| Abstract
| - The appropriate selection and application of quantitativestructure−activity relationships (QSARs) for the predictionof toxicity is based on the prior assignment of a chemicalto its mode of toxic action. This classification is often derivedfrom structural characteristics with the underlyingassumption that chemically similar compounds havesimilar mechanisms of action, which is often but notnecessarily the case. Instead of using structural characteristics for classification toward a mode of toxic action,we used Escherichia coli based bioanalytical assays toclassify electrophilic chemicals. Analyzing a series of reactiveorganochlorines, epoxides, and compounds with anactivated double bond, three subclasses of reactive toxicitywere distinguished: “glutathione depletion-relatedtoxicity”, “DNA damage”, and “unspecific reactivity”. Forboth subsets of specifically reacting compounds adirect correlation between effects and chemical reactivitywas found. Reaction rate constants with either glutathioneor 2‘-deoxyguanosine, which was used as a model for complexDNA, served well to set up preliminary QSARs for eitherglutathione depletion-related toxicity or toxicity based onDNA damage in the model organism E. coli. The applicabilityof QSARs for electrophilic chemicals based on mechanistic-ally relevant reaction rate constants is a priori limitedto a small subset of compounds with strictly identicalmechanism of toxic action and similar metabolic rates. Incontrast, the proposed bioanalytical assays not onlyallowed the experimental identification of molecularmechanisms underlying the observable toxicity but alsotheir toxicity values are applicable to quantitatively predicttoxic effects in higher organisms by linear correlationmodels, independent of the assigned mode of toxic action.
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