G.A. Ferron

Model for the Deposition of Aerosol Particles in the Respiratory Tract of the Rat. I. Nonhygroscopic Particle Deposition

Rats are used to test the toxicological and pharmacological effects of aerosol particles on the organism. For estimates of the delivered aerosol dose, lung deposition models provide a valuable tool. Here a previously developed deposition model for nonhygroscopic and hygroscopic aerosol particles in the lungs of man (Ferron et al., J. Aerosol Sci. 1988, 19:611) is adapted to the rat by implementing a lung structure for the rat combined with empirical equations for particle deposition due to impaction/sedimentation in the extrathoracic region and in bifurcations. To account for the effect of body weight (BW) on the physiological parameters (lung size, respiration frequency) we present BW-scaling laws with an estimated accuracy of about 16%. The present model shows good agreement with the measured total deposition (per breath) and other models from the literature to within the variability of the experimental data (20% absolute). Our calculations show that the variability of the experimental data is consistent with the combined effects from realistic variations in particle properties (mainly density) and physiological parameters (mainly activity level). For the alveolar region, which is of particular significance for pharmacological and health studies, we show that although the activity level may change the deposited dose by up to a factor of 2.2 for particles between 0.05 and 2.0 microm in diameter, the alveolar dose is almost independent (to within 10%) of activity level for particles between 0.5 and 1 microm, which makes this size range advantageous for pharmacological and toxicological experiments. The present model allows estimates of the total and regional particle dose deposited in the lungs of rats, which are consistent with experimental data. The advantage of the present model is that hygroscopic growth can be included in the calculations.

Health effects of sulfur-related environmental air pollution. III. Nonspecific respiratory defense capacities.

Recently concern has been raised about health effects related to environmental sulfur and/or acidic aerosols. To assess long-term effects on respiratory lung function, 8 beagle dogs were exposed over a period of 13 mo for 16.5 h/day to 1.0 microm neutral sulfite aerosol with a particle associated sulfur(IV) concentration of 0.32 mg m(-3) and for 6 h/day to 1.1 microm acidic sulfate aerosol providing an hydrogen ion concentration of 15.2 micromol m(-3) for inhalation. Prior to exposure the dogs were kept under clean air conditions for 16 mo to establish physiological baseline values for each dog. A second group of eight dogs (control) was kept for the entire study under clean air conditions. Nonspecific defense mechanisms in the airways and in the peripheral lung were studied during chronic exposure of the combination of neutral sulfur(IV) and acidic sulfur(VI) aerosols. No functional changes of tracheal mucus velocity were found, in agreement with unchanged morphometry of the airways. However, the exposure resulted in changes of several alveolar macrophage (AM) mediated particle clearance mechanisms: (1) Based on in vivo clearance analysis and cultured AM studies using moderately soluble cobalt oxide particles, intracellular particle dissolution was significantly reduced since phagolysosomal proton concentration was decreased. We deduce exposure-related malfunction of proton pumps bound to the phagolysosomal membrane as a result of an increase of cytosolic proton concentration. (2) Based on in vivo clearance analysis using insoluble polystyrene particles, AM-mediated particle transport from the lung periphery toward ciliated terminal bronchioli and further to the larynx was significantly reduced. Activation of epithelial type II cells at the entrance of alveoli was inferred from observed type II cell proliferation at those alveolar ridges and enhanced secretion of alkaline phosphatase in the fluid of bronchoalveolar lavages. As a result, hypersecretion of chemotactic mediators by activated type II cells at these loci led to the observed decrease of particle transport toward ciliated bronchioli. (3) Based on in vivo clearance analysis using insoluble polystyrene particles, particle transport from the alveolar epithelium into interstitial tissues was increased and (4) particle transport to the tracheobronchial lymph nodes was significantly enhanced. Particle transport into interstitial tissues is the most prominent clearance pathway from the canine alveolar epithelium. We conclude that the deteriorated particle transport toward ciliated terminal bronchioli resulted in an enhanced particle transport across the epithelial membrane into interstitial tissues and the lymphatic drainage. The observed alterations in alveolar macrophage-mediated clearance mechanisms during chronic exposure of these air pollutants indicate an increased risk of health.

Early Response of the Canine Respiratory Tract Following Long-Term Exposure to a Sulfur(IV) Aerosol at Low Concentration. I. Rationale, Design, Methodology, and Summary

AbstractThe present study was designed to investigate the effect of chronic inhalation of a low concentration of airborne sulfur(IV) on mammalian lungs. Eight beagle dogs were continuously exposed in whole-body chambers for 290 d to a respirable S(IV) aerosol with a mass median aerodynamic diameter of 0.6 µm (geometric standard deviation about 2) at a concentration of 0.3 mg m−3, equivalent to a sulfur dioxide concentration of 0.6 mg m−3. Three dogs served as sentinels.To establish baseline data for lung parameters, the dogs were first housed in the chambers for 400 d under clean air conditions. Biochemical and cellular parameters in the lung lavage fluids were evaluated repeatedly for each dog. During exposure, each lung parameter was again measured repeatedly for each dog and the values obtained were compared with the baseline values. Thus each individual served as its own control. Parameters of respiratory lung function and lung morphology were only evaluated at the end of the study The three sentinal ...

Lung clearance in Long-Evans rats after inhalation of porous, monodisperse cobalt oxide particles

Lung clearance of a well-defined uniform and respirable material was conducted to aid in the development of models used to relate inhalation of inorganic hazardous particles to organ doses and bioassay measurements, and in particular to aid in the extrapolation of animal data to humans. In the present study, lung clearance was investigated in Long-Evans rats using monodisperse, porous, 0.8- and 1.7-microns-diameter cobalt oxide (Co3O4) test particles. An advanced inhalation technique for rats using endotracheal intubation yielded exclusive particle deposition in the pulmonary region without external pelt contamination, thus allowing for clearance studies starting directly after inhalation. The kinetics of lung clearance was distinguished between the two dominant clearance mechanisms of mechanical particle transport to the larynx and translocation of dissolved particle material to blood. A particle fraction of about 40% was cleared by short-term particle transport to the larynx, both the long-term particle transport rate and the translocation rate of dissolved particle material given as fractional rates of the retained particle mass in the lungs were not constant with time. The former declined from 0.03 to 0.004 d-1 during 6 months after inhalation. The latter depended on the specific surface area of the porous particles and increased with time from 0.08 and 0.04 d-1 for 0.8- and 1.7-microns particles, respectively. The results obtained were compared to previously reported data obtained from Fischer-344 rats and HMT rats. These were part of a previously reported interspecies comparison of lung clearance followed in seven species, including humans, and using the same batches of Co3O4 test particles. Long-term lung retention was similar in Long-Evans rats and HMT rats but decreased faster for both particle sizes than in Fischer-344 rats, as a result of a significantly faster translocation of dissolved material from the test particles to blood. Mechanical particle transport to the larynx was comparable in all three species.

Early Response of the Canine Respiratory Tract Following Long-Term Exposure to a Sulfur(IV) Aerosol at low Concentration. III. Macrophage-Mediated Long-Term Particle Clearance

AbstractAfter a control period of 400 d in filtered, contaminant-free air, eight dogs were exposed continuously for 290 d to a respirable sulfur(IV) aerosol at an S(IV) concentration of 0.3mg−3, equivalent to a sulfur dioxide concentration of 0.6 mg m−3. Long-term particle clearance from the lungs was tested with uniform, moderately soluble cobalt oxide (Co3O4)particles and nearly insoluble fused aluminosilicate particles (FAP) after short-term inhalation. The former were used to analyze translocation of dissolved particle mass from the lungs to blood, and the latter to study mechanical particle transport from the lungs to the larynx and into the gastrointestinal tract, and via lymphatics to the lung-associated lymph nodes.The in vivo translocation rate of moderately soluble test particles was significantly increased (by a factor of 7.8) in three dogs during S(IV) exposure compared to the rate during the control period. The results were confirmed by in vitro measurements of intracellular dissolution of mo...

Health effects of sulfur-related environmental air pollution. I. Executive summary.

The motivation of simulating real-world environmental exposure in a number of long-term studies with dogs was to address the question of whether or not perpetual inhalation of air pollutants can initiate diseases in healthy lungs and can thus contribute to the increasing prevalence of respiratory diseases in industrialized countries. The major conclusion of this article is that this question has to be answered in the negative for the simultaneous inhalation of the major constituents of combustion-related air pollution, particle-associated sulfur(IV), and particle-associated hydrogen ions. Over 13 mo, 8 healthy beagle dogs were exposed in 2 whole-body chambers daily for 16.5 h to 1 microm neutral sulfite [sulfur(IV)] particles at a mass concentration of 1.5 mg m-3 and for 6 h to 1.1 microm acidic sulfate particles carrying 15 micromol m-3 hydrogen ions into the canine lungs. This longitudinal study was characterized by repeated observations of individual respiratory response patterns. To establish baseline data the dogs were repeatedly examined preexposure while the chambers were ventilated over 16 mo with clean air. Each individual served thus as its own control. Another eight dogs served as additional controls. They were housed in 2 chambers ventilated with clean air over the entire study period of 29 mo. To assess response patterns, respiratory lung function tests were performed pre- and postexposure, segmental lung lavages were repeatedly performed to obtain epithelial lining fluid from the lungs for analysis of cell content, cell function, and biochemical indicators of lung injury, and radiolabeled test particles were used to study pathways of intrapulmonary particle elimination. At the end of the study, the lungs of all animals were morphologically and morphometrically examined. Functional and structural responses were finally compared to those observed previously as a result of a sole exposure of canine lungs to neutral sulfite particles over 10 mo (Heyder et al., 1992). Interactions between responses induced by neutral sulfite and acidic sulfate particles occurred, but antagonism rather than synergism was observed. The responses induced by sulfur(IV) were less pronounced, not detectable, or even reversed when hydrogen ions were also delivered to the lungs. On the other hand, responses not induced by the sole exposure to sulfur(IV) were observed: The activity of alkaline phosphatase was elevated and type II pneumocytes proliferated. It can, however, be concluded that long-term exposure of healthy lungs to particle-associated neutral sulfur(IV) and hydrogen ions at concentration close to ambient levels causes subtle respiratory responses but does not initiate pathological processes in the lungs. In other words, the perpetual inhalation of sulfur(IV) and hydrogen ions from the atmospheric environment presents no health risk to the healthy lungs. It is thus also very unlikely that respiratory diseases can be initiated by the inhalation of these pollutants.

Calculation of hygroscopic particle deposition in the human lung.

Abstract Context: Inhaled hygroscopic aerosols will absorb water vapor from the warm and humid air of the human lung, thus growing in size and consequently changing their deposition properties. Objective: The objectives of the present study are to study the effect of a stochastic lung structure on individual particle growth and related deposition patterns and to predict local deposition patterns for different hygroscopic aerosols. Materials and methods: The hygroscopic particle growth model proposed by Ferron et al. has been implemented into the stochastic asymmetric lung deposition model IDEAL. Deposition patterns were calculated for sodium chloride (NaCl), cobalt chloride (CoCl2 · 6H2O), and zinc sulfate (ZnSO4 · 7H2O) aerosols, representing high, medium and low hygroscopic growth factors. Results: Hygroscopic growth decreases deposition of submicron particles compared to hydrophobic particles with equivalent diameters due to a less efficient diffusion mechanism, while the more efficient impaction and sedimentation mechanisms increase total deposition for micron-sized particles. Due to the variability and asymmetry of the human airway system, individual trajectories of inhaled particles are associated with individual growth factors, thereby enhancing the variability of the resulting deposition patterns. Discussion and conclusions: Comparisons of model predictions with several experimental data for ultrafine and micrometer-sized particles indicate good agreement, considering intersubject variations of morphometric parameters as well as differences between experimental conditions and modeling assumptions.

The macrotransport properties of aerosol particles in the human oral-pharyngeal region

Abstract A method is described for evaluating the mean velocity, dispersion coefficient and deposition rate constant characterizing aerosol transport in a finite, computationally tractable, three-dimensional domain of the human lungs. The methodology is applied specifically to deduce (mesoscale) transport coefficients in an anatomically realistic human mouth and throat. In this method aerosol particles are introduced into a numerically simulated airflow in the vicinity of the entrance region of the airway unit (e.g. the mouth); the aerosol bolus is inspired such that it travels through the airway unit before being expired. The exhaled concentration of nondeposited aerosols is determined numerically, and used to deduce the three aerosol transport coefficients. The deduced transport coefficients, representing “mesoscale” averages of the microscale simulated flow, are determined as functions of air flow rate, particle size, bolus parameters, and dimensionality; these values are then incorporated into a mesoscale lung model and used to simulate macroscale aerosol transport behavior in the lungs. Special attention is given to the numerical simulation of an aerosol bolus inspired into the lungs. The calculated half-width, mode and deposition fraction agree favorably with recent macrotransport simulations, minus the upper airway generation. In these comparisons, the major influence of the upper airways is to increase aerosol deposition. Half-width and deposition fraction are also significantly affected by lung size.

Estimation of the size distribution of aerosols produced by jet nebulizers as a function of time

Abstract The evaporation of polydisperse aerosol droplets produced by a jet nebulizer is estimated by means of a particle evaporation theory [Ferron and Soderholm (1990) J. Aerosol Sci., 21, 415] and a method to divide polydisperse distributions in monodisperse size fractions [Ferron, (1977) J. Aerosol Sci., 8, 407]. Each monodisperse size fraction is characterized by a mean particle size and a mass fraction. The evaporation is calculated by iteration using sufficiently small time steps. After each iteration step the new air and particle parameters are calculated. This iteration process is repeated until a preset time is reached. Input data for the calculations are the mass of water and solute in the aerosol supplied by the nebulizer, the humidity of the air delivered to the nebulizer and the final air temperature. The method is used to estimate the size distributions of aerosols produced by jet nebulizers as a function of time. Calculations for three jet nebulizers with mass median aerodynamic diameters (MMAD) of 1.0, 2.8 and 9.0 μm and geometric standard deviations (GSD) of about two are performed. It is found that the droplets smaller than 1 pm evaporate rapidly and are in equilibrium with the relative humidity of the air within 0.1 s. Ninety-five percent of the total evaporated water mass took place within 0.1 s. However, equilibrium was not reached within 3 s. For all three nebulizers the largest increase (up to 30%) of the MMAD and GSD of the total mass distribution occurred in the first 0.1 s. Differences in the MMADs of the total mass and the salt mass distributions up to 60% were found. These results indicate that the aerosol distribution critically depends on the time after production and that the total mass and salt mass distributions differ substantially.

Long-term exposure of dogs to a sulphite aerosol: III. Effect of lung clearance

Abstract Eight dogs were exposed to a sodium bisulphite aerosol during 290 days. Lung clearance was tested with moderately soluble and insoluble aerosol particles after a single inhalation. Three dogs showed significant changes in clearance rate of moderately soluble particles during the sulphite exposure compared to the clearance rate during clean air exposure. The results were confirmed by in vitro clearance measurements in alveolar macrophages.