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TOXICOLOGY AND APPLIED PHARMACOLOGY 49, 15-2/(1979) ,
Risk of Angiosarcoma in Workers Exposed to Vinyl Chloride as Predicted from Studies in Rats
P. J. Gehring, P. G. Watanabe, and C. N. Park
Toxicology Research Laboratory, Health and Environmental Research, and Computations Research Laboratory, Dow Chemical USA., Midland, Michigan 4664)
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 epidemioloc.cal cohort of 9677 workers whereas five have occurred. Linear models and that based c.*. the equation, Risk = 1 --e~f`, where x ** dose, do not appear as reliable. For an S-hr day. J 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 al., 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 al., 1975; Barbin et al., 1975; Kappus et al., 1976; Malavielle et al., 1975; Bolt et al., 1975; Watanabe et al., 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 K,, 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 al. (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, p, microgram equivalents VC metabolized per day. The probit equation is:
Probit percentage incidence =
- VmSKKm + S)
(1)
-1.625+1.543 Log v. (2)
(Watanabe et al., 1976a,b,c; Bolt et al., Hypothesizing that the biotransformation 1976) . In this equation, v and Vm are velocity of VC is related directly to body surface area,
15 0(HI -008X/T/OTOO15-07502,00,0 Copyright 1979 by Acsdcrme Press, Inc.
All righis of reproduction in any form reserved. Printed in Crest Britain
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TABLE I
Predicted Incidence of Angiosarcoma in Rats Exposed to Vinyl Chloride Using Various Models Versus Dose (v, fig VC Metabolized per day) Compared to Experimental Results
Exposure* (ppm)
10,000 6,000 2,500
500 250
50
Dose* (. Ag/day)
Experimental* (%)
5521 5403 5030 , 3413 2435 739
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 12.2 122 8.1 8.0 8.7 8.8 1.4 ` 1.4 2.6 ZS
* From Maltoni and Lefemine (1975). * Calculated from o = [5706 (jjg VC/4hr)-S(;/g/liter)]'[S60(^g/liter)+SO'g/liter)), where S = 2.56 Oig/ppm/liter) x exposure (ppm) (Gehring el a1978). 'Model A, Probit % --1.625+1.543 Log (dose); Model B, % * -- l,48+0.389x I0~J (dose); Model C, % = 0.3565 x io*1 (dose); Model D, % - [1-*-<*">] 100, where fi - 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 cf 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, c, 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
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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
A 500* 200
B 500 200
c 500 200
D 500 200
4384 2339
946 1007 677 324
Total 9677
1
02 0.0
0
0
9.4 SJ J0.0 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 32.1 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 Vir.yi 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+0.3S9x 10*1 (dose); Model C. % 0.3565 x 10-1 (dose); Model D, % = (1 --100 where = 0.38x I0~J. The constants in these models were obtained using the biotransformation and angiosarcoma incidence data for rats exposed to vinyl chloride (Gehring er a/., 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 prohit 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 nits 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-vear 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
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Maltoni, 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. J. Occup. Med. 16, 509-518.
Watanabe, P. G-, McGowan, G. R., Madrid, E. O., and Gehring, 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 [,4CJvinyl 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 nonprotein 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.
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