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. The mechanistic approach addresses all of these issues: (1) mechanistic considerations are included in the selection of chemicals for validation; (2) the failure of a particular test to identify a given toxin means that the toxin does not act through the mechanism evaluated by the test, which is useful toxicological information; (3) any chemical that acts by the mechanism evaluated by the test will be identified. The major limitation of the mechanistic approach is our lack of knowledge concerning in vivo mechanistic toxicology.