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Adverse outcome pathways: opportunities, limitations and open questions

Marcel Leist 1 Ahmed Ghallab 2 Rabea Graepel 3 Rosemarie Marchan 4 Reham Hassan 5 Susanne Hougaard Bennekou 6 Alice Limonciel 7 Mathieu Vinken 8 Stefan Schildknecht 1 Tanja Waldmann 1 Erik Danen 9 Ben van Ravenzwaay 10 Hennicke Kamp 10 Iain Gardner 11 Patricio Godoy 4 Frédéric Bois 12 Albert Braeuning 13 Raymond Reif 4 Franz Oesch 14 Dirk Drasdo 15 Stefan Höhme 16 Michael Schwarz 17 Thomas Hartung 18 Thomas Braunbeck 19 Joost Beltman 9 Harry Vrieling 9 Ferran Sanz 20 Anna Forsby 21 Domenico Gadaleta 22 Ciarán Fisher 21 Jens Kelm 23 David Fluri 23 Gerhard Ecker 24 Barbara Zdrazil 24 Andrea Terron 24 Paul Jennings 25 Bart van der Burg 26 Steven Dooley 27 Annemarie Meijer 9 Egon Willighagen 28 Marvin Martens 28 Chris Evelo 28 Enrico Mombelli 12 Olivier Taboureau 29, 30 Albert Mantovani 31 Barry Hardy 32 Bjorn Koch 9 Sylvia Escher 33 Chris van Thriel 5 Cristina Cadenas 5 D. Kroese 34 Bob van de Water 9 Jan Hengstler 4
1 University of Konstanz
2 Department of Forensic Medicine and Veterinary Toxicology [Qena]
3 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 [Austria]
8 VUB - Vrije Universiteit Brussel
9 Universiteit Leiden [Leiden]
10 BASF [Ludwigshafen]
11 SimCYP Ltd
12 INERIS - Institut National de l'Environnement Industriel et des Risques
13 BfR - Bundesinstitut für Risikobewertung - Federal Institute for Risk Assessment
14 JGU - Johannes Gutenberg - Universität Mainz
15 MAMBA - Modelling and Analysis for Medical and Biological Applications
Inria de Paris, LJLL (UMR_7598) - Laboratoire Jacques-Louis Lions
16 Universität Leipzig [Leipzig]
17 Medical University Graz
18 Johns Hopkins Bloomberg School of Public Health [Baltimore]
19 University of Heidelberg, Medical Faculty
20 Universitat Pompeu Fabra [Barcelona]
21 Karolinska Institutet [Stockholm]
22 IRCCS - Istituto di Ricovero e Cura a Carattere Scientifico
23 InSphero [Schlieren]
24 University of Vienna [Vienna]
25 UGA UFRM [ ?-2019] - Université Grenoble Alpes - UFR Médecine [ ?-2019]
26 BioDetection Systems
27 Universität Mannheim [Mannheim]
28 Maastricht University [Maastricht]
29 INSERM - Institut National de la Santé et de la Recherche Médicale
30 IT University of Copenhagen
31 Istituto Superiore di Sanita [Rome]
32 Douglas Connect GmbH
33 Fraunhofer ITEM - Fraunhofer Institute for Toxicology and Experimental Medicine
34 Carl Zeiss SMT AG
Abstract : 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.
Keywords : Multi-scale integration Systems biology Regulatory toxicology Prioritization of compounds Proof of non-toxicity Multiple hit events Binning of events Vinyl acetate Tumor promotion CCl4 Paracetamol Liver fibrosis Computational toxicology Interspecies extrapolation Metabolism Pathway unidirectionality
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Journal articles
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https://hal.inria.fr/hal-01968849
Contributor : Dirk Drasdo <>
Submitted on : Thursday, January 3, 2019 - 1:26:26 PM
Last modification on : Monday, September 28, 2020 - 5:06:50 PM

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CNRS | INERIS | TDS-MACS | INRIA | SORBONNE-UNIVERSITE | LJLL | UNIV-PARIS7 | USPC | SU-SCIENCES | UNIV-PARIS | UP-SCIENCES

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

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