Structure activity relationship (SAR) toxicological assessments: The role of expert judgment

Regulatory Toxicology and Pharmacology : RTP
Cathy LesterKaren Blackburn

Abstract

Structure activity relationships (SAR) and read-across are widely used animal alternative approaches for filling toxicological data gaps. A framework describing the use of expert judgment in evaluating analogs for SAR has been published and widely cited, however, reliance on expert judgment can introduce inconsistent results across experts and hinder transparency. Here we explore the use of a quantitative similarity score between an analog and a Structure of Interest (SOI) to see if these scores correlate with the expert judgement-based suitability rankings. We find these global similarity scores representing a "whole-molecule" view of similarity to be insensitive to differences in local structure which may be important for toxicity, and, therefore, cannot be substituted for expert judgement-based similarity rankings. In this paper, we suggest that the next step in the progression of SAR approaches retains the insights from expert judgment, but facilitates consistency and transparency through the development of rating "rules". This report outlines and defines analog rating rules for several compound categories. While not comprehensive, the exercises demonstrate the development of rules for categories with a large spread in mole...Continue Reading

Citations

Jul 23, 2019·Journal of Toxicology and Environmental Health. Part a·Hyang Yeon KimKyu-Bong Kim
Nov 24, 2020·Regulatory Toxicology and Pharmacology : RTP·Pim N H WassenaarWillie J G M Peijnenburg

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