Document DM7D9wozMgn9ndo2KKmn7wwYO

CHEMICAL MANUFACTURERS ASSOCIATION August 24, 1994 Dear Vinyl Chloride Health Committee Members: The National Research Council's monograph on Spacecraft Maximum Allowable Concentration for vinyl chloride is enclosed. The monograph briefly reviews toxicology literature and could be a useful reference document. Jonathon Ramlow should review the developmental and reproductive effects sections to see if there are references that could be useful in preparation of the industry position on the need for additional teratogenic or reproductive effects testing. I also have enclosed a proposal from Richard Reitz for his services. I will seek your approval of his proposal on our September 9 conference call. I am looking forward to talking to you on September 9. Sincerely, Enclosures KEYWORDS: SL 107466 2501 M Street, NW, Washington, DC 20037 Telephone 202-887-1100 Fax 202-887-1237 VINYL CHLORIDE Co o "j a Ch xj NATIONAL ACADEMY PRESS The National Academy Press was created by the National Academy of Sciences to publish the reports issued by the Academy and by the National Academy of Engineering, the Institute of Medicine, and the National Research Council, all operating under the charter granted to the National Academy of Sciences by the Congress of the United States. VINYL CHLORIDE Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants Volum 1 COMMITTEE ON TOXICOLOGY NATIONAL RESEARCH COUNCIL VINYL CHLORIDE 107468 fat*' 1 -w-- *,. h Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants Volume 1 Subcommittee on Spacecraft Maximum Allowable Concentrations Committee on Toxicology Board on Environmental Studies and Toxicology Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS Washington, D.C., 1994 BU Vinyl Chloride King Lit Wong, Ph.D. Johnson Space Center Toxicology Group Biomedical Operations and Research Branch Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Vinyl chloride is a colorless gas with a high flammability and an odor CO like that of ether (ACG1H, 1986). It1 o Synonyms: Chloroethene, chloroethylene <i Formula: CH2CHCi 0% CAS number: 75-01-4 CO Molecular weight: 62.5 Boiling point: -13.9C Melting point: Not applicable Vapor pressure: 2530 mm Hg at 20C Conversion factors at 25C, 1 atm: I ppm = 2.55 mg/m3 1 mg/m3 = 0.39 ppm OCCURRENCE AND USE Vinyl chloride is used primarily in the manufacture of polyvinyl chloride resins (ACGIH, 1986). It is also used in organic syntheses. There is no known use of vinyl chloride in spacecraft, and it has never been found in air samples taken during space-shuttle missions. However, vinyl chloride has been predicted to be off-gassed in the space station (Leban and Wag ner, 1989). 185 SL 107470 186 SMACS FOR SELECTED AIRBORNE CONTAMINANTS PHARMACOKINETICS AND METABOLISM When inhaled, vinyl chloride is absorbed quite well by human subjects. In male human volunteers exposed to 7.5-60 mg/m3 (3-24 ppm) for 6 h, about 42% of the inhaled vinyl chloride was retained by the respiratory system; i.e., the exhaled concentration was 42% less than the inhaled concentration (Krajewskj et al., 1980). The degree of respiratory retention achieved a relatively stable level 30 min into the 6-h exposure and appeared not to vary significantly with the exposure concentration, which ranged from 3 to 24 ppm. Rats tend to readily absorb vinyl chloride in inhalation exposure. In rats exposed to >4C-labeted vinyl chloride at 20,000 ppm for 5 min, radioac tivity was detected in the liver, bile duct, kidney, and gastrointestinal tract within 10 min (Duprat et al., 1977). Similarly, in rats exposed to MClabeled vinyl chloride at 50 or 100 ppm for 5 or 6 h, liver and kidney had the highest concentration of radioactivity among all the tissues after the exposure (Bolt et al., 1976; Watanabe et al., 1976). In rats exposed to vinyl chloride at 1000 ppm for 1-6 h, it has been postulated that vinyl chloride was oxidized to 2-chloroacetaldehyde via three pathways, listed as follows (Hefner et al., 1975). (1) At low con centrations, vinyl chloride is oxidized first to 2-chloroethanol, which is further oxidized by alcohol dehydrogenase to 2-chloroaceialdehyde. (2) When the first pathway is saturated, vinyl chloride is oxidized by mixed function oxidase to an epoxide, 2-chloroethylene oxide, which arranges to 2'Chloroacetaldehyde. (3) Alternatively, when the first pathway is satu rated, vinyl chloride is oxidized by catalase to 2-chloroethyl hydro peroxide, which in turn is converted to 2-chloroacetaldehyde. Because pretreatment of rats with 6-nitro-l,2,3-benzothiadiazole, which inhibits some microsomal cytochrome P-450 pathways, completely blocked vinyl chloride metabolism in rats exposed to vinyl chloride, Bolt et al. (1977) postulated that microsomal mixed function oxidase is the major enzyme for vinyl chloride metabolism. Most of the 2-chloroacetaldehyde formed from vinyl chloride reacts with sulfhydryl groups in the cells, but some of it is oxidized by aldehyde dehydrogenase to 2-chloroacetic acid (Hefner et al., 1975). The reaction of 2-chloroacetaldehyde with sulfhydryl groups explains the formation of n-acetyl-S-(2-hydroxyethyl) cysteine, S-(2-hydroxyelhyl) cysteine, and captoacetic acid in the urine of rats exposed to vinyl chloride (Wata VINYL CHLORIDE 187 nabe et al., 1976, 1978a). Urinary mercaptoacetic acid has also been found in workers exposed to vinyl chloride (Shu, 1986). Bolt et al. (1977) exposed rats to vinyl chloride at 50-1200 ppm in a closed inhalation system and they found that vinyl chloride metabolism was saturated at about 250 ppm. Similarly, Buchter et al. (1980) discovered that vinyl-chloride metabolism in rhesus monkeys was saturated at 200 ppm. In rats exposed to vinyl chloride at 10, 1000, or 5000 ppm for 6 h, Watanabe1 s group presented evidence that vinyl chloride metabolism appeared to be saturated at 1000 ppm (Watanabe et al., 1976, 1978a; Watanabe and Gehring, 1976). At 10 ppm, 68% of the body burden was excreted in the urine, 12% was expired as CO*. 4% was excreted in the feces, and about 2% was expired unchanged (Watanabe et al., 1976; Watanabe and Gehring, 1976). When the exposure level was increased to 1000 ppm, however, the fraction of the body burden eliminated in the urine was reduced to 56% and that expired as vinyl chloride increased to 12%. There is evidence that vinyl chloride's epoxide metabolite, 2-chlor oethylene oxide, and its rearrangement product, 2-chloroacetaldehyde, could bind to macromoiecules in rats. Watanabe and his colleagues showed that, in rats exposed to vinyl chloride, the amount of macromolecular binding directly increased with the exposure concentration or phenobarbital pretreatment (Watanabe et al., 1978a,b; Guengerich and Watanabe, 1979). It has been postulated that the epoxide metabolite is the active metabolite of vinyl chloride and the macromolecular binding if responsible for vinyl chloride's carcinogenicity. There are few data on vinyl chloride metabolism in humans. However, it has been shown that incubation of Salmonella lyphimurium with S-( fraction isolated from human liver increased the mutational frequency in; similar magnitude as incubation with rat S-9 fraction (Sabadie et al., 1980) This indicates that electrophilic metabolites could be formed by the actioi of human mixed function oxidase on vinyl chloride. TOXICITY SUMMARY Acute and Short-Term Toxicity Mucosal Irritation Vinyl chloride is known to cause mucosal irritation er 500 ppm i 188 SMACS FOR SELECTED AIRBORNE CONTAMINANTS humans (Lefaux, 1968). Baretta et al. (1969) reported that two of seven human subjects complained of dryness of nose and eyes in an exposure to 500-ppm vinyl chloride lasting for 3.5 h. The dryness of nose and eyes was probably an indication of very slight mucosal irritation. It appears that 500 ppm is probably the threshold for vinyl chloride's mucosal irritation. Since none of the four subjects exposed to 250 ppm for 7.5 h complained of dryness of nose or eyes (Baretta et al., 1969), the no-observed-adverseeffect level (NOAEL) for mucosal irritation is 250 ppm. Miscellaneous Symptoms In a study by Lester et al. (1963) nausea was reported in five of six human subjects exposed to vinyl chloride at 16,000 ppm for 5 min. In that study, one of six human subjects exposed to vinyl chloride at 20,000 ppm for 5 min experienced headache, which lasted for 30 min. Baretta et al. (1969) reported that two of seven men exposed to 500 ppm for 3.5 h complained of mild headache, but they did not complain of nausea. There fore, the concentration of vinyl chloride causing headache is lower than that causing nausea. Because nausea was detected only at such a high exposure concentration (it was absent in a 5-min exposure at 12,000 ppm or less), nausea will not be relied on in setting the SMACs. None of the four men in the study of Baretta et al. (1969) complained of headache in a 7.5-h exposure to 250-ppm vinyl chloride. The NOAEL for headache is 250 ppm in acute vinyl chloride exposures. Liver Toxidty As will be discussed later, liver is the major target organ of vinyl chlo ride in subchronic and long-term exposures. Whether vinyl chloride could cause non-neoplastic liver toxicity in humans in acute exposures is debat able. A group of Hungarian scientists exposed mice, rats, and rabbits to vinyl chloride at 1500 ppm for 24 h (Tatrai and Ungvary, 1981). No liver pathology was found in rats and rabbits. However, in mice, vasomotor paralysis and shock developed during the exposure, followed by hepatic histopathology, which included coagulation necrosis and confluent hemor rhages in die centrilobular zone, and ultrastmctura) changes, such as tfilalion of the cisterns of rough endoplasmic reticulum and Golgi apparatus SL 107471 VINYL CHLORIDE 189 and atrophy of some mitochondria. All the mice died as a result of the 24h exposure at 1500 ppm, whereas a 12-h exposure killed 16 of 20 mice. In contrast, no rats or rabbits were killed by the 24-h exposure (Tatrai and Ungvary, 1981). In a human study, Baretta et al. (1969) failed to detect any changes in the serum levels of glutamyl pyruvate transaminase, alka line phosphatase, lactic dehydrogenase, bilirubin, blood urea nitrogen, and creatinine in four men 24 h after a 7.5-h exposure to vinyl chloride at 500 or 250 ppm. Therefore, if vinyl chloride is indeed acutely toxic to the liver in humans, 500 ppm appears to be the NOAEL. Central Nervous System Toxicity Vinyl chloride could impair the central nervous system (CNS). Lester et at. (1963) reported that light-headedness, dizziness, and dulling of vision ami hearing were detected in five of six human subjects exposed at 16,000 ppm for 5 min. When these six subjects were exposed at 12,000 ppm for 5 min, two subjects felt slight dizziness. At 8000 ppm, only one of six subjects felt light-headed. No CNS symptoms were detected in a 5-min exposure at 4000 ppm (Lester et al., 1963). According to Lefaux (1968), vinyl chloride at 1000 ppm produces drowsiness, slight visual disturbances, tingling sensation on the limbs, numbness, and faltering gait. Vinyl chlo ride has no perceptible action on the CNS below 1000 ppm (Lefaux, 1968). Baretta et al. (1969) reported no CNS impairment in seven subjects ex posed to vinyl cldoride at 500 ppm for 3.5 h or in four subjects exposed for 7.5 b. The NOAEL for acute CNS impairment is, therefore, 500 ppm. Mortality A person was reported lulled by a massive exposure to vinyl chloride al an unknown concentration (Damziger, 1966). Although the lethal concen tration of vinyl chloride in humans is not known for certain, it is probably over 10,000 ppm based on the animal data of Mastromatteo et al. (I960). This group of scientists exposed five mice, five rats, and five guinea pigs to various concentrations of vinyl chloride for 30 min. No deaths occurred at 10.000 ppm. One of five mice died but no rats or guinea pigs died at 20.000 ppm. At 30,000 ppm, all five mice and ail five rats died, and one of the five guinea pigs died. Because the lethal concentration of vinyl SL 107472 190 SMACS FOR SELECTED AIRBORNE CONTAMINANTS chloride is estimated to be much higher than ihe concentrations required to cause other toxic effects, mortality is not used as a toxic end point in deriving the SMACs. Liver Toxicity Subchronic and Chronic Toxicity Liver is the major target organ of vinyl chloride. Liver function impair ment and hepatic histological changes have been reported in workers employed in places where vinyl chloride was manufactured or used (Lillis et al., 1975; Popper and Thomas, 1975; Tamburro et al., 1984). Clini cally, occupational exposure to vinyl chloride might cause abdominal pain in the upper right-hand quadrant, hepatomegaly, portal hypertension, esophageal varices, and liver cirrhosis (Lillis et at., 1975; Popper and Thomas, 1975; Lee et al., 1977). No exposure-concentration data were given in these reports. In a study conducted with 168 workers in two Romanian factories where they were exposed to vinyl chloride from 1962 to 1972, the investigators compared, among other things, the rates of nervous symptoms and gastroenterological symptoms in the workers in 1962 with those in 1966 (Suciu et al., 1975). Without specifying the analytical method, the investigators reported that the average vinyl chloride concentrations in 1962 and 1966 were 2298 and 98 mg/nr (896 and 38 ppm), respectively (Suciu et al., 1975). They detected a higher rate of euphoria, dizziness, somnolence, nervousness, headache, complete narcosis, weight loss, anorexia, epigastric pains, and hepatomegaly in the year the workers were exposed to 896 ppm than in the year (hey were exposed to 38 ppm (Suciu et at., 1975). The rate of pains in die right hypochondrium was lower, however, at 896 ppm than at 38 ppm. Because no control group was used and because of a lack of infor mation on how the exposure concentrations were determined, the Roma nian data are not used in setting SMACs. Nevertheless, the data illustrate the potential toxicity of vinyl chloride in the CNS and liver in human workers. Kramer and Mutchler (1972) did a medical study with 98 workers employed over two decades in two vinyl chloride polymerization facilities. These workers were exposed mainly to vinyl chloride, but there were ^^posures to vinylidene chloride, which was at lower concentrations. VINYL CHLORIDE 191 The exposures to vinylidene chloride in the second decade of the occupa tional exposure were probably negligible because vinylidene chloride was frequently detected only at trace levels. During the two decades of em ployment, there were environmental monitoring and medical surveillance. The investigators did not report all the results of the environmental moni toring during the two decades, but they stated that "in more recent mea surements, infrared and gas chromatographic techniques have established that the vinyl chloride concentrations average 10 ppm." When compared with a control group, the vinyl-chloride workers bad no significant disease. There were no differences in chest x-rays and electrocardiograms between the two groups. No acroosleoiysis was detected. Based on the medical history taken periodically in the medical surveillance program, the exposed workers reported a higher history of asthma and kidney stone and blood urine but a lower history of gastrointestinal and hepatic trouble and nervous symptoms. By physical examinations, the investigators found a higher rate of anal and rectal abnormalities in the exposed workers than in the con trols. From a regression analysis of the data collected, the investigators estimated that, in 60-y-old workers who had been on Ihe job for 20 y, vinyl chloride at 300 ppm time-weighted average (TWA) would increase tin bromsulphatein clearance time by five-fold, 150 ppm would raise it by two fold, and 50 ppm would increase it by 80%. They concluded that repeats exposure to vinyl chloride at 300 ppm or higher for a working lifetiim could cause some impairment in liver function. In a study by Ho et al. (1991) 12 of over 100 workers in a polyviny chloride plant in Singapore were found to have elevated serum glutami pyruvic transaminase and gamma glutamyl transpeptidase levels, when the worked in an environment with the vinyl chloride concentrations rangin between 1 and 21 ppm, with a geometric mean of 6 ppm for 1-13 y. Nin of the 12 workers had mild-to-moderate nonspecific fatty changes on live biopsies. None of them had a history of jaundice, Raynaud's disease, o blood transfusion. No liver function impairment attributable to vim chloride was detected in the workers after the vinyl chloride was lowere to 0.6-2.9 ppm, with a geometric mean of 1.5 ppm, in 1983. In worker afflicted by vinyl-cbloride-induced liver disease, their liver function in proved within 0.5-2 y after they were removed from ftirtber exposure (H et al., 1991). Based on the human data of Ho et al., the NOAEL f< non-neoplastic liver toxicity is about 1.5 ppm. Lee et al. (1977) showed that increased cell turnover and DN A synthes were detected in the livers of rats exposed to vinyl chlgade at 50 or 2` SL 107473 192 SMACS FOR SELECTED AIRBORNE CONTAMINANTS ppm, 6 h/d, 5 d/w for 12 mo. Because increased cell turnover and DNA synthesis, by themselves, are not considered adverse clinically, the SMACs are not set to prevent them. Similarly, increased liver weight by itself is not considered a significant toxic end point. So the SMACs are not derived from the discovery made by Bi et al. (198S) that the liver weight increased in rats exposed to vinyi chloride at 10, 100, or 3000 ppm, 6 h/d, 6 d/w for 6 mo. Torkelson el al. (1961) found that there were species differences in the sensitivity to vinyl chloride's liver toxicity. In a 6-mo exposure, at 7 b/d, S d/w, of guinea pigs, rats, and rabbits to 200-ppm vinyl chloride, no changes were seen in guinea pigs, but increased liver weight was delected in rats and the liver in rabbits developed centrilobular degeneration and necrosis(Torlcelson et al., 1961). Therefore, the rat is more sensitive than the guinea pig. However, it is not clear whether the rabbit is more sensi tive than the rat because only three male and three female rabbits were used in the experiment, making it difficult to draw a conclusion. In the study of Torkelson et al. (1961) a 4.5-mo exposure of rats at 500 ppm resulted in centrilobular degeneration in liver. A similar exposure of rats at 100 or 200 ppm led to increased liver weight, but an exposure at 50 ppm failed to cause any significant changes. There are reports of liver toxicity in animals subchronically exposed to very high concentrations of vinyl chloride. The group of Feron showed that an exposure of rats to 5000 ppm, 7 h/d, 5 d/w for 52 w produced degeneration, hyperplasia, hepatocellular carcinoma, and angiosarcoma in the liver (Feron and Kroes, 1979). Viola (1970) discovered hepatomegaly, hepatitis, and liver necrosis in male rats exposed to vinyl chloride at 30,000 ppm for 4 h/d, 5 d/w for 1 y. Kidney Toxicity Kidney is the second major organ affected by vinyl chloride. At a very high concentration of 30,000 ppm, Viola (1970) found ihat vinyl chloride produced tubular nephrosis and chronic interstitial nephritis in rats exposed 4 h/d, 5 d/w for 1 y. Tubular nephrosis was also produced in rats exposed to vinyl chloride at 5000 ppm for 7 h/d, 5 d/w for 1 y (Feron and Kroes, 1979). Torkelson et at. (1961) discovered that 500-ppm vinyl chloride could cause histopathology in the interstitial and tubular areas of the kidney VINYL CHLORIDE 193 in rats exposed 7 h/d, 5 d/w for 4.5 mo. Because a similar exposure of rats at 200 ppm failed to produce any histological changes (Torkelson et al., 1961), the NOAEL for kidney toxicity is 200 ppm. Neurological Toxicity Psychiatric disease and mild distal axonal neuropathy have been reported in workers exposed to vinyl chloride repetitively at unknown concentrations (Halama et al., 1985; Perticonti et al., 1986). Since the exposure concen trations were not measured, these human data cannot be used to set the SMACs. In the experiment conducted by Viola (1970) an exposure to vinyl chloride at 30,000 ppm for 4 h/d, 5 d/w for 1 y led to diffuse degen eration of the white and gray matter in the brain and atrophy of granular cells in the cerebellum in rats. Because Feron and Kroes (1979) showed that 5000 ppm failed to cause any nonneoplastic injuries in the brain of rats exposed 7 h/d, 5 d/w for 1 y, the NOAEL for brain toxicity is 5000 ppm. Effects on the Extremities Occupational exposures to vinyl chloride are known to cause circulatory disturbance in the extremities, Raynaud's disease (Lillis et al., 1975; Preston et al., 1976), acroosteolysis, and scleroderma (Dinman et al., 1971; Wilson et al., 1967; Sakabe, 1975). Unfortunately, the exposure concentrations at which these effects were seen in workers are not known. Because Raynaud's disease was usually detected before acroosteolysis in vinyl-chloride workers, vascular lesion is believed to precede the bone changes (Dodson and Dinman, 1971). Viola (1970) reported that an exposure of rats at 30,000 ppm for 4 h/d, 5 d/w for 1 y resulted in pathol ogy in the paws, such as metaplasia of metatarsal bones, chondroid meta plasia, epidermal edema, epidermal hyperkeratosis, and degeneration of basal cells. These pathological changes in rats somewhat resemble the acroosteolysis and scleroderma seen in vinyl-chloride workers. Because there are no concentration-response data and 30,000 ppm is a very high concentration, Viola's data on the paws of rats are not suitable for setting the SMACs. SL 107474 194 SMACS FOR SELECTED AIRBORNE CONTAMINANTS Effects on the Respiratory System In an epidemiology study performed by Wong et at. (1991), a significant mortality excess from emphysema and chronic obstructive pulmonary disease was found in vinyl-chloride workers. Since emphysema and chronic obstructive pulmonary disease have not been found to be associated with occupational vinyl chloride exposures in other epidemiology studies, it is uncertain whether vinyl chloride causes emphysema or chronic obstruc tive pulmonary disease in humans. However, there is some evidence of die pulmonary toxicity of vinyl chloride in animals. Suzuki (1978, 1980) exposed male mice to vinyl chloride at 2500 or 6000 ppm for 5 h/d, 5 d/w for 5 or 6 mo. In the exposed mice, he found hyperplasia of the alveolar epithelium, degeneration of the alveolar septal cells, hypertrophy and hyperplasia of Clara cells and ciliated epithelial cells in the terminal bronchioles, and bronchiolitis. It appears that the lowest-observed-effect level (LOEL) for lung toxicity is 2500 ppm. Taken together, the epidemi ology data of Wong et al. and Suzuki's data in mice show that vinyl chlo ride might produce lung injuries in humans, so the SMACs are prudendy set to prevent this toxic end point. Effects on the Reproductive System There were two Soviet reports on the reproductive effects of vinyl chloride in workers (Makarov, 1984;Makarovetal., 1984). Adeclinein sexual function, which was evaluated by questionnaire, was found in men and women exposed to vinyl chloride occupationally. In the exposed women workers, gynecological examinations revealed increased incidences of ovarian dysfunction, benign uterine growths, and prolapsed genital organs. The Agency for Toxic Substances and Disease Registry character ized the two reports as "not adequately reported for proper evaluation; therefore, such data cannot be used to identify thresholds" (ATSDR, 1989). So the SMACs are not set relying on the Soviet data. Instead the animal data of Bi et al. (1985) are used. In the study of Bi et al., 74 or 75 male rats were exposed to vinyl chloride at 0, 10, 100, or 3000 ppm, 6 h/d, 6 d/w for 1 y. Sacrifices were made of 8, 30, 6, and 10 rats at the 3rd, 6th, 9th, and 12th mo, respecti^y, and the surviving rats were killed 6 mo after the 12-mo exposure. ^Prcular histology was evaluated in the rats sacrificed and also in rats that VINYL CHLORIDE 19; died before the interim and final sacrifices. A reduction in the testicular to-body-weight ratio was found in the 100- and 3000-ppm groups after < mo of exposure. With the rats killed at different time points taken to gether, Bi et al. (1985) reported a statistically higher rate of testiculai injuries in the 100- and 3000-ppm groups, but not in the 10-ppm group There was fusion of spermatids or spermatocytes into giant cells. Sperma tids disappeared first, followed by sloughing of secondary and priman spermatocytes into the lumen of seminiferous tubules, leaving behim spermatogonia and Sertoli cells. The degeneration and necrosis distribute* randomly in the testis without any relationship to the vascular system. Carcinogenicity Vinyl chloride was found to cause liver cancers, especially angjosar coma, in vinyl-chloride workers in the 1970s (Health et al., 1975; Tabei shaw and Gaffey, 1974; Nicholson et al., 1975; Fox and Collier, 1977) An epidemiology study showed that the mortality excess from liver cancel increased with duration of employment (Health et al., 1975). Other tha liver cancers, there have been epidemiological reports that vinyl-chlorid exposures may produce cancer in other tissues. For instance, Heldaas t al. (1987) observed 6 cases of malignant melanoma in 454 vinyl-chlorid and polyvinyl-chloride workers in Norway, where only 1.1 cases wer expected. Nevertheless, Heldaas et al. admitted that it was difficult t make a solid conclusion on the causality between vinyl chloride and malii nant melanoma. More recently, there have been reports of a multiplant cohort study i the United States by Wong et al. (1991) and one in Europe by Simonato * al. (1991). Both the U.S. and European studies confirmed the findings < earlier epklemiology studies on the excesses of liver cancers in general an angiosarcoma in particular caused by occupational exposures to vim chloride (Wong et al., 1991; Simonato et al., 1991). Both studies ah found an increase in brain tumors in vinyl-chloride workers. In addition an increase in biliary-tract cancers was discovered in the U.S. study and a increase in lymphoma was found in the European study. In the Europe? study, the mortality excess from liver cancers was found to be related time since initial exposure to vinyl chloride, duration of employment, ai estimated exposure levels (Simonato et al., 1991). 196 SMA CS FOR SELECTED AIRBORNE CONTAMINANTS The mortality excesses from lymphoma and brain tumor, however, were not correlated with these exposure variables in the European study (Simonato et ai., 1991). That makes it doubtful whether vinyl chloride could cause lymphoma and brain tumor. Similarly, a case-control study by Wu et al. (1989) found mortality excesses due to liver, lung, and brain cancers in 3635 workers exposed to vinyl chloride. Wu et al. also demon strated that, among tumors in those three sites, only the excess mortality for liver cancer was significantly associated with the cummulative dose of vinyl chloride. It can be concluded from these recent epidemiology studies that vinyl chloride could cause liver cancers in humans, but the evidence that vinyl chloride also causes tumors in other sites in humans is rather weak. Viola et al. (1971) were the first group to demonstrate vinyl chloride's carcinogenicity in laboratory animals. They exposed rats to vinyl chloride at 30,000 ppm for 4 h/d, 5 d/w for 1 y and found that vinyl chloride caused lung carcinoma, osteochondroma, and epidermoid carcinoma in the skin. In a study conducted by Lee et al. (1978), an exposure of rats or mice to vinyl chloride at 50, 250, or 1000 ppm for 6 h/d, 5 d/w for 1 y resulted in liver hemangiosarcoma in rats at 250 ppm or greater and liver hemangiosarcoma and bronchoalveolar adenoma in the lung in mice at 50 ppm or greater. The most extensive animal bioassay was done by Maltoni and co workers (Maltoni, 1977; Maltoni et al., 1981). They also exposed rats to vinyl chloride for 1 y (4 b/d, 5 d/w) but held the rats for 83-103 w after exposure before sacrificing them. Maltoni et al. found that, in SpragueDawtey rats, vinyl chloride produced liver angiosarcoma at as low as 100 ppm and nephroblastoma in the kidney at 25 ppm or greater. The inci dences of these tumors in male and female rats combined are shown in Table 11-1. Maltoni and co-workers also tested with mice and hamsters in the bioas says. In mice exposed to vinyl chloride 4 h/d, 5 d/w for 30 w and held for observation for 51 w, increased incidences of liver angiosarcoma and lung tumor were detected at 250 ppm or greater. They found that 79 w after hamsters were exposed to vinyl chloride at 2500 ppm or greater for 30 w, papillomas and acanthomas of the forestomach were increased. The data gathered in the literature indicate that vinyl chloride is a potent carcinogen in rodents because many studies showed that vinyl chloride was carcinogenic after an exposure for less than half of die normal lifespan of the test species (Viola et ai., 1971; Lee et al., 1978; Maltoni, 1977; SL 107475 VINYL CHLORIDE 197 TABLE 11-1 Incidence of Liver Angiosarcoma and Nephroblastoma in Rats Concentration, TEE_________ 10,000 6000 2500 500 250 200 150 100 50 25 10 5 1 0 Liver Angiosarcoma 18/60 13/59 13/60 6/60 3/59 12/120 6/119 1/120 1/60 5/120 1/119 0/119 0/118 0/363 Kidney Nephroblastoma 5/60 5/59 6/60 6/60 5/59 7/120 11/119 10/120 1/60 1/120 0/119 0/110 0/118 0/363 Maltoni et al., 1981). Hong et al. (1981) showed that vinyl chloride was carcinogenic in mice for an exposure lasting as Jittle as 1 mo. It took a vinyl chloride exposure of only I mo at 6 h/d, 5 d/w to cause bronchoalveolar tumors in mice at 250 ppm or greater (Hong et al., 1981). Age also plays a rote in the carcinogenicity of vinyl chloride in rats. Drew et al. (1983) found that the earlier in life a rat is exposed to vinyl chloride, the higher the tumor risk. In a 2-y study, Drew et al. exposed three groups of rats to vinyl chloride at 50 ppm and three groups to 200 ppm for 6 h/d, 5 d/w for 12 mo and then held the rats without exposure for the remaining 12 mo. For two groups of rats, they started the exposures (50 or 200 ppm) at the beginning of the 2-y study. For four other groups, . the exposures (two groups at 50 ppm and two at 200 ppm) were started 6 or 12 mo into the 2-y study. For each of die exposure concentrations. Drew et al. then compared the tumor incidences in the three groups ex posed to the same concentration at three different ages. The rats that were exposed for 12 mo at the beginning of the 2-y study had the highest inci- SL 107476 198 SMACS FOR SELECTED AIRBORNE CONTAMINANTS deuces of hepatocellular carcinomas, hemangiosarcomas, and mammary gland carcinomas. The rats that were held for 6 mo before being exposed also developed tumors, albeit at lower incidences. However, there were no statistically significant increases in tumor incidences in the rats exposed in the last 12 mo of die 2-y study. Based on the data available, the International Agency for Research on Cancer concluded that there is sufficient evidence to support vinyl chlo ride's carcinogenicity to both humans and animals (IARC, 1987). The U.S. Environmental Protection Agency also classified vinyl chloride as a known human carcinogen (EPA, 1984). Genotoxidty There are in vivo data showing that vinyl chloride is genotoxic in hu mans. Hansteen et al. (1978) found an increase in the percent of peripheral lymphocyu.. with chromosomal aberrations in workers exposed to 25-ppm vinyl chloride but not in workers exposed to I-ppm. In another study, an increase in peripheral lymphocytes with chromosomal aberrations was noted in workers exposed to about 50-ppm vinyl chloride (Anderson etal., 1960). No significant increase in chromosomal aberrations was seen in the workers after the vinyl chloride concentration had been lowered to a level estimated to be less than S ppm (Anderson et al., 1980). There is also in vivo evidence of the genotoxicity of vinyl chloride in animals. Vinyl chloride was tested negative in the dominant lethal test and positive in the micronucleus test in mice (Jenssen and Ramel, 1980; Purchase et al., 1975). Vinyl chloride has been shown to be genotoxic in various in vitro assays in numerous reports. Only some of them will be summarized here. Vinyl chloride was shown to be mutagenic in the Ames test, with or without activation by S-9 fraction, by Bartsch et al. (1975) and Andrews et al. (1976). Even without S-9 activation, vinyl chloride produced forward mutation in Chinese hamster cell V79 and cell transformation of neonatal hamster kidney cells (Drevon and Kuroki, 1979; Styles, 1977). Developmental Toxicity ^^tere is conflicting evidence on whether vinyl chloride causes develJ VINYL CHLORIDE 199 opmental toxicity in humans. In an Ohio city, Edmonds et al. (1975) found no differences between how for parents of malformed infonts lived from a local polyvinyl chloride plant and how far parents of normal infonts lived from it. They concluded that malformations were not associated with parental exposures to vinyl chloride. Theriault et al. (1983) conducted a similar study in a Canadian town with a polyvinyl chloride plant and arrived at the same conclusion as Edmonds et al. In contrast. Infante et al (1976) reported a higher rate of fetal loss, based on questionnaires, in pregnant wives of vinyl-chloride workers than in rubber workers noi exposed to vinyl chloride. Infante (1976) also found a higher incidence ot malformations in three Ohio cities that have a polyvinyl chloride production plant than in other parts of the counties where the three cities are situated These two studies of Infante have been criticized as being deficient in the way the studies were conducted and in the data analyses, so the "positive' Endings are highly questionable (Hatch et al., 1981; Stallones, 1987). Animal data showed that vinyl chloride caused some malformations ii rats at concentrations that also caused maternal toxicity (lohn et al., 1977) Vinyl chloride did not produce any malformations in mice and rabbit (lohn et al., 1977). Therefore, it can be concluded that vinyl chloride doe: not appear to be a serious teratogenic threat, lohn et al. (1977) showei that vinyl chloride, at 500 or 2500 ppm, foiled to produce developments toxicity and maternal toxicity in rabbits exposed 7 h/d on gestation days 6 18. In the same study, a similar exposure of rats to vinyl chloride at 250t ppm on gestation days 6-15 increased the incidence of dilated ureters in tin fetuses and reduced the body-weight gain and food consumption in di< mothers. An exposure of rats to 500 ppm increased the incidence o lumbar spurs in the fetuses and reduced the body-weight gain in the moth ers. In mice, an exposure of 500 ppm for 7 h/d on gestation days 6-V foiled to produce any malformations, but vinyl chloride caused increase) fetal resorption, decreased fetal weight, reduced litter size, retarded ossifi cation of the cranium and sternum in the fetuses. Vinyl chloride exposun at 500 ppm was also toxic to the mothers, causing mortality, reduced body weight gain, and decreased liver weight (John et al., 1977). It should b noted that the measurement of maternal body weight for days 6-18 o gestation might not be adequate. Nevertheless, these data indicate tha vinyl chloride does not have selective developmental toxicity because i produced developmental effects only in the exposure range that also at fected the mothers. 200 SMACS FOR SELECTED AIRBORNE CONTAMINANTS Synergistic Effects Pretreatments of rats with chemicals, such as phenobarbital and polychlorinated biphenyls, which induce microsomal enzymes, are known to potentiate vinyl chloride's acute hepatotoxicity (Jaeger et ah, 1974; Reynolds et al., 1975). These findings support the theory that vinyl chlo ride acts through its epoxide metabolite formed via microsomal oxidation. Therefore, in the event that an astronaut is exposed to vinyl chloride and a known microsomal inducer, one should be aware of die potential toxicity of vinyl chloride. M co f o 'J <1 3 201 ZLfLOT as bLEU-2 (Continutd) Concentration 16,000 ppm Expomic Duration 5 min Species Human 20,000 ppm S mm Human 10 ppm 6 h/d, 6 d/w for Rat 3-12 mo SO ppm 7 h/d, 5 d/w for 6 Rat mo 50 ppm 7 h/d on Mouse gestation d 6-15 SO or 100 ppm 7 h/d, 5 d/w for 6 Rabbit mo 50,100, or 200 7 h/d, 5 d/w for 6 Guinea pig ppm mo 50 or 250 ppm 6 h/d, 5 d/w for Rat 12 mo 100 or 200 ppm 7 h/d, 5 d/w for 6 Rat mo 100 or 3000 ppm 6 h/d, 6 d/w for Rat 3-12 mo 200 ppm 7 h/d, 5 d/w for 6 Rabbit mo Effects Reference Light-handedness, dizziness, nausea, dulling of hearing and vision in Lester etal., 1963 S/6 subjects. Same symptoms as in 16,000-ppm exposure in 6/6 subjects, but symptoms were more intense and appeared sooner. Lester etal., 1963 lncrcued liver weight No change in tetticular weight. Noteabcular Bietal., 1985 injury. No change in histology, organ weight, and serum levels of enzymes Torkelson et al., 1961 No malformations, no fetotoxicity, and no maternal toxicity. John etal., 1977 No significant changes. No significant changes. Increased cell turnover and DNA synthesis in liver. Torkelson et at, 1961 Torkelson et at, 1961 Leeet at, 1977 Increased liver weight No histopathology. Torkelson et at, 1961 Increased testicular weight. Fusion of spermatids and spermatocytes. Bietal., 1985) Degeneration and necrosis of some seminiferous tubules. Centrilobular degeneration and necrosis in liver. Torkelson et at, 1961 500 ppm 7 h/d, 5 d/w for Rat 4.5 mo Mate and female: Centrilobular degeneration in liver, tubular and interstitial changes in kidneys. Male: Increased liver weight 500 ppm 7 h/d on Mouse gestation d 6-15 No malformation. FetoCoxicity: Increased fetal resorption, reduced fetal weight and litter szc, retarded ossification ofcranium and sternum. Maternal toxicity. Death and reduced body weight 500 ppm 7 h/d on gestation d 615 Rat Increased incidence oflumbar spurs, reduced fetal weight. Maternal toxicity: Reduced body-weight gain. 500 or 2500 ppm 7 h/d on Rabbit gestation d 6-18 No malformation, fetotoxicity, or maternal toxicity. 1500 ppm 24 h Rat, mouse, Rats and rabbits: no pathology in liver. Mice: vasomotor paralysis, rabbit shock, pathological changes in liver and lung. 2500 ppm 2500 or 6000 ppm 7 h/d on Rat gestation d 6-15 5 h/d, 5 d/w for 5 Mouse mo Increased incidence of dilated ureters. Maternal toxicity: Death, reduced food consumption, and increased liver weight. Proliferation of cells lining the terminal bronchioles, epithelial hyperplasia in alveoli, and degeneration ofalveolar septal cells. 5000 ppm 7 h/d, 5 d/w for 4 Rat or 13 w 4 w: uhrastructural changes in liver morphology. 13 w histopathology at light microscopic level. 5000 ppm ^^^Oppm 7 h/d, 5 d/w for 52 w 7 h/d, 5 d/w for 52 w Rat Rat Liver angiosarcoma, hepatocellular carcinoma, hyperplasia, and degeneration. Increased mortality. Tumors of the nasal cavity, ceruminous glands, brain, and lungs. Increased hematopoiesis in spleen, mild focal degeneration of myocardium, and tubular nephrosis. Torkelson et al., 1961 John et al., 1977 John et al., 1977 John etal., 1977 Tatrai and Ungvary, 1981 John et al., 1977 Suzuki, 1978 Feronetal., 1979a Feton et al., 1979b Feron and Kroes, 1979 204 VINYL CHLORIDE 205 TABLE 11-3 Exposure Limits Set by Other Organizations Organization Concentration, ppm ACGIH's TLV 5 (TWA) OSHA's PEL 1 (TWA) 5 (ceiling) NIOSH's REL Lowest reliably detectable concentration TLV = threshold limit value. TWA = time-weighted average. PEL = permissible exposure limit. REL = recommended exposure limit. TABLE 11-4 Spacecraft Maximum Allowable Concentrations Duration ppm mg/m3 Target Toxicity 1 h 130 330 Liver dysfunction, CNS impairment, headache 24 h 30 80 Liver dysfunction, CNS impairment 7 d* 1 2.6 Testicular toxicity 30 d 1 2.6 Testicular toxicity ISOd 1 2.6 Testicular toxicity "Former 7-d SMAC = 0.1 ppm. RATIONALE For each toxic end point worth considering, an acceptable concentration (AC) is derived for each of the exposure durations, namely 1 h, 24 h, 7 d, 30 d, and 180 d. The lowest AC among all the toxic end points is then chosen to be the SMAC for that exposure duration. Mucosal Irritation Lefaux (1968) reported that vinyl chloride irritates human eyes at a concentration over 500 ppm. According to the data of Baretla et al TABLE 11-2 {Continued) SL 107480 206 SMACS FOR SELECTED AIRBORNE CONTAMINANTS (1969), 500 ppm appears to be the threshold for mucosal irritation in acute exposures of human subjects, and 250 ppm is the NOAEL in a 7.5-h exposure. Two of seven human subjects experienced dryness of the nose and eyes at 500 ppm (Baretla etal., 1969). Since slight mucosal irritation is acceptable in contingency situations, the l-h and 24-h ACs are derived from die LOAEL of 500 ppm. l-h and 24-h ACs based on mucosal irritation 3.5-h LOAEL - 500 ppm - 500 ppm. The 7-d, 30-d, and 180-d ACs, however, should be established at a no-effect level. The 7.5-h NOAEL of 250 ppm is based on the data of only four men (Baretta et al., 1969), so a safety margin is needed by applying a factor for "small n." 7-d, 30-d, and 180-d ACs based on mucosal irritation - 7.5-h NOAEL x 1/safety factor for small n = 250 ppm x (square root of n)/10 = 250 ppm x (square root of 4)/10 = 50 ppm. The same value is chosen for the 7-d, 30-d, and 180-d ACs because mucosal irritation is not expected to get worse when die exposure is ex tended beyond 7.5 b. Headache Vinyl chloride produced mild headache in two of seven men at 500 ppm in 3.5 h, but all of the four men exposed to 250 ppm for 7.5 h were free of any headache (Baretta et al., 1969). Since mild headache is acceptable in contingency situations, the l-h AC based on headache is set at the LOAEL of 500 ppm. Unlike mucosal irritation, headache tends not to diminish in severity as the exposure continues, so the 24-h AC for headache should be set lower than the l-h AC. The 7.5-h NOAEL of 250 ppm is chosen to be warting point for the 24-h AC based on headache. VINYL CHLORIDE 207 24-h AC based on headache = 7.5-h NOAEL x (square root of n)/10 x time adjustment = 250 ppm x (square root of 4)/10 x 7.5 h/24 h = 50 ppm. Because the use of Haber's rule to extrapolate from the 7.5-h NOAEL to an AC for an exposure lasting 7-d, 30-d, or 180-d is probably not valid, the setting of 7-d, 30-d, and 180-d ACs for headache is not attempted. CNS Impairment The NOAEL for CNS impairment was 500 ppm for 3.5 h based on the data of seven men; it was 500 ppm for 7.5 h based on the data from four men (Baretta et al., 1969). l-h AC based on CNS effects = 3.5-h NOAEL x 1/safety factor for small n = 500 ppm x (square root of n)/IO = 500 ppm x (square root of 1)110 = 130 ppm. 24-h AC based on CNS effects = 7.5-h NOAEL x 1/safety factor for small n x time adjustmen1 = 500 ppm x (square root of n)/10 x 7.5 h/24 h = 500 ppm x (square root of 4)/10 x 7.5 h/24 h = 30 ppm. Due to a lack of data on the time response of vinyl chloride's CN` impairment, no acceptable concentrations are estimated beyond 24 h. Non-neoplastic CNS Injury In long-term exposures, vinyl chloride has been shown to cause degen eration of the white and gray matter of the brain and atrophy of the granu lar cells in the cerebellum of rats (Viola, 1970). The NOAEL for CN.` injury, based on a l-y exposure of rats, is 5000 ppm. SL 107481 208 SMACS FOR SELECTED AIRBORNE CONTAMINANTS 7-d and 30-d ACs based on CNS injury = 1-y NOAEL x 1 /species factor = 5000 ppm x 1/10 = 500 ppm. Hie time adjustment for 180 d = 1820 h/(24 h/d x 180 d) = 1820 h/4320 h. 180-d AC based on CNS injury = 1-y NOAEL X time adjustment x 1/species factor = 5000 ppm x (7 h/d x 5 d/w x 52 w}/(24 h/d x 180 d) x 1/10 = 5000 ppm x 0.42 x 1/10 = 210 ppm. Because vinyl chloride is not known to cause CNS injuries acutely, no 1-h and 24-h ACs are needed for this end point. Liver Toxicity Tatrai and Ungvary (1981) discovered liver histopathology in mice exposed to vinyl chloride at 1500 ppm for 24 h. In contrast, Baretta et ai. (1969) did not detect any changes in the serum levels of SGPT, alkaline Phosphatase, lactic dehydrogenase, and bilirubin in seven workers exposed to vinyl chloride at 500 ppm for 3.5 h or in four workers exposed for 7.5 h (Baretta et al., 1969). Therefore, the NOAEL for acute vinyl chloride exposures appears to be 500 ppm. 1-h AC based on non-neoplastic liver toxicity = 3.5-h NOAEL x 1/safety factor for small n -- 500 ppm X (square root of/i)/10 = 500 ppm X (square root of 7)/10 = 130 ppm. 24-h AC based on non-neoplastic liver toxicity - 7.5-h NOAEL x 1/safety factor for small n x time adjustment = 500 ppm x (square root of n)/10 x 7.5 h/24 h VINYL CHLORIDE 209 = 500 ppm x (square root of 4)/10 x 7.5 h/24 h = 30 ppm. Based on the occupational data of Ho et al. (1991), liver dysfunction is possible when the vinyl chloride concentration in the workplace averages 6 ppm and no liver dysfunction would be found at about 1.5 ppm. It appears that the NOAEL for non-neoplaslic liver toxicity is about 1-5 ppm in occupational exposure. The NOAEL of 1.5 ppm is based on data from over 100 workers exposed to vinyl chloride for at least 1 y since 1983 (Ho et al., 1991). For simplicity sake, the NOAEL is assumed to be based on a 1-y occupational exposure. Because this type of liver dysfunction is believed to be reparable, a NOAEL for a 1-y occupational exposure ought to be devoid of liver toxicity for 7, 30, or 180 d. 7-d, 30-d, and 180-d ACs based on non-neoplastic liver toxicity = i-y NOAEL = 1.5 ppm. Kidney Toxicity As discussed in "Toxicity Summary," the NOAEL for non-neoplastic kidney toxicity is 200 ppm, based on data from a 6-mo exposure of rats (Torkelson et al., 1961). 7-d and 30-d ACs based on kidney toxicity = 6-mo NOAEL x 1/species factor = 200 ppm x 1/10 = 20 ppm. Because vinyl chloride's kidney injuries are believed to be reparable, the 180-d AC is set to equal the 30-d AC of 20 ppm. Since kidney injuries have never been reported in acute vinyl chloride studies, no 1-h and 24-1. ACs are needed for this end point. Lung Toxicity Vinyl chloride has been shown to produce non-neoplastic lung injuries u 107482 210 SMACS FOR SELECTED AIRBORNE CONTAMINANTS mice (Suzuki, 1978, 1980). The LOAEL based on a 6-mo exposure of mice is 2500 ppm (Suzuki, 1978, 1980), so the NOAEL is estimated to be 250 ppm. 7-d and 30-d ACs based on lung toxicity = 6-mo NOAEL x 1/species factor - 250 ppm x 1/10 = 25 ppm. 180-d AC based on lung toxicity = 6-mo NOAEL x time adjustment x 1/species factor = 250 ppm x (5 h/d x 5 d/w x 26 w)/(24 h/d x 180 d) x 1/10 = 250 ppm x 650 h/4320 h x 1/10 = 250 ppm x 0.15 x 1/10 = 4 ppm. No I-h and 24-h ACs are needed because vinyl chloride is not known to cause lung toxicity acutely. Testicular Toxicity According to the data of Bi et al. (1985), vinyl chloride is known to cause testicular injuries in rats in long-term exposures. A reduction in testicular weight was noted in rats exposed to vinyl chloride at 100 or 3000 ppm for 6 h/d, 6 d/w for 6 mo. Bi et al. expressed the pathology data by combining the histopathological data of rats sacrificed after a 3-, 6-, 9-, or 12-mo exposure to vinyl chloride at 0, 10, 100, or 3000 ppm. They found that exposures to 100 or 3000 ppm produced a higher percent of rats with fusion of cells and degeneration of seminiferous tubules in the testis than the control. The NOAEL was 10 ppm. Since the number of rats sacrificed tr1 after 6 mo of exposure approximately equaled the combined number of rats sacrificed immediately after a 3-, 9-, or 12-mo exposure, the NOAEL of 10 ppm is assumed to represent a NOAEL based on a 6-mo exposure. 7-d and 30-d ACs based on testicular toxicity = 6-mo NOAEL x 1/species factor = 10 ppm x 1/10 = 1 ppm. VINYL CHLORIDE 211 Because the cell types that could be injured by vinyl chloride arc spermatids and spermatocytes, vinyl chloride's testicular injuries art believed to be reversible. As a result, the 180-d AC is set to equal the 30-t AC. 180-d AC based on testicular toxicity = 30-d AC = 1 ppm. Because there is no evidence that acute vinyl chloride exposures ar< toxic to the testis, the 1-h and 24-h ACs are not derived. Carcinogenicity Vinyl chloride exposures could lead to the production of tumors i several organs, especially in the liver. Based on the rat data from Maltoi and his colleagues (Maltoni, 1977), the U.S. Environmental Protectio Agency, using the linearized multistage model, estimated that a life-tim exposure of humans at 1 ppm has a tumor risk of 6.80 x 103 (EPA 1984). The life-time exposure concentration that would yield a 10 4 tumc risk, which is the tumor risk accepted by NASA, is calculated as follows Life-time exposure concentration that would generate a 10"4 tumor risl = (I ppm/6.80 X Iff3) x 10"* = 0.0147 ppm. This life-time exposure concentration is converted to the ACs using th Crump and Howe approach as suggested by the NRC's Committee <: Toxicology (NRC, 1992; Crump and Howe, 1984). Setting k = 3, t 25,550 d, and s, = 10,950 d, the adjustment factor is calculated to I 26,082 for estimating a near-instantaneous exposure level that would yiel the same excess tumor risk as a continuous life-time exposure. 24-h AC based on carcinogenicity = 0,0147 ppm x 26,082 = 380 ppm. For the 7-d, 30-d, and 180-d ACs based on carcinogen! the adjustme SL 107483 212 SMACS FOR SELECTED AIRBORNE CONTAMINANTS factors are 3728, 871, and 146.7, respectively, assuming k = 3, t = 25,550 d, and the earliest age of exposure to be 30 y. 7-d AC based on carcinogenicity = 0.0147 ppm x 3728 = 55 ppm. 30-d AC based on carcinogenicity = 0.0147 ppm x 871 = 13 ppm. 180-d AC based on carcinogenicity = 0.0147 ppm x 146.7 = 2 ppm. Establishment of SMACs By selecting the lowest ACs among the various toxic end points for an exposure duration, the 1-h, 24-h, 7-d, 30-d, and 180-d SMACs are set at 130, 30, 1, 1, and 1 ppm, respectively. Because these toxic end points are not expected to be affected by any microgravity-induced physiological changes, the SMACs are not adjusted any further. TABLE 11-5 Acceptable Concentrations Toxic End Point Mucoul irritation Headache CNS impairment Liver toxicity Kidney toxicity Lung toxicity Teaticutar toxicity Carcinogenicity Acceptable Concentration, ppm 1h 24 h 7d 500 500 50 130 so - 130 30 - 130 30 1.5 - - 20 - - 25 -- 1 -- 380 55 30 d 50 -- -- 1.5 20 25 1 (30 SMAC 130 30 1 1 180 d 50 -- -- 1.5 20 4 I 2 1 VINYL CHLORIDE 213 REFERENCES ACG1H. 1986. Vinyl chloride. Pp. 623-626 in Threshold Limit Values and Biological Exposure Indices. American Conference of Govern mental Industrial Hygienists, Cincinnati, Ohio. Anderson, D., C.R. Richardson, T.M. Weight, and W.G. Adams. 1980. Chromosomal analyses in vinyl chloride exposed workers. Results from analysis 18 and 42 months after an initial sampling. Mutat. Res. 79:151-162. Andrews, A.W., E.S. Zawistowski, and C.R. Valentine. 1976. A com parison of the mutagenic properties of vinyl chloride and methyl chlo ride. Mutat. Res. 40:273-275. ATSDR. 1989. P. 51 in Toxicology Profile for Vinyl Chloride. ATSDR/TP-88/25. Agency for Toxic Substances and Disease Registry, U.S. Public Health Service, and U.S. Environmental Protection Agen cy, Washington, D.C. Baretta, E.D., R.D. Stewart, and J.E. Mutchler. 1969. Monitoring exposures to vinyl chloride vapor breath analysis and continuous air sampling. Am. Ind. Hyg. Assoc. J. 30:537-544. Bartsch, H.,C. Malaveille, and R. Montesano. 1975. Human, rat and mouse liver-mediated mutagenicity of vinyl chloride in S. fyphimurium strains. Int. J. Cancer 15:429-437. Bi, W., Y. Wang, M. Huang, and D. Meng. 1985. Effect of vinyl chloride on testis in rats. Ecotoxicol. Environ. Safety 10:281-289. Bolt, H.M., H. Kappus, A. Buchter, and W. Bolt. 1976. Disposition of (1,2-I4C) vinyl chloride in the rat. Arch. Toxicol. 35:153-162. Bolt, H.M., R.J. Laib, H. Kappus, and A. Buchter. 1977. Pharmaco kinetics of vinyl chloride in the rat. Toxicology 7:179-188. Buchter, A., I.G. Ftlser, H. Peter, and H.M. Bolt. 1980. Pharmaco kinetics of vinyl chloride in the rhesus monkey. Toxicol. Lett. 6:33-36. Crump, K.S. and R.B. Howe. 1984. The multistage model with a time- dependent dose pattern: Applications to carcinogenic risk assessment. Risk Anal. 4:163-176. Damziger, H. 1966. Accidental poisoning by vinyl chloride: Report of two cases. Can. Med. Assoc. J. 82:828. Dinman, B.D., W.A. Cook, W.M. Whitehouse, H.l. Magnuson, and T. Ditcheck. 1971. Occupational acroosteolysis. I. An epidemiological study. Arch. Environ. Health 22:61-73. Dodson, V.N. and B.D. Dinman. 1971. Occupational acroosteolysis. H(. SL 107484 214 SMACS FOR SELECTED AIRBORNE CONTAMINANTS A clinical study. Arch. Environ. Health 22:83-91. Drevon, C. and T. Kuroki. 1979. Mutagenicity of vinyl chloride, vinyl- idene chloride and chloroprene in V79 Chinese hamster cells. Mutat. Res. 67:173-182. Drew, R.T., G.A. Boorman, J.K. Haseman, E.E. McConnell, W.M. Busey, and J.A. Moore. 1983. The effect of age and exposure duration on cancer induction by a known carcinogen in rats, mice, and hamsters. Toxicol. Appl. Pharmacol. 68:120-130. Duprat, P., J.P. Fabry, D. Gradiski, and J.L. Magadur. 1977. Metabolic approach to industrial poisoning: Blood kinetics and distribution of l4Cvinyl chloride (VCM), Acta Pharmacol. Toxicol. Suppl. (Kbh). 41:142143. Edmonds, L.D., H. Falk, and J.E. Nissim. 1975. Congenital malfor mations and vinyl chloride. Lancet 2(7944): 1098. EPA. 1984. Health Effects Assessment for Vinyl Chloride. EPA/540/186-036. U.S. Environmental Protection Agency, Washington, D.C. Feron, V.J. and R. Kroes. 1979. One-year time-sequence inhalation toxicity study of vinyl chloride in rats. II. Morphological changes in the respiratory tract, ceruminous glands, brain, kidneys, heart, and spleen. Toxicology 13:131-141. Feron, V.I., B.J. Spit, H.R. Immel, and R. Kroes. 1979a. One-year time-sequence inhalation toxicity study of vinyl chloride in rats. III. Morphological changes in the liver. Toxicology 13:143-154. Feron, V.J., A. Kruysse, and H.P. Til. 1979b. One-year time-sequence inhalation toxicity study of vinyl chloride in rats. I. Growth, mortality, haematology, clinical chemistry, and organ weights. Toxicology 13:2535. Fox, A.J. and P.F. Collier. 1977. Mortality experience of workers exposed to vinyl chloride monomer in the manufacture of polyvinyl chloride. Br. J. lnd. Med. 34:1-10. Guengerich, F.P. and P.G. Watanabe. 1979. Metabolism of (MC)- and (^Cl)-labeled vinyl chloride in vivo and in vitro. Biochem. Pharmacol. 28:589-5%. Halama, J., S. Becker-Stone, and J.M. Halama. 1985. Das haemangiosarkom der bei arbeitern in der PVC-inductrie and andere VCbedingte erkrankungen mit angiologish-dermatologischer, heptalogischer, radiologischer and neurologischer symptomatik. Der Radiolog. 25:22-29. VINYL CHLORIDE 21 Hansteen, I.L., L. Hillestad, E. Thiis-Evensten, and S.S. Heldaas. 1978 Effects of vinyl chloride in man: A cytogenetic follow-up study. Muta Res. 51:271-278. Hatch, M., J. Kline, and Z. Stein. 1981. Power considerations in studit of reproductive effects of vinyl chloride and some structural analog: Environ. Health Perspect. 41:195-201. Health, C.W., Jr., H. Fable, and J.L. Creech, Jr. 1975. Characteristic of cases of angiosarcoma of the livers among vinyl chloride workers i the United States. Ann. N.Y. Acad. Sci. 246:231-236. Hefner, R.E., Jr., P.G. Watanabe, and P.J. Gehring. 1975. Preliminar studies of the fate of inhaled vinyl chloride monomer in rats. Am N.Y. Acad. Sci. 246:135-148. Heldaas, S.S., A.A. Andersen, and S. Langard. 1987. Incidence t cancer among vinyl chloride and polyvinyl chloride workers: Furtin evidence for an association with malignant melanoma. Br. J. Ind. Mec 44:278-280. Ho, S.F., W.H. Phoon, S.L. Gan, and Y.K. Chan. 1991. Persistent livt dysfunction among workers at a vinyl chloride monomer polymerizatk plant. J. Soc. Occup. Med. 41:10-16. Hong, C.B., J.M. Winston, L.P. Thornburg, and C.C. Lee. 198 Follow-up study on the carcinogenicity of vinyl chloride and vinylidet chloride in rats and mice: Tumor incidence and mortality subsequent' exposure. J. Toxicol. Environ. Health 7:909-924. IARC. 1987. Pp. 373-376 in IARC Monographs on the Evaluation i Carcinogenic Risks to Humans, Suppl. 7. International Agency ft Research on Cancer, Lyon, France. Infante, P.F. 1976. Oncogenic and mutagenic risks in communities wf polyvinyl chloride production facilities. Ann. N.Y. Acad. Sci. 271:4` 57. Infante, P.F., J.K. Wagoner, A.J. McMichael, R.J. Waxweiler, and 1 Falk. 1976. Genetic risks of vinyl chloride. Lancet. 1:734-735. Jaeger, R.J., E.S. Reynolds, R.B. Conolly, M.T. Moslen, S. Szabo, ai S.D. Murphy. 1974. Acute hepatic injury by vinyl chloride in ra pretreated with phenobarbital. Nature 252:724-726. Jenssen, D. and C. Ramel. 1980. The micronucleus test as part ot short-term mutagenicity test program for the prediction of carcinogen city evaluated by 143 agents tested. Mutat. Res. 75:191-202. John, J.A., F.A. Smith, B.K.J. Leong, and B.A. Schwetz. 1977. 11 216 SMACS FOR SELECTED AIRBORNE CONTAMINANTS effects of maternally inhaled vinyl chloride on embryonal and fetal development in mice, rats, and rabbits. Toxicol. Appl. Pharmacol. 39:497-513. Krajewski, J., M. Dobecki, and J. Gromiec. 1980. Retention of vinyl chloride in the human lung. Br. J. Ind. Med. 37:373-374. Kramer, C.G. and J.E. Mutchler. 1972. Hie correlation of clinical and environmental measurements for workers exposed to vinyl chloride. Am. Ind. Hyg. Assoc. J. 33:19-30. Lehan, M.I. and P.A. Wagner. 1989. Space Station Freedom Gaseous Trace Contaminant Load Model Development. SAE Technical Paper Series 891513. Society of Automotive Engineers, Warrendale, Pa. C.C., J.C. Bhandari, and J.M. Winston. 1977. Inhalation toxicity of vinyl chloride and vinylidene chloride. Environ. Health Perspect. 21:25-32. Lee, C.C., J.C. Bhandari, J.M. Winston, W.B. House, R.L. Dixon, and J.S. Woods. 1978. Carcinogenicity of vinyl chloride and vinylidene chloride. J. Toxicol. Environ. Health 4:15-30. Lefaux, R. 1968. Industrial toxicology. Pp. 63-83 in Practical Toxicol ogy of Plastics, P.P. Hopf, ed. CRC Press, Boca Raton, Fla. Lester, D., L.A. Greenberg, and W.R. Adams. 1963. Effects of single and repeated exposures of humans and rats to vinyl chloride. Am. Ind. Hyg. Assoc. J. 24:265-275. Lillis, R-, H. Anderson, W.J. Nicholson, S. Daum, A.S. Fischbein, and 1.1. Selikoff. 1975. Prevalence of disease among vinyl chloride and polyvinyl chloride workers. Ann. N.Y. Acad. Sci. 246:22-41. Makarov, LA. 1984. Sexual disorders in male workers occupationally exposed to methyl-methacrylate vinyl chloride. Gig. Tr. Prof. Zabol. 6:19-23. Makarov, I.A., M.S. Solovyeva, and G.I. Vnelitsky. 1984. On sexual disorders in women chronically exposed to methylmethacrylate and vinyl chloride. Gig. Tr. Prof. Zabol. 3:22-27. Maitoni, C. 1977. Recent findings on the carcinogenicity of chlorinated olefins. Environ. Health Perspect. 21:1-5. Maltoni, C., G. Lefemine, A. Ciliberti, G. Cold, and D. Carretti. 1981. Carcinogenicity bioassay of vinyl chloride monomer: A model of risk assessment on an experimental basis. Environ. Health Perspect. 41:329. Mastromatteo, E., A.M. Fischer, H. Christie, and H. Danziger. i960. SL 107485 VINYL CHLORIDE in Acute inhalation toxicity of vinyl chloride to laboratory animals. Am. Ind. Hyg. Assoc. J. 21:394-398. Nicholson, W.J., E.C. Hammond, H. Seidman, and I.J. Selikoff. 1975. Mortality experience of a cohort of vinyl chloride-polyvinyl chloride workers. Ann. N.Y. Acad. Sci. 246:225-230. NRC. 1992. Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants. National Academy Press, Washington, D.C. Perticonti, G.F., G. Abbritti, T.A. Cantisani, L. Bond, and L. Mauro. 1986. Polineuropathy in workers with long exposure to vinyl chloride. Electro-physiological study. Electromyogr. Clin. Neurophysiol. 26:41- 47. Popper, H. and L.B. Thomas. 1975. Alterations of liver and spleen among workers exposed to vinyl chloride. Ann. N.Y. Acad. Sci. 246:172-194. Preston, B.J., K.L. Jones, and R.G. Grainger. 1976. Clinical aspects of vinyl chloride disease. Proc. Soc. Med. 69:284-306. Prodan, L., I. Suciu, V. Pilaru, E. Ilea, and L. Pascu. 1975. Experi mental chronic poisoning with vinyl chloride (monochloroethane). Ann. N.Y. Acad. Sci. 246:159-163. Purchase, I.F.H., C.R. Richardson, and D. Anderson. 1975. Chromo somal and dominant lethal effects of vinyl chloride. Lancet. 2:410- 411. Reynolds, E.S., M.T. Moslen, and S. Szabo. 1975. Hepatotoxicity of vinyl chloride and 1,1-dichloroethylene. Am. J. Pathol. 81:219-231. Sabadie, N., C. Malaveilte, A.M. Camus, and H. Bartsch. 1980. Com parison of the hydroxylation of benzo(a)pyrene with the metabolism of vinyl chloride, n-nitrosomorpholine, and n-nitroso-n-methylpiperazine to mutagens by human and rat liver microsomal fractions. Cancer Res. 409:119-126. Sakabe, H. 1975. Bone lesions among polyvinyl chloride production workers in Japan. Ann. N.Y. Acad. Sci. 246:78-79. Shu, P. 1986. Study of excretion regularity of thiodiglycolic acid in urine of vinyl chloride-exposed workers. Clin. J. Prev. Med. 20:87- 89. Simonato, L., K.A. L'Abbe, A. Andersen, S. Belli, P. Comba, G. Engbolm, G. Ferro, L. Hagmar, and S. Langard. 1991. A collabora tive study of cancer incidence and mortality among vinyl chloride SL 107486 218 SMACS FOR SELECTED AIRBORNE CONTAMINANTS workers. Scand. J. Work Environ. Health. 17:159-169. Stallones, R.A. 1987. The use and abuse of subgroup analysis in epi demiological research. Prev. Med. 16:183-194. Styles, J.A. 1977. A method for detecting carcinogenic organic chemi cals using mammalian cells in culture. Br. J. Cancer 36:558-563. Sudu, I., L. Prodan, E. Ilea, A. Paduraru, and L. Pascu. 1975. Clinical manifestations in vinyl chloride poisoning. Ann. N.Y. Acad. Sci. 246:53-69. Suzuki, Y. 1978. Pulmonary tumors induced in mice by vinyl chloride monomer. Environ. Res. 16:285-301. Suzuki, Y. 1980. Nonneopiastic effects of vinyl chloride in mouse lung. Environ. Res. 21:235-253. Tabershaw, l.R. and W.R. Gaffey. 1974. Mortality study of workers in the manufacture of vinyl chloride and its polymers. J. Occup. Med. 16:509-518. Tamburro, C.H., L. Makk, and H. Popper. 1984. Early hepatic his tologic alterations among chemical (vinyl monomer) workers. Hepa tology 4:413-418. Tatrai, E. and G. Ungvary. 1981. On the acute hepalotoxicity of inhaled vinyl chloride. Acta Morphol. Acad. Sci. Hung. 29:221-226. Theriault, G., H. Ituna, and S. Gingras. 1983. Evaluation of the as sociation between birth defects and exposure to ambient vinyl chloride. Teratology 27:359-370. Torkelson, T.R., F. Oygen, and V.K. Rowe. 1961. The toxicity of vinyl chlroide as determined by repeated exposure of laboratory animals. Am. lnd. Hyg. Assoc. J. 22:354-361. Viola, P.L. 1970. Pathology of vinyl chloride. Med. Lav. 61:174-180. Viola, P.L., A. Bigotti, and A. Caputo. 1971. Oncogenic response of rat sldn, lungs, and bones to vinyl chloride. Cancer Res. 31:516-522. Watanabe, P.G. and P.J. Gehring. 1976. Dose-dependent fete of vinyl chloride and its possible relationship to oncogenicity in rats. Environ. Health Perspect. 17:145-152. Watanabe, P.G., G.R. McGowan, E.O. Madrid, and P.J. Gehring. 1976. Fate of (t4C) vinyl chloride following inhalation exposure in rats. Toxicol. Appl. Pharmacol. 37:49-59. Watanabe, P.G., J.A. Zempel, and P.J. Gehring. 1978a. Comparison of the fete of vinyl chloride following single and repeated exposure in rats. ^Toxicol. Appl. Pharmacol. 44:391-399. VINYL CHLORIDE 21 Watanabe, P.G., J.A. Zempel, D.G. Pegg, and P.J. Gehring. 1978f Hepatic macromolecular binding following exposure to vinyl chloride Toxicol. Appl. Pharmacol. 44:571-579. Wilson, R.H., W.E. McCormick, C.F. Tatum, and J.L. Creech. 1967 Occupational acroosteolysis report of 31 cases. J. Am. Med. Assoi 201:577-580. Wong, O., M.D. Whorton, D.E. Foliart, and D. Ragland. 1991. A industry-wide epidemiology study of vinyl chloride workers, 1942 1982. Am. J. ind. Med. 20:317-334. Wu, W., K. Sleenland, D. Brown, V. Wells, J. Jones, P. Schulte, and V, Halperin. 1989. Cohort and case-control analyses of workers expose to vinyl chloride: An update. J. Occup. Med. 31:518-523.