AOP | what is an AOP?

An Adverse outcome pathways (AOP) describes causal Key Events (KEs) between a molecular initiating event (MIE) and an adverse outcome (AO). Events are linked by Key Event Relationships (KERs), which require a weight of evidence (WoE) assessment. AOPs may provide ways of presenting the weight of evidence for an effect, of identifying biomarkers and of identifying endpoints that require test development.

AOPs originated in ecotoxicology (Ankley et al. 2010) and have been translated to toxicology (OECD 2013). Probably the most developed example of an AOP is one linking covalent protein binding to skin sensitisation OECD, 2012 part 1, part 2.

A lot of AOP research interest is coordinated at OECD level and two initiatives that should facilitate and harmonize AOP activities are the OECD AOP Wiki (public access should be available in 2014…) and the Effectopedia platform which is being developed further at the European Commission’s Joint Research Centre (JRC) as part of their AOP activities.

Unilever’s Safety and Environment Assurance Centre (SEAC) are also involved in AOP research, for example see www.tt21c.org.

AOPs and systems toxicology – what’s the link?

AOPs could be a pragmatic way of applying systems toxicology concepts to the activities of toxicology, in particular as part of the drive towards ‘Toxicology in the 21st Century’, an approach lead by US toxicologists but widely recognized as a possible way forward for toxicology in general. The ambitious aim of this approach is the replacement of animal testing with predictive models based on in vitro and chemical data, and AOPs could help in the identification and design of alternative tests, provide a framework for presenting, organising and assessing the causal evidence linking observed effects to human outcomes, allowing read-across between species (for example in assessing human relevance, comparing data to rodents and alternative tests).

To some authors, the development of “executable, computational AOP models” is the  “grand challenge” of computational toxicology (Sturla et al. 2014), including systems toxicology.

References

Ankley GT, Bennett RS, Erickson RJ, Hoff DJ, Hornung MW, Johnson RD, Mount DR, Nichols JW, Russom CL, Schmieder PK, Serrrano JA, Tietge JE, Villeneuve DL. Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment. Environ Toxicol Chem. 2010 Mar;29(3):730-41. doi: 10.1002/etc.34. Review. PubMed PMID: 20821501.

Sturla SJ, Boobis AR, FitzGerald RE, Hoeng J, Kavlock RJ, Schirmer K, Whelan M, Wilks MF, Peitsch MC. Systems toxicology: from basic research to risk assessment. Chem Res Toxicol. 2014 Mar 17;27(3):314-29. doi: 10.1021/tx400410s. Epub 2014 Jan 21. PubMed PMID: 24446777; PubMed Central PMCID: PMC3964730.

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