Interaction of alpha particles at the cellular level--implications for the radiation weighting factor

Since low dose effects of alpha particles are produced by cellular hits in a relatively small fraction of exposed cells, the present study focuses on alpha particle interactions in bronchial epithelial cells following exposure to inhaled radon progeny. A computer code was developed for the calculation of microdosimetric spectra, dose and hit probabilities for alpha particles emitted from uniform and non-uniform source distributions in cylindrical and Y-shaped bronchial airway geometries. Activity accumulations at the dividing spur of bronchial airway bifurcations produce hot spots of cellular hits, indicating that a small fraction of cells located at such sites may receive substantially higher doses. While presently available data on in vitro transformation frequencies suggest that the relative biological effectiveness for alpha particles ranges from about 3 to 10, the effect of inhomogeneous activity distributions of radon progeny may slightly increase the radiation weighting factor relative to a uniform distribution. Thus a radiation weighting factor of about 10 may be more realistic than the current value of 20, at least for lung cancer risk following inhalation of short-lived radon progeny.     

Microdosimetry of inhomogeneous radon progeny distributions in bronchial airways

A Monte Carlo code, initially developed for the calculation of microdosimetric spectra for alpha particles in cylindrical airways, has been extended to allow the computation (i) of additional microdosimetric parameters and (ii) for realistic exposure conditions in human bronchial airways with respect to surface activity distribution and airway geometry. The objective of the present study was to investigate the effects of non-uniform distributions of radon progeny activities in bronchial airways on cellular energy deposition parameters. Significant variations of hit frequencies, doses and microscopic energy deposition patterns were observed for epithelial cell nuclei, depending strongly on the assumed activity distributions. Thus, epithelial cells located at different positions in a given bronchial airway may experience a wide range of biological responses. The results obtained suggest that the hit frequency may be the primary physical parameter for alpha particles, supplemented by microdosimetric single event spectra, to be related to biological effects for chronic low level exposures.     

Microdosimetry of radon progeny alpha particles in bronchial airway bifurcations

A Monte Carlo code, initially developed for the calculation of microdosimetric spectra for alpha particles in cylindrical airways, has been extended to allow the computation of microdosimetric parameters for multiple source-target configurations in bronchial airway bifurcations. The objective of the present study was to investigate the effects of uniform and non-uniform radon progeny surface activity distributions in symmetric and asymmetric bronchial airway bifurcations on absorbed dose, hit frequency, lineal energy, single hit specific energy and LET spectra. In order to assess the effects of multiple hits, dose-dependent specific energy spectra were calculated by solving the compound Poisson process by iterative convolution. While the simulations showed significant differences of cellular dose quantities at different cell locations for uniformly distributed surface activities, even higher variations, as high as several orders of magnitude, were observed for non-uniform surface activity distributions, depending on the location of the cell and the local activity distribution.     

Modelling the effect of non-uniform radon progeny activities on transformation frequencies in human bronchial airways

The effects of radiological and morphological source heterogeneities in straight and Y-shaped bronchial airways on hit frequencies and microdosimetric quantities in epithelial cells have been investigated previously. The goal of the present study is to relate these physical quantities to transformation frequencies in sensitive target cells and to radon-induced lung cancer risk. Based on an effect-specific track length model, computed linear energy transfer (LET) spectra were converted to corresponding transformation frequencies for different activity distributions and source-target configurations. Average transformation probabilities were considerably enhanced for radon progeny accumulations and target cells at the carinal ridge, relative to uniform activity distributions and target cells located along the curved and straight airway portions at the same exposure level. Although uncorrelated transformation probabilities produce a linear dose-effect relationship, correlated transformations first increase depending on the LET, but then decrease significantly when exceeding a defined number of hits or cumulative exposure level.     

Radon lung dosimetry models

Two different modelling approaches are currently used to calculate short-lived radon progeny doses to the lungs: the semi-empirical compartment model proposed by the International Commission on Radiological Protection and deterministic and stochastic airway generation models. The stochastic generation model IDEAL-DOSE simulates lung morphometry, transport, deposition and clearance of inhaled radionuclides, and cellular dosimetry by Monte Carlo methods. Specific dosimetric issues addressed in this paper are: (1) distributions of bronchial doses among and within bronchial airway generations; (2) relative contributions of radon progeny directly deposited in a given airway generation and those passing through from downstream generations to the bronchial dose in that generation; (3) distribution of bronchial doses among the five lobes of the human lung; (4) inhomogeneity of surface activities and resulting doses within bronchial airway bifurcations; (5) comparison of bronchial doses between non-smokers and smokers; (6) relative contributions of sensitive target cells in bronchial epithelium to lung cancer induction and (7) intra- and intersubject variations of bronchial doses.     

Killing of target cells due to radon progeny in the human lung

The dose conversion coefficient (DCC) is used to assess the risk due to inhaled radon progeny in the human lung. The present work uses the microdosimetric approach and determines the linear energy transfer in the target cell nuclei. Killing of target cells was also taken into account through an effect-specific track length model. To focus on the relevant part of the absorbed dose in the cell nuclei, the absorbed dose, which causes cell-killing is discarded in the final calculations of the DCC. Following this approach, the calculated DCC has become 3.4 mSv WLM(-1) which is very close to the epidemiologically derived value of approximately 4 mSv WLM(-1).     

Monte Carlo code for microdosimetry of inhaled alpha emitters

A Monte Carlo code has been developed to calculate the local energy deposited by alpha emitters deposited on the inner surface in the lung airway. Developed to deal further with airway bifurcations, this code has been as a first step validated in a cylindrical airway configuration by comparison with well-established analytical codes in the case of contamination of bronchiolar airways with actinides. The code has then been applied to the study of uniform and non-uniform contamination of cylindrical bronchial airways by radon progeny in indoor and mine exposure conditions. In addition to the microdosimetric spectra, the average microdosimetric parameters (zp, n, z) have been evaluated. The work currently in progress consists in adapting this developed Monte Carlo code to the configuration of an airway bifurcation with realistic particles deposition.     

Incorporation of microdosimetric concepts into a biologically-based model of radiation carcinogenesis

The generalised state-vector model of radiation carcinogenesis (SVM) simulates radiation induced biological effects by expressing the transition rates between the various initiation and promotion stages in terms of dose rate for low and high linear energy transfer (LET) particles. In the present work, the SVM has been reformulated to incorporate single track characteristics of particles with varying LET. Transition rates of the initiation phase were expressed as functions of LET by describing the complexity and clustering of DNA double strand breaks (DSBs) and its effect on repair kinetics, while the promotion phase was reformulated based on a multi-target single-hit hypothesis. Such an approach allows the consideration of hit frequencies and the variability of the specific energy and LET spectra of radon progeny alpha particles in bronchial target cells for different exposure conditions.     

Prediction of lung cancer risk for radon exposures based on cellular alpha particle hits

To explore the role of the multiplicity of cellular hits by radon progeny alpha particles for lung cancer incidence, the number of single and multiple alpha particle hits were computed for basal and secretory cells in the bronchial epithelium of human airway bifurcations. Hot spots of alpha particle hits were observed at the branching points of bronchial airway bifurcations. The effect of single and multiple alpha particle intersections of bronchial cells during a given exposure period, selected from a Poisson distribution, on lung cancer risk were simulated by a transformation frequency--tissue response model, based on experimentally observed cellular transformation and survival functions. Calculations of lung cancer risk at low radon exposure levels suggest that single hits produce a linear-dose response relationship, while the superposition of single and increasing multiple hits at higher exposure levels may also be approximated by a quasi-linear dose-effect curve. The simulations predict a carcinogenic enhancement effect for radon progeny accumulations at bifurcation branching sites, which may increase current risk estimates.     

Effect of inhomogeneous activity distributions and airway geometry on cellular doses in radon lung dosimetry

The human tracheobronchial system has a very complex structure including cylindrical airway ducts connected by airway bifurcation units. The deposition of the inhaled aerosols within the airways exhibits a very inhomogeneous pattern. The formation of deposition hot spots near the carinal ridge has been confirmed by experimental and computational fluid and particle dynamics (CFPD) methods. In spite of these observations, current radon lung dosimetry models apply infinitely long cylinders as models of the airway system and assume uniform deposition of the inhaled radon progenies along the airway walls. The aim of this study is to investigate the effect of airway geometry and non-uniform activity distributions within bronchial bifurcations on cellular dose distributions. In order to answer these questions, the nuclear doses of the bronchial epithelium were calculated in three different irradiation situations. (1) First, CFPD methods were applied to calculate the distribution of the deposited alpha-emitting nuclides in a numerically constructed idealised airway bifurcation. (2) Second, the deposited radionuclides were randomly distributed along the surface of the above-mentioned geometry. (3) Finally, calculations were made in cylindrical geometries corresponding to the parent and daughter branches of the bifurcation geometry assuming random nuclide activity distribution. In all three models, the same 218Po and 214Po surface activities per tissue volumes were assumed. Two conclusions can be drawn from this analysis: (i) average nuclear doses are very similar in all three cases (minor differences can be attributed to differences in the linear energy transfer (LET) spectra) and (ii) dose distributions are significantly different in all three cases, with the highest doses at the carinal ridge in case 3.     

Dosimetric calculations for uranium miners for epidemiological studies

Epidemiological studies on uranium miners are being carried out to quantify the risk of cancer based on organ dose calculations. Mathematical models have been applied to calculate the annual absorbed doses to regions of the lung, red bone marrow, liver, kidney and stomach for each individual miner arising from exposure to radon gas, radon progeny and long-lived radionuclides (LLR) present in the uranium ore dust and to external gamma radiation. The methodology and dosimetric models used to calculate these organ doses are described and the resulting doses for unit exposure to each source (radon gas, radon progeny and LLR) are presented. The results of dosimetric calculations for a typical German miner are also given. For this miner, the absorbed dose to the central regions of the lung is dominated by the dose arising from exposure to radon progeny, whereas the absorbed dose to the red bone marrow is dominated by the external gamma dose. The uncertainties in the absorbed dose to regions of the lung arising from unit exposure to radon progeny are also discussed. These dose estimates are being used in epidemiological studies of cancer in uranium miners.     

Performance of the first Japanese large-scale facility for radon inhalation experiments with small animals

A radon test facility for small animals was developed in order to increase the statistical validity of differences of the biological response in various radon environments. This paper illustrates the performances of that facility, the first large-scale facility of its kind in Japan. The facility has a capability to conduct approximately 150 mouse-scale tests at the same time. The apparatus for exposing small animals to radon has six animal chamber groups with five independent cages each. Different radon concentrations in each animal chamber group are available. Because the first target of this study is to examine the in vivo behaviour of radon and its effects, the major functions to control radon and to eliminate thoron were examined experimentally. Additionally, radon progeny concentrations and their particle size distributions in the cages were also examined experimentally to be considered in future projects.     

Lung dosimetry for inhaled long-lived radionuclides and radon progeny

The current version of the stochastic lung dosimetry model IDEAL-DOSE considers deposition in the whole tracheobronchial (TB) and alveolar airway system, while clearance is restricted to TB airways. For the investigation of doses produced by inhaled long-lived radionuclides (LLR) together with short-lived radon progeny, alveolar clearance has to be considered. Thus, present dose calculations are based on the average transport rates proposed for the revision of the ICRP human respiratory tract model. The results obtained indicate that LLR cleared from the alveolar region can deliver up to two to six times higher doses to the TB region when compared with the doses from directly deposited particles. Comparison of LLR doses with those of short-lived radon progeny indicates that LLR in uranium mines can deliver up to 5 % of the doses predicted for the short-lived radon daughters.     

Are radon gas measurements adequate for epidemiological studies and case control studies of radon-induced lung cancer?

The lung dose derived from radon is not attributed to the radon gas itself, but instead to its short-lived progeny. However, in many epidemiological studies as well as in case control studies of the radon risk, the excess number of cancers are related to the radon gas exposure, and not to the radon progeny exposure. A justification for such an approach has resorted to the assumption that there is self-compensation between the radiation doses from the unattached and attached fractions. In the present study, we used the Jacobi model to calculate the radon progeny concentrations in a room by varying the attachment rate and then calculated the resulting lung dose. It was found that self-compensation was not fully realised, and the effective dose can vary by a factor up to approximately 2 for the same radon gas concentration. In conclusion, the radon gas concentration alone does not provide adequate information on the effective dose.     

Cellular burdens and biological effects on tissue level caused by inhaled radon progenies

In the case of radon exposure, the spatial distribution of deposited radioactive particles is highly inhomogeneous in the central airways. The object of this research is to investigate the consequences of this heterogeneity regarding cellular burdens in the bronchial epithelium and to study the possible biological effects at tissue level. Applying computational fluid and particle dynamics techniques, the deposition distribution of inhaled radon daughters has been determined in a bronchial airway model for 23 min of work in the New Mexico uranium mine corresponding to 0.0129 WLM exposure. A numerical epithelium model based on experimental data has been utilised in order to quantify cellular hits and doses. Finally, a carcinogenesis model considering cell death-induced cell-cycle shortening has been applied to assess the biological responses. Present computations reveal that cellular dose may reach 1.5 Gy, which is several orders of magnitude higher than tissue dose. The results are in agreement with the histological finding that the uneven deposition distribution of radon progenies may lead to inhomogeneous spatial distribution of tumours in the bronchial airways. In addition, at the macroscopic level, the relationship between cancer risk and radiation burden seems to be non-linear.     

A theoretical model for the microdosimetry of discontinuous distributions of heavy particle tracks

A novel approach to solving microdosimetry problems using conditional probabilities and geometric concepts has been developed. This approach is valid for cases where a convex site is immersed in uniform or discontinuous distributions of heavy charged particle tracks and assumes no restrictions in site geometry or the kind of randomness. These conditions are relevant to the study of microdosimetry in applications such as neutron capture therapy (NCT), irradiation experiments using heavy ion particle beams, environmental radon, or occupational exposure to radioactive materials. Expressions applicable to the case of surface-distributed sources of tracks are presented that may represent situations such as NCT, where boron compounds are bound to the membranes of cellular nuclei. Microdosimetric spectra, specific energy averages, and mean number of 10B capture reactions for cell inactivation are calculated, showing their dependence on 10B localisation.     

On the relationship between dose-, energy- and LET-response of thermoluminescent detectors

Measurements of the response of thermoluminescent (TL) detectors after gamma ray doses high enough to observe signal saturation provide input to microdosimetric models which relate this gamma-ray response with the energy response after low doses of photons (gamma rays and low-energy X rays) and after high-LET irradiation. To measure their gamma ray response up to saturation, LiF:Mg,Ti (MTS-7 and MTT), LiF:Mg,Cu,P (MCP-7), CaSO4:Dy (KCD) and Al2O3:C detectors were irradiated with 60Co gamma rays over the range 1-5000 Gy. The X-ray photon energy response and TL efficiency (relative to gamma rays) after doses of beta rays and alpha particles, were also measured, for CaSO4:Dy and for Al2O3:C. Microdosimetric and track structure modelling was then applied to the experimental data. In a manner similar to LiF:Mg,Cu,P, the experimentally observed under response of alpha-Al2O3:C to X rays <100 keV, compared with cross-section calculations, is explained as a microdosimetric effect caused by the saturation of response of this detector without prior supralinearity (saturation of traps along the tracks). The enhanced X-ray photon energy response of CaSO4:Dy is related to the supralinearity observed in this material after high gamma ray doses, similarly to that in LiF:Mg,Ti. The discussed model approaches support the general rule relating dose-, energy- and ionisation density-responses in TL detectors: if their gamma ray response is sublinear prior to saturation, the measured photon energy response is lower, and if it is supralinear, it may be higher than that expected from the calculation of the interaction cross sections alone. Since similar rules have been found to apply to other solid-state detector systems, microdosimetry may offer a valuable contribution to solid-state dosimetry even prior to mechanistic explanations of physical phenomena in different TL detectors.     

Microdosimetric analysis for high LET radiation

For short range high linear energy transfer (LET) radiation therapy the biological effects are strongly affected by the heterogeneity of the specific energy (z) distribution delivered to tumour cells. Three-dimensional (3-D) dosimetry information at the cellular level is required for this study. An ideal approach would be the reconstruction of the cell and the radiation source microdistribution from sequential autoradiographic sections, which is, however, not a practical solution. In this paper, a novel microdosimetry analysis method, which obtains the specific energy (z) distribution directly from the morphological information in individual autoradiographic sections, is applied to human glioblastoma multifore (GBM) and normal brain tissue specimens in boron neutron capture therapy. The results are consistent with Monte Carlo simulation and demonstrate a uniform radiation source distribution in both GBM and normal brain tissues. We also hypothesise a biophysical model based on specific energy for survival analysis. The specific energy distributions to cell nuclei were calculated with a uniform radiation source distribution. By combining this microdosimetric analysis with measured cell survival data at the low dose region, a cell survival curve at high doses is predicted, which is consistent with the commonly used simple exponential curve model for high LET radiation.     

Microdosimetric one hit detector model for calculation of dose and energy response of some solid state detectors

A microdosimetric one hit detector model has been applied to calculate dose response, energy response and relative efficiency of thermoluminescent LiF:Mg,Cu,P (MCP-N), CaF2:Tm (TLD-300) and ESR alanine detectors on radiation of different qualities. For each detector type two model parameters, the target size and the saturation parameter, alpha, have been derived. Using those parameters and the microdosimetric distributions in nanometre size targets calculated using Monte Carlo track structure codes TRION and MOCA-14 it was possible to predict a great variety of experimental data for photons, X rays, beta electrons, protons, alpha particles and heavy ions. Due to a good reproducibility of experimental data some solid state detectors might be useful to test biophysical models of radiation action. Furthermore, these models can give some insight into the physics of radiation action in solid state detectors such as the range of charge interaction, energy levels etc.