Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are formed as a result of natural cellular processes, intracellular signaling, or as adverse responses associated with diseases or exposure to oxidizing chemical and non-chemical stressors. The action of ROS and RNS, collectively referred to as reactive oxygen and nitrogen species (RONS), has recently become highly relevant in a number of adverse outcome pathways (AOPs) that capture, organize, evaluate and portray causal relationships pertinent to adversity or disease progression. RONS can potentially act as a key event (KE) in the cascade of responses leading to an adverse outcome (AO) within such AOPs, but are also known to modulate responses of events along the AOP continuum without being an AOP event itself. A substantial discussion has therefore been undertaken in a series of workshops named "Mystery or ROS" to elucidate the role of RONS in disease and adverse effects associated with exposure to stressors such as nanoparticles, chemical, and ionizing and non-ionizing radiation. This review introduces the background for RONS production, reflects on the direct and indirect effects of RONS, addresses the diversity of terminology used in different fields of research, and provides guidance for developing a harmonized approach for defining a common event terminology within the AOP developer community.

Canadian Nuclear Laboratories Chalk River ON Canada

Center for Gender specific Medicine Italian National Institute of Health Rome Italy

Centre for Environmental Radioactivity Norwegian University of Life Sciences Ås Norway

Department of Toxicology University of Würzburg Würzburg Germany

Division of Risk Assessment Center for Biological Safety and Research National Institute of Health Sciences Kawasaki Japan

Group of Alternative Method Development for Environmental Toxicity Testing IUF Leibniz Research Institute for Environmental Medicine Duesseldorf Germany

Health Canada Ottawa ON Canada

Independent Researcher Ohrid North Macedonia

Korea Institute of Science and Technology Europe Saarbrücken Germany

National Research Centre for the Working Environment Copenhagen Denmark

Norwegian Institute for Water Research Oslo Norway

Norwegian University of Life Sciences Ås Norway

Organisation for Economic Co operation and Development Paris France

Philip Morris International R and D Philip Morris Products SA Neuchatel Switzerland

RECETOX Faculty of Science Masaryk University Brno Czech Republic

Silent Spring Institute Newton MA United States

U S Army Engineer Research and Development Center Vicksburg MS United States

UK Health Security Agency Public Health England London United Kingdom

Universities of Basel and Geneva Basel Switzerland

University of Helsinki Ecosystems and Environment Research Programme Faculty of Biological and Environmental Sciences Lahti Finland and Helsinki Institute of Sustainability Science Helsinki Finland

University of Ottawa Ottawa ON Canada

Wildlife Toxicology Research Section Environment and Climate Change Canada Toronto ON Canada

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Application of AOPs to assist regulatory assessment of chemical risks - Case studies, needs and recommendations