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Non-targeted effects (NTE) have been generally regarded as a low-dose ionizing radiation (IR) phenomenon. Recently, regarding long distant abscopal effects have also been observed at high doses of IR) relevant to antitumor radiation therapy. IR is inducing NTE involving intracellular and extracellular signaling, which may lead to short-ranging bystander effects and distant long-ranging extracellular signaling abscopal effects. Internal and "spontaneous" cellular stress is mostly due to metabolic oxidative stress involving mitochondrial energy production (ATP) through oxidative phosphorylation and/or anaerobic pathways accompanied by the leakage of O 2 - and other radicals from mitochondria during normal or increased cellular energy requirements or to mitochondrial dysfunction. Among external stressors, ionizing radiation (IR) has been shown to very rapidly perturb mitochondrial functions, leading to increased energy supply demands and to ROS/NOS production. Depending on the dose, this affects all types of cell constituents, including DNA, RNA, amino acids, proteins, and membranes, perturbing normal inner cell organization and function, and forcing cells to reorganize the intracellular metabolism and the network of organelles. The reorganization implies intracellular cytoplasmic-nuclear shuttling of important proteins, activation of autophagy, and mitophagy, as well as induction of cell cycle arrest, DNA repair, apoptosis, and senescence. It also includes reprogramming of mitochondrial metabolism as well as genetic and epigenetic control of the expression of genes and proteins in order to ensure cell and tissue survival. At low doses of IR, directly irradiated cells may already exert non-targeted effects (NTE) involving the release of molecular mediators, such as radicals, cytokines, DNA fragments, small RNAs, and proteins (sometimes in the form of extracellular vehicles or exosomes), which can induce damage of unirradiated neighboring bystander or distant (abscopal) cells as well as immune responses. Such non-targeted effects (NTE) are contributing to low-dose phenomena, such as hormesis, adaptive responses, low-dose hypersensitivity, and genomic instability, and they are also promoting suppression and/or activation of immune cells. All of these are parts of the main defense systems of cells and tissues, including IR-induced innate and adaptive immune responses. The present review is focused on the prominent role of mitochondria in these processes, which are determinants of cell survival and anti-tumor RT.

Until recently, radiation effects have been considered to be mainly due to nuclear DNA damage and their management by repair mechanisms. However, molecular biology studies reveal that the outcomes of exposures to ionizing radiation (IR) highly depend on activation and regulation through other molecular components of organelles that determine cell survival and proliferation capacities. As typical epigenetic-regulated organelles and central power stations of cells, mitochondria play an important pivotal role in those responses. They direct cellular metabolism, energy supply and homeostasis as well as radiation-induced signaling, cell death, and immunological responses. This review is focused on how energy, dose and quality of IR affect mitochondria-dependent epigenetic and functional control at the cellular and tissue level. Low-dose radiation effects on mitochondria appear to be associated with epigenetic and non-targeted effects involved in genomic instability and adaptive responses, whereas high-dose radiation effects (>1 Gy) concern therapeutic effects of radiation and long-term outcomes involving mitochondria-mediated innate and adaptive immune responses. Both effects depend on radiation quality. For example, the increased efficacy of high linear energy transfer particle radiotherapy, e.g., C-ion radiotherapy, relies on the reduction of anastasis, enhanced mitochondria-mediated apoptosis and immunogenic (antitumor) responses.

Purpose: Humans are increasingly exposed to ionizing radiation (IR). Both low (<100 mGy) and high doses can cause stochastic effects, including cancer; whereas doses above 100 mGy are needed to promote tissue or cell damage. 10-15% of radiotherapy (RT) patients suffer adverse reactions, described as displaying radiosensitivity (RS). Sensitivity to IR's stochastic effects is termed radiosusceptibility (RSu). To optimize radiation protection we need to understand the range of individual variability and underlying mechanisms. We review the potential mechanisms contributing to RS/RSu focusing on RS following RT, the most tractable RS group. Conclusions: The IR-induced DNA damage response (DDR) has been well characterized. Patients with mutations in the DDR have been identified and display marked RS but they represent only a small percentage of the RT patients with adverse reactions. We review the impacting mechanisms and additional factors influencing RS/RSu. We discuss whether RS/RSu might be genetically determined. As a recommendation, we propose that a prospective study be established to assess RS following RT. The study should detail tumor site and encompass a well-defined grading system. Predictive assays should be independently validated. Detailed analysis of the inflammatory, stress and immune responses, mitochondrial function and life style factors should be included. Existing cohorts should also be optimally exploited.

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.

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., (Copyright © 2018. Published by Elsevier B.V.)

Purpose: To analyze the dose rate influence in hyper-radiosensitivity (HRS) of human melanoma cells to very low doses of fast neutrons and to compare to the behaviour of normal human skin fibroblasts., Materials and Methods: We explored different neutron dose rates as well as possible implication of DNA double-strand breaks (DSB), apoptosis, and energy-provider adenosine-triphosphate (ATP) levels during HRS., Results: HRS in melanoma cells appears only at a very low dose rate (VLDR), while a high dose rate (HDR) induces an initial cell-radioresistance (ICRR). HRS does not seem to be due either to DSB or to apoptosis. Both phenomena (HRS and ICRR) appear to be related to ATP availability for triggering cell repair. Fibroblast survival after neutron irradiation is also dose rate-dependent but without HRS., Conclusions: Melanoma cells or fibroblasts exert their own survival behaviour at very low doses of neutrons, suggesting that in some cases there is a differential between cancer and normal cells radiation responses. Only the survival of fibroblasts at HDR fits the linear no-threshold model. This new insight into human cell responses to very low doses of neutrons, concerns natural radiations, surroundings of accelerators, proton-therapy devices, flights at high altitude. Furthermore, ATP inhibitors could increase HRS during high-linear energy transfer (high-LET) irradiation.

In 2009, the European High Level and Expert Group identified key policy and scientific questions to be addressed through a strategic research agenda for low-dose radiation risk. This initiated the establishment of a European Research Platform, called MELODI (Multidisciplinary European Low Dose Research Initiative). In 2010, the DoReMi Network of Excellence was launched in the Euratom 7th Framework Programme. DoReMi has acted as an operational tool for the sustained development of the MELODI platform during its early years. A long-term Strategic Research Agenda for European low-dose radiation risk research has been developed by MELODI. Strategic planning of DoReMi research activities is carried out in close collaboration with MELODI. The research priorities for DoReMi are designed to focus on objectives that are achievable within the 6-y lifetime of the project and that are in areas where stimulus and support can help progress towards the longer-term strategic objectives., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)