Document mq6q4D1ONyGkj5L4rne8K44jd

82-9.2 Risk Assessment for Vinyl Chloride in Perspective AP00023057 For Presentation at the 75th Annual Meeting of the Air Pollution Control Association New Orleans, Louisiana June 20-25,1962 82-7.2 Introduction The combination of circumstances which fbwnd the carcinogenic hazard of vinyl chloride (VC) being disceverod at abowt the seat tine as the science of risk analysis was undergoing rapid development, and the great cemnerclal interest and long history of use of the substance has resulted In a body of literature and phaTMcoioglcal data greater than nno can expect to have for most substances. It Is therefore instruc tive to review the many risk assessments which have been prepared for VC against the available biological information to determine If we can evaluate the extrapolation methods used, and ta discuss the current regulations for VC in light of this co^wrison. Hazards of Vinyl Chloride It is necessary to decide first which of the hazards presented by VC should be the basis for the risk estimation. The substance presents the acute hazards of frostbite from exposure te the liquid, of anes thesia at concentrations over 8,006 ppm and suffocation at hitter concentrations (von Oettinger, 1955). It also fonts explosive mixtures In air above 3.75 volume percent, end so the efforts to control the physical safety of operations generally preclude exposure to acutely taxfc concentrations. These control efforts were reinforced in the aid-1960's where It was discovered (Suciu, 1963) that workers whh had been exposed te very high levels of VC developed "vinyl chloride disease," the primary manifestation of which was acroosteotysis (Ml), a degenerative disease of the bone tufts fe the hands, and more rarely of the feet and luabsr region. Although crippling to some degree, this disease is not fatal, end Is at least partially reversible if exposure is eliminated (Granigcr, Walker and Ward, i960). Alaost ten years later It was found that some of the workers having siailar exposure also were developing angiosarcoma of the liver (ASl), a rapidly fata) disease. Oddly enough, there Is only one possible case of a worker developing both MX. and ASL (Stafford. 1981) among the 60-plus cases of A0L and 90-plus cases of Ail now known worldwide, although both art diseases ef the vascular system. Several large epidemiology studies were conducted on workers exposed to VC (Baxter and fox, 1976; Chiazze, 1986; Duck, Carter and Cooobu, 1975; Equitable Environmental Health, 1978; Fox and Collier, 1977; Frentzel-Seyme, Scholtz, and Theiss. 1978; Theriault and Allard, 1981), end ASL was the only fatal disease found consistently to be in excess in these 2 persons. Aniual studies have shown an excess of tumors at other sites, but the lowest exposures at which these occur are considerably higher than that for ASL. For example, Haltont (1979) reported the following data: 82- Site Concentration For Significant Elevation Forestomach papillomas: Neuroblastomas: Zymbal gland carcinomas: Nephroblastomas: Liver angiosarcoma male: female: Mammary adenocarcinoma: 30.000 ppm 10.000 ppm 10,000 ppm 2S0 ppm 200 ppm, 56 mg/kg 50 ppm, 16.7 mg/kg S ppm The low concentration for onset of awry tours was of concern when a'preliminary study of fabrication employees reported an excess of breast tumOrs (Chiazze, et al., 1979) but a follow-up case-controlled study (Chiazze, I960) found no association between the cases and VC exposure. The largest study of VC-PVC workers in the United States reported slight excesses of brain and lung tumors (Equitable Environmeatal Health, 1970), but this was net seen in the other studies referenced above. The excess or brain tumors was small, and not doseor exposure-related. The overall excess of lung tumors resulted from an excess in one plant only, and reexamination of those cases also showed no association with VC exposure (Waxweiler, 1978). Vinyl chloride Ms been found to be active in several in vitro outa genetic tests with bacteria and yeasts (Hopkins, 1979) and it appears ti cause chromosome abnormalities in exposed workers, but these changes are reversible when exposure is reduced (Hansteene, 1978) and several studies of neighborhoods around PVC plants have failed to show a supportable association with birth defects (Edmonds, 1975, 1976). It it not a teratogen in rodents (Johns, 1977). Therefore it appears reasonable to assume that If there is any signif icant chronic risk other than ASL, it is considerably samller than that for ASL, and that an adequate risk assessment can be based on only the liver tumors. NOTE TO EDITORS Under the nmur hdsnl copyright law, publication rights to this paper are ratalmod by tha authors). !8 os| 3 llwfw of Msfc <lneiMWta 1. Schnelderman, 1975 One of the first attempts te utilize anlexl date to estimate risks at very low exposures ms that of Schneiderman, Mantel end Brown (1975). They used preliminary Haltonl results to compare the estimates obtained fro* three possible mathematical aodels. Thg,99S assurance level of a "safe" dose at a lifetime risk of 10 s estimated free several extrapolation models as follows: Log Probit (slope * 1) Logit (slope * 3.45) Logit (slope 2.3, ena-Mt) 73 ppb 119 ppb 2.1 ppb the authors discussed the recognized difficulties of extending these rat data to humans and of providing anioal experiments that ceuld answer satisfactorily the guestion ef human risk at very lew doses. 2. Kuzmack and HeCaughy, 197S The EPA wes the first group to attest a human risk assessment fer vlayl chloride (Kuzmack and NcGaughy, 1975). This pioneering effort etteapted to use both animal and human date, end to show comparative results from both the linear and log-probit models. It concluded that there was an Individual risk of 71 x 10 per ppm of lifetime exposure to VC by the linear extrapolation method, ead that the log-problt results were one-tenth to one-hundredth of that. This effort is subject te several serious criticisms. The exposure data used for human experience was that from a group with less then average exposure, while the ASL rate was chosen from only those plants which did report cases, and Ignored the remainder of the population. Thus, their incidence rate of 7.5X compares to an actual figure of about 0.1X. They used as their primary method d linear extrapolation of rat data, which often has been seen te overestimate the actual rates by at laast two orders of magnitude, and they assumed Uw total cancer rate to be twice that found far ASL. This sane estimate was used by the EPA (1979) to estimate the concentration of VC in drinking water which would produce various levels of risk. These estimates are, of course, subject to the same criticisms. Nisbet (197B) challenged the estimate of Kuzmack and HeCaughy (1975) when it 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 (1978) suggested several flaws 82-9.2 9 In the Nisbet procedure, including th fact that he chose for his extrapolation one point at 2S ppm from Mai tool experiment BT-15, and that this point is net in good agreement with the whole body ef data. Further, he chose to use total cancer Incidence in the rats. Including these at zymbal glands, which have no counterpart in humans. Both Wilson and Kuzmack and HeCaughy had used a factor of two times ASL to account for possible cancer at ether sites. Wilson did acknowledge a mathematical error which aade his results half the proper number. Albert (1978) applied this same general procedure to other poten tially carcinogenic air pollutants in the United States and calculated the expected annual cancer deaths as follows: Arsenic Benzene Cadmium Coke ovens VC (after regulation) 15.6 77.8 26.2 149.5 1.0 3. Gehrlng. 1979 Gehriag, et al., (1979) applied an experimentally derived bio- transformation correction (Gehrlng, et al., 1976) to rat data and estimated the incidence in humans at too different exposures by cans of four different extrapolation aodels. Their estimates at 500 and 200 ppm TWA bracket the observed experience for hunans when derived from the probit end the unconstrained linear models. The 11 near-through-zero and one-hit models consistently over estimated the incidence. Although not considered by the authors, the linear and probit models match rather closely the total U.S. experience ef occupational ASL at an assuned 1,000 ppm exposure. The linear model predicts no Incidence below 99 ppm^n humans. The probit model predicts a human risk of 1.5 x 10 at 1 ppm Thus, a mechanism for adjusting for the difference In metabolism between animals and humans appears to be useful. A limitation of the Gehrlng procedure Is that it uses partial Haltonl data, and tests the results against the CMA epidemiology study. That study was net the "end of the experiment*'; it stopped at the end of 1973, and several deaths have occurred since then. Neither did It cover the entire population, but only the employees of those plants which net certain criteria fer data retention and length ef operation. Tbe Stafford (1961) data dees cover the entire population and extends the history fer seven years. The size of the population 1$ net known, but a reasonable estimate, based on normal worker turnover rates and the number ef plants not included In the CMA study. Is certainly not less than 25,000. This would give a gross Incidence of about 0.IX. Of these, the number actually exposed to substantial exposures would be about 25*30 per plant at any one tine. Multiplication by'25 plants, and a factor of three for tlx turnover during this period, would give about 2,000 highly exposed persons. for aa effective inci- 82 s AP00023059 dene* of Just over 1%. Person*) experience would Indicate that, for the period prior to 1964, when all of the first exposures of the fatal 26 cases had occurred, the average exposures of this highly exposed group certainly was in excess of 1,000 ppo for the working day. Maltoni (1979) found a T* incidence at about 1-10 ppo in rats. Calculation of tha dose equivalent to a IX incidence In rats gives 0 ppo by the linear oethod end 7.5 ppn from the log-probit equation for the contained Maltoni inhalation experiments. This credo and subjective estimate would then say that nan is about 100 tioes as resistant as the rat to VC inhala tion, a figure generally in agreeoent with other estimates (NCAB, 1979). 4. food Safety Council 1978, 1980 The Food Safety Council hat rocoooeaded (FSC, 1978) tho use of the |wi oulti-hlt node) because of its flexibility in handling dose response data of varying curvtllnearity at low doses. It has calculated (FSC, 1980) the maximum likely and lower 97.5X Unit doses for substances at various risk levels end with different oodels. For VC, at 10 risk, these results are as follews (based on early Maltoni data): One-hit Aral tage*Doll Weibull Multi-hit 2.0 x >0'| ppo 2.0 x 10 ppo 2.1 x lO.ioPpa 3.9 x 10 l(rpeo For this substance, the goodness of fit of the Weibull model (0.56) was superior to that of the multi-hit (0.32). Neither of the other two oodels gave acceptable fits. This was in part because of the concave shape of the curve, which included all of the high doses in the dese response data. 5. Oow, 1979 A Oow Heath Teas perfumed a relative risk estimation for several coapounds (Lunger, et el., 1979) which considered probable expo sure, the consequence ef exposure, the physical state of the substance during processing, and the current exposure standards. This resulted in a valee of 480 for VC in a "closed system but with employees io the vicinity." The (Me procedure assigned hazard rating values te soee other substances as follows: benzene, 10; phosgene, 410; hydroged sulfide, 5; arsine, 9,700; and bls-chloromethyl ether, 69,700. In a batch operation with occasional manual handling, the hazard rating for VC Increased to 9,700 by this method. 6. Hehir, 1980 Hehir, et al., (1980) conducted a series of tests for the Consumer Product Safety Coemlssfon, a part of which consisted of exposing rats and mice to a series of short, high exposures, rather than the usual extended low dosage. They included one-hour exposures to rats and mice at 50, 500, 5,000, and 50,000 ppm, 10 and 40 hour exposures at 500 ppm, and 49 and 100 one-hour exposures at 50 ppm. After lifetime observation they found no effects on rats, or their offspring, nor on mice exposed to less than 500 ppm. Those exposed to over 500 ppe developed pulmonary adenomas, but they also had suffered from pneumonitis. They considered the published data on animal exposures and concluded that there was a lifetime dose below which no oncogenic response is seen. This was estimated to be 5,000 pparhrs for ice and greater than 50,000 ppm for rats, regardless ef whether the dose was administered over a short or long period. This concept of equality of effectiveness for all modes of exposure does not have general acceptance and would not appear to be correct, based on our present understanding of carcinogenesis. Dose-rate effects are, of course, well known, however, the degree to whjch this can be extended to all types of effects is not known. These authors also used the Cruap-Cuass model (Crump, Guess and Deal, 1977) t* evaluate their data on mouse pulmonary cancer, and estimated that exposure to 5,000 ppm VC doubles the probability of cancer, while 50,000 ppm increased the risk nine-fold. In view ef the fact that pneumonitis was present in all animals exposed above 500 ppm. It is questionable if this was a direct oncogenic response, or the result of an nongenntic event because of severe lung damage. Maltoni (1979) also reports an increase in lung tumors in mice, but not in rats or boosters. Thus, the significance of this finding to risk In humans is questionable. 7. Anderson, 1980 Anderson, et at., (1980) extended the work of Behring, et al., (1978 and 1979) to incorporate the amount of metabolic products from VC which actually was bound to the DMA of exposed rats. (Behring and Blau, 1977) rather than the total amount metabolized. They assigned various values to the parameters in a Michael:*Menten equation depicting the kinetics of the metabolic process, and compared the results from extrapolation to low doses by log-probit and multi-hit models. They found that the two extrap olation models responded quite differently to these variations at very low doses, and that it was not possible to select one model as the more appropriate from the high-dosc data. Use of the values of Behring for the primary parameter}.gave estimates of the dose equivalent to lifetime risks ef 10 ' of less than 1 ppm for the probit model aod less than 2 ppm for the multistage model, a correspondence which the authors pointed out was better than the precision of interspecios comparisons. 82-9. 7 AP00023060 8. EM, 1989 The final version of the water duality criteria document for VC (EM, i960) used a different approach for risk estimation. The slope of the Incidence of ell tuners at the lowest doses of Hal tool experiment 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 Uithey and Collins, 1976), and the ratio of the surface area of humtnsx*. rats, to produce an estimate that a lifetime risk of 10 9 would be caused by drinking 2 I/day of water containing 20 g/1. There is some confusion in the mathematics given In the report, and the assumptions on which the adjustments aro made are far from having general acceptance, although generally fallowing Ml recommendations. It appears that this procedure overstates the risk by several orders of magnitude. 9. MS. 1900 The National Academy of Science (1977) calculated the upper 95* confidence Unit for risk from drinking water containing vinyl chloride from the probabilistic multistage nodel and eerjy Naltonl rat data. They report (NAS- 1900) a lifetime risk of 10 9 as being equivalent to 3.0810 9 mg/kg/day. For a 70 kg person consuming 2 1/day, this would cAlculate to an acceptable level of 1 g/1. The di fforesee between the EM and NAS numbers comes from the different curve-fitting methods for the animal data, 10. Gaylor and Kodell (1900) applied linear "interpolation- to the seme early Naltonl data used by the Food Safety Council (1978) to arrive at a predicted maximum risk of 10 . The upper 97.SX confidence limit of the animal data was taken as one point on the interpolatlve line, and zero incidence at zero exposure as the other. Ibis produced a lower 97.SX confidence limit dosage of 7.1 n ! 0 ppm for a lifetime risk of 10 6 in rats. Thai ^appli cation of the Armitue-Ooll multistage model gave S.2 g,10"* ppm as the dosage at 10 B lifetime fitk coopered to 2 x 10 ` by the Food Safety Council. The difference is due to alternative assump tions on the value of the exponential dose term. 11.. Cnap and Guess (1980) reviewed seme ef the earlier risk estimates for vinyl chloride In drinking water, and recalculated the risks, using the one-hit and multistage models. They arrived at an ipper 951 confidence limit of lifetime risk for drinking water containing I g/1 of VC of * x 10 , based on early Naltonl Inhalation data. Using the assumption that a 0.2* incidence ef ASL In workers had resulted from a lifetime exposure of 70 g/kg, they obtained a naxinum likelihood risk of 10 9 from 0.34 g/1 by both the multistage and linear models, with 95* lower confidence limits of the same risk at 0.24 g/1. These two models reduce to a linear form when used at very low doses ami with the assumption of no threshold value. 82-9.2 8 These authors cite EM data oa the occurrence of VC in public water supplies tdtich by their methods yield a lifetime risk of 3.7 x 10 , or 12 deaths par year from this cause In the United States. None of these has been observed, despite the accumula tion of IS years' data oa ASL deaths (Popper, 1978). 82-9. 12. Scott (1961) ascribed the decreased incidence of tumors In rats at the higher doses te a cell killing process, and adopted the Ueibull model to account for this. Application of the model to some early Naltonl data produced a curve which fit the data from 50-10,000 ppm. Ha did not attempt to extrapolate to doses beyond the experimental rang*. 13. Carlborg, 1981, alsa applied the Ueibull model to 31 bioassay reports on a variety of animal carcinogens. He concluded that the one-hit model was not appropriate and that carcinogens could be divided Into categories according to the shape of the curve, e.g., concave or convex. Hn found that the early Naltonl data on VC fell into the former category. Applicatiom of Ms parameter estimates te those data, assmilng no spontaneous incidence of ASL, gives 2.5 x 10 0 ppm for a lifetime risk of 10 9 for rats. Later calculations Including all of the publIshed Naltonl data did not change the results significantly (personal communi cation). He found the Ueibull shape parameter to be approximately 0.5, which is assumed to bo the nuobor of stages for tumor Initiation. This is consistent with the finding by Gebring (1977) of a satur able metabolic path which produces the proximate carcinogen. It also suggests that the number of `stages" is the number of finiterate steps before the rate-limiting step. There may be other stages following, but they are net rate controlling. Actually, there appears te be at least two saturable mechanisms Involved In the pharmacokinetics ef VC. the metabolism to the ultimate carcin ogen and the detoxification by selfhydryl groups. 14. One further evaluation of human risk can be made from the experi ence of persons residing near VC-PVC plants. The EPA estimated (Kuzmacfc and HcGaughy, 1975) that five aillfon persons lived within five miles of these plants, and were exposed to an annual average concentration ef 17 ppb. The present distribution of plants was generally well-established by 1959, thus we hove 22 years of history, or about 110 nillion person-years. About fiva or six ef these plants, with 1-2 million neighbors, go back another 20 years, but these data are not firm enough for inclusion. The fact that no case of ASL has been confirmed as arising from these ambient exposures places the upper bound of risk at less than 2.7 x 10 per ppn-yr. It Is believed that the exposure data were overestimated by EPA, and thus this result may be too low, but it Is in UK same general rang* as that arrived at t>y Gebring (1979) and Anderson (1900) after making corrections for pharmacokinetics. i AP00023061 Extending this crude calculation, these five ailHon persons are now supposed by EPA to be exposed to 0.2 ppb (probably a high figure), which would predict no aore than 0.0003 deaths per year, er one per 3,700 years in that whole population due to VC exposure. But it also oust be recognized that with approximately 20 cases per year of ASl in the general population, there can be expected from a purely statistical basis that there should be one cese every two years ar so among this group of S million plant neigh bors. The results of these estimates discussed above are compared In Table I, after conversion to a uniform I0~ lifetime risk. Estimates 5, (Bow 1979) and 12 (Scott, 1961) wen not In a fora to permit this comparison. See OSHA, (I960), for references to a fdw other estimates that were .not considered here. It can be seen that'the results fall lute two major categories, those which project that the risk of 10 * occurs at exposures of greater than 1 ppm, and those which find that risk In the ppb range. The estimates which yield the higher allowable exposures are based on humen data (Nos. 3, 7 and Id) or use a log-probit extrapolation model (No. 2, second estimate), er predict a threshold (No. 6). The remainder generally arc based on the linear, non-threshold model, and moke no biological correction. The result Is a difference of 3 or d orders of magnitude. The estimates which yield the higher allowable exposures are in better agreement with humen experience than are those of the other group. , Additional Data AH of the extrapolations reported here have used for the original Haltonl data from his experiment BT-1. He has now reported (Naltonl, 1979) three other comparable inhalation experiments on the same strain of rats, and mm on another strain, In Addition to two Ingestion studies. The results of these experiments ar* shown in Figure l, on a log-probit scale. It can be seen that they all follow a similar pattern, but that there are large variations in slope between the various data groups. Table III contains the log-probit equations calculated from some of the individual experiments, and various groups *f experiments. Excellent fits are obtained for a single experiment, as would bo expected from the small number of data paints, but adequate fits are obtained for the group as a whole. Inclusien of the historic control data on ASL (0.09* spontaneous Incidence) did not afreet the fit substantially, except for the very low dose data. Inclusion of the 0,0 (origin) as a data point did give significantly poorer fits. The Cort>ined experiments indicate that a lifetime risk of t0~* for rats Is obtained from a dese In the 1-2 ppb range. Similar variation Is seen with the other mathematical expressions, such as linear er exponential equations. 82-9.2 10 82- Rcgulatory Status The current regulatory status of vinyl chloride is summarized in Table 11. The first regulatory action on VC was taken in 1973 when the Bureau of Tax, Alcohol and Firearms prohibited the use of rigid PVC as liquor containers. This was based on It being present as an adulterant, and not on any consideration of risk. The Consumer Product Safety Commission (CPSC), the Food and Orug Administration, (FDA), and the EPA all acted to ban the use of VC as an aerosol propellant thus establishing a zero risk position. The FDA proposed (FDA, 1975) to withdraw the prior sanction status of rigid PVC as food package component because or the concern for residual VC that might migrate. The FDA has taken no further action on this proposal, and now is considering a "constituent" policy which would permit a lifetime exposure at some gcceptable risk level. This risk has been proposed recently to be 10 * lifetime for the gluttonous consumer. As was discussed above, the EPA required a best available technology approach which reduces the average exposure to those within 5 miles of a plant to.about 0.2 ppb, by EPA estimates. OSHA established a rule In 1974 which set 1 ppm for B hoars as the maximum permissible exposure, and also set 0.9 ppm as an action level below which most features of the regulation did not apply. These were chosen as feasible levels, and not necessarily "$afec dases (OSHA, 1974; EPA, 1976). The EPA has established an exposure to the general population only 0.1* of that allowed In the workplace. The CPSC has required zero exposure, and the FOA has considered that approach. Depending on which method of estimation the FOA may choose, its allowable exposure could be either greater ar less than those currently set by EPA aud OSHA. It has been estimated that the maximum amount of VC Ingested by the average European, who uses much morn plastic packaging than we, is !e}t than j. g/Oay. (CEF1C, 1976) which would be in the order of a 10. or 10 * lifetime risk by even the most conservative models. There have been various estimates awde of the cost-effectiveness of the Federal regulation far vinyl chloride, firaham and Vaupel (1961) estimated that the OSHA rule cost $7.5 million per life saved, and $490 thousand per life-year saved over the option of leaving the exposure limit et SB ppm. Luken and Miller (1981) state that the imputed value of a life from the OSHA standard is $4 million. Morrell (1982) uses an annual cost of $20 million and an annual benefit of 0.1 life saved te derive e cest/benefit of $200 pillion per life for the OSHA rale. The EPA has reported (EPA, 1979) that the cost of coapl1ance with its VC standard was $296 million through July 7, 1961, and will be an additional $470 million during the next five years, all In 1977 dollars. If the EPA estimate of up to 20 dealths per year were correct, this would be a cost of $4.7 million per life. However, as discussed her*, there Is no evidence that any lives have been seved by this rale. There are many difficulties In obtaining accurate estimates of this type, and serious problems in determining the proper value to be assigned to a life, nevertheless, the doubtful nature of the claims 11 AP00023062 far any significant benefit Iron that# ruin iuggtiU that at best, these regulations are excessively costly to society. Therefore, we auat atteapt to iuprove both our data basa and our Methods for inter preting and applying the data. Discussion What can be learned fron this exercise other than the already recognized fact that various extrapolation aadels can yield very different results? In ttils case, at least, there are several points which are worth considering. 1. Vinyl ehtorlde Is no exception to the rule that hunn data always oust be incorporated whenever possible. The epideolc of occupa tionally induced ASl which was feared In 1974 has not Materialized, probably duo to the stops that were take* in the early 1980's to reduce exposure because of the discovery of AOL. Ho Instances of ASL fraa exposure to VC in the general population have been substantiated. The overprediction or occupational cases was duo to the (mderestloatlon of worker exposure and overreliance on raw aninal data without proper phamacokinetic adjustment. We are not now able to extrapolate reliably between sinilar species and certainly not fraa rodents to humans, without ouch additional data. 2. The regulations for vinyl chldride were not based prinarily on scientific data, but on socioccononic and political decisions. This is no surprise (Crandall and Lave, 1981), but is a fact which should be acknowledged dpenly, along with the understanding that this position will continue to penalize good science. 3. Mathematical extrapolation Models are net adequate ia thenselvas for predictions of risks Much beyond the experiaental range, no natter how good the fit Is to the data in the observed range. The variability of relotively snail experiaental groups odds to the error range. Thus, bioassays intended for quantitative risk assessment applications should be at as low doses as possible, and as large as possible, end should be interpreted very cau tiously. 4. The current state of the art Is Such that quantitative risk assessments may be useful for determiniog relative risks from similarly acting carcinogens, but are not suitable for acrossthe-board application to all Mechanism of carcinogenesis. This Is not tn say that we shduld abandeo efforts at developing more effective risk assessment Methods. We must, however, recognize the problems Inherent in blind application of Mathematical Models without proper assessaent of the available biochemical data, or an understanding of how applicable the experimental data are to humans. 82-*,2 12 Wo havo available to us at least as auch data regarding vinyl chloride . wo have for any other substance, and wo still have difficulty Ifi deriving a suitable expression for risk from purely aathematlcol or statistical basis. Only when hunan relevance is considered can we arrive at a prediction that approximates actual experience. 82-9. The regulators are faced with tremendously difficult task when they are presented with a few pieces of animal data which suggest the need for concern and potential regulation. We must develop o suitable program to obtain and use as much relevant data as possible to assure that rational regulations are possible. The vinyl chloride experience can help us understand the kind of data which are needed. 3785-AI 2/19/82 >bh 13 AP00023063 References Albert. I. letter to It. S. Naveen, EM, `Covertson of vinyl chloride carcinogenic ricks with risk from other pollutants". Washingtoo* DC, 16 June 1976. Anderson, H. .. t al., Tuc tool. Pham. S5, 154 (I960). Baxter, P. J., and A. J. Fox, lancet. 1976 245. Carlborg, f. W., fd. Cosnet. Tom. 19 255 (1981). CEFIC Ceenittee lor the Toxicity of Vinyl Chloride, "Vinyl Chloride Toxicity and the use of PVC for Packaging Foodstuffs," Brussels, Feb. 1976. Chiazte, L., X Qccuo. Hod. 22 (10) 677 (1960). Chiatte, L., Jr., W. E. NlchoU, and 0. Wong, X OccUP. Med.. 19 623 (1977). Crandall, R. W.. and L. Lave, "The Scientific Basis of Health and Safety Regulations," Brookings Institution, Washington, 1961. Crump, K. S., and H. A. 6ue$s, "Drinking Water and Cancer", PB61-126167, Deceeber, I960. Crimp, 6. S., H. A. Guess, and *- L. Deal, Bloeetries. 33 4370451 (1977). Duck. B. W,, J. T. Carter, and E. J. Ceoebes, Lancet 1975 1i, 1197. Edmonds, L.. "Birth Defects and Vinyl Chloride". Prof- Conference on Uaeen and the Wnrkolace. Washington. DC, 1976. alsoleratology, 17T37 IT575)t------------------- Edmnds, L. 0., H. Folk and J. E. Nissla, The lancet 1975 1098. Environmental Protection Agency, SUndard for Vinyl Chloride, 41 led,. Rea. 46.560 (1976). Environmntal Protection Agency "Vinyl Chloride, Anient Water Quality Criteria", PS-292446, Washington, DC, 1979. Environmental Protection Agency "Aohlent Water Quality Criteria for Vinyl Chloride," EPA 440/5-60-078, October. 1960. Envlrnonental Protection Agency "The Cost of Clean Air and Clean Water", Annual Report to the Congress, December, 1979b. Senate Document No. 96-36. U.S. Government Printing Office, Washington, DC. 82-9.2 14 Equitable Environmntal Health, Inc., "Epidemiological Study of Vinyl Chloride Workers, Final Report". Prepared for Manufacturing Chemists Assoc., Washington, DC, January, 1978. Food and Drug Adainistratlon, Notice of proposed rulemaking, 40 Fed. Bog., 40,529 (1975). ------ Food Safety Council Final Report "Proposed System for Food Safety Assessment", Washington, 0C, June, 1960. Food Safety Council, Scientific Committee "Proposed System for Food Safety Assessment." Food and Cotmei. To*. 16 Suppl. 2 December 1976. Fox, A. J., and P. F. Collier, Bi\ jh Ind, Med. 34 1 (1977). Frentzel-Beyme, R., T. Schmitz, and A. N. Thfess. Art. Soclalmed. Pravent.. 13 216 (1976). ------------------------ Gaylor, 0. If., and R. L. Kodel). B. L.. J. Environ. Pathol. Tox. 4 305 (1980). ------------------------------------------ Gening, P. J-. and G. E. Blau, J. Environ. Pathol. Toxicol. 1 163 Gehring, P. J., P. G. Watanabe, and C. N. Park. Tox. and Appl. Pham. 49 15 (1979). ---------------------------------- Gehring, P. J.. et al., Tox. Appl, Pharmacol. 44 561 (1978). Graham, J. 0., and J. W. Vaupel, Bisk Analysis 1 69 (1981). Graniger, R. G., A. E. Walker, and A. N. Ward "Vinyl Chloride Monomer-induced Disease: Clinical, Radiological and Immunological Aspects," Chapter 11 in "Induced Disease; Drug, Irradiation, Occupation", L. Preger, ed., Crum and Strattan, London, I960. Hanstoene, l.-L., et al., Hut. Res. 78 211 (1978). Hehir, R. 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B2--9.2 16 FIGURE 1 GRAPHICAL REPRESENTATION OF TABLE III LOG-PROBIT PLOT 2-5.2 LEGEND INHALATIO) PT-1 T-2 nt-p ar6 O -A o -B- INGESTION ST-11 BT-27 #- AP00023065 TABLE I SUMMARY OF QUANTITATIVE RISK ASSESSMENTS FOR VC Bi-9.2 3T1MATE NO. AUTHOR 1 SCHNEIDERMAN. 1978 2 KUSMACK ft McGAOGHY. 1979 3 GEHRING. 1976 BASE SPECIES EXPOSURE FOR Iff4 LIFETIME RISK RAT RAT. HUMAN RAT. HUMAN 73 ppb ItOppfe 2pp6 14 ppb 140-1400 ppb >1 ppm 4 7000 SAFETY COUNCIL, IM RAT 2 XI04 p*0 HEHIR.1B60 RAT. MOUSE THRESMOLOSSEEN IN BOTH SPECIES 7 ANDERSON, ISM RAT. HUMAN >1 ppm EPA.MM RAT 4 fiG/DAY NAS. 1980 RAT 3 X Iff5 MG/KG/DAY ID GAYLOR A KOOELL. 1960 RAT 0.7 ppb It CRUMPS GUESS, 1980 HUMAN O-Spptt 9.7 jiG/DAY 13 CARL80RG, IM1 14 THIS PAPER RAT RAT HUMAN 0.6pG/DAY J.S X Iff5 ppb >1 ppm COMMENTS LOG-PROMT LOGIT SLOPE - 3.49 LOGIT SLOPE 2.3.1-HIT LINEAR THROUGH ZERO LOG-PROBIT BIOTRANSPORMAL DATA AND LINEAR OR LOG-PROSIT WEI9ULL DNABINOING POOD OH WATER WATER UPPER 97.5% CONFIDENCE LIMIT OF LINEAR MODEL ARMITAGEDOLL MODEL. APPLYING WORKER DATA TO WATER. UPPER 95% CONFIDENCE LIMITS WIEBULL NEGATIVE EPIDEMIOLOGY i TABLE II REGULATORY STATUS OF VINYL CHLORIDE AP0002J066 > Oo CQ < htk. UJ I> o UI a o< AC 111 h* -I 3 Q < Y (/> CC a: ui N a< o o o2 0(C UI J CD < <> < h 10 UI CD m U<i ChO* Ui PE UI -J 1F o CD CC o 3 o _J Ui < o 3 o o cc a. a: UI S 3 in z o <J z O Z 6 < X o < a. Q o o u. oa CL a in o 2 A a. a 3 2 Cl X d< >5 -I UJ g-J 1- < 2 cc ui a UJ z z a UI Z Z CC o UJ UJ x o nDC X -1 CO Z e2 a. h- < < V) 3 a. QO CD CQ 30 < r- < u. <oa Ou0.i o < o u_ < < a. Xto UI O I I TABLE III EQUATIONS FOR CURVES FITTED TO VARIOUS SINGLE AND COMBINED MALTONI EXPERIMENTS EXPERIMENT BT-1 PLUS CONTROLS BT-2 PLUS CONTROLS 8T-15 PLUSCONTROLS ALL INHALATION STUDIES (4) PLUS CONTROLS ALL INGESTION STUDIES (21 PLUS CONTROLS ALL STUDIES (} PLUS CONTROLS ALL STUDIES; LOW DOSES ONLY PLUSCONTROLS LINEAR V>ax * b a br 0.26 0.27 3.05 1.52 6.5 6.28 0.26 0.27 1.76 1.74 0.29 0.29 3.36 2.47 8 59 T.13 1.06 0.30 3.07 2.60 0.16 0.20 3.60 3.41 0.97 0.97 1.0 o.ss t.o 0.95 0.91 0.91 0.96 0.95 0.73 0.72 1.03 0.97 0.79 LOG PROSIT IN POSE b a bi 0.35 2.76 0.99 1.60 0.88 1.0 0.69 3.46 ia 0.27 2.98 0.82 0.30 3.22 0.88 0.27 3.05 0.82 0.51 0.17 2.83 2.71 0.75 0.49 CONCENTRATION AT 10" RISK, ILOG RROBIT). ppm 003 23 0.34 0.002 0.002 0.001 0.42 0.0002 J V e-ra AP00023067 B **d. I *1PI3 yUMM ptm `fiWIHt MfO . t*l**tJWW9 y *fWwWrMHdi Aul*4iwi|jydiiwn m ni^eM ** ma mq 1|pj rn QN y U>*^ ^J0| tow < - m M >"< wi^ V. 'JHMiaM-WWV m am awn is to ^IF4 it-rX...*...X.....2....m......3....t. t. 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K to* y*TOj *M y mm* p to awnnay wpuwwih inw wm*tToOimww*iiit>a>ili*tton ow *uju.4A*N*a j33ueo,j3/\!| DUjpuy. ui 8|qej|3j ]sai M8M CV m 'iS^rr AVa63NOM'TTVOSI^3Hl ri. ' 1? />yC, AP00025068 r!S