DYNAMIC QUALITIES OF VALIDATION AND THE EVOLUTION OF NEW IN-VITRO TOXICOLOGICAL TESTS

This review summarises some aspects of the dynamics of the evolution o f toxicological test methods based on cell biology. Within the multice ntre evaluation of in vitro cytotoxicity (MEIC) programme, some genera l principles for validation have been proposed: a) a human database sh ould he used as the source of reference data in the validation of new methods aimed at predicting human toxicity; b) the relevance of a test should be determined before its reliability is assessed; c) a paralle l validation of methods is preferable to a serial validation; and d) t oxicokinetic data should be included in the validation process to impr ove the predictivity of cytotoxicity test results. These toxicokinetic data can be used to extrapolate the cytotoxic in vitro concentrations to provide human toxic exposure levels. As part of test development, the cytotoxic concentration can also be compared directly with the cri tical toxic human blood or tissue concentration. This approach is bein g explored in the ERGATT/CFN integrated toxicity testing scheme (ECITT S) prevalidation project. The critical toxic concentrations are determ ined by using a set of neurospecific cellular tests, chosen and combin ed on the basis of knowledge of common neurotoxicity mechanisms. Anoth er approach to selecting tests for prevalidation is through the develo pment of tests that are found to he necessary and complementary to exi sting tests. Such a programme has been initiated on the basis of the r esults of the MEIC study. The progress made so far in this ''missing t ests programme'' is presented in this paper.