Proposing a scientific confidence framework to help support the application of adverse outcome pathways for regulatory purposes

• Published in: Regulatory toxicology and pharmacology Vol. 71; no. 3; pp. 463 - 477
• Main Authors: Patlewicz, Grace, Simon, Ted W., Rowlands, J. Craig, Budinsky, Robert A., Becker, Richard A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.04.2015
• Subjects: (Q)SAR; Adverse outcome pathway (AOP); Animals; Carcinogenicity Tests; Carcinogens - toxicity; Computer Simulation; Databases, Factual; Decision Support Techniques; Dose-Response Relationship, Drug; Drug Approval; Endocrine Disruptors - toxicity; Estrogens - toxicity; Exposure:activity ratio (EAR); Humans; Integrated approaches to testing and assessment (IATA); Irritants - toxicity; Liver Neoplasms - chemically induced; Mode of action (MoA); Models, Biological; Quantitative Structure-Activity Relationship; Read-across; Risk Assessment; Scientific confidence framework (SCF); Skin Irritancy Tests; Toxicity Tests - methods; Toxicity Tests - standards; Read-across; Adverse outcome pathway (AOP); Scientific confidence framework (SCF); Mode of action (MoA); Integrated approaches to testing and assessment (IATA); Exposure:activity ratio (EAR); (Q)SAR
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2015.02.011

•Application of AOPs is context dependent.•Regulatory context will drive the scientific confidence needed.•A scientific confidence framework is proposed.•Case studies to highlight the utility of this framework are presented. An adverse outcome pathway (AOP) describes the causal linkage between initial molecular events and an adverse outcome at individual or population levels. Whilst there has been considerable momentum in AOP development, far less attention has been paid to how AOPs might be practically applied for different regulatory purposes. This paper proposes a scientific confidence framework (SCF) for evaluating and applying a given AOP for different regulatory purposes ranging from prioritizing chemicals for further evaluation, to hazard prediction, and ultimately, risk assessment. The framework is illustrated using three different AOPs for several typical regulatory applications. The AOPs chosen are ones that have been recently developed and/or published, namely those for estrogenic effects, skin sensitisation, and rodent liver tumor promotion. The examples confirm how critical the data-richness of an AOP is for driving its practical application. In terms of performing risk assessment, human dosimetry methods are necessary to inform meaningful comparisons with human exposures; dosimetry is applied to effect levels based on non-testing approaches and in vitro data. Such a comparison is presented in the form of an exposure:activity ratio (EAR) to interpret biological activity in the context of exposure and to provide a basis for product stewardship and regulatory decision making.