Radiation track, DNA damage and response-a review.

The purpose of this paper has been to review the current status and progress of the field of radiation biophysics, and draw attention to the fact that physics, in general, and radiation physics in particular, with the aid of mathematical modeling, can help elucidate biological mechanisms and cancer therapies. We hypothesize that concepts of condensed-matter physics along with the new genomic knowledge and technologies and mechanistic mathematical modeling in conjunction with advances in experimental DNA (Deoxyrinonucleic acid molecule) repair and cell signaling have now provided us with unprecedented opportunities in radiation biophysics to address problems in targeted cancer therapy, and genetic risk estimation in humans. Obviously, one is not dealing with 'low-hanging fruit', but it will be a major scientific achievement if it becomes possible to state, in another decade or so, that we can link mechanistically the stages between the initial radiation-induced DNA damage; in particular, at doses of radiation less than 2 Gy and with structural changes in genomic DNA as a precursor to cell inactivation and/or mutations leading to genetic diseases. The paper presents recent development in the physics of radiation track structure contained in the computer code system KURBUC, in particular for low-energy electrons in the condensed phase of water for which we provide a comprehensive discussion of the dielectric response function approach. The state-of-the-art in the simulation of proton and carbon ion tracks in the Bragg peak region is also presented. The paper presents a critical discussion of the models used for elastic scattering, and the validity of the trajectory approach in low-electron transport. Brief discussions of mechanistic and quantitative aspects of microdosimetry, DNA damage and DNA repair are also included as developed by the authors' work.

Evaluation of the dose enhancement of combined ¹°B + ¹57Gd neutron capture therapy (NCT).

An innovative molecule, GdBLDL, for boron neutron capture therapy (BNCT) has been developed and its effectiveness as a BNCT carrier is currently under evaluation using in vivo experiments on small animal tumour models. The molecule contains both (10)B (the most commonly used NCT agent) and (157)Gd nuclei. (157)Gd is the second most studied element to perform NCT, mainly thanks to its high cross section for the capture of low-energy neutrons. The main drawback of (157)Gd neutron capture reaction is the very short range and low-energy secondary charged particles (Auger electrons), which requires (157)Gd to be very close to the cellular DNA to have an appreciable biological effect. Treatment doses were calculated by Monte Carlo simulations to ensure the optimised tumour irradiation and the sparing of the healthy organs of the irradiated animals. The enhancement of the absorbed dose due to the simultaneous presence of (10)B and (157)Gd in the experimental set-up was calculated and the advantage introduced by the presence of (157)Gd was discussed.

Genome-based, mechanism-driven computational modeling of risks of ionizing radiation: The next frontier in genetic risk estimation?

Research activity in the field of estimation of genetic risks of ionizing radiation to human populations started in the late 1940s and now appears to be passing through a plateau phase. This paper provides a background to the concepts, findings and methods of risk estimation that guided the field through the period of its growth to the beginning of the 21st century. It draws attention to several key facts: (a) thus far, genetic risk estimates have been made indirectly using mutation data collected in mouse radiation studies; (b) important uncertainties and unsolved problems remain, one notable example being that we still do not know the sensitivity of human female germ cells to radiation-induced mutations; and (c) the concept that dominated the field thus far, namely, that radiation exposures to germ cells can result in single gene diseases in the descendants of those exposed has been replaced by the concept that radiation exposure can cause DNA deletions, often involving more than one gene. Genetic risk estimation now encompasses work devoted to studies on DNA deletions induced in human germ cells, their expected frequencies, and phenotypes and associated clinical consequences in the progeny. We argue that the time is ripe to embark on a human genome-based, mechanism-driven, computational modeling of genetic risks of ionizing radiation, and we present a provisional framework for catalyzing research in the field in the 21st century.

Microdosimetry of the full slowing down of protons using Monte Carlo track structure simulations.

The article investigates two approaches in microdosimetric calculations based on Monte Carlo track structure (MCTS) simulations of a 160-MeV proton beam. In the first approach, microdosimetric parameters of the proton beam were obtained using the weighted sum of proton energy distributions and microdosimetric parameters of proton track segments (TSMs). In the second approach, phase spaces of energy depositions obtained using MCTS simulations in the full slowing down (FSD) mode were used for the microdosimetric calculations. Targets of interest were water cylinders of 2.3-100 nm in diameters and heights. Frequency-averaged lineal energies ([Formula: see text]) obtained using both approaches agreed within the statistical uncertainties. Discrepancies beyond this level were observed for dose-averaged lineal energies ([Formula: see text]) towards the Bragg peak region due to the small number of proton energies used in the TSM approach and different energy deposition patterns in the TSM and FSD of protons.

Lineal energy and radiation quality in radiation therapy: model calculations and comparison with experiment.

Microdosimetry is a recommended method for characterizing radiation quality in situations when the biological effectiveness under test is not well known. In such situations, the radiation beams are described by their lineal energy probability distributions. Results from radiobiological investigations in the beams are then used to establish response functions that relate the lineal energy to the relative biological effectiveness (RBE). In this paper we present the influence of the size of the simulated volume on the relation to the clinical RBE values (or weighting factors). A single event probability distribution of the lineal energy is approximated by its dose average lineal energy (y[overline](D)) which can be measured or calculated for volumes from a few micrometres down to a few nanometres. The clinical RBE values were approximated as the ratio of the α-values derived from the LQ-relation. Model calculations are presented and discussed for the SOBP of a (12)C ion (290 MeV u(-1)) and the reference (60)Co γ therapy beam. Results were compared with those for a conventional x-ray therapy beam, a 290 MeV proton beam and a neutron therapy beam. It is concluded that for a simulated volume of about 10 nm, the α-ratio increases approximately linearly with the y[overline](D)-ratio for all the investigated beams. The correlation between y and α provides the evidence to characterize a radiation therapy beam by the lineal energy when, for instance, weighting factors are to be estimated.

A Monte Carlo track structure simulation code for the full-slowing-down carbon projectiles of energies 1 keV u(-1)-10 MeV u(-1) in water.

The paper presents a new Monte Carlo track structure code (KURBUC_carbon) for simulations of full-slowing-down carbon projectiles C(0)-C(6+) of energies 1 keV u(-1)-10 MeV u(-1) in water vapour. The code facilitates investigation of the spatial resolution effect for scoring track parameters under the Bragg peak of a carbon ion beam. Interactions of carbon projectiles and secondary electrons were followed interaction-by-interaction down to a 1 keV u(-1) cutoff for primary ions and down to 10 eV for electrons. Electronic interactions and nuclear elastic scattering were taken into account, including charge exchange reactions and double electronic interactions for the carbon projectiles. The reliability of the code was tested for radial dose, range and W-value. The calculated results were compared with the published experimental data and other model calculations. The results obtained showed good agreement in most cases where comparisons could be made. Depth dose profiles for 1-10 MeV u(-1) C(6+) were used to form a spread-out Bragg peak (SOBP) of 0.35 mm width in water. At all depths of the SOBP, the energy distributions of the carbon projectiles varied appreciably with the change in the scoring volume. The corresponding variation was nearly negligible for the track average linear energy transfer (LET), except at the distal end of the SOBP. By varying the scoring slab thickness from 1 to 100 µm, the maximum track average LET decreased by ∼30%. The Monte Carlo track structure simulation in the full-slowing-down mode is a powerful tool for investigation of the biophysical properties of radiation tracks under the Bragg peak and SOBP of a carbon ion beam. For estimation of radiation effectiveness under the Bragg peak the new Monte Carlo track structure code provides yet another accurate and effective dosimetry tool at a single cell level. This is because radiobiology within tissue elements can be understood better with dosimetry at cellular and subcellular level.

Inelastic scattering of low-energy electrons in liquid water computed from optical-data models of the Bethe surface.

PURPOSE: We provide a short overview of optical-data models for the description of inelastic scattering of low-energy electrons (10-10,000 eV) in liquid water. The effect on the inelastic scattering cross section due to different optical data and extension algorithms is examined with emphasis on some recent developments. MATERIALS AND METHODS: The optical-data method whereby experimental optical data and theoretical extension algorithms are used to describe the dependence of the dielectric response function on energy- and momentum-transfer and obtain the Bethe surface of the material, currently represents the most used method for computing the inelastic scattering of low-energy electrons in condensed media. Two sets of experimental optical data for liquid water obtained from reflectance and inelastic X-ray scattering spectroscopy, respectively, and the extension algorithms of Ritchie, Penn, and Ashley are examined. Recent developments are discussed along with the role of corrections to the random phase approximation (RPA) of electron gas theory. RESULTS: The inelastic scattering cross section in the energy range 200-10,000 eV was found to be rather insensitive (to within 10%) to the choice of optical data or the extension algorithm. In contrast, differences between model calculations increase rapidly below 200 eV with the influence of the extension algorithm being dominant. CONCLUSION: The choice of the extension algorithm used to extrapolate optical data to finite momentum transfer and obtain the Bethe surface is crucial in modelling the inelastic scattering of electrons with energies below 200 eV. A new set of measurements on the dielectric response function of liquid water beyond the optical limit and the development of extension algorithms that will go beyond RPA by considering the effect of (short-range) electron exchange and correlation should be of some priority.

Microdosimetry and radiation quality determinations in radiation protection and radiation therapy.

Beams of different radiation qualities may, for equal absorbed dose, lead to important differences in the degree of harm for a specific biological endpoint. In many practical situations absorbed dose is then not a sufficient measure when for instance the same treatment result or risk level is the focus of attention. In radiation protection, the absorbed dose may be different by a factor of 20 between the most and least effective radiation qualities. In radiation therapy the corresponding factor is approximately 3. Two physical quantities related to the charged particle track structure, LET, and lineal energy, y, are used to characterise radiation quality. Their values are dependent on whether focus is on targets in the micrometer range (chromosomes, cell nucleus, etc.) or in the nanometre range (DNA structures). The two quantities, LET, and y, have important differences, which emphasise different characteristics of a track. Applications will be discussed.

EDDIX--a database of ionisation double differential cross sections.

The use of Monte Carlo track structure is a choice method in biophysical modelling and calculations. To precisely model 3D and 4D tracks, the cross section for the ionisation by an incoming ion, double differential in the outgoing electron energy and angle, is required. However, the double differential cross section cannot be theoretically modelled over the full range of parameters. To address this issue, a database of all available experimental data has been constructed. Currently, the database of Experimental Double Differential Ionisation Cross sections (EDDIX) contains over 1200 digitalised experimentally measured datasets from the 1960s to present date, covering all available ion species (hydrogen to uranium) and all available target species. Double differential cross sections are also presented with the aid of an eight parameter functions fitted to the cross sections. The parameters include projectile species and charge, target nuclear charge and atomic mass, projectile atomic mass and energy, electron energy and deflection angle. It is planned to freely distribute EDDIX and make it available to the radiation research community for use in the analytical and numerical modelling of track structure.

A database of frequency distributions of energy depositions in small-size targets by electrons and ions.

Linear energy transfer (LET) is an average quantity, which cannot display the stochastics of the interactions of radiation tracks in the target volume. For this reason, microdosimetry distributions have been defined to overcome the LET shortcomings. In this paper, model calculations of frequency distributions for energy depositions in nanometre size targets, diameters 1-100 nm, and for a 1 µm diameter wall-less TEPC, for electrons, protons, alpha particles and carbon ions are reported. Frequency distributions for energy depositions in small-size targets with dimensions similar to those of biological molecules are useful for modelling and calculations of DNA damage. Monte Carlo track structure codes KURBUC and PITS99 were used to generate tracks of primary electrons 10 eV to 1 MeV, and ions 1 keV µm(-1) to 300 MeV µm(-1) energies. Distribution of absolute frequencies of energy depositions in volumes with diameters of 1-100 nm randomly positioned in unit density water irradiated with 1 Gy of the given radiation was obtained. Data are presented for frequency of energy depositions and microdosimetry quantities including mean lineal energy, dose mean lineal energy, frequency mean specific energy and dose mean specific energy. The modelling and calculations presented in this work are useful for characterisation of the quality of radiation beam in biophysical studies and in radiation therapy.

Can a system approach help radiobiology?

This paper explores some of the basic considerations entailed in a system approach to radiobiology, which, in contrast to the traditional molecular approach, focuses on the processes that bring about change to the state of the system, in the case of the cell its phenotype. Radiation can be seen as 'stressing' these processes leading to phenotypic transitions independent of the genotype, that is, epigenetic changes. It is argued that, in this context, the physics that traditionally underpins biology is inappropriate and acts to impair the intuition essential to model building.

Monte Carlo single-cell dosimetry of Auger-electron emitting radionuclides.

A hybrid Monte Carlo transport scheme combining event-by-event and condensed-history simulation with a full account of energy-loss straggling was used to study the dosimetric characteristics of the Auger-emitting radionuclides 67Ga, 99mTc, 111In, 123I, 125I and 201Tl at the single-cell level. The influence of the intracellular localization of the Auger radionuclide upon cellular S-values, radial dose rate profiles and dose-volume-histograms (DVHs) was investigated. For the case where the radiopharmaceutical was either internalized into the cytoplasm or remained bound onto the cell surface (non-internalized), the dose to the cell nucleus was found to differ significantly from the MIRD values and other published data. In this case, the assumption of a homogeneous distribution throughout the cell is shown to significantly overestimate the nuclear dose. A dosimetric case study relevant to the radioimmunotherapy of single lymphoma B-cells with 125I and 123I is presented.

The consideration of biological effectiveness of low energy protons using biophysical modeling of the effects induced by exposure of V79 cells.

We have applied Monte Carlo track structure simulations to estimate relative biological effectiveness (RBE) of low-energy protons using biophysical modelling of radiation effects induced by exposure of V79 cells growing in mono-layer. The microscopic energy deposition in cell nucleus and sub-nucleus volumes was investigated in order to understand the reasons of enhanced biological effectiveness near Bragg peak. Theoretical estimations of RBE based on frequency/dose average lineal energy and calculated yields of initial DNA breaks were collated with experimental RBE(M) data. It was found: 1) dose average lineal energy for whole cell nucleus as a function of proton energy shows a distinct peak at 550 keV; 2) the peak values for sub-nucleus volumes are large compared with the whole cell nucleus; 3) the yield of complex DNA breaks correlates with experimental RBE(M) data.

A Monte Carlo study of cellular S-factors for 1 keV to 1 MeV electrons.

A systematic study of cellular S-factors and absorbed fractions for monoenergetic electrons of initial energy from 1 keV to 1 MeV is presented. The calculations are based on our in-house Monte Carlo codes which have been developed to simulate electron transport up to a few MeV using both event-by-event and condensed-history techniques. An extensive comparison with the MIRD tabulations is presented for spherical volumes of 1-10 microm radius and various source-to-target combinations relevant to the intracellular localization of the emitted electrons. When the primary electron range is comparable to the sphere radius, we find significantly higher values from the MIRD, while with increasing electron energy the escape of delta-rays leads gradually to the opposite effect. The largest differences with the MIRD are found for geometries where the target region is at some distance from the source region (e.g. surface-to-nucleus or cytoplasm-to-nucleus). The sensitivity of the results to different transport approximations is examined. The grouping of inelastic collisions is found adequate as long as delta-rays are explicitly simulated, while the inclusion of straggling for soft collisions has a negligible effect.

A dielectric response study of the electronic stopping power of liquid water for energetic protons and a new I-value for water.

The electronic stopping power of liquid water for protons over the 50 keV to 10 MeV energy range is studied using an improved dielectric response model which is in good agreement with the best available experimental data. The mean excitation energy (I) of stopping power theory is calculated to be 77.8 eV. Shell corrections are accounted for in a self-consistent manner through analytic dispersion relations for the momentum dependence of the dielectric function. It is shown that widely used dispersion schemes based on the random-phase approximation (RPA) can result in sizeable errors due to the neglect of damping and local field effects that lead to a momentum broadening and shifting of the energy-loss function. Low-energy Born corrections for the Barkas, Bloch and charge-state effects practically cancel out down to 100 keV proton energies. Differences with ICRU Report 49 stopping power values and earlier calculations are found to be at the approximately 20% level in the region of the stopping maximum. The present work overcomes the limitations of the Bethe formula below 1 MeV and improves the accuracy of previous calculations through a more consistent account of the dielectric response properties of liquid water.

The Auger effect in physical and biological research.

PURPOSE: The paper reports on progress in physics of radiationless transitions and new Auger spectra of (125)I and (124)I. We report progress in Monte Carlo track structure simulation of low energy electrons comprising majority electrons released in decay most Auger emitters. MATERIALS AND METHODS: The input data for electron capture (EC) and internal conversion(IC) were obtained from various physics data libraries. Monte Carlo technique was used for the simulation of Auger electron spectra. Similarly, electron tracks were generated using Monte Carlo track structure methods. RESULTS: Data are presented for the EC, IC and binding energy (BE) of radionuclides (124)I and (125)I. For each of the radionuclides (125)I and (124)I some examples of electron spectra of individual decays are given. Because most Auger electrons are low energy and short range, data and a short discussion are presented on recent Monte Carlo track structure development in condensed media and their accuracy. CONCLUSIONS: Accuracy of electron spectra calculated in the decay of electron shower by Auger emitting radionuclides depends on availability of accurate physics data. There are many gaps in these libraries and there is a need for detailed comparison between analytical method and Monte Carlo calculations to refine the method of calculations. On simulation of electron tracks, although improved models for sub-keV electron interaction cross sections for liquid water are now available, more experimental data are needed for benchmarking. In addition, it is desirable to make data and programs for calculations of Auger spectra available online for use by students and researchers.

Subcellular S-factors for low-energy electrons: a comparison of Monte Carlo simulations and continuous-slowing-down calculations.

PURPOSE: To study the energy deposition by low-energy electrons in submicron tissue-equivalent targets by comparing two widely used methodologies, namely, the continuous-slowing-down-approximation (CSDA) convolution integral and the Monte Carlo (MC) simulation. METHODS: An MC track-structure code that simulates collision-by-collision the complete slowing down process is used to calculate the energy deposition in spherical volumes of unit density water medium. Comparisons are made with calculations based on the CSDA convolution integral using both empirical and MC-based range-energy analytic formulae. RESULTS: We present self-irradiation absorbed fractions and S-factors for monoenergetic electrons of initial energies from 0.1-10 keV distributed uniformly in spheres of 5, 10, 50, 100, 500, and 1000 nm radius. The MC and CSDA results were found, in some cases, to differ by a factor of 2 or more; differences generally increase with decreasing sphere size. Contrary to high energies, the uncertainties associated with the straight-ahead approximation implicit in the CSDA calculations are of the same order as those related to straggling and delta-ray effects. CONCLUSION: The use of the CSDA methodology may be unsuitable for the sub-micron scale where a more realistic description of electron transport becomes important.

A Monte Carlo study of absorbed dose distributions in both the vapor and liquid phases of water by intermediate energy electrons based on different condensed-history transport schemes.

Monte Carlo transport calculations of dose point kernels (DPKs) and depth dose profiles (DDPs) in both the vapor and liquid phases of water are presented for electrons with initial energy between 10 keV and 1 MeV. The results are obtained by the MC4 code using three different implementations of the condensed-history technique for inelastic collisions, namely the continuous slowing down approximation, the mixed-simulation with delta-ray transport and the addition of straggling distributions for soft collisions derived from accurate relativistic Born cross sections. In all schemes, elastic collisions are simulated individually based on single-scattering cross sections. Electron transport below 10 keV is performed in an event-by-event mode. Differences on inelastic interactions between the vapor and liquid phase are treated explicitly using our recently developed dielectric response function which is supplemented by relativistic corrections and the transverse contribution. On the whole, the interaction coefficients used agree to better than approximately 5% with NIST/ICRU values. It is shown that condensed phase effects in both DPKs and DDPs practically vanish above 100 keV. The effect of delta-rays, although decreases with energy, is sizeable leading to more diffused distributions, especially for DPKs. The addition of straggling for soft collisions is practically inconsequential above a few hundred keV. An extensive benchmarking with other condensed-history codes is provided.

Nanodosimetric measurements and calculations in a neutron therapy beam.

A comparison of calculated and measured values of the dose mean lineal energy (y(D)) for the former neutron therapy beam at Louvain-la-Neuve is reported. The measurements were made with wall-less tissue-equivalent proportional counters using the variance-covariance method and simulating spheres with diameters between 10 nm and 15 microm. The calculated y(D)-values were obtained from simulated energy distributions of neutrons and charged particles inside an A-150 phantom and from published y(D)-values for mono-energetic ions. The energy distributions of charged particles up to oxygen were determined with the SHIELD-HIT code using an MCNPX simulated neutron spectrum as an input. The mono-energetic ion y(D)-values in the range 3-100 nm were taken from track-structure simulations in water vapour done with PITS/KURBUC. The large influence on the dose mean lineal energy from the light ion (A > 4) absorbed dose fraction, may explain an observed difference between experiment and calculation. The latter being larger than earlier reported result. Below 50 nm, the experimental values increase while the calculated decrease.