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Dosimetry provides information linking environmental exposures to sites of deposition, removal from these sites, and translocation of deposited materials. Dosimetry also aids in extrapolating laboratory animal and in vitro data to humans. Recent progress has shed light on: properties of particles in relation to their fates in the body; influence of age, gender, body size, and lung diseases on inhaled particle doses; particle movement to the brain via the olfactory nerves; and particle deposition hot spots in the respiratory tract. Ultrafine size has emerged as an important dosimetric characteristic. Particle count, composition, and surface properties are recognized as potentially important toxicology-related considerations. Differences in body size influence airway sizes, inhaled particle deposition, specific ventilation, and specific doses (e.g. per unit body mass). Related to body size, age, gender, species, and strain are also dosimetric considerations. Diseases, such as chronic obstructive pulmonary disease (COPD) and bronchitis, produce uneven doses within the respiratory tract. Traditional concepts of the translocation and clearance of deposited particles have been challenged. Ultrafine particles can translocate to the brain via olfactory nerves, and from the lung to other organs. The clearance rates of particles from tracheobronchial airways are slowed by respiratory tract infections, but newer evidence implies that slow particle clearance from this region also exists in healthy lungs. Finally, hot spots of particle deposition are seen in hollow models, lung tissue, and dosimetric simulations. Local doses to groups of epithelial cells can be much greater than those to surrounding cells. The new insights challenge dosimetry scientists.

A mobile whole-body exposure system was developed for exposing mice to concentrated ambient particulate matter smaller than 2.5 microm in mass median aerodynamic diameter (MMAD). Each 20-L exposure cage was designed to hold 9 mice within individual compartments. This allowed for transport and subsequent exposure. Airflow mixing and the potential for stagnant areas within the compartments were modeled using computational fluid dynamic modeling (CFD). CFD analysis showed no stagnant areas and good mixing throughout the exposure cage. The actual performance of the exposure system was determined for 0.5 to 2.0 microm diameter aerosols by measuring (1) uniformity of aerosol distribution and (2) particle deposition in the tracheobronchial and pulmonary regions of mice exposed in the system. A 0.6-microm MMAD (GSD=2.0) cigarette smoke aerosol was used to experimentally measure the uniformity of aerosol distribution to the nine individual compartments. The average data from three runs showed no statistically significant difference among individual compartments. Particle deposition efficiency in adult male BALB/c mice was measured after exposure (30 min) in the system using monodisperse fluorescent polystyrene latex particles (0.5, 1, and 2 microm aerodynamic diameter). The measured deposition efficiency in this mobile exposure system for the combined tracheobronchial and pulmonary regions of the adult male BALBc mice was 21% for 0.5 microm, 11% for 1.0 microm, and 6.5% for 2.0 microm particles. These deposition efficiencies are similar to those reported for mice exposed in a nose-only exposure system, which indicates that particle losses to animal fur and exposure system surfaces were acceptable.

This study assessed the effects of repeated exposure to environmentally realistic levels of two urban air pollutants nitric acid vapor (HNO3) and ozone (O3) - on tracer particle clearance from the rat respiratory tract. The measurement of particle clearance efficiency is important because failure of this function could contribute to a buildup of foreign matter in the respiratory tract. Separate groups of rats (30 rats per group) were exposed nose-only for 4 h/day, 3 days/wk (a surrogate for an air pollution episode) for 40 wk to 4 atmospheres: purified air; 0.15 ppm O3; 50 μg/m3 HNO3; and 0.15 ppm O3 + 50 μg/m3 HNO3. At 4 wk prior to the end of the exposure, the rats inhaled radiolabeled tracer particles nose-only for 30 min. A clearance measurement protocol was then followed to estimate the rates of early and late clearance. Early (presumably upper respiratory tract) clearance was monitored during the 48 h following tracer deposition by the analysis of radioactivity excreted in the feces, while late (presumably deep lung) clearance was characterized by a combination of chest counting and 30 day postexposure sacrifice radioactivity analyses. The exposure to O3, both alone and in combination with HNO3, produced a more than 30% (statistically significant) delay during the initial phase of upper respiratory tract clearance, and all of the pollutant exposures may have stimulated deep lung clearance. The directions of these effects were the same as those observed previously when rats were acutely exposed to O3- containing atmospheres.

This study was performed to assess the effects of two high concentrations (about 380 mg/m3 and about 38 mg/m3) of inhaled cigarette smoke on tracer particle clearance from the head airways region and the thoracic (primarily deep lung) region of ferrets exposed during postnatal respiratory tract development. Ferrets were exposed 2 h/days, 5 days/wk to purified air or to the smoke aerosols starting at 5 wk of age, for a total of 15 wk of exposure. Three weeks prior to the end of the 15-wk exposure regimen, radiolabeled tracer particles were deposited by inhalation, and the clearance rates from the head airways and thoracic regions were monitored for 18 days. The head airways counting data were accurately fit by a double exponential function, reflecting fast-clearing and slow-clearing components. The thoracic counting data were adequately fit by a single exponential function. Statistically significant accelerations of particle clearance rates were observed for the slow-clearing and fast-clearing phases of clearance from the head airways region for both the higher and lower concentration groups; the results implied a dose-response relationship. Only in the case of the higher concentration group was significant slowing observed in the thoracic region analysis, indicating that the head airways region was perhaps the area of greater impact of the smoke aerosol. © 1994 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

Computational fluid dynamic (CFD) techniques have provided unprecedented opportunity for investigating inhaled particle deposition in realistic human airway geometries. Several recent articles describing local aerosol deposition predictions based upon “validated” CFD models have highlighted the challenges in validating local aerosol deposition predictions. These challenges include: (1) defining what is meant by validation; (2) defining appropriate experimental data for validation; and (3) determining when the agreement is not fortuitous. The term validation has numerous meanings, depending on the field and context in which it is used. For example, in computer programming it means the code executes as intended, to the experimentalist it means predicted results agree with matched experimental measurements, and to the risk assessor it implies that predictions using new parameters can be trusted. Based on the current literature it is not clear that a consensus exists for what constitutes a validated CFD model. It is also not clear what types of experimental data are needed or how closely the CFD input values and experimental conditions should be matched (similar or identical airway geometries, entrance airflow, or aerosol profiles) to validate CFD derived predictions. Due to the complexity of CFD computer codes and the multiplicity of deposition mechanisms, it is possible that total aerosol deposition may be accurately predicted and the resulting local particle deposition patterns are incorrect, or vice versa. Specific examples and suggestions for several challenges to experimentalists and modelers are presented. [ABSTRACT FROM AUTHOR]

Most current deterministic computer dosimetry models use idealized dichotomous symmetrical infant, child, and adolescent tracheobronchial geometries for dosimetry predictions. These tracheobronchial geometries were derived from either the morphometric measurements of J. D. Mortensen and colleagues or those of R. F. Phalen and colleagues. The airway growth curves used to create these geometries are typically means from all airways within a single generation in the tracheobronchial tree. This idealized approach implies that the growth rate of all airways in the same generation is identical (symmetric growth, SG), which is unlikely. In this study, existing morphometric measurements of airway dimensions were used to determine growth equations for airway length, diameter, branch angle, and inclination to gravity as a function of body height for each airway in the first four tracheobronchial generations. Tracheobronchial geometries (asymmetrical growth, AG) were created from these growth curves for the first 4 tracheobronchial generations representing a 4- and 11-yr-old child and an adult. Particle deposition predictions for steady inspiratory flow using 0.1- to 20-μm diameter monodisperse particles in these AG geometries were compared with predictions using the SG geometries using the uniform growth rate approach. Each airway in the first four generations had a unique airway length and diameter growth rate. Airway branch angle and inclination to gravity did not change as a function of body height. The unique airway growth rates resulted in significant differences in predicted deposition efficiency between the AG and SG geometry. Use of AG geometry may provide improved estimates of regional particle deposition in infants, children, and adolescents. [ABSTRACT FROM AUTHOR]

A foreword to "Inhalation Toxicology" is presented.

In order to better understand aerosol dynamics and deposition in the complex flow field of the respiratory tract, both in vitro experiments and numerical modeling techniques have widely been employed. Computational fluid dynamics (CFD) modeling offers the flexibility of easily modifying system parameters such as flow rates, particle sizes, system geometry, and heterogeneous outlet conditions. However, a number of numerical errors and artifacts can lead to nonphysical CFD results. Experimental methods offer the advantage of physical realism; however, parameter variation is often difficult. The objective of this study is to illustrate the use of CFD to enhance the understanding of experimental results. In parallel, the selected experimental results have been used to partially validate the CFD predictions. A specific case study has been considered focusing on 1-mum particle depositions in a physiologically realistic bifurcation (PRB) model of respiratory generations 3-5. Previous experiments in this system report a deposition rate of approximately 0.01%. An in-depth CFD analysis has been employed to evaluate two cases of the empirical model. The first case consists of only the PRB double bifurcation geometry. The second case includes a portion of the experimental particle delivery system, which may influence the entering velocity and particle profiles. To assess the influence of upstream transition and turbulence, each of the two cases considered has been evaluated using laminar and low Reynolds number k-omega approximations. Results indicate that both upstream flow effects and turbulent or transitional flow play a significant role in determining the deposition of 1-mum particles in the model considered. Simulating upstream flow effects and laminar flow was required to match the empirically reported deposition fraction and provided a two orders of magnitude improvement over initial CFD estimates. This study highlights the need to consider the effects of experimental particle generation systems on velocity and particle profiles entering respiratory models. Future work is necessary to investigate the mechanisms responsible for the experimentally observed local deposition patterns.