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Chauhan, V.P.* ; Hamada, N.* ; Monceau, V.* ; Ebrahimian, T.G.* ; Adam, N.* ; Wilkins, R.C.* ; Sebastian, S.* ; Patel, Z.S.* ; Huff, J.L.* ; Simonetto, C. ; Iwasaki, T.* ; Kaiser, J.C. ; Salomaa, S.* ; Moertl, S.* ; Azimzadeh, O.*

Expert consultation is vital for adverse outcome pathway development: A case example of cardiovascular effects of ionizing radiation.

Int. J. Radiat. Biol., DOI: 10.1080/09553002.2021.1969466 (2021)
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BACKGROUND: The circulatory system distributes nutrients, signaling molecules, and immune cells to vital organs and soft tissues. Epidemiological, animal, and in vitro cellular mechanistic studies have highlighted that exposure to ionizing radiation (IR) can induce molecular changes in cellular and subcellular milieus leading to long-term health impacts, particularly on the circulatory system. Although the mechanisms for the pathologies are not fully elucidated, endothelial dysfunction is proven to be a critical event via radiation-induced oxidative stress mediators. To delineate connectivities of events specifically to cardiovascular disease (CVD) initiation and progression, the adverse outcome pathway (AOP) approach was used with consultation from field experts. AOPs are a means to organize information around a disease of interest to a regulatory question. An AOP begins with a molecular initiating event and ends in an adverse outcome via sequential linkages of key event relationships that are supported by evidence in the form of the modified Bradford-Hill criteria. Detailed guidelines on building AOPs are provided by the Organisation for Economic Cooperation and Development (OECD) AOP program. Here, we report on the questions and discussions needed to develop an AOP for CVD resulting from IR exposure. A recent workshop jointly organized by the MELODI (Multidisciplinary European Low Dose Initiative) and the ALLIANCE (European Radioecology Alliance) associations brought together experts from the OECD to present the AOP approach and tools with examples from the toxicology field. As part of this workshop, four working groups were formed to discuss the identification of adverse outcomes relevant to radiation exposures and development of potential AOPs, one of which was focused on IR-induced cardiovascular effects. Each working group comprised subject matter experts and radiation researchers interested in the specific disease area and included an AOP coach. Conclusion: The working group identified the critical questions of interest for AOP development, including the exposure scenario that would inform the evidence, the mechanisms of toxicity, the initiating event, intermediate key events/relationships, and the type of data currently available. This commentary describes the four-day discussion of the CVD working group, its outcomes, and demonstrates how collaboration and expert consultation is vital to informing AOP construction.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Review
Schlagwörter Adverse Outcome Pathway ; Adverse Outcome ; Cardiovascular Disease ; Circulatory Disease ; Key Events ; Low Dose Radiation ; Vascular Disease; Inflammatory Plaque Phenotype; Ischemic-heart-disease; Endothelial-cells; Apoe(-/-) Mice; Atherosclerotic Plaque; Cardiac Toxicity; Mortality; Irradiation; Strategies; Exposure
Sprache englisch
Veröffentlichungsjahr 2021
HGF-Berichtsjahr 2021
ISSN (print) / ISBN 0955-3002
e-ISSN 1362-3095
Zeitschrift International Journal of Radiation Biology
Verlag Informa Healthcare
Verlagsort 2-4 Park Square, Milton Park, Abingdon Or14 4rn, Oxon, England
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Radiation Medicine (IRM)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Radiation Sciences
PSP-Element(e) G-501391-001
Förderungen Human Health and Performance
Human Research Program of the Human Exploration and Operations Mission Directorate of the National Aeronautics and Space Administration
DOI 10.1080/09553002.2021.1969466
WOS ID WOS:000692329300001
Scopus ID 85114242213
PubMed ID 34402738
Erfassungsdatum 2021-10-04
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