A general scheme for the incorporation of pharmacokinetics in low-dose risk estimation for chemical carcinogenesis: example--vinyl chloride.

Abstract A general scheme is proposed which relates the carcinogenic responses to the amount of DNA-carcinogen adduct formed instead of applied dose. Based on the present understanding of the mechanism of carcinogenesis, we believe this to be a more rational approach to the low-dose extrapolation problem. In addition to specifying the low-dose extrapolation routine, it is necessary in this scheme to construct a pharmacokinetic model relating exposure concentration to the amount of DNA-chemical adduct formed. Two pharmacokinetic models are constructed for vinyl chloride. Low-dose risk estimates are determined from dose-response functions corresponding to the probit and multistage models. The estimates obtained using the probit model vary considerably when the pharmacokinetics parameters are changed whereas for the multistage model the low-dose estimates have less variability, varying in general by no more than one order of magnitude. This is not unexpected since the probit dose-response function is very “flat” in the low-dose region whereas the multistage dose-response function is analytic. In some cases a detailed pharmacokinetic study of the carcinogen may be as important as the bioassay study for lowdose and across-species extrapolation. However, it is important to realize that even though the incorporation of pharmacokinetics into the low-dose estimation process better reflects reality, it does not help in resolving the issue of which underlying model to use for the low-dose extrapolation, e.g., probit versus multistage.