Monte Carlo simulation of the spatial distribution of energy deposition for an electron microbeam.

Dosimetry calculations characterizing the spatial variation of the energy deposited by the slowing and stopping of energetic electrons are reported and compared with experimental measurements from an electron microbeam facility. The computations involve event-by-event, detailed-histories Monte Carlo simulations of low-energy electrons interacting in water vapor. Simulations of electron tracks with starting energies from 30 to 80 keV are used to determine energy deposition distributions in thin cylindrical rings as a function of penetration and radial distance from a beam source. Experimental measurements of the spatial distribution of an electron microbeam in air show general agreement with the density-scaled simulation results for water vapor at these energies, yielding increased confidence in the predictions of Monte Carlo track-structure simulations for applications of the microbeam as a single-cell irradiator.

Microdosimetry of electron microbeams.

Track structures of 25, 50 and 80 keV primary electrons, simulated by the detailed-history Monte Carlo method, were analyzed for the frequency distributions of energy deposited in spheres with a diameter of 1 microm, placed in a cylindrically symmetrical array around the projected initial direction of the primary electron. The frequency mean of specific energy, the dose mean of lineal energy, and the parameters of lognormal functions fit to the dose distributions were calculated as a function of beam penetration and radial distance from the projected beam axis. Given these data, the stochastics of dose and radiation quality for micrometer-scale sites targeted by a medium-energy electron microbeam can be predicted as a function of the site's location relative to the beam entry point.

Analysis of low-energy electron track structure in liquid water.

An implementation is presented of interaction cross sections for non-relativistic electron track structure simulations. The model, incorporating liquid-phase cross sections for inelastic interactions and improved algorithms for elastic scattering, is applied to Monte Carlo simulation of the track structure of low-energy electrons. Benchmark distributions and mean values are presented for several measures of penetration distances that characterize the general physical extent of the track structure. The results indicate that, except for the last approximately 500 eV of energy loss, electron tracks have a quasi-linear character; this suggests that a major part of an electron track may be reasonably described by a lineal-energy-like characterization.

Monitoring of particulate matter outdoors.

Recent studies of the size and composition of atmospheric particulate matter (PM) have demonstrated the usefulness of separating atmospheric PM into its fine and coarse components. The need to measure the mass and composition of fine and coarse PM separately has been emphasized by research in exposure, epidemiology, and toxicology of atmospheric PM. This paper provides a background on the size distribution and properties of PM relevant to the differences between fine and coarse particles. Various decisions that must be made when deciding how to separate, collect, and measure PM are discussed. Techniques for monitoring fine and coarse particles, including the US Federal Reference Method for PM2.5 and several techniques for PM10-2.5, are presented. Problems encountered in collecting semivolatile PM and in weighing atmospheric PM collected on a filter are described. Continuous monitoring methods for PM mass and for PM components (carbon, nitrate, and sulfate) are described and brief descriptions are given of analytical techniques for the chemical characterization of collected PM. This information should be especially useful for environmental workers familiar with monitoring methods for total suspended particles or PM10 but who will need to measure PM2, and PM10-2.5 in the future.

Microdosimetric properties of ionizing electrons in water: a test of the PENELOPE code system.

The ability to simulate the tortuous path of very low-energy electrons in condensed matter is important for a variety of applications in radiobiology. Event-by-event Monte Carlo codes such as OREC, MOCA and PITS represent the preferred method of computing distributions of microdosimetric quantities. However, event-by-event Monte Carlo is computationally expensive, and the cross sections needed to transport simulations to this level of detail are usually only available for water. In the recently developed PENELOPE code system, 'hard' electron and positron interactions are simulated in a detailed way while soft' interactions are treated using multiple scattering theory. Using this mixed simulation algorithm, electrons and positrons can be transported down to energies as low as 100 eV. To our knowledge, PENELOPE is the first widely available, general purpose Monte Carlo code system capable of transporting electrons and positrons in arbitrary media down to such low energies. The ability to transport electrons and positrons to such low energies opens up the possibility of using a general purpose Monte Carlo code system for microdosimetry. This paper presents the results of a code intercomparison study designed to test the applicability of the PENELOPE code system for microdosimetry applications. For sites comparable in size to a mammalian cell or cell nucleus, single-event distributions, site-hit probabilities and the frequency-mean specific energy per event are in reasonable agreement with those predicted using event-by-event Monte Carlo. Site-hit probabilities and the mean specific energy per event can be estimated to within about 1-10% of those predicted using event-by-event Monte Carlo. However, for some combinations of site size and source-target geometry, site-hit probabilities and the mean specific energy per event may only agree to within 25-60%. The most problematic source-target geometry is one in which the emitted electrons are very close to the tally site (e.g., a point source on the surface of a cell). Although event-by-event Monte Carlo will continue to be the method of choice for microdosimetry, PENELOPE is a useful, computationally efficient tool for some classes of microdosimetry problem. PENELOPE may prove particularly useful for applications that involve radiation transport through materials other than water or for applications that are too computationally intensive for event-by-event Monte Carlo, such as in vivo microdosimetry of spatially complex distributions of radioisotopes inside the human body.

Long-term ambient air pollution levels in four Chinese cities: inter-city and intra-city concentration gradients for epidemiological studies.

The field data collection of an air pollution epidemiologic study was carried out from 1993 to 1996 in four Chinese cities of Lanzhou, Chongqing, Wuhan, and Guangzhou. In each city, an urban district and a suburban district were selected. Ambient concentrations of total suspended particles (TSP), size-fractionated particulate matter including PM2.5, PM2.5-10, and PM10, sulfur dioxide (SO2), and oxides of nitrogen (NOx) were measured in these districts. The results indicate the presence of wide inter-city and intra-city gradients in long-term ambient levels of these measured pollutants. Across the eight districts, the 1993-1996 4-year means of TSP, SO2, and NOx ranged from 198 to 659 microg/m3, from 14.6 to 331 microg/m3, and from 31.5 to 239 microg/m3, respectively, and the 1995-1996 2-year means of PM2.5, PM2.5-10, and PM10 ranged from 51.5 to 142 microg/m3, from 29.2 to 107 microg/m3, and from 80.7 to 232 microg/m3, respectively. These pollution ranges substantially extended the upper end of the pollution ranges of previous air pollution epidemiologic studies conducted in North America and Europe. In each district, significant correlations among the measured pollutants were observed for daily concentrations. However, the gradient patterns in long-term means of different pollutants were different across the eight districts. (e.g., PM2.5-10 and TSP were highest in the Lanzhou urban district, PM2.5 and PM10 were highest in the Guangzhou urban district, SO2 was highest in the Chongqing urban district, and NOx was highest in the Guangzhou urban district). In general, seasonal variations were present in the ambient concentrations with high levels often occurring in winter months. The eight districts may be classified into four district clusters based on integrated levels of all measured pollutants. These features of the ambient air pollution have important implications for epidemiological studies and may provide unique opportunities to study exposure-effects relationships in the four Chinese cities.

Computational approach for determining the spectrum of DNA damage induced by ionizing radiation.

To study the characteristics of molecular damage induced by ionizing radiation at the DNA level, Monte Carlo track simulation of energetic electrons and ions in liquid water, a canonical model of B-DNA, and a comprehensive classification of DNA damage in terms of the origin and complexity of damage were used to calculate the frequencies of simple and complex strand breaks. A threshold energy of 17.5 eV was used to model the damage by direct energy deposition, and a probability of 0.13 was applied to model the induction of a single-strand break produced in DNA by OH radical reactions. For preliminary estimates, base damage was assumed to be induced by the same direct energy threshold deposition or by the reaction of an OH radical with the base, with a probability of 0.8. Computational data are given on the complexity of damage, including base damage by electrons with energies of 100-4500 eV and ions with energies of 0.3-4.0 MeV/nucleon (59-9 keV microm(-1) protons and 170-55 keV microm(-1) alpha particles). Computational data are presented on the frequencies of single- and double-strand breaks induced as a function of the LET of the particles, and on the relative frequencies of complex single- and double-strand breaks for electrons. The modeling and calculations of strand breaks show that: (1) The yield of strand breaks per unit absorbed dose is nearly constant over a wide range of LET. (2) The majority of DNA damage is of a simple type, but the majority of the simple single-strand breaks are accompanied by at least one base damage. (3) For low-energy electrons, nearly 20-30% of the double-strand breaks are of a complex type by virtue of additional breaks. The proportion of this locally clustered damage increases with LET, reaching about 70% for the highest-LET alpha particles modeled, with the complexity of damage increasing further, to about 90%, when base damage is considered. (4) The extent of damage in the local hit region of the DNA duplex is mostly limited to a length of a few base pairs. (5) The frequency of base damage when no strand breaks are present in the hit segment of DNA varies between 20-40% as a function of LET for protons and alpha particles.

Semi-volatile species in PM2.5: comparison of integrated and continuous samplers for PM2.5 research or monitoring.

Fine particles in urban atmospheres contain substantial quantities of semi-volatile material [e.g., NH4NO3 and semi-volatile organic compounds (SVOCs)] that are lost from particles during collection on a filter. Several diffusion denuder samplers have been developed for the determination of both NO3- and organic semi-volatile fine particulate components. The combination of technology used in the BOSS diffusion denuder sampler and the Harvard particle concentrator has resulted in the Particle Concentrator-Brigham Young University Organic Sampling System (PC-BOSS) for the 24-hr (or less) integrated collection of PM2.5, including NH4NO3 and semi-volatile organic material. Modification of the BOSS sampler allows for the weekly determination of these same species. Combination of BOSS denuder and tapered element oscillating microbalance (TEOM) monitor technology has resulted in the real-time ambient mass sampler (RAMS) for the continuous measurement of PM2.5, including the semi-volatile components. Comparison of the results obtained with the BOSS and with each of the newly developed modifications of the BOSS indicates that the modified versions can be used for the continuous, daily, or weekly monitoring of PM2.5, including semi-volatile species, as appropriate to the design of each sampler.

Microdosimetry of a 25 keV electron microbeam.

Electron microbeam experiments are planned or under way to explore in part the question regarding whether the bystander effect is a general phenomenon or is restricted to high-LET radiation. Since low-LET radiations scatter more readily compared to high-LET radiations, identifying bystander cells and assessing the potential dose that they may receive will be crucial to the interpretation of radiobiological results. This paper reports on initial calculations of the basic information needed for a stochastic model of the penetration of energetic electrons in tissue-like matter; the model will be used to predict doses delivered to adjacent regions in which bystander cells may reside. Results are presented of calculations of the stochastics of energy deposition by 25 keV electrons slowing down in a homogeneous water medium. Energy deposition distributions were scored for 1-micrometer spheres located at various penetration and radial distances up to 10 micrometer from the point of origin. The energy of 25 keV was selected because experiments are planned for that energy. At 25 keV there is a high probability that the entire electron track will be contained within a typical mammalian cell. Individual tracks are scored because of their primacy; data for higher doses can be obtained by convoluting single-track distributions. The event frequency decreases approximately exponentially after the first micrometer to 1% at about 8 micrometer of penetration. Radially, the 1% contour extends to 3.5 micrometer at a penetration of 5.5 micrometer. The frequency-mean energy deposited decreases from 1.5 to 1 keV/micrometer at a penetration of 3.5 micrometer, then increases back to about 1.5 at a penetration of 6.5 micrometer. The mean energy increases to about 3 keV/micrometer at a radial distance of 8.5 micrometer.

Requirements for autoimmune responses to mouse gastric autoantigens.

Autoimmune gastritis, in which the H+/K(+)-ATPase of parietal cells is the major antigen, is one of the most common autoimmune diseases. Here we examined if specific properties of the H+/K(+)-ATPase or parietal cells are involved in rendering them autoimmune targets. The model antigens beta-galactosidase and ovalbumin (OVA) were expressed in parietal cells of transgenic mice. On experimental induction of autoimmune gastritis by neonatal thymectomy, autoantibodies to beta-galactosidase developed in mice expressing beta-galactosidase in parietal cells, a response that was independent of either the response to the gastric H+/K(+)-ATPase or gastric inflammation. In contrast, mice that expressed OVA in parietal cells did not exhibit an antibody response to OVA after thymectomy. However, increasing the frequency of anti-OVA T lymphocytes in OVA-expressing mice resulted in autoantibodies to OVA and gastritis. These studies indicate that parietal cells can present a variety of antigens to the immune system. Factors such as the identity and expression level of the autoantigen and the frequency of autoreactive T cells play a role in determining the prevalence and outcome of the particular immune response. In addition, as not all mice of a particular genotype displayed autoimmunity, random events are involved in determining the target of autoimmune recognition.

Monte Carlo track structure for radiation biology and space applications.

Over the past two decades event by event Monte Carlo track structure codes have increasingly been used for biophysical modelling and radiotherapy. Advent of these codes has helped to shed light on many aspects of microdosimetry and mechanism of damage by ionising radiation in the cell. These codes have continuously been modified to include new improved cross sections and computational techniques. This paper provides a summary of input data for ionizations, excitations and elastic scattering cross sections for event by event Monte Carlo track structure simulations for electrons and ions in the form of parametric equations, which makes it easy to reproduce the data. Stopping power and radial distribution of dose are presented for ions and compared with experimental data. A model is described for simulation of full slowing down of proton tracks in water in the range 1 keV to 1 MeV. Modelling and calculations are presented for the response of a TEPC proportional counter irradiated with 5 MeV alpha-particles. Distributions are presented for the wall and wall-less counters. Data shows contribution of indirect effects to the lineal energy distribution for the wall counters responses even at such a low ion energy.

Identification of the Gasa3 and Gasa4 autoimmune gastritis susceptibility genes using congenic mice and partitioned, segregative and interaction analyses.

BALB/c mice thymectomized on their third day of life develop a high incidence of experimental autoimmune gastritis (EAG) which closely resembles human chronic atrophic (type A, autoimmune) gastritis. Linkage analysis of (BALB/cCrSlcxC57BL/6)F2 mice previously demonstrated that the Gasa1 and Gasa2 genes on distal Chromosome (Chr) 4 have major effects on the development of EAG in this murine model, while other loci displayed a trend towards linkage. Here, we implemented partitioned chi(2)-analysis in order to develop a better understanding of the genotypes contributing to susceptibility and resistance at each linkage region. This approach revealed that linkage of Gasa1 and Gasa2 to EAG was due to codominant and recessive BALB/cCrSlc alleles, respectively. To identify additional EAG susceptibility genes, separate linkage studies were performed on Gasa1 heterozygotes and Gasa2 C57BL/6 homozygotes plus heterozygotes so as to minimize the effects of these disease genes. The enhanced sensitivity of these analyses confirmed the existence of a third EAG susceptibility gene (designated Gasa3) on Chr 6. Epistatic interactions between the Gasa2 EAG susceptibility gene and the H2 were also identified, and the presence of an H2-linked susceptibility gene (Gasa4) confirmed by analysis of H2 congenic mice.

Monte Carlo simulation of single-cell irradiation by an electron microbeam.

A model is presented for irradiation of a cellular monolayer by an electron microbeam. Results are presented for two possible window designs, cells plated on the vacuum-isolation window and cells plated on Mylar above the vacuum-isolation window. Even for the thicker dual-membrane window that facilitates tissue culture and allows the target cell to be centered relative to the electron beam, the majority of the calculated beam spreading was contained in a volume typical of the mammalian HeLa cell line. None of the 10(4) electrons simulated at 25 keV were scattered into the spatial region occupied by neighbors of the target cell. Dose leakage was largest at 50 keV where the mean energy deposited in all neighbors was 21% of that deposited in the target cell. This ratio was reduced to 5% at 90 keV, the highest beam energy simulated. Lineal energy spectra of energy deposition events scored in the nucleus of the target cell became progressively more like the gamma-ray spectrum as the electron beam energy increased. Hence, our simulations provide strong support for the feasibility of a low-LET, single-cell irradiator.

Estimating separately personal exposure to ambient and nonambient particulate matter for epidemiology and risk assessment: why and how.

This paper discusses the legal and scientific reasons for separating personal exposure to PM into ambient and nonambient components. It then demonstrates by several examples how well-established models and data typically obtained in exposure field studies can be used to estimate both individual and community average exposure to ambient-generated PM (ambient PM outdoors plus ambient PM that has infiltrated indoors), indoor-generated PM, and personal activity PM. Ambient concentrations are not highly correlated with personal exposure to nonambient PM or total PM but are highly correlated with personal exposure to ambient-generated PM. Therefore, ambient concentrations may be used in epidemiology as an appropriate surrogate for personal exposure to ambient-generated PM. Suggestions are offered as to how exposure to ambient-generated PM may be obtained and used in epidemiology and risk assessment.

A Monte Carlo code for positive ion track simulation.

An ion interaction model has been described for simulating positive ion tracks in a variety of media with the capability of interfacing with several secondary electron transport codes. Data are presented for single-and double-differential cross-sections, binding energies, probability density distribution for delocalisation parameters for conductors and tissue, branching ratios and ionisation efficiencies for water vapour and liquid water.

Track structure in radiation biology: theory and applications.

PURPOSE: A brief review is presented of the basic concepts in track structure and the relative merit of various theoretical approaches adopted in Monte-Carlo track-structure codes are examined. In the second part of the paper, a formal cluster analysis is introduced to calculate cluster-distance distributions. METHOD: Total experimental ionization cross-sections were least-square fitted and compared with the calculation by various theoretical methods. Monte-Carlo track-structure code Kurbuc was used to examine and compare the spectrum of the secondary electrons generated by using functions given by Born-Bethe, Jain-Khare, Gryzinsky, Kim-Rudd, Mott and Vriens' theories. The cluster analysis in track structure was carried out using the k-means method and Hartigan algorithm. RESULTS: Data are presented on experimental and calculated total ionization cross-sections: inverse mean free path (IMFP) as a function of electron energy used in Monte-Carlo track-structure codes; the spectrum of secondary electrons generated by different functions for 500 eV primary electrons; cluster analysis for 4 MeV and 20 MeV alpha-particles in terms of the frequency of total cluster energy to the root-mean-square (rms) radius of the cluster and differential distance distributions for a pair of clusters; and finally relative frequency distribution for energy deposited in DNA, single-strand break and double-strand breaks for 10MeV/u protons, alpha-particles and carbon ions. CONCLUSIONS: There are a number of Monte-Carlo track-structure codes that have been developed independently and the bench-marking presented in this paper allows a better choice of the theoretical method adopted in a track-structure code to be made. A systematic bench-marking of cross-sections and spectra of the secondary electrons shows differences between the codes at atomic level, but such differences are not significant in biophysical modelling at the macromolecular level. Clustered-damage evaluation shows: that a substantial proportion of dose ( 30%) is deposited by low-energy electrons; the majority of DNA damage lesions are of simple type; the complexity of damage increases with increased LET, while the total yield of strand breaks remains constant; and at high LET values nearly 70% of all double-strand breaks are of complex type.

Fine particles and coarse particles: concentration relationships relevant to epidemiologic studies.

Fine particles and coarse particles are defined in terms of the modal structure of particle size distributions typically observed in the atmosphere. Differences between the various modes are discussed. The fractions of fine and coarse particles collected in specific size ranges, such as total suspended particulate matter (TSP), PM10, PM2.5, and PM(10-2.5), are shown. Correlations of 24-h concentrations of PM2.5, PM10, and PM(10-2.5) at the same site show that, in Philadelphia and St. Louis, PM2.5 is highly correlated with PM10 but poorly correlated with PM (10-2.5). Among sites distributed across these urban areas, the site-to-site correlations of 24-h PM concentrations are high for PM2.5 but not for PM(10-2.5). This indicates that a PM measurement at a central monitor can serve as a better indicator of the community-wide concentration of fine particles than of coarse particles. The fraction of ambient outdoor particles found suspended indoors is greater for fine particles than for coarse particles because of the difference in indoor lifetimes. Consideration of these relationships leads to the hypothesis that the statistical associations found between daily PM indicators and health outcomes may be the result of variations in the fine particle component of the atmospheric aerosol, not of variations in the coarse component. As a result, epidemiologic studies using PM10 or TSP may provide more useful information on the acute health effects of fine particles than coarse particles. Fine and coarse particles are separate classes of pollutants and should be measured separately in research and epidemiologic studies. PM2.5 and PM(10-2.5) are indicators or surrogates, but not measurements, of fine and coarse particles.

The quality of DNA double-strand breaks: a Monte Carlo simulation of the end-structure of strand breaks produced by protons and alpha particles.

The quality of DNA damage induced by protons and alpha-particles of various linear energy transfer (LET) was studied. The aim was to single out specific lesions in the DNA molecule that might lead to biological endpoints such as inactivation. A DNA model coupled with a track structure code (MOCA-15) were used to simulate the lesions induced on the two helixes. Four categories of DNA breaks were considered: single-strand breaks (ssb), blunt-ended double-strand breaks (dsb, with no or few overlapping bases), sticky-ended double-strand breaks (with cohesive free ends of many bases), and deletions (complex lesions which involve at least two dsb within a small number of base pairs). Calculations were carried out assuming various sets of parameters characterizing the production of these different DNA breaks. No large variations in the yields of ssb and blunt- or sticky-ended dsb were found in the LET range between 10 and 200 keV/mu m. On the other hand, the yield of deletions increases up to about 100 keV/mu m and seems to reach a plateau at higher LET values. In the LET interval from 30 to 60 keV/mu m, protons proved to be more efficient than alpha-particles in inducing deletions. The induction of these complex lesions is thus dependent not simply on LET but also on the characteristics of the track structure. Comparison with RBE values for cell killing shows that this special class of dsb might play an important role in radiation-induced cell inactivation.

Randomized phase II comparison of standard CHOP with weekly CHOP in elderly patients with non-Hodgkin's lymphoma.

PURPOSE: To determine whether modifying the standard regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) from full doses given every 3 weeks to one-third doses given weekly (chop) increases the received chemotherapy dose-intensity in elderly patients with advanced-stage intermediate-grade lymphoma. PATIENTS AND METHODS: Consenting patients, age > or = 65 years who had acceptable cardiac, renal, and liver function and an Eastern Cooperative Oncology Group (ECOG) performance status less than 4, were stratified by bone marrow and performance status and randomized to receive standard CHOP or weekly chop. Drug doses were attenuated or escalated according to a defined dose-modification schedule. The primary outcome was average relative received dose-intensity. Secondary outcomes included response, progression-free and overall survival, toxicity, and performance status. RESULTS: Nineteen patients were allocated to each group. No difference in received dose-intensity was seen. When dose-intensity was calculated for the first six cycles of therapy, average relative received dose-intensity was .92 with CHOP versus .89 with weekly chop (P = .5); when calculated for the first 18 weeks of therapy, values were .88 with CHOP versus .89 with weekly chop (P = .8). The complete response rate was 68% with CHOP versus 74% with weekly chop (P = .9). At 2 years, the progression-free survival rate was 57% with CHOP versus 46% with weekly chop (P = .16) and the survival rate was 74% with CHOP versus 51% with weekly chop (p = .05). More myelotoxicity was seen with CHOP. CONCLUSION: We conclude that CHOP can be given in sufficient doses to elderly patients and that weekly chop does not increase received dose-intensity. Progression-free and overall survival are unlikely to be superior with weekly chop, and may be worse. CHOP should remain the standard against which new therapies for elderly patients with intermediate-grade lymphoma are compared.