Proceedings of the 4 th Environmental Physics Conference, 10-14 March 2010, Hurghada, Egypt
LUNG DEPOSITION AND BIOLOGICAL EFFECTS OF INHALED RADON PROGENIES
I. Balásházy 1, Á. Farkas 1, M. Moustafa 2, I. Szıke 1, G. Kudela 3
1Health and Environmental Physics Department, Hungarian Academy of Sciences KFKI Atomic Energy Research Institute, Konkoly Thege M. út 29-33, 1121 Budapest, Hungary 2Physics Department, Faculty of Science, Minia University, Minia, Egypt 3Eötvös Loránd University, 1117 Budapest, Pázmány Péter s. 1/c, Hungary
Inhaled radon progenies provide more than half of the natural radiation burden. One of our objectives was the characterisation of the distribution of cellular exposure of radon. At first, total and regional deposition and deposition density distributions of inhaled radon progenies in the human respiratory system were computed by the stochastic lung deposition model. Histological studies of former uranium miners presented neoplastic lesions along the carinal regions of the large bronchial airways. Thus, secondly, computational fluid dynamics approaches have been applied to simulate deposition and cellular dose distributions of inhaled radon progenies in the central human airways.
Keywords: numerical modelling, health effects of radon progenies, radon microdosimetry
INTRODUCTION
Understanding of the biological and health effects of low dose ionising radiation is one of the key issues of current radiation protection. Actual radiation dose limits are based on the assumption that any small dose represents a finite health risk which is linear with the received dose down to zero. However, this hypothesis is questioned by many scientists and generates scientific debates for several years. Since low doses correspond to the exposure level of the large population, beyond its scientific and economic importance, answering the question would result health related and social consequences, as well. More than a half of the natural radiation burden is due to the inhalation of radon and its progenies. The radon studies of former uranium mines and homes are the largest available radiation related epidemiological datasets, most of the scientists focus on the effect of these isotopes. The related epidemiological efforts demonstrated that there is a causal relationship between the high radon levels and increased lung cancer, thyroid cancer and leukaemia incidences [1]. However, epidemiology provides controversial and statistically poor information regarding the biological effects of low doses. Since radon and its daughter products can be inhaled and deposited in the lung, one of the ways studying their effects is to establish relationships between the exposure levels and the lung cancer formation probability.
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This can be performed by modelling the airway deposition and mechanisms of action of the inhaled radio aerosols. Current deposition and dosimetry models cannot describe the local inhomogeneities of aerosol deposition and operates with average deposition densities and activities. At the same time, histological studies revealed that the cancer formation could be localised to local environments containing a limited number of cells [2]. The existence of preferential deposition sites was demonstrated experimentally, as well [3]. These observations suggest that there is an increasing need for models, which can quantify the realistic local deposition distributions and compute microdosimetric quantities in a cellular level. Thus, the objective of this work was to compute the total, regional and local deposition density distributions of inhaled radon progenies and to develop a computational fluid dynamics based lung deposition and microdosimetric model for the characterisation of cellular burdens of these radioaerosols.
METHODS
The total and regional deposition of inhaled radon progenies have been computed by the newest version of the stochastic lung deposition model [4, 5]. This model originally was developed by Koblinger and Hofmann [6] and it is based on the statistical evaluation of the largest available database of the human airway system [7]. This Monte Carlo transport and deposition model is a stochastic morphometric model of the human lung, which describes the inherent asymmetry and variability of the respiratory system [8]. This variability of airway diameters, lengths, branching and gravity angles, constrained by correlations among some of these parameters, is described mathematically by probability density and correlation functions [6]. For the simulation of particle transport through this stochastic lung structure, individual paths of inspired particles are randomly selected by Monte Carlo methods from these mathematical functions. The random walk of individual inhaled particles upon inspiration and expiration is simulated by Monte Carlo methods. Flow splitting in an airway bifurcation between the two asymmetric daughter airways is assumed to be related to the peripheral air volume supported by each of the two daughter airways. Deposition of particles in a given airway generation is computed by analytical equations describing the average deposition of many particles in cylindrical airways for inertial, gravitational and Brownian forces [8]. In the oro and nasopharyngeal regions, particle deposition is computed by empirical equations derived from measurements in human volunteers [9]. Due to the variability of the airway geometry and related flows, particle deposition may vary along different paths. Thus, penetration probabilities to a given airway generation, i.e. the probability of inhaled particles to reach that airway generation, exhibits significant fluctuations, depending on the individual history of each particle in upstream airways. This model is under permanent development and several publications have demonstrated its reliability and validity, e.g. [4, 5, 9]. In this study the regional deposition and deposition densities of inhaled radon progenies were computed by this model. The inhomogeneity of bronchial aerosol deposition is characterised by computational fluid dynamics (CFD) methods in this study. CFD as a tool in microdosimetry is not fully employed yet. In this work, we applied such a numerical model for the quantification of local radio aerosol deposition. The first step of this CFD approach was the construction of three dimensional airway geometries. Based on the open literature the occurrence of the radon induced malignant tumours is the highest in the carinal regions of the first five bronchial airway generations especially in the right upper lobe. Thus, this study refers to a central airway segment including the trachea, two main bronchi, right upper lobe bronchus, bronchus intermedius, two segmental and four subsegmental bronchi leading to the right upper lobe.
72 Proceedings of the 4 th Environmental Physics Conference, 10-14 March 2010, Hurghada, Egypt
The digital airway geometry was then discretized by meshing. The applied mathematical mesh was unstructured inhomogeneous and boundary adapted. The isothermal Navier Stokes and continuity equations describing the motion of air were solved in each discrete volumetric unit (cell) of the computational domain, and then discrete particles were injected and tracked by Lagrangean method. For statistical reasons trajectories of ten million inhaled particles were computed at breathing conditions characteristic of uranium mines and homes. This number of particles is inhaled in about five minutes in the New Mexico uranium mine and in about one week in an average dwelling. The number of particles deposited in the upper airways (nose pharynx larynx) was computed by the stochastic lung model described above. Trajectories of particles entering the trachea were computed by numerical integration of force balance equations. The deposition locations were the intersection of the trajectories with the bronchial walls. For the characterisation of local deposition distributions, enhancement factors (EF) has been introduced, defined as the ratio of local and average deposition densities. For this purpose, the whole surface of the studied airway segment was scanned by a pre specified surface element. For microdosimetric reasons, the size of this surface element was selected to be equal to the area of a cluster of about one thousand epithelial cells. Based on histological data [12] the cell structure of the bronchial epithelium was reconstructed and alpha tracks penetrating into epithelium were computed. Basal, goblet, other secretory, ciliated, preciliated and indeterminate cells were considered. Alpha hit probability and cell nucleus dose distributions were computed applying Monte Carlo techniques. The computations were performed at breathing and exposure conditions characteristic of the New Mexico uranium mine and an average home. The corresponding model parameters were derived from the literature [1 and 13].
100 90 1 nm 200 nm 80 70 60 50 40 30 Deposition fraction (%) 20 10 0 upper- bronchial- acinar- total
Figure 1. Deposition fractions of unattached and attached radon progenies in the upper , bronchial , and acinar airways and in the whole respiratory system at light physical activity breathing conditions.
73 Proceedings of the 4 th Environmental Physics Conference, 10-14 March 2010, Hurghada, Egypt
RESULTS
The stochastic lung deposition model was applied to compute the total and regional deposition of unattached and attached radon progenies represented by 1nm and 200 nm aerodynamic diameter particles, respectively. In Figure 1, deposition fractions in the upper airways, in the bronchial region, in the acinar part and in the whole respirator system are presented at light physical activity breathing condition computed for an adult human. The fraction of unattached fraction is much less than that of the attached fraction. The unattached fraction is only a few percent both in mine and home environments. Thus, the dose contributions of unattached radon progenies will usually be less than that of the attached one in the central airways. The computation of the deposition fractions does not explain why most of the preneoplastic and neoplastic lesions occurred mostly in the central airways of the former uranium miners. However, determining the distributions of deposition densities and not only deposition fractions of attached radon progenies as a function of airway generation number, that is dividing the deposition fractions in each airway generation with the surface of the generation, a sharp peak appears at airway generations 2 5. Figure 2 presents these deposition density distributions. It is the region where the majority of lung tumours developed in case of uranium miners.
0.030 2 0.025
0.020 bronchial acinar 0.015
0.010
0.005 Deposition density (%)/cm
0.000 0 5 10 15 20 25 30 Airway generation number
Figure 2. Deposition density distributions of attached radon progenies as a function of airway generation number at light physical activity breathing conditions.
Based on the computations performed by the stochastic lung model, assuming exposure conditions characteristic of the New Mexico uranium mine the extrathoracic deposition efficiency was 3.3 % for the attached and 82 % for the unattached radon progenies. Assuming exposure conditions characteristic of an average home the same values were 4.37 % and 89.8 % respectively. Health effects of aerosols may occur when the local, cellular burden defeats the defending capacity of the cells and tissue fragments. Thus, the characterisation of the local distribution of burden was also performed. This task needs three dimensional computational fluid dynamics approaches in the large central airways. We have selected the airways leading
74 Proceedings of the 4 th Environmental Physics Conference, 10-14 March 2010, Hurghada, Egypt to the right upper lobe, where most of the neoplastic lesions occurred [14]. Figure 3 presents a single bifurcation unit and a complex central airway segment of our generated geometry. The computed airways form so called morphologically realistic bifurcations [15] with smooth transitions between the cylindrical segments of the geometry with curved carinal regions. The main geometric parameters, that is, the lengths, diameters, gravity and branching angles were selected by the stochastic lung deposition model. An unstructured inhomogeneous tetrahedral three dimensional mathematical mesh was generated. The mesh is denser in the vicinity of the surface and at the carinal ridge where the air velocity gradients may be high. For this purpose, the so called size function technique was applied [16]. Figure 4 demonstrates different segments of the constructed mathematical mesh in the five bifurcation geometry.
Figure 3. Three dimensional bifurcation unit (left panel) and the constructed geometry leading to the right upper lobe representing one part of airway generations 1 5 (right panel).
The mesh is denser in the carinal region
The mesh is dense in the vicinity of the wall
Figure 4. The generated three dimensional unstructured tetrahedral mathematical mesh which is denser in the vicinity of the surface and at the carinal ridge.
75 Proceedings of the 4 th Environmental Physics Conference, 10-14 March 2010, Hurghada, Egypt
The air flow field, particle trajectories and particle deposition patterns have been computed by the commercial FLUENT computational fluid dynamic code [16] applying laminar stationer flow during inspiration. Tracheobronchial deposition patterns of attached (left panels) and unattached (right panels) radon progenies in airway generations 1 5 are presented in Figure 5 at light physical activity (upper panels) and at sitting breathing conditions (bottom panels). The upper panels represent the deposition patterns of ten million inhaled particles in the New Mexico uranium mine and the bottom panels correspond to the deposition patterns of the same amount of particles inhaled in an average home where the radon concentration is 26.6 Bq/m 3. As the figure demonstrates, the deposition is inhomogeneous in all these studied cases. The deposition distribution of unattached radon progenies is less inhomogeneous than that of the attached ones due to thermal diffusion, which is quite strong deposition mechanism in case of nanoparticles.
a) kitapadtatta ched kiun nematta tapadtched Q = 50 l/min Q = 50 l/min Q = 50 l/perc Q = 50 l/perc η == 0,94 0.94 % % ηη = =27,8 27.8 % %
b)
akitapadttta ched kiun nematta tapadtched Q = 18 l/min Q Q= =18 18 l/min l/perc Q = 18 l/perc ηη = = 0.73 0,73 % ηη = = 36,88 36.9 % %
Figure 5. Deposition distribution of the attached ( 218 Po, 214 Pb and 214 Bi) and unattached ( 218 Po) radon progenies in the central human airways for radiation exposure conditions characteristic of a) uranium mines b) homes. The number of inhaled particles was ten millions in both cases. Q – tracheal flow rate; η − deposition efficiency.
76 Proceedings of the 4 th Environmental Physics Conference, 10-14 March 2010, Hurghada, Egypt
Deposition enhancement factors (EF), that is the ratio of local and average deposition densities, were computed by scanning along the surface of the geometry with a unit surface element which size was 100 m x 100 m. The maximum enhancement factors computed from the deposition patterns in Figure 5 are demonstrated in Figure 6. The unattached fraction is higher in dwellings than in mines due to the lower dust concentration. In addition, the molecular diffusion driven deposition is more intensive in homes because of the slower breathing. As a consequence, the deposition in homes is less heterogeneous and thus the maximum enhancement factors are lower than in case of uranium mines. The maximum of the total (unattached plus attached) deposition enhancement factors are also higher in mines than in homes, indicating that even for the same macroscopic dose the local burden is a little bit higher in mines than in homes. The activity concentration values in uranium mines are about three orders of magnitude higher than the same values in homes.
FKT max EF max minebányaMine home Homelakás 500 487 461.1 460
400 343.4
300
200
100 64.2 25.9
kunattachedUnattachedi nem tapadt attachedAttachedkitapadt totalteljesTotal
Figure 6. Maximum deposition enhancement factors (EF max ) of attached and unattached short lived radon progenies in mine (left panel) and in home (right panel).
238 5.5 MeV U DECAY CHAIN ααα 210Tl 0,02% 5.49 MeV 6 MeV 99.98% 1.32 min ααα ααα γγγ γγγ 222 Rn 218 Po 214 Pb 214 Bi 214 Po γγγ βββ βββ 3.823 d 3.05 min 26.8 min 19.7 min 164 s
7.69 MeV ααα 5.3 MeV ααα βββγγγ 206 Po 210 Po 210 Bi 210 Pb γγγ βββ (stable) 138.4 d 5.01 d 21 a
Figure 7. The decay chain of 238 U from the isotope of 222 Rn.
77 Proceedings of the 4 th Environmental Physics Conference, 10-14 March 2010, Hurghada, Egypt
Figure 7 demonstrates a section of the decay chain of 238 isotope of uranium from 222 Rn till 206 Po which is already stable. The biological effects of alpha radiation is much more significant than that of the beta and gamma radiations. Thus, the model computes cell nucleus alpha hit probabilities and cell nucleus doses originates only from alpha particles. For deposition calculations it was necessary to compute the deposition distributions of attached 218 Po, 214 Pb and 214 Bi isotopes, in addition the deposition distribution of unattached 218 Po. The unattached fraction of the other isotopes is negligible because during the time interval from the formation of 218 Po till the formation of the other isotopes, the unattached progenies deposits in aerosol particles in the atmosphere with high probability. The deposition pattern of 214 Po was not computed because it’s half life is very short (164 s), and thus, it’s deposition on the surface of the airways is negligible. Of course, the dose contribution of 214 Po to the total burden can be high, because 214 Po is originated from the other deposited progenies.
Figure 8. Cell nuclei of the goblet cells of the epithelium in a unit surface of the geometry.
Cell nuclei of the epithelium were generated based on the size and depth distributions of the epithelial cells, applying the experimental data of Mercer et al. (1991) [12]. The shape of the cell nuclei were approximated with ellipsoids. Figure 8 depicts the distribution of goblet cell nuclei (secretory cells which produce the mucus) in a unit surface element of the mathematical grid. The initial energies of the alpha particles originating from the decay of 218 Po and 214 Po are known from the literature (5.49 MeV and 7.69 MeV). The ranges of alpha particles in air and tissue are also known, thus, the alpha tracks can be generated applying Monte Carlo techniques. Figure 9 demonstrates far wall and near wall alpha tracks generated in a single airway bifurcation. One half of the alpha tracks are emitted to the direction of the lumen of the airway and they penetrate at first through the air then hit on the other side of the airway with a little bit lower energy. These are the so called far wall alpha tracks. The other half of the alpha tracks penetrates immediately to the tissue (near wall alpha tracks). The far wall alpha tracks are usually much longer then the near wall alpha tracks.
78 Proceedings of the 4 th Environmental Physics Conference, 10-14 March 2010, Hurghada, Egypt
FAR- & NEAR-WALL ααα-TRACKS IN AIR & TISSUE
NEAR-WALL ααα-TRACKS IN THE TISSUE
Figure 9. Far wall (upper panel) and near wall (bottom panel) alpha tracks in an airway bifurcation characteristic to airway generations 4 5. The deposition distribution of radon progenies was computed at sitting breathing condition in the atmosphere of an average home.
near wall α-track
far wall α-tracks
basal cells goblet cells ciliated cells
Figure 10. Alpha hits in the epithelium of the central airways with cell nuclei of basal, goblet and ciliated cells in one computational cell of the mathematical mesh. The mucus is on the right side and the basal membrane is on the left side of the computational cells.
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Near wall and far wall alpha tracks originating from 30 000 deposited particles in airway generations 4 5 in an average home environment supposing sitting position breathing condition are demonstrated in Figure 10. The figure also depicts the cell nuclei of basal cells (left panel), goblet cells (middle panel) and ciliated cells (right panel) in a computational element of the mathematical mesh. The basal membrane (left side of the panels) and the 5 m thick mucus layer (right side of the panels) are also illustrated. By the computation of the absorbed energies and the masses of the cell nuclei one receive the absorbed doses in the cell nuclei. Figure 11 demonstrates the distribution of absorbed doses in the New Mexico uranium mine (upper panel) and in an average home (bottom panel) in airway generations 1 5 presented in Figure 3 right panel. Considering all the nuclei, the average dose per nucleus for the modelled time period (five minutes in the mine and one week in the average home) was about 1 mGy. The average dose of the nuclei receiving at least one hit was 250 mGy. At the same time the most exposed nucleus received a dose of 2.7 Gy in the New Mexico uranium mine environment and 1.5 Gy in the average home environment. These values are three orders of magnitude higher than the average doses in the geometry.
minebánya frequency gyakoriság gyakoriság
csejtmagdózisell nucleus dose (Gy) (Gy )
homelakás gyakoriság gyakoriság frequency
cellsejtmagdózis nucleus dose (Gy) (Gy )
Figure 11. Distribution of cell nucleus doses in the New Mexico uranium mine (upper panel) and in an average home (bottom panel).
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CONCLUSIONS The work demonstrated that the computations of regional deposition fractions do not explain why lung cancer develops preferentially in the large central airways. However, the simulation of deposition densities per airway generations already presents a sharp peak at airway generations 2 5. The characterisation of local burdens within airway bifurcations presents strong inhomogeneity in local deposition densities. There are two three orders of magnitude difference between the maximal and the average deposition densities. Another conclusion of the applied technique is that the computational fluid and particle dynamics method can be a powerful tool for the characterisation of local cellular radiation burden. Based on the results, the burden of clusters of cells, namely the cells in the so called deposition hot spots located in the vicinity of the peak of the airway bifurcations, can be high even at low macroscopic exposure levels. Integration of our models with a mechanistic lung cancer model will lead to a biophysical mechanisms based complex risk model of radon inhalation. By the application of the integrated model, useful information regarding the health effects of low doses and the LNT (linear nonthreashold hypothesis) is expected.
Acknowledgements This research was supported by the K61193 OTKA and ETT 317 08 Hungarian Projects.
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