Abstract  A stochastic model for the calculation of aerosol deposition in human lungs has been developed. In this model the geometry of the airways along the path of an inhaled particle is selected randomly, whereas deposition probabilities are computed by deterministic formulae. The philosophy of the airway geometry selection, the random walk of particles through this geometry and the methods of aerosol deposition calculation in conductive and respiratory airways during a full breathing cycle are presented. The main features of the Monte Carlo code IDEAL-2, written for the simulation of random walks of particles in a stochastic lung model, are briefly outlined.

Abstract  We recorded maximum expiratory flow-volume curves in 3046 healthy persons, blacks and whites, age 7 and over — a representative population of lifetime nonsmokers except for some black adults males, who were healthy smokers or ex-smokers. We computed regression equations for lung function measurements (FVC, FEV1.0, FEV1.0/FVC, PEF, MEF, 50% and MEF 25%) as a function of age, height and weight terms for eight subgroups (by sex and race, and for children or adults). Objective statistical criteria were used to select the optimal equations. Simple linear regressions on age and height are inaccurate, in particular for young adults and for the elderly. Weight affects most function measurements: lung function first increases with weight (‘muscularity effect’)_ and decreases with further increases in weight (‘obesity effect’). The regression equations allow more accurate prediction of normal lung function. In addition, the lower 95% confidence limits are closer to the predicted values and are valid regardless of height, weight and age within each subgroup.

Abstract  The alveolo-bronchial and the lymphatic pathways are most important in pulmonary clearance of relatively insoluble particles. We were interested in studying the effect of the lung burden on the size of the fraction cleared via the lymphatic system. TiO2 particles, representing the “inert and insoluble” class of particulate matter, were used in rats utilizing both intratracheal instillation and inhalation exposures. After a single exposure about 40–45% of the deposited particles are cleared from the lung in 25 days and about 0.7% are found in the hilar lymph nodes at low exposures. At high exposures lung clearance decreases, in some experiments to zero values, and the lymph node content increases to ∼4%. At low exposures both exposure techniques result in similar clearance values; however, the lymphatic node content rises with increased lung burden faster after intratracheal instillation. The possible mechanisms involved are discussed.

Abstract  A new method for recording the respirograms of laboratory animals has been devised. Animals breathe into a headpiece connected by large tubing to a system of chambers which provide a constant flow of fresh air through the headpiece. As the animal breathes, the pressure within the chambers varies, minutely displacing the leaves of an electrical condenser, and by means of a special electrical apparatus a wave is made to rise and fall on the screen of an oscilloscope. The respirogram is then recorded by a continuous camera. Respiratory vols. measured by this method and by valve methods were found to be (in ml./min): mouse 24.5, cotton rat 39.6, hamster 60.9, white rat 72.9, guinea pig 155.6, rabbit 800.0, monkey 863.5, man 8732. It was found that the respiratory vol./min. varies from mice to men approx. with the 3/4 power of the wt.

Abstract  In five normal subjects the total deposition for nose- and mouth-breathing of monodisperse airborne di-2-ethylhexyl sebacate droplets in the diameter range from 0·1 to 3·2 μm was studied for a variety of breathing patterns without respiratory pauses. The calculation of deposition was based upon measurements of the particle number concentration and the respiratory flow rate at the mouth or the nose. For all subjects and all particle sizes deposition fell with increasing gas volume of the respiratory tract. However, when inhalations were initiated at the subjects' normal functional residual capacities no individual differences in deposition for mouth-breathing were found in contrast to nose-breathing deposition. For a constant flow rate the deposition rose with increasing tidal volume, whereas for a constant tidal volume the deposition fell with increasing breathing frequency indicating that time-dependent deposition mechanisms are more effective than velocity-dependent mechanisms. Whenever the mean residence time of the particles in the respiratory tract was short deposition for mouth-breathing was found to be almost independent of particle size in the diameter range below 1 μm revealing the significance of mixing. The deposition values obtained were lower than those usually accepted. The reasons for this are discussed.

Abstract  Data were collected from the literature on respiratory variables and cor-related aginast body weight on the assumption of log-log relationships (allometry) with the use of computer regression analysis. Statistically validated power law formulas, with correlation coefficients of 0. 99-0. 90, are presented for lung weight, VC[long dash]vital capacity, TLC[long dash]total lung capacity, FRC[long dash]functional residual capacity, VT-tidal volume, VD, O2, E. f[long dash]number of breaths/min, Cl[long dash]pulmonary compliance, DLCO-Diffusing capacity of the lung for CO, DLO2-Diffusing capacity of the lung for 02, total respiratory flow resistance, work per breath, and several nonrespiratory parameters. The study deals principally with the rat-human size range, but the prediction formulas probably cover mice to steer and possibly all mammals. Predicted and observed values are compared for the rat, cat, dog, and man; good agreement is demonstrated. Size-independent dimensionless and dimensional respiratory invariants or design parameters may be obtained by forming simple and complex quotients from the individual power laws that have net residual mass exponents (dependency on body weight) approaching zero.

Abstract  A previously developed deposition model is used to determine the total and regional deposition of inhaled aerosols in a population of human lungs by taking into account variability in airway dimensions. The results for particle sizes ranging from 0.1 micron to 8 micron aerodynamic diameter agree favorably with experimental data, thus suggesting that observed intersubject deposition variability is caused primarily by difference in airway dimensions.

Abstract  By extrapolation from the rat study, a mathematical model of deposition, clearance, and retention kinetics for inhaled Ni compounds (high-temperature (green) NiO, Ni(3)S(2), and NiSO(4). 6H(2)O) in the alveolar region of the human lung has been developed. For human deposition, an updated version of an earlier model (C. P. Yu and C. K. Diu, 1982, Am. Ind. Hyg. Assoc. J.) was used in this study. Because of the profound differences in physiological and ventilation conditions between humans and rats, humans were found to have a higher alveolar deposition fraction than rats when exposed to the same Ni compounds. However, when normalized to the lung weight, the deposition rate per gram of lung in humans is much smaller than in rats. In the development of a clearance model, a single-compartment model in the lung was used and a general assumption was made that the clearance of the insoluble and moderately soluble nickel compounds (high-temperature (green) NiO and Ni(3)S(2), respectively) depends highly on the volume of retained particles in the lungs. As for the highly soluble nickel compound (NiSO(4). 6H(2)O), the clearance rate coefficient was assumed to depend on the retained particle mass and total alveolar surface. These clearance rate coefficients were extrapolated from the rat data. The retention half-times for high temperature (green) NiO and Ni(3)S(2) particles in humans were found to be much longer than in rats, whereas the retention half-time for NiSO(4). 6H(2)O particles was about the same for both species. The lung burden results in humans for various exposure conditions are predicted and the equivalent exposure concentrations for humans which lead to the same lung burdens found in rats were calculated.

Abstract  This paper utilizes a comparative approach to establish the relationship between morphometric diffusing capacity for oxygen (DLo2) and maximal oxygen consumption (Vo2max). DLo2 and Vo2max were determined on the same 21 individuals in African mammals spanning a range in body mass from 0.4 to 240kg. We confirmed earlier findings that Dlo2 was proportional to Mb0.99 while Vo2max was proportional to Mb0.79. Thus, the ratio of Dlo2/Vo2 is approximately proportional to Mb0.20. We conclude that large animals require a larger pulmonary diffusing capacity to transfer oxygen at the same rate from air to blood.

Abstract  Ultrafine particles (UFP, particles <100 nm) are ubiquitous in ambient urban and indoor air from multiple sources and may contribute to adverse respiratory and cardiovascular effects of particulate matter (PM). Depending on their particle size, inhaled UFP are efficiently deposited in nasal, tracheobronchial, and alveolar regions due to diffusion. Our previous rat studies have shown that UFP can translocate to interstitial sites in the respiratory tract as well as to extrapulmonary organs such as liver within 4 to 24h postexposure. There were also indications that the olfactory bulb of the brain was targeted. Our objective in this follow-up study, therefore, was to determine whether translocation of inhaled ultrafine solid particles to regions of the brain takes place, hypothesizing that UFP depositing on the olfactory mucosa of the nasal region will translocate along the olfactory nerve into the olfactory bulb. This should result in significant increases in that region on the days following the exposure as opposed to other areas of the central nervous system (CNS). We generated ultrafine elemental 13C particles (CMD = 36 nm; GSD = 1.66) from [13C] graphite rods by electric spark discharge in an argon atmosphere at a concentration of 160 microg/m3. Rats were exposed for 6 h, and lungs, cerebrum, cerebellum and olfactory bulbs were removed 1, 3, 5, and 7 days after exposure. 13C concentrations were determined by isotope ratio mass spectroscopy and compared to background 13C levels of sham-exposed controls (day 0). The background corrected pulmonary 13C added as ultrafine 13C particles on day 1 postexposure was 1.34 microg/lung. Lung 13C concentration decreased from 1.39 microg/g (day 1) to 0.59 microg/g by 7 days postexposure. There was a significant and persistent increase in added 13C in the olfactory bulb of 0.35 microg/g on day 1, which increased to 0.43 microg/g by day 7. Day 1 13C concentrations of cerebrum and cerebellum were also significantly increased but the increase was inconsistent, significant only on one additional day of the postexposure period, possibly reflecting translocation across the blood-brain barrier in certain brain regions. The increases in olfactory bulbs are consistent with earlier studies in nonhuman primates and rodents that demonstrated that intranasally instilled solid UFP translocate along axons of the olfactory nerve into the CNS. We conclude from our study that the CNS can be targeted by airborne solid ultrafine particles and that the most likely mechanism is from deposits on the olfactory mucosa of the nasopharyngeal region of the respiratory tract and subsequent translocation via the olfactory nerve. Depending on particle size, >50% of inhaled UFP can be depositing in the nasopharyngeal region during nasal breathing. Preliminary estimates from the present results show that ~20% of the UFP deposited on the olfactory mucosa of the rat can be translocated to the olfactory bulb. Such neuronal translocation constitutes an additional not generally recognized clearance pathway for inhaled solid UFP, whose significance for humans, however, still needs to be established. It could provide a portal of entry into the CNS for solid UFP, circumventing the tight blood-brain barrier. Whether this translocation of inhaled UFP can cause CNS effects needs to be determined in future studies.

Abstract  National Institute of Environmental Health Sciences.Dosimetry parameters such as deposition, clearance, retention, and translocation and dissolution of inhaled particles in and to different lung compartments may be important for the persistence of particles in the lung and may correlate with adverse pulmonary effects. We investigated such correlations using a model involving TiO2 particles of two particle sizes (20 nm diameter, ultrafine; 250 nm diameter, fine) of the same crystalline structure (anatase). A 12-week inhalation experiment in rats resulted in a similar mass deposition of the two particle types in the lower respiratory tract. The ultrafine particles elicited a persistently high inflammatory reaction in the lungs of the animals compared to the larger-sized particles. In the postexposure period (up to 1 year) retention in the alveolar space per se was not different between fine and ultrafine TiO2. However, the following differences between the particle types were noted: a significantly different total pulmonary retention, both quantitatively (significantly prolonged retention of the ultrafine TiO2) and qualitatively (increased translocation to the pulmonary interstitium and persistence there of the ultrafine TiO2); greater epithelial effects (Type II cell proliferation; occlusion of pores of Kohn) and the beginning of interstitial fibrotic foci with ultrafine TiO2; significant sustained impairment of alveolar macrophage function after ultrafine TiO2 exposure as measured by the clearance of test particles. A correlation between particle surface area and effects was observed. A comparison of the adverse reactions with dosimetric parameters of TiO2 in different lung compartments in the postexposure period showed a correlation of the persistence of effects in both the alveolar and interstitial space with the persistence of particles in the respective compartment.

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 5 microm). 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 2 microm in the small airways and >3 microm 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 microm 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.

Abstract  Regional deposition of inhaled particles was studied experimentally in a hollow cast of the human larynx-tracheobronchial tree extending through the first six branching levels, and in twenty-six non-smoker human volunteers in vivo. Results of the hollow cast study indicated a linear dependence of particle deposition efficiency on the Stokes number for aerosols with aerodynamic diameters greater than 2 micrometers. Alveolar and total respiratory tract in vitro deposition in healthy non-smokers was minimal for particles of approximately 0.4 micrometers, and alveolar deposition for mouthpieces inhalations peaked for particles of approximately 3 micrometers. A new anatomic parameter, the bronchial deposition size (BDS), is introduced to permit the classification of various individuals and populations according to their tracheobronchial deposition efficiencies. The average BDS's were 1.20 cm for 26 healthy non-smokers, 1.02 cm for 46 cigarette smokers, 0.90 cm for 19 clinical patients being treated for obstructive lung disease and 0.60 cm for six severely disabled patients.

Abstract  A thorough analysis of aerosol particle deposition in the human lung requires the knowledge of the distribution of inspired air at respiration. In this paper, a mathematical model of ventilation distribution has been developed using a five-lobe airway model. The model accounts for the nonlinear effects of compliance and resistance on airway dynamics. Ventilation distributions were determined under different gravitational force conditions. A larger gravity leads to a greater nonuniformity of ventilation between the upper and lower lobes of the lung. Ventilation distributions in different lobes of the lung at various inspiratory flow rates were also calculated. At slow inspiratory flow rates, ventilation was found to be nonuniform with more air entering the lower lobes. As the flow rate increased, this nonuniformity became smaller. The calculated results compare favorably with existing experimental data. When a different gas was inspired instead of air, a preferential distribution of ventilation to the upper lobes was found if the density of the inspired gas was greater than that of the air.

Abstract  Lung diseases caused by the inhalation of various particulate pollutants have often been reported to occur at specific sites in the lung with some diseases preferentially occurring in one of the lobes. Models for the dosimetry of particulate matter in the lung, therefore, need to be developed at a level of resolution that allows for the study of lobar- and airway-specific patterns of deposition. Using an approach best described as a combination of multiple- and single-path approaches to modeling lung geometry, we calculated deposition of particulate matter (PM) ranging from ultrafine to coarse particles in each airway down to the level of the lobar bronchi. Further down the airway tree, we calculated deposition averaged over an airway generation in each lung lobe. We compared our results for regional and lobar deposition with various experimental data as well as with results from other models. The calculated results compared reasonably well with experimental data. Significant variations in deposition were observed among the lobar bronchi as well as among the five lobes. The differences among the lobes were accentuated as one examined generation-specific deposition. Deposition per unit surface area of each lobar bronchus was considerably elevated relative to that calculated for the whole lung. The relative distribution of aerosol deposited per unit surface area among the various lobar bronchi was altered by breathing condition and aerosol size. Our observations suggest that a multiple-path model that incorporates the heterogeneous structure of airways in the lung is likely to reduce uncertainties in PM health risk assessments.

Abstract  Models of the lung airways of a rat were developed from complete measurements of the tracheobronchial airways. A silicone rubber cast of the tracheobronchial airways of a rat lung was prepared and all individual airway segments down to and including the terminal bronchioles were measured to obtain the segment diameters, lengths, branching angles and angles of inclination to gravity. Models of the rat tracheobronchial airways were constructed based on the original measurements and the subsequent analysis. Some mathematical assumptions about acinar anatomy distal to terminal bronchioles were made to extend the models to include pulmonary regions. Emphasis was placed on the "Typical Path Lung Model" which used one typical pathway to represent either a whole lung or a lobe of the lung. The models are simple and can be applied in calculation of physiologic variables or particle deposition during inhalation in various lobes of the lung.

Abstract  A quantitative study of postnatal lung growth has been made and shows that the number of alveoli increases over tenfold between birth and adult life. This increase occurs mainly in the first eight years. After this age, increase in lung volume takes place by increase in linear dimensions of existing alveoli. The mean number of generations of airways increases from 21 to 23, from 3 months to 8 years of age. This increase takes place in the most distal respiratory airways. There is a linear relationship between the surface area of the air-tissue interface and the body surface area during the period of growth. It is suggested that information of this type may well be useful in assessing such conditions as pulmonary hypoplasia, respiratory syndrome of the newborn, and the lung in prematurity.

Abstract  Assessing risk of inhaled materials is a challenging endeavor because of the profound interspecies differences in respiratory tract anatomy, physiology, and biochemistry. Recent advances in the availability of mechanistic data and mathematical models for describing dosimetry behavior of particles and gases has lead to improvements in default approaches to risk assessment of inhaled materials. An overview of some of the more well-understood differences between species in factors controlling dosimetry and response, and the default approach of the U.S. Environmental Protection Agency that accounts for many of these factors, are presented. The default methodology also creates a framework which inhalation toxicologists can use to direct research at reducing uncertainty in risk assessments that might otherwise be handled through default uncertainty factors. The optimal approach to risk assessment is to develop chemical-specific mode of action and dosimetry data that can be used quantitatively to replace the entire default approach. The toxicology of vinyl acetate and recent efforts to develop data to supplant assumptions made in the default approach are presented. The conclusion is drawn that the future of inhalation toxicity risk assessment lies in reducing uncertainties associated with interspecies extrapolation and that to do this effectively requires approaches to toxicology that are outside of routine testing paradigms, and are aimed at elucidating mechanisms of action through hypothesis-driven research.

Abstract  There is increasing evidence that inspiratory airflow patterns play a major role in determining the location of nasal lesions induced in rats by reactive, water-soluble gases such as formaldehyde and chlorine. Characteristic lesion patterns have also been seen in inhalation toxicity studies conducted in rhesus monkeys, the nasal anatomy of which resembles that of humans. To examine the hypothesis that regions of high airflow-dependent uptake and lesions occur in similar nasal locations in the primate, airflow and gas uptake patterns were simulated in an anatomically accurate computer model of the right nasal airway of a rhesus monkey. The results of finite-element simulations of steady-state inspiratory nasal airflow for the full range of resting physiological flow rates are reported. Simulated airflow patterns agreed well with experimental observations, exhibiting secondary flows in the anterior nose and streamlined flow posteriorly. Simulated airflow results were used to predict gas transport to the nasal passage walls using formaldehyde as an example compound. Results from the uptake simulations were compared with published observations of formaldehyde-induced nasal lesions in rhesus monkeys and indicated a strong correspondence between airflow-dependent transport patterns and local lesion sites. This rhesus computer model will provide a means for confirming the extrapolation of toxicity data between species by extrapolating rat simulation results to monkeys and comparing these predictions with primate lesion data.

Abstract  In laboratory studies of rodents, the inhalation of organic vapors often results in preferential damage to olfactory epithelium. Such focal lesion formation may be due either wholly or in part to a corresponding nonuniformity in the spatial distribution of vapor uptake within the nasal cavities. As a tool for determining this dose distribution, a mathematical model based on a combination of computational fluid dynamics (CFD) and physiologically based pharmacokinetic (PBPK) modeling was developed for simulating toxicant vapor uptake in the rat nose. The nasal airways were subdivided into four distinct meatuses selected such that each contained a major air flow stream. Each meatus was further divided into four serial regions attached to separate tissue stacks containing mucus, epithelial, and subepithelial compartments. Values for the gas-phase mass transfer coefficients and gas flows in the 16 airway regions were determined by a solution of the Navier-Stokes and convection-diffusion equations using commercially available CFD software. These values were then input to a PBPK simulation of toxicant transport through the 16 tissue stacks. The model was validated by using overall uptake data from rodent inhalation studies for three "unreactive" vapors that were either completely inert (i.e., acetone), reversibly ionized in aqueous media (i.e., acrylic acid), or prevented from being metabolized by an enzyme inhibitor (i.e., isoamyl alcohol). A sensitivity analysis revealed that accurate values of the mass transfer coefficient were not necessary to simulate regional concentrations and uptake of unreactive vapors in the rat nose, but reliable estimates of diffusion coefficients in tissue were crucial for accurate simulations.

Abstract  Currently, translocation of inhaled insoluble nanoparticles (NP) across membranes like the air-blood barrier into secondary target organs (STOs) is debated. Of key interest are the involved biological mechanisms and NP parameters that determine the efficiency of translocation. We performed NP inhalation studies with rats to derive quantitative biodistribution data on the translocation of NP from lungs to blood circulation and STOs. The inhaled NP were chain aggregates (and agglomerates) of either iridium or carbon, with primary particle sizes of 2-4 nm (Ir) and 5-10 nm (C) and aggregate sizes (mean mobility diameters) between 20 and 80 nm. The carbon aggregates contained a small fraction ( < 1%) of Ir primary particles. The insoluble aggregates were radiolabeled with (192)Ir. During 1 h of inhalation, rats were intubated and ventilated to avoid extrathoracic NP deposition and to optimize deep lung NP deposition. After 24 h, (192)Ir fractions in the range between 0.001 and 0.01 were found in liver, spleen, kidneys, heart, and brain, and an even higher fraction (between 0.01 and 0.05) in the remaining carcass consisting of soft tissue and bone. The fractions of (192)Ir carried with the carbon NP retained in STOs, the skeleton, and soft tissue were significantly lower than with NP made from pure Ir. Furthermore, there was significantly less translocation and accumulation with 80-nm than with 20-nm NP aggregates of Ir. These studies show that both NP characteristics--the material and the size of the chain-type aggregates--determine translocation and accumulation in STOs, skeleton, and soft tissue.