DOSE-RESPONSE ANALYSES OF EXPERIMENTAL CANCER DATA

Abstract

Dose-response analysis provides a powerful tool to determine causality from experimental cancer data, estimate low-dose risk, and evaluate mechanistic hypotheses. However, the interpretation of cancer dose-response data can be influenced by how the dose and response terms are characterized. Using the poly-3 quantal response method to adjust for the extensive and early development of lethal lymphomas in butadiene-exposed mice provided a means of obtaining a better representation of dose-response relationships for late-developing tumors induced by this chemical. Fitting a Weibull model to survival-adjusted tumor data for chloroprene and butadiene indicated similar carcinogenic potencies for these chemicals in mice. In conjunction with the rodent toxicity and carcinogenicity studies conducted by the National Toxicology Program, toxicokinetic studies are performed to characterize relationships between exposure and tissue concentrations of parent compound and metabolites. A physiologically based pharmacokinetic model (PBPK) of butadiene dosimetry indicated that differences in carcinogenic response between rats and mice are not simply due to differences in tissue concentrations of epoxybutene, a mutagenic metabolic intermediate. Thus, factors beyond tissue dosimetry of this metabolite must be important in butadiene-induced carcinogenesis. A PBPK model for isoprene indicated that blood concentrations of isoprene epoxides are a better indicator of kidney cancer risk than care measurements of isoprene-exposure concentrations. An evaluation of dose-response relationships for cytotoxicity, regenerative hyperplasia, and tumor induction by trihalomethanes indicates that for this family of chemicals, cell proliferation is not a reliable predictor of tumor response.