Journal
REGULATORY TOXICOLOGY AND PHARMACOLOGY
Volume 56, Issue 1, Pages 67-81Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.yrtph.2009.09.006
Keywords
Structural-similarity; Reactive-similarity; Metabolic-similarity; Bioactivation; Chemical analogs identification; Structure activity relationship (SAR); Toxicological assessments
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A systematic expert-driven process is presented for evaluating analogs for read across in SAR (Structure activity relationship) toxicological assessments. The approach involves categorizing potential analogs based upon their degree Of structural, reactivity, metabolic and physicochemical similarity to the chemical with missing toxicological data (target chemical). It extends beyond structural similarity, and includes differentiation based upon Chemical reactivity and addresses the potential that an analog and target could show toxicologically significant metabolic convergence or divergence. In addition, it identifies differences in physicochemical properties, which could affect bioavailability and consequently biological responses observed in vitro or in vivo. The approach provides a stepwise decision tree for categorizing the suitability of analogs, which qualitatively characterizes the strength of the evidence supporting the hypothesis of similarity and level of uncertainty associated with their use for read across. The result is a comprehensive framework to apply chemical, biochemical and toxicological principles in a systematic manner to identify and evaluate factors that can introduce uncertainty into SAR assessments, while maximizing the appropriate use of all available data. (C) 2009 Published by Elsevier Inc.
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