Applicability and limitation of QSARs for the toxicity of electrophilic chemicals

The appropriate selection and application of quantitative structure-activity relationships (QSARs) for the prediction of toxicity is based on the prior assignment of a chemical to its mode of toxic action. This classification is often derived from structural characteristics with the underlying assumption that chemically similar compounds have similar mechanisms of action, which is often but not necessarily the case. Instead of using structural characteristics for classification toward a mode of toxic action, we used Escherichia coli based bioanalytical assays to classify electrophilic chemicals. Analyzing a series of reactive organochlorines, epoxides, and compounds with an activated double bond, three subclasses of reactive toxicity were distinguished: "glutathione depletion-related toxicity", "DNA damage", and "unspecific reactivity". For both subsets of specifically reacting compounds a direct correlation between effects and chemical reactivity was found. Reaction rate constants with either glutathione or 2'-deoxyguanosine, which was used as a model for complex DNA, served well to set up preliminary QSARs for either glutathione depletion-related toxicity or toxicity based on DNA damage in the model organism E coli. The applicability of QSARs for electrophilic chemicals based on mechanistically relevant reaction rate constants is a priori limited to a small subset of compounds with strictly identical mechanism of toxic action and similar metabolic rates. In contrast, the proposed bioanalytical assays not only allowed the experimental identification of molecular mechanisms underlying the observable toxicity but also their toxicity values are applicable to quantitatively predict toxic effects in higher organisms by linear correlation models, independent of the assigned mode of toxic action