Biokinetic modeling and in vitro-in vivo extrapolations.

The introduction of in vitro methodologies in the toxicological risk assessment process requires a number of prerequisites regarding both the toxicodynamics and the biokinetics of the compounds under study. In vitro systems will need to be relevant for measuring those structural and physiological changes that are good indicators for adverse effects. Furthermore, the dose metric found to have an effect in the in vitro system should be relevant. One element in defining the appropriate dose metric is related to the kinetic behavior of the compound in the in vitro system: binding to proteins, binding to plastic, evaporation, and the interaction between the culture medium and the cells. Ways to measure and model "in vitro biokinetics" are described. Second, the appropriate dose metric in vitro, e.g., the effective concentration, will need to be extrapolated to relevant in vivo exposure scenarios. The application of physiologically based biokinetic modelling is essential in such extrapolations. The parameters needed to build these models often can be estimated based on nonanimal data, namely chemical properties (QSARs) and in vitro experiments.