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

Abstract

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.

Keywords:

• Reactivity toxicity
• Thiol reactivity
• Molecular initiating events
• QSAR

Acknowledgement

This article presents the framework for predicting reactive toxicity developed by the participants of the 1st Annual Knoxville Workshop on Reactive Toxicity organized by the International QSAR Foundation and held at the University of Tennessee, College of Veterinary Medicine in Knoxville, Tennessee, in May 2005.