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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.

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.

Objective: Evidence suggests that the poorer mental health associated with attention deficit hyperactivity Disorder (ADHD) is partially explained by adverse psychosocial correlates of the condition. As recent studies show that self-compassion is negatively associated with ADHD, this study investigates if levels of self-compassion may explain the mental health outcomes in people with ADHD compared to people without ADHD., Method: A total of 543 adults with ADHD (62.72% female, 18-67 years), and 313 adults without ADHD (66.45% female, 18-82 years) completed questionnaires online to measure levels of self-compassion and mental health. A Structural Equation Model assessed the mediating effect of self-compassion on the relationships between ADHD and well-being (psychological, emotional, and social), and ADHD and ill-being (depression, anxiety, and stress)., Results: Findings suggest that low self-compassion contributes to poorer mental health in adults with ADHD compared to adults without ADHD., Conclusions: Thus, self-compassion may be a potential target to improve mental health in this population., Public Health Significance: This study shows that self-compassion is an important factor in the mental health of adults with ADHD and provides preliminary evidence for the use of self-compassion interventions to improve mental health outcomes in adults with ADHD., (© 2022 The Authors. Journal of Clinical Psychology published by Wiley Periodicals LLC.)

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., Competing Interests: KL and HY were employed by the company Philip Morris International (PMI). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tanabe, O’Brien, Tollefsen, Kim, Chauhan, Yauk, Huliganga, Rudel, Kay, Helm, Beaton, Filipovska, Sovadinova, Garcia-Reyero, Mally, Poulsen, Delrue, Fritsche, Luettich, La Rocca, Yepiskoposyan, Klose, Danielsen, Esterhuizen, Jacobsen, Vogel, Gant, Choi and FitzGerald.)

People with ADHD are at high risk of receiving criticism from others, yet criticism has not been well researched in this population. This study aimed to provide a rich understanding of what experiences adults with ADHD traits have with criticism. As part of a larger study, 162 participants with ADHD and high ADHD traits provided a written response to an open question asking about their experiences of criticism from other people. Thematic analysis was used to identify five common themes in the responses. Behaviours associated with inattention were perceived as the most criticised, whilst impulsive behaviours were mostly criticised in social contexts. Criticism was perceived via numerous conducts and was reported to have negative consequences for self-worth and wellbeing. To cope, some participants avoided criticism or changed how they reacted, including trying to accept themselves as they are. The responses indicated that receiving understanding from others played an important role in whether criticism was perceived. Overall, the findings highlight the need for more knowledge, understanding and acceptance towards neurodiversity from the general population., Competing Interests: The authors have declared that no competing interests exist.

Background: The Organisation for Economic Co-operation and Development (OECD), through its Chemical Safety Programme, is delegated to ensure the safety of humans and wildlife from harmful toxicants. To support these needs, initiatives to increase the efficiency of hazard identification and risk management are under way. Amongst these, the adverse outcome pathway (AOP) approach integrates information on biological knowledge and test methodologies (both established and new) to support regulatory decision making. AOPs collate biological knowledge from different sources, assess lines of evidence through considerations of causality, and undergo rigorous peer-review before being subsequently endorsed by the OECD. It is envisioned that the OECD AOP Development Programme will transform the toxicity testing paradigm by leveraging the strengths of mechanistic and modeling based approaches and enhance the utility of high throughput screening assays. Since its launch, in 2012, the AOP Development Programme has matured with a greater number of AOPs endorsed, and the attraction of new scientific disciplines (e.g. the radiation field). Recently, a radiation and chemical (Rad/Chem) AOP Joint Topical Group has been formed by the OECD Nuclear Energy Agency High-level Group on Low-dose Research (HLG-LDR) under the auspices of the Committee on Radiological Protection and Public Health (CRPPH). The topical group will work to evolve the development and use of the AOP framework in radiation research and regulation. As part of these efforts, the group will bring awareness and understanding on the program, as it has matured from the chemical perspective. In this context, this paper provides the radiation community with a high-level overview of the OECD AOP Development Programme, including examples of application using knowledge gleaned from the field of chemical toxicology, and their work toward regulatory implementation., Conclusion: Although the drivers for developing AOPs in chemical sector differ from that of the radiation field, the principles and transparency of the approach can benefit both scientific disciplines. By providing perspectives and an understanding of the evolution of the OECD AOP Development Programme including case examples and work toward quantitative AOP development, it may motivate the expansion and implementation of AOPs in the radiation field.

Background: Epidemiological studies have indicated that exposure of the heart to doses of ionizing radiation as low as 0.5 Gy increases the risk of cardiac morbidity and mortality with a latency period of decades. The damaging effects of radiation to myocardial and endothelial structures and functions have been confirmed radiobiologically at high dose, but much less are known at low dose. Integration of radiation biology and epidemiology data is a recommended approach to improve the radiation risk assessment process. The adverse outcome pathway (AOP) framework offers a comprehensive tool to compile and translate mechanistic information into pathological endpoints which may be relevant for risk assessment at the different levels of a biological system. Omics technologies enable the generation of large volumes of biological data at various levels of complexity, from molecular pathways to functional organisms. Given the quality and quantity of available data across levels of biology, omics data can be attractive sources of information for use within the AOP framework. It is anticipated that radiation omics studies could improve our understanding of the molecular mechanisms behind the adverse effects of radiation on the cardiovascular system. In this review, we explored the available omics studies on radiation-induced cardiovascular disease (CVD) and their applicability to the proposed AOP for CVD., Results: The results of 80 omics studies published on radiation-induced CVD over the past 20 years have been discussed in the context of the AOP of CVD proposed by Chauhan et al. Most of the available omics data on radiation-induced CVD are from proteomics, transcriptomics, and metabolomics, whereas few datasets were available from epigenomics and multi-omics. The omics data presented here show great promise in providing information for several key events (KEs) of the proposed AOP of CVD, particularly oxidative stress, alterations of energy metabolism, extracellular matrix (ECM), and vascular remodeling., Conclusions: The omics data presented here shows promise to inform the various levels of the proposed AOP of CVD. However, the data highlight the urgent need of designing omics studies to address the knowledge gap concerning different radiation scenarios, time after exposure, and experimental models. This review presents the evidence to build a qualitative omics-informed AOP and provides views on the potential benefits and challenges in using omics data to assess risk-related outcomes.

Background: Studies on human health and ecological effects of ionizing radiation are rapidly evolving as innovative technologies arise and the body of scientific knowledge grows. Structuring this information could effectively support the development of decision making tools and health risk models to complement current system of radiation protection. To this end, the adverse outcome pathway (AOP) approach is being explored as a means to consolidate the most relevant research to identify causation between exposure to a chemical or non-chemical stressor and disease or adverse effect progression. This tool is particularly important for low dose and low dose rate radiation exposures because of the latency and uncertainties in the biological responses at these exposure levels. To progress this aspect, it is essential to build a community of developers, facilitators, risk assessors (in the private sector and in government), policy-makers, and regulators who understand the strengths and weaknesses of, and how to appropriately utilize AOPs for consolidating our knowledge on the impact of low dose ionizing radiation. Through co-ordination with the Organisation of Economic Co-operation and Development (OECD) Nuclear Energy Agency (NEA) High-Level Group on Low-Dose Research (HLG-LDR) and OECD's AOP Programme, initiatives are under way to demonstrate this approach in radiation research and regulation. Among these, a robust communications strategy and stakeholder engagement will be essential. It will help establish best practices for AOPs in institutional project development and aid in dissemination for more efficient and timely uptake and use of AOPs. In this regard, on June 1, 2021, the Radiation and Chemical (Rad/Chem) AOP Joint Topical Group was formed as part of the initiative from the NEA's HLG-LDR. The topical group will work to develop a communication and engagement strategy to define the target audiences, establish the clear messages and identify the delivery and engagement platforms., Conclusion: The incorporation of the best science and better decision making should motive the radiation protection community to develop, refine and use AOPs, recognizing that their incorporation into radiation health risk assessments is critical for public health and environmental protection in the 21st century.

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.

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.

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.

Tritium ( 3 H) is a radioactive isotope of hydrogen. In the environment, the most common form of tritium is tritiated water (HTO). However, tritium can also be incorporated into organic molecules, forming organically bound tritium (OBT). The present study characterized the effects of tritium on the health of the fathead minnow, Pimephales promelas. Fish were exposed to a gradient of HTO (activity concentrations of 12,000, 25,000, and 180,000 Bq/L) and OBT using food spiked with tritiated amino acids (OBT only, with an activity concentration of 27,000 Bq/L). A combined exposure condition where fish were placed in 25,000 Bq/L water and received OBT through feed was also studied. Fish were exposed for 60 days, followed by a 60-day depuration period. A battery of health biomarkers were measured in fish tissues at seven time points throughout the 120 days required to complete the exposure and depuration phases. HTO and OBT were also measured in fish tissues at the same time points. Results showed effects of increasing tritium activity concentrations in water after 60 days of exposure. The internal dose rates of tritium, estimated from the tissue free-water tritium (TFWT) and OBT activity concentrations, reached a maximum of 0.65 μGy/h, which is relatively low considering background levels. No effects were observed on survival, fish condition, and metabolic indices (gonado-, hepato-, and spleno-somatic indexes (GSI, HSI, SSI), RNA/DNA and proteins/DNA ratios). Multivariate analyses showed that several biomarkers (DNA damages, micronucleus frequency, brain acetylcholinesterase, lysosomal membrane integrity, phagocytosis activity, and reactive oxygen species production) were exclusively correlated with fish tritium internal dose rate, showing that tritium induced genotoxicity, as well as neural and immune responses. The results were compared with another study on the same fish species where fish were exposed to tritium and other contaminants in natural environments. Together with the field study, the present work provides useful data to identify biomarkers for tritium exposure and better understand modes of action of tritium on the fathead minnow.

Discharge of groundwater contaminant plumes has created elevated concentrations of Sr in some aquatic sediments at Chalk River Laboratories. Tree swallows (Tachycenita bicolor) feed and supply their nestlings almost exclusively with airborne insects that developed as larvae in aquatic sediments. To monitor the uptake and test for potential detriment due to Sr in a terrestrial animal, we measured the gross beta concentrations in the bone of 12-d-old tree swallow nestlings in areas having sediments with elevated levels of gross beta (Sr and Y) and in several control areas where sediment gross beta was primarily due to naturally occurring K. Nesting behavior and reproductive success of the tree swallows were similar regardless of the gross beta concentrations in sediments near their nest boxes. Radiation can damage DNA and cause micronuclei to form in cells, so we examined the frequency of micronuclei in erythrocytes of nestlings. The formation of micronuclei in the erythrocytes of the nestlings was also similar wherever nestlings were analyzed. The results revealed no significant increases even near sediments with the highest gross beta levels. At Perch Lake, where Chalk River Laboratories has a large area of Sr-contaminated sediments, the bones of 12-d-old nestlings contained gross beta concentrations as high as 29 Bq g. This would produce a skeletal dose rate of 9 μGy h, which is one-fourth of the threshold dose rate of 40 μGy h, above which detriment could occur. Failing to find any indication of detriment in the field study, we irradiated wild eggs in the lab and returned them to their nest for natural incubation, hatching, and feeding by the parents. There was an increase in formation of micronuclei following a dose of 3.2 Gy, and the other results were consistent with existing literature.

Deep geologic repositories (DGR) in Canada are designed to contain and isolate low- and intermediate-level radioactive waste. Microbial degradation of the waste potentially produces methane, carbon dioxide and hydrogen gas. The generation of these gases increase rock cavity pressure and limit water ingress which delays the mobility of water soluble radionuclides. The objective of this study was to measure gas pressure and composition over 7 years in experiments containing cellulosic material with various starting conditions relevant to a DGR and to identify micro-organisms generating gas. For this purpose, we conducted experiments in glass bottles containing (1) wet cellulosic material, (2) wet cellulosic material with compost Maker, and (3) wet cellulosic material with compost Accelerator. Results demonstrated that compost accelerated the pressure build-up in the containers and that methane gas was produced in one experiment with compost and one experiment without compost because the pH remained neutral for the duration of the 464 days experiment. Methane was not formed in the other experiment because the pH became acidic. Once the pressure became similar in all containers after 464 days, we then monitored gas pressure and composition in glass bottle containing wet cellulosic material in (1) acidic conditions, (2) neutral conditions, and (3) with an enzyme that accelerated degradation of cellulose over 1965 days. In these experiments, acetogenic bacteria degraded cellulose and produced acetic acid, which acidity suppressed methane production. Microbial community analyses suggested a diverse community of archaea, bacteria and fungi actively degrading cellulose. DNA analyses also confirmed the presence of methanogens and acetogens in our experiments. This study suggests that methane gas will be generated in DGRs if pH remains neutral. However, our results showed that microbial degradation of cellulose not only generated gas, but also generated acidity. This finding is important as acids can limit bentonite swelling and potentially degrade cement and rock barriers, thus this requires consideration in the safety case as appropriate.

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.