Quantitative weight of evidence to assess confidence in potential modes of action - PubMed (original) (raw)
Comparative Study
doi: 10.1016/j.yrtph.2017.02.017. Epub 2017 Feb 20.
Vicki Dellarco 2, Jennifer Seed 3, Joel M Kronenberg 4, Bette Meek 5, Jennifer Foreman 6, Christine Palermo 7, Chris Kirman 8, Igor Linkov 9, Rita Schoeny 10, Michael Dourson 11, Lynn H Pottenger 12, Mary K Manibusan 13
Affiliations
- PMID: 28232103
- DOI: 10.1016/j.yrtph.2017.02.017
Free article
Comparative Study
Quantitative weight of evidence to assess confidence in potential modes of action
Richard A Becker et al. Regul Toxicol Pharmacol. 2017 Jun.
Free article
Abstract
The evolved World Health Organization/International Programme on Chemical Safety mode of action (MOA) framework provides a structure for evaluating evidence in pathways of causally linked key events (KE) leading to adverse health effects. Although employed globally, variability in use of the MOA framework has led to different interpretations of the sufficiency of evidence in support of hypothesized MOAs. A proof of concept extension of the MOA framework is proposed for scoring confidence in the supporting data to improve scientific justification for MOA use in characterizing hazards and selecting dose-response extrapolation methods for specific chemicals. This involves selecting hypothesized MOAs, and then, for each MOA, scoring the weight of evidence (WOE) in support of causality for each KE using evolved Bradford Hill causal considerations (biological plausibility, essentiality, dose-response concordance, consistency, and analogy). This early proof of concept method is demonstrated by comparing two potential MOAs (mutagenicity and peroxisome proliferator activated receptor-alpha) for clofibrate, a rodent liver carcinogen. Quantitative confidence scoring of hypothesized MOAs is shown to be useful in characterizing the likely operative MOA. To guide method refinement and future confidence scoring for a spectrum of MOAs, areas warranting further focus and lessons learned, including the need to incorporate a narrative discussion of the weights used in the evaluation and an overall evaluation of the plausibility of the outcome, are presented.
Keywords: Carcinogenesis; Evidence integration; Mode of action; Risk assessment; Weight of evidence.
Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
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