Non-uniform radiation-induced biological responses at the tissue level involved in the health risk of environmental radiation: a radiobiological hypothesis
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The conventional concept of radiation protection is based on epidemiological studies of radiation that support a positive correlation between dose and response. However, there is a remarkable difference in biological responses at the tissue level, depending on whether radiation is delivered as a uniform or non-uniform spatiotemporal distribution due to tissue sparing effects (TSE). From the point of view of radiation micro-dosimetry, environmental radiation is delivered as a non-uniform distribution, and radiation-induced biological responses at the tissue level, such as TSE, would be implicated in individual risk following exposure to environmental radiation.
We hypothesize that the health risks of non-uniform radiation exposure are lower than the same dose at a uniform exposure, due to TSE following irradiation. Testing the hypothesis requires both radiobiological studies using high-precision microbeams and the epidemiological data of environmental radiation-induced effects. The implications of the hypothesis will lead to more personalized approaches in the field of environmental radiation protection.
The detection of spatiotemporal dose distribution could be of scientific importance for more accurate individual risk assessment of exposure to environmental radiation. Further radiobiological studies on non-uniform radiation-induced biological responses at the tissue level are expected.
KeywordsEnvironmental radiation Radiation-induced biological effects Tissue sparing effects Health risk assessment Radiological protection
Immunogenic cell death
International Commission on Radiological Protection
Life Span Study of Japanese atomic bomb survivors
National Council on Radiation Protection and Measurements, USA
Radiation-induced effects on biological tissues were recognized immediately after the pivotal discovery of X-rays by Wilhelm Röntgen in 1895 . The first radiation-related solid cancer was reported in 1902, arising in an ulcerated area of the skin, and, as reported in 1911, leukemia was diagnosed in five radiation workers . According to the results of previous epidemiological studies, including the Life Span Study (LSS) of Japanese atomic bomb survivors, these biological effects seem to be dose-dependent with or without a threshold [3, 4, 5, 6], thus the current concept of radiological protection is based on the dose-response model. In fact, for more than four decades, according to reports and statements of radiation research organizations, such as the US National Council on Radiation Protection and Measurements (NCRP) and the International Commission on Radiological Protection (ICRP), a linear non-threshold (LNT) model has been used for radiological protection purposes [7, 8]. In May 2018, NCRP published the Commentary No. 27, which supports the LNT model for radiological protection, based on recent results of epidemiological studies of radiation , although there are technical limitations to epidemiology, such as study design, sample size and confounding factors. Thus, the risk assessment of environmental radiation exposure is still based on the LNT model, although quantifying the risk still remains problematic and subject to uncertainty .
From the perspective of recent radiobiology, we highlight a specific challenge: the contribution of spatiotemporal dose distribution might be underestimated in the field of radiological protection. In an epidemiological cohort study of radiation, the researchers collected the data of the total radiation dose each participant was exposed to; however, it is technically difficult to have a clear grasp of their accurate irradiation situations, such as radiation dose rates or spatial distributions in the whole body. This is one of the possible technical limitations of the current epidemiological approach to radiation.
In clinical practice, the tissue-sparing response in non-uniform radiation fields was recognized more than one century ago. In 1909, Alban Köhler reported the first clinical observation of a tissue-sparing response during grid radiotherapy in which spatially fractionated radiation was delivered using a grid-like pattern of beams . In 1995, a notable tissue-sparing was reported in rat brain tissues during a microbeam radiation therapy (MRT) study , performed at the National Synchrotron Light Source, Brookhaven National Laboratory. Since then, the tissue-sparing effect (TSE) of MRT, which is based on a spatial fractionation of synchrotron-generated X-ray microbeams at the microscale level, has been confirmed in a large variety of species and tissue types, although the underlying mechanism of TSE remains to be established [19, 20, 21, 22, 23, 24, 25]. The TSE of spatial-fractionated radiation indicates significant implications not only for clinical applications, but also for the improvement of risk assessment of exposure to non-uniform radiation, such as environmental radiation. For a more accurate risk assessment of exposure to environmental radiation, the assessment of the spatiotemporal dose distribution could be of scientific importance due to the TSE.
Presentation of the hypothesis
We do not intend to question the conventional LNT concept for radiological protection purposes. Our aim is to suggest further studies on the mechanisms of radiation-induced biological responses at the tissue level for a more accurate estimation of environmental radiation risk. We hypothesize that the health risks of environmental radiation exposure are prone to be overestimated because at the very least radiation-induced biological responses at the tissue level, especially TSE, are not adequately considered. Conventionally, animal studies have been commonly used to investigate the radiation-induced biological responses at the tissue level. However, most of these studies have been performed by uniform radiation exposure, such as total body irradiation, thus the knowledge on tissue homeostasis responses following exposure to non-uniform radiation, such as environmental radiation, appears to be insufficient even now.
Testing the hypothesis
Because the technology of MRT has only recently been developed, the molecular mechanisms of TSE in response to non-uniform radiation fields have not yet been fully determined. As we suggest in this paper, there appears to be several potential biological responses involved in tissue homeostasis after exposure to non-uniform radiation, such as environmental radiation. Given the use of high-precision microbeams, further radiobiological studies on such biological responses are foreseen. Key to this will be an appropriate assessment of the interrelationship between dose and its localization in tissue volumes.
Also, epidemiological studies of non-uniform radiation-induced biological effects will provide a more comprehensive radiological understanding of response mechanisms, leading to improved accuracy in the estimations of environmental radiation risk. The confirmation of spatiotemporal dose distribution of environmental radiation will be of scientific importance in such studies.
Implications of the hypothesis
The hypothesis will suggest reconsidering the concept of the health-risk assessment of environmental radiation from the viewpoint of precision medicine. If the evidence for the hypothesis can be strengthened by appropriate radiobiological and epidemiological studies, the target of current environmental radiation risk assessment approaches will show a dramatic change from the “average person” to “each person”. To consider individual spatiotemporal exposure to radiation will provide a novel insight into individual risk assessment of environmental radiation. For the coming era of precision medicine, in addition to the consideration of genomic factors , the global scientific community, including such bodies as NCRP and ICRP, need to consider how to integrate similar personalized approaches into a future concepts of radiological protection. We hope that our hypothesis will stimulate scientific debate in the field.
Since the large-scale nuclear disasters in Chernobyl, in 1986, and in Fukushima, in 2011, there has been a great deal of public concern about the possible health effects of long-term and low-dose radiation exposure on current and future generations [37, 38, 39]. Previous data based on population cohorts, such as the LSS, estimate that the risk of cancer from radiation exposure will increase at doses exceeding approximately 100 mSv [4, 5], although there are technical limitations and biases . These data, however, are mainly based on acute irradiation situations, such as the explosion of the atomic bomb, and could not take weighting factors of spatiotemporal dose distributions into consideration. The hypothesis we suggest would provide a novel approach for more accurate individual risk assessment of such low-dose and long-term environmental radiation exposures.
Risk assessment of exposure to environmental radiation is essential for human activity in space. As future missions explore beyond low-Earth orbit (LEO) and away from the protection of the Earth’s magnetic shielding, the nature of radiation exposure that astronauts encounter will include higher radiation exposures . During transit outside of LEO, every cell nucleus within an astronaut’s body would be traversed by a proton or electron ray every few days, and by a heavier galactic cosmic ray ion (e.g., O, Si, Fe) every few months . For a more accurate risk assessment of exposure to such an environment, the understanding of non-uniform, radiation-induced biological responses at the tissue level will be of scientific importance.
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H.F. and K.M.P. co-developed the concept of this manuscript. H.F. wrote the first draft manuscript. K.M.P. provided comments and amendments to the draft manuscript. Both authors read and approved the final manuscript.
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