Representing the process of inflammation as key events in adverse outcome pathways

Daniel L. Villeneuve, Brigitte Landesmann, Paola Allavena, Noah Ashley, Anna Bal-Price, Emanuela Corsini, Sabina Halappanavar, Tracy Hussell, Debra Laskin, Toby Lawrence, David Nikolic-Paterson, Marc Pallardy, Alicia Paini, Raymond Pieters, Robert Roth, Florianne Tschudi-Monnet

Research output: Contribution to journalArticleOtherpeer-review

48 Citations (Scopus)


Inflammation is an important biological process involved in many target organ toxicities. However, there has been little consensus on how to represent inflammatory processes using the adverse outcome pathway (AOP) framework. In particular, there were concerns that inflammation was not being represented in a way that it would be recognized as a highly connected, central node within the global AOP network. The consideration of salient features common to the inflammatory process across tissues was used as a basis to propose 3 hub key events (KEs) for use in AOP network development. Each event, "tissue resident cell activation", "increased pro-inflammatory mediators", and "leukocyte recruitment/activation," is viewed as a hallmark of inflammation, independent of tissue, and can be independently measured. Using these proposed hub KEs, it was possible to link together a series of AOPs that previously had no shared KEs. Significant challenges remain with regard to accurate prediction of inflammation-related toxicological outcomes even if a broader and more connected network of inflammation-centered AOPs is developed. Nonetheless, the current proposal addresses one of the major hurdles associated with representation of inflammation in AOPs and may aid fit-for-purpose evaluations of other AOPs operating in a network context.

Original languageEnglish
Pages (from-to)346-352
Number of pages7
JournalToxicological Sciences
Issue number2
Publication statusPublished - 1 Jun 2018


  • Adverse outcome pathway
  • Cell activation
  • Damage repair
  • Knowledge management
  • Networks

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