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Journal Articles Archives of Toxicology Year : 2017

Adverse outcome pathways: opportunities, limitations and open questions

1 University of Konstanz
2 Department of Forensic Medicine and Veterinary Toxicology [Qena]
3 Universiteit Leiden = Leiden University
4 IFADO - Leibniz Research Centre for Working Environment and Human Factors [Dortmund]
5 TU - Technische Universität Dortmund [Dortmund]
6 The Danish Epidemiology Science Centre
7 IMU - Innsbruck Medical University = Medizinische Universität Innsbruck
8 VUB - Vrije Universiteit Brussel [Bruxelles]
10 SimCYP Ltd
11 INERIS - Institut National de l'Environnement Industriel et des Risques
12 BfR - Bundesinstitut für Risikobewertung - Federal Institute for Risk Assessment
13 JGU - Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University
14 MAMBA - Modelling and Analysis for Medical and Biological Applications
15 Leipzig University / Universität Leipzig
16 Medical University Graz
17 Johns Hopkins Bloomberg School of Public Health [Baltimore]
18 University of Heidelberg, Medical Faculty
19 UPF - Universitat Pompeu Fabra [Barcelona]
20 Karolinska Institutet [Stockholm]
21 IRCCS - Istituto di Ricovero e Cura a Carattere Scientifico
22 InSphero [Schlieren]
23 Universität Wien = University of Vienna
24 UGA UFRM - Université Grenoble Alpes - UFR Médecine
25 BioDetection Systems
26 Universität Mannheim
27 Maastricht University [Maastricht]
28 INSERM - Institut National de la Santé et de la Recherche Médicale
29 ITU - IT University of Copenhagen
30 ISS - Istituto Superiore di Sanità = National Institute of Health
31 Douglas Connect GmbH
32 Fraunhofer ITEM - Fraunhofer Institute for Toxicology and Experimental Medicine
33 Carl Zeiss SMT AG
Marcel Leist
  • Function : Author
  • PersonId : 897070
Ben van Ravenzwaay
  • Function : Author
Hennicke Kamp
  • Function : Author
Iain Gardner
  • Function : Author
Michael Schwarz
  • Function : Author
  • PersonId : 994580
Ferran Sanz
Jens Kelm
  • Function : Author
David Fluri
  • Function : Author
Paul Jennings
  • Function : Author
  • PersonId : 1022827
Egon Willighagen
Marvin Martens
Chris Evelo
Barry Hardy
  • Function : Author
Dinant Kroese
  • Function : Author


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.

Dates and versions

hal-01968849 , version 1 (03-01-2019)



Marcel Leist, Ahmed Ghallab, Rabea Graepel, Rosemarie Marchan, Reham Hassan, et al.. Adverse outcome pathways: opportunities, limitations and open questions. Archives of Toxicology, 2017, 91 (11), pp.3477-3505. ⟨10.1007/s00204-017-2045-3⟩. ⟨hal-01968849⟩
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