Survey of the QSAR and in vitro approaches for developing non-animal methods to supersede the in vivo LD50 test.

Quantitative structure-activity relationship (QSAR) studies and in vitro studies in which correlations with LD50 have been sought are reviewed. QSAR methods have shown some success in relating LD50 to certain physicochemical properties of the compound, particularly lipophilicity, but have been less successful in correlating LD50 with electronic properties of molecules (related to reactivity) or structural variables. It is concluded that insufficient evidence is available to determine whether QSAR methods can be of general use in predicting the acute toxicity (LD50) of chemicals, and that until further work is undertaken to develop QSARs for a much wider range of homologous series of compounds, this situation is unlikely to be resolved. New chemical descriptors that are more directly relevant to the mechanism of toxic action of the chemical should be identified. Cytotoxicity in vitro is poorly correlated with LD50, but good correlations have been obtained between toxicity in vivo and in vitro, using systems in which the toxic endpoint reflects the probable mechanism(s) of acute toxicity of the test chemical (e.g. the assessment of neurotoxins using neural cell systems). Therefore, it seems that the successful application of in vitro methods requires a better understanding of the mechanisms of acute toxicity in vivo and the development of mammalian cell culture systems that can model more closely the metabolic fate of the chemicals in vivo.