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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.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.

The understanding of radiation-induced non-cancer effects on the central nervous system (CNS) is essential for the medical setting (e.g., radiotherapy), and occupational exposures, such as nuclear workers or astronauts. Herein, the adverse outcome pathway (AOP) approach was used to consolidate relevant studies in the area of cognitive decline for identification of research gaps, countermeasure development, and for eventual use in risk assessments. AOPs are an analytical construct describing critical events to an adverse outcome (AO) in a simplified form beginning with a molecular initiating event (MIE). An AOP was constructed utilizing mechanistic information to build empirical support for the key event relationships (KERs) between the MIE of deposition of energy to the AO of learning and memory impairment through multiple key events (KEs). The evidence for the AOP was developed through a scoping review of the literature. In this AOP, the MIE is connected to the AO via six KEs of increased oxidative stress, increased deoxyribonucleic acid (DNA) strand breaks, altered signaling pathways, tissue resident cell activation, increased pro-inflammatory mediators and neural remodeling. Deposition of energy directly leads to oxidative stress, increased DNA strand breaks, an increase of pro-inflammatory mediators and tissue resident cell activation. These KEs, which are themselves interconnected, converge through increased DNA strand breaks, altered signaling pathways and pro-inflammatory routes and directly lead to neural remodeling. Broadly, it is envisioned that the outcome of these efforts could be applied to other cognitive disorders and support ongoing work by international authorities to review the system of radiological protection.

Bone loss, commonly seen in osteoporosis, is a condition that entails a progressive decline of bone mineral density and microarchitecture, often seen in post-menopausal women. Bone loss has been widely reported in astronauts exposed to a plethora of stressors and in patients with osteoporosis following radiotherapy for cancer. Studies on mechanisms are well documented but the causal connectivity of events to bone loss development remains incompletely understood. Herein, the adverse outcome pathway (AOP) framework was used to organize data and develop a qualitative AOP beginning from deposition of energy (the molecular initiating event) to bone loss (the adverse outcome). A literature review was conducted to compile and evaluate the state of knowledge based on the modified Bradford Hill criteria. Following review of 1865 studies, an empirically supported AOP was developed, showing the progression to bone loss through many factors affecting the activities of bone-forming osteoblasts and bone-resorbing osteoclasts. The structural, functional, and quantitative basis of each proposed relationship was defined, for inference of causal changes between key events. Current knowledge and its gaps relating to dose-, time- and incidence-concordance across the key events were identified, as well as modulating factors that influence linkages. The new priorities for research informed by the AOP highlight areas for improvement to enable development of a quantitative AOP used to support risk assessment strategies for space travel or cancer radiotherapy.

Cardiovascular diseases (CVDs) are complex, encompassing many types of heart pathophysiologies and associated etiologies. It has been shown that fractionated radiation exposure at high doses (3-17 Gy) to the heart increases the incidence of CVD, as evident from radiotherapy studies. However, the effects of low doses of radiation on the cardiovascular system or the effects from space travel, where radiation and microgravity are important contributors to damage, are not clearly understood. Herein, the adverse outcome pathway (AOP) framework was applied to develop an AOP to vascular remodeling from the deposition of energy. Following the creation of a preliminary pathway with the guidance of field experts and authoritative reviews, a scoping review was conducted which informed final key event (KE) selection and facilitated evaluation Bradford Hill criteria of the key event relationships (KERs). The AOP begins with a molecular initiating event of deposition of energy; ionization events increase oxidative stress, which concurrently causes the release of pro-inflammatory mediators and alters signaling pathways. These KEs alter nitric oxide levels leading to endothelial dysfunction and subsequent vascular remodeling (the adverse outcome). The work identifies evidence needed to strengthen understanding of the causal associations for the KERs, emphasizing where there are knowledge gaps and uncertainties in both qualitative and quantitative understanding. The AOP is anticipated to direct future research to better understand the effects of space on the human body and potentially develop countermeasures to better protect future space travelers.

Cataracts are one of the leading causes of blindness, with estimated 95 million people affected worldwide. A hallmark of cataract development is lens opacification, typically associated not only with aging, but also radiation exposure as encountered by interventional radiologists and astronauts during the long-term space mission. To better understand radiation-induced cataracts, the adverse outcome pathway (AOP) framework was used to structure and evaluate knowledge across biological levels of organization. AOPs identify a sequence of key events (KEs) connected by key event relationships (KERs) beginning with a molecular initiating event (MIE) to an adverse outcome (AO) of relevance to regulatory decision-making. To construct the cataract AOP, a scoping review methodology was used to filter, screen, and review studies based on the modified Bradford Hill criteria. Eight KEs were moderately supported by empirical evidence across the adjacent (directly-linked) relationships using well-established endpoints. Over half of the evidence collected was informed by biological plausibility. Early KEs of oxidative stress and protein modifications could be the focus of countermeasures. Several identified knowledge gaps and inconsistencies in the AOP can be the basis of future research, most notably directed to experiments at low or moderate doses and dose-rates, relevant to radiation workers and other occupational exposures.

For improvement of the radiation protection system it is crucial to know the factors that modify the radiation dose–response relationship. One of such key factors is the ionizing radiation dose rate. There are, however, very few studies that examine the impact of the dose rate on radiogenic risks observed in human cohorts exposed to radiation at various dose rates. Here we investigated the impact of the dose rate (in terms of the recorded annual dose) on ischemic heart disease (IHD) mortality among Russian nuclear workers chronically exposed to radiation. We observed significantly increased excess relative risks (ERR) of IHD mortality per unit of external gamma-ray absorbed dose accumulated at higher dose rates (0.005–0.050 Gy/year). The present findings provide evidence for the association between radiation dose rate and ERRs of IHD mortality in occupationally chronically exposed workers per unit total dose. IHD mortality risk estimates considerably increased with increasing duration of uninterrupted radiation exposure at high rates. The present findings are consistent with other studies and can contribute to the scientific basis for recommendations on the radiation protection system.

In April 2011, the International Commission on Radiological Protection recommended reducing the occupational equivalent dose limit for the lens. Such a new occupational lens dose limit has thus far been implemented in many countries, and there are extensive discussions toward its regulatory implementation in other countries. In Japan, discussions in the Japan Health Physics Society (JHPS) began in April 2013 and in Radiation Council in July 2017, and the new occupational lens dose limit was implemented into regulation in April 2021. To share our experience, we have published a series of papers summarizing situations in Japan: the first paper based on information available by early 2017, and the second paper by early 2019. This paper (our third paper of this series) aims to review updated information available by mid-2022, such as regarding regulatory implementation of the new occupational lens dose limit, recent discussions by relevant ministries based on the opinion from the council, establishment process of safety and health management systems, the JHPS guidelines on lens dose monitoring and radiation safety, voluntary countermeasures of the licensees, development of lens dose calibration method, and recent studies on exposure of the lens in nuclear workers and biological effect on the lens.

Assessment of the effect of low dose and low-dose-rate exposure depends critically on extrapolation from groups exposed at high dose and high-dose rates such as the Japanese atomic bomb survivor data, and has often been achieved via application of a dose and dose-rate effectiveness factor (DDREF). An important component of DDREF is the factor determining the effect of extrapolation of dose, the so-called low-dose extrapolation factor (LDEF). To assess LDEF models linear (or linear quadratic) in dose are often fitted. In this report LDEF is assessed via fitting relative rate models that are linear or linear quadratic in dose to the latest Japanese atomic bomb survivor data on solid cancer, leukemia and circulatory disease mortality (followed from 1950 through 2003) and to data on solid cancer, lung cancer and urinary tract cancer incidence. The uncertainties in LDEF are assessed using parametric bootstrap techniques. Analysis is restricted to survivors with3 Gy dose. There is modest evidence for upward curvature in dose response in the mortality data. For leukemia and for all solid cancer excluding lung, stomach and breast cancer there is significant curvature (P0.05). There is no evidence of curvature for circulatory disease (P0.5). The estimate of LDEF for all solid cancer mortality is 1.273 [95% confidence intervals (CI) 0.913, 2.182], for all solid cancer mortality excluding lung cancer, stomach cancer and breast cancer is 2.183 (95% CI 1.090,100) and for leukemia mortality is 11.447 (95% CI 2.390,100). For stomach cancer mortality LDEF is modestly raised, 1.077 (95% CI 0.526,100), while for lung cancer, female breast cancer and circulatory disease mortality the LDEF does not much exceed 1. LDEF for solid cancer incidence is 1.186 (95% CI 0.942, 1.626) and for urinary tract cancer is 1.298 (95% CI0, 7.723), although for lung cancer LDEF is not elevated, 0.842 (95% CI 0.344,100).

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.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.

In medical and occupational settings, ionizing irradiation of the circulatory system occurs at various dose rates. We previously found sparing and enhancing dose protraction effects for aortic changes in wild-type mice at 6 months after starting irradiation with 5 Gy of photons. Here, we further analyzed changes at 12 months after stating irradiation. Irrespective of irradiation regimens, irradiation little affected left ventricular function, heart weight, and kidney weight. Irradiation caused structural disorganizations and intima-media thickening in the aorta, along with concurrent elevations of markers for proinflammation, macrophage, profibrosis, and fibrosis, and reductions in markers for vascular functionality and cell adhesion in the aortic endothelium. These changes were qualitatively similar but quantitatively less at 12 months than at 6 months. The magnitude of such changes at 12 months was not smaller in 25 fractions (Frs) but was smaller in 100 Frs and chronic exposure than acute exposure. The magnitude at 6 and 12 months was greater in 25 Frs, smaller in 100 Frs, and much smaller in chronic exposure than acute exposure. These findings suggest that dose protraction changes aortic damage, in a fashion that depends on post-irradiation time and is not a simple function of dose rate.

Cataract (opacification of the ocular lens) is a typical tissue reaction (deterministic effect) following ionizing radiation exposure, for which prevention dose limits have been recommended in the radiation protection system. Manifestations of radiation cataracts can vary among individuals, but such potential individual responses remain uncharacterized. Here we review relevant literature and discuss implications for radiation protection. This review assesses evidence for significant modification of radiation-induced cataractogenesis by age at exposure, sex and genetic factors based on current scientific literature.In addition to obvious physical factors (e.g. dose, dose rate, radiation quality, irradiation volume), potential factors modifying individual responses for radiation cataracts include sex, age and genetics, with comorbidity and coexposures also having important roles. There are indications and preliminary data identifying such potential modifiers of radiation cataract incidence or risk, although no firm conclusions can yet be drawn. Further studies and a consensus on the evidence are needed to gain deeper insights into factors determining individual responses regarding radiation cataracts and the implications for radiation protection.

The lessons learned from the Coronavirus Disease 2019 (COVID-19) pandemic are numerous. Low dose radiotherapy (LDRT) was used in the pre-antibiotic era as treatment for bacterially/virally associated pneumonia. Motivated in part by these historic clinical and radiobiological data, LDRT for treatment of COVID-19-associated pneumonia was proposed in early 2020. Although there is a large body of epidemiological and experimental data pointing to effects such as cancer at low doses, there is some evidence of beneficial health effects at low doses. It has been hypothesized that low dose radiation could be combined with immune checkpoint therapy to treat cancer. We shall review here some of these old radiobiological and epidemiological data, as well as the newer data on low dose radiation and stimulated immune response and other relevant emerging data. The paper includes a summary of several oral presentations given in a Symposium on "Low dose RT for COVID and other inflammatory diseases" as part of the 67th Annual Meeting of the Radiation Research Society, held virtually 3-6 October 2021.

Heart diseases are one of the main causes of death. The incidence risks were assessed for various types of heart diseases (HDs) in a cohort of Russian nuclear workers of the Mayak Production Association (PA) who had been chronically occupationally exposed to external gamma and/ or internal alpha radiation. The study cohort included all workers (22,377 individuals) who had been hired at the Mayak PA during 1948-1982 and followed up until 31 December 2018. The mean gamma-absorbed dose to the liver (standard deviation) was 0.43 (0.63) Gy, and the mean alpha-absorbed dose to the liver was 0.25 (1.19) Gy. Excess relative risk (ERR) per unit liver-absorbed dose (Gy) was calculated based on maximum likelihood. At the end of the follow-up, 559 chronic rheumatic heart disease (CRHD), 7722 ischemic heart disease (IHD) [including 2185 acute myocardial infarction (AMI) and 3976 angina pectoris (AP)], 4939 heart failure (HF), and 3689 cardiac arrhythmia and conduction disorder (CACD) cases were verified in the study cohort. Linear model fits of the gamma dose response for HDs were best once adjustments for non-radiation factors (sex, attained age, calendar period, smoking status and alcohol consumption) and alpha dose were included. ERR/Gy in males and females was 0.17 (95% confidence intervals: 0.10, 0.26) and 0.23 (0.09, 0.38) for IHD; 0.18 (0.09, 0.29) and 0.26 (0.08, 0.49) for AP; - 0.01 (n/a, 0.1) and - 0.01 (n/a, 0.27) for AMI; 0.27 (0.16, 0.40) and 0.27 (0.10, 0.49) for HF; 0.32 (0.19, 0.46) and 0.05 (- 0.09, 0.22) for CACD; 0.73 (- 0.02, 2.40) and - 0.12 (- 0.50, 0.69) for CRHD, respectively. Sensitivity analyses demonstrated the persistence of a significant dose-response regardless of exclusion/inclusion of adjustments for known potential non-radiation confounders (smoking, alcohol consumption, body mass index, hypertension, diabetes mellitus), and it was only the magnitude of the risk estimate that varied. The risks of HD incidence were not modified with sex (except for the CACD risk). This study provides evidence for a significant association of certain types of HDs with cumulative dose of occupational chronic external exposure to gamma radiation.

Since early April 2020, there has been intense debate over proposed clinical use of ionizing radiation to treat life-threatening pneumonia in Coronavirus Disease 2019 (COVID-19) patients. At least twelve relevant papers appeared by 20 May 2020. The radiation dose proposed for clinical trials are a single dose (0.1-1 Gy) or two doses (a few mGy followed by 0.1-0.25 Gy involving a putative adaptive response, or 1-1.5 Gy in two fractions 2-3 days apart). The scientific rationale for such proposed so-called low dose radiotherapy (LDRT) is twofold (note that only doses below 0.1 Gy are considered as low doses in the field of radiation protection, but here we follow the term as conventionally used in the field of radiation oncology). Firstly, the potentially positive observations in human case series and biological studies in rodent models on viral or bacterial pneumonia that were conducted in the pre-antibiotic era. Secondly, the potential anti-inflammatory properties of LDRT, which have been seen when LDRT is applied locally to subacute degenerative joint diseases, mainly in Germany. However, the human and animal studies cited as supportive evidence have significant limitations, and whether LDRT produces anti-inflammatory effects in the inflamed lung or exacerbates ongoing COVID-19 damage remains unclear. Therefore, we conclude that the available scientific evidence does not justify clinical trials of LDRT for COVID-19 pneumonia, with unknown benefit and known mortality risks from radiogenic cancer and circulatory disease. Despite the significant uncertainties in these proposals, some clinical trials are ongoing and planned. This paper gives an overview of current situations surrounding LDRT for COVID-19 pneumonia.

This letter addresses our concerns regarding a paper by Salomaa et al. entitled ‘Low dose radiation therapy for COVID-19 pneumonia: is there any supportive evidence?’ published in International Jou...

Precise evaluation of the relative biological effectiveness (RBE) for skin reactions is indispensable for the treatment planning of particle therapy and boron-neutron capture therapy. The evaluation is also needed for the future radiation protection system for mixed radiation fields. Such RBE is often evaluated based on in vitro cell survival data, but its validity remains incompletely understood. This study aimed to develop a model for estimating RBE for skin reactions and dermal cell survival in the same framework and quantitatively discuss a possible link between them.The microdosimetric kinetic model, which was originally developed for estimating cell surviving fractions for various radiations, was improved to be capable of estimating the mean and uncertainty of RBE for skin reactions. The parameter used in the model was independently determined from in vitro measurements of dermal cell survival and in vivo measurements of skin reactions taken from 8 and 23 articles, respectively. In the parameter determination, the characteristics of the radiation fields employed in each measurement were reproduced in detail by the Particle and Heavy Ion Transport Code System.Our model quantitatively revealed that RBE for skin reactions tend to be higher than those for dermal cell survival. RBE of various monoenergetic radiations calculated from this model confirmed that the past evaluations made by the International Commission on Radiological Protection and the National Council on Radiation Protection and Measurements a few decades ago are still supported by recent experimental data.Our model can play important roles not only in medical physics for avoiding unnecessary skin reactions in particle therapy and boron-neutron capture therapy but also in radiation protection for future decision-making of the recommended RBE values.

Cesium-bearing microparticles (Cs-BMPs) can reach the human respiratory system after inhalation, resulting in chronic local internal exposure. We previously investigated the spatial distribution of DNA damage induced in areas around a Cs-BMP; however, the biological impacts have not been fully clarified due to the limited amount of data. Here, we investigated the inflammatory signaling and DNA damage responses after local exposure to a Cs-BMP in vitro. We used two normal human lung cell lines, i.e., lung fibroblast cells (WI-38) and bronchial epithelial cells (HBEC3-KT). After 24 h exposure to a Cs-BMP, inflammation was evaluated by immunofluorescent staining for nuclear factor κB (NF-κB) p65 and cyclooxygenase 2 (COX-2). The number of DNA double-strand breaks (DSBs) was also detected by means of phospholylated histone H2AX (γ-H2AX) focus formation assay. Cs-BMP exposure significantly increased NF-κB p65 and COX-2 expressions, which were related to the number of γ-H2AX foci in the cell nuclei. Compared to the uniform (external) exposure to 137Cs γ-rays, NF-κB tended to be more activated in the cells proximal to the Cs-BMP, while both NF-κB p65 and COX-2 were significantly activated in the distal cells. Experiments with chemical inhibitors for NF-κB p65 and COX-2 suggested the involvement of such inflammatory responses both in the reduced radiosensitivity of the cells proximal to Cs-BMP and the enhanced radiosensitivity of the cells distal from Cs-BMP. The data show that local exposure to Cs-BMP leads to biological effects modified by the NF-κB pathway, suggesting that the radiation risk for Cs-BMP exposure can differ from that estimated based on conventional uniform exposure to normal tissues.

Background:There is accumulating evidence of excess risk of cancer in various populations exposed at acute doses below several tens of mSv or doses received over a protracted period. There is also evidence that relative risks are generally higher after radiation exposures in utero or in childhood. Methods and findings:We reviewed and summarised evidence from 89 studies of cancer following medical diagnostic exposure in utero or in childhood, in which no direct estimates of radiation dose are available. In all of the populations studied exposure was to sparsely ionizing radiation (X-rays). Several of the early studies of in utero exposure exhibit modest but statistically significant excess risks of several types of childhood cancer. There is a highly significant (p p > 0.3). In relation to postnatal exposure there are significant excess risks of leukaemia, brain and solid cancers, with indications of variations in risk by cancer type (p = 0.07) and type of exposure (p = 0.02), withfluoroscopyand computedtomographyscans associated with the highest excess risk. However, there is highly significant inter-study heterogeneity (p Conclusions:Overall, this large body of data relating to medical diagnostic radiation exposure in utero provides support for an associated excess risk of childhood cancer. However, the pronounced heterogeneity in studies of postnatal diagnostic exposure, the implied uncertainty as to the meaning of summary measures, and the distinct possibilities of bias, substantially reduce the strength of the evidence from the associations we observe between radiation imaging in childhood and the subsequent risk of cancer being causally related to radiation exposure.

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. 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. 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. 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.

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.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.

Secondary glaucoma is a typical normal tissue complication following radiation therapy involving ocular radiation exposure at high fractionated dose (several tens of Gy). In contrast, recent studies in acutely exposed Japanese atomic bomb survivors showed a significantly increased risk for normal-tension glaucoma (NTG, a subtype of primary open-angle glaucoma) at much lower dose, but such information is not available in any other cohorts. We therefore set out to evaluate the incidence of risk for primary glaucoma and its subtypes in a Russian cohort of Mayak Production Association nuclear workers who received chronic radiation exposure over many years. Of these, we found a significantly increased relative risk (RR) of NTG incidence (RR = 1.88 95% confidence intervals (CI): 1.01, 3.51; p = 0.047) in workers exposed to gamma rays at cumulative brain absorbed dose above >1 Gy. We observed the linear relationship between NTG incidence and brain absorbed gamma dose with an excess relative risk per unit brain absorbed dose of 0.53 (95% CI: 0.01, 1.68; p < 0.05), but not for any other subtypes nor for total primary glaucoma. Such elevated risk of radiogenic NTG incidence, if confirmed in other cohorts, has significant implications for normal tissue complications in radiotherapy patients receiving ocular radiation exposure, and for ocular radiation protection in radiation workers.

Recent epidemiological and experimental animal data, as well as reanalyses of data previously accumulated, indicate that the lens of the eye is more radiosensitive than was previously thought. This has resulted in a reduction of the occupational lens dose limit within the European Union countries, Japan and elsewhere. This Commentary introduces the work done by the LDLensRad Consortium contained within this Focus Issue, towards advancement of understanding of the mechanisms of low dose radiation cataract.

This paper reports on the findings from the study of mortality from diseases of the circulatory system (DCS) in Russian nuclear workers of the Mayak Production Association (22 377 individuals, 25.4% female) who were hired at the facility between 1948 and 1982 and followed up until the end of 2018. Using the AMFIT module of the EPICURE software, relative risks (RRs) and excess RRs per unit absorbed dose (ERR/Gy) for the entire Mayak cohort, the subcohort of workers who were residents of the dormitory town of Ozyorsk and the subcohort of migrants from Ozyorsk were calculated based on maximum likelihood. The mean cumulative liver absorbed gamma-ray dose from external exposure was 0.45 (0.65) Gy (mean (standard deviation)) for men and 0.37 (0.56) Gy for women. The mean cumulative liver absorbed alpha dose from internal exposure to incorporated plutonium was 0.18 (0.65) Gy for men and 0.40 (1.92) Gy for women. By the end of the follow-up, 6019 deaths with DCS as the main cause of death were registered among Mayak Production Association workers (including 3828 deaths in the subcohort of residents and 2191 deaths in the subcohort of migrants) over 890 132 (622 199/267 933) person-years of follow-up. The linear model that took into account non-radiation factors (sex, attained age, calendar period, smoking status and alcohol drinking status) and alpha radiation dose (via adjusting) did not demonstrate significant associations of mortality from DCS, ischaemic heart disease (IHD) and cerebrovascular disease with gamma-ray exposure dose in the entire cohort, the resident subcohort or the migrant subcohort (either in men or women). For the subcohort of residents, a significant association with gamma dose was observed for mortality from ischaemic stroke in men with ERR/Gy = 0.43 (95% CI 0.08; 0.99); there were no significant associations with liver absorbed gamma dose for any other considered outcomes. As for internal exposure, for men no significant associations of mortality from any DCS with liver absorbed alpha dose were observed, but for women positive associations were found for mortality from DCS (the entire cohort and the resident subcohort) and IHD (the entire cohort). No significant associations of mortality from various types of DCS with neutron dose were observed either in men or women, although neutron absorbed doses were recorded in only 18% of the workers.

Purpose: In 2011, the International Commission on Radiological Protection (ICRP) recommended an equivalent dose limit for the lens of the eye of 20 mSv/year, averaged over defined periods o...

The International Journal of Radiation Biology (IJRB) celebrates its 60th birthday this year. Ahead of this very special issue, we wanted to produce strong representations of the journal's publication history in order to celebrate the current status of the journal and to look forward to its future. This was accomplished using 'reference maps'. Reference data were used from 1959 onward from the highest-cited paper in IJRB, for each respective year, to create a figure displaying when those articles were cited in IJRB since their publication. This was done to show the relative impact of historical IJRB papers to future research. Common themes of research were also examined by decade. Additionally, to show the historical impact of the journal outside of its immediate area of research and its practical applications, information on IJRB articles cited by the International Commission on Radiological Protection (ICRP) was collected. It was in 1959 when IJRB published the first issue, and when ICRP also issued Publication 1. Among all Publications (1-139), 43 publications have thus far cited 320 IJRB papers and each of which have been cited 1-7 times. Most notably, Publications 90, 99, 118, and 131 cited more than 40 IJRB papers. Further research was done into references for IJRB's contemporary journal: Radiation Research. The most highly cited IJRB articles for each year together since its inception were cited 16,760 times since they were published and cited 1385 times in Radiation Research. Together, these three datasets and their representations show the diversity of historical IJRB publications, the impact of historical IJRB articles in both future research in the journal and outside of it, and articles which new prospective authors contributing to IJRB might find useful in their own research.

For more than a century, ionizing radiation has been indispensable mainly in medicine and industry. Radiation research is a multidisciplinary field that investigates radiation effects. Radiation research was very active in the mid- to late 20th century, but has then faced challenges, during which time funding has fluctuated widely. Here we review historical changes in funding situations in the field of radiation research, particularly in Canada, European Union countries, Japan, South Korea, and the US. We also provide a brief overview of the current situations in education and training in this field. A better understanding of the biological consequences of radiation exposure is becoming more important with increasing public concerns on radiation risks and other radiation literacy. Continued funding for radiation research is needed, and education and training in this field are also important.

Incidence risks for cerebrovascular diseases (CeVD) and some types of stroke in a cohort of 22,377 Russian Mayak nuclear workers chronically exposed to ionising radiation and followed up until the end of 2018 are reported. Among total 9469 cases of CeVD, 2078 cases were strokes that included 262 hemorrhagic strokes (HS) and 1611 ischemic strokes (IS). Data evaluation was performed with categorical and dose-response analyses estimating the relative risk (RR) and excess relative risk (ERR) per unit cumulative liver absorbed dose of external gamma-ray or internal alpha-particle exposure based on a linear model utilizing the AMFIT module of the EPICURE software. CeVD incidence was found to be significantly associated with cumulative radiation dose: ERR/Gy was 0.37 (95% confidence interval (CI) 0.27, 0.47) in males and 0.47 (95% CI 0.31, 0.66) in females for external exposure, and 0.31 (95% CI 0.11, 0.59) in males and 0.32 (95% CI 0.11, 0.61) in females for internal exposure. When the model for the analysis of external radiation effect did not include an adjustment for alpha radiation dose (and vice versa), the radiogenic risk estimate increased notably both for males and for females. In contrast, exclusion from or inclusion in the model of additional adjustments for non-radiation factors did not notably change the risk estimates. ERR/Gy of external gamma dose for CeVD incidence significantly decreased with increasing attained age (males and females) and duration of employment (females). No significant associations of either stroke or its types with cumulative gamma-ray dose of external exposure or alpha-particle dose of internal exposure were found.

Dr. William Francis Morgan, known as Bill by many of his friends and colleagues, was a leading figure in the field of radiation research. He passed away on 13 November 2015, at the age of 62 years ...

Radiation detriment is a concept to quantify the burden of stochastic effects from exposure of the human population to low-dose and/or low-dose-rate ionising radiation. As part of a thorough review of the system of radiological protection, the International Commission on Radiological Protection (ICRP) has compiled a report on radiation detriment calculation methodology as Publication 152. It provides a historical review of the detriment calculation with details of the procedure used in ICRP Publication 103. A selected sensitivity analysis was conducted to identify the parameters and calculation conditions that can be major sources of variation and uncertainty. It has demonstrated that sex, age at exposure, dose and dose-rate effectiveness factor, dose assumption in the lifetime risk calculation, and lethality fraction have a substantial impact on the calculated values of radiation detriment. Discussions are also made on the issues to be addressed and possible ways for improvement toward the revision of general recommendations. These include update of the reference population data and cancer severity parameters, revision of cancer risk models, and better handling of the variation with sex and age. Finally, emphasis is placed on transparency and traceability of the calculation, along with the need to improve the way of expressing and communicating the detriment.

Dr. William Francis Morgan, known as Bill to many of his friends and colleagues, passed away on 13 November 2015, at the age of 62 years (Hamada et al. 2016, 2017). To commemorate the first anniver...

Currently, there are 14 ongoing clinical studies on low dose radiotherapy (LDRT) for COVID-19 pneumonia. An underlying assumption is that irradiation of about 1 Gy is effective at ameliorating viral pneumonia. Its rationale, however, relies on early human case series or animal studies mostly obtained in the pre-antibiotic era, where rigorous statistical analyses were not performed. It therefore remains unclear whether those early data support such assumptions. With standard statistical survival models, and based on a systematic literature review, we re-analyzed 14 radiobiological animal datasets in which animals received mostly fractionated doses of radiation before or after bacterial/viral inoculation, and assessing various health endpoints (mortality, pneumonia morbidity). In most datasets absorbed doses did not exceed 7 Gy. Various different model systems and types of challenging infection are considered. For 7 studies that evaluated post-inoculation radiation exposure (more relevant to LDRT for COVID-19 pneumonia) the results are heterogeneous, with 2 studies showing a significant increase (p, 2 tables, 7 figures, 15 Appendix Tables, 36 references, 49 double spaced pages

Use of computed tomography (CT) scanning has increased worldwide over the decades, and Japan is one of the leading countries in annual frequency of diagnostic CT. While benefits of CT scan are undisputable, concerns have been raised about potential health effects of ionizing radiation exposure from CT, particularly among children who are likely more susceptible to radiation than adults. This study aims to evaluate the cumulated lifetime risk of the brain/central nervous system (CNS) cancer due to head CT examinations performed on Japanese children at age 0-10 years in 2012, 2015, and 2018. The frequency and dose distribution of head CT examinations were estimated based on information from recent national statistics and nationwide surveys. The lifetime risk attributable to exposure was calculated by applying risk models based on the study of Japanese atomic-bomb survivors. In contrast to the overall increasing trend, the frequency of childhood CT, especially at age

Background The detrimental health effects associated with the receipt of moderate (0.1–1 Gy) and high (>1 Gy) acute doses of sparsely ionising radiation are well established from human epidemiological studies. There is accumulating direct evidence of excess risk of cancer in a number of populations exposed at lower acute doses or doses received over a protracted period. There is evidence that relative risks are generally higher after radiation exposures in utero or in childhood. Methods and findings We reviewed and summarised evidence from 60 studies of cancer or benign neoplasms following low- or moderate-level exposure in utero or in childhood from medical and environmental sources. In most of the populations studied the exposure was predominantly to sparsely ionising radiation, such as X-rays and gamma-rays. There were significant (p Conclusions Overall, the totality of this large body of data relating to in utero and childhood exposure provides support for the existence of excess cancer and benign neoplasm risk associated with radiation doses

Two types of dose were proposed for use in the treatment planning of boron neutron capture therapy (BNCT) for expressing its high relative biological effectiveness (RBE). On one hand, the RBE-weighted dose is the sum of the absorbed doses weighted by fixed RBE for each dose component of BNCT. On the other hand, photon-isoeffective dose is the photon dose to give the same biological effect calculated considering the dose dependence of RBE and the synergetic effect between different types of radiation. In this study, the depth distributions of the two types of dose in a phantom placed at an accelerator-based BNCT field were calculated using Particle and Heavy Ion Transport code System, PHITS, coupled with an extended stochastic microdosimetric kinetic model. Compared with the corresponding RBE-weighted dose, the calculated photon-isoeffective dose was larger at lower absorbed dose and was smaller at higher absorbed dose, primarily due to the consideration of the dose dependence of RBE. In addition, our calculation revealed that the large variance of the intercellular 10B concentration greatly reduces the photon-isoeffective doses. These results suggest that the considerations of the dose dependence of RBE as well as the intercellular heterogeneity in 10B distribution are indispensable for the precise estimate of the biological effect of BNCT.

Purpose: To estimate incidence risk for senile cataracts in a cohort of workers employed at nuclear production facility, that were occupationally exposed to radiation taking into account non-radiation risk factors. Material and methods: Senile cataract incidence (cataracts) is studied in the cohort of Mayak PA workers first employed at one of the main facilities (reactors, radiochemical or plutonium production plants) during 1948–1982 (22,377 individuals). All members of the study cohort were occupationally exposed to gamma-rays or neutrons over a prolonged period. Absorbed doses from external and/or neutron exposure used in the study were provided by MWDS-2008. Relative risk (RR) and excess relative risk per unit dose (ERR/Gy) were estimated based on maximum likelihood using AMFIT module of EPICURE software. Results: 4159 cataract diagnoses were verified in the study cohort of workers during 482217 person-years of follow-up. The majority of cataracts were diagnosed in cohort members included in the age group 61–70 years old in both males and females. The mean age at cataract diagnosis was 63.1 ± 0.2 years in males and 64.8 ± 0.2 years in females, respectively. RR of cataract incidence was statistically significant in all dose categories when compared to a reference category (0–0.25 Gy) and increased with increasing dose from external gamma-rays and was the highest in workers exposed to external gamma-rays at doses exceeding 2.0 Gy (1.61 95 % CI: 1,41–1,83). Significant linear association of cataracts with dose from external gamma-rays was observed with ERR/Gy = 0.28 (95 % CI: 0.20, 0.37). The risk estimate varied slightly with inclusion of additional adjustments for different non-radiation factors (smoking status and alcohol consumption, smoking index, hypertension, body mass index, severe myopia diagnosed). After adjusting for dose from neutrons ERR/Gy of external gamma-rays for cataracts increased considerably (0.31; 95 % CI: 0.22, 0.40). Significant ERR/Gy of external gamma-rays for senile cataract was revealed in both male and female workers of the study cohort, however the variations between the sexes were insignificant (p = 0.09). ERR/Gy of external gamma-rays for senile cataract was significant in all age groups except for workers under 40 years, but the differences among the age groups were insignificant (p > 0.5). Conclusion: Risk of senile cataract incidence in the cohort of Mayak PA workers, occupationally exposed to radiation over prolonged periods, was significantly associated with dose from external gamma-rays.

Since the International Commission on Radiological Protection recommended reducing the occupational equivalent dose limit for the lens of the eye in 2011, there have been extensive discussions in various countries. This paper reviews the current situation in radiation protection of the ocular lens and the discussions on the potential impact of the new lens dose limit in Japan. Topics include historical changes to the lens dose limit, the current situation with occupational lens exposures (e.g., in medical workers, nuclear workers, and Fukushima nuclear power plant workers) and measurements, and the current status of biological studies and epidemiological studies on radiation cataracts. Our focus is on the situation in Japan, but we believe such information sharing will be useful in many other countries.

Metastasis represents the leading cause of breast cancer deaths, necessitating strategies for its treatment. Although radiotherapy is employed for both primary and metastatic breast cancers, the difference in their ionizing radiation response remains incompletely understood. This study is the first to compare the radioresponse of a breast cancer cell line with its metastatic variants and report that such metastatic variants are more radioresistant. A luciferase expressing cell line was established from human basal-like breast adenocarcinoma MDA-MB-231 and underwent in vivo selections, whereby a cycle of inoculations into the left cardiac ventricle or the mammary fat pad of athymic nude mice, isolation of metastases to the bone, lung and lymph nodes visualized with bioluminescence imaging, and expansion of obtained cells was repeated twice or three times. The established metastatic cell lines were assessed for cell proliferation, wound healing, invasion, clonogenic survival, and apoptosis. The established metastatic cell lines possessed an increased proliferative potential in vivo and were more chemotactic, invasive, and resistant to X‑ray-induced clonogenic inactivation and apoptosis in vitro. Breast cancer metastasis to the bone, lung, and lymph nodes promotes radioresistance.