Inhalative uptake of airborne radionuclides by people breathing air that has been contaminated in any way mentioned above commonly depends on a large number of diverse factors. If radioactive elements occur in particulate rather than in gaseous form, which is realized by their attachment to ambient aerosol particles, the geometry, size, density, and hygroscopicity of the particulate matter have to be regarded as most important determinants controling the extent of radionuclide uptake. Numerous experimental studies (6-8) could demonstrate that the physical factors noted above as well as the mode of breathing (i.e., inspiration through the nose or mouth) and physiological breathing characteristics (tidal volume, breathing frequency) determine, whether inhaled radioactive substances are deposited in the respiratory tract or again exhaled. In the case of deposition, the properties outlined here additionally control the penetration depth of specific radionuclides, their sites of maximal deposition, their retention times or clearance rates, and their rates of absorption into the blood and subsequent translocation to adjacent tissues.

As soon as a particle attached by a radioactive element has deposited on the epithelial surface of the respiratory tract, it starts to unfold its unwholesome efficacy on the adjacent tissue. The grade of this impairment among other depends on the solubility of the radioactive isotopes adsorbed on the carrier aerosol. Regarding the development of lung cancer, specific progenitor cells of the epithelium and especially their DNA molecules represent preferential targets for α-, β-, or γ-radiation. Whilst α-particles and γ-rays are mainly responsible for the generation of single strand breaks (SSB) or double strand breaks (DSB), γ-rays (and x-rays) may additionally affect the base-strand bonds, and β-particles preferably attack the connections between two bases (9-13). Normally, point or cluster damages of the DNA molecule are restored with the help of various reparation mechanisms. A failure of this restoration may generally occur in two forms: first, DSBs of the DNA remain unrejoined, resulting in cytotoxic effects; second, DNA damages are repaired incorrectly, causing the development of mutations (14,15).

Due to the ubiquitous occurrence of progenitor cells radiation-induced cancers may develop in both the extrathoracic and thoracic region of the human respiratory tract. Regarding the extrathoracic air passages tumor types mainly include squamous cell carcinomas, nonsquamous, mainly undifferentiated carcinomas, adenocarcinomas, sarcomas, epidermoid carcinomas, and, in extremely rare cases, esthesioneuroblastomas (5,16). Preferential target tissues of cancer formation are situated in the posterior nose and the nasopharynx, but also the larynx and the glottis bear a valuable potential for the growth of site-specific tumors.

Particle deposition in individual airways due to various deposition forces is computed by using analytical deposition equations (23,24,31) which are valid for straight cylindrical tubes and spherical spaces (Table 1). Generally, three deposition mechanisms, i.e., Brownian motion, inertial impaction, and gravitational settling, are distinguished. Regarding particle deposition forced by Brownian motion, the related empirical equation outlined by Cohen and Asgharian (32), which considers an increase in deposition in the upper bronchial airways due to developing flow, is used additionally to the standard formulae. For the computation of particle deposition in more peripheral airway tubes, the respective diffusion equation proposed by Ingham (33) is applied. Deposition of particles in the upper airways caused by inertial impaction includes possible accumulation of particulate matter in the trachea (generation 0) due to turbulent flow (laryngeal jet) by the use of correction factors that are added to the respective standard equation. Regarding the estimation of extrathoracic deposition efficiencies, expressing the ability of nasal and oral airways to filter inspired particulate material, empirical equations were derived either from in vivo measurements (34) or from collected experimental data (35).

An increase of the tidal volume but maintenance of the flow rate (breathing scenario 2) causes an enhancement of total deposition. In addition, the related deposition curve tends to change from U-shape with wide minimum into V-shape with narrow minimum (Fig 2B). At the minimum (dae = 0.5 µm), total deposition adopts values of 14 % (mouth breathing) and 19 % (nose breathing). Nanoparticles are deposited with amounts of 93 % (mouth breathing) and 100 % (nose breathing), whilst largest inhalable particles exhibit deposition values of 87% (mouth breathing) and 100 % (nose breathing).

Concerning the deposition of radioactive particles with variable size in the extrathoracic passages, deposition curves are again characterized by more or less perfect U-shapes (Fig 3). According to breathing scenario 1 particles with dae ranging from 0.07 µm to 1 µm are not characterized by a measureable deposition in the oral path, whereas their deposition in the nasal airways varies between 7 and 15 %. This discrepancy between oral and nasal deposition is also recognizable for ultrafine and large particles. For particles with dae = 0.001 µm nasal deposition efficiency exceeds that of the mouth by a factor of 2.4 (34 % vs 82 %), whereas particles with dae = 10 µm exhibit a nasal deposition that exceeds oral deposition by a factor of 2.7 (32 % vs 86 %; Fig 3A). An increase of the tidal volume and maintenance of the flow rate (breathing scenario 2) has only negligible effects on the deposition curves (Fig 3B). Enhancement of the flow rate (breathing scenario 3) does not cause a remarkably change of intermediate-sized particle deposition with respect to breathing scenario 1. In contrast, large particles exhibit a partly dramatic increase in deposition (10 µm: 45 % in mouth, 96 % in nose), whilst ultrafine particles deposit in the extrathoracic passages with reduced efficiencies (1 nm: 23 % in mouth, 48 % in nose; Fig 3C). By reducing the flow rate (breathing scenario 4), large particle deposition is again subject to a decrease, and ultrafine particle deposition tends to a maximum (Fig 3D).

The main difference between extrathoracic and bronchial particle deposition consists in the circumstance that particles inhaled through the mouth are more effectively accumulated in the bronchial tubes than particles inhaled through the nose (Fig 4). The graphs of Fig 4 reveal phenomena differing in some parts from those introduced above. In general, deposition based on oral breathing varies between 3 % and 60 %, whilst deposition following the breathing through the nose exhibits values between 2 % and 20 %. Increase of the tidal volume but maintenance of the flow rate causes an increase of ultrafine and large particle deposition (Fig 4B). Accumulation of particles with intermediate sizes remains unaffected. Due to the increase of the flow rate (breathing scenario 3) ultrafine particles are subject to an enhanced collision with the bronchial walls (Fig 4C). By decreasing the flow rate (breathing scenario 4), deposition of large particles is enhanced again, thereby partly exceeding the respective accumulation efficiency of ultrafine particles (Fig 4D).

As revealed by the total deposition graphs, highest deposition efficiencies in the human respiratory system may be attested for those particles which either are very small, thereby commonly adopting diameters ae ≈ 3-10 µm), whilst particles with intermediate sizes are to a significant extent expired from the respiratory tract again. Hence, highest danger for both the irradiation of epithelial cells and the malignant transformation of lung tissues emanates from aerosols containing either ultrafine or large particles (5,38). The reason for ultrafine and large carrier particles being deposited in high amounts in the respiratory tract is given by the deposition mechanisms affecting these specific particle classes. Whilst aerosols adopting diameters Table 1), particles with diameters >2 µm increasingly tend to be deposited by inertial impaction and gravitational settling (Table 1) (5,22,23,38,40). For intermediately sized aerosols the very specific phenomenon of pulmonary particle transport with low influence of deposition forces may be observed, resulting in the U-shaped total deposition functions presented in Fig 2.

Predictions of regional aerosol depositions clearly demonstrate that particles belonging to the two size categories mentioned above are preferably accumulated in the extrathoracic compartment and the upper bronchi, so that resulting carcinomas may be also localized at the respective sites. Intermediately sized particles, as far as being deposited in the human respiratory system, are chiefly accumulated in the distal bronchioles and the alveoli. As demonstrated by respective computations maximal alveolar deposition is restricted to rather small particle diameter intervals: particles with d_ae ≈ 0.04 µm and d_ae ≈ 2 µm have the alveolar region as their primary target and, thus, may cause enhanced cellular damage within this part of the lung. As already demonstrated in earlier investigations (40,41), distribution of cancer progenitor cells (e.g., goblet cells, brush cells, basal cells) differs among the single compartments of the respiratory tract (Fig 7). Besides this significant factor also the airway surface area, serving for the computation of doses per cm² (doses per g) is subject to a remarkable change from proximal to distal lung regions, with alveolar surface being ≈ 3,500 times larger than bronchial and ≈ 600 times larger than bronchiolar surface (5). The consequence of this circumstance is a much higher probability of malignant transformation and carcinoma growth in the bronchi with respect to the alveoli. The predictions of regional particle deposition are confirmed by the generations-specific deposition plots, where 0.001 µm and 10 µm particles clearly tend to deposit in the proximal airway generations, whereas the remaining particle sizes studied here (0.01 µm, 0.1 µm, 1 µm) preferentially accumulate in intermediate to distal airway generations (40,41).

As undoubtedly illustrated in the deposition graphs of Figs 2-5, model predictions, especially those carried out for mouth breathing, are not always subject to a remarkable correspondence with the respective experimental results. For large particles with dae > 1 µm, theoretical values for extrathoracic deposition (oral path) are significantly underestimated, whilst related values for bronchial deposition are partly much to high. The disagreement of extrathoracic deposition has its main reason in the use of empirical deposition formulae within the model (24) that allow the application of variable extrathoracic volumes but are not sensitive enough for the consideration of intersubject variabilities. Concerning the aspect of variable particle deposition in the mouth and oropharynx of test subjects, the model has to be significantly improved in future by the implementation of current numerical results.

Since the development of lung cancer has to be understood as a long-term process, specific clearance pathways of particulate matter deposited in the bronchial airways and alveoli have to be additionally considered in respective theoretical approaches. In general, large and very small particles chiefly accumulated in the extrathoracic region and proximal airways are preferably removed from the respiratory tract by fast clearance processes (mucociliary elevator), whereas particles with intermediate size and high ability to reach more distal lung parts (see above) are preferably subject to slow clearance mechanisms, significantly increasing their residence times in the bronchial and alveolar compartment (40,42,43).

An essential question concerns the possible effect of breathing mode on deposition. Therefore, the number of hazardous particles reaching the bronchial and alveolar region is remarkably declined by inhalation through the nose. Any change of breathing frequency and tidal volume may handicap deposition of one particle size category but favor deposition of the other. Due to its anatomical specificity including conchae dividing the inhaled air stream and sharply bent airways, the nose acts as a highly efficient filtering system (5), with hazarduous particles being already accumulated in the extrathoracic region. Low breathing frequencies and high tidal volumes decelerate the inhaled air stream, thereby causing an increase of diffusion and sedimentation efficiency but a remarkable decrease of impaction efficiency (5,35,36). High breathing frequencies in combination with low tidal volumes result in a contrary effect.