Adverse outcome pathways : opportunities, limitations and open questions

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2017
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Ghallab, Ahmed
Graepel, Rabea
Marchan, Rosemarie
Hassan, Reham
Bennekou, Susanne Hougaard
Hengstler, Jan G.
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Archives of toxicology. 2017, 91(11), pp. 3477-3505. ISSN 0340-5761. eISSN 1432-0738. Available under: doi: 10.1007/s00204-017-2045-3
Zusammenfassung

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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ISO 690LEIST, Marcel, Ahmed GHALLAB, Rabea GRAEPEL, Rosemarie MARCHAN, Reham HASSAN, Susanne Hougaard BENNEKOU, Stefan SCHILDKNECHT, Tanja WALDMANN, Thomas HARTUNG, Jan G. HENGSTLER, 2017. Adverse outcome pathways : opportunities, limitations and open questions. In: Archives of toxicology. 2017, 91(11), pp. 3477-3505. ISSN 0340-5761. eISSN 1432-0738. Available under: doi: 10.1007/s00204-017-2045-3
BibTex
@article{Leist2017-11Adver-40552,
  year={2017},
  doi={10.1007/s00204-017-2045-3},
  title={Adverse outcome pathways : opportunities, limitations and open questions},
  number={11},
  volume={91},
  issn={0340-5761},
  journal={Archives of toxicology},
  pages={3477--3505},
  author={Leist, Marcel and Ghallab, Ahmed and Graepel, Rabea and Marchan, Rosemarie and Hassan, Reham and Bennekou, Susanne Hougaard and Schildknecht, Stefan and Waldmann, Tanja and Hartung, Thomas and Hengstler, Jan G.}
}
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