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Adverse outcome pathways: opportunities, limitations and open questions
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Number of Authors: 53
2017 (English)In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 91, no 11, 3477-3505 p.Article in journal (Refereed) Published
Abstract [en]

Adverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory purposes. AOP links a molecular initiating event (MIE) to the adverse outcome (AO) via key events (KE), in a way specified by key event erelationships (KER). Although this approach to formalize mechanistic toxicological information only started in 2010, over 200 AOPs have already been established. At this stage, new requirements arise, such as the need for harmonization and re-assessment, for continuous updating, as well as for alerting about pitfalls, misuses and limits of applicability. In this review, the history of the AOP concept and its most prominent strengths are discussed, including the advantages of a formalized approach, the systematic collection of weight of evidence, the linkage of mechanisms to apical end points, the examination of the plausibility of epidemiological data, the identification of critical knowledge gaps and the design of mechanistic test methods. To prepare the ground for a broadened and appropriate use of AOPs, some widespread misconceptions are explained. Moreover, potential weaknesses and shortcomings of the current AOP rule set are addressed (1) to facilitate the discussion on its further evolution and (2) to better define appropriate vs. less suitable application areas. Exemplary toxicological studies are presented to discuss the linearity assumptions of AOP, the management of event modifiers and compensatory mechanisms, and whether a separation of toxicodynamics from toxicokinetics including metabolism is possible in the framework of pathway plasticity. Suggestions on how to compromise between different needs of AOP stakeholders have been added. A clear definition of open questions and limitations is provided to encourage further progress in the field.

Place, publisher, year, edition, pages
2017. Vol. 91, no 11, 3477-3505 p.
Keyword [en]
Regulatory toxicology, Systems biology, Multi-scale integration, Computational toxicology, Interspecies extrapolation, Metabolism, Pathway unidirectionality, Liver fibrosis, Paracetamol, CCl4, Vinyl acetate, Tumor promotion, Binning of events, Multiple hit events Proof of non-toxicity, Prioritization of compounds
National Category
Biological Sciences Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:su:diva-150001DOI: 10.1007/s00204-017-2045-3ISI: 000415760700003PubMedID: 29051992OAI: oai:DiVA.org:su-150001DiVA: diva2:1168597
Available from: 2017-12-21 Created: 2017-12-21 Last updated: 2018-01-13Bibliographically approved

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Forsby, AnnaJennings, PaulWillighagen, EgonMartens, Marvin
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