Document zoEEOnRN7e62nvLy77dxMRZ3n

HAZARD EVALUATION AND RISK ASSESSMENT FOR VINY'L CHLORIDE Prepare d for the American Industrial Health Coi ncil Risk Assessment Subcommittee Revised Working Draft John T. Barr Air Products and Chemicals, Inc. Allentown, PA March, 1982 SPI-00602 Summary I. INTRODUCTION . . II. ENVIRONMENTAL EFFECTS| III. ANIMAL METABOLISM IV. ACUTE TOXICITY . A. Plants and Lower prganisms B. Animals............... C. Humans ............... V. CHRONIC TOXICITY . . A. Animals .... B. Humans ............... VI. MUTAGENICITY .... VII. REPRODUCTIVE EFFECTS VIII. CARCINOGENICITY. . . A. Animal ............... B. Human................... IX. HAZARD EVALUATION. . X. RISK ASSESSMENT. . . A. Previous Risk Asst ssments. . . B. Further Calculati Ons............... C. Suggestions for Additional Work Tables Figures References Page iii 1 3 5 7 7 7 10 11 11 11 15 17 19 19 22 27 30 30 35 40 SPI-00603 List of Tables 1. Physical Properties o Vinyl Chloride 2. Angiosarcoma Cases in the VC/PVC Industry by Country 3. Angiosarcoma Cases in the U.S. by Company 4. Chronology of U.S. Deiiths from Angiosarcoma 5. Listing of Fully-Reported Mai torn' Experiments 6. LAS Incidence (%) in Fats, Inhalation 7. LAS Incidence (%) in Fats, Ingestion 8. Equations for Curves F itted to Various Single and Combined Maltoni Experiments 9. LAS Incidence in Wistar Rats, Ingestion 10. Summary of Quantitativ e Risk Assessments for VC Figures 1. Graphical representati Dn of Tables 6 and 7, probit vs. In dose 2. Graphical representati jn of Tables 6 and 7, log-log 3. Graphical representati on of low dose results, linear. SPl-00604 iummarv A re'/iaw of the environment^ 1 and health effects of v'nyl chloride (VC) was performed in order to reconf irm that the risk of angiosarcoma of the liver (ASL) from chronic exposure is the major human health concern, and is therefore the appropriate risk on which to base risk assessments. Vinyl chloride may be found in trace amounts from the combustion of chloridecontaminated organic materi ls; it is not otherwise known to be produced naturally. Emissions from ^C-producing and handling operations is controlled by OSHA and EPA. The FDA regnl ates its presence in food-contact materials. The metabolism of VC is via the mixed - function oxidase route, primarily in the hepatocytes of mammals, a nd is similar in rodents and humans. The reactive intermediate me Sabolates such as chioroethylene oxide are thought to be the source of chronic lamage to the liver cells because of their ability to combine with sulfhydryl groups. Detoxification appears to be a saturable mechanism which depends on co ijugation with glutathione. The toxic effect on plants i reported to be similar to that of ethylene. VC is not degraded by lower spfecies of plant, but is photochemically reactive with a half-life of a few hour s. Acute toxic effects in animal ; include reversible liver damage, cardiac arrhythmi and lung edema. It is an ef ective anesthetic and causes respiratory failure at high concentrations. VC is very flammable, but with a relatively high ignition temperature, and foil"ms explosive mixtures over a wide range of concentrations with air. Contact w th the liquid will result in frostbite. Extended exposure by humans s associated with acroosteolysis, a degenerative disease of the bone tufts, ind causes ASL in both humans and rodents. There is an increased incidence of tumors at other sites in rodents at higher concentrations, but this has not ber n confirmed in humans. Studies suggest that reversi 11 e chromosomal changes in somatic cells occur in humans at elevated concentral ions. Rodent tests do not show teratogenicity or dominant lethal effects, althp ugh there are some indications of delayed development and various skeletal va riiations. Studies of human birth defects provide no correlation with parental exposure to VC. A review of the quantitative risk assessments which have been published shows a wide variety of results dep ending on the data base chosen, the mathematical model used, and the assumpti ons made. The best correspondence with actual experience is found when biotr ansformed animal data are applied to unconstrained probit and linear models. Suggestions are made for further calculations and experiments which may clarify the appropriate model and imprfove the precision of the estimates. 11 i SPI-00605 INTRODUCTION ANO BACKGROUND vinyl chloride (VC) s a classical procarcinogen (becomes active upon metabolism by the ho t), in that it exhibits dose response effects in humans and several S|) ecies of mammals, shows binding to DNA, and is mutagenic with activ tion in bacteria. Its industrial importance has led to one of the la rger bodies of scientific data available on toxicity and metabolism, and several attempts at risk asssessments have been made. There have beeti a number of reviews of the literature on specific aspects of vinyl chlo ride, but none that has attempted a complete view of all of its toxic aspects so that their relative hazards can be evaluated. That is th e purpose of this effort. A. Occurrence and Us; Vinyl chloride wa s first prepared about 1833 (Herrle, 1963). The French chemist Reg nault first observed its polymerization in 1838, and his work was ixtended by the German scientist Baumann in 1872, and further deve oped by Qstromislensky, Staudinger, and others during the first tiw>o decades of this century. Plastisol and organosol applications were the first industrial uses. See, e.g., German patent 281,877, n 1915 to Klatte and Rolette and U.S. Patent 1,721,034 to Ostromislensky (Whittington, 1962). Its industrial use in this count ry dates from the late 1930s (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 Stktes is about 8 billion pounds per year (C&EN, 1980, Cameron, Lur deen and McCulley, 1980), and the worldwide capacity is about four tim<es that. There are minor us es of the material as a manufacturing intermediate for other chlori Hated products. It was used as a propellant in aerosol container^ until the early 1970s, when this application was withdrawn by the uppliers, and later officially banned (FDA, 1974, CPSC, 1974). Consideration has been given to the use of VC as an anesthetic, but it was considered jnsatisfactory because of possible cardiac effects (Peoples and Leake 1933, Oster, et al. , 1947). It now appears th<i vinyl chloride may have been a minor constituent of the environment from natural causes. Hoffman and co-workers (1976) reported tiinding 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 ha: been recognized for several decades as an anesthetic, and as be ing toxic to the liver of mammals. (See later sections for a fu Her discussion of these points.) During the early 1960s a heilalth problem was recognized in polymerization reactor cleaners termed acroosteolysis (AOL) (Dinman, 1971). I SP1-00606 ENVIRONMENTAL EFFECTS As the physical prope rjties in Table I indicate, vinyl chloride has low water solubility, and is easily lost to the atmosphere from streams and discharges (Hill, et al., 1976). Unpublished reports cited by EPA (1974) state that a stirred beaker lost 96% of its original 16 ppm in two hours, while an ujnstirred beaker lost 25%, at 22C. Plots of log concentrations versus time gave straight lines, indicating volatility to be the only importjant loss mechanism. There was no difference in loss rates between dis billed water, river water, or industrial effluent, 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, Eggl iston, and Sandalls, 1974, Gay, Noonan and Bufalini, 1976) in the reaction with NO , and considerably less in the reactions with ozone. The resi qence tifrle in the atmosphere was estimated as 1.8 days by Singh, et al. (1980), with a 43% loss per 12 hours of sunlight, based on the rate of reaction with hydroxyl radical only. It does not appear to be absorbed by microorganisms, as shown by tests with five mixed bacteria popul ai. ions, three mixed fungal populations, two axenic bacterial cultures, aidd one algae. The mixed bacteria did not degrade the VC, nor was it tc xic 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 p jb range. The concentration was higher in the finished than in the raw water, indicating that it may be produced in the chlorination step Dressman and McFarren (1978) have found VC in the ppb range in wat r from distribution systems using PVC pipe, Banzer (1979) states tjhat no extraction of VC occurs from pipe containing less than 1 ppm re s idual by a test sensitive to 2 ppb. It is also present in the dischajrge of some VC handling plants in the low ppm range (EPA, 1974). The EPA has since imposed stripping requirements on industrial effluents (EPA, 1976). Conventional water treatment systems are capable of remov ng VC from wastewater streams (Minott, 1973, Crider, et al., 1977). The EPA has conducted three ambient monitoring programs around VC handling plants (EPA, 1975, Dimmick, 1981). The first, in 1974, found measurable quantities at distances up to 0.5 km from a PVC plant. The third program failed to find significant quantities at the fence line of five large fabrica ting plants. The results of the second program have not been released but analysis of the data has shown (Air Products, 1976) that the averagt concentration in early 1975 at the plant tested was about 40 ppb at 530 meters from the plant center, 10 ppb at 1 km, and 2 ppb at 2 km. The EPA has calculated (EPA, 1975) an average exposure of 17 ppb tc persons residing within five miles of a typical PVC plant, using emi sion data and modeling techniques which were strongly disputed by ndustry. 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 SP1-00608 ANIMAL METABOLISM Clapp and co-workers (Clapp, 1969) identified cysteine derivatives in the urine of rats trs ated with vinyl chloride (VC) or vinyl acetate, and postulated that ntermediates were formed in the metabolism of these compounds which vere reactive with glutathione. Vazin and Plokhova (1969) reported an i ncrease in adrenaline derivatives in the blood of chinchilla rabbits exposed to VC. Hefner and co-worker; (Hefner, 1975) proposed a saturable metabolic pathway in rats via lcohol dehydrogenase which gives rise to chloroethylene oxide or chloroacetaldehyde as the first active intermediate, and which is the prinary metabolic route at concentrations below 100 ppm. The final excret ion products appeared to be the result of binding with glutathione and ''or cysteine at the sulfhydryl group. Higher concentrations, or thr addition of alcohol, were believed to 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 homogonates exposed to VC. (See also Muller, Norpoth, ian Duuren (1975) also postulated that the epoxide route was active. Kappus, et al., (1975) reported that the addition of glutathione reduces the binding of VC-products to protein in rat liver microsomes, 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 phrnobarbitol, an alcohol metabolism suppressor, increased the liver toxicity of VC (Jaeger, 1974). Watanabe, et al., (1976) found, howeve*. that the suppression of hepatic nonprotein sulfhydryl was not s<>en at exposures below 50 ppm. Bolt, et al., (1975) found that the presence of NADPH was required for binding of VC metabolites to protei in either rat or human liver microsomes. Bolt, et al., (1977, 1979) Reported a change in the rate of metabolism of VC by rats at 250 ppm, very nearly the same critical concentration as found by Hefner and c (-workers (1975). Du, et al., (1979, 1981) Laib, Guinner and Bolt (1981 ) and Guengerich, et al., (1981) all have reconfirmed these findings on the importance of glutathione in the detoxification mechanism. These workers also foil nd (Bolt, 1976) that respiratory uptake of VC by rats was completely b ocked by cytochrome P-450 inhibitors, presumably because of interference with the metabolic pathway. Green and Hathaway (19|75) isolated and identified the cysteinecontaining metabolic products o VC, but postulated a free-radical initiated direct addition of VC o the -SH group, rather than an epoxide intermediate, However, these worker s concluded later that the epoxide route was compatible with experimental data. (Green and Hathaway, 1977, 1978, Hathaway, 1977.) Guejigerich and Strickland (1977) disputed both the epoxide and free-radi :al mechanisms in a study which found that both NADPH and cytochrome P 450, together with molecular oxygen, were necessary for the metabolism o' VC, and proposed a mixed-function oxidation route. 5 SPI-00610 metabolite must leave the hepatocytes to act on the sinusoidal ceils, the site of neoplasti development. Tamburro (1978) had made the same proposal for human cas| IV. ACUTE TOXICITY A. Plants and Lower Crqanisms There are few pub ished data on the effect of VC on flora. Hill, et al. , (1976) re jorted that VC does not appear to be absorbed by bacteria, fungi, r algae, nor was the VC degraded by the bacteria, No toxic effects ere seen. Heck and Pines (1962) found no effect on several plant secies from seven days' exposure at 10 ppm, with moderate damage at 100 and 1000 ppm, an effect very similar to that of ethylene. The ;PA states (1975) that vegetational damage around VC-handling plant' has not been documented. See Section VI. for further discussion of effects on lower organisms. B. Animals The principal acut dangers from VC are anesthesia, which can cause death from respi rjatory paralysis, reversible liver damage, and cardiac arrhythmia A summary of the ei rly literature was prepared by von Oettingen in 1955, and an exerpt is reproduced below: "Like other chlorinated hydrocarbons, vinyl chloride has narcotic propjerties. According to Peoples and Leake (1933) the narcotic ange 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 an<# not followed by untoward effects even after prolonged expjosure. Schaumann (1934) determined the vinyl chloride leve in the blood of cats anesthetized with 10 to 13 vol. percent as 15 to 17 mg. percent. Oster, Carr, Krantz, Jr. , and Saue "wald (1947) used vinyl chloride stabilized with 0.5 percent Qf 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 indiction was rapid, but that "crowing" continued even during de ep anesthesia and that there was profuse salivation, During narcos is the relaxation of the abdominal muscles was good but the legs remained rigid showing, throughout the anesthesia, i icoordinated movements. The recovery was rapid but associatec with violent excitation. As to the effe :t of vinyl chloride on the circulation, Schaumann (1934) studiec its effects in the Starling heart-lung preparation of cats judgi i|ig the action by the effect on the intra-auricular pressure. He found that similar effects were produced by 1.3 percent of sd laesthin (dichloroethylene), 3 vol. percent of ether, and 18 vol. percent of vinyl chloride. Higher concentrations (20 \ ol. percent) of vinyl chloride caused a more or 7 SPI-00612 expired after 10 minutes at blood levels of 15-17 mg. percent. He reported that the UC in the blood was distributed 85% in the corpuscles ana 15% in the pi asma. He found no harmful effects on the heart, and recommended it s use as an anesthetic, especially in combination with nitrous oxide . However, Oster (1947) and Carr (1949) reported that with dogs, at an anesthetic level of 8-12%, they found serious cardiac arrhythmi .is and there was development of sensitization. Peoples and Leake (1933) had commented on this effect earlier. Clarke and Tinstoin (1973) commented on the rapid reversi bility of this effect. Mastromatteo, et 1., (1960) exposed mice, rats, and guinea pigs to 10, 20, 30, and 4Z% VC in air for 30 minutes and found 1 of 5 mice died at 20%, all it ice and rats and one guinea pig died at 30%, and 2 of 5 guinea pi gs died at 40%. Deaths were due to narcosis and some pulmonary edama was reported. Kuebler (1964) reported "no histological dama^e" to several species exposed to as much as 5% for 100 days. Prodan (1975) stu died the two-hour lethal dose of VC in mice, rabbits, guinea p gs 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. A three-month exposure of guinea pigs at 10,000 ppm for 2 hours daily over 3 months produced lung fibrosis. This has not been reported :or other rodents. Muratov and Takhi rov (1979) report that the toxic effect of VC on rats is more pron >unced at 36C than at 18C, and recommend lower allowable exposures at higher temperatures. Torkelson, Oyen, a id Rowe (1961) found that repeated 7-hour exposures to 100 ppm for si* months resulted in increase in rat 1iver weights, but no observable effect in guinea pigs, rabbits or dogs. Similar exposure to 200 ppm resulted in micropathological 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 any species, nor from daily 10C and 200 ppm doses for one hour, but longer daily exposure times caijised slight increases in liver weights in rats, They then suggestnd 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 w.'brk at much higher concentrations, and this was accepted by the An|.erican Conference of Governmental and Industrial Hygiene first as TWA, then as a ceiling concentration (ACGIH, 1963). This was adopted by the Occupational Safety and Health Administration in May, 1971 as a formal regulation. The ACGIH recommended a redbiction to 200 ppm TWA in its Third Edition in 1971. Rowe and To rkelson (1977) have since commented: "Had our recommendations ba sed upon relatively simple toxicology been followed then, the difficu ies of today (cancer) may never have occurred." 9 SP1-00614 CHRONIC TOXICITY A. Animals Few animal studies extending more than six months have been reported apart from bioassa:ys for carcinogenicity. Viola's attempt (1970) to reproduce AOL n rats used exposure of 25 rats at 3% for four hrs/day, five day sj/week for 12 months. He reported that the animals were slightly sopc rific, and began to show a decrease in weight and reaction to exterr al stimuli. Half of the animals died of cardiorespiratory compli cations and two of hematoperitoneum. Most showed pathological invo vement of the brain, liver, kidney and thyroid, Six showed patholod ical 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 0.030.04 mg/1. Few de:ails were given, and these results have not been duplicated. Feron and Krees (jl979) exposed rats to 5,000 ppm, 7 hr/day, 5 day/week for up to one year and found tubular nephrosis, focal degeneration of tt e myocardium, and spleen damage, in addition to various primary tunors. B. Humans An article which las been cited frequently as supplying an early warning of the tc xicity of VC is that by Tribukh (1949) which discusses health Conditions in a PVC processing plant in Russia, The author actual y does not ascribe the health problems to any specific material, but mentions diphenyl chloride, hydrogen chloride, and other toxic m,^terials 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 < ppeared before 1974 describing what has come to be called "VC poi joning" 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 symptom:s as the exposure was reduced. Some of these reports are listed briefly below: Filatova, et a (1958) reported spastic angioneurosis in workers that had been expo ^ed to 20-315 ppm VC in a PVC process. Gabor, et al. , (1 962 ) observed a decrease in catalase and an increase in peroxidase acti vities and glutathione levels for VC and other exposures. SP1-00616 of data relating tjo the respiratory functionality of VC/PVC workers supplied no signi ficant data associating VC exposure with lung acnormalities. A second area of doncern for humans exposed to VC over long periods is a degenerative isease of the bone tufts, accompanied by Reynauld' syndrome, and, freh uently, scleraderma. Suciu (1963) first reported this disease, the* Cordier (1966). These were followed by Harris and Adams (1967), Wilson, et al. , (1967), and Basalaev (1970). One industry-sponsorec survey (Dinman, 1971) identified 25 definite cases and 16 sus dect cases in the U.S. No certain etiological agent was found, )ut the cases were clearly associated with hand cleaning of reacto rs, (Cook, 1971), where there is a combination of physical joint in: ult and VC exposure. The disease is most often seen in the hands and fingers, but occasionally in the feet or back (Harris, 1967) or jaw (Jayson, et al., 1976). Dodson (1971) could find no obvious misdical reason for predeliction to the disease in the four cases whi ch he studied. It appears to be reversible after cessation of expc sure (Graniger, Walker and Ward, 1980, Hess, Schneider and Roush 1967). Maricq (1976) foun d a strong association of capillary abnormalities in the hands with workers suffering from AOL. Li 1 is (1975) reported that an abnormal Al len test for circulatory efficiency was found in many affected wor cers, as well as many other organic symptoms related to the liv r and circulatory systems. This disease (AOL) is seen occasionally in patients not exposed to VC, Cheney (1965 , Wilson (1967) Meyerson (1972). There is no question that VC e,|<posure is associated with the cases seen in the industry, but the exact cause or mechanism for development of the disease has not b een determined. It appears to be a result of circulatory defici encies perhaps brought on by VC exposure, and possibly aggravatejd by physical insult. Bretza and Goldman (1979) have discussed non occupational cases of scleraderma and AOL. Bertozzi, et al., (1979) studied the status as of 1975 of a group of 4,777 workers, some of whom had been employed since 1952 in VC/PVC production facilities. No control or comparison data are given, and many d Ifferent laboratories performed the analyses so only relative tre ijds within the cohort can be identified. They stated that the hi g best exposures were "above 800 ppm." Confirmed and suspected cas es of AOL increased with the degree of exposure and the age of thr worker, but not with the length of exposure, "Abnormal" liver ti! st results increased with length of exposure but not the degree, Heavy drinking appeared to act synergistically with duration of ejxposure in affecting hepatomegaly and elevated GGT. Czernielewski, et - il., (1979) described 30 cases with severe scleraderma, 3 of which had progressed to AOL, and 9 had abnormal liver scans. Twenty-fiv > had Reynauld's syndrome. They stressed the importance of skin :hanges as warning signs. 13 SP1-00618 MUTAGENICITY Hopkins (1979) and Mor tesano, et al., (1976) have published reviews of the mutagenicity data on VC. Although it is clear that VC is mutagenic in several strains o Salmonella when activated by rat liver cells (Rannung, et al. , 19t4, Bartscn, 1975, Grein, et al., 1975), some studies have shown it to be effective without activation (McCann, et al. , 1975, Andrews, elt 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 n i crosomes are effective in this, and thus bacteria may be also. Garro, (t 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, chloro ethylene oxide and chloro aceta dehyde, are also mutagenic to Salmonel1 a (Malavielle, 1975, Rannung, 1976). These metabolites also were effective in transforming Bacillus subtill is (Elmore, et al., 1976) and Chinese hamster cells in vitro (Huberman, et al., 1975). Laumbach, et al., (1978) studied the effect of VC and its metabolites on Salmon* 11a and BL_ subtil!is strains, and concluded that recombination repair is the mechanism for correcting VC-metabolite damage. Mouse liver microsome:; were necessary in some tests for VC to have an effect on various Sacc haromnycces varieties (Loprieno, et al., 1976), but not in others (Bartsci , 197?) while chloro ethylene oxide was active directly (Loprieno, et al., 1977). Chloro acetaldehyde was only weakly active and chloro eth*nol was inactive. The mouse-mediated assay with Saccharomyces was posi :ive with VC, also (Loprieno, 1976). Mattern, et al., (191 7) were not successful in obtaining positive results in Salmonella with urine from either exposed men or rats, even in the presence of A ochlor-treated rat liver cell preparation and glucuronidase. Thereto re, 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 cau<i e a detectable change in two species of Neurospora crassa. Verburgt and Vogel (1 >77) found only recessive lethal effects with VC in Orosophila. Magnu son and Romel (1978) found that pretreatment of the Drosophila with bk.rbiturate enhanced the activity of VC, but did not eliminate the thres hold limit on activity seen by them and Verburgt. They agreed with Bart ch and Montesano (1975) that the mixed-function oxidase system was emp loyed in the activation of VC. Haellstrom, et al. , (1981) called VC "fairly weak mutagen" in a test system utilizing Drosophila microsomal fractions to activate VC when Salmonella was the indicator organism. SPI-00620 Picciano, et al. , (19 77) concluded that any cytogenic observations were probably related to 1 ength and degree of exposure, and that any genetic risks were avoidable by adequate control of exposure. Easier and Ronrborn (1980) found that this was true for the bone marrow cells of Chinese hamsters expo sled to high levels of VC in vivo. REPRODUCTIVE EFFECTS Purchase, et al., (1 975 ) 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 les 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 ells. Short, et al., (1979) performed a similar experiment with longer exposures to lower concentrations, and also found no effect on reproduction or survival. Hehir, et al., (1980) included an Regeneration study in their program, Parent rats were expo spd to 50 or 500 ppm VC one hr/day, 5 days/week for 10 weeks before ma: ing and the subsequent three generations were examined for litter si :e, percent stillborn, growth, viability, and reproductive anomalies No effect of Fq generation exposure was seen. Studies by Schwetz, et al (1975) and by John, et al., (1977) found no excess fetal wastage i mice, rats or rabbits at VC exposures sufficient to cause maternal toxi :ity. The authors also found that VC, either alone or in combinati o i with ethanol, was not teratogenic when dams were exposed on days 6 15 at 50-2500 ppm VC. The combination of alcohol and VC did cause delay id development and a higher incidence of some skeletal variations Mirkova, et al., (1978) reported skeletal ossification effects, increased embryo resorption and jther effects in rats, at exposures considerably below those used by other workers, but adequate details of the study are not available for :horough evaluation of the report. A recent review of ani nal data for the Council on Environmental Quality (1981) cites two other studies which suggest increased embryo toxicity and fetal mortality in rats exposed during the entire pregnancy. In one of these, Ungvary, et al., (1978) reported embryotoxicity and increased resorption i rats exposed to 1,500 ppm during the first third of pregnancy. Rice (1981) concluded :hat there is no evidence that exposure to VC or any other carcinogen hks produced increased tumors in the offspring. One portion of the Mai oni (1977) program was an examination of the second generation rats whose dams were exposed. Experiment BT-5 found zymbal gland carcinomafe , angiosarcomas at sites other than the liver, and subcutaneous tumors in 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 contrb Is for these experiments, and relatively little 17 SPl-00622 recheck (CDC, 1975, Edmonds, 1976) of this report had adequate power to detect a significant ffect, as did the CDC (1976) study in West Virginia, which also was negati ve Similarly, the worker study (Infante, et al., 1975) on abortions anc miscarriages had design deficiencies that prevented its results from beinc accurate. Her conclusion was that "there are no data which point unamqiguously to a relation between VC and reproductive outcome." In summary, VC does no t appear to be teratogenic, nor to cause excess fetal wastage in animal s or humans. It can cause reversible chromosome damage in somatic cell s, but apparently not in stem cells. It may be a transplacental carcino gen at high exposures in rats, but the data are not conclusive. VIII. CARCINOGENICITY A. Animal Viola (1970, 1971) was the first to report the carcinogenici ty of VC, as the result 3f an attempt to reproduce AOL in rats. (See Sections I and IV above.) His experiments were at such high exposures that 1ife-shorteni ig of the animals was evident, so a second series of experiments by dal torn- (1977) was sponsored by the same group of VC/PVC producers, Several other studies by industrial and governmental groups were also u idertaken at about the same period. Viola found princi )ally tumors of the zymbal gland. This is an organ near the ear which secretes oil, and is found only in rodents, He also reported 11imors of the skin, bone and lung. These are generally thought ,o have been metastasized zymbal tumors, and not primary cancer. Caputo, et al., (1 974) exposed Wistar rats to 50-20,000 ppm of VC for 4 hrs/day, 5 d. ilys/wk for 12 months, and found ASL and skin carcinomas in thos4 exposed at 500 ppm and above, and lung adenocarcinomas in thos* exposed to 2,000 ppm and above. Rabbits exposed to 10,000 ppm VC f<> r 15 months had lung and skin tumors at the end of the experiment Keplinger, et al (1975) reported the preliminary results of tests with mice, rats, aijid hamsters which confirmed the carcinogenicity of VC. It appeared that mice were much more sensitive to VC than were rats and hamsders less so. However, the study contained procedural flaws wti ich precludes its use in quantitative risk assessment (Garmon 1981). It has been shown dRadike, et al., 1977, 1981) 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., (19 8, 1979, 1981) administered VC to rats which was absorbed into PVC o as to constitute dosages of 1.7, 5.0 and 14.1 mg/kg/day, and by davage in soya oil at 300 mg/kg/day. This assured a 24 hr/day exposu ne as the VC desorbed (Feron, et al., 1975). An 19 SPI-00624 Mai tom' summarized (1979) his extensive series of experiments with rats exposed to VC by inhalation and gavage by stating that tumors at various sites :ollowed different dose response curves. The lowest doses at wfi ich statistically significant elevations of various tumors we'e seen were: Forestomach papi11omas: Neuroblastomi s: Zymbal gland carcinomas: Nephroblastoijtias: Liver angiosaircoma male: female: Mammary 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 reported find ng of an increase in mammary adenoma at very 1 ow exposures led to Concern for female workers, particularly when a study of fabricate r employees found an excess of breast cancer among females (Ch azze, Nichols, and Wong, 1977). However, a case-control foil c w up (Chiazze, 1980) found no relationship to VC exposure in the c ses found in those workers. In any event, the very high and var able incidence of such tumors in the controls, about which Mai tor i has often commented in his oral presentations, makes it very difl icult to support a conclusion that the test animals did respo rd at such doses. Tomatis, et al., (1978) have noted that "the t rget organs in animals are more often multiple than in humans." Early unpublished analyses of the two very large animal studies by the NCTR similarly show that the no-response levels of various organs are substantially different in each of these studies, as was found by Maltoni. Two injection expe riments were included in the Maltoni study. Mice were injected with 4.25 mg. VC in olive oil at intervals ranging from once per life time to two times per month for life. There was no dose-related st atistically significant change in either benign or malignant tumor s at the end of 144 weeks, (Maltoni, et al., 1981) and no cases of ASL. Much emphasis has been placed on the fact that ASL is a rare tumor, and Maltoni found none among his 465 controls. He did report four cases among 4,200 historical controls in his colony, for an incidence of 0.0952%. (Sumding his seven lifetime experiments yields a total of 881 Sprague-Oawl ey controls for a total of 2,534 exposed animals, so some groups may have served as controls for more than one experiment.) The control groups were not given the same housing treatment as the exposed animals, but experienced more stress. This also may help explain the questi on of mammary tumor incidence (Tassignon, personal communication). It is interesting to note that in Sprague-Dawley rats from a different colony (FDA, 1980) a crude spontaneous incidence of 12/573, or 2.1% was reported in th five control groups, with an adjusted incidence, after allowing f. or competing risks, of 7.15%. The actual incidences recorded were 0- 4. 3% in the 65-70 animal groups, with males running 21 SP1-00626 Ten cases of ASL have been reported in one plant in Canada, the last in 1976, witf no new cases since that time (Delorme and Theriault, 1978, Theriault a r|d Allard, 1981). These cases are completely typical, both as to the clustering and the medical symptoms. It is also worthy of note that there is, at most, one case of both AOL and ASL in the same person (Stafford, 1982) although both of these diseases are associated with VC exposure as a reactor cleaner. An industry-sponso red epidemiological survey of workers in the VC/PVC industry ccvered 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, respir atory, and at unknown sites, and of lymphoma. This study was expi|anded to 10,173 workers (Equitable Environmental Health, 1978, Coop|e r, 1981), where the excess of brain and respiratory cancers continued to be seen without, however, an association between the brain ancer and exposure. Plans are being made for a follow-up study of this cohort to determine the status of the workers as of the land of 1979. Several studies ha/ e been conducted on smaller groups of workers which are also sub|s ets of the larger study discussed above. Monson, Peters and Johnson (1974) found an excess of brain and lung cancers in the Goodrich pi int which developed the most ASL cases in the United States, Wa,c:weiler, 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 this opinion that it was not VC exposure that was responsible for this excess of respiratory cancer, and speculated that it may be due to PVC dust (see also Waxweiler, 1981). However, preliminary resul t;i on a study of subsequent lung cancer cases in that same plant (G eenberg, 1980) do not show an association with PVC dust. See al so Theriault and Allard (1981), Falk and Waxweiler (1976). This cone usion came from the application of an elaborate method for determi ijiation of exposure indices for workers potentially exposed to several chemicals (Greenburg and Tamburro, 1981). 8eaumont and Bresl dW (1981) evaluated the statistical power of nine epidemiological st tidies dealing with possible lung cancer from VC exposure and concl tided that the lack of a general trend in these results indicated that VC is not a human lung carcinogen. This was supported by the n^gative results in the two studies with the highest statistics power (Equitable Environmental Health, 1978, Fox and Collier, 15 77). They concluded that the reported studies were compatible wi 1 h a relationship between VC and brain cancer, This was based, hov|ever, on the assumption that the result of the EEH study was posi ti ve, a conclusion that is not altogether clear. Tamburro and his ^sociates at the University of Louisville have fo1 lowed closely e histories of the ASL cases at the Goodrich plant. This work Has been summarized by Dannaher, et al., (1981). Diagnostic methods, treatment, and survival are described. The 23 SPI-00628 deaths in German porkers, but the authors have since found calculation errors in the proc essing of the data. A later summary of this study (Weber, Reir 1, and Greiser, 1981) found an elevation of lymphatic tumors n addition to the expected ASL cases, but no elevation of lung or brain tumors. Molina, et al., (1981) found that the Swedish v ork group had an elevated heart disease rate, but not tumors other iihan ASL. Workers who fabri cated PVC were of interest as a group whose exposure to VC was signifi cantly less than the workers in the VC/PVC industry (Dimmick, 1981), but much higher than any expected exposure to the general population Chiazze, Nichols, and Wong (1977) studied 4,341 deaths from employees of 17 PVC fabricators, and found no ASL. There was an excess of deaths from intestinal cancer in both sexes, and breast and urinary system cancer in females, using proportionate mort|a lity ratios based on an external standard. A case-study follow up on the breast cancer deaths showed (Chiazze, 1981) no relatiionsn ip to VC exposure. Baxter and Fox (1976) found very similar resul ts in a study of 707 deaths of male fabrication workers in Great Br itain. There was no excess of lung or brain cancers in either :ohort. Several studies ha/e been made of the general population using ASL as the marker dise;&se in an effort to detect an association with possible environmejptal exposure to VC. There was no association with living near a VC handling plant in the general U.S. survey conducted by the Center for Qisease Control (Popper, et al., 1978). Brady, et al., (19 7) surveyed 26 ASL deaths in New York State between 1970 and T)75, and found five who lived nearer VC handling plants than did thwir matched controls, but could not establish a direct connection with the disease to exposure. Ten cases of ASL in Wisconsin were uxamined for possible connection with VC exposure, and none was found (Fiechtner, et al., 1976). Baxter, et al., (1977) found no re ationship between distance of residence from VC emitters and the 4'' cases of ASL in the general population of Great Britain reported in 1963-1973. A later update (Baxter, et al., 1981) found one ca: e which had lived the last six years of his life near a PVC plant aid three cases where the man had worked in the plastics fabricating industry, but for whom there were no records to indicate exposure to VC. The lack of relationship between residence and case: of unknown etiology was confirmed. Sardi, et al., (1976) studiec the deaths during the years 1968-1971 iri 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 c ommunities near a Swedish plant which had operated since 1945 and had found four ASL cases showed (Elinder and Pershagen, 1978) no unexpectec elevation of fetal mortality, deaths from all cancers, or cancer of the liver or lungs during the years 1961-1974. Pancreatic cancer iin 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 (Dalderup, et al., 1976). 25 SP1-00630 HAZARD EVALUATION The hazards to humans from exposure to vinyl chloride may be summarized as follows: Acute 1. Frostbite froim skin contact with liquid VC. 2. Fire and expjl<osion from ignition of spills above 3.5% concen- tration 3. Anesthesia a^d cardiac arrhythmia from exposure to concentrations around 1%. These hazards are abated by conventional safety practices in equipment design and operating srocedures which are beyond the scope of this discussion. The pote|i tial seriousness of the effect of these hazards should not be overl100 <jed in the concern for chronic effects. Chronic 1. Damage to liver, spleen, and circulatory system. 2. AOL and associate^ symptoms, 3. ASL, and possibly cancer at other sites. No precise threshold for time or concentration can be given for the onset of these effect^ 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 whfc le generation of the entire industry experienced exposures at least an order of magnitude above those which elicited chronic response in r its, and harmful effects were seen in only a few of the higher exposed members of the group. Even larger populations have been exposed to :race concentrations with no detected effect. The number of persons expused 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. If humans were as sensitive to VC as are rats, the expected number of cases would be above 10% (NCAB, 1979, Reitz, et al., 1979). Even 0.1% is an unacceptable hazard to permit to continue, and substan^ial steps have been taken to abate the risks, but it is of importance understand the degree of abatement which has been achieved by thes^ steps, and to determine if it has been adequate, and if a significant nisk exists for the non-occupationally exposed population. The metabolism of vin;H chloride seems to be carried out in the microsomes of the hepatocyte liv nr 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 g^nerated in quantities too large for detoxification, or if there is a depl ion of sulfhydryl groups by competing reactions, or for some other rea; on, then there is a greater probability that some of the active intermec iate may escape .the microsome, and eventually, some of it may cause cjamage to the genetic material of the chromosomes. Ottenwalder and Bolt ( 1980) suggest that the active metabolite must 27 SPI-00632 There has been a deer iasing incidence of new cases of AOL reported in recent, years, and the current medical surveillance on workers is such that chronic organ daifi age is being prevented. Concern for exposure to single doses high eno ugh to cause acute or chronic effects is unnecessary in the general popula ion, and very unlikely in workers under present conditions. Occupati ijinal exposures were reduced by a large factor in 1974-5 (Jones, et al. 1976, 1981, Barnhart, et al., 1975), and further reductions of workpl ac e and environmental emissions have continued since that time. Thetefore, we conclude that the only reasonable possibility of harm humans today is from long-term exposure to low doses, and the remaincler 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 ASL (see data in Section VII at ove). Watanabe, et al., (1976) show that the metabolic products of VC are distributed in many organs of test animals, but there is no infornjation as to whether these are the final detoxified products, or the poter tially carcinogenic intermediates. Human epidemiology may show a su ^gestive increase in brain and lung tumors at past high exposures; the dc ta are inconclusive. But, if present, these risks are at least an order of magnitude less than that for ASL (Monson, 1980). Therefore, the risks for ASL will be taken as representing all potential risks for tjimors from VC exposure. In summary, the risk for development of ASL is thought to be the most likely chronic hazard facing the working or general population from exposure at the prese rt time, if, indeed, there is any risk. Other chronic hazards are 1 aw 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 either very low or very high exposures is unlikely to be linear, but probably is "S" shaped. 29 SPI-00634 This same es imate was used by the EPA (1979) to estimate the concentratior of VC in drinking water which would produce various level s of risk. These estimates are, of course, subject to trte same criticisms. Nisbet (1978) challenged the estimate of Kuzmack and McGaughy (1975) when iit was used by Wilson in testimony before the OSHA hearing on its generic cancer policy. Nisbet 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 Yisbet procedure, including the fact that he extrapolation one point at 25 ppm from Maltoni experiment BTh15, and that this point is not in good agreement with the who! body of data. Further, he chose to use total cancer incideice in the rats, including those at zymbal glands, counterpart in humans. Both Wilson and Kuzmack and McGaughy had used a factor of two times ASL to account for possible canc>r at other sites. Wilson did acknowledge a mathematical irror which made his results half the proper number. Albert (1978) applied this same general procedure to other potentially ca rcinogenic air pollutants in the United States and calculate* the expected annual cancer deaths from exposure to ambient co riicentrations as follows: Arsinic Ben;.ene Cadrium Cok Ovens VC (jafter regulation) 15.6 77.8 26.2 149.5 1.0 Gehring, 1979 Gehring, et all. , (1979) applied an experimentally derived biotransformation correction (Gehring, et al., 1978) to rat data and esti(rated the incidence in humans at two different exposures by ireans of four different extrapolation models. Their estimates at 500 and 200 ppm TWA bracket the observed (Cooper, 1981) experience for humans when derived from the probit and the unconstrained linear models. The linearthrough-zero and one-hit models consistently overestimated the incidence. Although not considered by the authors, the linear and probit models match rather closely the total U.S. experience of occupational ASL at an assumed 1,000 ppm exposure. The linear model predicts no incidence below 99 ppm inbumans. The probit modal predicts a human risk of 1.5 x 10 3 at 1 ppm. Thus, a mechanism for adjusting for the difference in metabolism between animals and humans appears to be useful. Food Safety Cojncil 1978, 1980 The Food Safety Council has recommended (FSC, 1978) the use of the gamma mult -hit model because of its flexibility in handling dose response data of varying curvi1inearity at low doses. It 31 SPi-00636 which this ckn be extended is not known, See Section XB for further discussion. These authorfc also used the Crump-Guess model (Crump, Guess and Oeal, 19 7) to evaluate their data on mouse pulmonary cancer, and isstimated that exposure to 5,000 ppm VC doubles the probabil ty of cancer, while 50,000 ppm increased the risk nine-fold, n view of the fact that pneumonitis was present in all anima s exposed above 500 ppm, it is questionable if this was a d rect oncogenic response, or the result of an epigenetic e lent because of severe lung damage. Maltoni (1977) also reports an increase in lung tumors in mice, but not in rats (|r hamsters. Thus, the significance of this finding to r sk in humans is questionable. Anderson, 194 0 Anderson, et al., (1980) extended the work of Gehring, et a 1. , (1978 and 19 9) to incorporate the amount of metabolic products from VC whict was bound to the ONA of exposed rats, (Gehring and Blau, 19 7) rather than the total amount metabolized. They assignee various values to the parameters in a MichaelisMenten equat- on depicting the kinetics of the metabolic process and compared the results from extrapolation to low doses by log-probit a Hd multi hit models. They found that the two extrapolatior models responded quite differently to these variations at very low doses, and that it was not possible to select one middel as the more appropriate form from the highdose data, l|se of the values of Gehring for the primary parameters g ve estimates of the dose equivalent to lifetime risks of 10 of less than 1 ppm for the probit model and less than 2 ppm fc r the multistage model, a correspondence which the authors po inted out was better than the precision of interspecies comparisons. EPA, 1980 The final ver sion of the water quality criteria document for VC (EPA, 1198D) used a different approach for risk estimation, The slope of the incidence of all tumors at the lowest doses of Maltoni exp eriment BT-1 was adjusted for the fraction of exposure, the equivalent feeding level to give the same blood concentration of VC as by inhalation (see Withey and Collins, 1976), and the ratio of the surface area of humansevs. rats, to produce an estimate that a lifetime risk of 10 3 would be caused by dri nking 2 1/day of water containing 20 g/1. There i s some confu|s ion over the mathematics given in the report, and the assum3 tions on which the adjustments are made are far from having g eneral acceptance, although generally following NAS recommendations. It appears that this procedure overstates the risk by s averal orders of magnitude. 33 SPI-00638 13. Carlborg, 19J 1, also applied the Weibull model to 31 bioassay reports on a variety of animal carcinogens. He concluded that the one-hit ijodel was not appropriate and that carcinogens could be div- ded into categories according to the shape of curve, e.g., concave or convex. He found that the early Mai toni data on VC fe 11 into the former category. Application of his param' ter esti mates to the early Mai torn' _gata, assuming no spontaneoi s incidg nee of ASL, gives 2.5 x 10 ppm for a lifetime ris 1 of 10 for rats. He found the Weibull shape parameter, which often is assumed to be half tt e number of stages for tumor initiation, to be approximately 0.5. This is consistent with the finding by Gehring (1977) of a saturable metabolic path which produces the proximate carcinogen. It also suggests that the number of "stages" is the number of finite-rate steps before the ratelimiting step There may be other stages following, but they are not rate controlling. Actually, there appears to be at least two sat urable mechanisms involved in the pharmacokinetics of VC, the me tabolism to the ultimate carcinogen (which itself may have more than one route) and the detoxification by sulfhydryl groups. These estimates arle compared in Table 10, using the sequential numbers of this sec tion for reference. Estimates 5, (Dow 1979) and 12 (Scott, 1981 ) were not in a form to permit a 10 6 lifetime risk estimate. See OSHA, (1980), for references to a few other estimates that were not considered here. OSHA (1980) has st ated that this wide range of results from attempts to quantify the ri ks from VC is an indication of the unsuitability of the entire cone >pt of quantitative risk assessment. This variability is, in part, a refl ection of the early stage of development of the procedure. Subject ivity and necessarily (in some cases) arbitrary assumptions applied in the evaluation of the data are also responsible as are also differ nces in the mathematical treatment. It is apparent that some mathematical models fit the data better than do others. A reasonap le fit with human experience was obtained when suitably biotransfi rmed rat data were fitted by the product model, e.g., Gehring (197p ) and Anderson (1980). The Food Safety Council (1980) has emphasi :ed the need for appropriate consideration of biological factors in the application of mathematical models. Further Calculations 1. Mathematical Considerations Almost all of the risk assessments to date have been based on experiment BT 1 of Maltoni (Maltoni, 1977). Tassignon (1979) analyzed the esults of some of Maltoni's work, and commented on a systemic toxicity of VC which caused a general dose-related life shorteni ng in these experiments. After correcting for these effects he agreed generally with the statistical evaluation by Maltoni of malignant tumors, and found the extent of specific 35 SPI-00640 observed inc denca at finite exposures, but very small values, approximate!; 10 3, were used rather than zero with the logarithmic and expotent al programs to avoid machine error. These result are presented in Table 8. Various comb nations 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 < Iculations, the experiment column contains the notation "pli controls". The results cf several individual experiments fit various types of cur\es with high reliability. For example, BT-1 yields r valies of 0.95-0.99 for linear, power, and log-probit curves, and ET-2 does also for linear, logarithmic, and power curves. Thus, mathematical manipulations are not helpful in evaluating the biochemical aspects of low dose response. Inclusion of the historical controls usually lower the goodness of fit, altho|u gh 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- (or fewer) point urves (8T-2); these fits are to be expected. The apparent n fference in slopes that is seen in Figure 1 is reflected herfe in the greatly different values for the calculated constants fro|n experiment to experiment. The combined ngestion experiments, BT-11 and 27, were tested with the orig n as an included point for the linear equation, This reduced ignificantly the goodness of fit. Selection of data points also had a large effect on the resulting equation. 0m ssion of points above 15 g/kg/yr (about 500 ppm) significantly altered the slope and intercept of the lines (1 ast few 1 i n< i s of Table 8). These data points are shown on a log-log plot n Figure 2, and the low dose points are given on a linear plot in Figure 3. Omission of these points is based on the conclus ion that competing toxicity resulted in incorrectly low death rat s being ascribed to ASL. The intuitive (and mathematical) conclusion is that a poorer goodness of fi t with more data points is more reliable than a higher degree of fit for fewer points, if the data are for the same substance by the same procedure, but are independent and of equal degree of precision. Thus, it appears appropriate in this case to use the equation derived from the combined low dose experime:nts for further discussion for the limited value which it may Have. BT-1, the comb|ined ingestion studies, the combined inhalation studies, and tie combined ingestion and inhalation studies, with and wiithout the controls, all showed a positive y-intercept, That is, the dbta do not extrapolate to predict a no-observed- 37 SPI-00642 Biological Considerations The only di f'r iculty with the Gehring risk estimation procedure is that it u des partial Maltoni data, and tests the results against the (MA epidemiology study. That study was not the "end of the Experiment"; it stopped at the end of 1973, and several deati s have occurred since then. Neither did it cover the entire p dpulation, but only the employees of those plants which met ce itain criteria for data retention and length of operation, he Stafford (1981) data does cover the entire population a rd extends the history for seven years. The size of the popul i t ion is not known, but a reasonable estimate, based on nonna 1 worker turnover rates and the number of plants not included in the CMA study, is certainly not less than 25,000 (Heatf , 1975). This would give a gross incidence of about 0.1% Of these, the number actually exposed to substantial exposures wol Id be about 25-30 per plant at any one time, Multiplicatic n by 25 plants, and a factor of three for the turnover duri ng this period, would give about 2,000 highly exposed perse ns, for an effective incidence of just over 1%. This compares to a risk in the general population of about 10-/ or 10'3 from reported cases, although autopsy ratios show higher rates. Personal expe rience would indicate that, for the period prior to 1962, when all of the first exposures of the fatal 26 cases had occurred, the average exposures of this highly exposed group certai nly was in excess of 1,000 ppm for the working day. Refere nce to Figure 1 and Tables 6 and 7 indicate that Mai torn' found a 1% incidence at about 1-10 ppm. Calculation of the dose equivvalent to a 1% incidence in rats gives 0 ppm by the linear equations in Table 8, and 7.5 ppm from the log-probit eqluation for the combined inhalation experiments, This crude an d subjective estimate would then say that man is about 100 ti m> s as resistant as the rat to VC inhalation, a figure generap ly in agreement with other estimates (NCAB, 1979). Recent experience with extremely large bioassay experiments leads t 3 the conclusion that no reliable estimate of human risk can be o stained from raw animal data alone, but must include suitable biol sgical adjustments (Joint Conference, 1981). Attempts to c ilculate the incidence for rats (or man) at low doses by the linear extrapolation method fail because the derived equatfions yield a positive y-intercept. That is, they predict a spo itaneous response at zero dose. One further e valuation of human risk can be made from the experience of persons residing near VC-PVC plants. The EPA estimated (Laji dau, Charles, and Manos, 1975) that nearly five mi 11 ion persoji s lived within five miles of these plants, and were exposed ;o an annual average concentration of 17 ppb. The present d stribution of plants was generally well-established by 1959, thus we have 22 years of history, or about 110 million 39 SPI-00644 Suggestions are mi^de below for additional work in this direction which should be u se ful for further delineation of the risks faced by humans from exp osure to VC. 1. Extend the Ge hring-Anderson procedures to the total available rat data froir the Maltoni (1979) series and compare it to the currently ava ilable human data from the Cooper (1980)-Stafford (1982) reports 2. Apply the Fooid Safety Council (1980) methodology to the full Maltoni (1979) report, in an effort to see if the extended data range cain help elucidate the form of the curve at lower doses. Data at very high exposures should not be included because of t he confounding effect of competing risks. 3. Examine the riginal Maltoni data for time-to-tumor records, The rapid coujirse of the disease in humans suggests that time-to-obse rjved-tumor in rats should correspond well to time-to-onset but serial sacrifice may be necessary to determine thi s. The shape of this curve would be very valuable in further development of the risk evaluation. 4. Explore furthe r the applicability of Tassignon's (1979) factorial analysis to thle evaluation of actual human risks. 5. Perform the proposed update of the epidemiological study sponsored by the CMA. An additional five- or six-year history will be valuaia1e in estimating the risk from tumors at other sites. 6. Continue efforts to understand more fully the human metabolic/ detoxification processes for VC. 41 SPI-00646 TABLE 1 Selected Phyi ical Prooerties of Vinyl Chloride Formula Weight Heat of Formation, 25C, gas Kcal/mol Free Energy of Formation BTU/ lb. Density, liquid, g/ml 32F, 0C 50F, 10C 68F, 20C 86F, 30C 104F, 40C Refractive Index, d^ 62.50 7.5 -3310 0.9471 0.9293 0.9109 0.8918 0.8721 1.398 Freezing Point, C/F Boiling Point, 760 mm C/F -153.7/-244. -13.37/7.9 Liquid Viscosity, absolute, C P 32F 50F 68 F 86F 0.225 0.207 0.193 0.181 Heat of Fusion, cal/g Heat of Vaporization @ 57F, 3TU/lb. 18.14 158.4 Specific Heat . Liquid, 25C K cal/kg Vapor 25C, constant p ressure, Kcal/Kg-mol Vapor, constant volume 0.38 12.83 10.84 Heat of Polymerization, BTU/1 ) -720 Explosive Limits in Air Lower, wt, % vol.X Upper wt.% vol.% 8.3 3.6 37.8 33.0 Flash Point, open cup Autoignition temperature -78C 47 2 C Critical Temperature K Critical Pressure, atm Critical Density g/cc 431.4 52.7 0.370 Vapor cloud explosion yield. lbs. to yield the equivalent if 1 ton of TNT 24,305 SPI-00647 TABLE 2 Angiosarccma Cases in the VC/PVC Industry by Country as of January, 1982___________ United Staites West Gernja ny France Canada United Ki ngdom Sweden Yugoslavi i Italy Czechoslo /akia Japan Norway Belgium 28* 21 14 10 7 5 4 3 2 2 1 J_ Total 98 Data From Stafford (1982), except that the U.S. total includes one case reported only in the press. ^Includes one case still aliv SPI-00649 TABLE 4 Chronology of U.S. Deaths From Angiosarcoma Deaths Year of First Exposure 1961 1 1946 1962 0 1963 1964 0 1 1944 1965 0 1966 1967 0 0 1968 3 1944, 1951, 1952 1969 1970 1971 2 1949, 1950 1 1946 1 1955 1972 0 1973 3 1945, 1948, 1958 1974 1 1942 1975 4 1945, 1947, 1954, 1962 1976 3 1943, 1947, 1955 1977 1 1946 1978 2 1941, 1944 1979 0 1980 4 1942, 1951, 1955, 1964 1981 (as of July) _0 Total 27 Data From Stafford (1982). Fi rst exposure of living case was 1946. SPI-00651 o C O -- *>o pC--O 43-> C/> c 01 s l/> 0) vw p lo OS LU c 0) O<Q S3 H- i/> Oo. 0> X (cJ LU 0o) i/> -X 0J U c <u CM un <-n < in in o cn O uO 00 CM o oin in oo o cn o LO in oo o CM o o in un CM oo un m o o n un CM O oo o 00 uo oo o oo o cn o co o' co O^ 00 o in o cn nm CM CM CM <sO CM uo CM s a. & 0) S3 in O a. X LU a cn oo "O z 4U --j cue s0> > -- r0 . -- > CJ u -- X 01 3 \ a. 3" X LU OLU * CM C*** On Wistar Rats, A ll Others S-0. CO <0 o o I a. cn osJ 4w*yfUqoCc--O0lj----woU- Q4 ^3W--'cs-.* m o <> cj CM T O cn o do CM o o d -- o o 3 CM O CM Oo d Uow't eo: 01 05 3 J) ui 3w o*- ca; s- S > WU<T3 * Wo aX. Ta3) UJ *- GO wc wo C>3s<<Ju-* Sin *3---CaO> oS+-- oso I/) ^ cc O <0 UOf3OJ* sJO + 0) w <J5 *-- o o 3 i- a. 4- JO cn <z o --i it & ITS 05 3 d *3 CM 3 cn d c ex GC 3 3 3 CM 00 CM 3 <75 O 00 GO oo -J o d d d d 3 T 0005 CM CM 3 a cn *-- 3 r** cn CM cn cn CM CM 05 o --> c** 3 CM cn CM 3 o o d o dd r0*5* 05 oo o 0G3O o O 305 <-- d 05 05 do 305 035 dd mr-* cr*m*. ao 05 d 3 s- a<>3 c X3 ii > 3cn r^** cn cm 035 c/*n di i 3o Ocn o 11 r* o O GO cn cm 3r-- OCM dd o10 --'Jco cn oo -- oo 05. o > 3 CM O tA i/i 01 0) <S) o *3 *o 3 W J5 l/ --* 3 2 o ^5 3 -- 3O .o s- wO 4. o . - s- --- +J U5 <*J i/> w c W3 </> o 41 C --O a> 3 ~ O s4J a> u *o U u 05 3 3 C Jl W </5 W </) Lm 3 U5 3 W5 3 <v >-- n. -- Ol -- 3. -- Q. x LU C C < SPI-00655 \ \ --1 in m 'm--i <3 43 o V/5 4C0s31 <oS-1 11 cm -w--oaaa.>4--yaa-i;i. *--aiaofil. 43 o0)0o)0o) 43 a t0C*o-) .oaaOoai .) tEaoo IcS) <a3 <o3 a 3 oi 3 Oc) wa^a0i *-*cQ--o oz<c ao 4*oo-o +ao->i 3 U0c1 -- ^*--uco301 ^ Toe3O1 <0eaT1J uO 0) <+- C30aa1L.*<4*--#s--3- *T--0oEO1 <o--Oo0--1 1) 43 <0sa" wo ro 4-1 3 U1 .oL0aX1. 3 C05 lD <75 L0aa1... 3 --S 0ouC1i 0Qa>""..4<L03J31.-*aOUC3!-- *-- L--03O1 2 Oo>.) o 0so1 C01L 0>1 mm +m> O0c<10) 1mCo"Co*O1LC/3 Summary of Q uantitative Risk Assessments for VC c> f-- fC *3 CT-X c '-- l/> 01 JD 01 .X CL OS J3 J0 VI) u) \ Cl a. & 01 O) >) >> 01 Q. a. W) s a lD s O *4 3 3 3 o 01 aa a Vfc^ aaa Q.<- 1 m or cm ^ o <wO .B 5o n. (-- X o u '-- 01 O CL Z vn vn 01 3! &- ^1 >> kT5 S -a 1 a. \ O a. Q) --.. X o -3 1 No -Q 05 35 1-- CL & & & X 'W ox X r^ Lf) r-' urs LD E Q. Q. r* -- -- <r 4 s CM J= O 43 yV ) ro d o d d A CM U5 01 u 01 4-1 a <0 V/5 W uo r**. <7) C <0 s a 01 TO &. o 01 .e c wz 3u <c u*> c *5 s 3 | Z 01 c (/) <T3 3E O3 6 j3 - -- 43 43 43 43 43 * 9 (Q <0 to to a Uu u u &. im >v JI 05 3 * O U X *3 c .x u S uT) u) r-- 3 7) ^ <- o 00 or * u c 3 O u5 o r c) > o 4-1 00 01 CD -- ? s nj m LO i . T3 O <i O c. j u. * J= 01 z o CO 7) f-- * 01 o TO 00 o <7) T3 o O C c CO 00 o vn *<--7) <J\ u uo 01 -- -- *o <c LD > zc C3- <c rO c LU O oc g 43 43 i 2 (O <0 3 G, Sm u -C * CD O x: CO <n c o m3 \n U ui 0-- 3 01 00 LD 3 05 O &-- *D 01 C 3) a. f0 a <3 o& Om s IS) 3a a 03 Z C_1 ai 1-- zo U VV) CM o u3 00 O) o -- m *r 0-- PROBITS (P) o CD COOO a! C/3 u>t o> o\oA FIGURE 3 Graphical Representation o f the Low-Dose Data of Tables 6 and 7 Linear Plot REFERENCES Air Products and Chemicals, nc., "Comments on the Proposed Standard for Vinyl Chloride", letter to D. R. Go odwin, EPA, 23 September 1976. Albert, R. E., letter to R. !l Naveen, EPA, "Comparison of vinyl chloride carcinogenic risks with risk from other pollutants", Washington, DC, 16 June 1978. Albert, R. E., Statements at the 4-5 Sept, meeting of the Science Advisory Board Subcommittee on Airborr e Carcinogens, transcript p. 21, 36-3 Sept. session. Washington, DC, 19J 0. American Conference of Goverr mental and Industrial Hygienists, "Documentation of the Threshold Limit Value11 1963. American Public Health Associ ation, 1977. Andersen, M. E., et al., Tox. Appl. Pharm. 47, 385 and 395 (1979). Anderson, D., et al., Mut. Res. , 40 359 (1976). Anderson, M. W., et al., Tox, Appl. Pharm. 55, 154 (1980). Anderson, 0., C. R. Richardson, I.F.H. Purchase et al., Mutat. 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