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Raymond S.H. Yang,^1,2 Russell S. Thomas,^1,2 Daniel L. Gustafson,^1,2 Julie Campain,^1,2 Stephen A. Benjamin,^1,3 Henk J.M. Verhaar,⁴ and Moiz M. Mumtaz⁵

¹Center for Environmental Toxicology and Technology;
²Department of Environmental Health;
³Department of Pathology, Colorado State University, Fort Collins, Colorado;
⁴Research Institute of Toxicology, Utrecht University, Utrecht, The Netherlands;
⁵Agency for Toxic Substances and Disease Registry, Atlanta, Georgia

Abstract

Systematic toxicity testing, using conventional toxicology methodologies, of single chemicals and chemical mixtures is highly impractical because of the immense numbers of chemicals and chemical mixtures involved and the limited scientific resources. Therefore, the development of unconventional, efficient, and predictive toxicology methods is imperative. Using carcinogenicity as an end point, we present approaches for developing predictive tools for toxicologic evaluation of chemicals and chemical mixtures relevant to environmental contamination. Central to the approaches presented is the integration of physiologically based pharmacokinetic/ pharmacodynamic (PBPK/PD) and quantitative structure-activity relationship (QSAR) modeling with focused mechanistically based experimental toxicology. In this development, molecular and cellular biomarkers critical to the carcinogenesis process are evaluated quantitatively between different chemicals and/or chemical mixtures. Examples presented include the integration of PBPK/PD and QSAR modeling with 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 carcinogenicity of the series of 12 chlorobenzene isomers. Also presented is an ongoing effort to develop and apply a similar approach to chemical mixtures using in vitro cell culture (Syrian hamster embryo cell transformation assay and human keratinocytes) methodologies and in vivo studies. The promise and pitfalls of these developments are elaborated. When successfully applied, these approaches may greatly reduce animal usage, personnel, resources, and time required to evaluate the carcinogenicity of chemicals and chemical mixtures. -- Environ Health Perspect 106(Suppl 6) :1385-1393 (1998) .

http://ehpnet1.niehs.nih.gov/docs/1998/Suppl-6/1385-1393yang/abstract.html

Key words: physiologically based pharmacokinetic/pharmacodynamic modeling, PBPK/PD modeling, quantitative structure-activity relationship, QSAR, alternative toxicology, predictive toxicology, chemical mixtures