A microdosimetric-based (μD) dose-response model was recently proposed linking microdosimetry quantities to endpoints related to carcinogenesis for exposures relevant to the space radiation environment. In the μD model, the biological response to radiation is assumed to solely arise from microscopic spherical targets that received energy, which can be divided into: (1) targets not traversed by ions but that have received energy from δ-electrons of distant tracks (unhit irradiated targets), (2) targets traversed by one ion (singly hit targets), and (3) targets traversed by multiple tracks (multiply hit targets). The μD dose-response model was initially calibrated and validated using three experimental datasets, establishing its applicability and usefulness for exposures and biological endpoints of interest to space radiation induced carcinogenesis. Here, the μD dose-response model is used to study the global behavior of the three model components as a function of macroscopic absorbed dose, radiation quality, and spherical target size – major parameters influencing space radiation induced biological effects. Specifically, this work analyzes the effects of total macroscopic absorbed dose (10–4 Gy to 2 Gy), radiation quality (kinetic energy in the range 50 MeV/n to 5000 MeV/n, ion charge in the range 6 to 41, linear energy transfer (LET) > 10 keV/μm), and target size (2.76 μm to 10 μm) on the key components of the μD dose-response model for each of the irradiated subpopulations of cells: specific energy distribution, subpopulation fraction, mean specific energy, and mean target population dose. In the μD dose-response model, this latter quantity is directly related to the biological outcome. It is found that the total mean target dose is dominated by singly hit targets at low macroscopic doses and by multiply-hit targets at higher macroscopic doses, while the contribution of unhit irradiated targets is marginal. Overall, the trends of the analyzed microdosimetric quantities are driven by differences in track structure and fluences between low- and high-LET ions, for equal macroscopic doses. Identical quantities are found when dose-related quantities (beam dose, specific energy distribution, mean specific energy and mean target population dose) are scaled with the square of the radius. Establishing the global behavior of these μD dose-response model components for space radiation exposures will support future advancements of the μD model and subsequent understanding of radiation quality.

Microdosimetry can be used to estimate or evaluate quality factors for risk assessment in radiation protection and to quantify relative biological effectiveness for treatment planning of hadron radiation therapy. Radiation physics has shown that energetic ions deposit energy at the sub-cellular level in a complex manner: the track structure. Amorphous track models such as the Local Effect Model (LEM) and the Kiefer-Chatterjee Model are often used as an approximation of the complex ion track structure. We have previously calculated an analytical expression for the dose to a spherical target fully located in the penumbra of an ion track using the LEM. In this work, the analytical calculation has been extended to include almost all impact parameters. Furthermore, using the dose as a function of the impact parameter, it was possible to obtain the theoretical energy deposition spectra to a sphere irradiated uniformly. The analytical calculations were compared with simulations performed using the radiation track structure code RITRACKS (Relativistic Ion Tracks) using six ions of interest (1H+, 1,000 MeV; 4He2+, 250 MeV/n; 12C6+, 290 MeV/n; 16O8+, 325 MeV/n; 28Si14+, 300 MeV/n; 56Fe26+, 1,000 MeV/n). The results show an excellent agreement of the dose as a function of impact parameter. The dose deposition spectra show better agreement with RITRACKS at high Linear Energy Transfer (LET) than at low LET. This model could be useful in situations where microdosimetry calculations are needed without requiring the use of Monte-Carlo track structure codes.

Purpose Radiation-induced carcinogenesis remains one of the main hurdles for long duration missions in deep space. The space radiation environment is diverse and includes high linear energy transfer (LET) ions that are particularly effective at inducing adverse health outcomes including cancer. Quantifying the health effects of these high-LET ions is difficult, and large uncertainties remain in cancer risk projections. Chromosome aberrations are a biomarker of radiation-induced cancer used to assess radiation quality effects. Fluorescence in situ hybridization (FISH) measurements of simple and complex exchanges have inherent detection limitations that might underestimate the overall number of chromosomal rearrangements, possibly affecting estimates of the relative biological effectiveness of high-LET ions. Material and methods In this work, we introduced a new chromosome aberration classification approach in the simulation code RITCARD (Radiation induced tracks, chromosome aberrations, repair, and damage), that accounts for FISH detection threshold and the use of different chromosome painting probes. We also modified our 3D nuclear architecture model using Hi-C data to generate the DNA distribution within cell nuclei with the tool G-NOME. This new approach allowed the discrimination of true simple and complex exchanges from apparently simple exchanges (complex exchanges detected as simple), as well as undetected exchanges. Results We compared the results of this new classification method in the RITCARD tool with experimental FISH data obtained for the staining of 3 pairs of chromosomes (referred to as 3-FISH), and found an overall good agreement of the total exchanges for fibroblasts (hTERT 82-6) and lymphocytes (whole blood) for high LET ions, a slight underestimation in the low LET range (< ∼ 20 keV/µm), and a slight imbalance between simple and complex exchanges for lymphocytes. The model reproduced well the higher yield of aberrations for lymphocytes, compared to fibroblasts. Remarkably, in our model, this higher yield was solely due to differences in nuclear geometries and repair time between the two cell types, both derived from experimental data. For both cell types, we observed an increased number of complex exchanges detected as simple, and an increased number of undetected simple exchanges for high LET ions when we increased the detection threshold. For lymphocytes, this resulted in an overall increased number of simple exchanges, while, for fibroblasts, simple exchanges remained largely unchanged. Overall, the number of total exchanges decreased with increased detection threshold for both cell types. We also found that, for high LET ions, the majority of detected simple exchanges were true complex exchanges, due to many intra-chromosomal rearrangements that are undetected with traditional FISH technique. Perspectives Our new chromosome aberration classification approach allows us to go beyond FISH detection limitations and quantify how they impact aberration yields. Our simulation results suggest that, for high LET exposure, 3-FISH underestimates the total number of exchanges as well as their complexity, due to the inability to detect small fragments and intra-chromosomal rearrangements. Future work will focus on optimizing the model parameters to better reproduce low LET measurements. Once validated, RITCARD predictions may be used in the NASA cancer model to inform radiation quality factors as part of an ensemble framework. We also intend to investigate how predictions obtained with partial chromosome staining (3-FISH) compares with predictions obtained with whole genome staining (mFISH), and how both compare with predictions of true exchanges, where all exchanges are accounted for, included those undetectable by traditional FISH such as inversion or small deletions.

Chromosome aberrations, a biomarker of space radiation-induced carcinogenesis, are a direct consequence of DNA double-strand break (DSB) misrepair and play an important role in the fate of irradiated cells. Their formation is a function of different physical and biological factors including the 3D DNA architecture. At the nanometric scale, the DNA is wrapped around histone proteins to form nucleosomes, which fold together to form the chromatin fiber. Different levels of DNA density exist, namely the less compact euchromatin (EC) and the denser heterochromatin (HC). Recent studies showed that EC is more prone to DNA damage than HC at the same dose, suggesting that DNA compaction might influence chromosome aberration formation. In this work, we investigated how DNA compaction at the nucleosome level influences the formation of DSBs and total exchanges for exposure to high charge and energy ions (HZE) with linear energy transfer (LET) in the range 0.4 - 235 keV/μm. The radiation transport tool RITRACKS and DNA damage and chromosome aberration model RITCARD allow the transport of HZE ions in cell nuclei and evaluate the yield of DNA damage and chromosome aberrations but does not provide detailed geometries of the DNA with different compaction levels. In contrast, Geant4-DNA provide atomic scale models of HC or EC DNA and can be used to evaluate DNA damage. We combined Geant4-DNA and RITCARD to model radiation transport, DNA damage and DNA repair in fibroblast cell nuclei filled with EC or HC and compared the results to those obtained by RITRACKS/RITCARD. For all cell nuclei, the 3D distribution of the DNA was obtained with the tool G-NOME using experimental chromosome conformation capture (Hi-C) data. Large differences were obtained for the yield of DSB between RITRACKS/RITCARD and Geant4 DNA (-25% - 125% for HC nuclei), reflecting major differences in how the two models score DNA damage, which were responsible for large differences (-50% - 150% for HC nuclei) in the yield of total exchanges. For Geant4-DNA, we found that DNA decompaction increased the yield of DNA DSB by 4-8%, depending on the ion LET. The effect was more pronounced for total exchanges, with an increased yield of 50-75% for EC nuclei compared to HC nuclei. This larger total exchange yield was attributed mainly to differences in DNA distribution across the cell nucleus and, to a lesser extent, the increased DSB yield. Euchromatin nuclei presented chromosome domains that were more spread out, likely favoring inter-chromosomal proximity at the periphery of chromosome territories and, therefore, chromosome rearrangements. These findings provide further evidence that DNA compaction could be a factor of cell radiosensitivity.

Cosmic radiation, composed of high charge and energy (HZE) particles, causes cellular DNA damage that can result in cell death or mutation that can evolve into cancer. In this work, a cell death model is applied to several cell lines exposed to HZE ions spanning a broad range of linear energy transfer (LET) values. We hypothesize that chromatin movement leads to the clustering of multiple double strand breaks (DSB) within one radiation-induced foci (RIF). The survival probability of a cell population is determined by averaging the survival probabilities of individual cells, which is function of the number of pairwise DSB interactions within RIF. The simulation code RITCARD was used to compute DSB. Two clustering approaches were applied to determine the number of RIF per cell. RITCARD outputs were combined with experimental data from four normal human cell lines to derive the model parameters and expand its predictions in response to ions with LET ranging from similar to 0.2 keV/mu m to similar to 3000 keV/mu m. Spherical and ellipsoidal nuclear shapes and two ion beam orientations were modeled to assess the impact of geometrical properties on cell death. The calculated average number of RIF per cell reproduces the saturation trend for high doses and high-LET values that is usually experimentally observed. The cell survival model generates the recognizable bell shape of LET dependence for the relative biological effectiveness (RBE). At low LET, smaller nuclei have lower survival due to increased DNA density and DSB clustering. At high LET, nuclei with a smaller irradiation area-either because of a smaller size or a change in beam orientation-have a higher survival rate due to a change in the distribution of DSB/RIF per cell. If confirmed experimentally, the geometric characteristics of cells would become a significant factor in predicting radiation-induced biological effects. Insight Box High-charge and energy (HZE) ions are characterized by dense linear energy transfer (LET) that induce unique spatial distributions of DNA damage in cell nuclei that result in a greater biological effect than sparsely ionizing radiation like X-rays. HZE ions are a prominent component of galactic cosmic ray exposure during human spaceflight and specific ions are being used for radiotherapy. Here, we model DNA damage clustering at sub-micrometer scale to predict cell survival. The model is in good agreement with experimental data for a broad range of LET. Notably, the model indicates that nuclear geometry and ion beam orientation affect DNA damage clustering, which reveals their possible role in mediating cell radiosensitivity.

This work aims at investigating the impact of DNA geometry, compaction and calculation chain on DNA break and chromosome aberration predictions for high charge and energy (HZE) ions, using the Monte Carlo codes Geant4-DNA, RITRACKS and RITCARD. To ensure consistency of ion transport of both codes, we first compared microdosimetry and nanodosimetry spectra for different ions of interest in hadrontherapy and space research. The Rudd model was used for the transport of ions in both models. Developments were made in Geant4 (v11.2) to include periodic boundary conditions (PBC) to account for electron equilibrium in small targets. Excellent agreements were found for both microdosimetric and nanodosimetric spectra for all ion types, with and without PBC. Some discrepancies remain for low-energy deposition events, likely due to differences in electron interaction models. The latest results obtained using the newly available Geant4 example “dsbandrepair” will be presented and compared to DNA break predictions obtained with RITCARD.

For missions beyond low Earth orbit to the moon or Mars, space explorers will encounter a complex radiation field composed of various ion species with a broad range of energies. Such missions pose significant radiation protection challenges that need to be solved in order to minimize exposures and associated health risks. An innovative galactic cosmic ray simulator (GCRsim) was recently developed at the NASA Space Radiation Lab-oratory (NSRL) at Brookhaven National Laboratory (BNL). The GCRsim technology is intended to represent major components of the space radiation environment in a ground analog laboratory setting where it can be used to improve understanding of biological risks and serve as a testbed for countermeasure development and vali-dation. The current GCRsim consists of 33 energetic ion beams that collectively simulate the primary and sec-ondary GCR field encountered by humans in space over the broad range of particle types, energies, and linear energy transfer (LET) of interest to health effects. A virtual workshop was held in December 2020 to assess the status of the NASA baseline GCRsim. Workshop attendees examined various aspects of simulator design, with a particular emphasis on beam selection strategies. Experimental results, modeling approaches, areas of consensus, and questions of concern were also discussed in detail. This report includes a summary of the GCRsim workshop and a description of the current status of the GCRsim. This information is important for future advancements and applications in space radiobiology.

Ionizing radiation causes chromosome aberrations, which are possible biomarkers to assess space radiation cancer risks. Using the Monte Carlo codes Relativistic Ion Tracks (RITRACKS) and Radiation-Induced Tracks, Chromosome Aberrations, Repair and Damage (RITCARD), we investigated how geometrical properties of the cell nucleus, irradiated with ion beams of linear energy transfer (LET) ranging from 0.22 keV/μm to 195 keV/μm, influence the yield of simple and complex exchanges. We focused on the effect of (1) nuclear volume by considering spherical nuclei of varying radii; (2) nuclear shape by considering ellipsoidal nuclei of varying thicknesses; (3) beam orientation; and (4) chromosome intermingling by constraining or not constraining chromosomes in non-overlapping domains. In general, small nuclear volumes yield a higher number of complex exchanges, as compared to larger nuclear volumes, and a higher number of simple exchanges for LET < 40 keV/μm. Nuclear flattening reduces complex exchanges for high-LET beams when irradiated along the flattened axis. The beam orientation also affects yields for ellipsoidal nuclei. Reducing chromosome intermingling decreases both simple and complex exchanges. Our results suggest that the beam orientation, the geometry of the cell nucleus, and the organization of the chromosomes within are important parameters for the formation of aberrations that must be considered to model and translate in vitro results to in vivo risks.

The space radiation environment is qualitatively different from Earth, and its radiation hazard is generally quantified relative to photons using quality factors that allow assessment of biologically-effective dose. Two approaches exist for estimating radiation quality factors in complex low/intermediate-dose radiation environments: one is a fluence-based risk cross-section approach, which requires very detailed in silico characterization of the radiation field and biological cross sections, and thus cannot realistically be used for in situ monitoring. By contrast, the microdosimetric approach, using measured (or calculated) distributions of microdosimetric energy deposition together with empirical biological weighting functions, is conceptually and practically simpler. To demonstrate feasibility of the microdosimetric approach, we estimated a biological weighting function for one specific endpoint, heavy-ion-induced tumorigenesis in APC1638N/+ mice, which was unfolded from experimental results after a variety of heavy ion exposures together with corresponding calculated heavy ion microdosimetric energy deposition spectra. Separate biological weighting functions were unfolded for targeted and non-targeted effects, and these differed substantially. We folded these biological weighting functions with microdosimetric energy deposition spectra for different space radiation environments, and conclude that the microdosimetric approach is indeed practical and, in conjunction with in-situ measurements of microdosimetric spectra, can allow continuous readout of biologically-effective dose during space flight.

An intercomparison of microdosimetric and nanodosimetric quantities simulated Monte Carlo codes is in progress with the goal of assessing the uncertainty contribution to simulated results due to the uncertainties of the electron interaction cross-sections used in the codes. In the first stage of the intercomparison, significant discrepancies were found for nanodosimetric quantities as well as for microdosimetric simulations of a radiation source placed at the surface of a spherical water scoring volume. This paper reports insight gained from further analysis, including additional results for the microdosimetry case where the observed discrepancies in the simulated distributions could be traced back to the difference between track-structure and condensed-history approaches. Furthermore, detailed investigations into the sensitivity of nanodosimetric distributions to alterations in inelastic electron scattering cross-sections are presented which were conducted in the lead up to the definition of an approach to be used in the second stage of the intercomparison to come. The suitability of simulation results for assessing the sought uncertainty contributions from cross-sections is discussed and a proposed framework is described.

Studying energy deposition by space radiation at the cellular scale provides insights on health risks to astronauts. Using the Monte Carlo track structure code RITRACKS, and the chromosome aberrations code RITCARD, we performed a modeling study of single-ion energy deposition spectra and chromosome aberrations for high-energy (>250 MeV/n) ion beams with linear energy transfer (LET) varying from 0.22 to 149.2 keV/µm. The calculations were performed using cells irradiated directly by mono-energetic ion beams, and by poly-energetic beams after particle transport in a digital mouse model, representing the radiation exposure of a cell in a tissue. To discriminate events from ion tracks directly traversing the nucleus, to events from δ-electrons emitted by distant ion tracks, we categorized ion contributions to microdosimetry or chromosome aberrations into direct and indirect contributions, respectively. The ions were either ions of the mono-energetic beam or secondary ions created in the digital mouse due to interaction of the beam with tissues. For microdosimetry, the indirect contribution is largely independent of the beam LET and minimally impacted by the beam interactions in mice. In contrast, the direct contribution is strongly dependent on the beam LET and shows increased probabilities of having low and high-energy deposition events when considering beam transport. Regarding chromosome aberrations, the indirect contribution induces a small number of simple exchanges, and a negligible number of complex exchanges. The direct contribution is responsible for most simple and complex exchanges. The complex exchanges are significantly increased for some low-LET ion beams when considering beam transport.

In a previous work, we extended and benchmarked the MDM Monte Carlo code with available data for gold metallic media irradiated by electron beams. In this paper, we worked with the aim of improving the cross sections on which our Monte Carlo simulation is based, and which are essential for an accurate description of the transport of electrons in gold. The mesoscopic potential of solid gold has been predicted, and its sensitivity toward electron emission has been evaluated. This potential was derived from the calculation of the electrostatic and atomistic potential by density functional theory and used to calculate inelastic inverse mean free path for electron transport. After integrating these results into our Monte Carlo code, we evaluated the impact of these new cross sections on yields of electron emission from solid gold irradiated by monoenergetic electron beams. We obtained a mesoscopic potential value of − 12.77 eV for our model of bulk metal gold, 27% lower than the one commonly estimated from the Fermi energy. This result impacted on the inverse mean free path for plasmon excitations with a 10% decrease for electrons in the range of 6–30 eV. Regarding electron emission yields, there was no impact of the new mesoscopic potential on the primary electron yields, but for secondary electrons, the emission yields were increased by a factor of up to two depending on the primary beam energy and thickness of the gold foil.

Purpose To develop a particle transport code to compute w-values and stopping power of swift ions in liquid water and gases of interest for reference dosimetry in hadrontherapy. To analyze the relevance of inelastic and post-collisional processes considered. Methods The Monte Carlo code MDM was extended to the case of swift ion impact on liquid water (MDM-Ion). Relativistic corrections in the inelastic cross sections and the post-collisional Auger emission were considered. The effects of introducing different electronic excitation cross sections were also studied. Results The stopping power of swift ions on liquid water, calculated with MDM-Ion, are in excellent agreement with recommended data. The w-values show a strong dependence on the electronic excitation cross sections and on the Auger electron emission. Comparisons with other Monte Carlo codes show the relevance of both the processes considered and of the cross sections employed. W and w-values for swift electron, proton, and carbon ions calculated with the MDM and MDM-Ion codes are in very close agreement with each other and with the 20.8 eV experimental value. Conclusion We found that w-values in liquid water are independent of ion charge and energy, as assumed in reference dosimetry for hadrontherapy from sparse experimental results for electron and ion impact on gases. Excitation cross sections and Auger emission included in Monte Carlo codes are critical in w-values calculations. The computation of this physical parameter should be used as a benchmark for micro-dosimetry investigations, to assess the reliability of the cross sections employed.

To understand the biological effects of radiation, it is important to determine how ionizing radiation deposits energy in micrometric targets. The energy deposited in a target located in an irradiated tissue is a function of several factors such as the radiation type and the irradiated volume size. We simulated the energy deposited by energetic ions in spherical targets of 1, 2, 4, and 8 µm radii encompassed in irradiated parallelepiped volumes of various sizes using the stochastic radiation track structure code Relativistic Ion Tracks (RITRACKS). Because cells are usually part of a tissue when they are irradiated, electrons originating from radiation tracks in neighboring volumes also contribute to energy deposition in the target. To account for this contribution, we used periodic boundary conditions in the simulations. We found that the single-ion spectra of energy deposition in targets comprises two components: the direct ion hits to the targets, which is identical in all irradiation conditions, and the contribution of hits from electrons from neighboring volumes, which depends on the irradiated volume. We also calculated an analytical expression of the indirect hit contributions using the local effect model, which showed results similar to those obtained with RITRACKS.

Organized by the European Radiation Dosimetry Group (EURADOS), a Monte Carlo code intercomparison exercise was conducted where participants simulated the emitted electron spectra and energy deposition around a single gold nanoparticle (GNP) irradiated by X-rays. In the exercise, the participants scored energy imparted in concentric spherical shells around a spherical volume filled with gold or water as well as the spectral distribution of electrons leaving the GNP. Initially, only the electron spectra and the ratio of energy deposition with and without GNP were to be reported. During the evaluation of the exercise, however, the scope was extended to include the results for energy deposition in the presence and absence of the GNP. A GNP size of 50 nm and 100 nm diameter was considered as well as two different X-ray spectra (50 kVp and 100kVp). This introduced a redundancy that can be used to cross-validate the internal consistency of the simulation results. In this work, evaluation of the reported results is presented in terms of integral quantities that can be benchmarked against values obtained from physical properties of the radiation spectra and materials involved. The impact of different interaction cross-section datasets and their implementation in the different Monte Carlo codes is also discussed.

Organized by the European Radiation Dosimetry Group (EURADOS), a Monte Carlo code intercomparison exercise was conducted where participants simulated the emitted electron spectra and energy deposition around a single gold nanoparticle (GNP) irradiated by X-rays. In the exercise, the participants scored energy imparted in concentric spherical shells around a spherical volume filled with gold or water as well as the spectral distribution of electrons leaving the GNP. Initially, only the ratio of energy deposition with and without GNP was to be reported. During the evaluation of the exercise, however, the data for energy deposition in the presence and absence of the GNP were also requested. A GNP size of 50 nm and 100 nm diameter was considered as well as two different X-ray spectra (50 kVp and 100kVp). This introduced a redundancy that can be used to cross-validate the internal consistency of the simulation results. In this work, evaluation of the reported results is presented in terms of integral quantities that can be benchmarked against values obtained from physical properties of the radiation spectra and materials involved. The impact of different interaction cross-section datasets and their implementation in the different Monte Carlo codes is also discussed.

Results of a Monte Carlo code intercomparison exercise for simulations of the dose enhancement from a gold nanoparticle (GNP) irradiated by X-rays have been recently reported. To highlight potential differences between codes, the dose enhancement ratios (DERs) were shown for the narrow-beam geometry used in the simulations, which leads to values significantly higher than unity over distances in the order of several tens of micrometers from the GNP surface. As it has come to our attention that the figures in our paper have given rise to misinterpretation as showing 'the' DERs of GNPs under diagnostic X-ray irradiation, this article presents estimates of the DERs that would have been obtained with realistic radiation field extensions and presence of secondary particle equilibrium (SPE). These DER values are much smaller than those for a narrow-beam irradiation shown in our paper, and significant dose enhancement is only found within a few hundred nanometers around the GNP. The approach used to obtain these estimates required the development of a methodology to identify and, where possible, correct results from simulations whose implementation deviated from the initial exercise definition. Based on this methodology, literature on Monte Carlo simulated DERs has been critically assessed.