Analysis of hydrogen peroxide production in pure water: Ultrahigh versus conventional dose-rate irradiation and mechanistic insights.

BACKGROUND: Ultrahigh dose-rate radiation (UHDR) produces less hydrogen peroxide (H2O2) in pure water, as suggested by some experimental studies, and is used as an argument for the validity of the theory that FLASH spares the normal tissue due to less reactive oxygen species (ROS) production. In contrast, most Monte Carlo simulation studies suggest the opposite. PURPOSE: We aim to unveil the effect of UHDR on H2O2 production in pure water and its underlying mechanism, to serve as a benchmark for Monte Carlo simulation. We hypothesized that the reaction of solvated electrons ( e aq - ${\mathrm{e}}_{{\mathrm{aq}}}^ - $ ) removing hydroxyl radicals (•OH), the precursor of H2O2, is the reason why UHDR leads to a lower G-value (molecules/100 eV) for H2O2 (G[H2O2]), because: 1, the third-order reaction between e aq - ${\mathrm{e}}_{{\mathrm{aq}}}^ - $ and •OH is more sensitive to increased instantaneous ROS concentration by UHDR than a two-order reaction of •OH self-reaction producing H2O2; 2, e aq - ${\mathrm{e}}_{{\mathrm{aq}}}^ - $ has two times higher diffusion coefficient and higher reaction rate constant than that of •OH, which means e aq - ${\mathrm{e}}_{{\mathrm{aq}}}^ - $ would dominate the competition for •OH and benefit more from the inter-track effect of UHDR. Meanwhile, we also experimentally verify the theory of long-lived radicals causing lower G(H2O2) in conventional irradiation, which is mentioned in some simulation studies. METHODS AND MATERIALS: H2O2 was measured by Amplex UltraRed assay. 430.1 MeV/u carbon ions (50 and 0.1 Gy/s), 9 MeV electrons (600 and 0.62 Gy/s), and 200 kV x-ray tube (10 and 0.1 Gy/s) were employed. For three kinds of water (real hypoxic: 1% O2; hypoxic: 1% O2 and 5% CO2; and normoxic: 21% O2), unbubbled and bubbled samples with N2O, the scavenger of e aq - ${\mathrm{e}}_{{\mathrm{aq}}}^ - $ , were irradiated by carbon ions and electrons with conventional and UHDR at different absolute dose levels. Normoxic water dissolved with sodium nitrate (NaNO3), another scavenger of e aq - ${\mathrm{e}}_{{\mathrm{aq}}}^ - $ , and bubbled with N2O was irradiated by x-ray to verify the results of low-LET electron beam. RESULTS: UHDR leads to a lower G(H2O2) than conventional irradiation. O2 and CO2 can both increase G(H2O2). N2O increases G(H2O2) of both UHDR and conventional irradiation and eliminates the difference between them for carbon ions. However, N2O decreases G(H2O2) in electron conventional irradiation but increases G(H2O2) in the case of UHDR, ending up with no dose-rate dependency of G(H2O2). Three-spilled carbon UHDR does not have a lower G(H2O2) than one-spilled UHDR. However, the electron beam shows a lower G(H2O2) for three-spilled UHDR than for one-spilled UHDR. Normoxic water with N2O or NaNO3 can both eliminate the dose rate dependency of H2O2 production for x-ray. CONCLUSIONS: UHDR has a lower G(H2O2) than the conventional irradiation for both high LET carbon and low LET electron and x-ray beams. Both scavengers for e aq - ${\mathrm{e}}_{{\mathrm{aq}}}^ - $ , N2O and NaNO3, eliminate the dose-rate dependency of G(H2O2), which suggests e aq - ${\mathrm{e}}_{{\mathrm{aq}}}^ - $ is the reason for decreased G(H2O2) for UHDR. Three-spilled UHDR versus one-spilled UHDR indicates that the assumption of residual radicals reducing G(H2O2) of conventional irradiation may only be valid for low LET electron beam.

Comparison of two methods simulating inter-track interactions using the radiobiological Monte Carlo toolkit TOPAS-nBio.

Objective.To compare two independently developed methods that enable modelling inter-track interactions in TOPAS-nBio by examining the yield of radiolytic species in radiobiological Monte Carlo track structure simulations. One method uses a phase space file to assign more than one primary to one event, allowing for inter-track interaction between these primary particles. This method has previously been developed by this working group and published earlier. Using the other method, chemical reactions are simulated based on a new version of the independent reaction time approach to allow inter-track interactions.Approach.G-values were calculated and compared using both methods for different numbers of tracks able to undergo inter-track interactions.Main results.Differences in theG-values simulated with the two methods strongly depend on the molecule type, and deviations can range up to 3.9% (H2O2), although, on average, the deviations are smaller than 1.5%.Significance.Both methods seem to be suitable for simulating inter-track interactions, as they provide comparableG-values even though both techniques were developed independently of each other.

The influence of different versions of FLUKA and GEANT4 on the calculation of response functions of ionization chambers in clinical proton beams.

Objective.To investigate the influence of different versions of the Monte Carlo codesgeant4 andflukaon the calculation of overall response functionsfQof air-filled ionization chambers in clinical proton beams.Approach. fQfactors were calculated for six plane-parallel and four cylindrical ionization chambers withgeant4 andfluka. These factors were compared to already published values that were derived using older versions of these codes.Main results.Differences infQfactors calculated with different versions of the same Monte Carlo code can be up to ∼1%. Especially forgeant4, the updated version leads to a more pronounced dependence offQon proton energy and to smallerfQfactors for high energies.Significance.Different versions of the same Monte Carlo code can lead to differences in the calculation offQfactors of up to ∼1% without changing the simulation setup, transport parameters, ionization chamber geometry modeling, or employed physics lists. These findings support the statement that the dominant contributor to the overall uncertainty of Monte Carlo calculatedfQfactors are type-B uncertainties.

A method to implement inter-track interactions in Monte Carlo simulations with TOPAS-nBio and their influence on simulated radical yields following water radiolysis.

Objective.In FLASH radiotherapy (dose rates ≥40 Gy s-1), a reduced normal tissue toxicity has been observed, while maintaining the same tumor control compared to conventional radiotherapy (dose rates ≤0.03 Gy s-1). This protecting effect could not be fully explained yet. One assumption is that interactions between the chemicals of different primary ionizing particles, so-called inter-track interactions, trigger this outcome. In this work, we included inter-track interactions in Monte Carlo track structure simulations and investigated the yield of chemicals (G-value) produced by ionizing particles.Approach.For the simulations, we used the Monte Carlo toolkit TOPAS, in which inter-track interactions cannot be implemented without further effort. Thus, we developed a method enabling the simultaneous simulation ofNoriginal histories in one event allowing chemical species to interact with each other. To investigate the effect of inter-track interactions we analyzed theG-value of different chemicals using various radiation sources. We used electrons with an energy of 60 eV in different spatial arrangements as well as a 10 MeV and 100 MeV proton source. For electrons we setNbetween 1 and 60, for protons between 1 and 100.Main results.In all simulations, the totalG-value decreases with increasingN. In detail, theG-value for•OH , H3O and eaqdecreases with increasingN, whereas theG-value of OH-, H2O2and H2increases slightly. The reason is that with increasingN, the concentration of chemical radicals increases allowing for more chemical reactions between the radicals resulting in a change of the dynamics of the chemical stage.Significance.Inter-track interactions resulting in a variation of the yield of chemical species, may be a factor explaining the FLASH effect. To verify this hypothesis, further simulations are necessary in order to evaluate the impact of varyingG-values on the yield of DNA damages.

Experimental determination of modulation power of lung tissue for particle therapy.

In particle therapy of lung tumors, modulating effects on the particle beam may occur due to the microscopic structure of the lung tissue. These effects are caused by the heterogeneous nature of the lung tissue and cannot be completely taken into account during treatment planning, because these micro structures are too small to be fully resolved in the planning CT. In several publications, a new material parameter called modulation power (Pmod) was introduced to characterize the effect. For various artificial lung surrogates, this parameter was measured and published by other groups and ranges up to approximately 1000µm. Studies investigating the influence of the modulation power on the dose distribution during irradiation are using this parameter in the rang of 100-800µm. More precise measurements forPmodon real lung tissue have not yet been published. In this work, the modulation power of real lung tissue was measured using porcine lungs in order to produce more reliable data ofPmodfor real lung tissue. For this purpose,ex-vivoporcine lungs were frozen in a ventilated state and measurements in a carbon ion-beam were performed. Due to the way the lungs were prepared and transferred to a solid state, the lung structures that modulate the beam could also be examined in detail using micro CT imaging. An optimization of the established methods of measuring the modulation power, which takes better account of the typical structures within lung tissue, was developed as well.

Monte Carlo calculation of beam quality correction factors in proton beams using FLUKA.

Purpose.To provide Monte Carlo calculated beam quality correction factors (kQ) for monoenergetic proton beams using the Monte Carlo codefluka.Materials and methods.The Monte Carlo codeflukawas used to calculate the dose absorbed in a water-filled reference volume and the air-filled cavities of six plane-parallel and four cylindrical ionization chambers. The chambers were positioned at the entrance region of monoenergetic proton beams with energies between 60 and 250 MeV. Based on these dose values,fQas well askQfactors were calculated whilefQ0factors were taken from Andreoet al(2020Phys. Med. Biol.65095011).Results. kQfactors calculated in this work were found to agree with experimentally determinedkQfactors on the 1%-level, with only two exceptions with deviations of 1.4% and 1.9%. The comparison offQfactors calculated usingflukawithfQfactors calculated using the Monte Carlo codesgeant4 andpenhshowed a general good agreement for low energies, while differences for higher energies were pronounced. For high energies, in most cases the Monte Carlo codesflukaandgeant4 lead to comparable results while thefQfactors calculated withpenhare larger.Conclusion.flukacan be used to calculatekQfactors in clinical proton beams. The divergence of Monte Carlo calculatedkQfactors for high energies suggests that the role of nuclear interaction models implemented in the different Monte Carlo codes needs to be investigated in more detail.

Investigating the feasibility of TOPAS-nBio for Monte Carlo track structure simulations by adapting GEANT4-DNA examples application.

Purpose.The purpose of this work is to investigate the feasibility of TOPAS-nBio for track structure simulations using tuple scoring and ROOT/Python-based post-processing.Materials and methods.There are several example applications implemented in GEANT4-DNA demonstrating track structure simulations. These examples are not implemented by default in TOPAS-nBio. In this study, the tuple scorer was used to re-simulate these examples. The simulations contained investigations of different physics lists, calculation of energy-dependent range, stopping power, mean free path andW-value. Additionally, further applications of the TOPAS-nBio tool were investigated, focusing on physical interactions and deposited energies of electrons with initial energies in the range of 10-60 eV, not covered in the recently published GEANT4-DNA simulations. Low-energetic electrons are currently of great interest in the radiobiology research community due to their high effectiveness towards the induction of biological damage.Results.The quantities calculated with TOPAS-nBio show a good agreement with the simulations of GEANT4-DNA with deviations of 5% at maximum. Thus, we have presented a feasible way to implement the example applications included in GEANT4-DNA in TOPAS-nBio. With the extended simulations, an insight could be given, which further tracking information can be gained with the track structure code and how cross sections and physics models influence a particle's fate.Conclusion.With our results, we could show the potentials of applying the tuple scorer in TOPAS-nBio Monte Carlo track structure simulations. Using this scorer, a large amount of information about the track structure can be accessed, which can be analyzed as preferred after the simulation.

Estimating the modulating effect of lung tissue in particle therapy using a clinical CT voxel histogram analysis.

To treat lung tumours with particle therapy, different additional tasks and challenges in treatment planning and application have to be addressed thoroughly. One of these tasks is the quantification and consideration of the Bragg peak (BP) degradation due to lung tissue: as lung is an heterogeneous tissue, the BP is broadened when particles traverse the microscopic alveoli. These are not fully resolved in clinical CT images and thus, the effect is not considered in the dose calculation. In this work, a correlation between the CT histograms of heterogeneous material and the impact on the BP curve is presented. Different inorganic materials were scanned with a conventional CT scanner and additionally, the BP degradation was measured in a proton beam and was then quantified. A model is proposed that allows an estimation of the modulation power by performing a histogram analysis on the CT scan. To validate the model for organic samples, a second measurement series was performed with frozen porcine lunge samples. This allows to investigate the possible limits of the proposed model in a set-up closer to clinical conditions. For lung substitutes, the agreement between model and measurement is within ±0.05 mm and for the organic lung samples, within ±0.15 mm. This work presents a novel, simple and efficient method to estimate if and how much a material or a distinct region (within the lung) is degrading the BP on the basis of a common clinical CT image. Up until now, only a direct in-beam measurement of the region or material of interest could answer this question.