The role of mechanistic toxicology in test method validation.

There are two approaches to in vitro toxicity test validation, phenomenological and mechanistic. The phenomenological approach uses correlative mathematical techniques, with no regard to the identification of mechanistic relationships, to relate in vitro measurements of toxicity to in vivo toxicological responses in order to establish the validity of the methods under consideration. This approach has three major limitations: (1) success or failure of a particular test will depend critically on the selection of test chemicals; (2) the reason why a chemical fails in a particular test is unknown; (3) without additional information there is no rational basis for extrapolation to new cases lying outside the domain of validation.