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Toxicol Sci. 2018 Jun 1;163(2):346-352. doi: 10.1093/toxsci/kfy047.

Representing the Process of Inflammation as Key Events in Adverse Outcome Pathways.

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Mid-Continent Ecology Division, United States Environmental Protection Agency, Office of Research and Development, Duluth, Minnesota 55804.
European Commission, Joint Research Centre, 21027 Ispra, Italy.
IRCCS Humanitas and Clinical Research Center, 20089 Rozzano, Milan, Italy.
Department of Biology, Western Kentucky University, Bowling Green, Kentucky 42101.
Department of Environmental Science and Policy, Università degli Studi di Milano, Milan, Italy.
Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario K1A 0K9, Canada.
Collaborative Centre for Inflammation Research, University of Manchester, Manchester M13 9NT, UK.
Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854.
Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université UM2, Inserm, U1104 CNRS UMR7280, Marseille, France.
Monash University Centre for Inflammatory Diseases, Medicine Monash Health, Monash University,Clayton, Victoria 3168, Australia.
Inflammation Chimiokines et Immunopathologie, INSERM, Fac. de Pharmacie-Univ. Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
IRAS-Utrecht University and University of Applied Sciences Utrecht, CM 3584 Utrecht, The Netherlands.
Department of Pharmacology and Toxicology, Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824.
Department of Physiology, University of Lausanne, CH 1005 Lausanne, Switzerland.


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.


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