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 are 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.