First steps towards a fast-neutron therapy planning program.

BACKGROUND: The Monte Carlo code GEANT4 was used to implement first steps towards a treatment planning program for fast-neutron therapy at the FRM II research reactor in Garching, Germany. Depth dose curves were calculated inside a water phantom using measured primary neutron and simulated primary photon spectra and compared with depth dose curves measured earlier. The calculations were performed with GEANT4 in two different ways, simulating a simple box geometry and splitting this box into millions of small voxels (this was done to validate the voxelisation procedure that was also used to voxelise the human body). RESULTS: In both cases, the dose distributions were very similar to those measured in the water phantom, up to a depth of 30 cm. In order to model the situation of patients treated at the FRM II MEDAPP therapy beamline for salivary gland tumors, a human voxel phantom was implemented in GEANT4 and irradiated with the implemented MEDAPP neutron and photon spectra. The 3D dose distribution calculated inside the head of the phantom was similar to the depth dose curves in the water phantom, with some differences that are explained by differences in elementary composition. The lateral dose distribution was studied at various depths. The calculated cumulative dose volume histograms for the voxel phantom show the exposure of organs at risk surrounding the tumor. CONCLUSIONS: In order to minimize the dose to healthy tissue, a conformal treatment is necessary. This can only be accomplished with the help of an advanced treatment planning system like the one developed here. Although all calculations were done for absorbed dose only, any biological dose weighting can be implemented easily, to take into account the increased radiobiological effectiveness of neutrons compared to photons.

Interaction of ion tracks in spatial and temporal proximity.

In the present work, a systematic analysis of the impact of spatial and temporal proximity of ion tracks on the yield of higher-order radiolytic species as well as of DNA damage patterns is presented. This potential impact may be of concern when laser-driven particle accelerators are used for ion radiation therapy. The biophysical Monte Carlo track structure code PARTRAC was used and, to this end, extended in two aspects: first, the temporal information about track evolution has been included in the track structure module and, second, the simulation code has been modified to enable parallel multiple track processing during simulation of subsequent modelling stages. Depending on the spatial and temporal separation between ion-track pairs, the yield of chemical species has been calculated for incident protons with start energies of 20 MeV, for He(2+) ions with start energies of 1 and 20 MeV, and for 60 MeV C(6+) ions. Provided the overlap of the considered ion tracks is sufficient in all four dimensions (space and time), the yield of hydroxyl radicals was found to be reduced compared to that of single tracks, for all considered ion types. The biological endpoints investigated were base damages, single-strand breaks, double-strand breaks, and clustered lesions for incident pairs of protons and He(2+) ions, each with start energies of 20 MeV. The yield of clustered lesions produced by 20 MeV protons turned out to be influenced by the spatial separation of the proton pair; in contrast, no influence was found for different start times of the protons. The yield of single-strand breaks and base hits was found neither to depend on the spatial separation nor on the temporal separation between the incident protons. For incident 20 MeV He(2+) ions, however, a dependence on the spatial and temporal separation of the ion pair was found for all considered biological endpoints. Nevertheless, spatial proximity conditions where such intertrack effects were obtained are not met in the case of tumour radiation therapy; thus, no impact on radiation effects due to short pulse duration of laser-driven accelerators can be expected from alterations during the chemical stage.

Time- and space-resolved Monte Carlo study of water radiolysis for photon, electron and ion irradiation.

Time-dependent yields of the most important products of water radiolysis E(aq)(-), (*)OH, H(*), H(3)O(+), H(2), OH(-) and H(2)O(2) have been calculated for (60)Co-photons, electrons, protons, helium- and carbon-ions incident onto water. G values have been evaluated for the interval from 1 ps to 1 mus after initial energy deposition as a function of time, as well as after 1 ns and at the end of the chemical stage as a function of linear energy transfer (LET), covering an interval from approximately 0.2 up to 750 keV/microm by means of different particle types. In this work, the modules of the biophysical Monte Carlo track structure code PARTRAC dealing with the simulation of prechemical and chemical stages have been improved to extend interaction data sets for heavier ions. Among other newly selected parameter values, the thermalisation distance between the point of generation and hydration of subexcitation electrons has been adopted from recent data in the literature. As far as data from the literature are available, good agreement has been found with the calculated time- and LET-dependent yields in this work, supporting the selection of the revised parameter values.

First steps towards systems radiation biology studies concerned with DNA and chromosome structure within living cells.

For the understanding of radiation action on biological systems like cellular macromolecules (e.g., DNA in its higher structures) a synergistic approach of experiments and quantitative modelling of working hypotheses is necessary. Further on, the influence on calculated results of certain assumptions in such working hypotheses must critically be evaluated. In the present work, this issue is highlighted in two aspects for the case of DNA damage in single cells. First, yields of double-strand breaks and frequency distributions of DNA fragment lengths after ion irradiation were calculated using different assumptions on the DNA target model. Compared to a former target model now a moderate effect due to the inclusion of a spherical chromatin domain model has been found. Second, the influence of assumptions on particular geometric chromosome models on calculated chromosome aberration data is illustrated with two target-modelling approaches for this end point.

Internal dose assessment of 210Po using biokinetic modeling and urinary excretion measurement.

The mysterious death of Mr. Alexander Litvinenko who was most possibly poisoned by Polonium-210 ((210)Po) in November 2006 in London attracted the attention of the public to the kinetics, dosimetry and the risk of this high radiotoxic isotope in the human body. In the present paper, the urinary excretion of seven persons who were possibly exposed to traces of (210)Po was monitored. The values measured in the GSF Radioanalytical Laboratory are in the range of natural background concentration. To assess the effective dose received by those persons, the time-dependence of the organ equivalent dose and the effective dose after acute ingestion and inhalation of (210)Po were calculated using the biokinetic model for polonium (Po) recommended by the International Commission on Radiological Protection (ICRP) and the one recently published by Leggett and Eckerman (L&E). The daily urinary excretion to effective dose conversion factors for ingestion and inhalation were evaluated based on the ICRP and L&E models for members of the public. The ingestion (inhalation) effective dose per unit intake integrated over one day is 1.7 x 10(-8) (1.4 x 10(-7)) Sv Bq(-1), 2.0 x 10(-7) (9.6 x 10(-7)) Sv Bq(-1) over 10 days, 5.2 x 10(-7) (2.0 x 10(-6)) Sv Bq(-1) over 30 days and 1.0 x 10(-6) (3.0 x 10(-6)) Sv Bq(-1) over 100 days. The daily urinary excretions after acute ingestion (inhalation) of 1 Bq of (210)Po are 1.1 x 10(-3) (1.0 x 10(-4)) on day 1, 2.0 x 10(-3) (1.9 x 10(-4)) on day 10, 1.3 x 10(-3) (1.7 x 10(-4)) on day 30 and 3.6 x 10(-4) (8.3 x 10(-5)) Bq d(-1) on day 100, respectively. The resulting committed effective doses range from 2.1 x 10(-3) to 1.7 x 10(-2) mSv by an assumption of ingestion and from 5.5 x 10(-2) to 4.5 x 10(-1) mSv by inhalation. For the case of Mr. Litvinenko, the mean organ absorbed dose as a function of time was calculated using both the above stated models. The red bone marrow, the kidneys and the liver were considered as the critical organs. Assuming a value of lethal absorbed dose of 5 Gy to the bone marrow, 6 Gy to the kidneys and 8 Gy to the liver, the amount of (210)Po which Mr. Litvinenko might have ingested is therefore estimated to range from 27 to 1,408 MBq, i.e 0.2-8.5 microg, depending on the modality of intake and on different assumptions about blood absorption.

Simulation of light ion induced DNA damage patterns.

The biophysical simulation code PARTRAC was extended by a module to handle ions heavier than alpha particles. Cross sections for ion-electron interactions were taken from He(++) ions of the same velocity and scaled by Z(eff(2))/4. Calculated linear energy transfer values, radial dose distributions and secondary electron spectra were found in agreement with experimental results. DNA damage due to irradiation of human fibroblast cells by several light ions from H to S was calculated for various energies complemented by 220 kV(p) X rays as reference radiation. With increasing linear energy transfer, the calculated total yield of double-strand breaks per dose showed saturation behaviour at about twice the value for reference radiation. When data analysis methods for experimental double-strand break yield determination were applied to the simulated DNA damage patterns, the two data sets were found in accord. The calculated patterns of DNA damage clusters were analysed on local and regional scale finding regional clusters in closer correlation to experimental cell inactivation data.

Low-level radiocaesium exposure alters gene expression in roots of Arabidopsis.

Radiocaesium is one of the main anthropogenic sources of internal and external exposure to beta- and gamma-radiation (e.g. from global fallout of atmospheric atomic bomb testing and from the Chernobyl reactor accident). Here we investigated gene expression by suppression subtractive hybridization (SSH) and reverse transcription-polymerase chain reaction (RT-PCR) in Arabidopsis thaliana, which was induced by the root uptake of 134Cs. SSH analysis resulted in the isolation of 46 clones that were differentially expressed at 30 Bq cm(-3) 134Cs. Most of the expressed sequence tags identified belonged to genes encoding proteins that were involved in cell growth, cell division and the development of plants, and in proteins controlling translation, general metabolism and stress defence, including a DNA excision repair protein. The accumulation of caesium in plant material was measured in plants grown for 5 wk on agar contaminated by up to 60 Bq cm(-3) 134Cs. 134Cs was found to accumulate, in particular, in leaf rosettes and was dependent on the activity concentration in the growth media. The data indicate that low-level ionizing radiation influences important cellular responses, resulting in a changed gene-expression profile.

Biokinetic modeling of uranium in man after injection and ingestion.

Uranium is a naturally occurring primordial radioactive element. Small amounts found in air, water, and food are regularly consumed and inhaled by humans. Even the military, medical, and industrial use of depleted uranium can affect humans. There is an appreciable retention of incorporated uranium in skeleton, kidneys, and liver, and a review of respective effective dose coefficients has been given by the International Commission on Radiological Protection (ICRP) in its "Publication 69"; however, data regarding retention in organs or tissues and rates of urinary and fecal excretion for different age groups are incomplete. Therefore, the present study provides retention data that have been calculated for uranium in all compartments and for urinary and fecal excretion, following acute and chronic injection and ingestion for six age groups. The calculations are based on the current ICRP biokinetic model for uranium, and the data can be plotted by using any mathematical software to obtain the retention data at any time after incorporation or to calculate the internal average organ dose induced by uranium provided that specific absorbed fractions are available. The dynamic relationship of the retention in plasma and blood after intravenously and orally administered uranium can easily be derived from the database for injection and ingestion. The calculated contents of uranium in organs or tissues (using the uranium concentration in foodstuffs published by UNSCEAR for Europeans) are compared with autopsy data available in the literature. According to this model, the whole body of a 75-year-old man contains 7 microg uranium, of which 76% is in the skeleton, 1% in the kidneys, and 2.1% in the liver.

Caesium-affected gene expression in Arabidopsis thaliana.

* Excessive caesium can be toxic to plants. Here we investigated Cs uptake and caesium-induced gene expression in Arabidopsis thaliana. * Accumulation was measured in plants grown for 5 wk on agar supplemented with nontoxic and up to toxic levels of Cs. Caesium-induced gene expression was studied by suppression-subtractive hybridization (SSH) and RT-PCR. * Caesium accumulated in leaf rosettes dependent upon the external concentration in the growth media, whereas the potassium concentration decreased in rosettes. At a concentration of 850 microM, Cs plants showed reduced development, and withered with an increase in concentration to 1 mM Cs. SSH resulted in the isolation of 73 clones that were differentially expressed at a Cs concentration of 150 microM. Most of the genes identified belong to groups of genes encoding proteins in stress defence, detoxification, transport, homeostasis and general metabolism, and proteins controlling transcription and translation. * The present study identified a number of marker genes for Cs in Arabidopsis grown under nontoxic Cs concentrations, indicating that Cs acts as an abiotic stress factor.

The role of atomic inner shell relaxations for photon-induced DNA damage.

The influence of relaxations of atoms making up the DNA and atoms attached to it on radiation-induced cellular DNA damage by photons was studied by very detailed Monte Carlo track structure calculations, as an unusually high importance of inner shell ionizations for biological action was suspected from reports in the literature. For our calculations cross sections for photons and electrons for inner shell orbitals were newly derived and integrated into the biophysical track structure simulation programme PARTRAC. Both the local energy deposition in a small sphere around the interacting relaxed atom, and the number of relaxations per Gy and Gbp were calculated for several target geometries and many monoenergetic photon irradiations. Elements with the highest order number yielded the largest local energy deposition after interaction. The atomic relaxation after ionization of the L1 shell was found to be more biologically efficient than that of the K shell for high Z atoms. Generally, the number of inner shell relaxations produced by photon irradiation was small in comparison to the total number of double strand breaks generated by such radiation. Furthermore, the energy dependence of the total number of photon-induced and electron-induced relaxations at the DNA atoms does not agree with observed RBE values for different biological endpoints. This suggests that the influence of inner shell relaxations of DNA atoms on radiation-induced DNA damage is in general rather small.

Simulation of (125)I decay in a synthetic oligodeoxynucleotide with normal and distorted geometry and the role of radiation and non-radiation actions.

Within the track structure code PARTRAC, DNA strand break induction by direct and indirect radiation action was calculated for the E. coli catabolite gene activator protein (CAP) DNA complex with (125)I located at the position of the H(5) atom of the cytosine near the center. The shape of the resulting DNA fragment size distributions was found to be in reasonable agreement with corresponding experimental results. However, the calculated yield was considerably lower than the measured one. To study possible reasons for this, recently published experimental data on DNA strand breaks in a 41-mer synthetic oligodeoxynucleotide (oligoDNA) with incorporated (125)I were analyzed aiming at an evaluation of the non-radiation-related component due to the neutralization of the initially highly charged (125m)Te daughter ion. This was done by assuming that the differences between simulated radiation-induced distribution and the measured total fragment size distributions were due to the neutralization process. The neutralization effect defined in this way was found to dominate the strand breakage frequency within a range of 5-7 base pairs around the (125)I decay site on both strands. After implementing this neutralization effect derived from the oligoDNA analysis into the PARTRAC simulation for the CAP-DNA complex, the agreement of the calculated DNA fragment distributions with the corresponding experimental data was considerably improved. The results indicate that DNA conformation may be explored by incorporation of (125)I into the DNA, measurement of fragment size distributions, and comparison with simulation calculation for various hypothetical DNA models.

Role of DNA organisation and environmental scavenging capacity in the evolution of radiobiological damage: models and simulations.

BACKGROUND AND PURPOSE: Theoretical models and Monte Carlo simulations were developed, aimed to investigate the role played by the organisation of interphase DNA and the environmental scavenging capacity conditions in the induction of radiobiological damage. METHODS: The induction of single- and double-strand breaks by gamma rays impinging on different DNA structures (e.g. linear DNA, SV40 minichromosome and cellular DNA) was simulated as a function of the environment scavenging capacity. Furthermore, yields of chromosome aberrations (CA) induced by gamma rays and light ions were simulated with a purposely developed MC code that explicitly takes into account the DNA higher-order organisation as chromosome territories. RESULTS AND CONCLUSIONS: Simulations performed with the PARTRAC code allowed quantification of the dependence of dsb and ssb both on the target structure, and on the scavenging capacity. The results relative to CA showed the importance of DNA damage complexity (nanometre scale) and interphase chromosome domains (micrometre scale) in the process of aberration formation. Very good agreement was found between the model predictions on ssb, dsb and CA and available experimental data.

Simulation of DNA damage after proton irradiation.

The biophysical radiation track simulation model PARTRAC was improved by implementing new interaction cross sections for protons in water. Computer-simulated tracks of energy deposition events from protons and their secondary electrons were superimposed on a higher-order DNA target model describing the spatial coordinates of the whole genome inside a human cell. Induction of DNA double-strand breaks was simulated for proton irradiation with LET values between 1.6 and 70 keV/microm and various reference radiation qualities. The yield of DSBs after proton irradiation was found to rise continuously with increasing LET up to about 20 DSBs per Gbp and Gy, corresponding to an RBE up to 2.2. About half of this increase resulted from a higher yield of DSB clusters associated with small fragments below 10 kbp. Exclusion of experimentally unresolved multiple DSBs reduced the maximum DSB yield by 30% and shifted it to an LET of about 40 keV/microm. Simulated fragment size distributions deviated significantly from random breakage distributions over the whole size range after irradiation with protons with an LET above 10 keV/microm. Determination of DSB yields using equations derived for random breakage resulted in an underestimation by up to 20%. The inclusion of background fragments had only a minor influence on the distribution of the DNA fragments induced by radiation. Despite limited numerical agreement, the simulations reproduced the trends in proton-induced DNA DSBs and fragment induction found in recent experiments.

Multistage models and the incidence of cancer in the cohort of atomic bomb survivors.

The analyses in this paper show that a number of biologically based models describe cancer incidence among the A-bomb survivors equally well. However, these different models can predict very different temporal patterns of risk after irradiation. No evidence was found to support the previous claim of Pierce and Mendelsohn that excess cancer risks for the solid tumors depend only upon attained age and not on age at exposure or time since exposure. Although the A-bomb survivor cohort is the largest epidemiological data set for the study of radiation and cancer, it is not large enough to discriminate among various possible carcinogenic mechanisms. Unfortunately for hypothesis generation, the data appear to be consistent with a number of different mechanistic interpretations of the role of radiation in carcinogenesis.