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

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.

Adverse outcome pathway: a path toward better data consolidation and global co-ordination of radiation research.

BACKGROUND: The purpose of toxicology is to protect human health and the environment. To support this, the Organisation for Economic Co-operation and Development (OECD), operating via its Extended Advisory Group for Molecular Screening and Toxicogenomics (EAGMST), has been developing the Adverse Outcome Pathway (AOP) approach to consolidate evidence for chemical toxicity spanning multiple levels of biological organization. The knowledge transcribed into AOPs provides a structured framework to transparently organize data, examine the weight of evidence of the AOP, and identify causal relationships between exposure to stressors and adverse effects of regulatory relevance. The AOP framework has undergone substantial maturation in the field of hazard characterization of chemicals over the last decade, and has also recently gained attention from the radiation community as a means to advance the mechanistic understanding of human and ecological health effects from exposure to ionizing radiation at low dose and low dose-rates. To fully exploit the value of such approaches for facilitating risk assessment and management in the field of radiation protection, solicitation of experiences and active cooperation between chemical and radiation communities are needed. As a result, the Radiation and Chemical (Rad/Chem) AOP joint topical group was formed on June 1, 2021 as part of the initiative from the High Level Group on Low Dose Research (HLG-LDR). HLG-LDR is overseen by the OECD Nuclear Energy Agency (NEA) Committee on Radiation Protection and Public Health (CRPPH). The main aims of the joint AOP topical group are to advance the use of AOPs in radiation research and foster broader implementation of AOPs into hazard and risk assessment. With global representation, it serves as a forum to discuss, identify and develop joint initiatives that support research and take on regulatory challenges. CONCLUSION: The Rad/Chem AOP joint topical group will specifically engage, promote, and implement the use of the AOP framework to: (a) organize and evaluate mechanistic knowledge relevant to the protection of human and ecosystem health from radiation; (b) identify data gaps and research needs pertinent to expanding knowledge of low dose and low dose-rate radiation effects; and (c) demonstrate utility to support risk assessment by developing radiation-relevant case studies. It is envisioned that the Rad/Chem AOP joint topical group will actively liaise with the OECD EAGMST AOP developmental program to collectively advance areas of common interest and, specifically, provide recommendations for harmonization of the AOP framework to accommodate non-chemical stressors, such as radiation.

Bringing together scientific disciplines for collaborative undertakings: a vision for advancing the adverse outcome pathway framework.

BACKGROUND: Decades of research to understand the impacts of various types of environmental occupational and medical stressors on human health have produced a vast amount of data across many scientific disciplines. Organizing these data in a meaningful way to support risk assessment has been a significant challenge. To address this and other challenges in modernizing chemical health risk assessment, the Organisation for Economic Cooperation and Development (OECD) formalized the adverse outcome pathway (AOP) framework, an approach to consolidate knowledge into measurable key events (KEs) at various levels of biological organisation causally linked to disease based on the weight of scientific evidence (http://oe.cd/aops). Currently, AOPs have been considered predominantly in chemical safety but are relevant to radiation. In this context, the Nuclear Energy Agency's (NEA's) High-Level Group on Low Dose Research (HLG-LDR) is working to improve research co-ordination, including radiological research with chemical research, identify synergies between the fields and to avoid duplication of efforts and resource investments. To this end, a virtual workshop was held on 7 and 8 October 2020 with experts from the OECD AOP Programme together with the radiation and chemical research/regulation communities. The workshop was a coordinated effort of Health Canada, the Electric Power Research Institute (EPRI), and the Nuclear Energy Agency (NEA). The AOP approach was discussed including key issues to fully embrace its value and catalyze implementation in areas of radiation risk assessment. CONCLUSIONS: A joint chemical and radiological expert group was proposed as a means to encourage cooperation between risk assessors and an initial vision was discussed on a path forward. A global survey was suggested as a way to identify priority health outcomes of regulatory interest for AOP development. Multidisciplinary teams are needed to address the challenge of producing the appropriate data for risk assessments. Data management and machine learning tools were highlighted as a way to progress from weight of evidence to computational causal inference.

The integration of the adverse outcome pathway framework to radiation risk assessment.

BACKGROUND: A large body of radiobiological data has been generated over the past century using in vitro, animal and epidemiological models. This information represents global efforts to understand the mechanistic basis of radiation-induced health effects. However, it has been difficult to effectively integrate this data to derive meaningful information for refining the guidance on chronic, low dose radiation exposure for workers and the public. METHODS: To increase our understanding of radiation risks and the biological processes that contribute to those risks, a paradigm shift is needed that will enable integration of information across levels of biological organization from a 'stressor' centric to an 'adverse outcome' approach to risk assessment. In chemical and ecological toxicity, a framework has been developed that captures available biologically-based knowledge in the literature and links it to outcomes of relevance to chemical toxicity, resulting in an adverse outcome pathway (AOP). RESULTS: In this paper, we discuss the AOP concept, how it can be applied to the radiation field, and our vision for the next steps. For the approach to be successful, the radiation research community will need to work collaboratively to vet the vast amount of literature and harness the data in a systematic manner for incorporation into a framework based on the AOP approach. CONCLUSION: We anticipate that AOPs could be adopted as a method to synthesize current available information to facilitate the identification of knowledge gaps, better co-ordinate research and qualitatively and quantitatively link key events to an adverse outcome. This can further assist in identifying biomarkers relevant to radiation exposures, refining risk from co-exposures and understanding critical events at the molecular, cellular, tissue, organ and whole animal level related to low dose/dose-rate exposures.

Collaborative efforts are needed among the scientific community to advance the adverse outcome pathway concept in areas of radiation risk assessment.

Disease prevention and prediction have led to the generation of phenotypically based methods for deriving the limits of safety across toxicological disciplines. In the ionizing radiation field, human data has formed the basis of the linear-no-threshold (LNT) model for risk estimates. However, uncertainties around its accuracy at low doses and low dose-rates have led to passionate debates on its effectiveness to derive radiation risk estimates under these conditions. Concerns arise from the linear extrapolation of data from high doses to low doses, below 0.1 Gy where there is considerable variability in the scientific literature. Efforts to address these controversies have led to a mountain of mechanistic data to improve the understanding of molecular and cellular effects related to phenotypic changes. These data provide fragments of information that have yet to be combined and used effectively to improve modeling, reduce uncertainties, and update radiation protection approaches. This paper suggests a better consolidation of mechanistic research may serve to guide priority research and facilitate translation to risk assessment. An effective approach that may be implemented is the organization of data using the adverse outcome pathway (AOP) framework, a programme that has been launched by the Organization for Economic Cooperation and Development in the chemical toxicology field. The AOP concept has proved beneficial to human health and ecological toxicological fields, demonstrating possibilities for better linkages of mechanistic data to phenotypic effects. A similar approach may be beneficial to the field of radiation research. However, for this to work effectively, collaborative efforts are needed among the scientific communities in the area of AOP development and documentation. Studies will need to be evaluated, re-organized and integrated into AOPs. Here, details of the AOP approach and areas it could support in the radiation field are discussed. In addition, challenges are highlighted and steps to integration are outlined. Organizing studies in this manner will facilitate a better understanding of our current knowledge in the radiation field and help identify areas where more focused work can be undertaken. This will, in turn, allow for improved linkage of mechanistic data to human relevance and better support radiation risk assessments.

International coordination of research: EPRI International Dose Effect Alliance.

Purpose: The key to increasing our understanding of low dose effects of ionizing radiation is cooperation and communication between research organizations around the world. The purpose of this article is to describe the Electric Power Research Institute (EPRI) program for such cooperation. Materials and methods: EPRI is an independent, non-profit organization dedicated to research support for the generation, transmission, and utilization of electricity. As part of its robust program, EPRI has sought to support research into low dose ionizing radiation health effects. Starting in 2016, one piece of the radiation safety program has been the International Dose Effect Alliance (IDEA), the mission of which is to organize collaborative meetings to bring together researchers from around the world to discuss research agendas, programs, and priorities. Results: IDEA workshops were held in the fall of 2016 and 2017, and were successful in starting the dialogue toward increased collaboration within the United States, Canada, Asia, and Europe. EPRI supports global collaboration and cooperation as a key opportunity to build upon the work being undertaken throughout the world to create a unified effort to answer the questions of low dose and dose rate ionizing radiation health effects. The International Workshop on the Biological Effects of Radiation, which was held in Osaka, Japan in March 2018, provided a further opportunity to expand upon the initiative for global collaboration. Conclusions: Significant advances are being achieved through the IDEA program, and the Osaka workshop held in Japan in March 2018 has further contributed to the initiative.

Health Risks From Low Doses and Low Dose-Rates of Ionizing Radiation. Session 5: Future of Radiation Protection Regulations.

The system of radiological protection is a prospective approach to protection of individuals in all exposure situations. It must be applied equitably across all age groups and all populations. This is a very different circumstance from dose assessment for a particular individual where the unique characteristics of the individual and the exposure can be taken into account. Notwithstanding the ongoing discussions on the possible shape of the dose response at low doses and dose rates, the prospective system of protection has therefore historically used a linear assumption as a pragmatic, prudent and protective approach. These radiation protection criteria are not intended to be a demarcation between "safe" and "unsafe" and are the product of a risk-informed judgement that includes inputs from science, ethics, and experience. There are significant implications for different dose response relationships. A linear model allows for equal treatment of an exposure, irrespective of the previously accumulated exposure. In contrast, other models would predict different implications. Great care is therefore needed in separating the thinking around risk assessment from risk management, and prospective protection for all age groups and genders from retrospective assessment for a particular individual. In the United States, the prospective regulatory structure functions effectively because of assumptions that facilitate independent treatment of different types of exposures, and which provide pragmatic and prudent protection. While the a linear assumption may, in fact, not be consistent with the biological reality, the implications of a different regulatory model must be considered carefully.

Summary of the NCRP 51st Annual Meeting.

Traditionally, the last presentation of the National Council on Radiation Protection and Measurements (NCRP) Annual Meeting is a summary of the presentations and discussions by the Program Committee Chair. Thus, it is now time to try to sum up a day and a half of very excellent presentations on a wide variety of subjects in this 51st Annual Meeting.