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Manuscript 116 Mechanisms: DNA Reactive Aagents
Citation:
PRESTON, J. AND J. A. ROSS. Manuscript 116 Mechanisms: DNA Reactive Aagents. Chapter 1.1, Charlene A. McQueen (ed.), Comprehensive Toxicology. ELSEVIER, AMSTERDAM, Holland, , 0-0, (2009).
Impact/Purpose:
Discusses link between two needs: understanding of and data on both the chemistry and biological effects of DNA-reactive chemicals
Description:
ABSTRACT The U.S. Environmental Protection Agency’s Guidelines for Carcinogen Risk Assessment (2005) uses an analytical framework for conducting a quantitative cancer risk assessment that is based on mode of action/key events and human relevance. The approach stresses the enhanced value of utilizing mechanistic data to inform the risk assessment process, in particular for dose-response assessment and risk characterization. A key component of this approach is to distinguish chemicals on the basis of a broad mode of action classification, namely DNA-reactivity versus the corollary non-DNA reactivity. This DNA-reactivity is a consequence of the parent chemical or a reactive metabolite binding covalently to DNA to produce a DNA adduct or some other DNA structural modification. The metabolism and DNA adduct (or modification) profiles are presented for the major DNA-reactive chemical or activity classes polycyclic aromatic hydrocarbons, arylamines and nitro-aryl hydrocarbons, aflatoxins, small alkylators, halogenated hydrocarbons, endogenous lipid peroxidation, DNA-DNA and DNA-protein crosslinkers, strand breakage, and DNA intercalators. The conversion of DNA adducts or other structural modifications into gene and chromosomal mutations by errors of DNA replication on the damaged template (or occasionally by errors of DNA repair) can lead to cells being initiated along the key events pathway to the development of neoplasms. For the conduct of a quantitative cancer risk assessment, it is necessary to have an understanding of and data on both the chemistry and biological effects of DNA-reactive chemicals. This chapter provides the links between those two needs.