title: Quantitative weight of evidence to assess confidence in potential modes of action.
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.
authors.affiliation: American Chemistry Council, 700 2nd St. NE, Washington, DC 20002, United States. Electronic address: rick_becker@americanchemistry.com.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Becker
authors.affiliation: Independent Consultant, Silver Spring, MD, United States.
authors.forename: Vicki
authors.initials: V
authors.lastname: Dellarco
authors.affiliation: Independent Consultant, Alexandria, VA, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Seed
authors.affiliation: Monsanto Company, St. Louis, MO, United States.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Kronenberg
authors.affiliation: University of Ottawa, Ottawa, ON, Canada.
authors.forename: Bette
authors.initials: B
authors.lastname: Meek
authors.affiliation: ExxonMobil Biomedical Sciences, Annandale, NJ, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Foreman
authors.affiliation: ExxonMobil Biomedical Sciences, Brussels, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Palermo
authors.affiliation: Summit Toxicology, Orange Village, OH, United States.
authors.forename: Chris
authors.initials: C
authors.lastname: Kirman
authors.affiliation: US Army Engineer Research and Development Center, Concord, MA, United States.
authors.forename: Igor
authors.initials: I
authors.lastname: Linkov
authors.affiliation: Independent Consultant, Washington, DC, United States.
authors.forename: Rita
authors.initials: R
authors.lastname: Schoeny
authors.affiliation: University of Cincinnati, Cincinnati, OH, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Dourson
authors.affiliation: Olin Corporation, Midland, MI, United States.
authors.forename: Lynn H
authors.initials: LH
authors.lastname: Pottenger
authors.affiliation: Exponent, Washington, DC, United States.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Manibusan
mesh_terms: D002273:Carcinogens / Q000633:toxicity*; D062067:Chemical Safety; D002994:Clofibrate / Q000633:toxicity*; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D009152:Mutagenicity Tests; D047493:PPAR alpha / Q000378:metabolism; D000075082:Proof of Concept Study; D018570:Risk Assessment
chemical_list: D002273:Carcinogens; D047493:PPAR alpha; D002994:Clofibrate
keywords: Carcinogenesis; Evidence integration; Mode of action; Risk assessment; Weight of evidence