Adverse outcome pathway

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An adverse outcome pathway (AOP) is structured representation of biological events leading to adverse effects and is considered relevant to risk assessment.[1][2][3] The AOP links in a linear way existing knowledge along one or more series of causally connected key events (KE) between two points — a molecular initiating event (MIE) and an adverse outcome (AO) that occur at a level of biological organization relevant to risk assessment.[2] The linkage between the events is described by key event relationships (KER) that describe the causal relationships between the key events.

AOPs are important for expanding the use of mechanistic toxicological data for risk assessment and regulatory applications with recent applications in further disciplines such as climate science.[2][4][5][6]

Schematic representation of AOP with hypothetical events


In 2012, the Organisation for Economic Co-operation and Development (OECD) launched a new programme on the development of adverse outcome pathways. A guidance document describes in detail how AOPs are to be developed, reviewed, agreed and published at the OECD level.[7] The AOP development and reviewing workflow is intended to take place via a web-based IT management tool: the Adverse Outcome Pathway Knowledge Base (AOP-KB)[8] which is currently still under development. It is the wiki-based, user-friendly tool providing open-source interface for collaborative sharing of established AOPs and building new AOPs. The AOP-KB gives the scientific community the possibility to enter, share and discuss their AOP-related knowledge at one central point of information. The AOP-KB allows for building AOPs by entering and then linking information about MIEs, KEs, AOs and Chemical Initiators. Knowing that pathway elements are not necessarily unique to a single AOP, value is added to existing knowledge by facilitating the re-use of MIE, KE and AO information in multiple AOPs, which prevents redundancy and make the collective knowledge about those entities available in all AOPs in which they appear.

The AOP-KB is a combination of individually developed applications, synchronised and orchestrated in a way that gives users the possibility to capture, review, browse and comment on AOPs shared by the AOP stakeholder community.

The AOP-KB project is an Organisation for Economic Co-operation and Development initiative, which is executed as close collaboration between the Joint Research Centre of European Commission, the United States Environmental Protection Agency and the Engineer Research and Development Center of United States Army Corps of Engineers for the purpose of the Organisation for Economic Co-operation and Development's programme on the development of AOPs [3]

The AOP has also been recently applied to better understand the effects of climate related stressors, further expanding the potential of AOPs to other scientific disciplines [6]

More recent developments have focused on the analysis of AOP networks[9] and the quantification of KERs with a view to developing mathematical models of AOPs, sometimes referred to as quantitative AOPs.[10]

Scientific workshops held for advancing the concept of AOP:

  • 2013
    • January 23–25, Baltimore, USA Building Shared Experience to Advance Practical Application of Pathway-Based Toxicology:Liver Toxicity Mode-of-Action[11]
  • 2014
    • March 2–7, Somma Lombardo, Italy Advancing Adverse Outcome Pathways (AOP) for Integrated Toxicology and Regulatory Applications [12]
    • August 24, Prague, Czech Republic AOPs 101: The How and Why of Development and Use [13]
    • September 3–5, Bethesda, USA Adverse Outcome Pathways: From Research to Regulation workshop held by NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) and the Physicians Committee for Responsible Medicine. Materials from the workshop, including links to the plenary session videocasts and summaries of the breakout group discussions, are available on the NTP website[14]


  1. ^ National Research Council; Division on Earth and Life Studies; Board on Environmental Studies and Toxicology; Institute for Laboratory Animal Research; Committee on Toxicity Testing and Assessment of Environmental Agents (2007). Toxicity testing in the 21st century : a vision and a strategy. Washington: The National Academic Press. ISBN 978-0-309-15173-3.
  2. ^ a b c Ankley GT, Bennett RS, Erickson RJ, Hoff DJ, Hornung MW, Johnson RD, et al. (March 2010). "Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment". Environmental Toxicology and Chemistry. 29 (3): 730–741. doi:10.1002/etc.34. PMID 20821501. S2CID 26011816.
  3. ^ a b "Adverse Outcome Pathways, Molecular Screening and Toxicogenomics". OECD.
  4. ^ Kramer VJ, Etterson MA, Hecker M, Murphy CA, Roesijadi G, Spade DJ, et al. (January 2011). "Adverse outcome pathways and ecological risk assessment: bridging to population-level effects". Environmental Toxicology and Chemistry. 30 (1): 64–76. doi:10.1002/etc.375. PMID 20963853. S2CID 40565681.
  5. ^ Schultz TW (2010). "Chapter 14:Adverse Outcome Pathways: A Way of Linking Chemical Structure to in Vivo Toxicological Hazards". In Cronin M, Madden J (eds.). In silico toxicology principles and applications. Issues in Toxicology. Cambridge: Royal Society of Chemistry. pp. 346–371. doi:10.1039/9781849732093-00346. ISBN 978-1-84973-209-3.
  6. ^ a b Ducker J, Falkenberg LJ (2020). "How the Pacific Oyster Responds to Ocean Acidification: Development and Application of a Meta-Analysis Based Adverse Outcome Pathway". Frontiers in Marine Science. 7: 597441. doi:10.3389/fmars.2020.597441.
  7. ^ "The Development of AOPs" (PDF). OECD.
  8. ^ "Adverse Outcome Pathway Knowledge Base (AOP-KB)".
  9. ^ Spinu N, Bal-Price A, Cronin MT, Enoch SJ, Madden JC, Worth AP (October 2019). "Development and analysis of an adverse outcome pathway network for human neurotoxicity". Archives of Toxicology. 93 (10): 2759–2772. doi:10.1007/s00204-019-02551-1. PMID 31444508. S2CID 201283568.
  10. ^ Paini A, Campia I, Cronin MT, Asturiol D, Ceriani L, Exner TE, et al. (February 2022). "Towards a qAOP framework for predictive toxicology - Linking data to decisions". Computational Toxicology. 21: 100195. doi:10.1016/j.comtox.2021.100195. PMC 8850654. PMID 35211660.
  11. ^ Willett C, Caverly Rae J, Goyak KO, Minsavage G, Westmoreland C, Andersen M, et al. (2014). "Building shared experience to advance practical application of pathway-based toxicology: liver toxicity mode-of-action". Altex. 31 (4): 500–519. doi:10.14573/altex.1401281. PMC 4779550. PMID 24535319.
  12. ^ Advancing Adverse Outcome Pathways (AOP) for Integrated Toxicology and Regulatory Applications. Workshop. Somma Lombardo, Italy. March 2014. Archived from the original on 19 November 2014. Retrieved 16 September 2014.
  13. ^ "AOPs 101: The How and Why of Development and Use". Retrieved 17 September 2014.
  14. ^ "Adverse Outcome Pathways: From Research to Regulation". NTP. Retrieved 16 September 2014.

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