Experimental measurements and computational predictions of regional particle deposition in a sectional nasal model.

BACKGROUND: Knowledge of the regional deposition of inhaled particles in the nose is important for drug delivery and assessment of the toxicity of inhaled materials. In this study, computational fluid dynamics (CFD) predictions and experimental measurements in a nasal replica cast were used to study regional deposition of inhaled microparticles. METHODS: The replica cast was sectioned into six regions of interest based on nasal anatomy: the nasal vestibule, nasal valve, anterior turbinates, olfactory region, turbinates, and nasopharynx. Monodisperse fluorescein particles with aerodynamic diameters of 2.6-14.3 µm were passed through the assembled cast in the presence of steady inspiratory airflow at 15 L/min. After each experiment, the cast was disassembled and the deposited fluorescein in each region was washed out and quantified with fluorescence spectrometry. A nasal CFD model was developed from the same magnetic resonance imaging scans that were used to construct the replica cast. Steady-state inspiratory airflow and particle deposition calculations were conducted in the CFD model using Fluent(™) at flow rates producing Stokes numbers comparable to experimental conditions. RESULTS: Total and regional particle deposition predictions from the CFD model were compared with experimental measurements from the replica cast. Overall, good agreement was observed between CFD predictions and experimental measurements with similar deposition trends in each region of interest. CFD predictions in central nasal regions demonstrated well-defined maximum values of 15%, 7%, and 12% in the anterior turbinates, olfactory, and turbinates regions, respectively, at particle sizes of 10-11 µm. CONCLUSIONS: These results demonstrate the use of a sectioned nasal CFD model based on anatomical regions of interest for nasal drug delivery to elucidate patterns of regional deposition within a human nasal cavity.

Inhalation dosimetry of hexamethylene diisocyanate vapor in the rat and human respiratory tracts.

Hexamethylene diisocyanate (HDI) is a reactive chemical used in the commercial production of polyurethanes. Toxic effects in rodents exposed to HDI vapor primarily occur in the nasal passages, yet some individuals exposed occupationally to concentrations exceeding current regulatory limits may experience temporary reduction in lung function and asthma-like symptoms. Knowledge of interspecies differences in respiratory tract dosimetry of inhaled HDI would improve our understanding of human health risks to this compound. HDI uptake was measured in the upper respiratory tract of anesthetized Fischer-344 rats. Nasal uptake of HDI was >90% in rats at unidirectional flow rates of 150 and 300 ml/min and a target air concentration of 200 ppb. Uptake data was used to calibrate nasal and lung dosimetry models of HDI absorption in rats and humans. Computational fluid dynamics (CFD) models of the nasal passages were used to simulate inspiratory airflow and HDI absorption. Transport of HDI through lung airways was simulated using convection-diffusion based mass transport models. HDI nasal uptake of 90% and 78% was predicted using the rat and human nasal CFD models, respectively. Total respiratory tract uptake was estimated to be 99% in rats and 97% in humans under nasal breathing. Predicted human respiratory uptake decreased to 87% under oral breathing conditions. Absorption rates of inhaled HDI in human lung airways were estimated to be higher than the rat due to lower uptake in head airways. Model predictions demonstrated significant penetration of HDI to human bronchial airways, although absorption rates were sensitive to breathing style.

Pharmacokinetics of radiolabeled tungsten ((188)W) in male Sprague-Dawley rats following acute sodium tungstate inhalation.

Aerosol cloud formation may occur when certain tungsten munitions strike hard targets, placing military personnel at increased risk of exposure. Although the pharmacokinetics of various forms of tungsten have been studied in animals following intravenous and oral administration, tungsten disposition following inhalation remains incompletely characterized. The objective of this study was to evaluate the pharmacokinetics of inhaled tungstate (WO(4)) in rats. Male, 16-wk-old, CD rats (n = 7 rats/time point) underwent a single, 90-min, nose-only exposure to an aerosol (mass median aerodynamic diameter [MMAD] 1.50 mum ) containing 256 mg W/m(3) as radiolabeled sodium tungstate (Na(2)(188)WO(4)). (188)W tissue concentrations were determined at 0, 1, 3, 7, and 21 days postexposure by gamma spectrometry. The thyroid and urine had the highest (188)W levels postexposure, and urinary excretion was the primary route of (188)W elimination. The pharmacokinetics of tungsten in most tissues was best described with a two-compartment pharmacokinetic model with initial phase half-lives of approximately 4 to 6 h and a longer terminal phase with half-lives of approximately 6 to 67 days. The kidney, adrenal, spleen, femur, lymph nodes, and brain continued to accumulate small amounts of tungsten as reflected by tissue:blood activity ratios that increased throughout the 21-day period. At day 21 all tissues except the thyroid, urine, lung, femur, and spleen had only trace levels of (188)W. Data from this study can be used for development and refinement of pharmacokinetic models for tungsten inhalation exposure in environmental and occupational settings.

Inhaled carbon nanotubes reach the subpleural tissue in mice.

Carbon nanotubes are shaped like fibres and can stimulate inflammation at the surface of the peritoneum when injected into the abdominal cavity of mice, raising concerns that inhaled nanotubes may cause pleural fibrosis and/or mesothelioma. Here, we show that multiwalled carbon nanotubes reach the subpleura in mice after a single inhalation exposure of 30 mg m(-3) for 6 h. Nanotubes were embedded in the subpleural wall and within subpleural macrophages. Mononuclear cell aggregates on the pleural surface increased in number and size after 1 day and nanotube-containing macrophages were observed within these foci. Subpleural fibrosis unique to this form of nanotubes increased after 2 and 6 weeks following inhalation. None of these effects was seen in mice that inhaled carbon black nanoparticles or a lower dose of nanotubes (1 mg m(-3)). This work suggests that minimizing inhalation of nanotubes during handling is prudent until further long-term assessments are conducted.

Interindividual variability in nasal filtration as a function of nasal cavity geometry.

BACKGROUND: Interindividual variability in nasal filtration is significant due to interindividual differences in nasal anatomy and breathing rate. Two important consequences arise from this variation among humans. First, devices for nasal drug delivery may furnish quite different doses in the nasal passages of different individuals, leading to different responses to therapeutic treatment. Second, people with poor nasal filtration may be more susceptible to adverse health effects when exposed to airborne particulate matter (PM) due to greater lung deposition. Although interindividual variability of nasal filtration has been reported by several authors, a relationship for predicting filtration efficiency from nasal anatomy and ventilation is still lacking. Such a relationship is needed to (1) devise nasal drug delivery systems and (2) define limits of exposure to PM that are effective for the human population at large. METHODS: Anatomically correct nasal replicas of five adults (four healthy individuals and one atrophic rhinitis patient) were used in aerosol experiments to measure nasal deposition of 1-12-microm particles. The dependence of nasal filtration on nasal anatomy and breathing rate was investigated using various definitions of the Stokes number as well as phenomenological Impaction Parameters proposed in the literature. RESULTS: Interindividual variability among the healthy adults was nearly eliminated when nasal filtration was plotted against a specific definition of the Stokes number or against a pressure-based Impaction Parameter. Nasal filtration in the atrophic rhinitis patient was lower than in the healthy subjects. CONCLUSIONS: The new definition of the Stokes number introduced in this study, which is based on a new definition of the characteristic diameter of the nasal passages, nearly eliminated interindividual differences in nasal filtration. Our results suggest that it is possible to estimate nasal filtering efficiency using measurements of transnasal pressure drop.

Inhaled multiwalled carbon nanotubes potentiate airway fibrosis in murine allergic asthma.

Carbon nanotubes are gaining increasing attention due to possible health risks from occupational or environmental exposures. This study tested the hypothesis that inhaled multiwalled carbon nanotubes (MWCNT) would increase airway fibrosis in mice with allergic asthma. Normal and ovalbumin-sensitized mice were exposed to a MWCNT aerosol (100 mg/m(3)) or saline aerosol for 6 hours. Lung injury, inflammation, and fibrosis were examined by histopathology, clinical chemistry, ELISA, or RT-PCR for cytokines/chemokines, growth factors, and collagen at 1 and 14 days after inhalation. Inhaled MWCNT were distributed throughout the lung and found in macrophages by light microscopy, but were also evident in epithelial cells by electron microscopy. Quantitative morphometry showed significant airway fibrosis at 14 days in mice that received a combination of ovalbumin and MWCNT, but not in mice that received ovalbumin or MWCNT only. Ovalbumin-sensitized mice that did not inhale MWCNT had elevated levels IL-13 and transforming growth factor (TGF)-beta1 in lung lavage fluid, but not platelet-derived growth factor (PDGF)-AA. In contrast, unsensitized mice that inhaled MWCNT had elevated PDGF-AA, but not increased levels of TGF-beta1 and IL-13. This suggested that airway fibrosis resulting from combined ovalbumin sensitization and MWCNT inhalation requires PDGF, a potent fibroblast mitogen, and TGF-beta1, which stimulates collagen production. Combined ovalbumin sensitization and MWCNT inhalation also synergistically increased IL-5 mRNA levels, which could further contribute to airway fibrosis. These data indicate that inhaled MWCNT require pre-existing inflammation to cause airway fibrosis. Our findings suggest that individuals with pre-existing allergic inflammation may be susceptible to airway fibrosis from inhaled MWCNT.

Respiratory deposition and inhalability of monodisperse aerosols in Long-Evans rats.

Because of limitations on conducting exposure experiments using human subjects to evaluate adverse health effects, the deposition and fate of airborne particles in animals are often studied. The results of such studies are extrapolated to humans to estimate equivalent dose and subsequent response. In this article, particle inhalability and respiratory deposition of micron-size particles are determined for female Long-Evans rats. Monodisperse aerosols were generated from a solution of radiolabeled iron chloride ((59)FeCl(3)). Long-Evans rats were exposed to the radiolabeled particles in a Cannon nose-only exposure tower to determine head, lung lobar, and total lung deposition fractions. Particle deposition fractions in a hypothetical situation, when all particles are inhalable, were found from an experimentally validated deposition model. Particle inhalability in a Cannon nose-only exposure scenario was obtained by comparing the measured deposition fractions with the predicted values for the case of 100% inhalability. Particle deposition fraction and inhalability were compared with data available in the literature. For large particles, the measured deposition fraction was lower than the literature values. Consequently, our inhalability estimates were found to be lower than previously published values. The findings here will directly affect health risk assessments in humans from exposure to airborne particles. The deposition results will improve the database on particle deposition in the lung airways of rats, and inhalability information will improve the accuracy of rat-to-human data extrapolation.