Particle Track Structure Research Articles

Ionization Detail Parameters for DNA Damage Evaluation in Charged Particle Radiotherapy: Simulation Study Based on Cell Survival Database.

Details of excitation and ionization acts hide a description of the biological effects of charged particle traversal through living tissue. Nanodosimetry enables the introduction of novel quantities that characterize and quantify the particle track structure while also serving as a foundation for assessing biological effects based on this quantification. This presents an opportunity to enhance the planning of charged particle radiotherapy by taking into account the ionization detail. This work uses Monte Carlo simulations with Geant4-DNA code for a wide variety of charged particles and their radiation qualities to analyze the distribution of ionization cluster sizes within nanometer-scale volumes, similar to DNA diameter. By correlating these results with biological parameters extracted from the PIDE database for the V79 cell line, a novel parameter R2 based on ionization details is proposed for the evaluation of radiation quality in terms of biological consequences, i.e., radiobiological cross section for inactivation. By incorporating the probability p of sub-lethal damage caused by a single ionization, we address limitations associated with the usually proposed nanodosimetric parameter Fk for characterizing the biological effects of radiation. We show that the new parameter R2 correlates well with radiobiological data and can be used to predict biological outcomes.

Estimation of relative biological effectiveness of 225Ac compared to 177Lu during [225Ac]Ac-PSMA and [177Lu]Lu-PSMA radiopharmaceutical therapy using TOPAS/TOPAS-nBio/MEDRAS

AimOver recent years, [225Ac]Ac-PSMA and [177Lu]Lu-PSMA radiopharmaceutical therapy have evolved as a promising treatment option for advanced prostate cancer. Especially for alpha particle emitter treatments, there is still a need for improving dosimetry, which requires accurate values of relative biological effectiveness (RBE). To achieve that, consideration of DNA damages in the cell nucleus and knowledge of the energy deposition in the location of the DNA at the nanometer scale are required. Monte Carlo particle track structure simulations provide access to interactions at this level. The aim of this study was to estimate the RBE of 225Ac compared to 177Lu. The initial damage distribution after radionuclide decay and the residual damage after DNA repair were considered.MethodsThis study employed the TOol for PArtcile Simulation (TOPAS) based on the Geant4 simulation toolkit. Simulation of the nuclear DNA and damage scoring were performed using the TOPAS-nBio extension of TOPAS. DNA repair was modeled utilizing the Python-based program MEDRAS (Mechanistic DNA Repair and Survival). Five different cell geometries of equal volume and two radionuclide internalization assumptions as well as two cell arrangement scenarios were investigated. The radionuclide activity (number of source points) was adopted based on SPECT images of patients undergoing the above-mentioned therapies.ResultsBased on the simulated dose–effect curves, the RBE of 225Ac compared to 177Lu was determined in a wide range of absorbed doses to the nucleus. In the case of spherical geometry, 3D cell arrangement and full radionuclide internalization, the RBE based on the initial damage had a constant value of approximately 2.14. Accounting for damage repair resulted in RBE values ranging between 9.38 and 1.46 for 225Ac absorbed doses to the nucleus between 0 and 50 Gy, respectively.ConclusionIn this work, the consideration of DNA repair of the damage from [225Ac]Ac-PSMA and [177Lu]Lu-PSMA revealed a dose dependency of the RBE. Hence, this work suggested that DNA repair is an important aspect to understand response to different radiation qualities.

Track Structure of Light Ions: The Link to Radiobiology.

It is generally recognized that the biological response to irradiation by light ions is initiated by complex damages at the DNA level. In turn, the occurrence of complex DNA damages is related to spatial and temporal distribution of ionization and excitation events, i.e., the particle track structure. It is the aim of the present study to investigate the correlation between the distribution of ionizations at the nanometric scale and the probability to induce biological damage. By means of Monte Carlo track structure simulations, the mean ionization yield M1 and the cumulative probabilities F1, F2, and F3 of at least one, two and three ionizations, respectively, were calculated in spherical volumes of water-equivalent diameters equal to 1, 2, 5 and 10 nm. When plotted as a function of M1, the quantities F1, F2 and F3 are distributed along almost unique curves, largely independent of particle type and velocity. However, the shape of the curves depends on the size of the sensitive volume. When the site size is 1 nm, biological cross sections are strongly correlated to combined probabilities of F2 and F3 calculated in the spherical volume, and the proportionality factor is the saturation value of biological cross sections.

Investigation into the foundations of the track-event theory of cell survival and the radiation action model based on nanodosimetry

This work aims at elaborating the basic assumptions behind the “track-event theory” (TET) and its derivate “radiation action model based on nanodosimetry” (RAMN) by clearly distinguishing between effects of tracks at the cellular level and the induction of lesions in subcellular targets. It is demonstrated that the model assumptions of Poisson distribution and statistical independence of the frequency of single and clustered DNA lesions are dispensable for multi-event distributions because they follow from the Poisson distribution of the number of tracks affecting the considered target volume. It is also shown that making these assumptions for the single-event distributions of the number of lethal and sublethal lesions within a cell would lead to an essentially exponential dose dependence of survival for practically relevant values of the absorbed dose. Furthermore, it is elucidated that the model equation used for consideration of repair within the TET is based on the assumption that DNA lesions induced by different tracks are repaired independently. Consequently, the model equation is presumably inconsistent with the model assumptions and requires an additional model parameter. Furthermore, the methodology for deriving model parameters from nanodosimetric properties of particle track structure is critically assessed. Based on data from proton track simulations it is shown that the assumption of statistically independent targets leads to the prediction of negligible frequency of clustered DNA damage. An approach is outlined how track structure could be considered in determining the model parameters, and the implications for TET and RAMN are discussed.

An Avalanche confinement TEPC as connecting bridge from micro to nanodosimetry

It is recognized today that the observable radiobiological effects of ionizing radiations are strongly correlated to the clustering of damages in micrometer- and nanometer-sized subcellular structures, hence to the particle track structure. The characteristic properties of track structure are directly measurable nowadays with bulky experimental apparatuses, which cannot be easily operated in a clinical environment. It is therefore interesting to investigate the feasibility of new portable detectors able to characterize the real therapeutic beams. With this in mind, a novel avalanche-confinement Tissue Equivalent Proportional Counter (TEPC) was constructed for simulating nanometric sites down to 25 nm. Experimental cluster size distributions measured with this TEPC were compared with Monte Carlo simulations of the same experiment and with cluster size distributions measured with the Startrack nanodosimeter.

Particle track structure measurements from 0.5 to 18 nm in nitrogen using the Jet Counter nanodosemeter

Experimental nanodosimetry aims at establishing a new concept of radiation quality that builds on measurable characteristics of the particle track structure at the nanometre scale. This article presents the capabilities and limits of the Jet Counter nanodosemeter for the whole range of experimentally available targets’ sizes. The Jet Counter device can be used for reliable measurements of ionisation cluster-size distributions for target sizes ranging from 1 to 16 nm in nitrogen. Measurements outside this range have also been performed, but their reliability has yet to be proven.

Impact of Target Oxygenation on the Chemical Track Evolution of Ion and Electron Radiation.

The radiosensitivity of biological systems is strongly affected by the system oxygenation. On the nanoscopic scale and molecular level, this effect is considered to be strongly related to the indirect damage of radiation. Even though particle track radiolysis has been the object of several studies, still little is known about the nanoscopic impact of target oxygenation on the radical yields. Here we present an extension of the chemical module of the Monte Carlo particle track structure code TRAX, taking into account the presence of dissolved molecular oxygen in the target material. The impact of the target oxygenation level on the chemical track evolution and the yields of all the relevant chemical species are studied in water under different irradiation conditions: different linear energy transfer (LET) values, different oxygenation levels, and different particle types. Especially for low LET radiation, a large production of two highly toxic species ( and ), which is not produced in anoxic conditions, is predicted and quantified in oxygenated solutions. The remarkable correlation between the and production yield and the oxygen enhancement ratio observed in biological systems suggests a direct or indirect involvement of and in the oxygen sensitization effect. The results are in agreement with available experimental data and previous computational approaches. An analysis of the oxygen depletion rate in different radiation conditions is also reported. The radiosensitivity of biological systems is strongly affected by the system oxygenation. On the nanoscopic scale and molecular level, this effect is considered to be strongly related to the indirect damage of radiation. Even though particle track radiolysis has been the object of several studies, still little is known about the nanoscopic impact of target oxygenation on the radical yields. Here we present an extension of the chemical module of the Monte Carlo particle track structure code TRAX, taking into account the presence of dissolved molecular oxygen in the target material. The impact of the target oxygenation level on the chemical track evolution and the yields of all the relevant chemical species are studied in water under different irradiation conditions: different linear energy transfer (LET) values, different oxygenation levels, and different particle types. Especially for low LET radiation, a large production of two highly toxic species ( and ), which is not produced in anoxic conditions, is predicted and quantified in oxygenated solutions. The remarkable correlation between the and production yield and the oxygen enhancement ratio observed in biological systems suggests a direct or indirect involvement of and in the oxygen sensitization effect. The results are in agreement with available experimental data and previous computational approaches. An analysis of the oxygen depletion rate in different radiation conditions is also reported.

Predictions of cognitive detriments from galactic cosmic ray exposures to astronauts on exploration missions

For the first-time we report on predictions on cognitive detriments from galactic cosmic ray (GCR) exposures on long-duration space missions outside the protection of the Earth's magnetosphere and solid body shielding. Estimates are based on a relative risk (RR) model of the fluence response for proton and heavy ion in rodent studies using the widely used novel object recognition (NOR) test, which estimates detriments in recognition or object memory. Our recent meta-analysis showed that linear and linear-quadratic dose response models were not accurate, while exponential increasing fluence response models based on particle track structure provided good descriptions of rodent data for doses up to 1 Gy. Using detailed models of the GCR environment and particle transport in shielding and tissue, we predict the excess relative risk (ERR) for NOR detriments for several long-term space mission scenarios. Predictions suggest ERR < 0.15 for most space mission scenarios with ERR<0.1 for 1-year lunar surface missions, and about ERR~0.1 for a 1000 day Mars mission for average solar cycle conditions. We discuss possible implications of these ERR levels of cognitive performance detriments relative to other neurological challenges such as rodent models of Alzheimer's disease (AD), Parkinson's disease (PD) and traumatic brain injury (TBI). Comparisons suggest a small but potentially clinically significant risk for possible space mission scenarios.

A cell-by-cell Monte Carlo simulation for assessing radiation-induced DNA double strand breaks

This paper presents a cell-by-cell Monte Carlo simulation study that combines charged particle track structure data with an interphase cell nucleus model to quantify DNA double strand breaks (DSBs), spatial distribution of DSBs in a cell nucleus, and resulting potentially lethal or mutagenic events (PLMEs) between DSBs in close proximity. Cell nucleus is simulated according to the chromosome territory-interchromatin compartment (CT-IC) model in that chromatin content is unevenly distributed in chromatin domains (CDs) and IC with a chromatin compaction ratio of 22:1. A particle track structure coordinate (PTSC) library was first generated for each particle type, energy, and dose based on a large number of particle track data obtained by running the Monte Carlo track structure code Geant4-DNA. To assess the DNA DSBs of a cell for a specific particle type, energy, and dose, the corresponding PTSC was selected and “map overlaid” onto 960 unique cell nucleus data sets containing chromatin fiber (CF) locations. Clustering algorithm DBSCAN was next used to identify the clustered energy deposition events occurring inside the CF. These events were then converted to DNA DSBs using a probabilistic approach. The locations of the DSBs thus obtained were, in turn, used to calculate PLMEs within the cell nucleus that can result from DSB proximity and complexity. The results obtained from this simulation study are correctly correlated to the experimental data of DSB yield and the RBE-LET relationships for various types of charged particles and of various energies. The results show agreement with other published radiobiological models.

PROSPECTS FOR METROLOGY RELATED TO BIOLOGICAL RADIATION EFFECTS OF ION BEAMS.

In recent years, several approaches have been proposed to provide an understanding of the enhanced relative biological effectiveness of ion beams based on multi-scale models of their radiation effects. Among these, the BioQuaRT project was the only one which focused on developing metrology for a multi-scale characterization of particle track structure. The progress made within the BioQuaRT project has motivated the formation of a department 'Radiation Effects' at PTB dedicated to metrological research on ionizing radiation effects. This paper gives an overview of the department's present research directions and shortly discusses ideas for the future development of metrology related to biological effects of ion beams that are based on a stakeholder consultation.

CONSIDERATIONS ON THE TARGET SIZE IN A WALL-LESS NANODOSIMETER.

In nanodosimetry, the ionization component of charged particle track structure is characterized by measuring the frequency distribution of ionizations in target volumes that simulate nanometric sites in liquid water. For the Ion Counter nanodosimeter at PTB, the sensitive volume is defined by the electrical field and the extraction aperture. In this paper, a procedure is presented to define a cylindrical effective measurement target based on the second moments of the detection efficiency map. An analytical model of the efficiency map is developed to investigate the dependence of the simulated site size on the nanodosimeter's operating parameters. Within the limits of the simplifying assumptions, the model gives a reasonable approximation of the efficiency map.

TRAX-CHEM: A pre-chemical and chemical stage extension of the particle track structure code TRAX in water targets

The production, diffusion, and interaction of particle beam induced water-derived radicals is studied with the a pre-chemical and chemical module of the Monte Carlo particle track structure code TRAX, based on a step by step approach. After a description of the model implemented, the chemical evolution of the most important products of water radiolysis is studied for electron, proton, helium, and carbon ion radiation at different energies. The validity of the model is verified by comparing the calculated time and LET dependent yield with experimental data from literature and other simulation approaches.

Biophysics Model of Heavy-Ion Degradation of Neuron Morphology in Mouse Hippocampal Granular Cell Layer Neurons.

Exposure to heavy-ion radiation during cancer treatment or space travel may cause cognitive detriments that have been associated with changes in neuron morphology and plasticity. Observations in mice of reduced neuronal dendritic complexity have revealed a dependence on radiation quality and absorbed dose, suggesting that microscopic energy deposition plays an important role. In this work we used morphological data for mouse dentate granular cell layer (GCL) neurons and a stochastic model of particle track structure and microscopic energy deposition (ED) to develop a predictive model of high-charge and energy (HZE) particle-induced morphological changes to the complex structures of dendritic arbors. We represented dendrites as cylindrical segments of varying diameter with unit aspect ratios, and developed a fast sampling method to consider the stochastic distribution of ED by δ rays (secondary electrons) around the path of heavy ions, to reduce computational times. We introduce probabilistic models with a small number of parameters to describe the induction of precursor lesions that precede dendritic snipping, denoted as snip sites. Predictions for oxygen (16O, 600 MeV/n) and titanium (48Ti, 600 MeV/n) particles with LET of 16.3 and 129 keV/μm, respectively, are considered. Morphometric parameters to quantify changes in neuron morphology are described, including reduction in total dendritic length, number of branch points and branch numbers. Sholl analysis is applied for single neurons to elucidate dose-dependent reductions in dendritic complexity. We predict important differences in measurements from imaging of tissues from brain slices with single neuron cell observations due to the role of neuron death through both soma apoptosis and excessive dendritic length reduction. To further elucidate the role of track structure, random segment excision (snips) models are introduced and a sensitivity study of the effects of the modes of neuron death in predictions of morphometric parameters is described. An important conclusion of this study is that δ rays play a major role in neuron morphological changes due to the large spatial distribution of damage sites, which results in a reduced dependence on LET, including modest difference between 16O and 48Ti, compared to damages resulting from ED in localized damage sites.

Fluctuations of ionizing particle track structure and energy resolution of scintillators

Fluctuations of ionizing particle track structure and energy resolution of scintillators

NANODOSIMETRY: TOWARDS A NEW CONCEPT OF RADIATION QUALITY.

The biological action of ionizing charged particles is initiated at the DNA level, and the effectiveness with which the initial physical effect changes into measurable biological damage is likely ruled by the stochastics of ionizations produced by the incident ions in subcellular nanometric volumes. Based on this hypothesis, experimental nanodosimetry aims at establishing a new concept of radiation quality that builds on measurable characteristics of the particle track structure at the nanometer scale. Three different nanodosimetric detection systems have been developed to date that allow measurements of the number of ionizations produced by the passage of a primary particle in a nanometer-size gas volume (in unit density scale). Within the Italian project MITRA (MIcrodosimetry and TRAck structure), funded by the Italian Istituto Nazionale di Fisica Nucleare (INFN) and the EMRP Joint Research Project 'BioQuaRT' (Biologically Weighted Quantities in Radiotherapy), experiments have been carried out, in which the frequency distribution of ionizations produced by proton and carbon ion beams of given energy was measured with the three nanodosimetric detectors. Descriptors of the track structure can be derived from these distributions. In particular, the first moment M1, representing the mean number of ionizations produced in the target volume, and the cumulative probability Fk of measuring a number ν ≥ k of ionizations. The correlation between measured nanodosimetric quantities and experimental radiobiological data available in the literature is here presented and discussed.

Measurement of track structure parameters of low and medium energy helium and carbon ions in nanometric volumes

Ionization cluster size distributions produced in the sensitive volume of an ion-counting wall-less nanodosimeter by monoenergetic carbon ions with energies between 45 MeV and 150 MeV were measured at the TANDEM-ALPI ion accelerator facility complex of the LNL-INFN in Legnaro. Those produced by monoenergetic helium ions with energies between 2 MeV and 20 MeV were measured at the accelerator facilities of PTB and with a 241Am alpha particle source. C3H8 was used as the target gas. The ionization cluster size distributions were measured in narrow beam geometry with the primary beam passing the target volume at specified distances from its centre, and in broad beam geometry with a fan-like primary beam. By applying a suitable drift time window, the effective size of the target volume was adjusted to match the size of a DNA segment. The measured data were compared with the results of simulations obtained with the PTB Monte Carlo code PTra. Before the comparison, the simulated cluster size distributions were corrected with respect to the background of additional ionizations produced in the transport system of the ionized target gas molecules. Measured and simulated characteristics of the particle track structure are in good agreement for both types of primary particles and for both types of the irradiation geometry. As the range in tissue of the ions investigated is within the typical extension of a spread-out Bragg peak, these data are useful for benchmarking not only ‘general purpose’ track structure simulation codes, but also treatment planning codes used in hadron therapy. Additionally, these data sets may serve as a data base for codes modelling the induction of radiation damages at the DNA-level as they almost completely characterize the ionization component of the nanometric track structure.

Non-Targeted Effects Models Predict Significantly Higher Mars Mission Cancer Risk than Targeted Effects Models

Cancer risk is an important concern for galactic cosmic ray (GCR) exposures, which consist of a wide-energy range of protons, heavy ions and secondary radiation produced in shielding and tissues. Relative biological effectiveness (RBE) factors for surrogate cancer endpoints in cell culture models and tumor induction in mice vary considerable, including significant variations for different tissues and mouse strains. Many studies suggest non-targeted effects (NTE) occur for low doses of high linear energy transfer (LET) radiation, leading to deviation from the linear dose response model used in radiation protection. Using the mouse Harderian gland tumor experiment, the only extensive data-set for dose response modelling with a variety of particle types (>4), for the first-time a particle track structure model of tumor prevalence is used to investigate the effects of NTEs in predictions of chronic GCR exposure risk. The NTE model led to a predicted risk 2-fold higher compared to a targeted effects model. The scarcity of data with animal models for tissues that dominate human radiation cancer risk, including lung, colon, breast, liver, and stomach, suggest that studies of NTEs in other tissues are urgently needed prior to long-term space missions outside the protection of the Earth’s geomagnetic sphere.

WE‐H‐BRA‐08: A Monte Carlo Cell Nucleus Model for Assessing Cell Survival Probability Based On Particle Track Structure Analysis

Purpose:To correlate the damage produced by particles of different types and qualities to cell survival on the basis of nanodosimetric analysis and advanced DNA structures in the cell nucleus.Methods:A Monte Carlo code was developed to simulate subnuclear DNA chromatin fibers (CFs) of 30nm utilizing a mean‐free‐path approach common to radiation transport. The cell nucleus was modeled as a spherical region containing 6000 chromatin‐dense domains (CDs) of 400nm diameter, with additional CFs modeled in a sparser interchromatin region. The Geant4‐DNA code was utilized to produce a particle track database representing various particles at different energies and dose quantities. These tracks were used to stochastically position the DNA structures based on their mean free path to interaction with CFs. Excitation and ionization events intersecting CFs were analyzed using the DBSCAN clustering algorithm for assessment of the likelihood of producing DSBs. Simulated DSBs were then assessed based on their proximity to one another for a probability of inducing cell death.Results:Variations in energy deposition to chromatin fibers match expectations based on differences in particle track structure. The quality of damage to CFs based on different particle types indicate more severe damage by high‐LET radiation than low‐LET radiation of identical particles. In addition, the model indicates more severe damage by protons than of alpha particles of same LET, which is consistent with differences in their track structure. Cell survival curves have been produced showing the L‐Q behavior of sparsely ionizing radiation.Conclusion:Initial results indicate the feasibility of producing cell survival curves based on the Monte Carlo cell nucleus method. Accurate correlation between simulated DNA damage to cell survival on the basis of nanodosimetric analysis can provide insight into the biological responses to various radiation types. Current efforts are directed at producing cell survival curves for high‐LET radiation.

Secondary ionisations in a wall-less ion-counting nanodosimeter: quantitative analysis and the effect on the comparison of measured and simulated track structure parameters in nanometric volumes

The object of investigation in nanodosimetry is the physical characteristics of the microscopic structure of ionising particle tracks, i.e. the sequence of the interaction types and interaction sites of a primary particle and all its secondaries, which reflects the stochastic nature of the radiation interaction. In view of the upcoming radiation therapy with protons and carbon ions, the ionisation structure of the ion track is of particular interest. Owing to limitations in current detector technology, the only way to determine the ionisation cluster size distribution in a DNA segment is to simulate the particle track structure in condensed matter. This is done using dedicated computer programs based on Monte Carlo procedures simulating the interaction of the primary ions with the target. Hence, there is a need to benchmark these computer codes using suitable experimental data. Ionisation cluster size distributions produced in the nanodosimeter’s sensitive volume by monoenergetic protons and alpha particles (with energies between 0.1 MeV and 20 MeV) were measured at the PTB ion accelerator facilities. C3H8 and N2 were alternately used as the working gas. The measured data were compared with the simulation results obtained with the PTB Monte-Carlo code PTra [B. Grosswendt, Radiat. Environ. Biophys. 41, 103 (2002); M.U. Bug, E. Gargioni, H. Nettelbeck, W.Y. Baek, G. Hilgers, A.B. Rosenfeld, H. Rabus, Phys. Rev. E 88, 043308 (2013)]. Measured and simulated characteristics of the particle track structure are generally in good agreement for protons over the entire energy range investigated. For alpha particles with energies higher than the Bragg peak energy, a good agreement can also be seen, whereas for energies lower than the Bragg peak energy differences of as much as 25% occur. Significant deviations are only observed for large ionisation cluster sizes. These deviations can be explained by a background consisting of secondary ions. These ions are produced in the region downstream of the extraction aperture by electrons with a kinetic energy of about 2.5 keV, which are themselves released by ions of the “primary” ionisation cluster hitting an electrode in the ion transport system. Including this background of secondary ions in the simulated cluster size distributions leads to a significantly better agreement between measured and simulated data, especially for large ionisation clusters.

Biophysics of NASA radiation quality factors.

NASA has implemented new radiation quality factors (QFs) for projecting cancer risks from space radiation exposures to astronauts. The NASA QFs are based on particle track structure concepts with parameters derived from available radiobiology data, and NASA introduces distinct QFs for solid cancer and leukaemia risk estimates. The NASA model was reviewed by the US National Research Council and approved for use by NASA for risk assessment for International Space Station missions and trade studies of future exploration missions to Mars and other destinations. A key feature of the NASA QFs is to represent the uncertainty in the QF assessments and evaluate the importance of the QF uncertainty to overall uncertainties in cancer risk projections. In this article, the biophysical basis for the probability distribution functions representing QF uncertainties was reviewed, and approaches needed to reduce uncertainties were discussed.