Approaches to developing alternative and predictive toxicology based on PBPK/PD and QSAR modeling

Systematic toxicity testing, using conventional toxicology methodologies, o f single chemicals and chemical mixtures is highly impractical because of t he immense numbers of chemicals and chemical mixtures involved and the limi ted scientific resources. Therefore, the development of unconventional, eff icient, and predictive toxicology methods is imperative. Using carcinogenic ity as an end point, we present approaches for developing predictive tools for toxicologic evaluation of chemicals and chemical mixtures relevant to e nvironmental contamination. Central to the approaches presented is the inte gration of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) and quantitative structure-activity relationship (QSAR) modeling with focus ed mechanistically based experimental toxicology. In this development, mole cular and cellular biomarkers critical to the carcinogenesis process are ev aluated quantitatively between different chemicals and/or chemical mixtures . Examples presented include the integration of PBPK/PD and QSAR modeling w ith a time-course medium-term liver foci assay, molecular biology and cell proliferation studies, Fourier transform infrared spectroscopic analyses of DNA changes, and cancer modeling to assess and attempt to predict the carc inogenicity of the series of 12 chlorobenzene isomers. Also presented is an ongoing effort to develop and apply a similar approach to chemical mixture s using in vitro cell culture (Syrian hamster embryo cell transformation as say and human keratinocytes) methodologies and in vivo studies. The promise and pitfalls of these developments are elaborated. When successfully appli ed. these approaches may greatly reduce animal usage, personnel, resources, and time required to evaluate the carcinogenicity of chemicals and chemica l mixtures.