The application of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling to understanding the mechanism of action of hazardous substances.

Much of toxicology research is focused on elucidating the nature of the mechanisms through which various xenobiotics exert their toxic effects. The central issue in extrapolating laboratory experiments to the human situation is whether mechanisms which are operative in laboratory animals are similar to mechanisms operating in humans. The underlying assumption is that understanding mechanisms permits rational extrapolation between species, across routes of exposure, or from high to low doses. There are two general classes of mechanisms of action. First, there are the mechanisms that result in the translation of an exposure concentration to the effective dose at the target site. The mechanisms that are operative at a pharmacokinetic level include those that are physiologically driven and those that are metabolically based. Second are mechanisms through which the dose at the target site elicits the ultimate adverse response. These are pharmacodynamic in nature and refer to the action of the effective dose at the target site. Altered gene regulation, cytotoxicity, and cell proliferation are examples of processes involving potential adverse effects at the target site. A quantitative understanding of the mechanisms involved in going from exposure to dose and dose to response can aid in answering the question of whether or not these mechanisms in animals and humans are similar or different.