Science Inventory

A Conceptual Framework for Predicting the Toxicity of Reactive Chemicals: Modeling Soft Electrophilicity

Citation:

SCHULTZ, T. W., R. E. CARLSON, M. T. CRONIN, J. L. HERMENS, R. D. JOHNSON, P. J. O'BRIEN, D. W. ROBERTS, A. SIRAKI, K. B. WALLACE, AND G. D. VEITH. A Conceptual Framework for Predicting the Toxicity of Reactive Chemicals: Modeling Soft Electrophilicity. SAR AND QSAR IN ENVIRONMENTAL RESEARCH. Taylor & Francis, Inc., Philadelphia, PA, 17(4):413-428, (2006).

Impact/Purpose:

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.

Description:

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.

Record Details:

Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Product Published Date: 08/01/2006
Record Last Revised: 09/21/2016
OMB Category: Other
Record ID: 239725

Organization:

U.S. ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF RESEARCH AND DEVELOPMENT

NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY

MID-CONTINENT ECOLOGY DIVISION

MOLECULAR & CELLULAR MECHANISMS RESEARCH