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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. 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. [ABSTRACT FROM AUTHOR]

BACKGROUND: Although high doses of ionizing radiation have long been linked to circulatory disease, evidence for an association at lower exposures remains controversial. However, recent analyses suggest excess relative risks at occupational exposure levels. OBJECTIVES: We performed a systematic review and meta-analysis to summarize information on circulatory disease risks associated with moderate- and low-level whole-body ionizing radiation exposures. METHODS: We conducted PubMed/ISI Thomson searches of peer-reviewed papers published since 1990 using the terms radiation AND heart AND disease, OR radiation AND stroke, OR radiation AND circulatory AND disease. Radiation exposures had to be whole-body, with a cumulative mean dose of < 0.5 Sv, or at a low dose rate (< 10 mSv/day). We estimated population risks of circulatory disease from low-level radiation exposure using excess relative risk estimates from this meta-analysis and current mortality rates for nine major developed countries. RESULTS: Estimated excess population risks for all circulatory diseases combined ranged from 2.5%/Sv [95% confidence interval (CI): 0.8, 4.2] for France to 8.5%/Sv (95% CI: 4.0, 13.0) for Russia. CONCLUSIONS: Our review supports an association between circulatory disease mortality and low and moderate doses of ionizing radiation. Our analysis was limited by heterogeneity among studies (particularly for noncardiac end points), the possibility of uncontrolled confounding in some occupational groups by lifestyle factors, and higher dose groups (> 0.5 Sv) generally driving the observed trends. If confirmed, our findings suggest that overall radiation-related mortality is about twice that currently estimated based on estimates for cancer end points alone (which range from 4.2% to 5.6%/Sv for these populations).

The overall aim of this contribution to the 'Second Bill Morgan Memorial Special Issue' is to provide a high-level review of a recent report developed by a Committee for the National Council on Radiation Protection and Measurements (NCRP) titled 'Approaches for Integrating Information from Radiation Biology and Epidemiology to Enhance Low-Dose Health Risk Assessment'. It derives from previous NCRP Reports and Commentaries that provide the case for integrating data from radiation biology studies (available and proposed) with epidemiological studies (also available and proposed) to develop Biologically-Based Dose-Response (BBDR) models. In this review, it is proposed for such models to leverage the adverse outcome pathways (AOP) and key events (KE) approach for better characterizing radiation-induced cancers and circulatory disease (as the example for a noncancer outcome). The review discusses the current state of knowledge of mechanisms of carcinogenesis, with an emphasis on radiation-induced cancers, and a similar discussion for circulatory disease. The types of the various informative BBDR models are presented along with a proposed generalized BBDR model for cancer and a more speculative one for circulatory disease. The way forward is presented in a comprehensive discussion of the research needs to address the goal of enhancing health risk assessment of exposures to low doses of radiation. The use of an AOP/KE approach for developing a mechanistic framework for BBDR models of radiation- induced cancer and circulatory disease is considered to be a viable one based upon current knowledge of the mechanisms of formation of these adverse health outcomes and the available technical capabilities and computational advances. The way forward for enhancing low-dose radiation risk estimates will require there to be a tight integration of epidemiology data and radiation biology information to meet the goals of relevance and sensitivity of the adverse health outcomes required for overall health risk assessment at low doses and dose rates. [ABSTRACT FROM AUTHOR]

Studies of the responses of hematopoietic stem and progenitor cells (HSPCs) to low doses of ionizing radiation formed an important aspect of the RISK-IR project (). A brief overview of these studies is presented here. The findings confirm the sensitivity of HSPCs to radiation even at low doses, and illustrate the substantial impact that differentiation state has upon cell sensitivity. The work provides mechanistic support for epidemiological findings of leukemia risk at dose levels used in diagnostic CT imaging, and further suggests that low-dose irradiation may facilitate bone marrow transplantation, a finding that could lead to refinements in clinical practice. [ABSTRACT FROM AUTHOR]

Ionizing radiation is considered a non-threshold carcinogen. However, quantifying the risk of the more commonly encountered low and/or protracted radiation exposures remains problematic and subject to uncertainty. Therefore, a major challenge lies in providing a sound mechanistic understanding of low-dose radiation carcinogenesis. This Perspective article considers whether differences exist between the effects mediated by high- and low-dose radiation exposure and how this affects the assessment of low-dose cancer risk. [ABSTRACT FROM AUTHOR]

A response from the authors of the article "Estimating Risk of Circulatory Disease from Exposure to Low-Level Ionizing Radiation" in the previous issue.

• There is mounting evidence of cancer risk from low dose radiation in childhood. • A systematic review was conducted of cancer after exposure in utero or childhood. • There were excess cancer risks associated with radiation exposure in childhood. • There were excess cancer risks associated with radiation exposure in utero. • Excess cancer risks were seen at levels approaching 0.02 Gy. 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. 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 < 0.001) excess risks for all cancers, and particularly large excess relative risks were observed for brain/CNS tumours, thyroid cancer (including nodules) and leukaemia. 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 < 0.1 Gy, and for certain groups exposed to natural background radiation, to fallout and medical X-rays in utero , at about 0.02 Gy. [ABSTRACT FROM AUTHOR]

Leukaemia is the prevailing neoplastic disorder of the hematopoietic system. Epidemiological analyses of the survivors of the Japanese atomic bombings show that exposure to ionising radiation (IR) can cause leukaemia. Although a clear association between radiation exposure and leukaemia development is acknowledged, the underlying mechanisms remain incompletely understood. A hemizygous deletion on mouse chromosome 2 (del2) is a common feature in several mouse strains susceptible to radiation-induced acute myeloid leukaemia (rAML). The deletion is an early event detectable 24 h after exposure in bone marrow cells. Ultimately, 15–25% of exposed animals develop AML with 80–90% of cases carrying del2. Molecular mapping of leukaemic cell genomes identified a minimal deleted region (MDR) on chromosome 2 (chr2) in which a tumour suppressor gene, Sfpi1 is located, encoding the transcription factor PU.1, essential in haematopoiesis. The remaining copy of Sfpi1 has a point mutation in the coding sequence for the DNA-binding domain of the protein in 70% of rAML, which alters a single CpG sequence in the codon for arginine residue R235. In order to identify chr2 deletions and Sfpi.1 /PU.1 loss, we performed array comparative genomic hybridization (aCGH) on a unique panel of 79rAMLs. Using a custom made CGH array specifically designed for mouse chr2, we analysed at unprecedentedly high resolution (1.4 M array- 148 bp resolution) the size of the MDR in low LET and high-LET induced rAMLs (32 X-ray- and 47 neutron-induced). Sequencing of Sfpi1 /PU.1DNA binding domain identified the presence of R235 point mutations, showing no influence of radiation quality on R235 type or frequency. We identified for the first time rAML cases with complex del2 in a subset of neutron-induced AMLs. This study allowed us to re-define the MDR to a much smaller 5.5 Mb region (still including Sfpi1 /PU.1), identical regardless of radiation quality. [ABSTRACT FROM AUTHOR]

Abstract: In this article we review health effects in offspring of human populations exposed as a result of radiotherapy and some groups exposed to chemotherapy. We also assess risks in offspring of other radiation-exposed groups, in particular those of the Japanese atomic bomb survivors and occupationally and environmentally exposed groups. Experimental findings are also briefly surveyed. Animal and cellular studies tend to suggest that the irradiation of males, at least at high doses (mostly 1Gy and above), can lead to observable effects (including both genetic and epigenetic) in the somatic cells of their offspring over several generations that are not attributable to the inheritance of a simple mutation through the parental germline. However, studies of disease in the offspring of irradiated humans have not identified any effects on health. The available evidence therefore suggests that human health has not been significantly affected by transgenerational effects of radiation. It is possible that transgenerational effects are restricted to relatively short times post-exposure and in humans conception at short times after exposure is likely to be rare. Further research that may help resolve the apparent discrepancies between cellular/animal studies and studies of human health are outlined. [Copyright &y& Elsevier]