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A conceptual framework for predicting the toxicity of reactive chemicals: modeling soft electrophilicity.

Schultz TW, Carlson RE, Cronin MT, Hermens JL, Johnson R, O'Brien PJ, Roberts DW, Siraki A, Wallace KB, Veith GD

Department of Comparative Medicine, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN 37996-4543, USA.

Although the literature is replete with QSAR models developed for many toxic effects caused by reversible chemical interactions, the development of QSARs for the toxic effects of reactive chemicals lacks a consistent approach. While limitations exit, an appropriate starting-point for modeling reactive toxicity is the applicability of the general rules of organic chemical reactions and the association of these reactions to cellular targets of importance in toxicology. The identification of plausible "molecular initiating events" based on covalent reactions with nucleophiles in proteins and DNA provides the unifying concept for a framework for reactive toxicity. This paper outlines the proposed framework for reactive toxicity. Empirical measures of the chemical reactivity of xenobiotics with a model nucleophile (thiol) are used to simulate the relative rates at which a reactive chemical is likely to bind irreversibly to cellular targets. These measures of intrinsic reactivity serve as correlates to a variety of toxic effects; what's more they appear to be more appropriate endpoints for QSAR modeling than the toxicity endpoints themselves.

Published 21 August 2006 in SAR QSAR Environ Res, 17(4): 413-28.
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