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James D. McKinney

National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711-2055, USA

Abstract

New approaches to the risk assessment process are needed that might be more definitive and satisfying to the scientific community, interest groups, and the public at large. This commentary examines an alternative approach that is based on understanding the relationships of chemical structure and reactivity properties to the toxicokinetic behavior of chemicals in biological systems. This approach is based on the likelihood that there is a limited number of triggering (reactivity) mechanisms by which chemicals can express their toxicity at the molecular level. The fundamental importance of electrophilic character of chemicals as a determinant of their critical molecular reactivities and interactions with biological material in the expression of toxicity is supported. Such an approach also takes advantage of the maturing field of theoretical/computational chemistry in understanding important molecular recognition and reactivity processes (both qualitatively and quantitatively) for chemicals that can underlie their biological/toxicological activity. A process that permits assessment of reaction equivalents delivered to biological systems may hold promise for grouping chemicals by common triggering mechanisms with clearly delineated toxicological endpoints. Key words: chemical reactivity, molecular mechanisms, protein binding, risk assessment, structure-activity relationships, toxicity. Environ Health Perspect 104:810-816 (1996)

Address correspondence to J.D. McKinney, Pharmacokinetics Branch (MD-74) , Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711-2055 USA.

The author thanks Chris Waller and Ann Richard and other members of the Pharmacokinetics Branch and scientists in the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, who provided constructive comments and research on the development of a reactivity based approach to chemical risk assessment.

This manuscript has been reviewed in accordance with the policy of the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the agency and mention of trade names or commercial products does not constitute endorsement or recommendation for use.

Received 25 January 1996 ; accepted 10 May 1996.