Document 1gGXoR0ryeRRMObnz60Gn39Mm

P. J. Gehring, P. G. Watanabe, and C. N. Park Toxicology Research Laboratory, Health and Environmental Research, and Computations Research Laboratory, Dow Chemical U.S.A,, Midland, Michigan 48640 Received June 1, 1978; accepted December 2, 1978 Risk of Angiosarcoma m workers Exposed to Vinyl Chloride as Predicted from Studies in Rats. Gehring, P. J., Watanabe, P. G., and Park, C. N. (1979). Toxicol. Appl. Phar macol. 49, 15-21. Dose-response data for the induction of angiosarcoma in rats exposed to various levels of vinyl chloride (VC) together with attendant biotransformation data were used to estimate the risk of developing angiosarcoma in persons exposed to VC. Since a biotransformation product of VC, not VC per se, is responsible for the induction of angiosarcoma, the body surface area of people relative to rats was used to estimate the dose of the carcinogen biotransformed from VC by the former. Four models were used to extrapolate the data. Using a probit model, 10 hepatic angiosarcomas were pre dicted to occur in a recently reported epidemiological cohort of 9677 workers whereas five have occurred. Linear models and that based on the equation. Risk = I where x ** dose, do not appear as reliable. For an 8-hr day, 5 days/week, 35-year time-weighted- average exposure of 1 ppm, the predicted incidence of hepatic angiosarcoma using the probit model is 1.5 x 10~*. 1. cm. iPfV Exposure of rats (Maltoni and Lefemine, 1975) and humans (Creech and Johnson, 1974; Tabershaw and Gaffey, 1974; Makk et ai, 1976; Fox and Collier, 1977) to vinyl chloride (VC) has been associated with the development of hepatic angiosarcoma. Nu merous studies in rats indicate that it is not VC per se which is responsible for production of angiosarcoma but rather a reactive meta bolite formed from it in the body (Bartsch et ai, 1975; Barbin et a!., 1975; Kappus et al., 1976; Malavielle et al., 1975; Bolt et ai, 1975; Watanabe et ai, 1978). Biotransfor mation of VC in rats is a nonlinear process occurring in accordance with MichaelisMenten kinetics: and maximum velocity, respectively, for the biotransformation of VC expressed as micro gram equivalents VC metabolized daily. S and Km are the concentration of VC being inhaled and the Michaelis constant expressed as micrograms of VC per liter of air, res pectively. Utilizing the foregoing information, Gehring et ai (1978) revealed a good corre lation between the probit percentage inci dence of angiosarcoma in rats exposed to varying concentrations of VC, 4 hr daily, and the amount of vinyl chloride biotransformed, v, microgram equivalents VC metabolized per day. The probit equation is: Probit percentage incidence -- v- VB,Sf(Km + S) (1) -1.625+1.543 Log v. (2) (Watanabe et ai, 1976a,b,c; Bolt et ai, Hypothesizing that the biotransformation 1976) . In this equation, v and Vm are velocity of VC is related directly to body surface area, (XMI-008X/79/070013-07S02.00/0 Copyright C 1979 by Academic Press, Inc. All rights of reproduction in any form reserved. Printed in Great Britain Gehring et al. (1978) determined that the amount of VC transformed to a reactive form by man on a mass equivalent basis to rat is: K^g/8 hr = 1675 /rg/hr S //g/liter 860 |ig/liter + S /rg/liter' (3) Utilizing this relationship together with the foregoing probit equation, it was deter mined that incidence of hepatic angiosarcoma in workers exposed to 200 ppm should be approximately 1%. This incidence is 50-fold higher than that experienced (Fox and Collier, 1977). Various plausible explana tions were put forth to explain this difference including greater sensitivity of rats and in creasing latency for development as v decreases. One plausible explanation not mentioned was that in worker populations studied todate, many were exposed for only fractions of their working life. Furthermore, for some, the duration since initial exposure was likely insufficient for development of clinically detectable disease. Recently available is a comprehensive epidemiological study1 entitled, "Epidemio logical Study of Vinyl Chloride Workers, Final Report." In this study, reasonably detailed information on 10,173 workers has been obtained for duration of exposure and lapsed time since first exposure. Thus, much better information is available now to assess the reliability of the model proposed by Gehring et al. (1978) for pre dicting the incidence of hepatic angiosarcoma in humans utilizing data collected in rats. This assessment is reported here. In ad dition, three other models for estimating the incidence have been used for comparison of their reliability for predicting the incidence being experienced by workers exposed to vinyl chloride. METHODS Four mathematical models were selected to analyze their reliability for calculating the incidence of hepatic angiosarcoma in rats as function of micro gram equivalents of VC metabolized daily by rats exposed 4 hr/day, 5 days/week for 1 year. These models were as follows: (A) Probit % Probit % = a+WLogc) = --1.625+ l.543(Logi>). (B) Linear % * a + 6(v) -1.48 + 0.389 x 10~2(t0. (C> Linear forced through origin % = bu - 0.3565 x 10-J(r). (D) One-hit model (Cancer Assessment Group, National Cancer Institute) %= - {l-exp(-0.38x 10-4xr)]l00. The constants given for the preceding models were determined by linear regression analysis and rep resent the best fit of the data for the incidence of hepatic angiosarcoma versus the amount of VC metabolized daily in rats exposed to different con centrations of VC (Gehring et al., 1978). The data used to derive the constants are given in Table I. Using the equations derived for the models, the predicted incidence of angiosarcoma for the groups of rats exposed to different concentrations of VC were calculated. These results are shown also in Table I. All four models overpredict the incidence of hepatic angiosarcoma in rats exposed to 10,000 ppm VC. This is as expected because this exposure resulted in excessive mortality unrelated to development of angiosarcoma. With respect to the predicted versus experimental incidence of hepatic angiosarcoma experienced by groups of rats exposed to the remaining concentra tions of VC, none of the four models is unequivocally more reliable than any other. Thus, any one of the four models represents adequately the experimental data. Since no clear preference is discernible, all four models will be used to predict the incidence of hepatic angiosarcoma experienced or to be experienced by workers exposed to VC. URL 19099 VINYL CHLORIDE--RISK ASSESSMENT 17 TABLE 1 Predicted Incidence of Angiosarcoma in Rats Exposed to Vinyl Chloride Using Various Models Versus Dose (v, tig VC Metabolized per day) Compared to Experimental Results Exposure* (ppm) 10,000 6,000 2,500 500 250 so Dose* {v, /ig/day) 5521 5403 5030 3413 2435 739 Experimental* (%) 14.8 (9/61) 21.7 (13/60) 22.0(13/59) . 11.9(7/59) 6.8 (4/59) 1.7 (1/59) Predicted percentage (Models)' A B CD 19.8 20.0 19.7 18.9 19.3 20.5 19.3 18.6 17.9 18.1 17.9 17.4 12.1 11.8 12.2 12.2 8.1 8.0 8.7 8.8 1.4 1.4 2.6 2.8 * From Maltoni and Lefemine (1975). * Calculated from e * {5706 (tig VC/4 hr)-S(/g/liter)J/[8600/g/liter) + S0*g/Hter)], where 5 = 2.56 G/g/ppm/liter) x exposure (ppm) (Gehring et at., 1978). `Model A, Probit %= --1.625+1.543 Log (dose); Model B, % ** -- I.48 + 0.389x JO-* (dose); Model C, % - 0.3565 x I0-* (dose); Model D, % - [l _-#">] 100. where p = 0.38 x!0-\ RESULTS AND DISCUSSION The incidence of hepatic angiosarcoma in subgroups of 9677 workmen with respect to their duration of exposure are given in Table 2. These workers include 95.1 % of the 10,173 in the cohort study; the remainder could not be traced. The atmospheric concentrations of vinyl chloride to which these workers had been exposed were not quantitated, except sub jectively into high, medium, and low cate gories. Since the time-weighted-average (TWA) exposure recommended by the Ameri can Conference of Governmental Industrial Hygienists (ACG1H) prior to 1972 was 500 ppm and subsequently 200 ppm until adop tion of the Occupational Safety and Health Act standard of less than 1 ppm in 1974, it is assumed that even those exposures sub jectively deemed low were high: Indeed, it is reasonable to expect the TWA exposures of 200 ppm and greater for 8 hr were common rather than the exceptions. Table 3 depicts the average theoretical rat equivalent daily doses of biotransforma tion products of VC received by workers exposed to 200 or 500 ppm for 8 hr daily. 5 days/week adjusted for the fraction of their working life during which exposure occurred. The doses, v, are expressed as micrograms per 8 hr and were calculated from Eq. 3 (given under Introduction) multiplied by the fraction of an assumed 35-year working life during which exposure occurred. Having estimated the rat equivalent daily doses of biotransformation products of VC received by the various subgroups of 9677 workmen exposed to a TWA of 200 or 500 ppm VC, the predicted incidence of hepatic angiosarcoma for each subgroup was calculated (Table 4). Examination of the data in this table indicates that Models C and D overestimate the incidence of hepatic angiosarcoma experienced by these workers while Model B underestimates the incidences. Models C and D may overpredict because they do not address either the enzymatic biotransformation of VC or repair of the lesion leading to development of angio sarcoma, both of which are likely to be dis tributed normally in human or animal populations. It may be argued that Models C and D overpredict because the recommended TWA exposure values of 200 or 500 ppm VC are 18 GEHRING, WATANABE, AND PARK TABLE 2 Incidence op Angiosarcoma in 9677 Workmen Exposed to Vinyl Chloride* Population Duration of exposure (years) Mean exposure duration (years)* Fraction of working life* Observed angiosarcomas 4384 (0.31)' 2339 (0.27) 946 (0.58) 1007(1.0) 677 (1.0) 324 (t.O Total 9677 <4 5-9 10-14 15-19 20-24 25 + 2 7 12 17 22 27 0.06 0.20 0.34 0.49 0.63 0.77 1 (18 years)* 0 2 (15 and 23 years) 2 (18 and 19 years) 0 0 * From "Epidemiological Study of Vinyl Chloride Workers", Final Report January 1978, prepared by Equitable Environmental Health, Inc., Rockville, Md., for Manufacturing Chemists' Association, Washington, D.C. * Assumed mean duration of exposure. * Mean duration of exposure divided by 35 years. * Fraction of population incurring first exposure 15 or more years prior to study. * Duration between first exposure and diagnosis. higher than those actually incurred by workers included in the epidemiological study. Undoubtedly, some were exposed to smaller levels. Many were reported exposed to much higher levels; in some cases at or above the odor threshold of approximately 3500 ppm. Unfortunately, in the absence of TABLE 3 Average Theoretical Rat Equivalent Daily Doses of Biotransformahon Products Received by a 70*kg Human Exposed to 200 or 500 ppm Vinyl Chloride for Various Fractions of an Assumed 35-year Workino Life Mean exposure duration (years) Fraction of working . lire v, micrograms per 8 hr averaged over 35 hr* 500* 200 2 0.06 60 7 0.20 200 12 0.34 341 17 0.49 491 22 0.63 631 27 0.77 771 38 125 213 306 394 481 * v = [1675 //g/8 hr-5 ^g/litcr]/[860 //g/liter + 5 n%l liter] x (fraction of working life). * Parts per million. analytically determined exposure levels, ap proximations of the actual TWA values must be used. For a TWA exposure of 100 ppm VC, the predicted number of workers de veloping angiosarcoma in this epidemiological cohort are 4, 0, 30, and 32 for mathematical Models A, B, C, and D, respectively. For a 50-ppm TWA, the corresponding numbers are 1, 0, !7, and 18. Thus, utilizing values for TWA exposures which are thought to underestimate the actual exposures appear to overpredict still the number of workers developing angiosarcoma of the liver when mathematical Models C and D are used, albeit Model A apparently underpredicts when a TWA exposure of 50 ppm is used. When a TWA of 200 ppm is utilized to represent the atmospheric concentration to which these workers were exposed, the pre dicted incidence of angiosarcoma of 10 cases using Model A compares favorably with that experienced, five cases. For a significant number of workers, the time elapsed since initial exposure has yet to reach 15 years, the shortest time needed for development of angiosarcoma in 1 of 5 of the afflicted workers (Table 2). Thus, it may be \ i J i 33 O i I Pop 4 2 i Total $ *o Repo Chen *fv %= mode chlor. *P antic hepa popt of ci not i A; the p expe of h work serve biotr by h extra T! perc reve. rats hep? able mod tion VINYL CHLORIDE--RISK ASSESSMENT 19 TABLE 4 Predicted Number of Angiosarcomas in Workers Exposed to 500 or 200 ppm Vinyl Chloride 8 HR/DAY, 5 DAYS/WEEK FOR VARIOUS FRACTIONS OF A 35-YEAR WORKING LIFE VERSUS THE NUMBERS Observed Using Biotransformation and Angiosarcoma Incidence Data from Rats and Four models for Extrapolation* Angiosarcomas predicted (Models)11 Angiosarcomas Population observed A 500* 200 B 500 200 C 500 200 D 500 200 4384 2339 946 1007 677 324 Total 9677 1 0.2 0.0 0 0 9.4 5.9 10.0 6.3 0 2.4 0.8 0 0 16.7 10.4 17.7 11.1 2 3.0 1.1 0 0 11.5 7.2 12.1 7.6 2 6.8 2.7 4.0 0 17.6 11.0 18.6 11.7 0 7.3 3.0 6.6 0.3 15.2 9.5 16.0 10.1 0 4.9 2.1 4.9 1.3 8.9 5.6 9.4 5.9 5 25 10 16 2 79 50 84 53 * Observed number of angiosarcomas from "Epidemiological Study of Vinyl Chloride Workers," Final Report January 1978, prepared by Equitable Environmental Health Inc., Rockville, Md., for Manufacturing Chemists Association, Washington, D.C. * Model A, Probit %= --1.625 + 1.543 Log (dose); Model B, %= --1.48 + 0.389 x 10-J (dose); Model C, % 0.3565 x 10-s (dose); Model D, % [1 100 where fi = 0.38 x !0-. The constants in these models were obtained using the biotransformation and angiosarcoma incidence data for rats exposed to vinyl chloride (Gehring et al., 1978). * Parts per million. anticipated that a few additional cases of hepatic angiosarcoma will occur in this population. It is comforting that an epidemic of cases, as has been envisioned by some, is not to be anticipated. As indicated in the beginning of the paper, the previous attempt to extrapolate data from experiments in rats to predict the occurrence of hepatic angiosarcoma in vinyl chloride workers appeared to overpredict the ob served incidence even when differences in the biotransformation of VC to active products by humans and rats were incorporated in the extrapolation. The foregoing analysis using a probit percentage incidence model (Model A) has revealed that data collected in experiments on rats may be used to predict the incidence of hepatic angiosarcoma in humans with reason able accuracy. Further verification of this model will be assisted greatly by determina tion of the rate of biotransformation of VC by humans exposed to sufficient concentra tions of VC to allow such measurement. Currently, this must be estimated by the rate of biotransformation in rats and its assumed relationship to body surface area (Gehring et al., 1978). Nonetheless, the correlation between predicted and observed incidence of hepatic angiosarcoma in vinyl chloride workers seems to justify both the assumptions and the model (Model A, Probit %) used to make the predictions. Since the predicted incidence of hepatic angiosarcoma in humans using results from studies in rats appears justifiable, it is of interest to use the same procedures to esti mate the incidence in workers exposed to 1 ppm 8 hr/day for a 35-year working life, the upper limit of the current Occupational Safety and Health Act standard. These predictions are shown in Table 5 for all four models. Models C and D predict an incidence 20 GEHR1NG, WATANABE, AND PARK TABLE 5 Predicted Incidence of Angiosarcoma in Workers Exposed to 1 ppm Vinyl Chloride 8 hr/day, 5 days/week for 35 years Using Biotransformation and Angiosarcoma Incidence Data from Studies in Rats* estimate, reliably, the risk of developing angiosarcoma in persons exposed to VC. There is every reason to believe that similar data can and should be used in the assess ment of risk of exposure to specified levels of other substances. (A) Probit % or logarithm probability 1.5 x IO-6% or 1.5/100,000,000 (B) Linear not forced through origin None predicted below exposures of 98.7 ppm. (C) Linear forced through origin 1.7 x 10-*% or 1.7/10,000 or 177/1,000,000 (D) One-hit model (CAG) 1.89 x 10_1% or 1.9/10,000 or 189/1,000,000 ' Rat equivalent daily dose of biotransformation products received by workmen exposed for 8 hr to 1 ppm vinyl chloride is: V = (1675 ^g/hr-2.56 *g/JiterJ/[860 //g/Jiter + 2.56 /rg/liter] = 4.97 pg/H hr. comparable to that experienced by workers exposed to much higher levels, again revealing their inadequacy because of overprediction. Model B, although a linear model, predicts zero response at 98.7 ppm VC. Thus, ex posures to levels below this are not predicted to induce hepatic angiosarcoma. Using what appears to be the most reliable model (Model A, Probit %), the predicted inci dence of hepatic angiosarcoma is 1.5 x. !0-`% or 1.5 cases in 100,000,000 workers. It is emphasized that use of Models A, C, and D to predict the incidence of hepatic angiosarcoma in workers exposed to 1 ppm VC assumes no threshold or even an in flection point in the dose-response curve (even though a threshold might occur). In summary, the use of animal data for the assessment of risk in humans exposed to a chemical is not as mystical as frequently assumed. Dose-response data for the in duction of angiosarcoma in rats exposed to various levels of VC together with attendant biotransformation data have been used to REFERENCES Barbin, A., Brsil, H., Croisy, A., Jacquignon, P., Malavielle, C., Montesano, R., and Bartscii, H. (1975). Liver-microsome-mediated Formation of alkylating agents from vinyl bromide and vinyl chloride. Biochem. Biophys. Res. Comm. 67, 596603. Bartsch, H., Malavielle, C., and Montesano, R. (1975). Human, rat, and mouse liver mediated mutagenicity of vinyl chloride in Salmonella lyphimurium strains. Int. J. Cancer 15, 429-437. Bolt, H. M., Kappus, H., Kaufmann, R., Appel, K. E., Buchter, A., and Bolt, W. (1975). Metabolism of wC-vinyl chloride in vitro and in vivo. Inserm 52, 151-164. Bolt, H. M., Kappus, H., Buchter, A., and Bolt, W. (1976). Disposition of (l,2-wC)vinyl chloride in the rats. Arch. Toxicol. 35, 153-162. Creech, J. L., and Johnson, M. N. (1974). Angio sarcoma of liver in the manufacture of polyvinyl chloride. /. Occup. Med. 16, 150-151. Fox, A- L., and Coluer, P. F. (1977). Mortality ex perience of workers exposed to vinyl chloride monomer in the manufacture of polyvinyl chloride in Great Britain. Brit. J. Jnd. Med. 34, 1-10. Gehring, P. J., Watanabe, P. G., and Park, C. N. (1978). Resolution of dose-response toxicity data for chemicals requiring metabolic activation: Example--vinyl chloride. Toxicol. Appl. Pharmacol. 44, 581-591. Kappus, H., Bolt, H. M., Buchter, A., and Bolt, W. (1976). Liver microsomal uptake of [uCjvinyl chloride and transformation to protein alkylating metabolites in vitro. Toxicol. Appl. Pharmacol. 37, 461-471. Makk, L., Delmore, F., Creech, J. L., Ogden, L. L.r Fadell, E. H., Songster, C. L., Clanton, J., Johnson, M. N., and Christopherson, W. H. (1976). Clinical and morphologic effects of hepatic angiosarcoma in vinyl chloride workers. Cancer 37, 149-163. Malavielle, C., Bartsch, H., Barbin, A., Camus, A. M., and Montesano, R. (1975). Mutagenicity of vinyl chloride chloroethyleneoxide, chloroacetaldehyde, and chloroethanol. Biochem. Biophys. Res. Commun. 63, 363-370. URL 19104