Effects of Partial-Body, Continuous/Pulse Irradiation at Dose Rates from Flash to Conventional Rates on The Level of Surviving Blood Lymphocytes: Modeling Approach II. Two- and Multiple-Pulse Irradiation.

Mathematical models, which describe effects of partial-body, two- and multiple-pulse irradiation at high total doses D and at average dose rates N from FLASH to conventional rates on the level of surviving blood lymphocytes in humans and mice, have been developed originating in the previously proposed approach. These models predict that levels of surviving blood lymphocytes in humans and mice increase with increasing the dose rate from N = D / TR (TR is the time of the blood flowing into or out of the irradiated segment of the blood circulatory system) to FLASH rates and approach an upper limiting level equal to (1- vR), where vR is the fraction of blood volume in the irradiated segment of the blood circulatory system. Levels of surviving blood lymphocytes computed at total doses D of 10-40 Gy and at average of dose rates N, which are equal to or exceed 40 Gy/s for humans and 400 Gy/s for mice, are nearly indistinguishable from the upper limiting level. These results can be interpreted as the models reproducing the optimal blood lymphocyte sparing in these mammals after such exposures. With decreasing the dose rate from N = D/ TR to conventional rates, at multiple-pulse irradiation the levels of surviving blood lymphocytes in humans and mice decrease to lower limiting levels, whereas at two-pulse irradiation they change cyclically and do not fall below their values for the delivery time equal to TR. Additionally, effects of two- and multiple-pulse irradiation of the whole abdomen in mice on the level of surviving blood lymphocytes are simulated within the developed models. Regimens of two- and multiple-pulse irradiation are taken the same as those reported in experiments, where effects of such exposures on the level of surviving crypts in mice were studied. Juxtaposing the modeling results with the experimental data reveals that the level of surviving blood lymphocytes in mice after two- and multiple-pulse irradiation of the abdomen at average dose rates N from FLASH to conventional rates modulates the level of surviving crypts in these animals after such exposures. A hypothesis is proposed to explain this phenomenon.

Effects of Partial-Body, Continuous/Pulse Irradiation at Dose Rates from Flash to Conventional Rates on the Level of Surviving Blood Lymphocytes: Modeling Approach. I. Continuous Irradiation.

A mathematical model developed by Cucinotta and Smirnova is extended to describe effects of continuous, partial-body irradiation at high doses D and at dose N rates from FLASH to conventional rates on the level of surviving blood lymphocytes in humans and small laboratory animals (mice). Specifically, whereas the applicability of the model is limited to the exposure times shorter than a single cardiac cycle T0, the extended model is capable of describing such effects for the aforementioned and longer exposure times. The extended model is implemented as the algebraic equations. It predicts that the level of surviving blood lymphocytes in humans and mice increases with increasing the dose rate from N = D / T0 to FLASH rates and approaches the upper limiting level of 1 - v R where v R is the fraction of blood volume in the irradiated part of the blood circulatory system. Levels of surviving blood lymphocytes computed at doses from 10 Gy to 40 Gy and at dose rates N, which equal or exceed 40 Gy/s for humans and 400 Gy/s for mice, are nearly indistinguishable from the upper limiting level. In turn, the level of surviving blood lymphocytes in humans and mice decreases with decreasing the dose rate from N = D / T0 to conventional rates and approaches a lower limiting level. This level strongly depends on the dose D (it is smaller at larger values of D) with a slight dependence on the dose rate N. The model with the parameters specified for mice (together with the model of the dynamics of lymphopoietic system in mice after partial-body irradiation) reproduce, on a quantitative level, the experimental data, according to which the concentration of blood lymphocytes measured in mice in one day after continuous, partial-body irradiation at a high dose and conventional dose rate is smaller at the larger value of vR. Additionally, the model predicts at the same high dose (>10 Gy) a faster restoration of the blood lymphocyte population in humans exposed to continuous, partial-body irradiation at a FLASH dose rate compared to a conventional dose rate.

Transcriptome Analysis by RNA Sequencing of Mouse Embryonic Stem Cells Stocked on International Space Station for 1584 Days in Frozen State after Culture on the Ground.

As a space project, in "Stem Cells" by the Japan Aerospace Exploration Agency (JAXA), frozen mouse ES cells were stored on the International Space Station (ISS) in the Minus Eighty Degree Laboratory Freezer for ISS (MELFI) for 1584 days. After taking these cells back to the ground, the cells were thawed and cultured, and their gene expressions were comprehensively analyzed using RNA sequencing in order to elucidate the early response of the cells to long-time exposure to space radiation consisting of various ionized particles. The comparisons of gene expression involved in double-stranded break (DSB) repair were examined. The expressions of most of the genes that were involved in homologous recombination (HR) and non-homologous end joining (NHEJ) were not significantly changed between the ISS-stocked cells and ground-stocked control cells. However, the transcription of Trp53inp1 (tumor protein 53 induced nuclear protein-1), Cdkn1a (p21), and Mdm2 genes increased in ISS-stocked cells as well as Fe ion-irradiated cells compared to control cells. This suggests that accumulated DNA damage caused by space radiation exposure would activate these genes, which are involved in cell cycle arrest for repair and apoptosis in a p53-dependent or -independent manner, in order to prevent cells with damaged genomes from proliferating and forming tumors.

Residual radiation risk disparities across sex and race or ethnic groups for lifetime never-smokers on lunar missions.

Missions to the Earth's moon are of scientific and societal interest, however pose the problem of risks of late effects for returning crew persons, most importantly cancer and circulatory diseases. In this paper, we discuss NSCR-2022 model risk estimates for lunar missions for US racial and ethnic groups comparing never-smokers (NS) to US averages for each group and sex. We show that differences within groups between men and women are reduced for NS compared to the average population. Race and ethnic group dependent cancer and circulatory disease risks are reduced by 10% to 40% for NS with the largest decrease for Whites. Circulatory disease risks are changed by less than 10% for NS and in several cases modestly increased due to increased lifespan for NS. Asian-Pacific Islanders (API) and Hispanics NS are at lower risk compared to Whites and Blacks. Differences between groups are narrowed for NS compared to predictions for average populations, however disparities remain especially for Blacks and to a lesser extent Whites compared to API or Hispanic NS groups.

Cancer and circulatory disease risks for the largest solar particle events in the space age.

In this paper we use the NASA Space Cancer Risk (NSCR version 2022) model to predict cancer and circulatory disease risks using energy spectra representing the largest SPE's observed in the space age. Because tissue dose-rates behind shielding for large SPE's lead to low dose-rates (<0.2 Gy/h) we consider the integrated risk for several historical periods of high solar activity, including July-November, 1960 events and August-October 1989 events along with the February 1956 and August 1972 events. The galactic cosmic ray (GCR) contribution to risks is considered in predictions. Results for these largest historical events show risk of exposure induced death (REID) are mitigated to < 1.2 % with a 95 % confidence interval with passive radiation shielding of 20 g/cm2 aluminum, while larger amounts would support the application of the ALARA principle. Annual GCR risks are predicted to surpass the risks from large SPEs by ∼30 g/cm2 of aluminum shielding.

Non-targeted effects and space radiation risks for astronauts on multiple International Space Station and lunar missions.

Future space travel to the earth's moon or the planet Mars will likely lead to the selection of experienced International Space Station (ISS) or lunar crew persons for subsequent lunar or mars missions. Major concerns for space travel are galactic cosmic ray (GCR) risks of cancer and circulatory diseases. However large uncertainties in risk prediction occur due to the quantitative and qualitative differences in heavy ion microscopic energy deposition leading to differences in biological effects compared to low LET radiation. In addition, there are sparse radiobiology data and absence of epidemiology data for heavy ions and other high LET radiation. Non-targeted effects (NTEs) are found in radiobiology studies to increase the biological effectiveness of high LET radiation at low dose for cancer related endpoints. In this paper the most recent version of the NASA Space Cancer Risk model (NSCR-2022) is used to predict mission risks while considering NTEs in solid cancer risk predictions. I discuss predictions of space radiation risks of cancer and circulatory disease mortality for US Whites and US Asian-Pacific Islander (API) populations for 6-month ISS, 80-day lunar missions, and combined ISS-lunar mission. Model predictions suggest NTE increase cancer risks by about ∼2.3 fold over a model that ignores NTEs. US API are predicted to have a lower cancer risks of about 30% compared to US Whites. Cancer risks are slightly less than additive for multiple missions, which is due to the decease of risk with age of exposure and the increased competition with background risks as radiation risks increase. The inclusion of circulatory risks increases mortality estimates about 25% and 37% for females and males, respectively in the model ignoring NTEs, and 20% and 30% when NTEs are assumed to modify solid cancer risk. The predictions made here for combined ISS and lunar missions suggest risks are within risk limit recommendations by the National Council on Radiation Protection and Measurements (NCRP) for such missions.

Effects of UHDR and Conventional Irradiation on Behavioral and Cognitive Performance and the Percentage of Ly6G+ CD45+ Cells in the Hippocampus.

We assessed the effects of conventional and ultra-high dose rate (UHDR) electron irradiation on behavioral and cognitive performance one month following exposure and assessed whether these effects were associated with alterations in the number of immune cells in the hippocampus using flow cytometry. Two-month-old female and male C57BL/6J mice received whole-brain conventional or UHDR irradiation. UHDR mice were irradiated with 9 MeV electrons, delivered by the Linac-based/modified beam control. The mice were irradiated or sham-irradiated at Dartmouth, the following week shipped to OHSU, and behaviorally and cognitively tested between 27 and 41 days after exposure. Conventional- and UHDR-irradiated mice showed impaired novel object recognition. During fear learning, conventional- and UHDR-irradiated mice moved less during the inter-stimulus interval (ISI) and UHDR-irradiated mice also moved less during the baseline period (prior to the first tone). In irradiated mice, reduced activity levels were also seen in the home cage: conventional- and UHDR-irradiated mice moved less during the light period and UHDR-irradiated mice moved less during the dark period. Following behavioral and cognitive testing, infiltrating immune cells in the hippocampus were analyzed by flow cytometry. The percentage of Ly6G+ CD45+ cells in the hippocampus was lower in conventional- and UHDR-irradiated than sham-irradiated mice, suggesting that neutrophils might be particularly sensitive to radiation. The percentage of Ly6G+ CD45+ cells in the hippocampus was positively correlated with the time spent exploring the novel object in the object recognition test. Under the experimental conditions used, cognitive injury was comparable in conventional and UHDR mice. However, the percentage of CD45+ CD11b+ Ly6+ and CD45+ CD11b+ Ly6G- cells in the hippocampus cells in the hippocampus was altered in conventional- but not UHDR-irradiated mice and the reduced percentage of Ly6G+ CD45+ cells in the hippocampus might mediate some of the detrimental radiation-induced cognitive effects.

Ionising radiation and cardiovascular disease: systematic review and meta-analysis.

OBJECTIVE: To systematically review and perform a meta-analysis of radiation associated risks of cardiovascular disease in all groups exposed to radiation with individual radiation dose estimates. DESIGN: Systematic review and meta-analysis. MAIN OUTCOME MEASURES: Excess relative risk per unit dose (Gy), estimated by restricted maximum likelihood methods. DATA SOURCES: PubMed and Medline, Embase, Scopus, Web of Science Core collection databases. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Databases were searched on 6 October 2022, with no limits on date of publication or language. Animal studies and studies without an abstract were excluded. RESULTS: The meta-analysis yielded 93 relevant studies. Relative risk per Gy increased for all cardiovascular disease (excess relative risk per Gy of 0.11 (95% confidence interval 0.08 to 0.14)) and for the four major subtypes of cardiovascular disease (ischaemic heart disease, other heart disease, cerebrovascular disease, all other cardiovascular disease). However, interstudy heterogeneity was noted (P<0.05 for all endpoints except for other heart disease), possibly resulting from interstudy variation in unmeasured confounders or effect modifiers, which is markedly reduced if attention is restricted to higher quality studies or those at moderate doses (<0.5 Gy) or low dose rates (<5 mGy/h). For ischaemic heart disease and all cardiovascular disease, risks were larger per unit dose for lower dose (inverse dose effect) and for fractionated exposures (inverse dose fractionation effect). Population based excess absolute risks are estimated for a number of national populations (Canada, England and Wales, France, Germany, Japan, USA) and range from 2.33% per Gy (95% confidence interval 1.69% to 2.98%) for England and Wales to 3.66% per Gy (2.65% to 4.68%) for Germany, largely reflecting the underlying rates of cardiovascular disease mortality in these populations. Estimated risk of mortality from cardiovascular disease are generally dominated by cerebrovascular disease (around 0.94-1.26% per Gy), with the next largest contribution from ischaemic heart disease (around 0.30-1.20% per Gy). CONCLUSIONS: Results provide evidence supporting a causal association between radiation exposure and cardiovascular disease at high dose, and to a lesser extent at low dose, with some indications of differences in risk between acute and chronic exposures, which require further investigation. The observed heterogeneity complicates a causal interpretation of these findings, although this heterogeneity is much reduced if only higher quality studies or those at moderate doses or low dose rates are considered. Studies are needed to assess in more detail modifications of radiation effect by lifestyle and medical risk factors. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020202036.

Effects of Flash Radiotherapy on Blood Lymphocytes in Humans and Small Laboratory Animals.

A mathematical model, which describes the level of surviving lymphocytes in the blood after ultra-high (FLASH) and lower dose rates of partial-body irradiation, is developed. The model is represented by simple analytic formulae that involve a few parameters, namely, physiologic parameters (characteristics of the blood flow through the blood circulatory system and its irradiated part), a biophysical parameter (a characteristic of the blood lymphocytes radiosensitivity), and the physical parameters (characteristics of irradiation). The model predicts that the level of surviving blood lymphocytes increases as the dose rate increases and approaches the limiting level of (1 - vR), where vR is the fraction of the blood volume in the irradiated part of the blood circulatory system. The model also predicts that the level of surviving blood lymphocytes after the same exposure is higher for lower vR. It is found that FLASH irradiation in humans with doses of 10 to 40 Gy and with exposure times significantly less (<1 s) than the blood circulation time (∼60 s) leads to the maximal blood lymphocyte sparing. Simple formula, which determines effective dose rates for optimal blood lymphocyte sparing, is derived in the framework of the developed model. For the dose range specified above, the obtained modeling prediction of the range of effective dose rates for optimal blood lymphocyte sparing in humans (namely, N ≥40 Gy/s) coincides with the dose rate range in FLASH radiation therapy. It is revealed that the respective effective dose rates for mice are higher than those for humans (for the same dose range) due to the shorter blood circulation time in mice than in humans. Proceeding from the findings obtained in this paper, a hypothesis elucidating the mechanisms of the abscopal effect of FLASH radiation therapy (namely, an antitumor response on metastases located outside of irradiated part of a body) is proposed.

Isotopic production cross sections in proton-16O and proton-12C interactions for energies from 10 MeV/u to 100 GeV/u.

Proton interactions with 16O or 12C nuclei are frequent nuclear interaction leading to secondary radiation in tissues for space radiation and cancer therapy with protons or ion beams. The fragmentation of these ions by protons produces a large number of heavy ion (A>4) target or projectile fragments often with high ionization density. Here we develop an analytical model of energy dependent proton-16O and proton-12C cross sections for isotopic nuclei production. Using experimental data and a 2nd order optical model an accurate formula for the absorption cross section from <10 MeV/u to >10 GeV/u is obtained. The energy dependence of the elemental and isotopic cross sections is modeled as multiplicities scaled to absorption cross section with average isotopic fractions estimated from experimental data. We show that this approach results in accurate analytic formulae for isotopic fragmentation cross sections over the full energy range in hadron therapy and space radiation protection studies.

Comparison of biological measurement and physical estimates of space radiation in the International Space Station.

Nowadays, ordinary people can travel in space, and the possibility of extended durations in an environment such as moon of the Earth and Mars with higher space radiation exposures compared to past missions, is increasing. Until now, the physical doses of space radiation have been measured, but measurement of direct biological effects has been hampered by its low dose and low dose-rate effect. To assess the biological effects of space radiation, we launched and kept frozen mouse embryonic stem (ES) cells in minus eighty degree Celsius freezer in ISS (MELFI) on the International Space Station (ISS) for a maximum of 1,584 days. The passive dosimeter for life science experiments in space (PADLES) was attached on the surface of the sample case of the ES cells. The physical dosimeter measured the absorbed dose in water. After return, the frozen cells were thawed and cultured and their chromosome aberrations were analyzed. Comparative experiments with proton and iron ion irradiation were performed at particle accelerators on Earth. The wild-type ES cells showed no differences in chromosomal aberrations between the ground control and ISS exposures. However, we detected an increase of chromosome aberrations in radio-sensitized histone H2AX heterozygous-deficient mouse ES cells and found that the rate of increase against the absorbed dose was 1.54-fold of proton irradiation at an accelerator. On the other hand, we estimated the quality factor of space radiation as 1.48 ± 0.2. using formulas of International Commission of Radiation Protection (ICRP) 60. The relative biological effectiveness (RBE) observed from our experiments (1.54-fold of proton) was almost equal (1.04-fold) to the physical estimation (1.48 ± 0.2). It should be important to clarify the relation between biological effect and physical estimates of space radiation. This comparative study paves a way to reveal the complex radiation environments to reduce the uncertainty for risk assessment of human stay in space.

Flying without a Net: Space Radiation Cancer Risk Predictions without a Gamma-ray Basis.

The biological effects of high linear energy transfer (LET) radiation show both a qualitative and quantitative difference when compared to low-LET radiation. However, models used to estimate risks ignore qualitative differences and involve extensive use of gamma-ray data, including low-LET radiation epidemiology, quality factors (QF), and dose and dose-rate effectiveness factors (DDREF). We consider a risk prediction that avoids gamma-ray data by formulating a track structure model of excess relative risk (ERR) with parameters estimated from animal studies using high-LET radiation. The ERR model is applied with U.S. population cancer data to predict lifetime risks to astronauts. Results for male liver and female breast cancer risk show that the ERR model agrees fairly well with estimates of a QF model on non-targeted effects (NTE) and is about 2-fold higher than the QF model that ignores NTE. For male or female lung cancer risk, the ERR model predicts about a 3-fold and more than 7-fold lower risk compared to the QF models with or without NTE, respectively. We suggest a relative risk approach coupled with improved models of tissue-specific cancers should be pursued to reduce uncertainties in space radiation risk projections. This approach would avoid low-LET uncertainties, while including qualitive effects specific to high-LET radiation.

Race and ethnic group dependent space radiation cancer risk predictions.

Future space missions by national space agencies and private industry, including space tourism, will include a diverse makeup of crewmembers with extensive variability in age, sex, and race or ethnic groups. The relative risk (RR) model is used to transfer epidemiology data between populations to estimate radiation risks. In the RR model cancer risk is assumed to be proportional to background cancer rates and limited by other causes of death, which are dependent on genetic, environmental and dietary factors that are population dependent. Here we apply the NSCR-2020 model to make the first predictions of age dependent space radiation cancer risks for several U.S. populations, which includes Asian-Pacific Islanders (API), Black, Hispanic (white and black), and White (non-Hispanic) populations. Results suggest that male API and Hispanic populations have the overall lowest cancer risks, while White females have the highest risk. Blacks have similar total cancer rates than Whites, however their reduced life expectancy leads to modestly lower lifetime radiation risks compared to Whites. There are diverse tissue specific cancer risk ranking across sex and race, which include sex specific organ risks, female's having larger lung, stomach, and urinary-bladder radiation risks, and male's having larger colon and brain risks.

Study of Total, Absorption, and 3He and 3H Production Cross Sections in 4He-proton Collisions.

Light ion breakup cross sections are important for studies of cosmic ray interactions in the inter-stellar medium or radiation protection considerations of energy deposition in shielding and tissues. Abrasion cross sections for heavy ion reactions have been modeled using the Glauber model in the large mass limit or Eikonal form of the optical potential model. Here we formulate an abrasion model for 4He fragmentation on protons using the Glauber model avoiding the large mass limit and include a model for final state interactions. Calculations of energy dependent total, absorption, elastic and breakup cross sections for 4He into 3He or 3H with proton targets are shown to be in good agreement with experiments for energies from 100 to 100,000 MeV/u. The Glauber model for light nuclei with and without a large mass limit approximation is shown to be in fair agreement above 300 MeV/u, however important differences occur at lower energies.

Carbon Ion Radiotherapy in the Management of Hepatocellular Carcinoma.

Localized hepatocellular carcinoma (HCC) that is unresectable and non-transplantable can be treated by several liver-directed therapies. External beam radiation therapy (EBRT) is an increasingly accepted and widely utilized treatment modality in this setting. Accelerated charged particles such as proton beam therapy (PBT) and carbon ion radiation therapy (CIRT) offer technological advancements over conventional photon radiotherapy. In this review, we summarize the distinct advantages of CIRT use for HCC treatment, focusing on physical and biological attributes, and outline dosimetric and treatment planning caveats. Based on these considerations, we posit that HCC may be among the best indications for use of CIRT, as it allows for maximizing tumoricidal doses to the target volume while minimizing the dose to the organs at risk.

A proposed change to astronaut exposures limits is a giant leap backwards for radiation protection.

Addressing the uncertainties in assessing health risks from cosmic ray heavy ions is a major scientific challenge recognized by many previous reports by the National Academy of Sciences (NAS) and the National Council on Radiation Protection and Measurements (NCRP) advising the National Aeronautics and Space Administration (NASA). These reports suggested a series of steps to pursue the scientific basis for space radiation protection, including the implementation of age and sex dependent risk assessments and exposure limits appropriate for a small population of radiation workers, the evaluation of uncertainties in risk projections, and developing a vigorous research program in heavy ion radiobiology to reduce uncertainties and discover effective countermeasures. The assessment of uncertainties in assessing risk provides protection against changing assessments of risk, reveals limitations in information used in space mission operations, and provides the impetus to reduce uncertainties and discover the true level of risk and possible effectiveness of countermeasures through research. However, recommendations of a recent NAS report, in an effort to minimize differences in age and sex on flight opportunities, suggest a 600 mSv career effective dose limit based on a median estimate to reach 3% cancer fatality for 35-year old females. The NAS report does not call out examples where females would be excluded from space missions planned in the current decade using the current radiation limits at NASA. In addition, there are minimal considerations of the level of risk to be encountered at this exposure level with respect to the uncertainties of heavy ion radiobiology, and risks of cancer, as well as cognitive detriments and circulatory diseases. Furthermore, their recommendation to limit Sieverts and not risk in conjunction with a waiver process is essentially a recommendation to remove radiation limits for astronauts. We discuss issues with several of the NAS recommendations with the conclusion that the recommendations could have negative impacts on crew health and safety, and violate the three principles of radiation protection (to prevent clinically significant deterministic effects, limit stochastic effects, and practice ALARA), which would be a giant leap backwards for radiation protection.

Comparison between PHITS and GEANT4 Simulations of the Heavy Ion Beams at the BEVALAC at LBNL and the Booster Accelerator at BNL.

Heavy charged particles have been discussed for clinical use due to their superior dose-depth distribution compared to conventional radiation such as X-rays. In addition, high-charge and energy (HZE) ions in galactic cosmic rays (GCR) present important health risks for crewed space missions to the Earth's moon or Mars. Experiments at heavy ion accelerators are used in radiobiology studies; however, numerical simulations of track segment or Bragg peak irradiations are complicated by the details of the beam-line and dosimetry systems. The goal of the present work is in support of biophysics modeling of historical radiobiology data at Lawrence Berkeley National Laboratory (LBNL) and more recent results from the Brookhaven National Lab (BNL) facility (NASA Space Radiation Lab (NSRL)). In this work, the Spread-Out Bragg Peak (SOBP) of 4He, 12C, and 20Ne particles, and a Bragg curve of 56Fe ion have been simulated numerically in the geometries of LBNL and BNL using the Monte-Carlo based PHITS and GEANT4 simulation toolkits. The dose contributions of primary particles and secondary particles, including neutrons and photons, in the target material are computed and discussed as well. Comparisons suggest more contributions of secondaries in GEANT4 simulations compared to PHITS simulations, and less statistical fluctuation and better prediction of neutrons in PHITS simulations. Neutrons and gamma-rays are estimated to make minor contributions to absorbed doses for these beams.

Low-Dose Radiation Therapy (LDRT) for COVID-19: Benefits or Risks?

The limited impact of treatments for COVID-19 has stimulated several phase 1 clinical trials of whole-lung low-dose radiation therapy (LDRT; 0.3-1.5 Gy) that are now progressing to phase 2 randomized trials worldwide. This novel but unconventional use of radiation to treat COVID-19 prompted the National Cancer Institute, National Council on Radiation Protection and Measurements and National Institute of Allergy and Infectious Diseases to convene a workshop involving a diverse group of experts in radiation oncology, radiobiology, virology, immunology, radiation protection and public health policy. The workshop was held to discuss the mechanistic underpinnings, rationale, and preclinical and emerging clinical studies, and to develop a general framework for use in clinical studies. Without refuting or endorsing LDRT as a treatment for COVID-19, the purpose of the workshop and this review is to provide guidance to clinicians and researchers who plan to conduct preclinical and clinical studies, given the limited available evidence on its safety and efficacy.