Cancer-Risk Prediction for Carbon Tetrachloride Using Pharmacokinetic and Cell-Kinetic Multistage Models.

摘要

Multistage cancer risk models that account for clonal growth of intermediate, premalignant cell populations have been successfully used to describe age-specific incidence trends for human and experimentally induced animal tumors. Currently there is keen and growing interest in applying ''cell-kinetic multistage'' (CKM) models, which distinguish mutations and cell population kinetics as separate processes influencing the rate of tumor formation, to the problem of predicting human cancer risk that may be posed by environmental agents. This paper illustrates the application of such models to cancer-risk prediction for carbon tetrachloride (CCl sub 4 ), using data from rodent cancer bioassays and information on CCl sub 4 pharmacokinetics in rodents and humans. The presumption, made in most CKM models considered to date, that preneoplastic cell growth is exponential over time is critically evaluated along with the impact on predicted CCl sub 4 -induced cancer risk of using a more biologically realistic cell-growth model. Equations describing modeled exponential and geometric CKM-based risk from multiple exposure scenarios are developed and applied to the problem of risk population for CCl sub 4 . It is shown that if CCl sub 4 is assumed to be a ''pure'' promoter of carcinogenesis (i.e., to have no cancer-initiating capacity), the CKM approach predicts a low-dose carcinogenic potency for CCl sub 4 that is up to four orders of magnitude less than that predicted using a widely used standard approach that does not take into account the impact of induced cell proliferation. 46 refs., 6 figs. (ERA citation 14:023241)