Adverse outcome pathways: opportunities, limitations and open questions

Marcel Leist; Ahmed Ghallab; Rabea Graepel; Rosemarie Marchan; Reham Hassan; Susanne Hougaard Bennekou; Alice Limonciel; Mathieu Vinken; Stefan Schildknecht; Tanja Waldmann; Erik Danen; Ben van Ravenzwaay; Hennicke Kamp; Iain Gardner; Patricio Godoy; Frederic Y Bois; Albert Braeuning; Raymond Reif; Franz Oesch; Dirk Drasdo; Stefan Höhme; Michael Schwarz; Thomas Hartung; Thomas Braunbeck; Joost Beltman; Harry Vrieling; Ferran Sanz; Anna Forsby; Domenico Gadaleta; Ciarán Fisher; Jens Kelm; David Fluri; Gerhard Ecker; Barbara Zdrazil; Andrea Terron; Paul Jennings; Bart van der Burg; Steven Dooley; Annemarie H Meijer; Egon Willighagen; Marvin Martens; Chris Evelo; Enrico Mombelli; Olivier Taboureau; Alberto Mantovani; Barry Hardy; Bjorn Koch; Sylvia Escher; Christoph van Thriel; Cristina Cadenas; D Kroese; Bob van de Water; Jan G Hengstler

doi:10.1007/s00204-017-2045-3

Adverse outcome pathways: opportunities, limitations and open questions

Marcel Leist, Ahmed Ghallab, Rabea Graepel, Rosemarie Marchan, Reham Hassan, Susanne Hougaard Bennekou, Alice Limonciel, Mathieu Vinken, Stefan Schildknecht, Tanja Waldmann, Erik Danen, Ben van Ravenzwaay, Hennicke Kamp, Iain Gardner, Patricio Godoy, Frederic Y Bois, Albert Braeuning, Raymond Reif, Franz Oesch, Dirk DrasdoStefan Höhme, Michael Schwarz, Thomas Hartung, Thomas Braunbeck, Joost Beltman, Harry Vrieling, Ferran Sanz, Anna Forsby, Domenico Gadaleta, Ciarán Fisher, Jens Kelm, David Fluri, Gerhard Ecker, Barbara Zdrazil, Andrea Terron, Paul Jennings, Bart van der Burg, Steven Dooley, Annemarie H Meijer, Egon Willighagen, Marvin Martens, Chris Evelo, Enrico Mombelli, Olivier Taboureau, Alberto Mantovani, Barry Hardy, Bjorn Koch, Sylvia Escher, Christoph van Thriel, Cristina Cadenas, D Kroese, Bob van de Water, Jan G Hengstler

Disease Systems Biology Program

153 Citations (Scopus)

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.

Original language	English
Journal	Archives of Toxicology
Volume	91
Issue number	11
Pages (from-to)	3477-3505
Number of pages	29
ISSN	0340-5761
DOIs	https://doi.org/10.1007/s00204-017-2045-3
Publication status	Published - 1 Nov 2017

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Leist, M., Ghallab, A., Graepel, R., Marchan, R., Hassan, R., Bennekou, S. H., Limonciel, A., Vinken, M., Schildknecht, S., Waldmann, T., Danen, E., van Ravenzwaay, B., Kamp, H., Gardner, I., Godoy, P., Bois, F. Y., Braeuning, A., Reif, R., Oesch, F., ... Hengstler, J. G. (2017). Adverse outcome pathways: opportunities, limitations and open questions. Archives of Toxicology, 91(11), 3477-3505. https://doi.org/10.1007/s00204-017-2045-3

Leist, M, Ghallab, A, Graepel, R, Marchan, R, Hassan, R, Bennekou, SH, Limonciel, A, Vinken, M, Schildknecht, S, Waldmann, T, Danen, E, van Ravenzwaay, B, Kamp, H, Gardner, I, Godoy, P, Bois, FY, Braeuning, A, Reif, R, Oesch, F, Drasdo, D, Höhme, S, Schwarz, M, Hartung, T, Braunbeck, T, Beltman, J, Vrieling, H, Sanz, F, Forsby, A, Gadaleta, D, Fisher, C, Kelm, J, Fluri, D, Ecker, G, Zdrazil, B, Terron, A, Jennings, P, van der Burg, B, Dooley, S, Meijer, AH, Willighagen, E, Martens, M, Evelo, C, Mombelli, E, Taboureau, O, Mantovani, A, Hardy, B, Koch, B, Escher, S, van Thriel, C, Cadenas, C, Kroese, D, van de Water, B & Hengstler, JG 2017, 'Adverse outcome pathways: opportunities, limitations and open questions', Archives of Toxicology, vol. 91, no. 11, pp. 3477-3505. https://doi.org/10.1007/s00204-017-2045-3

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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.",

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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 - 2017/11/1

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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

SN - 0340-5761

VL - 91

SP - 3477

EP - 3505

JO - Archives of Toxicology

JF - Archives of Toxicology

IS - 11

ER -

Adverse outcome pathways: opportunities, limitations and open questions

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