Radiation adverse outcome pathways (AOPs) are on the horizon: advancing radiation protection through an international Horizon-Style exercise

Abstract

Purpose

The Adverse Outcome Pathway (AOP) framework, a systematic tool that can link available mechanistic data with phenotypic outcomes of relevance to regulatory decision-making, is being explored in areas related to radiation risk assessment. To examine the challenges including the use of AOPs to support the radiation protection community, an international horizon-style exercise was initiated through the Organisation for Economic Co-operation and Development Nuclear Energy Agency High-Level Group on Low Dose Research Radiation/Chemical AOP Joint Topical Group. The objective of the HSE was to facilitate the collection of ideas from a range of experts, to short-list a set of priority research questions that could, if answered, improve the description of the radiation dose-response relationship for low dose/dose-rate exposures, as well as reduce uncertainties in estimating the risk of developing adverse health outcomes following such exposures.

Materials and methods

The HSE was guided by an international steering committee of radiation risk experts. In the first phase, research questions were solicited on areas that can be supported by the AOP framework, or challenges on the use of AOPs in radiation risk assessment. In the second phase, questions received were refined and sorted by the SC using a best-worst scaling method. During a virtual 3-day workshop, the list of questions was further narrowed. In the third phase, an international survey of the broader radiation protection community led to an orderly ranking of the top questions.

Results

Of the 271 questions solicited, 254 were accepted and categorized into 9 themes. These were further refined to the top 25 prioritized questions. Among these, the higher ranked questions will be considered as ‘important’ to drive future initiatives in the low dose radiation protection community. These included questions on the ability of AOPs to delineate responses across different levels of biological organization, and how AOPs could be applied to address research questions on radiation quality, doses or dose-rates, exposure time patterns and deliveries, and uncertainties in low dose/dose-rate effects. A better understanding of these concepts is required to support the use of the AOP framework in radiation risk assessment.

Conclusion

Through dissemination of these results and considerations on next steps, the JTG will address select priority questions to advance the development and use of AOPs in the radiation protection community. The major themes observed will be discussed in the context of their relevance to areas of research that support the system of radiation protection.

Keywords:

• Adverse outcome pathway
• regulatory application
• survey
• low dose radiation
• radiation protection
• risk assessment

Acknowledgments

The authors wish to acknowledge the assistance of Annick Laporte (CNSC) and Veronica Grybas (Health Canada) with developing graphics and the Research and Support team at the CNSC. The authors also thank CNSC and Health Canada staff for their valuable insights in reviewing this manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The HSE was partially funded through the Canadian Organization on Health Effects from Radiation Exposure (COHERE), through project number R719.2 with the contract number 3000725863 provided by the Canadian Nuclear Safety Commission. The work of KET is partially funded by grants from the Research Council of Norway (RCN) through its Center of Excellence (CoE) funding scheme [Project No. 223268] and NIVAs Computational Toxicology Program, NCTP (www.niva.no/nctp, RCN Project no. 160016).

Notes on contributors

Julie J. Burtt

Julie J. Burtt is a radiation biologist with the Canadian Nuclear Safety Commission. Her research focuses on the potential health effects of exposure to low doses of ionizing radiation. She has experience as an advisor for Canada to the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) as well as a technical expert for the UNSCEAR Secretariat. She also serves as vice-chair of the National Energy Agency’s Expert Group on Non-radiological Public Health Aspects of Radiation Emergency Planning and Response. Julie is also a member of Committee 4 for the International Commission on Radiological Protection.

Julie Leblanc

Julie Leblanc Ph.D., is a radiation biologist with the Canadian Nuclear Safety Commission. Her research focuses on the potential health effects of exposure to low doses of ionizing radiation. She is a Canadian Delegate on the High-Level Group on Low Dose Research and International Commission on Radiological Protection mentee and member of Task Group 111.

Kristi Randhawa

Kristi Randhawa is a Radiation and Health Sciences Officer (epidemiology) with the Canadian Nuclear Safety Commission. Her research involves studying the health effects of ionizing radiation exposure, particularly exposure to low doses of radiation or radiation delivered at low dose-rates. She works as a coordinator and advisor for various research projects and working groups including for the International Society of Radiation Epidemiology and Dosimetry (ISoRED).

Addie Ivanova

Addie Ivanova is a Radiation and Health Sciences Officer with the Canadian Nuclear Safety Commission (CNSC). Her research focuses on health effects of ionizing radiation at low doses and the implications for radiation protection. She represents the CNSC on Theme 1 (Health) of Canada’s Federal Nuclear Science and Technology Committee and the CANDU Owner’s Group (COG) Strategic Research and Development Low Dose Program.

Murray A. Rudd

Murray Rudd Ph.D., is an economics and policy research consultant. He held prior academic appointments at World Maritime University (Sweden), Emory University (USA), the University of York (UK), and Memorial University (Canada). Dr. Rudd is an applied economist and policy researcher by training. Over recent years, much of his work has focused on assessing emerging research priorities for environmental science and on the ocean science-policy interface. He left academia in 2019 and has since been working as independent consultant in environmental economics and science horizon scanning.

Ruth Wilkins

Ruth C. Wilkins Ph.D., is a Research Scientist at the Consumer and Clinical Radiation Protection Bureau of Health Canada and the Chief of the Ionizing Radiation Health Sciences Division. She graduated with a Ph.D. in Medical Physics from Carleton University and has been employed at Health Canada for the past 25 years. She is an Adjunct Professor and lecturer in Radiobiology in the Department of Physics at Carleton University and the alternative representative of Canada to the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR).

Edouard I. Azzam

Edouard Azzam is a Radiation Biologist at Canadian Nuclear Laboratories. He is also Professor Emeritus at Rutgers New Jersey Medical School and member of the US National Council on Radiation Protection and Measurements. His research over the past three decades has focused on the role of intercellular communication and oxidative metabolism in expression of adaptive responses and bystander effects induced by low doses/low fluences of ionizing radiation from environmental, occupational, or medical sources.

Markus Hecker

Markus Hecker is a Professor and Canada Research Chair in Predictive Aquatic Toxicology, with 24 years of experience in conducting research in ecotoxicology and chemical hazard assessment. He is considered a global expert in environmental risk assessment, ecotoxicogenomics, hazard characterization of contaminants in native fishes and amphibians, and development of alternatives to live animal testing. Dr. Hecker is a member of the College of the Royal Society of Canada, and a visiting/guest professor at Xiamen University, China. He is the co-Editor-in-Chief of Aquatic Toxicology and has been a member of the board of directors of the Society of Toxicology and Chemistry (North America) for the past three years. Dr. Hecker served as an advisor/expert to several national and international organizations including Environment and Climate Change Canada, Health Canada, the U.S. Environmental Protection Agency, the European Food Security Agency and the Organization for Economic Cooperation and Development. He has authored or coauthored over 190 peer-reviewed papers, review articles, editorials and book chapters over his career.

Nele Horemans

Nele Horemans Ph.D., Leads the research group Biosphere Impact Studies at the Belgian Nuclear Research Center (SCK CEN). Additionally, she is guest docent at the Center of Environmental sciences at Hasselt University (Belgium) for courses on ‘ecotoxicology & environmental radioecology’ and ‘experimental design’. Within the radioecology platform ALLIANCE she leads the working group on transgenerational effects and species sensitivity to radiation. Her main research topic of interest is on the effects induced by ionizing radiation in plants from the molecular to the population level. This includes both lab and field-based studies. She is author of more than 90 peer reviewed papers and has an H-index of 30 (Web of Science).

Hildegarde Vandenhove

Hildegarde Vandenhove Ph.D., is the Director of the Institute for the Environment, Health, and Safety (EHS) at the Belgium Research Center.

Christelle Adam-Guillermin

Christelle Adam-Guillermin Ph.D., is a research scientist in radioecotoxicology at the French Institute for Radiological Protection and Nuclear Safety (IRSN). In 2012, she became head of the radionuclide ecotoxicology laboratory (LECO/IRSN) until 2019, when she moved to the dosimetry division to lead radiobiology research programs at the MIRCOM microbeam. Her research focuses on the biological effects of low ionizing radiation (IR) doses and charged particles of different LET, especially on DNA (nuclear and mitochondrial) and epigenetic factors, and on characterization of biomarkers of radiation effects applicable to reprotoxicity and neurodegeneration. She has been involved in several collaborative international research projects including the EC funded ERICA (FP6, 2004–2007) and COMET project (FP7, 2013-2017). She has led the ALLIANCE’s working group on IR transgenerational effects and radiosensitivity from 2015 to 2019 and is now member of the expert group on the development of radioprotection for non-human biota (ICRP Committee 1, IAEA/MODARIA group, OECD/NEA RAD/CHEM AOP working group of High-Level Group on Low-Dose Research, Article 31 Group of Experts of the European Commission).

Olivier Armant

Olivier Armant Ph.D., is a senior scientist at the French Institute of Radioprotection and Nuclear Safety (IRSN). His studies focus on the molecular mechanisms deregulated upon exposure to low dose of radiations during embryonic development and post-accidental effects on wild-life in Chernobyl and Fukushima. He is a member of the High-Level Group on Low-Dose Research (HLG-LDR) Rad/Chem Joint Topical Group.

Dmitry Klokov

Dmitry Klokov is a Ph.D., in radiobiology, head of the Laboratory of Experimental Radiotoxicology and Radiobiology at the Institute of Radioprotection and Nuclear Safety in France. He also holds an Adjunct Professor position at the Department of Biochemistry, Microbiology and Immunology of the University of Ottawa. For 12 years, Dmitry Klokov has led a low-dose radiobiology program at the Canadian Nuclear Laboratories. His research interests include various domains within the filed of low-dose radiation effects, with an overarching goal to understand mechanisms of early genotoxic and molecular responses and how they may contribute to long-term health outcomes, such as cancer, cardiovascular and neurological pathologies and multigenerational effects. Dmitry Klokov has published 50+ papers, several book chapters, gave multiple invited talks. He has also been involved in various international initiatives in low-dose radiobiological research and cooperation, including those coordinated by UNSCEAR, NEA, MELODI, DOE, and others.

Karine Audouze

Karine Audouze (KA), professor at the Université Paris Cité, is leading the Systems Toxicology group at INSERM. Her group has developed artificial intelligence-based tools to help the development of AOPs such as AOP-helpFinder (http://aop-helpfinder.u-paris-sciences.fr/). KA is member of the OECD advisory EAGMST working group, and of the AOP-KB and Rad/Chem AOP subgroups. KA is the coordinator of the H2020 OBERON project (https://oberon-4eu.com/) and is involved in various other ongoing EU projects such as Horizon Europe PARC and the H2020 RadoNorm.

Jan Christian Kaiser

Jan Christian Kaiser leads the working group ‘Integrative Modeling’ in the Institute of Radiation Medicine at the Helmholtz-Zentrum München, German Research Center for Environmental Health, in Munich, Germany. He holds a doctoral and masters’ degree in statistical physics. His research involves integration of molecular biology and radiation epidemiology in biologically-based risk models.

Simone Moertl

Simone Moertl Ph.D., PD, is head of the section of Radiation Biology at the Federal Office for Radiation Protection (BfS) and an Adjunct Professor (Docent) of Radiation Biology at Technical University Munich. Until September 2019 she led the group of Clinical Radiobiology at the Institute of Radiation Biology, Helmholtz Zentrum München. Her research focuses on the cellular radiation response of tumors and normal tissues with the aim to understand the mechanisms of individual radiation sensitivity. She is particularly interested in the vesicle-mediated transfer (e.g. by exosomes) of RNAs between cells. She is a member of the HLG-LDR Rad/Chem AOP Joint Topical Group.

Katalin Lumniczky

Katalin Lumniczky MD, Ph.D., is the head of the Unit of Radiation Medicine, Department of Radiobiology and Radiohygiene, National Public Health Center Budapest, Hungary. She is a radiation biologist with a more than 20 years experience in the field.

Ignacia B. Tanaka

Ignacia B. Tanaka III DVM, Ph.D., is a Senior Researcher with the Pathology Group, Radiobiology Department at the Institute for Environmental Sciences (IES) at Rokkasho Village, Aomori, Japan. She received her Ph.D. (Doctor of Veterinary Science) from Hokkaido University (Graduate School of Veterinary Medicine), Japan. She is also holds an MS in Agriculture (Ruminant Nutrition, Obihiro University, Japan) and is a veterinarian (DVM, University of the Philippines, Philippines). Current interests are veterinary pathology and radiation biology [in utero, transgeneration and late effects (e.g. life span, neoplasia and non-neoplastic disease) of chronic low dose-rate radiation exposure in mice].

Yutaka Yamada

Yutaka Yamada DVM, Ph.D., is a research scientist of the Department of Radiation Effects Research, National Institute of Radiological Sciences, QST, Japan. His main field is radiation biology and radiotoxicology, and he has been focused on radiation-induced pulmonary carcinogenesis.

Nobuyuki Hamada

Nobuyuki Hamada RT, Ph.D., is a Senior Research Scientist at CRIEPI and a Visiting Professor at Hiroshima University Research Institute for Radiation Biology and Medicine. He serves on ICRP Task Groups 102, 111 and 119, NCRP PAC 1, OECD/NEA/CRPPH/HLG-LDR/Rad/Chem AOP Joint Topical Group, IRPA Task Group on Tissue Reactions, and Consultation Committee on AOP development for space flight health outcomes (Canadian project).

Isaf Al-Nabulsi

Isaf Al-Nabulsi serves as the DOE Japan Program Manager since 2012. She also serves as the DOE Program Manager for the agency’s participation in the Study of One Million U.S. Radiation Workers and Veterans. She previously served as an Acting Director, Office of Domestic and International Health Studies within the Office of Health and Safety, Office of Environment, health, Safety and Security, and was responsible for managing and coordinating day-to-day activities associated with the domestic and international health studies, including enduring that office activities comply with departmental regulations and law. Dr. Al-Nabulsi also served as Senior Technical Advisor, from 2012–2020, to Director, Office of Health and Safety and provided advice on a wide range of topics related to the office’s mission. Prior to joining DOE, she worked at the National Council on Radiation Protection and Measurements and the National Research Council/National Academy of Sciences. She has more than thirty years of scientific research and technical program management experience. Her research interest includes understanding health effects of low dose radiation exposures. She is a member of the Radiation Research Society, Health Physics Society, American Association for Cancer Research, and the National Energy Agency Organization for Economic Co-operation and Development High-Level Group on Low-Dose Research as well as the National Energy Agency Rad/Chem AOP Joint Topical Group.

R. Julian Preston

R. Julian Preston Ph.D., has a Special Government Employee (Expert, Radiation Effects) appointment at the U.S. Environmental Protection Agency (EPA). He previously served as the Associate Director for Health (2007–2012) and the Director of the Environmental Carcinogenesis Division at EPA. Dr. Preston’s research and current activities have focused on how knowledge of the mechanisms of induction of radiation-induced adverse health effects can be used in cancer risk assessments. He has served in various capacities with NCRP, ICRP (including Chair, Committee 1, and Radiation Effects) and UNSCEAR (Representative and Head of Delegation). Dr Preston was the 2002 Lauriston S. Taylor Lecturer awarded by the NCRP and is a Fellow of the UK’s Royal Society for Radiation Protection. Dr. Preston has published over 250 peer reviewed papers. He has served on National Academies’ committees including in 2021 as Vice Chair of the committee ‘Space Radiation and Astronaut Health: Managing and Communicating Cancer Risks’. He also serves on an OECD/NEA committee addressing the use of Adverse Outcome Pathways in cancer risk assessment at low doses and dose-rates. He received his B.A. and M.A. from Peterhouse, Cambridge University, England, in genetics and his Ph.D. from Reading University, England, in radiation genetics.

Simon Bouffler

Simon Bouffler is the deputy director of the Radiation Protection Science at the UK Health Security Agency. He was trained as a biologist, receiving a BSc and Ph.D. from the University of Southampton. Simon is a member of the main commission of ICRP and the UK representative to UNSCEAR.

Kimberly Applegate

Kimberly Applegate (USA) is the chair of Committee 3 of the ICRP, focusing on radiation protection in medicine and a member of the National Council for Radiation Protection and Measurements (NCRP). Dr. Applegate is a retired professor of radiology and pediatrics from the University of Kentucky in Lexington. Dr. Applegate’s policy and research work, including 200 publications, has contributed to an improved understanding of the structure, process, and outcomes of how imaging, especially pediatrics, is practiced, including the volume and variation of imaging practice, toward its improvement and standardization. She has worked collaboratively around the world across medical specialties and geographic boundaries to improve access to best practices. From its start in 2007 to the present, she has worked on the Steering Committee for the Image Gently Campaign to improve children’s care worldwide. Kimberly has received several awards that include the 2019 AAPM’s Honorary Membership and the American Association for Women in Radiology’s Marie Sklowdoska Curie Award for her unique roles in leadership and outstanding contributions to the advancement of women in the Radiology professions. She and her husband, George Parker, MD, have three grown sons, David, and twins Andrew and Eric.

Donald Cool

Donald Cool is the Vice-Chair of the Main Commission of the International Commission on Radiological Protection. He was the Technical Executive for Radiation Safety with the Electric Power Research Institute (EPRI) until December 2021, and prior to EPRI spent nearly 33 years with U.S. Nuclear Regulatory Commission, where he served in various Senior Executive and Senior Advisor positions. Dr. Cool received his Master’s and Doctorate degrees in Radiation Biology from the University of Rochester, School of Medicine and Dentistry. He is a Council Member of the U.S. National Council on Radiation Protection and Measurements and the Co-Chair of NCRP Council Committee 1 which produced NCRP Report 180, Management of Exposure to Ionizing Radiation: Radiation Protection Guidance for the United States. He has served on numerous panels and expert groups of the International Atomic Energy Agency and Nuclear Energy Agency. He is a Fellow of the Health Physics Society.

Danielle Beaton

Danielle Beaton Ph.D., is a Research Scientist at Canadian Nuclear Laboratories. Her current research focuses on the effects of low dose radiation on biological systems. She is on the NEA HLG-LDR committee and assists the co-chairs of the HLG-LDR Rad/Chem AOP Joint Topical Group.

Knut Erik Tollefsen

Knut Erik Tollefsen Ph.D., is a Chief Scientist at the Norwegian Institute for Water Research (NIVA), an Adjunct professor at the Norwegian University of Life Sciences (NMBU) and is a principal investigator and research area co-lead in the Center for Environmental Radioactivity (CERAD CoE). He is also the Norwegian delegate of the HLG-LDR and OECD EAGMST, co-chairs the HLG-LDR Rad/Chem AOP Joint Topical Group, co-ordinates NIVA’s Computational Toxicology Program, NCTP (www.niva.no/nctp) and is a registered OECD AOP coach.

Jacqueline Garnier-Laplace

Jacqueline Garnier-Laplace Ph.D., a Senior Radiation Protection Specialist, is Deputy Head of the Division of Radiological Protection and Human Aspects of Nuclear Safety at the OECD Nuclear Energy Agency. She is the Scientific Secretary of the Committee on Radiological Protection and Public Health, and of the NEA HLG-LDR. Previously, she headed Radiation Protection research at France’s IRSN. She served as scientific secretary of ICRP Committee 1 from 2017 to 2021 and is currently serving on Committee 4 with the same function.

Dominique Laurier

Dominique Laurier Ph.D., is a Senior Epidemiologist and deputy director of health at the Health and Environment Division of the French Institute for Radiation Protection and Nuclear Safety (IRSN). He is Chair of Committee 1 of the International Commission on Radiological Protection (ICRP), French representative to UNSCEAR, and Chair of the NEA HLG-LDR.

Vinita Chauhan

Vinita Chauhan Ph.D., is a Senior Research Scientist at the Consumer and Clinical Radiation Protection Bureau of Health Canada. She is a Canadian delegate of the High-Level Group on Low Dose Research (HLG-LDR) and Extended Advisory Group on Molecular Screening and Toxicogenomics (EAGMST) of the OECD. She co-chairs the OECD/NEA/HLG-LDR Rad/Chem AOP Joint Topical Group and is the co-founder of the Canadian Organization of Health Effects from Radiation Exposure (COHERE) initiative. [ORCID: 0000-0002-4498-0915]