MEIC Evaluation of Acute Systemic Toxicity

Abstract

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.

The Integrated Acute Systemic Toxicity Project (ACuteTox) for the Optimisation and Validation of Alternative In Vitro Tests

“…It was shown in the MEIC study that, for 50 reference chemicals (9), average IC50 values from ten 24-hour exposure tests with human cell lines predicted human peak blood concentrations from LC50 curves better (R 2 = 0.74; Figure 1) than the prediction of human lethal doses by LD50 values for rats and mice (R 2 = 0.60-0.66). Furthermore, the accuracy of the prediction of human lethal concentrations increased considerably, if known human kinetic data, such as knowledge of the passage across the blood-brain barrier (BBB) and the timing of the lethal action, were used together with the cytotoxic concentrations obtained in the cell line assays.…”

“…Several studies have shown good correlations (over 70%) between in vitro basal cytotoxicity data (the 50% inhibitory concentration [IC50]) and rodent LD50 values (see Halle's Registry of Cytotoxicity [1]) or human lethal blood concentrations (see the MEIC study [2,3]). In the MEIC study, the relevance of using in vitro toxicity tests for predicting human acute systemic toxicity was evaluated under the management of Björn Ekwall (2)(3)(4)(5)(6)(7)(8)(9).…”

Integrated Decision-tree Testing Strategies for Acute Systemic Toxicity and Toxicokinetics with Respect to the Requirements of the EU REACH Legislation

“…The MEIC programme was a seven-year study, in which 59 laboratories worldwide, tested 50 reference chemicals selected by the Swedish Poison Information Centre, and obtained from various sources, according to in-house protocols (14). Information about human toxicity and kinetics from drug/chemical overdoses was available for each chemical, from which 50% lethal blood concentrations (LC50) were derived (15). These LC50s were compared with in vitro data produced via the testing laboratories.…”

Use of the PFGE Assay for Studies of DNA Breakage Induced by Toxic Chemicals

“…It was designed to evaluate the relevance of in vitro cytotoxicity tests for predicting human acute systemic toxicity and to select the best combination of in vitro toxicity tests (test battery). The three best cell systems were selected (7), but the need for additional in vitro tests was recently outlined (8,9).…”