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Adverse outcome pathways: opportunities, limitations and open questions.

Affiliation
In Vitro Toxicology and Biomedicine, Department inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, Box 657, Universitaetsstr. 10, 78457, Konstanz, Germany. marcel.leist@uni-konstanz.de.
Leist, Marcel;
Affiliation
Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt.
Ghallab, Ahmed;
Affiliation
Research Division of Drug Discovery and Safety, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
Graepel, Rabea;
Affiliation
Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, Germany.
Marchan, Rosemarie;
Affiliation
Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt.
Hassan, Reham;
Affiliation
The Danish EPA, Copenhagen, Denmark.
Bennekou, Susanne Hougaard;
ORCID
0000-0001-6588-5944
Affiliation
Division of Physiology, Department of Physiology and Medical Physics, Medical University of Innsbruck, 6020, Innsbruck, Austria.
Limonciel, Alice;
ORCID
0000-0001-5115-8893
Affiliation
Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
Vinken, Mathieu;
Affiliation
In Vitro Toxicology and Biomedicine, Department inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, Box 657, Universitaetsstr. 10, 78457, Konstanz, Germany.
Schildknecht, Stefan;
Affiliation
In Vitro Toxicology and Biomedicine, Department inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, Box 657, Universitaetsstr. 10, 78457, Konstanz, Germany.
Waldmann, Tanja;
Affiliation
Research Division of Drug Discovery and Safety, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
Danen, Erik;
Affiliation
BASF SE, Experimental Toxicology and Ecology, Ludwigshafen am Rhein, Germany.
van Ravenzwaay, Ben;
Affiliation
BASF SE, Experimental Toxicology and Ecology, Ludwigshafen am Rhein, Germany.
Kamp, Hennicke;
Affiliation
Simcyp (A Certara Company), Sheffield, UK.
Gardner, Iain;
Affiliation
Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, Germany.
Godoy, Patricio;
Affiliation
INERIS, DRC/VIVA/METO, Parc ALATA BP2, 60550, Verneuil en Halatte, France.
Bois, Frederic Y;
Affiliation
Department of Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, 10589, Berlin, Germany.
Braeuning, Albert;
Affiliation
Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, Germany.
Reif, Raymond;
Affiliation
Institute of Toxicology, University of Mainz, Mainz, Germany.
Oesch, Franz;
Affiliation
Laboratoire Jacques-Louis Lions, France Université of Paris 06, CNRS, UMR 7598, 4 pl. Jussieu, Paris, France.
Drasdo, Dirk;
Affiliation
Institute for Computer Science, University of Leipzig, Haertelstraße 16-18, 04107, Leipzig, Germany.
Höhme, Stefan;
Affiliation
Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University, Tübingen, Germany.
Schwarz, Michael;
Affiliation
Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Hartung, Thomas;
Affiliation
Aquatic Ecology and Toxicology Section, Centre for Organismal Studies, University of Heidelberg, Im Neuenheimer Feld 504, 69120, Heidelberg, Germany.
Braunbeck, Thomas;
Affiliation
Research Division of Drug Discovery and Safety, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
Beltman, Joost;
Affiliation
Department of Human Genetics, Leiden University Medical Center, Postal Zone S4-P, PO Box 9600, 2300 RC, Leiden, The Netherlands.
Vrieling, Harry;
Affiliation
Research Programme on Biomedical Informatics (GRIB), Department of Health and Life Sciences, Hospital del Mar Medical Research Institute (IMIM), Universitat Pompeu Fabra, Barcelona, Spain.
Sanz, Ferran;
Affiliation
Department of Neurochemistry, Stockholm University, Svante Arrhenius väg 16, SE-106 91, Stockholm, Sweden.
Forsby, Anna;
Affiliation
Laboratory of Environmental Chemistry and Toxicology, Department of Environmental Health Sciences, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Via la Masa 19, 20156, Milano, Italy.
Gadaleta, Domenico;
Affiliation
Simcyp (A Certara Company), Sheffield, UK.
Fisher, Ciarán;
Affiliation
InSphero AG, Wagistrasse 27, CH-8952, Schlieren, Switzerland.
Kelm, Jens;
Affiliation
InSphero AG, Wagistrasse 27, CH-8952, Schlieren, Switzerland.
Fluri, David;
Affiliation
Pharmacoinformatics Research Group, Department of Pharmaceutical Chemistry, University of Vienna, Althanstraße 14, 1090, Vienna, Austria.
Ecker, Gerhard;
Affiliation
Pharmacoinformatics Research Group, Department of Pharmaceutical Chemistry, University of Vienna, Althanstraße 14, 1090, Vienna, Austria.
Zdrazil, Barbara;
Affiliation
European Food Safety Authority (EFSA), Pesticide Unit, via Carlo Magno 1 A, 43126, Parma, Italy.
Terron, Andrea;
ORCID
0000-0002-6860-2898
Affiliation
Division of Molecular and Computational Toxicology, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.
Jennings, Paul;
Affiliation
BioDetection Systems b.v. (BDS), Science Park 406, 1098 XH, Amsterdam, The Netherlands.
van der Burg, Bart;
Affiliation
Section Molekular Hepatology, II. Medical Clinic, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
Dooley, Steven;
Affiliation
Institute of Biology, Leiden University, 2333 CC, Leiden, The Netherlands.
Meijer, Annemarie H;
ORCID
0000-0001-7542-0286
Affiliation
Open PHACTS Foundation, Cambridge, UK.
Willighagen, Egon;
ORCID
0000-0003-2230-0840
Affiliation
Department of Bioinformatics, BiGCaT, NUTRIM, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands.
Martens, Marvin;
Affiliation
Open PHACTS Foundation, Cambridge, UK.
Evelo, Chris;
Affiliation
INERIS, DRC/VIVA/METO, Parc ALATA BP2, 60550, Verneuil en Halatte, France.
Mombelli, Enrico;
Affiliation
Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Taboureau, Olivier;
Affiliation
Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Roma, Italy.
Mantovani, Alberto;
Affiliation
Douglas Connect GmbH, Bärmeggenweg 14, Zeiningen, 4314, Aargau, Switzerland.
Hardy, Barry;
Affiliation
Institute of Biology, Leiden University, 2333 CC, Leiden, The Netherlands.
Koch, Bjorn;
Affiliation
Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM) Chemical Risk Assessment Group Manager Structure Activity Relationships/databases, and expert systems Nikolai-Fuchs-Strasse 1, 30625, Hannover, Germany.
Escher, Sylvia;
ORCID
0000-0003-3215-9262
Affiliation
Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, Germany.
van Thriel, Christoph;
Affiliation
Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, Germany.
Cadenas, Cristina;
Affiliation
TNO (Department of Risk Analysis of Products in Development), Zeist, The Netherlands.
Kroese, D.;
Affiliation
Research Division of Drug Discovery and Safety, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
van de Water, Bob;
Affiliation
Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, Germany. hengstler@ifado.de.
Hengstler, Jan G.

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.

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