Adverse outcome pathways: opportunities, limitations and open questions

Marcel Leist, Ahmed Ghallab, Rabea Graepel, Rosemarie Marchan, Reham Hassan, Susanne Hougaard Bennekou, Alice Limonciel, Mathieu Vinken, Stefan Schildknecht, Tanja Waldmann, Erik Danen, Ben van Ravenzwaay, Hennicke Kamp, Iain Gardner, Patricio Godoy, Frederic Y. Bois, Albert Braeuning, Raymond Reif, Franz Oesch, Dirk DrasdoStefan Höhme, Michael Schwarz, Thomas Hartung, Thomas Braunbeck, Joost Beltman, Harry Vrieling, Ferran Sanz, Anna Forsby, Domenico Gadaleta, Ciarán Fisher, Jens Kelm, David Fluri, Gerhard Ecker, Barbara Zdrazil, Andrea Terron, Paul Jennings, Bart van der Burg, Steven Dooley, Annemarie H. Meijer, Egon Willighagen, Marvin Martens, Chris Evelo, Enrico Mombelli, Olivier Taboureau, Alberto Mantovani, Barry Hardy, Bjorn Koch, Sylvia Escher, Christoph van Thriel, Cristina Cadenas, D. Kroese, Bob van de Water, Jan G. Hengstler

Research output: Contribution to journalArticlepeer-review

153 Scopus citations


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 relationships (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.

Original languageEnglish (US)
Pages (from-to)3477-3505
Number of pages29
JournalArchives of Toxicology
Issue number11
StatePublished - Nov 1 2017


  • Binning of events
  • CCl
  • Computational toxicology
  • Interspecies extrapolation
  • Liver fibrosis
  • Metabolism
  • Multi-scale integration
  • Multiple hit events
  • Paracetamol
  • Pathway unidirectionality
  • Prioritization of compounds
  • Proof of non-toxicity
  • Regulatory toxicology
  • Systems biology
  • Tumor promotion
  • Vinyl acetate

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis


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