Bahman Asgharian

Particle deposition in a multiple-path model of the human lung

Predicting the amount of particle deposition in the human lung following exposure to airborne particulate matter is the first step toward evaluating risks associated with exposure to airborne pollutants. Realistic deposition models are needed for accurate predictions of deposition in the lung, but a major limitation is the degree to which the lung geometry can be accurately reconstructed. Morphometric data for the entire airway tree of the human lung are not available. So far, idealistic lung structures have been used for deposition calculations. In this study, 10 statistical lung structures based on morphometric measurements of Raabe et al. (1976) were generated for the conducting airways of the human lung. A symmetric, dichotomous branching alveolar airway structure was attached to the end of the conducting airway tree of each lung structure. The total volume of the alveolar region was the same among the lung geometries. Using a mathematical scheme developed previously (Anjilvel and Asgharian 1995), reg...

Reduction of benzene metabolism and toxicity in mice that lack CYP2E1 expression

Transgenic CYP2E1 knockout mice (cyp2e1-/-) were used to investigate the involvement of CYP2E1 in the in vivo metabolism of benzene and in the development of benzene-induced toxicity. After benzene exposure, absence of CYP2E1 protein was confirmed by Western blot analysis of mouse liver samples. For the metabolism studies, male cyp2e1-/- and wild-type control mice were exposed to 200 ppm benzene, along with a radiolabeled tracer dose of [14C]benzene (1.0 Ci/mol) by nose-only inhalation for 6 hr. Total urinary radioactivity and all radiolabeled individual metabolites were reduced in urine of cyp2e1-/- mice compared to wild-type controls during the 48-hr period after benzene exposure. In addition, a significantly greater percentage of total urinary radioactivity could be accounted for as phenylsulfate conjugates in cyp2e1-/- mice compared to wild-type mice, indicating the importance of CYP2E1 in oxidation of phenol following benzene exposure in normal mice. For the toxicity studies, male cyp2e1-/-, wild-type, and B6C3F1 mice were exposed by whole-body inhalation to 0 ppm (control) or 200 ppm benzene, 6 hr/day for 5 days. On Day 5, blood, bone marrow, thymus, and spleen were removed for evaluation of micronuclei frequencies and tissue cellularities. No benzene-induced cytotoxicity or genotoxicity was observed in cyp2e1-/- mice. In contrast, benzene exposure resulted in severe genotoxicity and cytotoxicity in both wild-type and B6C3F1 mice. These studies conclusively demonstrate that CYP2E1 is the major determinant of in vivo benzene metabolism and benzene-induced myelotoxicity in mice.

Particle Deposition in Human Nasal Airway Replicas Manufactured by Different Methods. Part II: Ultrafine Particles

Information on the deposition efficiency of aerosol particles in the nasal airways is used for optimizing the delivery of therapeutic aerosols into the nose and for risk assessment of toxic airborne pollutants inhaled through the nose into the respiratory system. Nasal particle deposition is often studied using plastic replicas of nasal airways. Deposition efficiency in a nasal replica manufactured by stereolithography has not been reported to date. We determined the inertial particle deposition efficiency of two replicas of the same nasal airways manufactured by different stereolithography machines and compared results with deposition efficiencies reported for models manufactured by other techniques from the same magnetic resonance imaging scans. Deposition in the replicas was measured for particles of aerodynamic diameter between 1 and 10 μm and constant inspiratory flow rates ranging from 20–40 Ipm. Deposition efficiency of the replicas increased from nearly 0–100% with increasing particle inertia. For a range of particle inertias, particle deposition in the replica made with higher resolution stereolithography machine was slightly less than in the replica made with a lower resolution stereolithography process. These data showed lower deposition efficiency when compared with other deposition studies in nasal replicas based on the same magnetic resonance imaging data. The differences in deposition efficiency can be attributed in part to differences in methods used to manufacture the replicas. There was little or no difference in deposition due to cutting tool size, some difference due to the use of assembly plates, and some difference due to surface roughness. These associations suggest that inertial nasal particle deposition is significantly influenced by small differences in nasal airways.

Deposition of Ultrafine (NANO) Particles in the Human Lung

Increased production of industrial devices constructed with nanostructured materials raises the possibility of environmental and occupational human exposure with consequent adverse health effects. Ultrafine (nano) particles are suspected of having increased toxicity due to their size characteristics that serve as carrier transports. For this reason, it is critical to refine and improve existing deposition models in the nano-size range. A mathematical model of nanoparticle transport by airflow convection, axial diffusion, and convective mixing (dispersion) was developed in realistic stochastically generated asymmetric human lung geometries. The cross-sectional averaged convective-diffusion equation was solved analytically to find closed-form solutions for particle concentration and losses per lung airway. Airway losses were combined to find lobar, regional, and total lung deposition. Axial transport by diffusion and dispersion was found to have an effect on particle deposition. The primary impact was in the pulmonary region of the lung for particles larger than 10 nm in diameter. Particles below 10 nm in diameter were effectively removed from the inhaled air in the tracheobronchial region with little or no penetration into the pulmonary region. Significant variation in deposition was observed when different asymmetric lung geometries were used. Lobar deposition was found to be highest in the left lower lobe. Good agreement was found between predicted depositions of ultrafine (nano) particles with measurements in the literature. The approach used in the proposed model is recommended for more realistic assessment of regional deposition of diffusion-dominated particles in the lung, as it provides a means to more accurately relate exposure and dose to lung injury and other biological responses.

Thoracic and respirable particle definitions for human health risk assessment.

BackgroundParticle size-selective sampling refers to the collection of particles of varying sizes that potentially reach and adversely affect specific regions of the respiratory tract. Thoracic and respirable fractions are defined as the fraction of inhaled particles capable of passing beyond the larynx and ciliated airways, respectively, during inhalation. In an attempt to afford greater protection to exposed individuals, current size-selective sampling criteria overestimate the population means of particle penetration into regions of the lower respiratory tract. The purpose of our analyses was to provide estimates of the thoracic and respirable fractions for adults and children during typical activities with both nasal and oral inhalation, that may be used in the design of experimental studies and interpretation of health effects evidence.MethodsWe estimated the fraction of inhaled particles (0.5-20 μm aerodynamic diameter) penetrating beyond the larynx (based on experimental data) and ciliated airways (based on a mathematical model) for an adult male, adult female, and a 10 yr old child during typical daily activities and breathing patterns.ResultsOur estimates show less penetration of coarse particulate matter into the thoracic and gas exchange regions of the respiratory tract than current size-selective criteria. Of the parameters we evaluated, particle penetration into the lower respiratory tract was most dependent on route of breathing. For typical activity levels and breathing habits, we estimated a 50% cut-size for the thoracic fraction at an aerodynamic diameter of around 3 μm in adults and 5 μm in children, whereas current ambient and occupational criteria suggest a 50% cut-size of 10 μm.ConclusionsBy design, current size-selective sample criteria overestimate the mass of particles generally expected to penetrate into the lower respiratory tract to provide protection for individuals who may breathe orally. We provide estimates of thoracic and respirable fractions for a variety of breathing habits and activities that may benefit the design of experimental studies and interpretation of particle size-specific health effects.

Modeling intersubject variability of particle deposition in human lungs

Abstract The morphological variability in human lungs was simulated by 10 multiple-path lung models, generated on the basis of probability distributions and correlations of airway parameters provided by the stochastic lung model of Koblinger and Hofmann (Phys. Med. Biol. 30 (1985) 541). Total, regional and generation-per-generation deposition was computed for particle sizes in the range of 0.01– 10 μm under resting breathing conditions. Our calculations suggest that structural and volumetric differences of lung morphologies among different individuals are primarily responsible for the experimentally observed intersubject variability in total and regional deposition under controlled breathing conditions. Individual differences in deposition among single airways can be substantially larger than those in total and regional deposition. Furthermore, variations are most pronounced for small (0.01 μm ) and large (10 μm ) particles.

Dosimetric Adjustments for Interspecies Extrapolation of Inhaled Poorly Soluble Particles (PSP)

Abstract Direct calculation of delivered dose in the species of interest potentially affects the magnitude of an uncertainty factor needed to address extrapolation of laboratory animal data to equivalent human exposure scenarios, thereby improving the accuracy of human health risk estimates. Development of an inhalation reference concentration (RfC) typically involves extrapolation of an effect level observed in a laboratory animal exposure study to a level of exposure in humans that is not expected to result in an appreciable health risk. The default dose metric used for respiratory effects is the average deposited dose normalized by regional surface area. However, the most relevant dose metric is generally one that is most closely associated with the mode of action leading to the response. Critical factors in determining the best dose metric to characterize the dose-response relationship include the following: the nature of the biological response being examined; the magnitude, duration, and frequency of the intended exposure scenario; and the mechanisms by which the toxicants exert their effects. Dosimetry models provide mechanistic descriptions of these critical factors and can compute species-specific dose metrics. In this article, various dose metrics are postulated based on potential modes of action for poorly soluble particles (PSP). Dosimetry models are used to extrapolate the internal dose metric across species and to estimate the human equivalent concentration (HEC). Dosimetry models for the lower respiratory tract (LRT) of humans and rats are used to calculate deposition and retention using the principle of particle mass balance in the lower respiratory tract. Realistic asymmetric lung geometries using detailed morphometric measurements of the tracheobronchial (TB) airways in rats and humans are employed in model calculations. Various dose metrics are considered for the TB and pulmonary (P) regions. Because time is an explicit parameter incorporated in species-specific constants such as mucociliary clearance rates used in the models, the impact of the application of optimal model structures to refine adjustments and assumptions used in default risk assessment approaches to address exposure duration are discussed. HEC estimates were found for particles ranging in sizes that corresponded to existing toxicity studies of PSP (0.3 to 5μm). A dose metric expressed as number of particles per biologically motivated normalization factors (e.g., number of ventilatory units, number of alveoli, and number of macrophages) was lower than the current default of mass normalized to regional surface area for either deposited or retained dose estimates. Retained dose estimates were lower than deposited dose estimates across all particle sizes evaluated. Dose metrics based on the deposited mass per unit area in small and large airways of the TB region indicate HECs of 1 to 5 times those of rats: that is, an equivalent exposure to humans which would achieve the same internal dose as in the rat would be 1 to 5 times greater. HEC estimates in the TB region increase with an increase in particle size for particles from 0.3 to ≤ 2μm, then decrease with an increase in particle size for particles >2 μm in the small airways and >3 μm in the large airways. The HEC decreases with increase in particle size in the P region across all particle sizes studied, and the decrease has a more significant slope for those particles >2 μm due to the limited inhalability of particles this size in rats relative to humans. Our modeling results elucidate a number of important issues to be considered in assessing current default approaches to dosimetry adjustment for inhaled PSP. Simulation of realistic, polydisperse particle distributions for the human exposure scenario results in reduced HEC estimates compared to estimates derived with the experimental particle distribution used in the laboratory animal study. Consideration should be given also to replacing the default dose metric of normalized deposited dose in the P region with normalized retained dose. Chronic effects are more likely due to retained dose and estimates calculated using retained versus deposited mass are shown to be lower across all particle sizes. Because dose metrics based on normalized particle number rather than normalized mass result in lower HEC estimates, use of inhaled mass as the default should also be revisited, if the pathogenesis suggests particle number determines the mode of action. Based on demonstrated age differences, future work should pursue the construction of “lifetime” estimates calculated by sequentially appending simulations for each specific age span.

Mucociliary clearance of insoluble particles from the tracheobronchial airways of the human lung

Mucociliary clearance of deposited particles in the conducting airways of the human lung was investigated using various symmetric and stochastically generated asymmetric models of the conducting tree. Mucous velocities in all airways of the conducting airways were calculated from the principle of mass balance for the mucus. These velocities were used to calculate particle residence time in all the airways of the conducting tree. Equations for the transport of particles by the mucous escalator were developed and solved numerically. The retained mass in the tracheobronchial region was calculated for a scenario of 1 h exposure followed by 2 days of post exposure. Initial deposition pattern of particles in the conducting airways was found to be crucial for the analysis of retention curves. Particles deposited in peripheral bronchiolar airways of asymmetric stochastic lungs cleared more slowly than those in more central airways. Consequently, the retention curves of the stochastic lungs with a greater number of bronchial generations exhibited longer tails than those of symmetric lungs. The results indicated that the asymmetric stochastic lung models may predict significant lung burdens even after 24 h. The extent of the difference in inter-subject variability in retained particle mass may partially explain the observation of investigators regarding greater than expected retained mass in the TB region after 24 h, without invoking any additional slow bronchial clearance mechanisms.

Inertial and Gravitational Deposition of Particles in a Square Cross Section Bifurcating Airway

Deposition of spherical particles in an airway bifurcation is studied numerically. Airway dimensions are based on the third airway generation of the Weibel symmetric lung model (1963). A square cross-sectional airway area is assumed, with parent and daughter tubes having different diameters. The flow field is solved by a finite element method for Reynolds numbers of 100 and 1000 with uniform and parabolic parent inlet velocities. The flow field is then used to calculate particle deposition in this geometry. Deposition by the mechanisms of impaction and sedimentation are incorporated. The results show that for particles larger than 10 μm, sedimentation losses are weakly dependent on the flow Reynolds number and the inlet condition, whereas impaction losses depend strongly on Reynolds number and inlet condition. Also, the calculated results gave good agreement with the predictive model of Pich (1972) for sedimentation losses in flows through parallel plates. For losses by impaction, the calculated results a...

A Model of Deposition of Hygroscopic Particles in the Human Lung

Many aerosols in the environment are hygroscopic and grow in size once inhaled into the humid respiratory tract. The deposited amount and the distribution of the deposited particles among airways differ from insoluble particles of the same initial diameter. As particles grow in size, diffusive behavior tends to diminish while impaction and sedimentation effects increase. A multiple-path model for deposition of hygroscopic particles in the respiratory tract was developed for symmetric and asymmetric lung geometries by implementing particle size change in a model of insoluble particle deposition in lungs. Particle growth by molecular diffusion of water vapor to the particle surface was formulated. The growth model included temperature depression, solute, Kelvin, and Fuchs effects. Particle growth during travel time in each lung airway was computed. Average loss efficiency per airway was calculated by incorporating contributions from particles of various sizes acquired in that airway. A mass balance on the number of particles that entered, exited, deposited, or remained suspended was performed per airway to obtain regional and local deposition fractions of particles in the lung. The deposition fractions calculated for salt particles showed a drop for submicrometer particles in the tracheobronchial region and a significant increase in deposition for micrometer particles or larger. Consequently, very few fine and coarse salt particles reached the alveolar region to be available for deposition. Overall, lung deposition of ultrafine particles decreased for salt particles. Deposition for fine and coarse salt particles in the lung was larger than that of insoluble particles of the same initial particle size.