The ICRP, MELODI, and ALLIANCE workshop on effects of ionizing radiation exposure in offspring and next generations: a summary of discussions.

PURPOSE: Task Group 121 - Effects of ionizing radiation exposure in offspring and next generations - is a task group under the Committee 1 of the International Commission on Radiological Protection (ICRP), approved by the Main Commission on 18th November 2021. The main goals of Task Group 121 are to (1) review and update the scientific literature of relevance to radiation-related effects in the offspring of parent(s) exposed to ionizing radiation in both human and non-human biota; (2) to assess preconceptional and intrauterine effects of radiation exposure and related morbidity and mortality; and, (3) to provide advice about the level of evidence and how to consider these preconceptional and postconceptional effects in the system of radiological protection for humans and non-human biota. METHODS: The Task Group is reviewing relevant literature since Publication 90 'Biological effects after prenatal irradiation (embryo and fetus)' (2003) and will include radiation-related effects on future generations in humans, animals, and plants. This review will be conducted to account for the health effects on offspring and subsequent generations in the current system of radiological protection. Radiation detriment calculation will also be reviewed. Finally, preliminary recommendations will be made to update the integration of health effects in offspring and next generations in the system of radiological protection. RESULTS: A Workshop, jointly organized by ICRP Task Group 121 and European Radiation Protection Research Platforms MELODI and ALLIANCE was held in Budapest, Hungary, from 31st May to 2nd June 2022. Participants discussed four important topics: (1) hereditary and epigenetic effects due to exposure of the germ cell line (preconceptional exposure), (2) effects arising from exposure of the embryo and fetus (intrauterine exposure), (3) transgenerational effects on biota, and (4) its potential impact on the system of radiological protection. CONCLUSIONS: Based on the discussions and presentations during the breakout sessions, newer publications, and gaps on the current scientific literature were identified. For instance, there are some ongoing systematic reviews and radiation epidemiology reviews of intrauterine effects. There are newer methods of Monte Carlo simulation for fetal dosimetry, and advances in radiation genetics, epigenetics, and radiobiology studies. While the current impact of hereditary effects on the global detriment was reported as small, the questions surrounding the effects of radiation exposure on offspring and the next generation are crucial, recurring, and with a major focus on exposed populations. This article summarizes the workshop discussions, presentations, and conclusions of each topic and introduces the special issue of the International Journal of Radiation Biology resulting from the discussions of the meeting.

Ionizing radiation exposure effects across multiple generations: evidence and lessons from non-human biota.

A Task Group (TG121) of the International Commission on Radiological Protection (ICRP) Committee 1 was launched in 2021 to study the effects of ionizing radiation in offspring and next generations. In this report, we summarize the evidence of multi- and trans-generational effects in non-human biota species that was discussed at the ICRP workshop entitled "Effects of Ionizing Radiation Exposure in Offspring and Next Generations" in June 2022. Epigenetic changes, including changes in DNA methylation, have been observed in trans- and multi-generational irradiation studies in both plants and animals. There were also reports of changes in offspring survival and reproduction. The reported evidence for altered reproduction is an area of potential concern, due to possible effects at the population or ecosystem level. Different considerations are also discussed regarding non-human biota data, such as transferability of data between different species or extending knowledge to humans, differences in species radiosensitivity, the presence of adaptive responses, and dose reconstruction for exposures that occur across multiple generations. Overall, there is a diverse range of available data of the effects in non-human biota, and it will require careful consideration when incorporating this evidence into the system of radiological protection of humans and of the environment.

Application of radiation omics in the development of adverse outcome pathway networks: an example of radiation-induced cardiovascular disease.

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.

The joint roadmap for radiation protection research: outreach and future.

During the last decade there has been remarkable integration of radiation protection research in Europe, driven by six research platforms. The platforms are associations of research centres, university research groups and funding bodies in Member States that are dedicated to specialised areas of research in radiation protection, such as health risks (MELODI), radioecology (ALLIANCE), radiological emergencies (NERIS), dosimetry (EURADOS), medical use of radiation (EURAMED) and societal aspects (SHARE). Recently these platforms established an umbrella organisation MEENAS, to endorse further integration and joint activities in research, education and training, and infrastructures. A milestone in this process of integration and priority setting was achieved in 2020 when the first edition of the joint roadmap for radiation protection research was finalised. In this paper we describe the various roles for research and development in the radiation protection context, ranging from basic scientific knowledge underpinning the system of protection to research supporting the development and application of international standards and research and development activities needed to ensure safety in radiation practices and in potential exposure scenarios. We describe the process of how the joint roadmap has been developed and how it could be implemented. Finally, we address the need to anticipate potential future exposure scenarios and to systematically consider the impact of emerging technologies and global challenges in the context of radiation protection. The joint roadmap is a living document that needs to be regularly updated to cover both current and potential exposures of humans and the environment.

Expert consultation is vital for adverse outcome pathway development: a case example of cardiovascular effects of ionizing radiation.

BACKGROUND: The circulatory system distributes nutrients, signaling molecules, and immune cells to vital organs and soft tissues. Epidemiological, animal, and in vitro cellular mechanistic studies have highlighted that exposure to ionizing radiation (IR) can induce molecular changes in cellular and subcellular milieus leading to long-term health impacts, particularly on the circulatory system. Although the mechanisms for the pathologies are not fully elucidated, endothelial dysfunction is proven to be a critical event via radiation-induced oxidative stress mediators. To delineate connectivities of events specifically to cardiovascular disease (CVD) initiation and progression, the adverse outcome pathway (AOP) approach was used with consultation from field experts. AOPs are a means to organize information around a disease of interest to a regulatory question. An AOP begins with a molecular initiating event and ends in an adverse outcome via sequential linkages of key event relationships that are supported by evidence in the form of the modified Bradford-Hill criteria. Detailed guidelines on building AOPs are provided by the Organisation for Economic Cooperation and Development (OECD) AOP program. Here, we report on the questions and discussions needed to develop an AOP for CVD resulting from IR exposure. A recent workshop jointly organized by the MELODI (Multidisciplinary European Low Dose Initiative) and the ALLIANCE (European Radioecology Alliance) associations brought together experts from the OECD to present the AOP approach and tools with examples from the toxicology field. As part of this workshop, four working groups were formed to discuss the identification of adverse outcomes relevant to radiation exposures and development of potential AOPs, one of which was focused on IR-induced cardiovascular effects. Each working group comprised subject matter experts and radiation researchers interested in the specific disease area and included an AOP coach. CONCLUSION: The CVD working group identified the critical questions of interest for AOP development, including the exposure scenario that would inform the evidence, the mechanisms of toxicity, the initiating event, intermediate key events/relationships, and the type of data currently available. This commentary describes the four-day discussion of the CVD working group, its outcomes, and demonstrates how collaboration and expert consultation is vital to informing AOP construction.

The future of our radiation protection profession.

There is widespread recognition of the challenge of an ageing profession and the need to recruit, train and retain the next generation of radiation protection professionals. This challenge was the topic of a special session at the International Radiation Protection Association IRPA15 International Congress. It is necessary to address three key aspects: capturing the future professional: gaining RP knowledge and skills: addressing retention, development and career progression. We must support the flow of students into science-based topics and attractively promote our profession. The availability of university and other training courses, together with research opportunities, must be supported. Mentoring of young professionals is key, supported by empathetic seniors in the profession. The overall challenge necessitates cooperation across a wide range of organisations at both international and national level.

Assessing radiation risk perception by means of a European stakeholder survey.

It is increasingly recognised that stakeholder views can be essential for ascertaining the credibility of those entrusted with protection of the public and workers against radiation risks, the robustness of the approaches to protection and the relevance of research underpinning radiation protection (RP). The CONCERT European Joint Programme of RP research included consideration of stakeholder views. These were evaluated by means of a publicly available survey, translated into 15 languages, to encourage responses from a wide range of European countries. The survey ran in 2017 and received some 1961 responses from many countries, although response rates varied widely between countries. The survey respondents were largely highly educated, with many having a professional connection to RP or the use of radiation in medicine or industry. Survey results indicated a high level of scientific/technical knowledge relevant to RP and indicated a general trust of most actors involved in the RP field, perhaps unsurprisingly given the nature of the sampled population. Most expressed a reasonable level of satisfaction with the information available to them on radiation risk, but there is clearly room for improvement. Additionally, the survey identified potential training needs amongst the groups who responded. It is concluded that, while the survey results are limited by the non-representativeness of the respondents by comparison with the population of the European Union as a whole, it has been successful in gaining insights into areas where communication could be improved, where professional training gaps are present and where research could help to build wider trust in RP.

Ionizing radiation-induced circulatory and metabolic diseases.

Risks to health are the prime consideration in all human situations of ionizing radiation exposure and therefore of relevance to radiation protection in all occupational, medical, and public exposure situations. Over the past few decades, advances in therapeutic strategies have led to significant improvements in cancer survival rates. However, a wide range of long-term complications have been reported in cancer survivors, in particular circulatory diseases and their major risk factors, metabolic diseases. However, at lower levels of exposure, the evidence is less clear. Under real-life exposure scenarios, including radiotherapy, radiation effects in the whole organism will be determined mainly by the response of normal tissues receiving relatively low doses, and will be mediated and moderated by systemic effects. Therefore, there is an urgent need for further research on the impact of low-dose radiation. In this article, we review radiation-associated risks of circulatory and metabolic diseases in clinical, occupational or environmental exposure situations, addressing epidemiological, biological, risk modelling, and systems biology aspects, highlight the gaps in knowledge and discuss future directions to address these gaps.

Is there any supportive evidence for low dose radiotherapy for COVID-19 pneumonia?

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.

Clinical and epidemiological observations on individual radiation sensitivity and susceptibility.

Purpose: To summarize existing knowledge and to understand individual response to radiation exposure, the MELODI Association together with CONCERT European Joint Programme has organized a workshop in March 2018 on radiation sensitivity and susceptibility.Methods: The workshop reviewed the current evidence on this matter, to inform the MELODI Strategic Research Agenda (SRA), to determine social and scientific needs and to come up with recommendations for suitable and feasible future research initiatives to be taken for the benefit of an improved medical diagnosis and treatment as well as for radiation protection.Results: The present paper gives an overview of the current evidence in this field, including potential effect modifiers such as age, gender, genetic profile, and health status of the exposed population, based on clinical and epidemiological observations.Conclusion: The authors conclude with the following recommendations for the way forward in radiation research: (a) there is need for large (prospective) cohort studies; (b) build upon existing radiation research cohorts; (c) use data from well-defined cohorts with good exposure assessment and biological material already collected; (d) focus on study quality with standardized data collection and reporting; (e) improve statistical analysis; (f) cooperation between radiobiology and epidemiology; and (g) take consequences of radiosensitivity and radiosusceptibility into account.

Potential screening assays for individual radiation sensitivity and susceptibility and their current validation state.

Purpose: The workshop on 'Individual Radiosensitivity and Radiosusceptibility' organized by MELODI and CONCERT on Malta in 2018, evaluated the current state of assays to identify sensitive and susceptible subgroups. The authors provide an overview on potential screening assays detecting individuals showing moderate to severe early and late radiation reactions or are at increased risk to develop cancer upon radiation exposure.Conclusion: It is necessary to separate clearly between tissue reactions and stochastic effects such as cancer when comparing the existing literature to validate various test systems. Requirements for the assays are set up. The literature is reviewed for assays that are reliable and robust. Sensitivity and specificity of the assays are regarded and scrutinized for modifying factors. Accuracy of an assay system is required to be more than 90% to balance risks of adverse reactions against risk to fail to cure the cancer. No assay/biomarker is in routine use. Assays that have shown predictive potential for radiosensitivity include SNPs, the RILA assay, and the pATM assay. A tree of risk guideline for radiologists is provided to assist medical treatment decisions. Recommendations for effective research include the setup of common retrospective and prospective cohorts/biobanks to validate current and future tests.

Mitochondrial DNA damage in the hair bulb: can it be used as a noninvasive biomarker of local exposure to low LET ionizing radiation?

Purpose: Our aim was to evaluate whether mitochondrial DNA (mtDNA) damage in hair bulbs could be a suitable biomarker for the detection of local exposure to ionizing radiation.Materials and methods: Mouse hair was collected 4 and 24 hours, 3 and 10 days after single whole-body exposure to 0, 0.1, and 2 Gy radiation. Pubic hair (treated area) and scalp hair (control area) were collected from 13 prostate cancer patients before and after fractioned radiotherapy with an average total dose of 2.7 Gy to follicles after five fractions. Unspecified lesion frequency of mtDNA was analyzed with long PCR, large mtDNA deletion levels were tested with real-time PCR.Results: Unspecified lesion frequency of mtDNA significantly increased in mouse hair 24 hours after irradiation with 2 Gy, but variance among samples was high. No increase in lesion frequency could be detected after 0.1 Gy irradiation. In prostate cancer patients, there was no significant change in either the unspecified lesion frequency or in the proportion of 4934-bp deleted mtDNA in pubic hair after radiotherapy. The proportions of murine 3860-bp common deletion, human 4977-bp common deletion and 7455-bp deleted mtDNA were too low to be analyzed reliably.Conclusions: Our results suggest that the unspecified lesion frequency and proportion of large deletions of mtDNA in hair bulbs are not suitable biomarkers of exposure to ionizing radiation.

Funding for radiation research: past, present and future.

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.

Progress in low dose health risk research: Novel effects and new concepts in low dose radiobiology.

People are more often exposed to low as opposed to high doses of ionising radiation (IR). Knowledge on the health risks associated with exposures to ionising radiation above 100 mGy is quite well established, while lower dose risks are inferred from higher level exposure information (ICRP). The health risk assessments are mainly based on epidemiological data derived from the atomic bombing of Hiroshima and Nagasaki, medical exposure studies and follow-up studies after nuclear accidents. For the estimation of long-term stochastic radiation health effects (such as cancer) and radiation protection purposes, a linear non-threshold (LNT) model is applied. However, the general validity of the LNT hypothesis for extrapolations from effects of high to low doses (<100 mGy) and low dose-rates (<6 mGy/h) has been questioned as epidemiological studies are statistically limited at low doses and unable to evaluate low dose and low dose-rate health risks (UNSCEAR). Thus, uncertainties on health risks need to be clarified with the help of mechanistic studies. The European Network of Excellence DoReMi (2010-2016) was designed to address some of the existing uncertainties and to identify research lines that are likely to be most informative for low dose risk assessment. The present review reports the results obtained from studies addressing the induction of cancer and non-cancer effects by low dose IR as well as on individual radiation sensitivity. It is shown that low dose and low dose-rate effects are the result of complex network responses including genetic, epigenetic, metabolic and immunological regulation. Evidence is provided for the existence of nonlinear biological responses in the low and medium dose range as well as effects other than the classical DNA damage. Such effects may have a bearing on the quantitative and qualitative judgements on health effects induced by low dose radiations.