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 th e mechanisms through which various xenobiotics exert their toxic effec ts. The central issue in extrapolating laboratory experiments to the h uman 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 extrapol ation between species, across routes of exposure, or from high to low doses. There are two general classes of mechanisms of action. First, t here 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 u ltimate adverse response. These are pharmacodynamic in nature and refe r to the action of the effective dose at the target site. Altered gene regulation, cytotoxicity, and cell proliferation are examples of proc esses involving potential adverse effects at the target site. A quanti tative understanding of the mechanisms involved in going from exposure to dose and dose to response can aid in answering the question of whe ther or not these mechanisms in animals and humans are similar or diff erent.