TY - JOUR

T1 - Adverse outcome pathways

T2 - opportunities, limitations and open questions

AU - Leist, Marcel

AU - Ghallab, Ahmed

AU - Graepel, Rabea

AU - Marchan, Rosemarie

AU - Hassan, Reham

AU - Bennekou, Susanne Hougaard

AU - Limonciel, Alice

AU - Vinken, Mathieu

AU - Schildknecht, Stefan

AU - Waldmann, Tanja

AU - Danen, Erik

AU - van Ravenzwaay, Ben

AU - Kamp, Hennicke

AU - Gardner, Iain

AU - Godoy, Patricio

AU - Bois, Frederic Y

AU - Braeuning, Albert

AU - Reif, Raymond

AU - Oesch, Franz

AU - Drasdo, Dirk

AU - Höhme, Stefan

AU - Schwarz, Michael

AU - Hartung, Thomas

AU - Braunbeck, Thomas

AU - Beltman, Joost

AU - Vrieling, Harry

AU - Sanz, Ferran

AU - Forsby, Anna

AU - Gadaleta, Domenico

AU - Fisher, Ciarán

AU - Kelm, Jens

AU - Fluri, David

AU - Ecker, Gerhard

AU - Zdrazil, Barbara

AU - Terron, Andrea

AU - Jennings, Paul

AU - van der Burg, Bart

AU - Dooley, Steven

AU - Meijer, Annemarie H

AU - Willighagen, Egon

AU - Martens, Marvin

AU - Evelo, Chris

AU - Mombelli, Enrico

AU - Taboureau, Olivier

AU - Mantovani, Alberto

AU - Hardy, Barry

AU - Koch, Bjorn

AU - Escher, Sylvia

AU - van Thriel, Christoph

AU - Cadenas, Cristina

AU - Kroese, D

AU - van de Water, Bob

AU - Hengstler, Jan G

PY - 2017/11

Y1 - 2017/11

N2 - 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.

AB - 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.

U2 - 10.1007/s00204-017-2045-3

DO - 10.1007/s00204-017-2045-3

M3 - Journal article

C2 - 29051992

VL - 91

SP - 3477

EP - 3505

JO - Archives of Toxicology

JF - Archives of Toxicology

SN - 0340-5761

IS - 11

ER -