Abstract  Background: Studies in monkeys with intranasally instilled gold ultrafine particles (UFPs; < 100 nm) and in rats with inhaled carbon UFPs suggested that solid UFPs deposited in the nose travel along the olfactory nerve to the olfactory bulb. Methods: To determine if olfactory translocation occurs for other solid metal UFPs and assess potential health effects, we exposed groups of rats to manganese (Mn) oxide UFPs (30 nm; ~ 500 μg/m3) with either both nostrils patent or the right nostril occluded. We analyzed Mn in lung, liver, olfactory bulb, and other brain regions, and we performed gene and protein analyses. Results: After 12 days of exposure with both nostrils patent, Mn concentrations in the olfactory bulb increased 3.5-fold, whereas lung Mn concentrations doubled; there were also increases in striatum, frontal cortex, and cerebellum. Lung lavage analysis showed no indications of lung inflammation, whereas increases in olfactory bulb tumor necrosis factor-α mRNA (~ 8-fold) and protein (~ 30-fold) were found after 11 days of exposure and, to a lesser degree, in other brain regions with increased Mn levels. Macrophage inflammatory protein-2, glial fibrillary acidic protein, and neuronal cell adhesion molecule mRNA were also increased in olfactory bulb. With the right nostril occluded for a 2-day exposure, Mn accumulated only in the left olfactory bulb. Solubilization of the Mn oxide UFPs was < 1.5% per day. Conclusions: We conclude that the olfactory neuronal pathway is efficient for translocating inhaled Mn oxide as solid UFPs to the central nervous system and that this can result in inflammatory changes. We suggest that despite differences between human and rodent olfactory systems, this pathway is relevant in humans.

Abstract  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.

Abstract  Accurate extrapolation of animal toxicity data for human health risk assessment requires determination of the effective dose to the target tissue and the sensitivity of the target tissue to that dose. The methodology for deriving reference doses [the U.S. Environmental Protection Agency's (EPA) benchmark values for gauging systemic toxicity] for oral exposures has not included dosimetry modeling. Dosimetry data facilitate evaluation of concentration-response data with respect to the dose-response relationships used in quantitative risk assessment. Extension of this methodology to derivation of inhalation reference doses (RfDi) should account for the dynamics of the respiratory system as the portal of entry. Predictive physiologically based modeling of the inhalation of reactive gases has recently been demonstrated (Overton and Miller 1988). Models that describe the deposition of hygroscopic particles and account for chemical factors that affect clearance mechanisms and gas uptake are under development. This paper presents a method for calculating a dosimetric adjustment factor based on the values for the initial deposited dose of insoluble particles in an animal species and in humans. The ratio of these two values serves as a scaling factor that can be applied in the R f D methodology to account for the dosimetric differences in the inhaled deposited dose. This application for insoluble particles illustrates the feasibility of interspecies dosimetry calculations for extrapolating the toxicological results of inhaled agents to human exposure conditions for more accurate risk estimation.

Abstract  About 2000 breathing experiments were performed, involving four breathing manoeuvres, four volunteers, a wide range of particle diameters and various breathing patterns. Monodisperse droplets of bis(2-ethylhexyl) sebacate served as aerosol particles. The deposition of particles in the nose was calculated from total deposition of particles in the whole respiratory tract for mouth, nose, mouth-nose and nose-mouth breathing. This method allowed the determination of nasal deposition and nasal efficiency for inspiration and expiration. Total deposition was determined from measurements of the particle concentration and the respiratory volume flow rate. Considerable scatter of nasal deposition in the four subjects was found. At a constant tidal volume it rose rapidly with increasing flow rate. The nasal efficiences were found to be independent of tidal volume. For inspiration as well as expiration the nasal passages removed particles very efficiently by inertial impaction. However, inspiratory and expiratory nasal efficiences were different. The scatter of individual inspiratory efficiency could be considerably reduced by employing a mathematical relationship to describe inspiratory nasal efficiency which makes use of the pressure difference across the nose and nasopharynx during nose breathing.

Abstract  Dust overloading of lungs was reported in various studies (Ferin and Feldstein, 1978; Vostal et al., 1982; Vincent et al., 1985). We investigated this effect in a variety of subchronic and chronic inhalation studies after exposure to benign or slightly toxic insoluble materials. The characteristic findings were accumulation of large quantities of insoluble material in the lung, impairment of the alveolar clearance and an inflammatory response.

Abstract  Because the retractive forces due to surface tension decrease with increasing radius of curvature, there should be a greater contribution to lung recoil attributable to the stress-bearing role of elastic elements in the lung parenchyma of species with larger alveoli. To examine alterations in lung structure that may relate to this stress-bearing role, the lungs of mice, hamsters, rats, rabbits, rhesus monkeys, baboons, and humans were preserved by vascular perfusion of fixative. The number of alveoli per lung, alveolar radius of curvature, surface area, and volume were measured by serial section reconstruction. Electron-microscopic determinations were made of the volume fraction and thickness of the epithelium, interstitium, and endothelium and of the connective tissue fibers of the alveolar septa and the portions of alveolar septa that form the alveolar ducts. The thickness of the alveolar septal interstitium increased linearly with the increase in radius of curvature of alveoli. The increase in interstitial thickness in lungs with larger alveoli was paralleled by large increases in the volume of collagen and elastin fibers present in this space. Comparable changes in the thickness of connective tissue fibers in alveolar duct walls were also found. This study demonstrates species-related changes in the structure of alveolar septa and in lung collagen and elastin fibers that are consistent with connective tissue fibers having a greater stress-bearing role in both the alveolar septa and alveolar ducts of species with larger alveoli.

Abstract  Morphometric procedures were used to determine the number of cells, cell volume, cell diameter, and surface areas of the airways in human and rat lungs. Nuclear sizes of epithelial cells from human bronchi were significantly larger than other lung cell nuclei. The average volume of human ciliated cell nuclei was 310 ± 30 Ám(3) and 167 ± 12 Ám(3) in bronchi and bronchioles, respectively. The smaller nuclei of human bronchioles were comparable to those of alveolar cells. In the pseudostratified epithelium of human bronchi, basal cells had a large surface area in contact with the basement membrane (51.3 ± 4.6 Ám(2) per cell) when compared with ciliated (1.1 ± 0.1 Ám(2)), goblet (7.6 ± 1.2 Ám(2)), or other secretory cells (12.0 ± 2.1 Ám(2)). In the first four airway generations distal to the trachea, basal cells account for 30% of the cells in human airway epithelium and 2% of the cells in rat airway epithelium. Total airway surface area from trachea to bronchioles was 2,471 ± 320 and 27.2 ± 1.7 cm(2) in human and rat lungs, respectively. These direct measurements of airway surface area are less than half of the estimates based on current lung models. The total number of airway epithelial cells were 10.5 x 10(9) for human and 0.05 X 10(9) for rat lungs. For both species, there were 18 times more alveolar cells than bronchial epithelial cells.

Abstract  Swedish Work Environment Foundation. The ability of human and rabbit alveolar macrophages to dissolve 0ò1-0ò5 Ám MnO2 particles in vitro was compared. The amount of Mn added and dissolved from the particles over periods of nought, one, and three days was determined by flame atomic absorption spectrophotometry. The amount dissolved by human and rabbit macrophages was similar; on average 43ò1% and 43ò9%, respectively, were dissolved within three days. But rabbit and human mac- rophages dissolved significantly more Mn than was dissolved in the respective culture medium without macrophages after one and three days. It is suggested that the dissolution of particles by alveolar macrophages should be one basic component in any model of alveolar clearance of inorganic particles.

Abstract  The growth of single dry salt aerosol particles during respiration in human airways is calculated with equations for the mass and heat transport to the particle surface (Ferron, J. Aerosol Sci. 8, 251, 1977) and with axial profiles for the temperature (T) and relative humidity (RH) of the air in the human respiratory tract as derived in a previous study (Ferron et al., J. Aerosol Sci. 19, 343, 1988). The calculations are performed for single dry NaCl, CoCl2.6H2O and ZnSO4.7H2O particles representing salts with large, medium and small increases of particle size in nearly saturated air. The growth of a salt particle is a function of the initial dry particle size, the molecular weight of the salt, its density, and its dissociation constant. It is affected by the profile of the RH of the air in the upper human respiratory tract. Pure salt particles with initial sizes below 1 μm reach their final size during inhalation, whereas particles with initial sizes larger than 7 μm change their size by less than 20% during inhalation. The growth of a salt particle with initial size below 3 μm is influenced by the inhalation airflow. The influence of the reduced transport of water vapor and heat in the lower bronchial tree simulated by a correction equation has hardly any effect on the growth of salt particles. The deposition of salt particles in the human respiratory tract is calculated with a model published before (Ferron et al., J. Aerosol Sci. 16, 133, 1985a). The model is adapted to calculate the deposition of particles with a changing particle diameter. The calculated total lung deposition is enhanced for particles with initial diameter larger than 0.2 μm and reduced for particles with initial diameter less than 0.15 μm with respect to the deposition of non-growing particles. The largest increase in total deposition is found for 1 μm-sized particles. As a first approximation the values for the regional deposition of growing and non-growing particles differ by the same factor as the total deposition is changed. Particles with an initial dry size between 1 and 7 μm have a deposition probability larger than 70% in the bronchial and pulmonary region. A recommendation to estimate the deposition of hygroscopic aerosol particles is derived.

Abstract  Airborne monodisperse particles in the size range 2.5–7.5 μm dia., labelled with 99mTc, were systematically administered to mouth breathing subjects under different but predetermined breathing patterns ranging from 0.5–2.01, tidal volume and 10–25 breaths/min. The subjects were all healthy, non-smoking males. Measurements were made of both total and regional deposition. The results show the increasing significance of pulmonary deposition as the particle size decreases and consequently the importance of accurate data in this range for the purposes of radiological protection. Both total and regional deposition are a function of the impaction parameter (D2F) suggesting that inertial impaction is the main mechanism of deposition under the conditions studied. The work supports the predicted values of deposition given in the lung model of the International Commission on Radiological Protection. Subsidiary experiments showed the value of faecal sampling in establishing the accuracy of total deposition estimates and in elucidating full regional deposition.

Abstract  A new growth equation for pure water and solution droplets with radii≳1µm has been developed which features discrete vapor and temperature fields at the surface of growing droplets. The discrete fields are created by the condensation and thermal accommodation coefficients in order to maintain steady state in the vapor and heat transfers. The newly derived equation is compared with previous theories, and their differences and ranges of applicability are clarified. It is shown that the newly derived equation includes some of the previous equations as special cases. The new equation is numerically evaluated and graphically examined for the case of pure water droplets. The results show a spreading tendency in size distribution of formed droplets at the start of their growth. The present theory and equations may also be applied to the evaporation of a droplet and the growth of an ice particle where the shape can he assumed to be spherical.

Abstract  In 4 subjects with normal lung function total deposition of monodisperse, hydrophobic, uncharged silver particles in the 0.005 to 0.08 μm size range was investigated for a variety of breathing patterns during steady state mouth- and nose breathing. The evaluation of deposition was based upon measurements of mean particle number concentration in inspired and expired air by means of a condensation nucleus counter. Owing to the diffusional particle transport, total deposition increases with decreasing particle size and increasing mean residence time of the aerosol in the lungs. With decreasing particle size the time dependence becomes less and the effect of tidal volume more significant. A semi-empirical formula is derived which fits the experimental data.

Abstract  The first of a series of reports recommending Annual Limits for Intakes (ALI’s) of radionuclides by workers. This report includes the main text for the whole series of Publication 30, and data on twenty one elements having radioisotopes that are of considerable importance in radiological protection. The actual ALI values in ICRP Publication 30 have become obsolete with the newer dosimetry and dose limits of ICRP Publication 60, and at present the dose coefficients in ICRP Publications 68, 69, 71, and 72 should be used to determine ALI’s. However, the vast body of biokinetic information in Publication 30 still forms the basis of much of the calculations underlying those later reports.

Abstract  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.

Abstract  National Science Foundation; Whitaker Foundation. #Airflow patterns within the human upper airways, including nasal airway, oral airway, laryngeal airway, and the first two generations of tracheobronchial airway, are investigated by numerically solving the corresponding full Navier-Stokes equations using the flow simulation software CFX-F3D. A body-fitted three-dimensional curvilinear grid system and a multiblock method have been employed to mimic the complex head airway geometry and to match the computational domain with the outline of a semirealistic nasal sagittal cross-section geometry. Effects of human breath patterns, i.e., nasal breath, oral breath and simultaneous nasal and oral breath, on airflow and ultrafine particle deposition are investigated. Results of ultrafine particle deposition generated by computer simulation show reasonable agreements with the experimental measurements.

Abstract  Models of the human respiratory tract were developed based on detailed morphometric measurements of a silicone rubber cast of the human tracheobronchial airways. Emphasis was placed on the “Typical Path Lung Model” which used one typical pathway to represent a portion of the lung, such as a lobe, or to represent the whole lung. The models contain geometrical parameters, including airway segment diameters, lengths, branching angles and angles of inclination to gravity, which are needed for estimating inhaled particle deposition. Aerosol depositions for various breathing patterns and particle sizes were calculated using these lung models and the modified Findeisen-Landahl computational scheme. The results agree reasonably well with recent experimental data. Regional deposition, including lobar deposition fractions, are also calculated and compared with results based on the ICRP lung deposition model.

Abstract  Dr. Yu's project addressed several important issues regarding improved quantification of dose from known concentrations of atmospheric particulate matter. By focusing first on a specific category of automotive-derived particles, diesel exhaust particulate, Dr. Yu was able to characterize those aerosol properties (such as the mass medican aerodynamic diameter and size distribution) that influence regional deposition. After formulating a mathematical deposition model, Dr. Yu calculated and compared the deposition of inhaled diesel exhaust particulate in laboratory animals and in humans of different ages.

Abstract  Regional deposition of inhaled particles was studied experimentally for 9 health subjects breathing the same aerosol under the same breathing conditions in order to evaluate intersubject variability of regional deposition. A great intersubject variability of extrathoracic, tracheobronchial and alveolar deposition was found. The highest one was observed for particle deposition in the extrathoracic airways. This biological variability of regional deposition has to be taken into account for considerations of health related aspects of aerosol inhalation.

Abstract  The respiratory anatomic dead space has been measured by the single breath nitrogen washout method of Fowler in 73 normal subjects ranging from 4 to 42 years of age. The volume of the anatomic dead space correlated closely with height (Vd (ml) = 7.585 x Ht (cm)2.363 x 10-4·ɣ = .917), but also with body weight, surface area, and functional residual capacity. When compared on the basis of any of these parameters there was no significant difference between the anatomic dead space values for males and females. Comparisons with available data for newborn infants suggest that the value of the anatomic dead space has a relatively constant relation to height from birth to adulthood. Dead space appears to increase more rapidly than weight, surface area, and functional residual capacity during, at least, the early period of somatic growth.