Adverse outcome pathway development II: Best practices

Daniel L. Villeneuve, Doug Crump, Natàlia Garcia-Reyero, Markus Hecker, Thomas H. Hutchinson, Carlie A. LaLone, Brigitte Landesmann, Teresa Lettieri, Sharon Munn, Malgorzata Nepelska, Mary Ann Ottinger, Lucia Vergauwen, Maurice Whelan

Research output: Contribution to journalArticlepeer-review

182 Scopus citations


Organization of existing and emerging toxicological knowledge into adverse outcome pathway (AOP) descriptions can facilitate greater application of mechanistic data, including those derived through high-throughput in vitro, high content omics and imaging, and biomarker approaches, in risk-based decision making. The previously ad hoc process of AOP development is being formalized through development of internationally harmonized guidance and principles. The goal of this article was to outline the information content desired for formal AOP description and some rules of thumb and best practices intended to facilitate reuse and connectivity of elements of an AOP description in a knowledgebase and network context. For example, key events (KEs) are measurements of change in biological state that are indicative of progression of a perturbation toward a specified adverse outcome. Best practices for KE description suggest that each KE should be defined as an independent measurement made at a particular level of biological organization. The concept of "functional equivalence" can help guide both decisions about how many KEs to include in an AOP and the specificity with which they are defined. Likewise, in describing both KEs and evidence that supports a causal linkage or statistical association between them (ie, a key event relationship; KER), best practice is to build from and contribute to existing KE or KER descriptions in the AOP knowledgebase rather than creating redundant descriptions. The best practices proposed address many of the challenges and uncertainties related to AOP development and help promote a consistent and reliable, yet flexible approach.

Original languageEnglish (US)
Pages (from-to)321-330
Number of pages10
JournalToxicological Sciences
Issue number2
StatePublished - Dec 1 2014

Bibliographical note

Funding Information:
The American Chemistry Council, BioDetection Systems, European Centre for Ecotoxicology and Toxicology of Chemicals, Environment Canada, European Commission Directorate General Joint Research Centre, Human Toxicology Project Consortium, International Life Sciences Institute—Health and Environmental Science Institute, The Research Council of Norway (Grant No. 221455), Society for Environmental Toxicology and Chemistry, US Army Engineer Research and Development Center, and the US Environmental Protection Agency contributed support for the workshop.

Publisher Copyright:
© The Author 2014.


  • Adverse outcome pathway
  • Extrapolation
  • Knowledgebase
  • Predictive toxicology
  • Regulatory toxicology


Dive into the research topics of 'Adverse outcome pathway development II: Best practices'. Together they form a unique fingerprint.

Cite this