Abstract
Advances in risk assessment methodologies invite the consideration of more pharmacokinetic, pharmacodynamic, and biochemical information than ever before. When toxicity data are adequate, the identification of enzymes responsible for detoxication or bioactivation motivate their consideration in risk assessment. Consideration should be given not only to the ontogeny of enzyme expression, but to other biochemical factors such as tissue lipid content and changes in relative organ size and blood flow during development. Dogma that enzyme alterations result in alterations of risk requires reexamination. Sometimes these do not alter risk, even though the enzymes form toxicologically active metabolites. Knowledge that a given enzyme is responsible for metabolism of an environmental contaminant often stimulates the search for and use of information on its variance in expression and/or activity. Separate data on enzyme expression (content) and enzymatic activity can be useful in human health risk assessment, but requires the application of physiologic constraints, which can vary with age. Without these constraints, data from otherwise well-conducted studies have fueled incomplete and misleading conclusions. This manuscript uses the generic example of variance in xenobiotic metabolizing enzymes to make some points on the proper conduct and interpretation of in vitro findings pertinent to risk and susceptibility, such as findings inferred from studies of genetic polymorphisms. This information must be integrated in the context of the intact animal and/or intact human. The technique of physiologically based pharmacokinetic modeling offers a platform on which to integrate findings from disparate areas of biochemical research, while maintaining the constraints of the intact body.