E. Walum et al., DYNAMIC QUALITIES OF VALIDATION AND THE EVOLUTION OF NEW IN-VITRO TOXICOLOGICAL TESTS, ATLA. Alternatives to laboratory animals, 24(3), 1996, pp. 333-338
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.