Implementation of new physics models for low energy electrons in liquid water in Geant4-DNA.

A new alternative set of elastic and inelastic cross sections has been added to the very low energy extension of the Geant4 Monte Carlo simulation toolkit, Geant4-DNA, for the simulation of electron interactions in liquid water. These cross sections have been obtained from the CPA100 Monte Carlo track structure code, which has been a reference in the microdosimetry community for many years. They are compared to the default Geant4-DNA cross sections and show better agreement with published data. In order to verify the correct implementation of the CPA100 cross section models in Geant4-DNA, simulations of the number of interactions and ranges were performed using Geant4-DNA with this new set of models, and the results were compared with corresponding results from the original CPA100 code. Good agreement is observed between the implementations, with relative differences lower than 1% regardless of the incident electron energy. Useful quantities related to the deposited energy at the scale of the cell or the organ of interest for internal dosimetry, like dose point kernels, are also calculated using these new physics models. They are compared with results obtained using the well-known Penelope Monte Carlo code.

Analysis of the CONRAD computational problems expressing only stochastic uncertainties: neutrons and protons.

Within the scope of CONRAD (A Coordinated Action for Radiation Dosimetry) Work Package 4 on Computational Dosimetry jointly collaborated with the other research actions on internal dosimetry, complex mixed radiation fields at workplaces and medical staff dosimetry. Besides these collaborative actions, WP4 promoted an international comparison on eight problems with their associated experimental data. A first set of three problems, the results of which are herewith summarised, dealt only with the expression of the stochastic uncertainties of the results: the analysis of the response function of a proton recoil telescope detector, the study of a Bonner sphere neutron spectrometer and the analysis of the neutron spectrum and dosimetric quantity H(p)(10) in a thermal neutron facility operated by IRSN Cadarache (the SIGMA facility). A second paper will summarise the results of the other five problems which dealt with the full uncertainty budget estimate. A third paper will present the results of a comparison on in vivo measurements of the (241)Am bone-seeker nuclide distributed in the knee. All the detailed papers will be presented in the WP4 Final Workshop Proceedings.

Computer simulation of strand break yields in plasmid pBR322: DNA damage following 125I decay.

This paper presents results of (125)I effects on plasmid pBR322 in aqueous solution, simulating the complete transport of Auger and X rays up to the chemical phase. In addition to new sampling algorithms, new electronic cross sections are included. Simulations were carried out both with (125)I, bound to plasmid, or free, in its vicinity. The influence of the hydroxyl radical scavenger dimethyl sulfoxyde (DMSO) has also been tested, underlying that, in naked DNA, double strand breaks (caused by the decay of bound (125)I) are mainly due to direct hits. The calculated yields of relaxation events (RE) and linearization events (LE) show good agreement with experimental ones: when (125)I is bound to the plasmid pBR322, 0.16 RE and 0.83 LE per decay (without DMSO) are then observed. Then, when 2 mol DMSO is added, RE and LE probabilities become 0.22 and 0.76. The very light differences with those from literature could arise from experimental conditions.

Estimation of a radiation weighting factor for 99mTc.

Decaying (99m)Tc does not only emit a gamma ray (140.5 keV), but also low-energy Auger and conversion electrons. These electrons cause a serious problem in the determination of a radiation weighting factor for (99m)Tc due to their extremely short range in tissue. Therefore, for comparison ultrasoft X rays are used here, which deposit their energy mainly via the photoeffect thus also initiating low-energy photoelectrons. Monte Carlo computer codes provided electron emission spectra of (99m)Tc and subsequent track structure calculations simulated the induction of DNA damage of different degrees of complexity. For the modelling of ultrasoft X rays carbon K photons with an energy of 270 eV were selected, for which experimental results are available from the literature. On average, four electrons were found to be emitted per (99m)Tc decay. Simulation of DNA damage revealed a nearly identical spectrum of primary strand breaks for (99m)Tc and C-K radiation. On this basis, a total radiation weighting factor of 1.2 was evaluated for (99m)Tc.

Pitfalls and modelling inconsistencies in computational radiation dosimetry: lessons learnt from the QUADOS intercomparison. Part I: Neutrons and uncertainties.

The QUADOS EU cost shared action conducted an intercomparison on the usage of numerical methods in radiation protection and dosimetry. The eight problems proposed were intended to test the usage of Monte Carlo and deterministic methods by assessing the accuracy with which the codes are applied and also the methods used to evaluate uncertainty in the answer gained through these methods. The overall objective was to spread good practice through the community and give users information on how to assess the uncertainties associated with their calculated results.

Pitfalls and modelling inconsistencies in computational radiation dosimetry: lessons learnt from the QUADOS intercomparison. Part II: Photons, electrons and protons.

'QUADOS', a concerted action of the European Commission, has promoted an intercomparison aimed at evaluating the use of computational codes for dosimetry in radiation protection and medical physics. This intercomparison was open to all users of radiation transport codes. Eight problems were selected for their relevance to the radiation dosimetry community, five of which involved photon and proton transport. This paper focuses on a discussion of lessons learned from the participation in solving the photon and charged particle problems. The lessons learned from the participation in solving the neutron problems are presented in a companion paper (in this issue).

QUADOS intercomparison: a summary of photon and charged particle problems.

QUADOS, a Concerted Action of the European Commission, has promoted an intercomparison aimed at evaluating the use of computational codes for dosimetry in radiation protection and medical physics. This intercomparison was open to all users of radiation transport codes. Eight problems were selected for their relevance to the radiation dosimetry community, five of which involved photon and proton transport. This paper focuses on the analysis of the photon and charged particle problems. The neutron problems were presented in a paper at the NEUDOS9 conference.

Intercomparison on the usage of computational codes in radiation dosimetry.

'QUADOS', a Concerted Action of the European Commission, has run an intercomparison aimed at evaluating the use of computational codes for dosimetry in radiation protection and medical physics. This intercomparison was open to all users of Monte Carlo, analytic and semi-analytic codes or deterministic methods. Its main aim was to provide a snapshot of the methods and codes currently in use. It also intended to furnish information on the methods used to assess the reliability of computational results and disseminate 'good practice' throughout the radiation dosimetry community. Eight problems were selected for their relevance to the radiation dosimetry community, three of which involve neutron transport. This paper focuses on the analysis of the neutron problems.

Computer evaluation of direct and indirect damage induced by free and DNA-bound iodine-125 in the chromatin fibre.

PURPOSE: When Iodine-125 decays within chromatin, several in vivo experiments have shown that the radiobiological effects are caused mainly by indirect mechanisms and that more than one DNA double strand break (DSB) is produced per decay. We present calculations to evaluate the contribution of direct and indirect effects of radiation tracks to produce DNA damage induced by bound and free I-125 in a model of chromatin DNA. MATERIALS AND METHODS: A solenoid model of chromatin with 18 nucleosomal elements placed in bulk water (more than 600,000 atoms) is used where the initial I-125 decay takes place. All physical and chemical events initiated by Auger and X-rays were taken into account. The yields of single strand breaks (SSB) and DSB were derived using direct effects on DNA and indirect reactions of all radical species generated in the radiolysis of the bulk water. RESULTS: The distribution of damage complexity for free and DNA-bound I-125 is presented. We obtained more than 1.3 DSB per decay, with nearly equal contributions from direct and indirect effects. However, for the most complex type of damage, located at the decay site, the direct effect is about 70% of the total number. To show the protective effect of histones, simulations were carried out with and without the presence of histones.

Computer simulation of 57Fe bleomycin auger effects in DNA.

The antibiotic bleomycin binds to the DNA and induces double strand breaks (DSBs). To increase the cleavages. 57Fe is used to form a complex suitable for Mössbauer effect. The de-excitation of the resonant excited 57Fe nucleus releases Auger electrons and X rays. The goal of this work is to evaluate the increase in yield of DSBs due to the 57Fe, using Monte Carlo simulation methods. Particles spectra and the yields of single strand breaks (SSBs) and DSBs were calculated by considering direct events on DNA and reaction of all radical species generated in the radiolysis of its environment. The Auger spectrum shows a large number of electrons with energies below 100 eV, mainly responsible for direct damage, while another group around 600-700 eV is responsible for indirect damage effects. Bleomycin receives about one fourth of the energy deposited in DNA and an average of 0.65 DSB per de-excitation is observed.

Modelling of DNA damage induced by energetic electrons (100 eV to 100 keV).

Modelling and calculations are presented for the spectrum of initial DNA damage produced by 100 eV to 100 keV energetic electrons. Analysis of the initial spectrum of damage, based upon the source (direct energy deposition and reactions with diffusing OH radicals) and complexity of damage, indicates that the majority of the interactions cause no damage to DNA and any damage that does occur is most likely to be a simple single strand break (SSB). The fraction of complex damage for energetic electrons is lower than that induced by low energy electrons and ultrasoft X rays but still represents an appreciable fraction (20-30%) of the total double strand breaks (DSBs). Relative yields of strand breaks are investigated for dependence on the assumed energy deposition threshold and on the probability of the hydroxyl radicals to produce a single strand break. The ratio of direct to indirect damage does not change significantly across the electron energy range investigated and the values lie well within the experimental data. The direct energy deposition in DNA represents a larger proportion of the damage although the contribution from the hydroxyl radicals is also substantial, both in terms of the absolute yield of the breaks and the complexity of the damage.

Ratio of complex double strand break damage induced by 125IUdR and 123IUdR correlates with experimental in vitro cell killing effectiveness.

The overall cellular damage induced by ionising radiation is determined by the number and spatial distribution of initial ionisations and excitations within the critical volume. This paper focuses on the physical and chemical phase of the radiation action chain following the decay of DNA-bound 123I and 125I. Monte Carlo simulations of these nuclides' decay provide electron emission spectra which are used as input data for track structure calculations. In combination with DNA models, these calculations allow the specific radiation source to be characterised in terms of DNA strand break patterns. The distribution of these patterns indicates that 125I produces much more severe breaks than 123I. The ratio of complex DSBs induced by both iodine isotopes correlates with the differences in cell killing effectiveness reported from in vitro survival experiments.

Distribution of strand breaks produced by Auger electrons in decay of 125I in triplex DNA.

In this study we investigate the possibility of using Auger electrons as a probing agent for the study of structures of nucleic acids. To this end, we present the distribution of breaks produced in strands of a DNA duplex and a triplex-forming oligonucleotide (TFO) carrying Auger emitting radionuclide 125I. The method of calculation includes use of a molecular model of plasmid DNA duplex with bound TFO carrying a labelled 125I at position C5 of a single deoxycytosine residue, a source of Auger spectra, Monte Carlo electron track structure and the ensuing chemistry codes, to simulate the distribution of breaks produced in both strands of a plasmid DNA. Frequencies of fragment length distributions were obtained for the TFO, the purine and the pyrimidine strands. The frequency of breaks in the purine strand showed good correlation with the published experimental results, while that for the pyrimidine strand is lower by a factor of 3. It is concluded that the true structure of triplex DNA may not be purely of B-form.

A method for radioprobing DNA structures using Auger electrons.

PURPOSE: To present a new method for radioprobing a DNA triple helix structure by Auger electrons emitted in the decay of 125I using theoretical/computational approaches. MATERIALS AND METHODS: A Monte Carlo track structure method was used to simulate the damage to a triplex resulting from Auger electrons emitted in the decay of an incorporated 125I atom in plasmid DNA. Comparison of the theoretical frequency distributions of single-strand breaks induced on the Pu and Py strands with the experimental data and a knowledge of the distances from the strand breaks to the iodine provide information on the structures otherwise difficult to obtain with X-ray crystallography. RESULTS: In comparing theoretical frequency distributions of single-strand breaks with the experimental data it is found that the results are very sensitive to the conformation of the triplex model used. It is found that the best fit to the experimental data results from using a hybrid triplex model, in which the base-step geometry is A-like, while the sugar puckers adopt the B-like C2'-endo conformation. CONCLUSIONS: The approach and technique presented here represent a valuable new addition to the methods available for DNA structure determination since they provide information on medium-range structure otherwize difficult to obtain in the absence of X-ray crystallography. It is concluded that currently accepted models for triplex structure are not optimal, and a modified structure is proposed that fits the radioprobing results better, while maintaining agreement with the fibre diffraction and NMR data. Although the method has proved to be very useful for scoring alternative trial solutions, further studies combining experimental data from multiple iodine positions with track structure modelling are required for directing structural optimization.

Quantitative modelling of DNA damage using Monte Carlo track structure method.

This paper presents data on modelling of DNA damage induced by electrons, protons and alpha-particles to provide an insight into factors which determine the biological effectiveness of radiations of high and low linear energy transfer (LET). These data include the yield of single- and double-strand breaks (ssb, dsb) and base damage in a cellular environment. We obtain a ratio of 4-15 for ssb:dsb for solid and cellular DNA and a preliminary ratio of about 2 for base damage to strand breakage. Data are also given on specific characteristics of damage at the DNA level in the form of clustered damage of varying complexity, that challenge the repair processes and if not processed adequately could lead to the observed biological effects. It is shown that nearly 30% of dsb are of complex form for low-LET radiation, solely by virtue of additional breaks, rising to about 70% for high-LET radiation. Inclusion of base damage increases the complex proportion to about 60% and 90% for low- and high-LET radiation, respectively. The data show a twofold increase in frequencies of complex dsb from low-LET radiation when base damage is taken into account. It is shown that most ssb induced by high-LET radiation have associated base damages, and also a substantial proportion is induced by low-energy electrons.

Computational modelling of low-energy electron-induced DNA damage by early physical and chemical events.

Modelling and calculations are presented as a first step towards mechanistic interpretation and prediction of radiation effects based on the spectrum of initial DNA damage produced by low energy electrons (100 eV-4.5 keV) that can be compared with experimental information. Relative yields of single and clustered strand breaks are presented in terms of complexity and source of damage, either by direct energy deposition or by reaction of OH radicals, and dependence on the activation probability of OH radicals and the amount of energy required to give a single strand break (ssb). Data show that the majority of interactions in DNA do not lead to damage in the form of strand breaks and when they do occur, they are most frequently simple ssb. However, for double-strand breaks (dsb), a high proportion (approximately 30%) are of more complex forms, even without considering additional complexity from base damage. The greater contribution is from direct interactions in the DNA but reactions of OH radicals add substantially to this, both in terms of the total number of breaks and in increasing the complexity within a cluster. It has been shown that the lengths of damaged segments of DNA from individual electron tracks tend to be short, indicating that consequent deletion length (simply by loss of a fragment between nearby dsb) would be short, very seldom exceeding a few tens of base pairs.

Modelling of Auger-induced DNA damage by incorporated 125I.

We have analyzed a newly available high resolution and precision repeat of the original Martin and Haseltine experiment which includes the influence of DMSO on the results. The new model includes the production and diffusion of radical species and .OH radical attack on DNA as well as the direct hits. Calculations of single-strand breaks use individual Auger electron along with the tracks of electrons and radical species superimposed on an atomistic model of B-DNA. Comparison of the preliminary calculations with the experiment supports the earlier choice of data for the amount of energy required to produce a single-strand break, i.e. 17.5 eV. In a separate simulation we found that an average of less than two ionizations inducing a single-strand break gave the best fit to experimental data. Direct hits were found to be predominantly occurring at short range while the damage by .OH radicals was mainly of the long-range type.

Modelling of initial events and chemical behaviour of species induced in DNA units by Auger electrons from 125I, 123I and carbon.

Auger electron spectra for 123I and 125I generated by Monte Carlo calculation and Auger electrons emitted from carbon after photoelectric effect on its K-shell as well as two DNA models (linear plasmid and nucleosome model) based on x-ray diffraction experiments have been used to simulate the behaviour of all species and radicals created during the physical and the chemical phase of the Auger's transport. By introducing appropriate assumptions for the induction of strand breaks the number of these breaks can also be determined and correlated to experimentally found numbers of lethal events. Efficiency differences between the iodine nuclides themselves and in comparison with the rather monoenergetic Auger electrons from carbon are shown with regard to the direct and indirect effects on the two DNA models. The characteristic products in the physical, chemical and biochemical phase are compared with corresponding results from the literature for low-LET radiation.

Modelling of radiation damage by 125I on a nucleosome.

Studies of early physical interactions of ionizing radiation in biological medium have evolved from water cylinders or spheres to structured volumes representing nucleosomal DNA, based on spatial co-ordinates for each individual atom. Regarding the physico-chemical and chemical stages, the models of DNA have evolved from inactive geometrical objects to active participation of DNA in the reactions with the radical species. In this paper data are presented on the modelling of the interaction of low energy electrons with nucleosomal DNA. The nucleosome core unit has been modelled as a 146-bp helical DNA, containing > 9000 atoms, wound around the core unit. The yields of strand breaks for low energy electrons has been obtained by placing the nucleosome target in a liquid water environment and introducing a number of assumptions for the induction of strand breaks. The calculated results for the induction of ssb and dsb by 125I decays agree with experimental data, confirming the plausibility of this nucleosome model as well as the characterization of the interaction of ionizing radiation in terms of the energy deposition and the assumptions made for the strand breaks.