Dose-response analyses of experimental cancer data

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 b e influenced by how the dose and response terms are characterized. Using th e poly-3 quantal response method to adjust for the extensive and early deve lopment of lethal lymphomas in butadiene-exposed mice provided a means of o btaining a better representation of dose-response relationships for late-de veloping tumors induced by this chemical. Fitting a Weibull model to surviv al-adjusted tamer data for chloroprene and butadiene indicated similar carc inogenic potencies for these chemicals in mice. In conjunction with the rod ent toxicity and carcinogenicity studies conducted by the National Toxicolo gy Program, toxicokinetic studies are performed to characterize relationshi ps between exposure and tissue concentrations of parent compound and metabo lites. A. physiologically based pharmacokinetic model (PBPK) of butadiene d osimetry indicated that differences in carcinogenic response between rats a nd mice are not simply due to differences in tissue concentrations of epoxy butene, a mutagenic metabolic intermediate. Thus, factors beyond tissue dos imetry of this metabolite must be important in butadiene-induced carcinogen esis. A PBPK model far isoprene indicated that brood concentrations of isop rene epoxides are a better indicator of kidney cancer risk than are measure ments of isoprene-exposure concentrations. An evaluation of dose response r elationships for cytotoxicity, regenerative hyperplasia, and tumor inductio n by trihalomethanes indicates that for this family of chemicals, cell prol iferation is not a reliable predictor of tumor response.