The multicentre evaluation of in vitro cytotoxicity (MEIC) study is a programme designed to evaluate the relevance of in vitro toxicity tests for predicting human toxicity, and is organised by the Scandinavian Society for Cell Toxicology. The project started in 1989 and is scheduled to be finished by June 1996. MEIC is a voluntary effort by international laboratories to test the same 50 reference chemicals in their own in vitro toxicity systems. At present, 31 laboratories have submitted results for the first 30 reference chemicals from a total of 68 in vitro cytotoxicity tests. In the definitive evaluation of the MEIC programme, these in vitro results will be compared with human lethal blood concentrations and other relevant acute systemic toxicity data, and the results will be published as a series of articles. This paper, which is the first article in this series, describes and analyses the methodologies used in the 68 tests. The origins and purities of the test chemicals, the biological systems and the toxicity endpoints are also discussed. Since MEIC is not centrally directed, the selection of tests was entirely dependent on the preferences of the individual laboratories. Thus, the collection of tests is not representative of the full range of existing in vitro toxicity tests. In our study, basal cytotoxicity tests and ecotoxicological tests are prevalent, while tests for toxicity to primary cultures of differentiated cells, measured by organotypic toxicity endpoints, are clearly under-represented.
Results from tests of the first 30 MEIC reference chemicals in 68 different toxicity assays are presented as a prerequisite to subsequent in vitro/in vivo comparisons of acute toxicity data. A comparative cytotoxicity study was also carried out. Firstly, the variability of all of the results was analysed by using principal components analysis (PCA), analyses of variance (ANOVAs) and pairwise comparisons of means according to Tukey's method. The first PCA component described 80% of the variance of all of the cytotoxicity data. Tukey's ANOVA indicated a similar sensitivity for the assays, of approximately 80%. Secondly, the influence of five major methodological components on the general variability of the results was evaluated by linear regression and ANOVA linear contrast analyses. The findings were that: a) the toxicity of many chemicals increased with exposure time; b) in general, human cytotoxicity was predicted well by animal cytotoxicity tests; c) this prediction was poor for two chemicals; d) the prediction of human cytotoxicity by the ecotoxicological tests was only fairly good; e) one organotypic endpoint used, i.e. contractility of muscle cells, gave different results to those obtained according to viability/growth toxicity criteria; f) twelve comparisons of similar test systems involving different cell types (including highly differentiated cells) showed similar toxicities regardless of cell type; and g) nine out often comparisons of test systems with identical cell types and exposure times revealed similar toxicities, regardless of the viability or growth endpoint measurement used. Factors b, f and g must be the main causes of the remarkable similarity between the total results, while factors a, c, d and e, together with other minor factors that were not analysed, contributed to the 20% dissimilarity. The findings strongly support the basal cytotoxicity concept, and will facilitate future in vitro toxicity testing.
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