Sub-keV corrections to binary encounter cross section models for electron ionization of liquid water with application to the Geant4-DNA Monte Carlo code.

INTRODUCTION: The electron ionization cross section of water is one of the most important input in Monte Carlo studies of cellular radiobiological effects. Analytical cross section models of the binary-encounter type have the potential of reducing simulation time and facilitate application to a variety of biological materials (other than water). The Binary-Encounter-Bethe (BEB) and Binary-Encounter-Dipole (BED) models of NIST are perhaps the most popular of such models giving reliable results for atoms and molecules in the gas-phase over a wide energy range. However, the use of such models to sub-keV electron energies in liquid water raises concerns due to the neglect of condensed phase effects that leads to a significant overestimation when compared to medium-specific dielectric models. PURPOSE: To modify the BEB and BED models towards better agreement with the recommended low-energy dielectric model of Geant4-DNA (Option 4). To implement the new modifications to the existing BEB model of the Option 6 physics constructor of Geant4-DNA and re-evaluate fundamental transport quantities for sub-keV electrons. METHODS: In analogy to a Yukawa potential a simple, yet physically-motivated, modification of the Burgess correction term is proposed to account for the reduction of the Coulomb interaction due to the polarizability of the target. The magnitude of the correction is guided by the dielectric-based ionization cross section implemented in Option 4. RESULTS: Differential, total and stopping ionization cross sections for low-energy electrons in liquid water are presented. When combined with the Vriens correction (which is not included in Option 6), the proposed modification to the BEB and BED models brings the ionization and stopping cross sections in much better agreement against those used in the Option 4 dielectric model of Geant4-DNA, with up to 30% and 10% deviation, respectively. Implementation of the new correction to the Option 6 constructor of Geant4-DNA and re-evaluation of fundamental transport quantities, such as electron penetration ranges and dose-point-kernels, reduced the discrepancies from Option 4 at sub-keV energies from 20 to 100% (or more) to well below 10% in most cases. CONCLUSIONS: A simple modification to the BEB and BED analytic models was found to improve their performance for sub-keV electrons in liquid water medium. Implementation of the new modification to the Option 6 constructor of Geant4-DNA significantly improved the agreement with the recommended low-energy Option 4 constructor for a variety of fundamental quantities related to electron transport.

Prediction of DNA rejoining kinetics and cell survival after proton irradiation for V79 cells using Geant4-DNA.

PURPOSE: Track structure Monte Carlo (MC) codes have achieved successful outcomes in the quantitative investigation of radiation-induced initial DNA damage. The aim of the present study is to extend a Geant4-DNA radiobiological application by incorporating a feature allowing for the prediction of DNA rejoining kinetics and corresponding cell surviving fraction along time after irradiation, for a Chinese hamster V79 cell line, which is one of the most popular and widely investigated cell lines in radiobiology. METHODS: We implemented the Two-Lesion Kinetics (TLK) model, originally proposed by Stewart, which allows for simulations to calculate residual DNA damage and surviving fraction along time via the number of initial DNA damage and its complexity as inputs. RESULTS: By optimizing the model parameters of the TLK model in accordance to the experimental data on V79, we were able to predict both DNA rejoining kinetics at low linear energy transfers (LET) and cell surviving fraction. CONCLUSION: This is the first study to demonstrate the implementation of both the cell surviving fraction and the DNA rejoining kinetics with the estimated initial DNA damage, in a realistic cell geometrical model simulated by full track structure MC simulations at DNA level and for various LET. These simulation and model make the link between mechanistic physical/chemical damage processes and these two specific biological endpoints.

A Geant4-DNA Evaluation of Radiation-Induced DNA Damage on a Human Fibroblast.

Accurately modeling the radiobiological mechanisms responsible for the induction of DNA damage remains a major scientific challenge, particularly for understanding the effects of low doses of ionizing radiation on living beings, such as the induction of carcinogenesis. A computational approach based on the Monte Carlo technique to simulate track structures in a biological medium is currently the most reliable method for calculating the early effects induced by ionizing radiation on DNA, the primary cellular target of such effects. The Geant4-DNA Monte Carlo toolkit can simulate not only the physical, but also the physico-chemical and chemical stages of water radiolysis. These stages can be combined with simplified geometric models of biological targets, such as DNA, to assess direct and indirect early DNA damage. In this study, DNA damage induced in a human fibroblast cell was evaluated using Geant4-DNA as a function of incident particle type (gammas, protons, and alphas) and energy. The resulting double-strand break yields as a function of linear energy transfer closely reproduced recent experimental data. Other quantities, such as fragment length distribution, scavengeable damage fraction, and time evolution of damage within an analytical repair model also supported the plausibility of predicting DNA damage using Geant4-DNA.The complete simulation chain application "molecularDNA", an example for users of Geant4-DNA, will soon be distributed through Geant4.

Review of the Geant4-DNA Simulation Toolkit for Radiobiological Applications at the Cellular and DNA Level.

The Geant4-DNA low energy extension of the Geant4 Monte Carlo (MC) toolkit is a continuously evolving MC simulation code permitting mechanistic studies of cellular radiobiological effects. Geant4-DNA considers the physical, chemical, and biological stages of the action of ionizing radiation (in the form of x- and γ-ray photons, electrons and ß±-rays, hadrons, α-particles, and a set of heavier ions) in living cells towards a variety of applications ranging from predicting radiotherapy outcomes to radiation protection both on earth and in space. In this work, we provide a brief, yet concise, overview of the progress that has been achieved so far concerning the different physical, physicochemical, chemical, and biological models implemented into Geant4-DNA, highlighting the latest developments. Specifically, the "dnadamage1" and "molecularDNA" applications which enable, for the first time within an open-source platform, quantitative predictions of early DNA damage in terms of single-strand-breaks (SSBs), double-strand-breaks (DSBs), and more complex clustered lesions for different DNA structures ranging from the nucleotide level to the entire genome. These developments are critically presented and discussed along with key benchmarking results. The Geant4-DNA toolkit, through its different set of models and functionalities, offers unique capabilities for elucidating the problem of radiation quality or the relative biological effectiveness (RBE) of different ionizing radiations which underlines nearly the whole spectrum of radiotherapeutic modalities, from external high-energy hadron beams to internal low-energy gamma and beta emitters that are used in brachytherapy sources and radiopharmaceuticals, respectively.

Fully integrated Monte Carlo simulation for evaluating radiation induced DNA damage and subsequent repair using Geant4-DNA.

Ionising radiation induced DNA damage and subsequent biological responses to it depend on the radiation's track-structure and its energy loss distribution pattern. To investigate the underlying biological mechanisms involved in such complex system, there is need of predicting biological response by integrated Monte Carlo (MC) simulations across physics, chemistry and biology. Hence, in this work, we have developed an application using the open source Geant4-DNA toolkit to propose a realistic "fully integrated" MC simulation to calculate both early DNA damage and subsequent biological responses with time. We had previously developed an application allowing simulations of radiation induced early DNA damage on a naked cell nucleus model. In the new version presented in this work, we have developed three additional important features: (1) modeling of a realistic cell geometry, (2) inclusion of a biological repair model, (3) refinement of DNA damage parameters for direct damage and indirect damage scoring. The simulation results are validated with experimental data in terms of Single Strand Break (SSB) yields for plasmid and Double Strand Break (DSB) yields for plasmid/human cell. In addition, the yields of indirect DSBs are compatible with the experimental scavengeable damage fraction. The simulation application also demonstrates agreement with experimental data of [Formula: see text]-H2AX yields for gamma ray irradiation. Using this application, it is now possible to predict biological response along time through track-structure MC simulations.

Monte Carlo dosimetry of a realistic multicellular model of follicular lymphoma in a context of radioimmunotherapy.

PURPOSE: Small-scale dosimetry studies generally consider an artificial environment where the tumors are spherical and the radionuclides are homogeneously biodistributed. However, tumor shapes are irregular and radiopharmaceutical biodistributions are heterogeneous, impacting the energy deposition in targeted radionuclide therapy. To bring realism, we developed a dosimetric methodology based on a three-dimensional in vitro model of follicular lymphoma incubated with rituximab, an anti-CD20 monoclonal antibody used in the treatment of non-Hodgkin lymphomas, which might be combined with a radionuclide. The effects of the realistic geometry and biodistribution on the absorbed dose were highlighted by comparison with literature data. Additionally, to illustrate the possibilities of this methodology, the effect of different radionuclides on the absorbed dose distribution delivered to the in vitro tumor were compared. METHODS: The starting point was a model named multicellular aggregates of lymphoma cells (MALC). Three MALCs of different dimensions and their rituximab biodistribution were considered. Geometry, antibody location and concentration were extracted from selective plane illumination microscopy. Assuming antibody radiolabeling with Auger electron (125 I and 111 In) and ß- particle emitters (177 Lu, 131 I and 90 Y), we simulated energy deposition in MALCs using two Monte Carlo codes: Geant4-DNA with "CPA100" physics models for Auger electron emitters and Geant4 with "Livermore" physics models for ß- particle emitters. RESULTS: MALCs had ellipsoid-like shapes with major radii, r, of ~0.25, ~0.5 and ~1.3 mm. Rituximab was concentrated in the periphery of the MALCs. The absorbed doses delivered by 177 Lu, 131 I and 90 Y in MALCs were compared with literature data for spheres with two types of homogeneous biodistributions (on the surface or throughout the volume). Compared to the MALCs, the mean absorbed doses delivered in spheres with surface biodistributions were between 18% and 38% lower, while with volume biodistribution they were between 15% and 29% higher. Regarding the radionuclides comparison, the relationship between MALC dimensions, rituximab biodistribution and energy released per decay impacted the absorbed doses. Despite releasing less energy, 125 I delivered a greater absorbed dose per decay than 111 In in the r ~ 0.25 mm MALC (6.78·10-2 vs 6.26·10-2  µGy·Bq-1 ·s-1 ). Similarly, the absorbed doses per decay in the r ~ 0.5 mm MALC for 177 Lu (2.41·10-2  µGy·Bq-1 ·s-1 ) and 131 I (2.46·10-2  µGy·Bq-1 ·s-1 ) are higher than for 90 Y (1.98·10-2  µGy·Bq-1 ·s-1 ). Furthermore, radionuclides releasing more energy per decay delivered absorbed dose more uniformly through the MALCs. Finally, when considering the radiopharmaceutical effective half-life, due to the biological half-life of rituximab being best matched by the physical half-life of 177 Lu and 131 I compared to 90 Y, the first two radionuclides delivered higher absorbed doses. CONCLUSION: In the simulated configurations, ß- emitters delivered higher and more uniform absorbed dose than Auger electron emitters. When considering radiopharmaceutical half-lives, 177 Lu and 131 I delivered absorbed doses higher than 90 Y. In view of real irradiation of MALCs, such a work may be useful to select suited radionuclides and to help explain the biological effects.

Assessment of Radio-Induced Damage in Endothelial Cells Irradiated with 40 kVp, 220 kVp, and 4 MV X-rays by Means of Micro and Nanodosimetric Calculations.

The objective of this work was to study the differences in terms of early biological effects that might exist between different X-rays energies by using a mechanistic approach. To this end, radiobiological experiments exposing cell monolayers to three X-ray energies were performed in order to assess the yields of early DNA damage, in particular of double-strand breaks (DSBs). The simulation of these irradiations was set in order to understand the differences in the obtained experimental results. Hence, simulated results in terms of microdosimetric spectra and early DSB induction were analyzed and compared to the experimental data. Human umbilical vein endothelial cells (HUVECs) were irradiated with 40, 220 kVp, and 4 MV X-rays. The Geant4 Monte Carlo simulation toolkit and its extension Geant4-DNA were used for the simulations. Microdosimetric calculations aiming to determine possible differences in the variability of the energy absorbed by the irradiated cell population for those photon spectra were performed on 10,000 endothelial cell nuclei representing a cell monolayer. Nanodosimetric simulations were also carried out using a computation chain that allowed the simulation of physical, physico-chemical, and chemical stages on a single realistic endothelial cell nucleus model including both heterochromatin and euchromatin. DNA damage was scored in terms of yields of prompt DSBs per Gray (Gy) and per giga (109) base pair (Gbp) and DSB complexity was derived in order to be compared to experimental data expressed as numbers of histone variant H2AX (γ-H2AX) foci per cell. The calculated microdosimetric spread in the irradiated cell population was similar when comparing between 40 and 220 kVp X-rays and higher when comparing with 4 MV X-rays. Simulated yields of induced DSB/Gy/Gbp were found to be equivalent to those for 40 and 220 kVp but larger than those for 4 MV, resulting in a relative biological effectiveness (RBE) of 1.3. Additionally, DSB complexity was similar between the considered photon spectra. Simulated results were in good agreement with experimental data obtained by IRSN (Institut de radioprotection et de sûreté nucléaire) radiobiologists. Despite differences in photon energy, few differences were observed when comparing between 40 and 220 kVp X-rays in microdosimetric and nanodosimetric calculations. Nevertheless, variations were observed when comparing between 40/220 kVp and 4 MV X-rays. Thanks to the simulation results, these variations were able to be explained by the differences in the production of secondary electrons with energies below 10 keV.

Electron track structure simulations in a gold nanoparticle using Geant4-DNA.

Gold Nanoparticles (GNPs) have recently gained a lot of attention due to their potential benefit to improve the efficacy of X-ray radiotherapy. Owing to their high atomic number, GNPs are able to absorb higher quantities of incident radiation with respect to the surrounding tissue, producing, in particular, photoelectrons and low energy Auger electrons. These additional low energy electrons increase the local energy deposition in the region surrounding the GNP. Monte Carlo simulations play a key role in the investigation of GNP radio-enhancement and it is widely recognised that track structure physics models are the state-of-the-art for nano-scale studies. In 2016, we have developed track structure physics models for the Geant4-DNA toolkit allowing electron transport for microscopic bulk gold (Geant4_DNA_AU_2016) and we have recently improved them in the low energy domain (Geant4_DNA_AU_2018). In this paper, we report the benchmarking of these newly developed physics models when calculating the physical dose and the Dose Enhancement Factor (DEF) around a GNP. We demonstrate that Geant4_DNA_AU_2018 models give similar azimuthal distribution of two dimensional absorbed dose around a single GNP, but result in larger absorbed dose and DEF than Geant4_DNA_AU_2016 models. In parallel, we investigated the performance of a newly developed multiple scattering model in Geant4 based on the Goudsmit-Saunderson (GS) model, when used together with the electromagnetic physics models with the Geant4 Livermore condensed-history approach. Our results show that the GS model does not affect the results of the simulations when studying GNP radio-enhancement with a condensed-history approach.

Evaluation of early radiation DNA damage in a fractal cell nucleus model using Geant4-DNA.

The advancement of multidisciplinary research fields dealing with ionising radiation induced biological damage - radiobiology, radiation physics, radiation protection and, in particular, medical physics - requires a clear mechanistic understanding of how cellular damage is induced by ionising radiation. Monte Carlo (MC) simulations provide a promising approach for the mechanistic simulation of radiation transport and radiation chemistry, towards the in silico simulation of early biological damage. We have recently developed a fully integrated MC simulation that calculates early single strand breaks (SSBs) and double strand breaks (DSBs) in a fractal chromatin based human cell nucleus model. The results of this simulation are almost equivalent to past MC simulations when considering direct/indirect strand break fraction, DSB yields and fragment distribution. The simulation results agree with experimental data on DSB yields within 13.6% on average and fragment distributions agree within an average of 34.8%.

Geant4-DNA track-structure simulations for gold nanoparticles: The importance of electron discrete models in nanometer volumes.

PURPOSE: Gold nanoparticles (GNPs) are known to enhance the absorbed dose in their vicinity following photon-based irradiation. To investigate the therapeutic effectiveness of GNPs, previous Monte Carlo simulation studies have explored GNP dose enhancement using mostly condensed-history models. However, in general, such models are suitable for macroscopic volumes and for electron energies above a few hundred electron volts. We have recently developed, for the Geant4-DNA extension of the Geant4 Monte Carlo simulation toolkit, discrete physics models for electron transport in gold which include the description of the full atomic de-excitation cascade. These models allow event-by-event simulation of electron tracks in gold down to 10 eV. The present work describes how such specialized physics models impact simulation-based studies on GNP-radioenhancement in a context of x-ray radiotherapy. METHODS: The new discrete physics models are compared to the Geant4 Penelope and Livermore condensed-history models, which are being widely used for simulation-based NP radioenhancement studies. An ad hoc Geant4 simulation application has been developed to calculate the absorbed dose in liquid water around a GNP and its radioenhancement, caused by secondary particles emitted from the GNP itself, when irradiated with a monoenergetic electron beam. The effect of the new physics models is also quantified in the calculation of secondary particle spectra, when originating in the GNP and when exiting from it. RESULTS: The new physics models show similar backscattering coefficients with the existing Geant4 Livermore and Penelope models in large volumes for 100 keV incident electrons. However, in submicron sized volumes, only the discrete models describe the high backscattering that should still be present around GNPs at these length scales. Sizeable differences (mostly above a factor of 2) are also found in the radial distribution of absorbed dose and secondary particles between the new and the existing Geant4 models. The degree to which these differences are due to intrinsic limitations of the condensed-history models or to differences in the underling scattering cross sections requires further investigation. CONCLUSIONS: Improved physics models for gold are necessary to better model the impact of GNPs in radiotherapy via Monte Carlo simulations. We implemented discrete electron transport models for gold in Geant4 that is applicable down to 10 eV including the modeling of the full de-excitation cascade. It is demonstrated that the new model has a significant positive impact on particle transport simulations in gold volumes with submicron dimensions compared to the existing Livermore and Penelope condensed-history models of Geant4.