Influences of mixed expiratory sampling parameters on exhaled volatile organic compound concentrations.

Breath gas analysis is a promising technology for medical applications. By identifying disease-specific biomarkers in the breath of patients, a non-invasive and easy method for early diagnosis or therapy monitoring can be developed. In order to achieve this goal, one essential prerequisite is the reproducibility of the method applied, i.e. the quantification of exhaled volatile organic compounds (VOCs). The variability of breath gas VOC measurements can be affected by many factors. In this respect, sampling-specific parameters like flow rate and volume of exhalation, exhalation with or without breath holding, exhalation in single or multiple breathing and volume of air inhaled before breath gas exhalation can play a vital role. These factors affecting the measurements must be controlled by optimizing the sampling procedure. For such an optimization, it is important to know how exactly the different parameters affect the exhaled VOC concentrations. Therefore, a study has been undertaken in order to identify some effects of different breath sampling-specific parameters on the exhaled VOC profile using the mixed expired breath sampling technique. It was found that parameters such as filling the sampling bag with high or low flow rate of exhalation, with multiple or single exhalations, in different volumes of exhalation, with breath holding and under different surrounding air conditions significantly affect the concentrations of the exhaled VOCs. Therefore, the specific results of this work should be taken into account before planning new breath gas studies or developing new breath gas collection systems in order to minimize the number of artefacts affecting the concentration of exhaled VOCs.

Monte Carlo evaluation of DNA fragmentation spectra induced by different radiation qualities.

The PARTRAC code has been developed constantly in the last several years. It is a Monte Carlo code based on an event-by-event description of the interactions taking place between the ionising radiation and liquid water, and in the present version simulates the transport of photons, electrons, protons, helium and heavier ions. This is combined with an atom-by-atom representation of the biological target, i.e. the DNA target model of a diploid human fibroblast in its interphase (genome of 6 Gigabase pairs). DNA damage is produced by the events of energy depositions, either directly, if they occur in the volume occupied by the sugar-phosphate backbone, or indirectly, if this volume is reached by radiation-induced radicals. This requires the determination of the probabilities of occurrence of DNA damage. Experimental data are essential for this determination. However, after the adjustment of the relevant parameters through the comparison of the simulation data with the DNA fragmentation induced by photon irradiation, the code has been used without further parameter adjustments, and the comparison with the fragmentation induced by charged particle beams has validated the code. In this paper, the results obtained for the DNA fragmentation induced by gamma rays and by charged particle beams of various LET are shown, with a particular attention to the production of very small fragments that are not detected in experiments.

Differences in exhaled gas profiles between patients with type 2 diabetes and healthy controls.

AIMS: Recent advances in analytical technology allow the detection of several hundred volatile organic compounds (VOCs) in human exhaled air, many of which reflect unidentified endogenous pathways. This study was performed to determine whether a breath gas analysis using proton transfer reaction-mass spectrometry (PTR-MS) could serve as a noninvasive method to distinguish between patients with type 2 diabetes mellitus and healthy controls. METHODS: Breath and room air samples were measured from 21 patients with insulin-treated type 2 diabetes and 26 healthy controls. VOCs in the mass range of 20-200 atomic mass units were analyzed using PTR-MS. RESULTS: We identified eight masses characteristic of endogenous VOCs that showed significant differences in the gas profiles of patients with type 2 diabetes and healthy control subjects. Using these VOCs for linear discriminant analysis, the sensitivity and specificity were found to be 90% and 92%, respectively. CONCLUSIONS: These results suggest that it is possible to separate patients with diabetes mellitus type 2 from healthy controls by multivariate analysis of exhaled endogenous VOCs. This is a first step towards the development of a noninvasive test using breath gas of at-risk persons and making it an attractive option for large-scale testing of at-risk populations. However, the establishment of exhaled volatiles as metabolic markers requires additional confirmatory investigations.

A Monte Carlo study of the radiation quality dependence of DNA fragmentation spectra.

We simulated the irradiation of human fibroblasts with gamma rays, protons and helium, carbon and iron ions at a fixed dose of 5 Gy. The simulations were performed with the biophysical Monte Carlo code PARTRAC. From the output of the code, containing in particular the genomic positions of the radiation-induced DNA double-strand breaks (DSBs), we obtained the DNA fragmentation spectra. Very small fragments, in particular those related to "complex lesions" (few tens of base pairs), are probably very important for the late cellular consequences, but their detection is not possible with the common experimental techniques. We paid special attention to the differences among the various ions in the production of these very small fragments; in particular, we compared the fragmentation spectra for ions of the same specific energy and for ions of the same LET (linear energy transfer). As found previously for iron ions, we found that the RBE (relative biological effectiveness) for DSB production was considerably higher than 1 for all high-LET radiations considered. This is at variance with the results obtainable from experimental data, and it is due to the ability to count the contribution of small fragments. It should be noted that for a given LET this RBE decreases with increasing ion charge, due mainly to the increasing mean energy of secondary electrons. A precise quantification of the DNA initial damage can be of great importance for both radiation protection, particularly in open-space long-term manned missions, and hadrontherapy.

DNA fragmentation induced in human fibroblasts by 56Fe ions: experimental data and Monte Carlo simulations.

We studied the DNA fragmentation induced in human fibroblasts by iron-ion beams of two different energies: 115 MeV/nucleon and 414 MeV/nucleon. Experimental data were obtained in the fragment size range 1-5700 kbp; Monte Carlo simulations were performed with the PARTRAC code; data analysis was also performed through the Generalized Broken Stick (GBS) model. The comparison between experimental and simulated data for the number of fragments produced in two different size ranges, 1-23 kbp and 23-5700 kbp, gives a satisfactory agreement for both radiation qualities. The Monte Carlo simulations also allow the counting of fragments outside the experimental range: The number of fragments smaller than 1 kbp is large for both beams, although with a strong difference between the two cases. As a consequence, we can compute different RBEs depending on the size range considered for the fragment counting. The PARTRAC evaluation takes into account fragments of all sizes, while the evaluation from the experimental data considers only the fragments in the range of 1-5700 kbp. When the PARTRAC evaluation is restricted to this range, the agreement between experimental and computed RBE values is again good. When fragments smaller than 1 kbp are also considered, the RBE increases considerably, since gamma rays produce a small number of such fragments. The analysis performed with the GBS model proved to be quite sensitive to showing, with a phenomenological single parameter, variations in double-strand break (DSB) correlation.

Measurements of secondary neutrons from cosmic radiation with a Bonner sphere spectrometer at 79 degrees N.

Air crew members and airline passengers are continuously exposed to cosmic radiation during their flights. Particles ejected by the sun during so-called solar particle events (SPEs) in periods of high solar activity can contribute to this exposure. In rare cases the dose from a single SPE might even exceed the annual dose limit of 1 mSv above which dose monitoring of air crews is legally required in Germany. Measurements performed by means of neutron monitors have already shown that the relative intensity of secondary neutrons from cosmic radiation is enhanced during an SPE, particularly at regions close to the magnetic poles of the Earth where shielding of the cosmic radiation by the geomagnetic field is low. Here we describe a Bonner sphere spectrometer installed at the Koldewey station at 79 degrees N, i.e. about 1,000 km from the geographic North pole, which is designed to provide first experimental data on the time-dependent energy spectrum of neutrons produced in the atmosphere during an SPE. This will be important to calculate doses from these neutrons to air crew members. The system is described in detail and first results are shown that were obtained during quiet periods of sun activity.

Promotion of initiated cells by radiation-induced cell inactivation.

Cells on the way to carcinogenesis can have a growth advantage relative to normal cells. It has been hypothesized that a radiation-induced growth advantage of these initiated cells might be induced by an increased cell replacement probability of initiated cells after inactivation of neighboring cells by radiation. Here Monte Carlo simulations extend this hypothesis for larger clones: The effective clonal expansion rate decreases with clone size. This effect is stronger for the two-dimensional than for the three-dimensional situation. The clones are irregular, far from a circular shape. An exposure-rate dependence of the effective clonal expansion rate could come in part from a minimal recovery time of the initiated cells for symmetric cell division.

Comparisons of calculations with PARTRAC and NOREC: transport of electrons in liquid water.

Monte Carlo computer models that simulate the detailed, event-by-event transport of electrons in liquid water are valuable for the interpretation and understanding of findings in radiation chemistry and radiation biology. Because of the paucity of experimental data, such efforts must rely on theoretical principles and considerable judgment in their development. Experimental verification of numerical input is possible to only a limited extent. Indirect support for model validity can be gained from a comparison of details between two independently developed computer codes as well as the observable results calculated with them. In this study, we compare the transport properties of electrons in liquid water using two such models, PARTRAC and NOREC. Both use interaction cross sections based on plane-wave Born approximations and a numerical parameterization of the complex dielectric response function for the liquid. The models are described and compared, and their similarities and differences are highlighted. Recent developments in the field are discussed and taken into account. The calculated stopping powers, W values, and slab penetration characteristics are in good agreement with one another and with other independent sources.

Promoting action of radiation in the atomic bomb survivor carcinogenesis data?

The age-time patterns of risk in the atomic bomb survivor data on incidence of solid cancers suggest an action of low-LET radiation not only on the initiating event but also on promotion in a biologically motivated model that allows for both actions. The favored model indicates a decrease of radiation risks with age at exposure due to the initiating effect and with time since exposure due to the promoting effect. These result in a relative risk that depends mostly on attained age for ages at exposure above 20 years. According to the model, a dose of 100 mGy is inducing about the same number of initiating events that occur spontaneously in 1 year. Assuming that several mutations are needed to obtain intermediate cells with growth advantage does not improve the quality of fit. The estimated promoting effect could be explained if the number of intermediate cells increases by 80% at 1 Gy, e.g. due to stimulated cell repopulation.

Measurement techniques for tracer kinetic studies with stable isotopes of zirconium.

Biokinetic models are used in radiation protection to assess internal radiation doses. Experiments with stable isotopes as tracers can be performed to obtain characteristic parameters of these models. Two methods for the measurement of zirconium isotopes in human biological samples are presented--thermal ionisation mass spectrometry (TIMS) and proton nuclear activation analysis (PNA). Descriptions include sample preparation, operating conditions, relative uncertainties and method detection limits as well as important properties of both methods.

Long-term measurements of cosmic ray neutrons by means of a Bonner spectrometer at mountain altitudes - first results.

A Bonner multi-sphere spectrometer has been installed in 2005 at the Environmental Research Station 'Schneefernerhaus' (2660 m above sea level) on the Zugspitze mountain, Germany, to measure the energy spectrum of cosmic-ray neutrons at high altitudes continuously. The system can be used to investigate small temporal variations in the cosmic radiation intensity. For example, measurements were done during periods of 2 Forbush decreases of the cosmic radiation intensity in July and September 2005, respectively. The results were compared with those obtained by using neutron monitors, and neutron fluence spectra measured during these events are presented and discussed.

Comparisons of 239Pu inhalation doses calculated with ICRP 67 and proposed systemic models.

The International Commission on Radiological Protection (ICRP) has issued an age-specific systemic biokinetic model for plutonium (Pu), which was later modified to give better agreement with measured urinary excretion data. Recently, the current ICRP systemic Pu model was improved by Leggett et al. based on recently developed data. Incorporation of 239Pu in the human body may result in significant internal radiation exposure. In the present work, the retentions in organs and tissues, the equivalent dose and effective dose from 239Pu for workers and members of the public were estimated and compared under the current ICRP and the proposed models. 239Pu contents in liver and in other soft tissue calculated with the proposed model are higher than predicted by the ICRP model, whereas bone content is lower than predicted by the ICRP model. Based on the proposed model, the inhalation equivalent dose coefficient in some organs, e.g. liver and kidneys, is increased, but there is no significant change in the effective inhalation dose coefficients of 239Pu for workers and members of the public.

Daily uranium excretion in German peacekeeping personnel serving on the Balkans compared to ICRP model prediction.

An investigation was performed to assess a possible health risk of depleted uranium (DU) for residents and German peacekeeping personnel serving on the Balkans. In order to evaluate a possible DU intake, the urinary uranium excretions of volunteers were collected and analysed using inductively coupled plasma mass spectrometry (ICP-MS). In total, more than 1300 urine samples from soldiers, civil servants and unexposed controls of different genders and ages were analysed to determine uranium excretion parameters. All participating volunteers, aged 3-92 y, were grouped according to their gender and age for evaluation. The results of the investigation revealed no significant difference between the unexposed controls and the peacekeeping personnel. In addition, the geometric means of the daily urinary excretion in peacekeeping personnel, ranging from 3 to 23 ng d(-1) for different age groups, fall toward the lower end of renal uranium excretion values published for unexposed populations in literature. The measured data were compared with the International Commission on Radiological Protection prediction for the intake of natural uranium by unexposed members of the public. The two data sets are in good agreement, indicating that no relevant intake of additional uranium, either natural or DU, has appeared for German peacekeeping personnel serving on the Balkans.

Measurements of daily urinary uranium excretion in German peacekeeping personnel and residents of the Kosovo region to assess potential intakes of depleted uranium (DU).

Following the end of the Kosovo conflict, in June 1999, a study was instigated to evaluate whether there was a cause for concern of health risk from depleted uranium (DU) to German peacekeeping personnel serving in the Balkans. In addition, the investigations were extended to residents of Kosovo and southern Serbia, who lived in areas where DU ammunitions were deployed. In order to assess a possible DU intake, both the urinary uranium excretion of volunteer residents and water samples were collected and analysed using inductively coupled plasma-mass spectrometry (ICP-MS). More than 1300 urine samples from peacekeeping personnel and unexposed controls of different genders and age were analysed to determine uranium excretion parameters. The urine measurements for 113 unexposed subjects revealed a daily uranium excretion rate with a geometric mean of 13.9 ng/d (geometric standard deviation (GSD)=2.17). The analysis of 1228 urine samples from the peacekeeping personnel resulted in a geometric mean of 12.8 ng/d (GSD=2.60). It follows that both unexposed controls and peacekeeping personnel excreted similar amounts of uranium. Inter-subject variation in uranium excretion was high and no significant age-specific differences were found. The second part of the study monitored 24 h urine samples provided by selected residents of Kosovo and adjacent regions of Serbia compared to controls from Munich, Germany. Total uranium and isotope ratios were measured in order to determine DU content. (235)U/(238)U ratios were within +/-0.3% of the natural value, and (236)U/(238)U was less than 2 x 10(-7), indicating no significant DU in any of the urine samples provided, despite total uranium excretion being relatively high in some cases. Measurements of ground and tap water samples from regions where DU munitions were deployed did not show any contamination with DU, except in one sample. It is concluded that both peacekeeping personnel and residents serving or living in the Balkans, respectively, were not exposed to significant amounts of DU.

Human exposure to space radiation: role of primary and secondary particles.

Human exposure to space radiation implies two kinds of risk, both stochastic and deterministic. Shielding optimisation therefore represents a crucial goal for long-term missions, especially in deep space. In this context, the use of radiation transport codes coupled with anthropomorphic phantoms allows to simulate typical radiation exposures for astronauts behind different shielding, and to calculate doses to different organs. In this work, the FLUKA Monte Carlo code and two phantoms, a mathematical model and a voxel model, were used, taking the Galactic Cosmic Rays (GCR) spectra from the model of Badhwar and O'Neill. The time integral spectral proton fluence of the August 1972 Solar Particle Event (SPE) was represented by an exponential function. For each aluminium shield thickness, besides total doses the contributions from primary and secondary particles for different organs and tissues were calculated separately. More specifically, organ-averaged absorbed doses, dose equivalents and a form of 'biological dose', defined on the basis of initial (clustered) DNA damage, were calculated. As expected, the SPE doses dramatically decreased with increasing shielding, and doses in internal organs were lower than in skin. The contribution of secondary particles to SPE doses was almost negligible; however it is of note that, at high shielding (10 g cm(-2)), most of the secondaries are neutrons. GCR organ doses remained roughly constant with increasing Al shielding. In contrast to SPE results, for the case of cosmic rays, secondary particles accounted for a significant fraction of the total dose.

Lung cancer risk in mice: analysis of fractionation effects and neutron RBE with a biologically motivated model.

Data from Argonne National Laboratory on lung cancer in 15,975 mice with acute and fractionated exposures to gamma rays and neutrons are analyzed with a biologically motivated model with two rate-limiting steps and clonal expansion. Fractionation effects and effects of radiation quality can be explained well by the estimated kinetic parameters. Both an initiating and a promoting action of neutrons and gamma rays are suggested. While for gamma rays the initiating event is described well with a linear dose-rate dependence, for neutrons a nonlinear term is needed, with less effectiveness at higher dose rates. For the initiating event, the neutron RBE compared to gamma rays is about 10 when the dose rate during each fraction is low. For higher dose rates this RBE decreases strongly. The estimated lifetime relative risk for radiation-induced lung cancers from 1 Gy of acute gamma-ray exposure at an age of 110 days is 1.27 for male mice and 1.53 for female mice. For doses less than 1 Gy, the effectiveness of fractionated exposure to gamma rays compared to acute exposure is between 0.4 and 0.7 in both sexes. For lifetime relative risk, the RBE from acute neutrons at low doses is estimated at about 10 relative to acute gamma-ray exposure. It decreases strongly with dose. For fractionated neutrons, it is lower, down to about 4 for male mice.

Role of DNA/chromatin organisation and scavenging capacity in USX- and proton- induced DNA damage.

DNA higher-order structures and (non-histonic) *;OH radical scavengers have well known protective effects in the induction of single- and double-strand breaks by ionising radiation. In a previous work, such protective roles have been quantified for gamma radiation (Valota et al., Int. J. Radiat. Biol. 79, 2003). As a starting base for the simulations, we used the PARTRAC Monte Carlo code, developed within a collaboration involving the University of Pavia and the GSF institute. The code can reproduce the track structure of photons, electrons, protons and heavier ions in liquid water, and it can simulate the DNA content of a human cell at different organisation levels, based on an atom-by-atom approach. In this work we extended the calculations to Ultra-Soft X rays (USX) and protons, separately analysing the effects of different radiation types on various DNA structures (i.e. linear DNA, SV40 'minichromosomes' and compact chromatin) as a function of the *OH scavenging capacity (SC). Both for USX and protons, the calculated damage yields decreased by increasing the SC for the three considered target types. Such decrease can be ascribed to the competition between the reactions *OH-DNA and *OH-scavenger, which becomes more and more likely by increasing the SC. Furthermore, linear DNA was found to be more radiosensitive than SV40 'minichromosomes', which in turn were more radiosensitive than compact chromatin, which is protected by histones. Comparisons with experimental data by Fulford et al. (Int. J. Radiat. Biol. 77, 2001) relative to USX irradiation showed very good agreement. The dependence of the modulating role played by DNA organisation and scavenging capacity on radiation quality is presented and discussed.

Bone cancer risk in mice exposed to 224Ra: protraction effects from promotion.

This paper analyzes data for the osteosarcoma incidence in life-time experiments of (224)Ra injected mice with respect to the importance of initiating and promoting action of ionizing high LET-radiation. This was done with the biologically motivated two step clonal expansion (TSCE) model of tumor induction. Experimentally derived osteosarcoma incidence in 1,194 mice following exposure to (224)Ra with different total radiation doses and different fractionation patterns were analyzed together with incidence data from 1,710 unirradiated control animals. Effects of radiation on the initiating event and on the clonal expansion rate, i.e. on promotion were found to be necessary to explain the observed patterns with this model. The data show a distinct inverse protraction effect at high doses, whereas at lower doses this effect becomes insignificant. Such a behavior is well reproduced in the proposed model: At dose rates above 6 mGy/day a longer exposure produces higher ERR per dose, while for lower rates the reverse is the case. The TSCE model permits the deduction of several kinetic parameters of a postulated two-step bone tumorigenesis process. Mean exposure rates of 0.13 mGy/day are found to double the baseline initiation rate. At rates above 100 mGy/day, the initiation rate decreases. The clonal expansion rate is doubled at 8 mGy/day, and it levels out at rates beyond 100 mGy/day.

The application of FLUKA to dosimetry and radiation therapy.

The FLUKA Monte Carlo code has been evolving over the last several decades and is now widely used for radiation shielding calculations. In order to facilitate the use of FLUKA in dosimetry and therapy applications, supporting software has been developed to allow the direct conversion of the output files from standard CT-scans directly into a voxel geometry for transport within FLUKA. Since the CT-scan information essentially contains only the electron density information over the scanned volume, one needs the specific compositions for each voxel individually. We present here the results of a simple algorithm to assign tissues in the human body to one of four categories: soft-tissue, hard-bone, trabecular-bone and porous-lung. In addition, we explore the problem of the pathlength distributions in porous media such as trabecular bone. A mechanism will be implemented within FLUKA to allow for variable multipal fixed density materials to accommodate the pathlength distributions discovered.

The ICRU (International Commission on Radiation Units and Measurements): its contribution to dosimetry in diagnostic and interventional radiology.

The ICRU (International Commission on Radiation Units and Measurements was created to develop a coherent system of quantities and units, universally accepted in all fields where ionizing radiation is used. Although the accuracy of dose or kerma may be low for most radiological applications, the quantity which is measured must be clearly specified. Radiological dosimetry instruments are generally calibrated free-in-air in terms of air kerma. However, to estimate the probability of harm at low dose, the mean absorbed dose for organs is used. In contrast, at high doses, the likelihood of harm is related to the absorbed dose at the site receiving the highest dose. Therefore, to assess the risk of deterministic and stochastic effects, a detailed knowledge of absorbed dose distribution, organ doses, patient age and gender is required. For interventional radiology, where the avoidance of deterministic effects becomes important, dose conversion coefficients are generally not yet developed.