A new international project to evaluate the relevance for human systemic and local toxicity of in vitro tests of general toxicity of chemicals has been organized by the Scandinavian Society of Cell Toxicology under the title Multicenter Evaluation of In Vitro Cytotoxicity (MEIC). The basic assumptions underlying the project, as well as the practical goals and the design of the program are outlined. The list of the first 50 reference chemicals is presented. The chemicals are an otherwise unbiased selection of compounds with known human acutely lethal dosage and blood concentrations, including LD50-values in the rat or mouse. Most agents also have other data on human toxicity and toxicokinetics, including more extensive animal toxicity data. International laboratories already using or developing in vitro tests of various partial aspects of general toxicity are invited to test the substances, the results of which will be evaluated by us. The predictivity of the in vitro results for both partial and gross human toxicity data will be determined with combined use of univariate regression analysis and soft multivariate modeling. The predictivity of the in vitro results will be compared with the predictivity of conventional animal tests for the same chemicals. Finally, batteries of tests with optimal prediction power for various types of human toxicity will be selected. The need for and possible uses of such batteries are discussed.

The MEIC (multicentre evaluation of in vitro cytotoxicity) programme is a five-year programme to validate in vitro tests for general toxicity, and is organised by the Scandinavian Society for Cell Toxicology. Interested laboratories are invited, on an international basis, to test 50 published reference chemicals in their respective assays. Submitted results will then be evaluated yearly by the MEIC Committee for their relevance to various types of human toxicity, including an evaluation for the same chemicals of the prediction by animal tests of human toxicity. To establish the validation methods, a preliminary validation cycle is being performed in 1989/90 with submitted results for the first ten MEIC chemicals. The present paper is the very first step of this preliminary validation process. The prediction of human toxicity by five cytotoxicity assays (altogether 14 different cell systems/endpoints) has been evaluated, and also compared with the predictive value of rodent LD50 tests. Mouse LD50 prediction of human lethal dosage for these substances was good, while rat LD50 prediction was less satisfactory. The collective predictions by all 14 cell systems/endpoints of human toxicity in the form of a multivariate PLS (partial least squares) model of human acute lethal blood concentrations, as well as the corresponding prediction by a HeLa cell assay, were comparable to the efficiency of mouse LD50 prediction of human lethal dosage. When combined with simple toxicokinetic data (absorption of chemicals in the intestine and distribution volumes), the PLS model and the HeLa assay were able to predict human lethal dosage of the ten chemicals as accurately as the mouse LD50 value. The small number of chemicals studied to date means that general conclusions cannot be drawn from these results. Further validation of more chemicals with the in vitro methods is essential and promises to be worthwhile.

The Multicenter Evaluation of In Vitro Cytotoxicity (MEIC) programme was set up to evaluate the relevance for acute human systemic toxicity of in vitro cytotoxicity tests. At the end of the programme in the summer of 1996, 29 laboratories had tested all 50 reference chemicals in 61 cytotoxicity assays. As a necessary prerequisite to the forthcoming evaluation papers of this series, this paper presents the animal and human toxicity data of the programme. This database contains tabulated handbook data for the 50 chemicals, on: a) oral rat and mouse LD50 values; b) acute oral lethal doses in humans; c) clinically measured acute lethal serum concentrations in humans; d) acute lethal blood concentrations in humans measured postmortem; e) peaks from curves of an approximate 50% lethal blood/serum concentration over time after ingestion (LC50 curves), derived from a compilation of human acute poisoning case reports; f) human kinetics of single doses, including absorption, peak time, distribution/elimination curve, plasma half-life, distribution volume, distribution to organs (notably brain), and blood protein binding; and g) qualitative human acute toxicity data, including lethal symptoms, main causes of death, average time to death, target organs, presence of histopathological injury in target organs, presence of toxic metabolites, and known or hypothetical mechanisms for the lethal toxicity. The rationales for selection of the human toxicity data are also noted. The methods used to compile the in vivo toxicity data are described, including a presentation of a new method of constructing LC50 curves. Finally, the merits and shortcomings of the various human toxicity data for evaluation purposes are discussed.

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In recent years, conventional toxicity testing in animals has been reinforced by in vitro methods. As a result, toxicity testing in some sectors has become more effective and at the same time more ethical. This trend is probably only at its beginning, as many of the newly-developed methods have not yet won general acceptance as a basis for the large-scale replacement and reduction of animal experimentation. What limits the wider use of these methods is validation, i.e. the evaluation of their reliability and relevance. The present paper is a short review of the validation efforts made hitherto, including projects being planned and under discussion. Our own MEIC approach is compared with other strategies. Finally, our opinion on the effectiveness of one large consensus project relative to several different smaller validation programmes is expressed — we advocate the latter strategy, because it will save time and reduce costs.