Document B54By94ey70dbJd83Eo1k2rjm

VINYL CHLORIDE--RISK ASSESSMENT 17 TABLE 1 Predicted Incidence of Angiosarcoma in Rats Exposed to Vinyl Chloride Using Various Models Versus Dose (u, pg VC Metabolized per day) Compared to Experimental Results Exposure* (ppm) 10,000 6,000 2,300 300 230 30 Dose* (r, /jg/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)* ABCD 19.8 20.0 19,7 18.9 19.3 20.3 19.3 18.6 17.9 18.1 17.9 17.4 12.1 11.8 12J 12.2 8.1 8.0 8.7 8.8 1.4 1.4 2.6 2.8 * From Maltoni and Lefemine (1973). * Calculated from v - [3706(^g VC/4hr)-50<g/liter)]/[8600<s/liter)+S0<g/Uter)], where S -- 2.36 (Af/PPm/litcr)x exposure (ppm) (Gehriog *i at., 1978). * Model A, Probit % - -1.623+1.343 Log (dose); Model B, V, - --1.48 + 0.389 x 10** (dose); Model C, % - 0.3365 x 10-1 (dose); Model D. % - [1-<-*'"*] 100, where ff - 0.38 x 10~*. 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 (ACGIH) 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 YC are A 18 GEHRING, WATANABE, AND PARK TABLE 2 Incidence of Angiosarcoma in 9677 Workmen Exposed to Vinyl Chloride4 Population 4384 (0.31)4 2339 (0.27) 946 (0.58) 1007 (1.0) 677 (1.0) 324(1.0 Total 9677 Duration of exposure (yean) <4 5-9 10-14 15-19 20-24 25 + Mean exposure duration (years)4 ,2 7 12 17 22 27 Fraction of working life* 0.06 0.20 0.34 0.49 0.63 0.77 Observed angiosarcomis 1 (18 years)4 0 2 (15 and 23 yean) 2 (18 and 19 yean) 0 0 * From "Epidemiological Study of Vinyl Chloride Worken", Final Report January 1978, prepared by Equitable Environmental Health, Inc., Rockville, Md., for Manufacturing Chemists' Association, Washington. D.C. 4 Assumed mean duration of exposure. 4 Mean duration of exposure divided by 35 years. 4 Fraction of population incurring first exposure 15 or more years prior to study. 4 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 Biotransformation Products Received by a 70-kg Human Exposed to 200 or 500 ppm Vinyl Chloride for Various Fractions of an Assumed 35-year Worjono Life Mean exposure duration (yean) Fraction e, mkrognm* per 8 hr of averagad over 35 hi4 working . life 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 'em [1675 0g/8 hr-,S i/g/liter1/(860 Ng/liter+S/ig/ liter) x (friction of working Ufa). 4 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, 17, 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 worken 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 worken (Table 2). Thus, it may be Predict 8 HR/DA Obsj Population 4384 2339 946 1007 677 324 Total 9677 4 Observed Report Janua Chemists Asm Model A, % - 0.3565 x models were e chloride (Ceh; 4 Parrs per r anticipated hepatic ang population, of cases, as not to be an As indicat the previous experiments of hepatic ; workers app served incide biotransform by humans a extrapolatior The foreg percentage ii revealed that rats may be hepatic angio able accurac model will b> tion of the r. VINYL CHLORIDE--RISK ASSESSMENT 19 TABLE 4 Predicted Number of Angiosarcomas in Workers Exfosed to 500 or 200 ffm Vinyl Chloride * 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* Population 4384 2339 946 1007 677 324 Total 9677 Angiosarcomas observed 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 Angiosarcomas predicted (Models)* BC 500 200 500 200 00 00 00 4.0 0 6.6 0.3 4.9 1.3 9.4 5.9 16.7 10.4 11.5 7.2 17.6 11.0 15.2 9.5 8.9 5.6 16 2 79 50 D 500 200 10.0 6.3 17.7 11.1 12.1 7.6 18l 11.7 16j0 10.1 9.4 5.9 84 53 * Observed number of engiosRicomas from "Epidemiological Study of Vinyl Chloride Worters," 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, %m - i.48 +0.389 x I0~J (dose); Model C, % " 0.3565 x 10-* (dose); Model D, % > [1 ioo where t " 0.38 x 10~*. The constants in these models were obtained using the biotransformation and angiosarcoma incidence dam for rats expand to vinyl chloride (Gehring it 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 gready 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 el 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 uge 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 GEHRINC, 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 BlOTRANSFORMATION 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 10-*% or 1.5/100,000,000 REFERENCES (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) 1.89x 10-% 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 j<g/hr-2.56 Ng/liter1/(860 ng/liter+2.56 iig/liter] m 4.97 jtg/8 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 10"*% 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 Barbin, A., BrEsil, H,, Croisy, A., Jacquignon, P., Malavielle, C., Montesano, R., and Bartsch, H. (1975). Liver-microsome-mediEtcd formation of alkylating agents from vinyl bromide and vinyl chloride. Bioehem. 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 typhimurium strains, lot. I. Cancer 15, 429-437. Bolt, H. M., Kappus, H., Kaufmann, R., Appel, K. E., Buchter, A, and Bolt, W. (1975), Meta bolism of 14C-vinyl chloride in oitra and in vivo. Imtrm 52, 151-164. Bolt, H. M,, Kappus, H., Buchter. a., and Bolt, W. (1976). Disposition of (l^-,4C)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. J. Occup. Med. 16, 150-151. Fox, A. L., and Collier, P. F. (1977). Mortality ex perience of workers exposed to vinyl chloride monomer in the manufacture of polyvinyl chloride in Great Britain. Brit. J. Ind. 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. Appt. Pharmacol. 44, 581-591. Kappus, H.. Bolt, H. M,, Buchter, A., and Bolt, W. (1976). Liver microsomal uptake of ['*Clvinyl chloride and transformation to protein elkylating metabolites in oitro. Toxicol. Appl. Pharmacol. 37, 461-471. Mark, L., Delmore, F.. Creech, J. L., Ogden, L. L.. 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., Barein, A., Camus, A. M.. AND Montesano, R. (1975). Mutagenicity of vinyl chloride chloroethyleneoxide, chloroacetaldchydc, and chloroethanol. Bioehem. Bio phys. Res. Common. 63, 363-370. Maltdm, C genidty as Ann. N. Y Tabershaw, Mortality vinyl chlo 16. 509-51 Watanabe, E. O., a [>*C]vinyl in rats. To Watanabe, ' sloping o VC. similar jassessivels of Non, P., Iartsch, lation of nd vinyl . #7, 396- Uso, R. ;Nnediated , Himanella 1-437. Arm, . Meta- z> Bolt, loride in Angiololyvinyl tality exchloride . 1 chloride IK. C. N, city data '>. auorr. annacol. 'D Bolt, `CJvinyl ' inflating local. 37, Ogden, l^ston, w. H. f hepatic 1 . Cancer ,, Camus, agenicity chlorotm. Bio- VINYL CHLORIDE--RISK ASSESSMENT 21 Maltoni, C., and Leeemine, G. (1975), Carcino genicity assays of vinyl chloride: Current resuits. Ann. N. Y. Acad. Set. 246, 195-224. Tabershaw, I. R,, and Gaffiy, W. R. (1974). Mortality study of workers in the manufacture of vinyl chloride and its polymers. /. Occup. Med. 16, J09-51S, Watanabe, P. G., McGowan, G. R., Madrid, E. 0,, and Gehrino, P. ]. (1976a). Fate of ["CJvinyl chloride following inhalation exposure in rats. Toxicol. Appl. Pharmacol. 37, 49-59. Watanabe, P. G., McGowan, G. R., and Gehrino, P. J. (1976b). Fate of ["CJviayl chloride after single oral administration in rata. Toxicol. Appl. Pharmacol. 36, 339-332. Watanabe, p, G., Hefner, R. E, Jr^ and Gehrino, P. J. (1976c). Vinyl chloride induced depression of hepatic nonprotein sulfhydryt content and effects on bromosulphthalein (BSP) clearance in rats. Toxicology 6, 1-6. Watanabe, P. G., Zemkl, J. H,, Pigo, D. G,, and Gehrino, P. J. (1978). Hepatic macromolecular binding following exposure to vinyl chloride. Toxi col. Appl. Pharmacol. 44, 371-579. ucc 002874