THE ROLE OF MECHANISTIC TOXICOLOGY IN TEST METHOD VALIDATION

There are two approaches to in vitro toxicity test validation, phenome nological and mechanistic. The phenomenological approach uses correlat ive mathematical techniques, with no regard to the identification of m echanistic 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 limi tations: (1) success or failure of a particular test will depend criti cally on the selection of test chemicals; (2) the reason why a chemica l fails in a particular test is unknown; (3) without additional inform ation there is no rational basis for extrapolation to new cases lying outside the domain of validation. The mechanistic approach addresses a ll of these issues: (1) mechanistic considerations are included in the selection of chemicals for validation; (2) the failure of a particula r test to identify a given toxin means that the toxin does not act thr ough the mechanism evaluated by the test, which is useful toxicologica l information; (3) any chemical that acts by the mechanism evaluated b y the test will be identified. The major limitation of the mechanistic approach is our lack of knowledge concerning in vivo mechanistic toxi cology.