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Creating Context for the Use of DNA Adduct Data in Risk Assessment
Citation:
POTTENGER, L. H., A. M. JARABEK, M. HIMMELSTEIN, P. J. BOOGAARD, L. S. ANDREWS, D. CASCIANO, J. CADET, M. EMBRY, P. B. FARMER, J. KIM, J. PRESTON, V. REDDY, R. S. SCHOENY, D. SHUKER, J. SKARE, J. A. SWENBERG, G. M. WILLIAMS, AND E. ZEIGER. Creating Context for the Use of DNA Adduct Data in Risk Assessment. Presented at 2009 Annual Society of Toxicology Meeting, Baltimore, MD, March 15 - 19, 2009.
Impact/Purpose:
This abstract will be presented at the 2009 Annual Society of Toxicology Meeting, March 15-19, 2009.
Description:
Assessments of human cancer risk require the integration of diverse types of data. Advancing technologies for quantitative measurements at the sub-cellular domain raise the critical issue of interpretation and use of DNA adduct data in context with current understanding of cancer as a multifaceted process. A HESI Committee is developing a framework for the use of DNA adduct data in risk assessment. The approach includes: 1) defining a preliminary framework for data organization, 2) assessing available methods for quantitative measurement of adducts; 3) using case studies to refine the framework and draw inferences. Conclusions to date include: DNA is not pristine; DNA adducts cannot be used in isolation to determine mode-of-action (MOA); and DNA adducts (biomarkers of exposure) are not equivalent to mutations (biomarkers of effect). The framework stresses the consideration of a variety of adduct data in context with traditional toxicology data to inform MOA characterization. Conclusions on the relevance and applicability of DNA adduct data to quantitative risk assessment will be further refined by subsequent review of selected case studies. The strategy for selection and evaluation of case studies of known DNA-reactive carcinogens is discussed. A complementary effort summarizes the methods used to identify and quantify DNA adducts, focusing on reliability and validation. That effort describes sensitivity and specificity as key factors for method selection, as is sample type. The reliability of oxidative DNA damage measurement techniques is reviewed. Assay limitations are discussed along with issues that have impact on results, i.e., sample collection, processing, and storage. This framework is a critical effort to aid understanding of issues underlying DNA adducts as biomarkers and to improve the context for data inference and application in cancer risk assessment. (This abstract does not reflect U.S. EPA policy.)