Árpád Farkas

Quantification of particle deposition in asymmetrical tracheobronchial model geometry

The primary objective of this study was to quantify the local inspiratory and expiratory aerosol deposition in a highly asymmetric five-generation tracheobronchial tree. User-enhanced commercial codes and self-developed software was used to compute the air velocity field as well as particle deposition distributions for a large size range of inhalable particles. The numerical model was validated by comparison of our results with experimental flow measurements and particle deposition data available in the open literature. Our simulations show highly localised deposition patterns for all particle sizes, but mainly for the larger particles. As expected, deposition efficiencies and deposition fractions proved to be very sensitive to the particle size. The deposition density in the hot spots can be hundreds and even thousand times higher than the mean deposition density. Present results can be of interest to researchers involved in the assessment of adverse health effects of inhaled aerosols or optimising the drug aerosol delivery into the lung.

Three-Dimensional Model for Aerosol Transport and Deposition in Expanding and Contracting Alveoli

Particle transport and deposition within a model alveolus, represented by a rhythmically expanding and contracting hemisphere, was modeled by a three-dimensional analytical model for the time-dependent air velocity field as a superposition of uniform and radial flow components, satisfying both the mass and momentum conservation equations. Trajectories of particles entrained in the airflow were calculated by a numerical particle trajectory code to compute simultaneously deposition by inertial impaction, gravitational sedimentation, Brownian diffusion, and interception. Five different orientations of the orifice of the alveolus relative to the direction of gravity were selected. Deposition was calculated for particles from 1 nm to 10 μm, for 3 breathing conditions, and for 5 different entrance times relative to the onset of inspiration. For the analyzed cases, the spatial orientation of the orifice of an alveolus has practically no effect on deposition for particles below about 0.1 μm, where deposition is dominated by Brownian motion. Above about 1 μm, where deposition is governed primarily by gravitational settling, deposition can vary from 0 to 100%, depending on the spatial orientation, while deposition of particles 0.1–1 μm falls between these two extreme cases. Due to the isotropic nature of Brownian motion, deposition of the 10-nm particles is practically uniform for all spatial orientations. However, for larger particles, deposition can be quite inhomogeneous, consistent with the direction of gravity. While nearly all particles are exhaled during the successive expiration phase, there are a few cases where particles still leave the alveolus even after many breathing cycles.

Non-linear relationship of cell hit and transformation probabilities in a low dose of inhaled radon progenies.

Cellular hit probabilities of alpha particles emitted by inhaled radon progenies in sensitive bronchial epithelial cell nuclei were simulated at low exposure levels to obtain useful data for the rejection or support of the linear-non-threshold (LNT) hypothesis. In this study, local distributions of deposited inhaled radon progenies in airway bifurcation models were computed at exposure conditions characteristic of homes and uranium mines. Then, maximum local deposition enhancement factors at bronchial airway bifurcations, expressed as the ratio of local to average deposition densities, were determined to characterise the inhomogeneity of deposition and to elucidate their effect on resulting hit probabilities. The results obtained suggest that in the vicinity of the carinal regions of the central airways the probability of multiple hits can be quite high, even at low average doses. Assuming a uniform distribution of activity there are practically no multiple hits and the hit probability as a function of dose exhibits a linear shape in the low dose range. The results are quite the opposite in the case of hot spots revealed by realistic deposition calculations, where practically all cells receive multiple hits and the hit probability as a function of dose is non-linear in the average dose range of 10-100 mGy.

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.

Modelling of cell deaths and cell transformations of inhaled radon in homes and mines based on a biophysical and microdosimetric model.

Purpose: In this study a biophysical mechanism-based microdosimetric model was applied to predict the biological effects of inhaled radon progenies in homes and in uranium mines. Materials and methods: The radon daughter concentrations of more than 2000 homes were averaged in case of home exposure and the New Mexico uranium mine data were used in case of exposure in mines. The complex microdosimetric model applied in this work was developed by combining a computational fluid and particle dynamics (CFPD) lung model with a lung dosimetry model that quantify the local distribution of radiation burden and the Unit-Track-Length Model, which characterizes the biological outcome of the exposure. Results: Our results show that the inhomogeneity of radon daughter deposition is stronger in the case of mines. Consequently, the numbers of cells which receive multiple hits and the maxima of radiation burdens are significantly higher in mines. In contrast to this, the distributions and maximum values of cell transformation probabilities are very similar in the two cases. Conclusions: If the same amounts of inhaled progenies are considered then primary cellular consequences are very similar in case of homes and mines, however, the local maxima of radiation burden are higher in mines.

Stochastic Aspects of Primary Cellular Consequences of Radon Inhalation

Abstract Szőke, I., Farkas, Á., Balásházy, I. and Hofmann, W. Stochastic Aspects of Primary Cellular Consequences of Radon Inhalation. Radiat. Res. 171, 96–106 (2009). In this study, a composite, biophysical mechanism-based microdosimetric model was developed for the assessment of the primary cellular consequences of radon inhalation. Based on the concentration of radio-aerosols in the inhaled air and the duration of exposure, this mathematical approach allows the computation of the distribution of cellular burdens and the resulting distribution of cellular inactivation and oncogenic transformation probabilities within the epithelium of the human central airways. The composite model is composed of three major parts. The first part is a lung-particle interaction model applying computational fluid and particle dynamics (CFPD) methods. The second part is a lung dosimetry model that quantifies the cellular distribution of radiation exposure within the bronchial epithelium. The third part of the composite model is the unit-track-length model, which allows the prediction of the biological outcome of the exposure at the cellular level. Computations were made for different exposure durations for a miner working in a New Mexico uranium mine. The spatial pattern of the exposed cell nuclei along the epithelium, the distributions of single and multiple α-particle hits, the distributions of cell nucleus doses, and cell inactivation and cell transformation probabilities as a function of the number of inhalations (length of exposure) were investigated and compared for up to 500 inhalations.

Simulation of bronchial mucociliary clearance of insoluble particles by computational fluid and particle dynamics methods

Abstract For a correct assessment of health consequences of inhaled aerosols as a function of dose, whether for environmental, occupational or therapeutic agents, knowledge of their deposition distribution in the respiratory tract and subsequent clearance is important. The objective of this study is to model particle clearance at bronchial airway bifurcation level and to analyze the combined effect of deposition and clearance. For this purpose, a numerical model has been implemented. Air and mucus flow fields were computed in a model bronchial airway bifurcation. Inhaled particles with 1 and 10 µm aerodynamic diameters were tracked to determine deposition and clearance patterns. Simulation results revealed the existence of a slow clearance zone around the peak of the airway bifurcation causing delayed clearance of the particles depositing or entering here. Particles clearing up from the deeper airways and crossing the studied bifurcation do not accumulate in this zone, because of their tendency to avoid it. The average residence time of these particles was around 20 min independently of particle size (whether it is 1 or 10 µm). However, as a result of the superposition of deposition and clearance mechanisms, the final spatial distribution of particles deposited primarily in the target bifurcation is size dependent, because deposition is size specific. Although deposition density of particles deposited in the slow clearance area is one-two orders of magnitude higher than the average deposition density, these values are reduced by clearance by the factors of 4–7, depending on the particle size and the surface area of the selected slow clearance zone. In conclusion, although particle deposition is inhomogeneous, clearance can significantly decrease the degree of spatial non-uniformity of the particles. Therefore, for a correct assessment of doses at local levels, it is important to consider both deposition and clearance. Although future research may overwrite some of the model assumptions on the nature of mucus, the authors think that most of the current predictions will hold.

Quantification of airway deposition of intact and fragmented pollens

Although pollen is one of the most widespread agents that can cause allergy, its airway transport and deposition is far from being fully explored. The objective of this study was to characterize the airway deposition of pollens and to contribute to the debate related to the increasing number of asthma attacks registered after thunderstorms. For the quantification of the deposition of inhaled pollens in the airways computer simulations were performed. Our results demonstrated that smaller and fragmented pollens may penetrate into the thoracic airways and deposit there, supporting the theory that fragmented pollen particles are responsible for the increasing incidence of asthma attacks following thunderstorms. Pollen deposition results also suggest that children are the most exposed to the allergic effects of pollens. Finally, pollens between 0.5 and 20 μm deposit more efficiently in the lung of asthmatics than in the healthy lung, especially in the bronchial region.

Simulation and minimisation of the airway deposition of airborne bacteria

Respiratory infections represent one of the most important bioaerosol-associated health effects. Bacteria are infectious micro-organisms that may, after inhalation, cause specific respiratory diseases. Although a large number of inhalable pathogenic bacteria have been identified and the related respiratory symptoms are well known, their airway transport and deposition are still not fully explored. The objective of this work was to characterise the deposition of inhaled bacteria in different regions of the lung and to find the optimum breathing modes, which ensure the minimum chance of a bacterial infection in a given environment. For this purpose a stochastic computer lung model has been applied. In order to find the breathing pattern that yields the lowest deposited fraction of the inhaled particles, multiple simulations were carried out with several combinations of tidal volumes ranging from 400 to 2000 ml, and breathing cycles ranging from 2 to 10 s. Particle aerodynamic diameters varied between 1 and 20 μm, and simulations were performed for both nose and mouth breathing conditions. Present computations demonstrated that regional (extrathoracic, tracheobronchial, acinar), lobar, and generation number-specific deposition distributions of the inhaled particles are highly sensitive to their aerodynamic diameter and to the breathing parameters. According to our results, mouth breathing with short breathing periods, no breath hold, and low tidal volumes minimises the total respiratory system deposition. On the other hand, lung (bronchial and acinar) deposition can be minimised by a breathing mode characterised by short breathing cycles through the nose with long breath holds after exhalations and high tidal volumes.

Modelling carcinogenic effects of low doses of inhaled radon progenies

In this study, cellular hit probabilities of alpha particles emitted by inhaled radon progenies in sensitive epithelial cell nuclei were simulated at low exposure levels to obtain useful data for the rejection or in support of the linear no-threshold dose-effect hypothesis. In this work, local distributions of deposited inhaled radon progenies in airway bifurcation models were computed at exposure conditions which are characteristic of homes and uranium mines. Then, maximum local deposition enhancement factors, that is, local per average deposition densities, were simulated, and the effects of the inhomogeneity of deposition on hit probabilities were characterised. Our results suggest that in the vicinity of the carinal regions of the central airways the probability of multiple hits can be quite high even at low doses.