Document OEkvjjG06JwwzgaVdwy2QKqBv

7W toxicology and applied pharmacology 49, 15--2K(1979) ,.d. - of p ' _'S Risk of Angiosarcoma in Workers Exposed to Vinyl Chloride ;vo- h[. as Predicted from Studies in Rats INC, P. J. Gehring, P. G. Watanabe, and C. N. Park 1 of '(.OlS Toxicology Research Laboratory, Health and Environmental Research, and / J1* Computations Research Laboratory, Dow Chemical U.S.A., Midland, Michigan 48640 Received June 1,1978; accepted December 2, 1978 Risk of Angiosarcoma in Workers Exposed to Vinyl Chloride as Predicted from Studies in Rats. Gehring, P. J., Watanabe, P. G., and Park, C. N. (1979). Toxicol. Appt, 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 = l--e~t", where x = dose, do not appear as reliable. For an 8-hr day, 5 days/week, 35-year time-weightedaverage exposure of 1 ppm, the predicted incidence of hepatic angiosarcoma using the probit model is 1.5 x 10-*. Exposure of rats (Maltoni and Lefemine, 1975) and humans (Creech and Johnson, 1974; Tabershaw and GafFey, 1974; Makk et ah, 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 ah, 1975; Barbin et ah, 1975; Kappus et ah, 1976; Malavielle et ah, 1975; Bolt et ah, 1975; Watanabe et ah, 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 ah (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= VmS/(Km + S) (1) -1.625+1.543 Log o. (2) (Watanabe et ah, 1976a,b,c; Bolt et ah, Hypothesizing that the biotransformation 1976). In this equation, v and are velocity of VC is related directly to body surface area, 15 . OWI-008X/79,070015-07502.00/0 Copyright 1979 by Academic Press, Inc. AH rights or reproduction in any form reserved. Printed in Great Britain SL 101986 VINYL CHLORIDE--RISK ASSESSMENT a 17 TABLE 1 Predicted Incidence of Angiosarcoma in Rats Exposed to Vinyl Chloride Using mVarious Models Versus Dose (v, VC Metabolized per day) Compared to Experimental Results Exposure* Dose* Experimental* Predicted percentage (Models)1 of (ppm) O'. Rg/day) (%) A B CD ro- a is 10,000 5521 14.8 (9/61) 19.8 20.0 19.7 18.9 cm: 6,000 5403 21.7(13/60) 19.3 20.5 19.3 18.6 2,500 5030 22.0(13/59) 17.9 18.1 17.9 17.4 500 3413 . 11.9(7/59) 12.1 11.8 12.2 12.2 250 2435 6.8 (4/59) 8.1 8.0 8.7 8.8 50 739 1.7 (1/59) 1.4 ' 1.4 2.6 2.8 * From Maltoni and Lefemine (1975). `Calculated from v = [5706 (pg VC/4 hr)-S0/g/liter)]/[860(//g/liter)+5(//g/liter)J, where S = 2.56 0<g/ppm/liter) x exposure (ppm) (Gehring et at., 1978). 'Model A, Probit %= -1.625+1.543 Log (dose); Model B, % = -1.48 +0.389 x 10-1 (dose); Model C, % = 0.3565 x 10-1 (dose); Model D, % = [l--*"-->] joo, where p - 0.38 x 10~*. RESULTS AND DISCUSSION 5 days/week adjusted for the fraction of their working life during which exposure occurred. The incidence of hepatic angiosarcoma in The doses, v, are expressed as micrograms subgroups of 9677 workmen with respect to per 8 hr and were calculated from Eq. 3 their duration of exposure are given in (given under Introduction) multiplied by the v.; c Table 2. These workers include 95.1 % of the fraction of an assumed 35-year working life 10,173 in the cohort study; the remainder during which exposure occurred. could not be traced. Having estimated the rat equivalent daily The atmospheric concentrations of vinyl doses of biotransformation products of VC chloride to which these workers had been received by the various subgroups of 9677 exposed were not quantitated, except sub workmen exposed to a TWA of 200 or r-1, jectively into high, medium, and low cate 500 ppm VC, the predicted incidence of tne gories. Since the time-weighted-average hepatic angiosarcoma for each subgroup was of (TWA) exposure recommended by the Ameri calculated (Table 4). Examination of the m can Conference of Governmental Industrial data in this table indicates that Models C and of Hygienists (ACGIH) prior to 1972 was 500 D overestimate the incidence of hepatic | 01 ppm and subsequently 200 ppm until adop angiosarcoma experienced by these workers tion of the Occupational Safety and Health while Model B underestimates the incidences. Act standard of less than 1 ppm in 1974, it is Models C and D may overpredict because assumed that even those exposures sub they do not address either the enzymatic f.i! jectively deemed low were high. Indeed, it is biotransformation of VC or repair of the reasonable to expect the TWA exposures of lesion leading to development of angio 200 ppm and greater for 8 hr were common sarcoma, both of which are likely to be dis rather than the exceptions. tributed normally in human or animal Table 3 depicts the average theoretical populations. rat equivalent daily doses of biotransforma It may be argued that Models C and D tion products of VC received by workers overpredict because the recommended TWA exposed to 200 or 500 ppm for 8 hr daily, exposure values of 200 or 500 ppm VC are SL 101987 <*. r V 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)* Angiosarcomas Population observed 4384 2339 946 1007 677 324 Total 9677 1 0 2 2 0 0 5 A 500* 200 0.2 0.0 2.4 0.8 3.0 1.1 6.8 2.7 7.3 3.0 4.9 2.1 25 10 B 500 200 00 00 00 4.0 0 6.6 0.3 4.9 1.3 16 2 C 500 200 9.4 5.9 16.7 10.4 11.5 7.2 17.6 11.0 15.2 9.5 8.9 5.6 79 50 D 500 200 10.0 6.3 17.7 11.1 12.1 7.6 18.6 11.7 16.0 10.1 9.4 5.9 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"1 (dose); Model C, % = 0.3565 x 10-1 (dose); Model D, % *= [1 _*-/>">] 100 where fi = 0.38x 10~*. The constants in these models were obtained using the biotransformation and angiosarcoma incidence data for rats exposed to vinyl chloride (Gehring tt at., 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 SL 101988 VINYL CHLORIDE--RISK ASSESSMENT 21 Maltont, C., and Lefemine, G. (1975). Carcino genicity assays of vinyl chloride: Current results. Ann. N. Y. Acad. Sci. 246, 195-224. Tabershaw, I. R,, and Gaffey, W. R. (1974), Mortality study of workers in the manufacture of vinyl chloride and its polymers. /. Occup. Med. 16, 509-518. Watanabe, P. G., McGowan, G, R., Madrid, E. O., and Gehrinc, P. J. (1976a). Fate of [`CJvinyl chloride following inhalation exposure in rats. Toxicol. Appl. Pharmacol. 37, 49-59. Watanabe, P. G., McGowan, G. R., and Gehring, P. J. (1976b), Fate of [l4C]viny! chloride after single oral administration in rats. Toxicol. Appl. Pharmacol. 36, 339-352. Watanabe, P. G., Hefner, R. E,, Jr., and Gehring, P. J. (1976c). Vinyl chloride induced depression of hepatic nonprotcin sulfhydryl content and effects on bromosulphthalein (BSP) clearance in rats. Toxicology 6, 1-8. Watanabe, P. G,, Zempel, J. H,, Pegg, D. G., and Gehring, P. J. (1978). Hepatic macromolecular binding following exposure to vinyl chloride. Toxi col. Appl. Pharmacol. 44, 571-579.