1976. Albert, R. E., letter to R. S. Naveen, EPA, "Comparson of vinyl clhoride carcinogenic risks with risk from other pollutants'1, Washington, D.C., 16 June, 1978.. ... Albert, R. E., Statements at the 4-5 Sept, meeting of the Science Advisory Board Subcommittee on Airborne Carcinogens, transcript p. 21, 36 - 3 Sept, session. Washington, D. C., 1980. American Conference of Governmental and Industrial Hygienists, "Documentation of the Threshold Limit Valve", 1963. American Public Health Association, 1977. Anderson, 0., et al., Mut^ Res^, 40 359 (1976). Andrews, A. W., et al., Hut. Res.. 40 273 (1976). Antonyuzhenko, V. A., Gig. Tr. Prof. 2abol 12 50 (1968). Barkin, A,, et al., Biochem. Blophys. Res. Comm. 67 596 (1975). Baretta, E. D., et al., Am^ Ind. Hyg. Assn. 30 537 (1969). Bartsch, H. , et al. , Int. Cancer, 15 429 (1975). Bartsch, H., and R. Montesano, Hut. Res., 32 93 (1975). Basalaev, A. V., Gig. Tr. Prof. Zabol 14 34 (1970). Basalaev, A. V., A. H. Vozin and A. G. Kochetkov, Glq Tr. Prof. Zabol 16 24 (1972). Basler, A., and G. Rohrbor*e, Arch. Toxoia. 45 1 (1980). Baxter, P. J., et al., Br^ Hed^ , 1977 919. Baxter, P. J., and A. J. Fox, Lancet. 1976 245. Berry, G., and C. E. Rossiter, Lancet. 1976 11, 416. Block, J. B. J.A.H.A., 229 53 (1974). Bolt, H. H., H. Kappus, A. Buchter, and W. Bolt, The Lancet 1975 1425. Bolt, H. M., H. Kappus, A Buchter, and W. Bolt, Arch. Toxical 35 153 (1976). Brady, J., et al., J. Natl. Cancer Inst.. 59 1383 (1977). AP00020988 Bretza, J. , and J. A. Goldman, O.Occup. Hed., 21 436 (1979). firetza, J., and J. A. Goldman, J. Occup. Hed.. 2] 436 (1979). Brown, E. T., et al., Ann. N.Y. Aud. Sci. 295 535 (1977). Brous, S. L., and W. L. Semou. Ind. Eng. Chem. 27 667 (1935). Buchter, A., H. M. Bolt, J. Filser, H. V. Goergens, R. J. lalb, and W. Bolt. Verb Deutsch Gas. Arbeitsmed 18 111 (1978). Cameron, J. B., A. J. Lundeen, and J. H. McCullev. Jr.. Hvdrocarbon Proc.. 39 (1980). ------------------------ Caputo, A., et al., IRCS 2 1582 (1974) cited in EPA, op. cit,. 1979. Carr, J., R. M. Burgison, I. F. Vitcha, and J. C. Krantz. J. Pharm. Expath. Ther. 97 (1949). -------------- CEFIC, "Vinyl Chloride Toxicity and the Use of PVC for Packaging Foodstuff.11 Conseil European des Federations de L'Industrle Chemique, Brussels, Feb. 1976. Center for Disease Control Morbidity and Mortality Weekly Report, 28 (34) 401 (1979). "* Chemical and Engineering News. July 7, 1980, page 9. Cheney, W. D., Amer. J. Roentgeu. 94 595 (1965). Chia22e, L., "Mortality Among Polyvinyl Chloride Fabricators", In "Joint Conference, op. cit.. 1980. Chiazze, L. , Jr., W. E. Nichols, and 0. Wong, jh Occup, Med. , 19 623 (1977), Clapp, J. J., C. M. Kaye and L. Young, Biochem J^_ 114 6P-7P (1969). Cole, J. "Inside Story on Vinyl Chloride at B. F. Goodrich in Avon Lake", The Journal. Lorain, Ohio, March 26, 1975. Consumers Product Safety Commission, Federal Register 39 30112, Aug. 21, 1979. Cook, W. A., et al,, Arch. Envir. Health 22 74 (1971). Cooper, C., "Epidemiological Study of Vinyl Chloride Workers", in Joint Conference, op. cit.. 1980. Council of Europe "Substances used in Plastics Materials Coming into Contact with Food", Strasburg, 1979. Cox, R. A., A. G. J. Eggleton, and F. J. Sandalls, "Photochemical Reactivity of Vinyl Chloride," U.K. At.Energy Res. Establ., Publ. No. AERE-R-7820, Sept., 1974. AP00020989 Creech, J. 1., and M. N. Johnson, J^ Occup, Had. 16 150 (1974). Creech, J. LJr., and L. Makk, Autl Acad. Sci.. 246 88 (1975). Creech, J. L., Jr., and M. N. Johnson, J^ Occup. Med. 16 150 (1974). Crump, K. S., H. A. Griess, and K. L. Deal, Biometrics. 33 4370451 (1977). Dalderup, L. M. , et al., Lancet. 1976. 246. Damziger, H., Can. Med. Assn. J. 82 828 (1968). Dinman, et al., Arch. Envir. Health 22 61 (1971). Dodson, V. N., et al., Arch Envir. Health 22 83 (1971). Downes, T. D.,R. A. Stallones, R, F. Frankowski, and D. R. Labarthe "Vinyl Chloride, Birth Defects, and Fetal Wastage - A Critical Review. Prepared for the Society of Plastic Industries, Inc., by Research Statistics Inc., Houston, Texas, September 16, 1977. Drozlowicz and Huang, Hut.' Res. '48 '43 '(1977). Oublin and Vane, 1935, cited in K. B. Lehman and F. Flury, "Toxicology and Hygiene of Industrial Solvents", 1938. Ducetman, A,, K. Hirshman, and I. 0. Selikoff, Mut. Res. 31 163 (1975). Duck, B. W., and J. T. Carter, Lancet 1976 195. Duck, B. W., J. T. Carter, and E. J. Coowba, Lancet 1975 11, 1197. Edmonds, L., "Birth Defects and Vinyl Chloride", Proc. Conference on Women and the Workplace. Washington, D. C., 1976. Edmonds, L. D., H. Falk and J. E. Nissini. The lancet 1975 1098. Elinder, C. G., and G. Pershagen, "Pilot Study Concerning the Mortality in Njurunda Community," Swedish Nature Conservancy Board, April, 1978. Elmore, et al.* Biochem. biophvs. Acta. 442 405 (1976). Environmental Protection Agency "National Emission Standard for Hazardous Air Pollutants. Standard for Vinyl Chloride." 41 Federal Reaister 46560, Oct. 21, 1976. 40CFRF61. -------- Environmental Protection Agency "Preliminary Assessment of the Environmental Problems Associated with Vinyl Chloride and Polyvinyl Chloride", EPA 500/ 4-74-001, 1974. Environmental Protection Agency "Scientific and Technical Assessment Report on Vinyl Chloride and Polyvinyl Chloride "EPA 600/675-004, June 1975. AP00020990 Environmental Protection Agency "Standard Support Document and Environmental Impact Statement; Emission Standard for Vinyl Chloride", EPA 450/2-75-009, September, 1975. Environmental Protection Agency, "Standard for Vinyl Chloride," 41 FR 46560, October 21, 1976. Environmental Protection Agency "Vinyl Chloride, Ambient Water Quality Criteria", PB-292446, Washington, D. C., 1979. Equitable Environmental Health, Inc., "Epidemiological Study of Vinyl Chloride Workers, Final Report". Prepared for Manufacturing Chemists Assoc., Washington, D. C., January, 1978. Falk, H., J. L. Creech, Jr., C. W. Heath, M. N. Johnson, and M. M. Key, JAMA 230 59 (1975). Feron, et al., Fd. Cosmet. Tox. 13 633 (1975). Feron, V. J., et al., "Life Span Oral Toxicity Study of Vinyl Chloride in Rats", Report No. R-5788, Centraal Instituut Voor Voedingsonderzoek (CIV0), Zeist, Neth. October 1978. Feron, V. J., et al., Toxicol.. 13 143 (1979). Feron, V. J., and R. Krees, Toxicol. 13 131 (1979). Fiechtner, J.. et al.. Center for Disease Control Morbidity and Mortality Weekly Report. 25 57 (1976). -- Filatova, V.S., et al., Gig. Tr. Prof, Zabol.. ^ 6 (1958). Fishbein, L., "Potential Industrial Carcinogens and Mutogens", Elsevier, 1979. Flelg, J., and A. M. Thiess, ASP, 9 282 (1974) Abstracts of Second Int. Conf. on Environmental Mutagens, p."7T9 T1977). Food and Drug Administration, Federal Register 39 30830, Aug. 26, 1974. Food and Drug Administration, "Report of the Interagency Working Group on Nitrite Research," Washington, D.C., August 15, 1980. Food Safety Council Final Report "Proposed System for Food Safety Assessment", Washington, D. C., June, 1980. Food Safety Council, Scientific Committee "Proposed System for Food Safety Assessment." Food and Cosmet. Tox. 16 Suppl. 2, December, 1978. Fox, A. J., Lancet, 1976 11, 416. Fox, A. J. , and P. F. Collier, J^ Xnd. Med. 34 1 (1977). Frentzel-Beyrne, R., T. Schmitz, and A. M. Thiess. Arb. Socialmed. Prevent.. 13 218 (1978). -------------------------------------- - AP00020991 Funes-Cravioto, F., Lancet 459 i (1975). G&bor, S., et al., Igiena (Bucharest) 21 409 0964). Gabor, 5., M. Lecea - Radu, and I. Manta. Prom. Toksikol. 1 Klinika Prof. Zabole KM a Etlol. V962 221. ---------------------- ----------------------- Gamble, J., L. Shuguey, A. J. McMiehael, and R. J. Waxweiler, J. Occup. Med. 19 659 (1976). ----------- ---------- Garro, A. J., et al., Mut. Res.. 38 81 (1976). Gay, B. W., Jr., P. L. Hanst, R. C. Noonan, and J. J. Bufallnl. Environ. Scl. Tech.. 10 58 0 976). ----------- -- Gedigk, P., R. Muller, and H. Bechtelsheimer. Am. N.Y. Acad. Scl.. 246 278 (1975). -------------------------------------- Gehring, P. J., P. G. Watanabe and J. D. Young, in Origins of Human Cancer, Hiatt, H. H., J. D. Watson, and J. A. Winsten, eds.. Cold Spring Harbor Laboratory, 1977, Vol. A, p. 187. Gehring, P. J., P. G. Watanbe, and C. N. Park, Tox. and Appl. Pharm. 49 15 (1979). ------------ ------------------ ~~ Gothe, R., C. J. Calleman, L. Esneuberg, and C. A, Wachtmelster, Ambio 3 234 (1974). ----------- Green, T., andD. E. Hathaway, Chew-Biol. Interactions 22 545 (1975). Green, T., and D. E. Hathaway, Chem-Blol. Interactions 21 13? (1977). Green, T., and0. E. Hathaway, ChenrBiol. Interactions 22 211 (1978). Greenberg, R., Discussion of paper by R. Waxweiler In Joint Conference, op. cit, 1980 transcript pages 337*342. 4 Greim, H., et al., Biochem. Pharmacol. 24 2013 (1975). Grigorescu, I., and Gh. Toba, Rev, Chlm. (Bucharest) 22 499 (1966). Groth, D., "The Role of Aging on Cancer Induced by Vinyl Chloride Monomer" in "Joint Conference", o^ cit. 1980. Grunard, K., P. Taft, and G. S. Wiberg, "Report of Task Force on Vinyl Chloride" Environmental Health Directorate, Ottawa, Canada, June, 1976. Guengerieh, F. P., and T. W. Strickland, Mo2. Pharmecol. 13 993 (1977). Hansteene, I.-L., et al.. Mut. Res. 78 211 (1978). Harris, D. K., and W. G. F. Adams, Brit. Med. J. 5567 712 (1967). APO6626992 Hart, R. W., and R. B. Setlow, Proc. Nat. Acad. Sci.. 71, 2169 (1974). Hass, J. F., and D. Schottenfeld, J. Oeeup. Med.. 21 607 (1979). Hatch, M., "Power Considerations in Studies of Reproductive Effects Associated with Vinyl Chloride and some Structural Analyses1' in "Joint Conference", op. cit. I960. Hathaway, D. E. , Environ. Health Persp. 21_ 55 (1977). Health, Dubrovnic, Hygo., Sept. 19, 1978. Heath, C. W., H. Falk, and S. L. Creech. Jr., Ann N.Y. Acad. Sci. 246 231 0975). Heck, W. W. and E. 6. Pines "Growth of Plants Fumigated with Saturated and Unsaturated Hydrocarbon Gases and their Derivatives" Texas Agricultural Experimental Station, Agricultural and Mechanical College of Texas, Publication No. MP603, 1962. Hefner, R. E. Jr., P. G. Watanabe, and P. J. Gehrlnq Ann. N.Y. Acad. Sci. 246 135 (1975). Hefner, R., P. Watanabe, and P. Gehring, "Percutaneous Absorption of Vinyl Chloride Gas in the Rhesus Monkey", Report prepared for the Manufacturing Chemicals Association, Washington, 0. C., August, 1974. Hehir, R. M., et a!., "Toxicology, Carcinogenicity and Reproductive Effects of Single and Multiple Exposures to Vinyl Chloride in Rats and Mice", Pre-publication draft, Feb. 6, 1980, U. S. Consumer Product Safety Commission, Washington, 0. Herrle, K. "Polyvinylchloride", In Ullmanns Encyklopadie der technischen Chemie, W. Faerst, Ed., Vol. 14, 3rd Edition, Urban S. Schwarzenberg, Munich, W. Germany, 1963. n . AU P-t 9 ''S't**-^***^ Hewlett Packard Company, Instruction Manual r* ** T* ^liU4V-fV 97. Hill, James, IV, H. P. Kollig, D. F. Paris, N. L. Wolfe, and R. G. Zepp. "Dynamic Behavior of Vinyl Chloride in Aquatic Ecostems." EPA - 600/ 3-76-001, Experimental Research Laboratory, Athens, Ga., January, 1976. Hoffmann, D., et al., Anal. Chem. 48 47 (1976). Hopkins, 0., Fd^ Cosmet. Toxicol.. 17 542 (1979). Huberman, E., et al., Int. J. Cancer. J_S 39 (1975). Infante, P. F., Ann. N.Y. Acad. Sci.. 271, 49 (1976), See also, Mut. Res. . 41 131 (1976). Center for Disease Control Morbidity and Mortality WeeklyTfeport, 24 (29) 245 (1975). S AP00020993 Infante, P. F., et al., The Lancet 1976 734. Iturra, H., "A Community Vinyl Chloride Mortality Analysis Study1'. Presented at the Air Environment Specialty Conference, Pittsburg, Pa., 1976. Proceeding page 96. Jaeger, R. J.t Anru Acad.-Sci. 246 150 (1975). Jaeger, R. J., et al., Nature 252 724 (1974). John, J. A., et al., Tox. and Appl. Pharmocol. 39 497 (1977). Johnson, R. V., et al., HCytogenetie Studies of Bone Marrow Cells front Rats Exposed to Vinyl Chloride" Report prepared for the Chemical Manufacturing Assocation by the Dow Chemical Co., April, 1976, unpublished. Joint Conference to Reevaluate the Toxicity of Vinyl Chloride, Polyvinyl Chloride, and Structural Analogues, National Institute of Environmental Health Sciences, National Institute of Occupational Safety and Health, and Occupational Safety and Health Administrative, Bethesda, Md., March 20-21, 1980. Proceeding to be publ-ished-in J. -Envir. -Health and- Path. Journal of Commerce, p. 5, July 3, 1960. Juhe, S., and C.-E. Lange, Ot^ med. Wschr. 97 1922 (1972). Juhe. S.. C.-E. Unae, G. Stein, and G. Veltman. Dt. fried. Wschr. 98 2034 (1973). Kappus, H., H. M. Salt, A. Buchter, and W. Balt. Nature 257 134 (1975). Keplinger, M. L., S. W. Goode, D. E. Gordon, and J. C. Calandra, Ann. N.Y. Acad. Sci. 246 219 (1975). Klllan, D. J., D. J. Plcclano, and C. B. Jacobson, Ann. N. Y. Acad. Sci.. 269 4 (1975). Klein, J., "The Plastic Coffin of Charlie Arthur", Rolling Stone, Jan. 15, 1976. e Kucerjva, et al., Hut. Res. 67 97 (1979). Kudryavtseva, D. G., Gig. Tr. Prof. Zabol, 14 54 (1970). Kuzmack, A. M., and R. E. McGaughy, "Quantitative Risk Assessment for Community Exposure to Vinyl Chloride", U.S. EPA, Washington, D.C., Dec. 5, 1975. . Laib. R. J.. G. Stock!e. H. M. Bolt, and W. Kunz. J. Cancer Res. Clin. Oncol. 94 139 (1979). Lange, C.-E., S. Juhe, G. Stein and G. Veltman, Int. Arch. Arbeltsmed. 32 1 (1974). AP00020994 Lange, C. E., Schwinger, E., and G. Veltman. Dt. Ges. f. Arbeitsmed.. Munich. 1975. Laskin, 5., et *1., J.N.C.I., 65, 751 (1980). Laumbach, A. 0., et al., "Studies on the Mutagenicity of Vinyl Chloride Metabolites and Related Chemiclas1' University of Louisville School of Medicine, Louisville, Ky. Unpublished results. Lee, C. C., et al., th Tox. and Envir. Health 4 15 (1978). Leonard, A., at il., 1 Toxical. Environ. - Health, 2 1135 (1977). Lester, D., L, A. Greenberg, and W. R. Adams, Ann. Ind. Hyg. Assn. J., 24 265 (1963). " Lilis, Lr., et al., Ahl Acad. Sci. 246 22 (1975). Loprieno, K., et al.. Cancer Res.. 36 253 0977). Loprieno, N., et al., Mut. Res.. 40 85 (1976). Lu, P. 4., et al., Arch. Environ. Contan. Toxical.. 6 129 (1977). MacMahon, B.. "Vinyl Chloride and Human Reproduction", Submitted by the Society of the Plastic Industry, Inc., in comments on the Proposed Amendment to the EPA Vinyl Chloride Standard, 1977. Malavielle, et al., Biochim. biophys. Res. Commun. 63 363 (1975). Maltoni, C., in "Origins of Human Cancer", H. H. Hiatt, J. D. Wilson, and J. A. Wlnsten eds., Cold Spring Harbor Laboratory, 1977, Vol. A., p. 119, Maltoni, C., "Results of Sputum Cytology Among Workers Exposed to Vinyl Chloride Monomer and to Polyvinyl Chloride'1, in "Joint Symposium", 0^ clt.. 1980 S. Maltoni, C., G. Lefenuine, A. Cilibertl, G. Colti, and 0. Carretti, "Vinyl Chloride Carcinogenecity Bioassays (B T Project) as an Experimental Model for Risk Identification and Assessment In Environments and Occupational Carcinogenesis" Presented at "Le Club de Cancergenese Chemique", Institute Curie, Paris, Nov. 10, 1979. See also the "Joint Conference", op., cit., 1980. Mapp, C., et al., Med^ Lavoro 69 151 (1978). Marcus, W., Comments during hearing on the Vinyl Chloride Standard, EPA, Washington 0. C., Feb. 3, 1976. transcript page 43. Maricq, H. R., M. N. Johnson, C. L. Whetstone, and E. C. LeRoy, JAMA 236. 1368 (1976). ------ Markowitz, S. S., C. J. McDonald, W. Fethiere. and M. S. Kerzner. Arch. Dermatol. 106 219 (1972). ----------------------- APb002b995 Marsteller, H. J., Dt^ Med,. Wschr. 98 2311 (1973). Mastromatteo, E., A. M. Fisher, H. Christie, and H. Danziger, Am. Ind, Hyg. Ass^ ^21 394 (1960). Mattem, I. E., W. fi. Van der Zwaau, and M. J. Willems, Hut. Res., 46 230 0977). McCann, J., et al., Proc. Hat. Acad. Scl., 72 3190 (1975). Meselson, H., and K. Russell, "Comparison of Carcinogenic and Mutagenic Potency", In M. H. Hiat, J. 0. Watson, and J. A. Winsten, eds., "Origin of Human Cancer", Book C, p. 1473. Cold Spring Harbor, N. Y., 1977. Meyerson, L. B., and G. C. Meier, Arch. Dermatol. 106 224 (1972). Miller, A., et al., Ann. N. Y. Acad. Scl. 246 42 (1975). Mirkova, E., A. Mihailova, and M. Nosko, Khiq. Zdraveopaz Z\_ 440 (1978). Monson, ft. R., J.-M.-Peters,-and M. N. Johnson,-lancet 2-397-(1974). Muller, G., Norpoth, K., and W. Owzarskl Int. Arch. Occup. Environ. Health 42 137 (1978). National Cancer Advisory Board, "The Relation of Bioassay Dose to the Assessment of the Risk of Carcinogens for Humans under Conditions of Low Exposure11, Subcommittee on Environmental Carcinogenesis, Draft of 1979, Citing data from Meselson and Russell, 1979. National Institute of Occupational Safety and Health, J. Occup. Med. 16 809 (1974). National Toxicology Program, "First Animal Report on Carcinogens; Vol. II, p. 190. Dept, of Health and Human Services, Washington, D. C., July, 1980. Nicholson. W. J., et al. Ann^ Acad. Scl. . 246 225 (1975). Nisbet, I.C.T., Post-hearing statement to 0SHA docket 090, September 15, 1978. Occupational Safety and Health Administration. "Identification, Classification and Regulation of Potential Occupational Carcinogens", 45 FR 5178-5200, Jan. 22, 1980. Oster, R. H., C. J. Carr, J. C. Krantz, and M. J. Saverwald, Anesthesiology B 358 (1947). Ott, M. G., R. R. Langner, and B. B. Holder, Arch. Envlr. Health, 30 333 0975). Paddle, G. M. The Lancet 1976 May 15. Patty, F. A., W. P. Yant, and C. F. Waite, Pub. Health Reports, 45 1963 (1930). Peoples, S. A. and S. D. Leake, Pharmacol. Exptl. Theory 46 284 (1933). AP00020996 Picciano, D. J., at al., Occup, Hed. T9 527 (1977). Popper, H., et al., AmL Pathol 92 349 (1978). Prodan, L., Anru Acad. Set., 246 154 (1975). Purchase, I. F. H. , C. R. Richardson, and D. Anderson, Lancet 417 11 (1975). Radike, M. J., "Carcinogenic Effects of Exposure to Vinyl chloride Monomer and Ethyl Alcohol on Rats", In "Joint Conference", cit.. 1980. Radike, M. J., et al., Envlr. Health Persspent. 21 (153) 1977. Rannung, H., et al., Cheniico-Blol. Ineract. 12 251 (1976). Reini, W., H. Weker, and E. Grelser, "Epidemiological Study of the Mortality of Workers Exposed to Vinyl Chloride In the FRG", Paper presented at the Nineteenth International Conference for Occupational Health, Oubrovnlc, Yugo, Sept. 19. 1978. Reitz, R. H., et al_., Science 205 1206, (1979.). Rowe, V. K., and T. R. Torkelson, Am^ Ind;_ Hyg^ Assn. J^ 38 A-25 (1977). Saric. M.. Z. Kulcar, M. Zorlca. and J. Gelic.. Envlr. Health Perso.. 17 189 (1976). " Schaffner, F., Falk Symp. 25 Primary Liver Tumors, p. 189, 1978. Schaumann, 0., see K. B. Lehman and F. Plug, "Toxikol. u. Hy9- d. technlochem Losungs mittel", J. Springer, Berlin, 1938, p. 130-143. Schauman, 0., Hedizin ik Chemie 2 139 (1934). Schneiderman, M. A., N. Mantel, and C. C. Brown "From Mouse to Man N.Y. Acad. Scf.. 246 237 (1975). Ann. ------ Semon, W. L-, U. S. Patent 1, 929, 453 (Oct. 18, 1933). Short. R. 0.. J. L. Minor, J. M, Winston, and C. C. Lee. J. Toxical. Environ. Health. 3 965 (1977). ------------------------------- Smirnova, N. A. and N. P. Granik, Gig. Tr. Prof. Zabol. 14 50 (1970). Spirltas, R., et al.. Ajtl Ind. Hyq. vh 36, 729 (1975). Stafford, J., private communication (1980). Stein, G., S. Juhe, C.-E. Lange and G. Veltman. Sonderdruck aus Rontaen-Blatter 26 3 (1973). ------------------------------------------------- Stockle, G.. R. J. Laib, J. G. Flbser. and H. M. Bolt. Toxicoloov Letters 3 337(1979). ------------------------------- AP00020997 Sucin, I., et al. , Ann. Acad. $ci. 246 53 (1975). Suciv, J., J. Drejman, and M. Valaskai, Med. Intern. 15 967 (1963). Suciv, F., J. Drejman, and M. Valaskai, Med. Lav 58 261 (1967). Tabershaw, I. R., and W. R. Gaffey, J. Occup. Med. 16 509 (1974). Tamburro, C., "Liver Screening Tests for Vinyl Chloride Exposed Workers1', In "Joint Conference", o^ clt. 1980. Taylor, K. J. W., "Toxic Substances In the Air Environment" Proceedings of the Air Pollution'Control Asociation, Pittsburgh Conference, 1977, p. 119. Theriault, G. P., and L. Goulet, "Birth Defects In a Community Located Near A Vinyl Chloride Plant" Presented at the Annual Meeting of the Am. Public Health Assn., 1977. Thomas, L. B., and H. Popper, Ann. N.Y. Acad. Sci.. 246 268 (1975). Torkelson, T. R., Statement before the Senate Subcommittee on Environment, Aug. 21, 1974. Committee on Commerce Serial No. 93-110. Torkelson, T. R., F. Oyen, and V. K. Rowe, Am. Ind. Hyg. Assn. J.. 22 354 0961). Trlbukh, S. L., N. P. Tikhomirova, S. V. Levina, and L. A. Kozlov, Giqiena i Sanit 10 38 (1949). Union Carbide, unpublished data, (1974). Vainio, H. Chem-Biol. Interactions 22, 117 (1978). 9Van Duuren, B. L., Anm Njr Acad. Sci. 246 258 (1975). Vazin, A. N., and E. I. Plokhova, Gig. Tr. Prof. Zabol 13 46 (1969). them. Abstracts 72 89621q. (1969). Veltman. G., et al., Anrh Acad. Sci. 246 6 (1975). Verburgt, F. G., and E. Vogel, MuiL Res^, 48 327 (1977). Viola, P. L., Hediclna del Lavoro 62 174 (1970). Viola, P. L., A. Bigotti, and A. Caputo, Cancer Research 32 5)6 (1971). von dettingen, W. F. Public Health Service Publication no. 414, U. S. Department of Health, Education and Welfare, Washington, D. C., 1955. Wagoner, J. K., P. F. Infante, and R. Saracci, Lancet, 1976 194. Wakeman, I. B., and H. R. Johnson, Pol. Eng. Sci.. 18 404 (1978). AP66b26998 Watanabe, P. G., R. E. Hefner, Jr., and P. J. Gehring, Toxicol. 5 (1976). Watanabe, P. G., G. R. McGowan, E. D. Madrid and P. J. Gehrina, Toxicol. Aool. Pharmacol. 37 49 (19761. ---------------- Watanabe, P. G., G. R. McGowan and P. J. Gehrina. Toxicol. AdoI. Pharmacol. 36 339 (1976). -------------------------------------------- Watanabe, P. G., J. H. Zenpel, D. G. Peao. and P. J. Gehrina, Appl. Pharmacol.. 44 571 (1978). -------------------- Watanabe, P. G., et al., Dev, in Tox. and Envir. Sci.. 6 69 (1980). Waxweiltr, et al., "A Cross-sectional Epidemiological Survey of Vinyl Chloride Workers" National Technical Information Service No. PB-274, 193, Springfield, VA., June, 1977. Waxweiler, et al., "An Epidemiological Investigation of an Excess Lung Cancer Risk in a Synthetic Chemicals Plant", Presented at the Nineteenth International Congress for Occupational Health, Dubrovnik, Yugo., Sept., 1978. Waxweiler, R., "A Case-controlled Study of Lung Cancer Among Vinyl Chloride- Polyvinyl Chloride Workers", In Joint Conference, cit.. 1980. Waxweiler, R. J., H. Falk, et al., "A Cross-sectional Epidemiologic Survey of Vinyl Chloride Workers" Center for Disease Control Division of Surveillance, Cincinnati, OH, April, 1977. Wilson, R. "Response to comments of I. C. Nisbet," Post-hearing record OSHA Docket D90, 1978. Wilson, R. H., W. E. McCormick, C. F. Tatum, and J. L Creech, JAMA 201 577 (1967). ------------- Withey, J. R., J^ Tox,, and Envir. Health 1 381 (1976). Withey, J. R., and B. T. Collins, J. Tox. Envir. Health. 2 311 (1976). Zajdela, F., et al., Cancer Research 40 352 (1980). AP00020999 in light of the above evidence that neither acute or chronic effects occur from repeated daily exposures after many years, and that irritation may be experiences at around 20 ppm, but not at 10 ppm, the recommended TLV for vinyl acetate if 10 ppm, with a STEL of 20 ppm. Other recommendations: USSR MAC (1976) 3 ppm; NIOSH (1978) 4 ppm ceiling. References: 1. Hukell Laboratory: Report of Toxicity of Vinyl Acetate, LI. du Pont de Nemours & Co,, Wilmington, DE (January 1967). 2. Mellon Institute; Communication to TLV Committee (October 14,1968). 3. Deese, D.EV loyner, ILL: Am. Ind. Hyg. Assoc. I. 30A49 (1969). 4 Union Carbide h Carbon Corp- Toxicology Range-finding Tests. Dept, of Ind. Med. & Tox. (December 1956). 5. Cage, J.C: Brit.). Ind. Med. 27:1 (1970). 4 Maltoni, Cj Vinyl Chloride Carcinogenicity, in Origins of Hu man Cancer, Vol. 4, pp. 119*146, Cold Spring Harbor Laboratory (1977). VINYL BENZENE See, STYRENE VINYL BROMIDE Bromoethylene QHjBr TLV, 5 ppm ( m 20 Carcinogen Appendix A2 -- Suspected Vinyl bromide has a molecular weight of 106.96 and the liquid has a specific gravity of 1.4933 at 20* C. it has a melt ing point of 139.54 and a boiling point of 15.60 at 760 mm tig. Insoluble in wafer, it is soluble in alcohol, ether, ace tone, benzene or chloroform. This substance has not been found suitable as an anes thetic, but is useful as a fire-retardant in plastics. The oral LO of the 50% solution in corn oil re 500 mg/Vg in male rats.<') Liquid vinyl bromide is slightly to moderately irritating to the eyes, but non-irritating to in tact or abraded rabbit skin. Acute inhalation studies show that 100,000 ppm is lethal to rats in 15 minutes; 50,000 ppm renders rats unconscious in 25 minutes and is lethal after 7 hours of exposure. At 25,000 ppm, rats are anesthetized, but recover rapidly even after 7 hours of exposure. Slight to moderate kidney damage was seen in rats surviving expo sure to 50,000; but no hlstopathoioglcal changes were seen in rats exposed 7 hours to 25,000 ppm. A sub-acute inhalation study in rats exposed to 10,000 ppm for 7 hours per day, 5 days per week, revealed signifi cantly depressed body weights after 15 days of exposure, but no compound-related gross or microscopic pathologi cal changes after 20 exposure days.u> In a chronic inhalation study, in which groups of rats, rabbits and monkeys were exposed to 250 or 500 p0m for 6 hours/day, 5 days/week for 6 months, no significant changes were detected in any of the following parameters: growth rates, food consumption (rats and rabbits only), he matology, gross pathology, organ to body weight ratios and histopathology.Q) Measurements of blood bromide showed that the levels increased with duration of exposure to all three species and were proportional to the concen tration of vinyl bromide in the test atmosphere. Estimated equilibrium values for blood bromide in monkeys exposed to 250 and 500 ppm were well below those levels at which signs of bromism were evident. Based on interim data obtained after 12 months of a lifetime inhalation study, there appear to be serious toxic effects in Charles River Sprague-Dawlev rats exposed to 1250 or 250 ppm 6 hours/day, 5 days/week.m The toxic effects include increased mortality, decreased body weight, angiosarcomas of the liver and carcinomas of the zymbal glands of the ears. These responses were dose re lated and did not occur in groups of male and female rats similarly exposed for 1 year to 50 ppm or 10 ppm. Based on these data a TLV of 5 ppm, the same as that for vinyl chloride, is recommended, as well as placement on the A2 listing as a suspected human carcinogen, References: 1. Torkelson, TJL: Unpublished data, Dow Chemical Company, Midland, Ml. 2. Leoftfr I.K.L, Torkelson, TJL: A. ind. Hyg. Assoc. J. 31-.1 (1970). 3. Huntington Research Laboratory; Unpublished Interim Report (1977). VINYL CHLORIDE CMoroethene CH, - CHC1 TLV, 5 ppm ( * 10 mg/m>) -- Appendix Ala Recognized Carcinogen A colorless, highly flammable gas with an ethereal odor, vinyl chloride has a molecular weight of 62.50. It boils at -13.9* C and freezes at -159.7 C Vinyl chloride is usually handled as a liquid under pressure, and containing a po lymerization inhibitor (phenol). It is slightly soluble in wa ter, but dissolved by alcohol and ether. The chief use of vinyl chloride is as a raw material for the manufacture of polyvinyl chloride resins. It is also em ployed in organic syntheses. Since vinyl chloride is a gas at room temperature and pressure, the common route of toxic exposure is by inhala tion. As with many liquified gases, contact of the skin or 427 AP00021000 eyes with escaping compressed vinyl chloride can produce freezing frostbite.'1' Vinyl chloride has long been considered to be very low in toxicity by acute inhalation. Lehmann and Flury sum marized the literature and reported work by Schauman who considered vinyl chloride to be a candidate surgical anesthetic. Schauman reported little pathological change even after repeated exposure to anesthetic concentrations. Further work on the anesthetic potential of vinyl chloride indicated that vinyl chloride was unsafe for use as a surgi cal anesthetic in dogs and that because of its flammability, poor efficacy and its ability to cause cardiac irregularities at anesthetic concentrations vinyl chloride was not suitable for use as an anesthetic in humans. Despite the early reports ascribing low toxicity to vinyl chloride, injury during the production of polyvinyl chloride |PVC) resins was reported as early as 1949. Significantly this report came from Europe where production of PVC in Eu rope preceded US. production by several years and today the quantity produced in Europe still exceeds US. produc tion by about two fold. In 1949, Tribuhk et a/J> reported numerous effects in PVC workers in what, by today's stan dards, must be considered as primitive production facil ities. These authors found a "considerable number ofcases of hepatitis among workers" but were more concerned with other hepatotoxic chemicals such as chlorinated di phenyl and chlorinated naphthylene (Holowax [sic]) than they were with vinyl chloride. As a result of two deaths in Canada, the acute inhalation toxicity of vinyl chloride was studied by Mastromatteo et aA4> who reported that exposure of mice, rats and guinea pigs to 10, 20 and 30 volume percent vinyl chloride caused the following mortality: NUMgEJt OP DEATHS IN DIFFERENT CROUPS OF FIVE MICE, RATS AND GUINEA PICS EXPOSED FOR THIRTY MINUTES TO VARYING CONCENTRATIONS OF VINYL CHLORIDE IN AIR Vinyl Chloride concentration (percent by volume in air) 10 20 30 40 Laboratory animal Mice Rats Gutnea pigs 0/5 0/5 1/5 0/5 5/5 5/5 ---- 0/5 0/5 1/5* 2/5* TOTAL OrtS 1/15 11/15 2/5 A delayed death occurred within 24 hours following exposure. Some pulmonary hyperemia and engorgement was ob served by these investigators, but liver and kidney injury were remarkably tow. Deaths were due to narcosis. The first report of studies to determine the effect of long-term repeated exposure (6 months) were summarized by Torkebon, Oyen and Rowem as follows: "Sepeared exposures of Laboratory animals at several concertfrafions of vinyf chloride In air were conduct ed to determine the chronic toxicity of this material towards animals in order to assess the hazard to hu mans. Vinyl chloride was found to have a slight ca pacity to cause liver and kidney Injury on repeated exposures. Male and female rats showed m/cropathological changes after repeated daily 7-hour exposures lu at 500 ppm for 4.5 months. Repeated 7-hour exposured at 200 ppm for six months resulted in micropathological changes in the livers ofrabbits and statisti cally significant increases In the average weight of the Overs of male and female rats, but no detectable changes in dogs and guinea pigs. Repeated 7-hour exposures at 100 ppm resulted in slight increases in the average weight of rat livers, the other species were not affected. All species studied tolerated re peated daily 7-hour exposures at 50 ppm for six months with no detectable injury. Repeated daily 1-hour exposures at 200 and 100 ppm of vinyl chloride were without effect, longer expo sures caused a slight increase in liver weight. The standard for evaluating regular daily 7- or 8-hour exposures may be defined as the concentration be low which practically all analytical results must fall, The value of 100 ppm is suggested as this standard for vinyl chloride, with a time-weighted average for all exposures not to exceed 50 ppm " Lester, Greenberg and Adamsm took exception to the conclusion of Torkelson et al (1961) that 50 ppm should be a maximum time-weighted average exposure for workers. On the basis of 3 months exposure of rats to 2 volume percent and 19 days to 5 volume percent, they concluded that 500 ppm was acceptable as a TLV despite minor changes which they observed in rat livers and which they considered "were within the normal range and were not pathologic in nature." Since 1949 numerous articles describing conditions and problems in PVC production plants have appeared particu larly in the Eastern European literature. Filatova and Gronsberg,<*> Gabor et al,m Suciu et */,<> Gabor et a/,m Crigorescu and Toba/xn Antonyuzhenko,w and Kudryavtsevann have all described the effects of apparent gross chronic exposure. These papers and abstracts are difficult to inter pret since there are generally inadequate descriptions of the exposure conditions and analysis of the workroom air, so no dose-response relationship can be determined. The injuries and effects described by the authors are not con sistent with the levels of exposures claimed by the authors nor are the levels of exposure consistent with past or even present-day chemical technology. Furthermore, mixtures of chemicals are involved making it possible to ascribe the effect to any one of them. For example, Suciu et a/> (through translation) de scribed nervous disorders including euphoria with whis tling and laughing, incoordination and dizziness similar to alcohol intoxication. However, Suciu et al ascribes these results to exposure of the order of 5.5 mg/rrp (2 ppm v/v) which is not consistent with other publications which indi cate these effects wilt be apparent only if concentrations greatly exceed 10,000 to 20,000 ppm v/v. Therefore, the fol lowing conclusions by the authors can be construed as being the result of massive and apparently repeated expo sures: 1. Vinyl chloride and the vinyl monomers possess narcotic action and produce, depending upon concentration, in addition to characteristic neuro logic manifestation, a state of euphoria (12%), fol lowed by a state of inebriation similar to that of alcohol intoxication. In certain cases narcosis can Appear. c c AP0662T601 After leaving the working environment, a state of somnolence (45%) persists, with hypersomnia. Vi nyl chloride acts on the skin and produces a sen sation of formication and of heat. 2. After repeated exposure, a neurologic asthenia sets in which somnolence predominates. 3. After a variable period of time, dyspeptic distur bances are added to the neurologic manifestations; these are at first not characteristic; they are in the form of epigastric pains (16%), swelling, discomfort, feeling of heaviness in the right hypochrondium (7%) or the left (5%) with anorexia, particularly for fats. In 303% of the cases, congestive hepatomegaly ap pears, which may mimic toxic hepatitis without jaundice; some cases may become chronic in 6% of the cases, the hepatomegaly is accompanied by splenomegaly. The proteinogram and the aldolas es are the most sensitive tests and show changes sim ilar to those of acute hepatitis: increase in a-globulins and of the fi- and r-globulins; and thymol test, Creenstedt's reaction and the zinc sulfate test are positive only in few of the cases. 4. After 3 years of exposure in 9% of the cases a syn drome typical of ulcer without radiologic changes becomes manifest. 5. In 6% of the cases the Raynaud syndrome has ap peared, particularly among the young men. Plethys mography shows in half of the cases an inhibition of the vasomotor centers. 6. In addition, allergic dermatitis in 4.4% of the cases, and scleroderma in 3.6%, has been observed. 7. The clinical and laboratory findings are of great im portance in occupational pathology because in num erous cases diseases appear in man that cannot be reproduced in the animal (Raynaud's syndrome and scleroderma). The sudden and frequent appearance of these mani festations in the PVC division of several plants, and in certain divisions in normal individuals who are still relatively young, and their disappearance in the ma jority of the cases after the institution of protective measures and change of work, have shown us deci sively that vinyl chloride and the vinyl monomers have played a part in the production of these mani festations. (End of author's summary). In 1967, reports appeared In the literature describing a condition known as acroosteolysis in workmen engaged in polymerization of vinyl chloride to polyvinyl chloride. Har ris and Adams(U) reported on two cases in Europe. Wilson t afn*> reported on 37 cases in the B. F. Goodrich Compa ny. fuhe et aft1*) described a syndrome consisting of (ar ranged in decreasing order of occurrence) thrombopenla, splenomegaly, liver damage, obstruction of ventilation, cir culatory obstruction, and skin and bone alteration. As a result of this problem, the University of Michigan in 1967 was retained by the Manufacturing Chemists Asso ciation to investigate acroosteolysis in sponsoring Ameri can companies. The results of large scale epidemiological study of workers then currently employed in vinyl chloride and polyvinyl chloride production were reported In three publications by this group Dinman et al,w Cook eraA'n and Dodson et */.<*> Dinman ef a*> summarized the study as follows: "An epa'demio/og/cal study was performed cov ering 5,011 employees with 27,570 man-years ex perience in various phases of vinyl chloride (VC) and polyvinyl chloride (PVC) manufacturing in 32 plants throughout the United States and Can ada. The total number of definitive cases of acroosteolysis (AOL) was 25; 16 other individuals were under suspicion. This condition H clearly associated with the hand cleaning of poly-mergers. Workers engaged In other phases of VC or PVC manufacturing do not appear to be at risk of developing AOL. The Importance of Raynaud's phenomenon as a concomitant of AOL us emphasized. Several statistical ap proaches for rapid medical survey are suggested. Acroosteolysis appears to be a systemic rather than local disease. Presently, neither the eti ological agent nor its portal of entry is known." Cook et akm describes the polyvinyl chloride produc tion process in considerable detail. They concluded that although no etiological agent could be identified, "There appeared to be a correlation between the extent of degas sing prior to entry into the reactor" and the incidence of acroosteolysis. Mutchler and Kramerim presented a paper at the I960 Gordon Research Conference which was subsequently published (1972), which reported on The Correlation of Clinical and Environmental Measurements for Workers Ex posed to Vinyl Chloride. The authors drew the following conclusion: "Our findings suggest that repeated exposure to vi nyl chloride at TWA levels of300 ppm or above for a working fifetime together with a very low level of vinylidene chloride may result in slight changes in certain physiologic and clinical laboratory parame ters. The pojifb///fy of some impairment in liver function tests must be considered, even though no overt clinical disease was evident in any of the indi viduals studied. We shall continue our study, but suggest that similar studies to help clarify the effects of this material be performed for other worker popu lations exposed to vinyl chloride alone." P. L. Viola, in an attempt to produce acroosteolysis in animals, exposed rats 4 hours per day, 5 days per week to 30,000 ppm (3%) vinyl chloride vapor. In his first report on the results of 12 months exposure, he described metaplas tic changes In the bones which he considered similar to the human disease acroosteolysis. He made no mention of having observed cancer in these animals until the Tenth International Cancer Congress in May 1970. In the abstracts of this meeting, and subsequently in May 1971, Viola, Bigotti and Caputo<*> reported tumors of the skin, lungs and bones occurring first after 10 months of exposure. The au thors summarized this work as follows: "Rats (Ar/IRE Wistar strain) exposed for 12 months to vapors of vinyl chloride developed tumors of the skin, lungs, and bones. The cutaneous tumors, which always appeared in the area in which submaxillary and parotid glands are located, have been histologi cally recognized as epidermoid carcinomas, papiliomas, and mucoepidermoid carcinomas. The morphological characteristics of lung tumors, which 429 AP00021002 occurred m a lower percentage, were mainly of the adenocarcinoma type, with the exception of a single epidermoid tumor originating from the epithelial covering ceils. In a minor number ofrats, a targe proBferadon of cartilaginous tissue diagnosed as osteoctondtoma developed in the metacarpal and meta tarsal regions of the four limbs The report by Viola et ***>> Is apparently the earliest piiMicHidn in which carcinogenic activity has been as cribed to vinyl chloride in man or animals. Although there were obvious deficiencies in Viola's study, such as his very impure sample, the presence of food and bedding in the exposure chamber, the excessive exposure concentration as well as in the statistical evaluation and interpretation of the lesions, the report was of serious concern and resulted in additional animal and epidemiological studies which are currently underway in Italy by Maltoni,<"* Mattoni and Lefemine*13'24) and in the U.S., Kepiinger et a/.<M) On January 22-23, 1974, the B. F. Goodrich Company notified its employees. NIOSH, the Kentucky State Depart ment of Labor, and the public, that three workers had died of angiosarcomas of the liver. The case reports of the first subject has been published by Creech and Johnson,w The subject, a 36 year old male, was hospitali2ed lanuary 5,1970 and subsequently succumbed September 27,1971. He had worked in PVC production from November 1955 until his illness. The history, clinical course and pathologic findings are consistent with the others who died of angiosarcoma. The work of Maltoni and lefemineo3-24) has been report ed publicly at the OSHA hearing, Washington, D.C., Febru ary IS, 1974, and included in the 1974 publication of the Second International Symposium on Cancer Detection and fteuenfkm, Bologna, Italy, April 9-12,1973. In these studies groups of rats as well as mice and hamsters have been ex posed at concentrations of 10,000 to 50 ppm vinyl chloride vapor. Maltoni and Lefemine (1974) reported carcinomas of the Zymbal glands, nephroblastoma and angiosarcomas of the livers of rats at concentrations of 250 ppm to 10,000 ppm but not at 50 ppm. Subsequent unpublished informa tion (August 31, 1974) reported, "7 liver angiosarcoma, 1 parahepatic angiosarcoma and T nephroblastoma, in three animals of the first experiment, exposed at SO ppm of VC for 7 year, and surviving 135 weeks from the beginning of the treatment." The authors conclude that, "a dose-response relationship clearly emerges, as tar as angiosarcomas and nephroblastomas are con cerned, in the lower dose ranges: from 500 ppm to 50 ppm for ang/osarcomas, and from 250 ppm to SOppm for nephroblastomas. A comparison of the results available at the present moment in rats exposed for 12 months and 4 months (BTl and BT3 experiments) stows that the neoplastic response, as far as angios arcomas and nephroblastomas are concerned, is af fected by the length of exposure to VC" In their eqwimant BT3 Maltoni and Lefemine reported posa?b*c in mero production of angiosarcomas in offspring of pregnant rats exposed at 10,000 and 6,000 ppm. Keplinger er alph in a study sponsored by American companies, have confirmed the findings of Maltoni and Lefemine. In this study, groups of 100 rats, mice end hamitcn of each sex are being exposed seven hours per day, five days per week to either 2,500, 200 to 500 ppm vinyl chloride monomer. After seven months of exposure an- 4M giosarcoma and lung adeaomas have been observed in mice at all exposure levels. Although the data are prelimi nary in nature and require confirmation, angiosarcomas were apparently also observed in rats at 2,500 and 200 ppm and in single hamster at 2,500 ppm. This study is still in progress and will not be completed until 1976 or 1977, Epidemiological studies on U.S, workers have been con ducted by Tabershaw-Cooper Associates for the Manufac turing Chemists Association.^ The summary of this study is as follows: .This historical prospective mortality study of 8384 men who had at (east one year of occupational exposure to vinyl chloride before December 31, 1972, demonstrated that cancers of the digestive system (primarily angiosarcoma), respiratory sys tem, brain, and cancers of unknown site, as well as lymphomas, occurred more often than expect ed in those members of the study population with the greatest estimated exposure. The mortality from other cancers was lower than that of the general male population, with the exception of cancers of the buccal cavity and pharynx. The ex planation for the latter finding is not apparent. The other major findings of the study are: (1) The over all mortality of the study population was approximately 75% of what would be expected in a comparable popu lation of U.S. males; (2) No cause of death showed a statistically significant excess over what would be ex pected in e comparable U.$. male population; and (3) No deaths identified as angiosarcoma of the liver were found other than those previously identified. This is the first epidemiological study which suggests f that in humans vinyl chloride may also be associated with cancer of multiple sites. It is difficult to derive a reasonable TLV from the data presented in the literature summarized above. There is in direct evidence that intermittent exposures to vinyl chlo ride of the order of thousands of ppm, in this country as well as Russia, have not been infrequent in PVC plants. No data on the past (or even present) concentrations of vinyl chloride in plants where angiosarcoma cases have oc curred, or not occurred, appear to be available. One re* portri*) indicates that 21 of 26 of the early cases of angiosar coma occurred in former reactor cleaners. Cleaning of reactors was apparently responsible for most of the acroosteolysis cases investigated by Cook and associates,!17) and has resulted in death from acute poisoning by vinyl chlo ride.!*) It Is the sense of the Committee ihat. If the average exposure to vinyl chloride does not exceed 5 ppm, there wil be no increase in the Incidence of cancer, specifically of angiosarcoma of the liver. It is probable that the cancers reported and attributed to vinyl chloride among PVC work ers resulted from exposures many times this level. NIOSH recommended a limit of 1 ppm as a TWA, with a ceiling of 5 ppm. The 1 ppm value was apparently based on the erroneous belief that this was the lowest concentration that could be readily measured. Gehrlng and co-workers,<> using a probit model, and based on sludles with rats, found the predicted incidence of hepatic angiosarcomas from 8 hour/day, 5 days/week, 35 year exposure at 1 ppm to be 1.5 times itH 's-- AP00021003 Recent papers have included a report of 4 cases of respi ratory cancer among vinyl chloride workers, but no doseresponse relationship.^1! On the other hand, Fox and Collier,in a study of 7000 men exposed to vinyl chloride in PVC manufacture be tween 1940 and 1974, found no evidence of cancers due to vinyl chloride at sites other than the liver. There are four liver cancen, two of them angiosarcomas. Delorme and Theriault*1** described 10 cases of liver an giosarcoma among workers in vinyl chloride polymerizing plant in Quebec, which were accompanied by fibrosis Of the liver. Details of 64 cases were presented by SpuUs and Kaminski.***! Mutufugi, in Japan, noted that in contrast to western countries, in which 70 angiosarcomas cases (associated with vinyl chloride exposure) had been reported, no can cer, but many poisoning cases, have been reported in the USSR.**** Based on the above data, an Ala classification as a con firmed carcinogen is given vinyl chloride and a TLV of S ppm as a time-weighted average is suggested. If this value is not exceeded, there should be no increase in the inci dence of cancer, especially angiosarcoma of the liver. Limits adopted in other countries, subsequent to the surfacing of vinyl chloride exposure associated cancers, as are follows, according to a 1977 summary: Australia (1973) 25 ppm; Finland (1975), Holland (1973), Poland (1976),. Switzerland (1976) and USSR (1977) about 10 ppm; Italy (1975) S ppm; Japan (1975) and Sweden (1978) 1 ppm. References: 1. TorkcUon, TJL ef at Am. Ind. Hyg. Assoc. J. 22(S)354 (1961). 1 Lehman, KJ., Flury, f.1 Toxicology A Hygiene of Industrial Solvents (1933). . TribuVh, et *h Arg. Stint. 70:38 (1949). 4. Mastromatteo, t et it Am. Ind. Hyg. Assoc, f. 21f5J'394 0961). 1 Inter, D. et it Ibid. 24:265 (1963). . fOatova, VA, Crsnsberg, LSu Ciglena I. Sink. 22(1):23, ab stract (1957). 7. Cabor, S. ef at. Prom. Toksikol. i. Klinika. Ptot. Zaholevanii Khim. (tiol. 5b. 221, abstract (1962). 0. Sucio, L ef at Medicins Interna (Bucharest) XV(B):Bf7 (1963). 9, Cabor, 1 et at Ingiena Bucharest 13(S):409 (1964). 10. Crigorescu, U Toba. Rev. ChiVn. I7f6J:499, abstract (1966). 11. Antonyuihenko, VAj Gig. Jr. Prof. Zabol. 12(3):S0, abstract (I960). 11 Kudryavtseva, O.F_* Ibid U{B):54. abstract (1970). 11 Harris, OX. Adams, W.G.Fj Brit. Mad. A 5567:712, abstract (1967), 14. W&son, ILK er at )AMA 201(8):577 (1967). 15. Juht, S. et a(: Dtsch, Med. Wsehr. 90:2034 (1973). 16 Dintnan, O.D. et ah Arch. Snv. Health 22:61 (1971). 17. Cook, WA et at. Ibid., p. 74. IB. Dodson, V.N. et at Ibid, p. 83. 19. Kramer, CC, MuttWer, |.t* Am. Ind Hyg. Assoc. ). 33(17:19 (1971). 20. Viola, P.Li Medicina del Lavoro 61(3) (^Aarch 1970). 21. Viola, P.L e( at Cancer Research 31:516 (1971). 21 Maltonl, Ct Proc. 2nd Inti. Symp. on Cancer Detection A Pre vention, Bologna, 1973, Excerpta Medica, Amsterdam (1974). 21 Maltonl, G, lefemhtc, Cu Lincei-Randiconta Della Oatse dl Science, Tesiche, Mathmatische 56:1 (1974). 24. Eidem: Carcinogenic Bioaftays of Vinyl Chloride, unpub lished data (1974). 25. Keptinger, J.L et at. Annals of HY Acad, ofSciences Working GfOt/p (May 10.1974). 26. Creech, J.L, Johnaon, M.KU JOM T6(3J:150 (1974). 27. Tabershaw, ML, Gaffey, WJLa Ibid., p. 506. 20. Patty, FA. er at. US Pub. Health Reports 45,1963, abstract (1930). 29. Current Intelligence, j. Occup. Med. 16:809 (1974). 30. Cehring, P.T. er at To* Appl. Warm. 49.15 (1979). tHD ab stract 7S3/79. 31. Buffier, PA et at. /. Occup. Med. 21:195 (1979), Ibid. 54/79. 32. fox, A.J, ColHer, P.Pa Brit. /. Ind. Med. 34:1 (1977). Ibid. 501/77, 31 Delorme, fH Theriault, Ca /. Occup. Med. 20:336 (1976). Ibid. 686/78. 21. Sputas, L, Kaminski, IU Ibid. p. 427. Ibid. 828/78. 35. Matufugi, H.; /, 5clnc* Labor 54:585 (1978). Ibid 54/79. 36. Massachusetts Div, of Occup. Hygiene: Unpublished report. VINYL CYANIDE See, ACRYLONITRILE VINYLCYCIOHEXENE DIOXIDE Vinyfhexarve dioxide CtHnOJ Skin TLV, 10 ppm ( to 60 mg/m1). Appendix A2 -- Suspected Carcinogen A colorless liquid which has a specific gravity of 1.0966 at 20* Q vinylcydohexene dioxide's molecular weight is 140.18. Its freezing point is -106.9* C and boiling point is 228* C The open cup flash point is 230* Fand the viscosity is 7,77 centipolse at 20* C. The vapor pressure is 0.1 mm Hg at 20* C and is very soluble in water. Vinylcydohexene dioxide has been used by the plastic industry since the 1950's in the formation of polymers and other types of organic syntheses.*1-*) 431 AP0b02lb04