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.
N1 - Publisher Copyright:
© 2017, Springer-Verlag GmbH Germany.
PY - 2017/11/1
Y1 - 2017/11/1
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.
KW - Binning of events
KW - CCl
KW - Computational toxicology
KW - Interspecies extrapolation
KW - Liver fibrosis
KW - Metabolism
KW - Multi-scale integration
KW - Multiple hit events
KW - Paracetamol
KW - Pathway unidirectionality
KW - Prioritization of compounds
KW - Proof of non-toxicity
KW - Regulatory toxicology
KW - Systems biology
KW - Tumor promotion
KW - Vinyl acetate
UR - http://www.scopus.com/inward/record.url?scp=85031799653&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85031799653&partnerID=8YFLogxK
U2 - 10.1007/s00204-017-2045-3
DO - 10.1007/s00204-017-2045-3
M3 - Article
C2 - 29051992
AN - SCOPUS:85031799653
SN - 0340-5761
VL - 91
SP - 3477
EP - 3505
JO - Archives of Toxicology
JF - Archives of Toxicology
IS - 11
ER -