This review summarises some aspects of the dynamics of the evolution of toxicological test methods based on cell biology. Within the multicentre evaluation of in vitro cytotoxicity (MEIC) programme, some general principles for validation have been proposed: a) a human database should be 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 parallel validation of methods is preferable to a serial validation; and d) toxicokinetic data should be included in the validation process to improve 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 critical toxic human blood or tissue concentration. This approach is being explored in the ERGATT/CFN integrated toxicity testing scheme (ECITTS) prevalidation project. The critical toxic concentrations are determined by using a set of neurospecific cellular tests, chosen and combined on the basis of knowledge of common neurotoxicity mechanisms. Another approach to selecting tests for prevalidation is through the development of tests that are found to be necessary and complementary to existing tests. Such a programme has been initiated on the basis of the results of the MEIC study. The progress made so far in this “missing tests programme” is presented in this paper.
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