Applications of mechanistic data in risk assessment: The past, present, and future

Mechanistic data, when available, have long been considered in risk assessm ent, such as in the development of the nitrate RfD based on effects in a se nsitive group (infants). Recent advances in biology and risk assessment met hods have led to a tremendous increase in the use of mechanistic data in ri sk assessment. Toxicokinetic data can improve extrapolation from animals to humans and characterization of human variability. This is done by the deve lopment of improved tissue dosimetry, by the use of uncertainty factors bas ed an chemical-specific data, and in the development Of physiologically bas ed pharmacokinetic (PBPK) models. The development of the boron RfD illustra tes the use of chemical-specific data in the improved choice of uncertainty factors. The draft cancer guidelines of the U.S. Environmental Protection Agency emphasize the use of mode of action data. The first choice under the guidelines is to use a chemical-specific, biologically based dose-response (BBDR) model. In the absence of a BBDR model, mode of action data are used to determine whether low-dose extrapolation is done using a linear or nonl inear (margin of exposure) approach. Considerations involved in evaluating a hypothesized mode of action are illustrated using 1,3-dichloropropene, an d use of a BBDR model is illustrated using formaldehyde. Recent development s in molecular biology, including transgenic animals, microarrays, and the characterization of genetic polymorphisms, have significant potential for i mproving risk assessments, although further methods development is needed. Overall, use of mechanistic data has significant potential for reducing the uncertainty in assessments, while at the same time highlighting the areas of uncertainty.