Geometrical Properties of the Nucleus and Chromosome Intermingling Are Possible Major Parameters of Chromosome Aberration Formation.

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.

Increased Chromosome Aberrations in Cells Exposed Simultaneously to Simulated Microgravity and Radiation.

Space radiation and microgravity (µG) are two major environmental stressors for humans in space travel. One of the fundamental questions in space biology research is whether the combined effects of µG and exposure to cosmic radiation are interactive. While studies addressing this question have been carried out for half a century in space or using simulated µG on the ground, the reported results are ambiguous. For the assessment and management of human health risks in future Moon and Mars missions, it is necessary to obtain more basic data on the molecular and cellular responses to the combined effects of radiation and µG. Recently we incorporated a µG⁻irradiation system consisting of a 3D clinostat synchronized to a carbon-ion or X-ray irradiation system. Our new experimental setup allows us to avoid stopping clinostat rotation during irradiation, which was required in all other previous experiments. Using this system, human fibroblasts were exposed to X-rays or carbon ions under the simulated µG condition, and chromosomes were collected with the premature chromosome condensation method in the first mitosis. Chromosome aberrations (CA) were quantified by the 3-color fluorescent in situ hybridization (FISH) method. Cells exposed to irradiation under the simulated µG condition showed a higher frequency of both simple and complex types of CA compared to cells irradiated under the static condition by either X-rays or carbon ions.

Reactivation of Latent Epstein-Barr Virus: A Comparison after Exposure to Gamma, Proton, Carbon, and Iron Radiation.

Among the many stressors astronauts are exposed to during spaceflight, cosmic radiation may lead to various serious health effects. Specifically, space radiation may contribute to decreased immunity, which has been documented in astronauts during short- and long-duration missions, as evidenced by several changes in cellular immunity and plasma cytokine levels. Reactivation of latent herpes viruses, either directly from radiation of latently infected cells and/or from perturbation of the immune system, may result in disease in astronauts. Epstein‒Barr virus (EBV) is one of the eight human herpes viruses known to infect more than 90% of human adults and persists for the life of the host without normally causing adverse effects. Reactivation of several latent viruses in astronauts is well documented, although the mechanism of reactivation is not well understood. We studied the effect of four different types of radiation, (1) 137Cs gamma rays, (2) 150-MeV protons, (3) 600 MeV/n carbon ions, and (4) 600 MeV/n iron ions on the activation of lytic gene transcription and of reactivation of EBV in a latently infected cell line (Akata) at doses of 0.1, 0.5, 1.0, and 2.0 Gy. The data showed that for all doses used in this study, lytic gene transcription was induced and median viral loads were significantly higher for all types of radiation than in corresponding control samples, with the increases detected as early as four days post-exposure and generally tapering off at later time points. The viability and size of EBV-infected Akata cells were highly variable and exhibited approximately the same trend in time for all radiation types at 0.1, 0.5, 1.0, and 2.0 Gy. This work shows that reactivation of viruses can occur due to the effect of different types of radiation on latently infected cells in the absence of changes or cytokines produced in the immune system. In general, gamma rays are more effective than protons, carbon ions, and iron ions in inducing latent virus reactivation, though these high-energy particles did induce more sustained and later reactivation of EBV lytic gene transcription. These findings also challenge the common relative biological effectiveness concept that is often used in radiobiology for other end points.

Simulation of Radiation-Induced DNA Damage and Protection by Histones Using the Code RITRACKS.

(1) Background: DNA damage is of great importance in the understanding of the effects of ionizing radiation. Various types of DNA damage can result from exposure to ionizing radiation, with clustered types considered the most important for radiobiological effects. (2) Methods: The code RITRACKS (Relativistic Ion Tracks), a program that simulates stochastic radiation track structures, was used to simulate DNA damage by photons and ions spanning a broad range of linear energy transfer (LET) values. To perform these simulations, the transport code was modified to include cross sections for the interactions of ions or electrons with DNA and amino acids for ionizations, dissociative electron attachment, and elastic collisions. The radiochemistry simulations were performed using a step-by-step algorithm that follows the evolution of all particles in time, including reactions between radicals and DNA structures and amino acids. Furthermore, detailed DNA damage events, such as base pair positions, DNA fragment lengths, and fragment yields, were recorded. (3) Results: We report simulation results using photons and the ions 1H+, 4He2+, 12C6+, 16O8+, and 56Fe26+ at various energies, covering LET values from 0.3 to 164 keV/µm, and performed a comparison with other codes and experimental results. The results show evidence of DNA protection from damage at its points of contacts with histone proteins. (4) Conclusions: RITRACKS can provide a framework for studying DNA damage from a variety of ionizing radiation sources with detailed representations of DNA at the atomic scale, DNA-associated proteins, and resulting DNA damage events and statistics, enabling a broader range of future comparisons with experiments such as those based on DNA sequencing.

Participation of gap junction communication in potentially lethal damage repair and DNA damage in human fibroblasts exposed to low- or high-LET radiation.

Existing research has not fully explained how different types of ionizing radiation (IR) modulate the responses of cell populations or tissues. In our previous work, we showed that gap junction intercellular communication (GJIC) mediates the propagation of stressful effects among irradiated cells exposed to high linear energy transfer (LET) radiations, in which almost every cells is traversed by an IR track. In the present study, we conducted an in-depth study of the role of GJIC in modulating the repair of potentially lethal damage (PLDR) and micronuclei formation in cells exposed to low- or high-LET IR. Confluent human fibroblasts were exposed in the presence or absence of a gap junction inhibitor to 200kV X rays (LET∼1.7keV/µm), carbon ions (LET∼76keV/µm), silicon ions (LET∼113keV/µm) or iron ions (LET∼400keV/µm) that resulted in isosurvival levels. The fibroblasts were incubated for various times at 37°C. As expected, high-LET IR were more effective than were low-LET X rays at killing cells and damaging DNA shortly after irradiation. However, when cells were held in a confluent state for several hours, PLDR associated with a reduction in DNA damage, occurred only in cells exposed to X rays. Interestingly, inhibition of GJIC eliminated the enhancement of toxic effects, which resulted in an increase of cell survival and reduction in the level of micronucleus formation in cells exposed to high, but not in those exposed to low-LET IR. The experiment shows that gap-junction communication plays an important role in the propagation of stressful effects among irradiated cells exposed to high-LET IR while GJIC has only a minimal effect on PLDR and DNA damage following low-LET irradiation. Together, our results show that PLDR and induction of DNA damage clearly depend on gap-junction communication and radiation quality.

Impact of Radiation Quality on Microdosimetry and Chromosome Aberrations for High-Energy (>250 MeV/n) Ions

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.

A practical approach for continuous in situ characterization of radiation quality factors in space.

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.

Cardiovascular Disease Risk Modeling for Astronauts: Making the Leap From Earth to Space.

NASA has recently completed several long-duration missions to the International Space Station and is solidifying plans to return to the Moon, with an eye toward Mars and beyond. As NASA pushes the boundaries of human space exploration, the hazards of spaceflight, including space radiation, levy an increasing burden on astronaut health and performance. The cardiovascular system may be especially vulnerable due to the combined impacts of space radiation exposure, lack of gravity, and other spaceflight hazards. On Earth, the risk for cardiovascular disease (CVD) following moderate to high radiation doses is well-established from clinical, environmental, and occupational exposures (largely from gamma- and x-rays). Less is known about CVD risks associated with high-energy charged ions found in space and increasingly used in radiotherapy applications on Earth, making this a critical area of investigation for occupational radiation protection. Assessing CVD risk is complicated by its multifactorial nature, where an individual's risk is strongly influenced by factors such as family history, blood pressure, and lipid profiles. These known risk factors provide the basis for development of a variety of clinical risk prediction models (CPMs) that inform the likelihood of medical outcomes over a defined period. These tools improve clinical decision-making, personalize care, and support primary prevention of CVD. They may also be useful for individualizing risk estimates for CVD following radiation exposure both in the clinic and in space. In this review, we summarize unique aspects of radiation risk assessment for astronauts, and we evaluate the most widely used CVD CPMs for their use in NASA radiation risk assessment applications. We describe a comprehensive dual-use risk assessment framework that supports both clinical care and operational management of space radiation health risks using quantitative metrics. This approach is a first step in using personalized medicine for radiation risk assessment to support safe and productive spaceflight and long-term quality of life for NASA astronauts.

Response of Arabidopsis thaliana and Mizuna Mustard Seeds to Simulated Space Radiation Exposures.

One of the major concerns for long-term exploration missions beyond the Earth's magnetosphere is consequences from exposures to solar particle event (SPE) protons and galactic cosmic rays (GCR). For long-term crewed Lunar and Mars explorations, the production of fresh food in space will provide both nutritional supplements and psychological benefits to the astronauts. However, the effects of space radiation on plants and plant propagules have not been sufficiently investigated and characterized. In this study, we evaluated the effect of two different compositions of charged particles-simulated GCR, and simulated SPE protons on dry and hydrated seeds of the model plant Arabidopsis thaliana and the crop plant Mizuna mustard [Brassica rapa var. japonica]. Exposures to charged particles, simulated GCRs (up to 80 cGy) or SPEs (up to 200 cGy), were performed either acutely or at a low dose rate using the NASA Space Radiation Laboratory (NSRL) facility at Brookhaven National Lab (BNL). Control and irradiated seeds were planted in a solid phytogel and grown in a controlled environment. Five to seven days after planting, morphological parameters were measured to evaluate radiation-induced damage in the seedlings. After exposure to single types of charged particles, as well as to simulated GCR, the hydrated Arabidopsis seeds showed dose- and quality-dependent responses, with heavier ions causing more severe defects. Seeds exposed to simulated GCR (dry seeds) and SPE (hydrated seeds) had significant, although much less damage than seeds exposed to heavier and higher linear energy transfer (LET) particles. In general, the extent of damage depends on the seed type.

A Monte-Carlo step-by-step simulation code of the non-homogeneous chemistry of the radiolysis of water and aqueous solutions--Part II: calculation of radiolytic yields under different conditions of LET, pH, and temperature.

The importance of the radiolysis of water in the initial events following irradiation of biological systems has motivated considerable theoretical and experimental work in the field of radiation chemistry of water and aqueous systems. These studies include Monte-Carlo simulations of the radiation track structure and of the non-homogeneous chemical stage, which have been successfully used to calculate the yields of radiolytic species (H(·), (·)OH, H(2), H(2)O(2), e (aq) (-) , …). Most techniques used for the simulation of the non-homogeneous chemical stage such as the independent reaction time (IRT) technique and diffusion kinetics methods do not calculate the time evolution of the positions of the radiolytic species. This is a major limitation to their extension to the simulation of the irradiation of radiobiological systems. Step-by-step (SBS) simulation programs provide such information, but they are very demanding in term of computer power and storage capacity. Recent improvements in computer performance now allow the regular use of the SBS method in radiation chemistry simulations. In the first of a series of two papers, the SBS method has been reviewed in details and the implementation of a SBS code has been discussed. In this second paper, the results of several studies are presented: (1) the time evolution of the radiolytic yields from the formation of the radiation track to 10(-6) s; (2) the effect of pH on yields (pH ~ 0.4-7.0); (3) the effect of proton energy (and LET) on yields (300 MeV-0.1 MeV), and iv) the effect of the ion type ((1)H(+), (4)He(2+), (12)C(6+)) on yields. Nonbiological applications, i.e., the study of the temperature on the yields (about 25-300°C) and the simulation of the time evolution of G(Fe(3+)) in the Fricke dosimeter are also discussed.

A Monte-Carlo step-by-step simulation code of the non-homogeneous chemistry of the radiolysis of water and aqueous solutions. Part I: theoretical framework and implementation.

The importance of the radiolysis of water in irradiation of biological systems has motivated considerable theoretical and experimental work in the radiation chemistry of water and aqueous solutions. In particular, Monte-Carlo simulations of radiation track structure and non-homogeneous chemistry have greatly contributed to the understanding of experimental results in radiation chemistry of heavy ions. Actually, most simulations of the non-homogeneous chemistry are done using the Independent Reaction Time (IRT) method, a very fast technique. The main limitation of the IRT method is that the positions of the radiolytic species are not calculated as a function of time, which is needed to simulate the irradiation of more complex systems. Step-by-step (SBS) methods, which are able to provide such information, have been used only sparsely because these are time consuming in terms of calculation. Recent improvements in computer performance now allow the regular use of the SBS method in radiation chemistry. In the present paper, the first of a series of two, the SBS method is reviewed in detail. To these ends, simulation of diffusion of particles and chemical reactions in aqueous solutions is reviewed, and implementation of the program is discussed. Simulation of model systems is then performed to validate the adequacy of stepwise diffusion and reaction schemes. In the second paper, radiochemical yields of simulated radiation tracks calculated by the SBS program in different conditions of LET, pH, and temperature are compared with results from the IRT program and experimental data.

A review of simulation codes and approaches for radiation chemistry.

Historically, the field of radiation chemistry began shortly after the discovery of radioactivity, and its development has been closely related to discoveries in other related fields such as radiation and nuclear physics. Radiolysis of water and radiation chemistry have been very important in elucidating how radiation affects living matter and how it induces DNA damage. Nowadays, we recognize the importance of chemistry to understanding the effects of radiation on cells; however, it took several decades to obtain this insight, and much is still unknown. The radiolysis of water and aqueous solutions have been the subject of much experimental and theoretical research for many decades. One important concept closely related to radiation chemistry is radiation track structure. Track structure results from early physical and physicochemical events that lead to a highly non-homogenous distribution of radiolytic species. Because ionizing radiation creates unstable species that are distributed non-homogenously, the use of conventional reaction kinetics methods does not describe this chemistry well. In recent years, several methods have been developed for simulating radiation chemistry. In this review, we give a brief history of the field and the development of the simulation codes. We review the current methods used to simulate radiolysis of water and radiation chemistry, and we describe several radiation chemistry codes and their applications.

Track Structure Components: Characterizing Energy Deposited in Spherical Cells from Direct and Peripheral HZE Ion Hits.

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.

Energy deposition and relative frequency of hits of cylindrical nanovolume in medium irradiated by ions: Monte Carlo simulation of tracks structure.

Radiation track structure simulations have been used for many years to study the DNA damage caused by heavy ions. These studies are highly relevant for treatment planning of heavy ion radiotherapy and space radiation risk assessment. Measurements of the frequency of delta-rays hits, mean specific energy per target hits and per ion, and the frequency of dose distribution in a cylindrical target volume placed at various radial distances from 4He 2+, 12C 6+ and 16O 8+ tracks have been performed by Schmollack et al. (in Radiat Res 153:469-478, 2000). In the present work, Monte Carlo simulation of radiation tracks has been performed with the RITRACKS and the RETRACKS codes along with a target volume to simulate the experiment of Schmollack et al. The results of these simulations are compared to those of previous deterministic models of the radial dependence of the mean specific energy. Our Monte Carlo simulations are consistent with the experimental data both in the core and in the penumbra of the beam, and are shown to provide a better description of the experimental data than deterministic codes.

Determination of Chromosome Aberrations in Human Fibroblasts Irradiated by Mixed Fields Generated with Shielding.

To better study biological effects of space radiation using ground-based facilities, the NASA Space Radiation Laboratory (NSRL) at the Brookhaven National Laboratory has been upgraded to rapidly switch ions and energies. This has allowed investigators to design irradiation protocols comprising a mixture of ions and energies more indicative of the galactic cosmic ray (GCR) environment. Despite these advancements, beam selection and delivery schemes should be optimized against facility and experimental constraints and validated to ensure such irradiations are a suitable representation of the space environment. Importantly, since experiments are time consuming and expensive, models capable of predicting biological outcomes over a range of irradiation conditions (single ion, sequential multi ion or mixed fields) are needed to support such efforts. In this work, human fibroblasts were placed behind 20 g/cm2 aluminum and 10.345 g/cm2 polyethylene and irradiated separately by 344 MeV hydrogen, 344 MeV/n helium, 450 MeV/n oxygen and 950 MeV/n iron ions at various doses. The fluorescence in situ hybridization (FISH) whole chromosome painting technique was then used to assess the cells for chromosome aberrations (CAs), notably simple exchanges. A multi-scale modeling approach was also developed to predict the formation of chromosome aberrations in these experiments. The Geant4 simulation toolkit was used to determine the spectra of particles and energies produced by interactions between the incident beams and shielding. The simulated mixed field generated by shielding was then transferred into the track structure code, RITRACKS (relativistic ion tracks), to generate three-dimensional (3D) voxelized dose maps at the nanometer scale. Finally, these voxel dose maps were input into the new damage and repair model, RITCARD (radiation-induced tracks, chromosome aberrations, repair and damage), to predict the formation of various CAs. The multi-scale model described herein is a significant advancement for the computational tools used to predict biological outcomes in cells exposed to highly complex, mixed ion fields related to the GCR environment. Results show that the simulation and experimental data are in good agreement for the complex radiation fields generated by all ions incident on shielding for most data points. The differences between model predictions and measurements are discussed. Although improvements are needed, the model extends current capabilities for evaluating beam selection and delivery schemes at the NSRL ground-based GCR simulator and for informing NASA risk projection models in the future.

DNA Damage Baseline Predicts Resilience to Space Radiation and Radiotherapy.

Deep space exploration will require real-time, minimally invasive monitoring of astronaut health to mitigate the potential health impairments caused by space radiation and microgravity. Genotoxic stress in humans can be monitored by quantifying the amount of DNA double-strand breaks (DSBs) in immune cells from a simple finger prick. In a cohort of 674 healthy donors, we show that the endogenous level of DSBs increases with age and with latent cytomegalovirus infection. To map the range of human responses to space radiation, we then study DSB induction and repair in immune cells from 319 healthy donors after the cells are exposed to galactic cosmic ray components and lymphocytes from 30 cancer patients after radiotherapy. Individuals with low baseline DSB have fewer clinical complications, enhanced DNA damage repair responses, and a functional dose-dependent cytokine response in healthy donor cells. This supports the use of DSB monitoring for health resilience in space.

A Bi-Exponential Repair Algorithm for Radiation-Induced Double-Strand Breaks: Application to Simulation of Chromosome Aberrations.

BACKGROUND: Radiation induces DNA double-strand breaks (DSBs), and chromosome aberrations (CA) form during the DSBs repair process. Several methods have been used to model the repair kinetics of DSBs including the bi-exponential model, i.e., N(t) = N1exp(-t/τ1) + N2exp(-t/τ2), where N(t) is the number of breaks at time t, and N1, N2, τ1 and τ2 are parameters. This bi-exponential fit for DSB decay suggests that some breaks are repaired rapidly and other, more complex breaks, take longer to repair. METHODS: The bi-exponential repair kinetics model is implemented into a recent simulation code called RITCARD (Radiation Induced Tracks, Chromosome Aberrations, Repair, and Damage). RITCARD simulates the geometric configuration of human chromosomes, radiation-induced breaks, their repair, and the creation of various categories of CAs. The bi-exponential repair relies on a computational algorithm that is shown to be mathematically exact. To categorize breaks as complex or simple, a threshold for the local (voxel) dose was used. RESULTS: The main findings are: i) the curves for the kinetics of restitution of DSBs are mostly independent of dose; ii) the fraction of unrepaired breaks increases with the linear energy transfer (LET) of the incident radiation; iii) the simulated dose-response curves for simple reciprocal chromosome exchanges that are linear-quadratic; iv) the alpha coefficient of the dose-response curve peaks at about 100 keV/µm.

RITCARD: Radiation-Induced Tracks, Chromosome Aberrations, Repair and Damage.

Chromosome aberrations (CAs) are one of the effects of radiation exposure and can have implications for human health in the space environment, since they are related to cancer risk. In radiation research, chromosome aberrations are a convenient biomarker for carcinogenesis. To shed light on the formation and quality of chromosome aberrations in the space environment, many experiments and simulations have been performed using chromosome aberrations in human cells, induced by heavy ions, which are present in galactic cosmic rays (GCRs). In this work, the new simulation program, radiation-induced tracks, chromosome aberrations, repair and damage (RITCARD), is presented. This software program is based on the algorithm used in the NASA Radiation Track Image (NASARTI) model with some improvements. NASARTI and RITCARD are both comprised of four parts: a random walk (RW) algorithm for simulating chromosomes in a nucleus; a deoxyribonucleic acid (DNA) damage algorithm; a break repair process; and a function to assess and count chromosome aberrations. Prior to running RITCARD, the code, relativistic ion tracks (RITRACKS), is used to simulate detailed radiation track structure and calculate time-dependent differential voxel dose maps in a parallelepiped centered on a cell nucleus. The RITCARD program reads the pre-calculated voxel dose and locates the intersections between the voxels and the chromosomes that were simulated by random walk. Radiation-induced breaks occur strictly at these intersections with a probability that is a function of the voxel dose. When a break occurs in the random walk, the corresponding chromosome piece is cut into two fragments where each has a free end at the position of the break. RITCARD generates a collection of all fragments, free ends, and enlists free end pairs. In the next step, the algorithm simulates the time-dependent rejoining of free end pairs, using different probabilities for pairs originating from a given break (proper) or from different breaks (improper), which results in the formation of fragment sequences. By grouping these sequences, the program determines the number and types of aberrations, based on the same criteria used in our experiment. The new program is used to assess the yields of various types of chromosome aberrations in human fibroblast cells for several ions (1H+, 4He2+, 12C6+, 16O8+, 20Ne10+, 28Si14+, 48Ti22+ and 56Fe26+) with energies varying from 10 to 1,000 MeV/n. The results show linear and linear-quadratic dose dependence for most chromosome aberrations types. The calculation results were compared with those obtained by fluorescence in situ hybridization (FISH) experiments that were performed by our group. The simulations and experiments are in better agreement at lower LET. Regarding the simulation results, the coefficient of the linear part of the dose-dependence curve also peaks at an LET value of approximately 100 keV/lm, which evokes a relative biological effectiveness (RBE) peak found by other researchers.

High-LET ion radiolysis of water: visualization of the formation and evolution of ion tracks and relevance to the radiation-induced bystander effect.

Ionizing radiation-induced bystander effects, commonly observed in cell populations exposed to high-linear energy transfer (LET) radiations, are initiated by damage to a cellular molecule which then gives rise to a toxic signal exported to neighboring cells not directly hit by radiation. A major goal in studies of this phenomenon is the identification of this initial radiation-induced lesion. Liquid water being the main constituent of biological matter, reactive species produced by water radiolysis in the cellular environment are likely to be major contributors to the induction of this lesion. In this context, the radiation track structure is of crucial importance in specifying the precise location and identity of all the radiolytic species and their subsequent signaling or damaging effects. We report here Monte Carlo track structure simulations of the radiolysis of liquid water by four different impacting ions 1H+, 4He2+, 12C6+ and 20Ne10+, with the same LET ( approximately 70 keV/ microm). The initial radial distribution profiles of the various water decomposition products (eaq(-), *OH, H*, H2 and H2O2) for the different ions considered are presented and discussed briefly in the context of track structure theory. As an example, the formation and temporal evolution of simulated 24 MeV 4He2+ ion tracks (LET approximately 26 keV/microm) are reported for each radiolytic species from 1 ps to 10 micros. The calculations reveal that the ion track structure is completely lost by approximately 1 micros.