Radiation Adverse Outcome pathways (AOPs): examining priority questions from an international horizon-style exercise.

PURPOSE: The Organisation for Economic Co-operation and Development (OECD) Adverse Outcome Pathway (AOP) Development Programme is being explored in the radiation field, as an overarching framework to identify and prioritize research needs that best support strengthening of radiation risk assessment and risk management strategies. To advance the use of AOPs, an international horizon-style exercise (HSE) was initiated through the Radiation/Chemical AOP Joint Topical Group (JTG) formed by the OECD Nuclear Energy Agency (NEA) High-Level Group on Low Dose Research (HLG-LDR) under the auspices of the Committee on Radiological Protection and Public Health (CRPPH). The intent of the HSE was to identify key research questions for consideration in AOP development that would help to reduce uncertainties in estimating the health risks following exposures to low dose and low dose-rate ionizing radiation. The HSE was conducted in several phases involving the solicitation of relevant questions, a collaborative review of open-ended candidate questions and an elimination exercise that led to the selection of 25 highest priority questions for the stated purpose. These questions were further ranked by over 100 respondents through an international survey. This final set of questions was judged to provide insights into how the OECD's AOP approach can be put into practice to meet the needs of hazard and risk assessors, regulators, and researchers. This paper examines the 25 priority questions in the context of hazard/risk assessment framework for ionizing radiation. CONCLUSION: By addressing the 25 priority questions, it is anticipated that constructed AOPs will have a high level of specificity, making them valuable tools for simplifying and prioritizing complex biological processes for use in developing revised radiation hazard and risk assessment strategies.

Application of the Cytokinesis-Block Micronucleus Assay for High-Dose Exposures Using Imaging Flow Cytometry.

The cytokinesis-block micronucleus assay is a well-established method to assess radiation-induced genetic damage in human cells. This assay has been adapted to imaging flow cytometry (IFC), allowing automated analysis of many cells, and eliminating the need to create microscope slides. Furthermore, to improve the efficiency of assay performance, a small-volume method previously developed was employed. Irradiated human blood samples were cultured, stained, and analyzed by IFC to produce images of the cells. Samples were run using both manual and 96-well plate automated acquisition. Multiple parameter-based image features were collected for each sample, and the results were compared to confirm that these acquisition methods are functionally identical. This paper details the multi-parametric analysis developed and the resulting calibration curves up to 10 Gy. The calibration curves were created using a quadratic random coefficient model with Poisson errors, as well as a logistic discriminant function. The curves were then validated with blinded, irradiated samples, using relative bias and relative mean square error. Overall, the accuracy of the dose estimates was adequate for triage dosimetry (within 1 Gy of the true dose) over 90% of the time for lower doses and about half the time for higher doses, with the lowest success rate between 5 and 6 Gy where the calibration curve reached its peak and there was the smallest change in MN/BNC with dose. This work describes the application of a novel multi-parametric analysis that fits the calibration curves and allows dose estimates up to 10 Gy, which were previously limited to 4 Gy. Furthermore, it demonstrates that the results from samples acquired manually and with the autosampler are functionally similar.

Considerations for application of benchmark dose modeling in radiation research: workshop highlights.

BACKGROUND: Exposure to different forms of ionizing radiation occurs in diverse occupational, medical, and environmental settings. Improving the accuracy of the estimated health risks associated with exposure is therefore, essential for protecting the public, particularly as it relates to chronic low dose exposures. A key aspect to understanding health risks is precise and accurate modeling of the dose-response relationship. Toward this vision, benchmark dose (BMD) modeling may be a suitable approach for consideration in the radiation field. BMD modeling is already extensively used for chemical hazard assessments and is considered statistically preferable to identifying low and no observed adverse effects levels. BMD modeling involves fitting mathematical models to dose-response data for a relevant biological endpoint and identifying a point of departure (the BMD, or its lower bound). Recent examples in chemical toxicology show that when applied to molecular endpoints (e.g. genotoxic and transcriptional endpoints), BMDs correlate to points of departure for more apical endpoints such as phenotypic changes (e.g. adverse effects) of interest to regulatory decisions. This use of BMD modeling may be valuable to explore in the radiation field, specifically in combination with adverse outcome pathways, and may facilitate better interpretation of relevant in vivo and in vitro dose-response data. To advance this application, a workshop was organized on June 3rd, 2022, in Ottawa, Ontario that brought together BMD experts in chemical toxicology and the radiation scientific community of researchers, regulators, and policy-makers. The workshop's objective was to introduce radiation scientists to BMD modeling and its practical application using case examples from the chemical toxicity field and demonstrate the BMDExpress software using a radiation dataset. Discussions focused on the BMD approach, the importance of experimental design, regulatory applications, its use in supporting the development of adverse outcome pathways, and specific radiation-relevant examples. CONCLUSIONS: Although further deliberations are needed to advance the use of BMD modeling in the radiation field, these initial discussions and partnerships highlight some key steps to guide future undertakings related to new experimental work.

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.

COHERE - strengthening cooperation within the Canadian government on radiation research.

PURPOSE: Canadian Organization on Health Effects from Radiation Exposure (COHERE) is a government initiative to better understand biological and human health risks from ionizing radiation exposures relevant to occupational and environmental settings (<100 mGy, <6 mGy/h). It is currently a partnership between two federal agencies, Health Canada (HC) and the Canadian Nuclear Safety Commission (CNSC). COHERE's vision is to contribute knowledge to reduce scientific uncertainties from low dose and dose-rate exposures. COHERE will advance our understanding by bridging the knowledge gap between human health risks and linkages to molecular- and cellular-level responses to radiation. Research focuses on identifying sensitive, early, and key molecular events of relevance to risk assessment. CONCLUSIONS: The initiative will address questions of relevance to better apprize Canadians, including radiation workers and members of the public and Indigenous peoples, on health risks from low dose radiation exposure and inform radiation protection frameworks at a national and international level. Furthermore, it will support global efforts to conduct collaborative undertakings and better coordinate research. Here, we describe a historical overview of the research conducted, the strategic research agenda that outlines the scientific framework, stakeholders, opportunities to harmonize internationally, and how research outcomes will better inform communication of risk to Canadians.

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.

Projecting thyroid cancer risk to the general public from radiation exposure following hypothetical severe nuclear accidents in Canada.

INTRODUCTION: A robust emergency management framework can limit radiation exposures and effectively minimize the potentially devastating consequences of a nuclear emergency. We projected thyroid cancer risk resulting from two hypothetical severe nuclear accidents occurring at the Darlington nuclear power plant (NPP) located in Ontario, Canada. METHODS: Single- and multi-unit accidents were considered. A dose assessment was previously performed using the MELCOR Accident Consequences Code System. The generic criteria used to select the appropriate protective actions are described in the Ontario Provincial Nuclear Emergency Response Plan (PNERP). We hypothesized protection actions only within the 10 kilometre (km) radius of the NPP given the time sensitivity of iodine thyroid blocking. The excess risk of developing thyroid cancer was projected using the US National Cancer Institute's radiation risk assessment tool RadRAT. RESULTS: We projected zero dose, and subsequently zero risk of developing thyroid cancer for people living within 10 km of the NPP, due to effective implementation of selected protective actions. Based on centreline doses, at the 12 km radius, excess childhood thyroid cancer risks of approximately 600% and 130% compared to the baseline were projected for the single- and multi-unit scenarios, respectively. The risk of developing thyroid cancer was projected to be low for adults for both scenarios. DISCUSSION: The results of this modelling study provide insights into the effectiveness of protective actions in reducing radiation-related thyroid cancer risk when considering hypothetical severe nuclear accidents. Implementation of select protective actions protects the population living near the Darlington NPP. The projected increase of developing thyroid cancer for children living beyond 10 km could potentially be eliminated with additional mitigation measures specified in the PNERP.

Radiation Biology and Its Role in the Canadian Radiation Protection Framework.

The linear no-threshold (linear-non-threshold) model is a dose-response model that has long served as the foundation of the international radiation protection framework, which includes the Canadian regulatory framework. Its purpose is to inform the choice of appropriate dose limits and subsequent as low as reasonably achievable requirements, social and economic factors taken into account. The linear no-threshold model assumes that the risk of developing cancer increases proportionately with increasing radiation dose. The linear no-threshold model has historically been applied by extrapolating the risk of cancer at high doses (>1,000 mSv) down to low doses in a linear manner. As the health effects of radiation exposure at low doses remain ambiguous, reducing uncertainties found in cancer risk dose-response models can be achieved through in vitro and animal-based studies. The purpose of this critical review is to analyze whether the linear no-threshold model is still applicable for use by modern nuclear regulators for radiation protection purposes, or if there is sufficient scientific evidence supporting an alternate model from which to derive regulatory dose limits.

Is there a role for the adverse outcome pathway framework to support radiation protection?

PURPOSE: In 2012, the Organization for Economic Cooperation and Development (OECD) formally launched the Adverse Outcome Pathway (AOP) Programme. The AOP framework has the potential for predictive utility in identifying early biological endpoints linked to adverse effects. It uses the weight of correlative evidence to identify a minimal set of measurable key events that link molecular initiating events to an adverse outcome. AOPs have the capability to identify knowledge gaps and priority areas for future research based on relevance to an adverse outcome. In addition, AOPs can identify pathways that are common among multiple stressors, thereby allowing for the possibility of refined risk assessments based on co-exposure considerations. The AOP framework is increasingly being used in chemical and ecological risk assessment; however, its use in the development of radiation-specific pathways has yet to be fully explored. To bring awareness of the AOP framework to the Canadian radiation community, a workshop was held in Canada in June 2018 that brought together radiation experts from Health Canada, the Canadian Nuclear Laboratories, and the Canadian Nuclear Safety Commission. METHODS: The purpose of the workshop was to share knowledge on the AOP framework, specifically (1) to introduce the concept of the AOP framework and its possible utility to Canadian radiation experts; (2) to provide examples on how it has advanced risk assessment; (3) to discuss an illustrative example specific to ionizing radiation; and lastly (4) to identify the broad benefits and challenges of the AOP framework to the radiation community. RESULTS: The participants showed interest in the framework, case examples were described and areas of challenge were identified. Herein, we summarize the outcomes of the workshop. CONCLUSIONS: Overall, participants agreed that by building AOPs in the radiation field, a network of data-sharing initiatives will enhance our interpretation of existing knowledge where current scientific evidence is minimal. They would provide new avenues to understand effects at low-dose and dose-rates and help to quantify the combined effect of multiple stressors on shared mechanistic pathways.

Non-targeted effects and radiation-induced carcinogenesis: a review.

Exposure to ionising radiation is clearly associated with an increased risk of developing some types of cancer. However, the contribution of non-targeted effects to cancer development after exposure to ionising radiation is far less clear. The currently used cancer risk model by the international radiation protection community states that any increase in radiation exposure proportionately increases the risk of developing cancer. However, this stochastic cancer risk model does not take into account any contribution from non-targeted effects. Nor does it consider the possibility of a bystander mechanism in the induction of genomic instability. This paper reviews the available evidence to date for a possible role for non-targeted effects to contribute to cancer development after exposure to ionising radiation. An evolution in the understanding of the mechanisms driving non-targeted effects after exposure to ionising radiation is critical to determine the true contribution of non-targeted effects on the risk of developing cancer. Such an evolution will likely only be achievable through coordinated multidisciplinary teams combining several fields of study including: genomics, proteomics, cell biology, molecular epidemiology, and traditional epidemiology.