Abstract  Large particles (10–150 μm) with systemic toxicity pose a health risk if inhaled regardless of where they deposit. This research seeks to better define particle inhalability, the fraction of airborne particles that are inhaled as a function of particle size. Measurements of inhalability were made for solid particles using a 1.6×1.6×5-m wind tunnel. Tunnel air velocities were 0.4, 1.0, and 1.6m/s. A full-size, full-torso mannequin was used to collect dust entering either the mouth or nose for breathing at minute volumes of 14.2, 20.8, and 3.73 1. The mannequin either faced the oncoming wind or rotated slowly (0.06rpm) during sample collection. At the test section, air velocity was uniform to within 10% and aerosol concentration was uniform to within 15% over the central 80% of the cross section. Orientation-averaged inhalability for mouth breathing was higher than the inhalable particulate mass (IPM) sampling criterion for particles smaller than 35μm and lower than the criterion for larger particles, leveling off at about 30% for particles >70μm. Facing-the-wind mouth inhalability showed the same trend as the IPM sampling criterion, but the measured values were 25% higher. Wind velocity and breathing pattern had little effect on inhalability for the range of conditions examined here. Orientation-averaged inhalability for nose breathing dropped quickly with particle size reaching less than 10% at 60μm. Facing-the-wind nose inhalability was slightly increased for particles smaller than 60μm compared to orientation averaged inhalability for nose breathing.

Abstract  An interspecies comparison of the lung clearance of a well-defined, moderately soluble material was conducted to aid in the development of models used to relate inhalation of radioactive particles to organ doses and bioassay measurements, and in particular to aid in the extrapolation of animal data to man. Lung retention and excretion of 57Co were followed for at least six months after inhalation of monodisperse 0.8 and 1.7 μm diameter cobalt oxide particles by human volunteers, baboons, dogs, guinea-pigs, rats (three strains) and hamsters, and of the 0.8 μm particles by mice. At six months after inhalation of the 0.8 μm particles, lung retention ranged from 1% of the initial lung deposit (ILD) in HMT and Sprague-Dawley rats to 45% ILD in man; and for the 1.7 μm particles from 8% ILD in HMT rats to 56% in man. Supplementary experiments were conducted to determine 57Co excretion patterns following injection of Co(NO3)2 into the blood and following ingestion of cobalt oxide particles, in order to calculate lung clearance rates due to translocation of dissociated 57Co to the blood, S(t), and due to particle transport to the GI tract, M(t). Initially, S(t) for 0.8 μm particles ranged from 0.4% of the contemporary lung content day−1 in humans and baboons to 1.6% day−1 in HMT rats. Initial values for 1.7 μm particles were lower in all species, and ranged from 0.2% in baboons to 0.6% day−1 in HMT rats. Estimated values of M(t) were consistent with the assumption that M(t) is similar for different materials in the same species. In the introductory paper the objectives of the project and methods common to the collaborating laboratories are described, and the results obtained in the various species compared and discussed. Details of the procedures used and of the results obtained at each laboratory are given in Parts II–VIII

Abstract  CONTEXT: The current data analysis tools in nuclear medicine have not been used to evaluate intra organ regional deposition patterns of pharmaceutical aerosols in preclinical species.

OBJECTIVE: This study evaluates aerosol deposition patterns as a function of particle size in rats and mice using novel image analysis techniques.

MATERIALS AND METHOD: Mice and rats were exposed to radiolabeled polydisperse aerosols at 0.5, 1.0, 3.0, and 5.0 µm MMAD followed by SPECT/CT imaging for deposition analysis. Images were quantified for both macro deposition patterns and regional deposition analysis using the LRRI-developed Onion Model.

RESULTS: The deposition fraction in both rats and mice was shown to increase as the particle size decreased, with greater lung deposition in rats at all particle sizes. The Onion Model indicated that the smaller particle sizes resulted in increased peripheral deposition.

DISCUSSION: These data contrast the commonly used 10% deposition fraction for all aerosols between 1.0 and 5.0 µm and indicate that lung deposition fraction in this range does change with particle size. When compared to historical data, the 1.0, 3.0, and 5.0 µm particles result in similar lung deposition fractions; however, the 0.5 µm lung deposition fraction is markedly different. This is probably caused by the current aerosols that were polydisperse to reflect current pharmaceutical aerosols, while the historical data were generated with monodisperse aerosols.

CONCLUSION: The deposition patterns of aerosols between 0.5 and 5.0 µm showed an increase in both overall and peripheral deposition as the particle size decreased. The Onion Model allows a more complex analysis of regional deposition in preclinical models.

Abstract  The effects of inhaled particles have focused heavily on the respiratory and cardiovascular systems. Most studies have focused on inhaled metals, whereas less information is available for other particle types regarding the effects on the brain and other extra-pulmonary organs. We review here the key available literature on nanoparticle uptake and transport through the olfactory pathway, the experimental data from animal and in vitro studies, and human epidemiological observations. Nanoparticles (<0.1μm in one dimension) may easily reach the brain from the respiratory tract via sensory neurons and transport from the distal alveoli into the blood or lymph as free particles or inside phagocytic cells. These mechanisms and subsequent biologic responses may be influenced by the chemical composition of inhaled particles. Animal studies with ambient particulate matter and certain other particles show alterations in neuro-inflammatory markers of oxidative stress and central neurodegeneration. Human observations indicate motor, cognitive, and behavioral changes especially after particulate metal exposure in children. Exposure to co-pollutants and/or underlying disease states could also impact both the biokinetics and effects of airborne particles in the brain. Data are needed from the areas of inhalation, neurology, and metal toxicology in experimental and human studies after inhalation exposure. An increased understanding of the neurotoxicity associated with air pollution exposure is critical to protect susceptible individuals in the workplace and the general population.

Abstract  To understand better the factors influencing the relationships among airborne particle exposure, lung burden, and fibrotic lung disease, we developed a biologically based kinetic model to predict the long-term retention of particles in the lungs of coal miners. This model includes alveolar, interstitial, and hilar lymph node compartments. The 131 miners in this study had worked in the Beckley, West Virginia, area and died during the 1960s. The data used to develop this model include exposure to respirable coal mine dust by intensity and duration within each job, lung and lymph node dust burdens at autopsy, pathological classification of fibrotic lung disease, and smoking history. Initial parameter estimates for this model were based on both human and animal data of particle deposition and clearance and on the biological and physical factors influencing these processes. Parameter estimation and model fit to the data were determined using least squares. Results show that the end-of-life lung dust burdens in these coal miners were substantially higher than expected from first-order clearance kinetics, yet lower than expected from the overloading of alveolar clearance predicted from rodent studies. The best-fitting and most parsimonious model includes processes for first-order alveolar-macrophage-mediated clearance and transfer of particles to the lung interstitium. These results are consistent with the particle retention patterns observed previously in the lungs of primates. The findings indicate that rodent models extrapolated to humans, without adjustment for the kinetic differences in particle clearance and retention, would be inadequate for predicting lung dust burdens in humans. Also, this human lung kinetic model predicts greater retained lung dust burdens from occupational exposure than predicted from current human models based on lower exposure data. This model is useful for risk assessment of particle-induced lung diseases, by estimating equivalent internal doses in rodents and humans and predicting lung burdens in humans with occupational dust exposures.

Abstract  New information on particle retention of inhaled insoluble material indicates that the ICRP Human Respiratory Tract Model (HRTM) significantly underestimates long-term retention in the lungs. In a previous paper, the information from three studies was reviewed, and a model developed to predict particle retention in the lungs of coal miners was adapted in order to obtain parameter values for general use to predict particle retention in the alveolar-interstitial (AI) region. The model is physiologically based and simpler than the HRTM, requiring two instead of three compartments to model the AI region. The main difference from the HRTM AI model is that a significant fraction, about 35 %, of the AI deposit of insoluble material remains sequestered in the interstitium. The new model is here applied to the analysis of two well-known contamination cases with several years of follow-up data.

Abstract  Beryllium metal was classified in Europe collectively with beryllium compounds, e.g. soluble salts. Toxicological equivalence was assumed despite greatly differing physicochemical properties. Following introduction of the Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) regulation, beryllium metal was classified as individual substance and more investigational efforts to appropriately characterize beryllium metal as a specific substance apart from soluble beryllium compounds was required. A literature search on toxicity of beryllium metal was conducted, and the resulting literature compiled together with the results of a recently performed study package into a comprehensive data set. Testing performed under Organisation for Economic Co-Operation and Development guidelines and Good Laboratory Practice concluded that beryllium metal was neither a skin irritant, an eye irritant, a skin sensitizer nor evoked any clinical signs of acute oral toxicity; discrepancies between the current legal classification of beryllium metal in the European Union (EU) and the experimental results were identified. Furthermore, genotoxicity and carcinogenicity were discussed in the context of the literature data and the new experimental data. It was concluded that beryllium metal is unlikely to be a classical nonthreshold mutagen. Effects on DNA repair and morphological cell transformation were observed but need further investigation to evaluate their relevance in vivo. Animal carcinogenicity studies deliver evidence of carcinogenicity in the rat; however, lung overload may be a species-specific confounding factor in the existing studies, and studies in other species do not give convincing evidence of carcinogenicity. Epidemiology has been intensively discussed over the last years and has the problem that the studies base on the same US beryllium production population and do not distinguish between metal and soluble compounds. It is noted that the correlation between beryllium exposure and carcinogenicity, even including the soluble compounds, remains under discussion in the scientific community and active research is continuing.

Abstract  Realistic predictions of inhaled particle deposition in various locations of the human lung depend mainly on accurate descriptions of the lung geometry and ventilation. Models of airflow distribution in the human lung by uniform and nonuniform lung expansions were used to calculate particle deposition in various lobes and regions of stochastically generated human lungs. To study the influence of lung geometry, 30 asymmetric stochastic lungs were generated and used in the calculations. Lobar airflow in each lung varied in accordance with lobar properties. The calculated airflow distributions indicated that the airflow rate entering each lobe of a given lung was similar for uniform and nonuniform lung expansions. Particle deposition was also found to be similar for uniform and nonuniform lung expansion models at rest breathing. The predicted deposition was in agreement with experimental measurements of regional and total depositions when considering lung size variation in a population. The coupled lung ventilation and deposition models can aid in detailed predictions of inhaled particle deposition in the human lungs. (c) 2006 Elsevier Ltd. All rights reserved.

Abstract  Previous reports by others establish that particle surface area is related to a change in macrophage function as measured by the ability to clear particles from the alveolar spaces. However, for nanoparticles the relation may not be strictly due to surface chemistry: The cumulative projected area of the particles may reflect the degree to which the inner or outer surface of the macrophage is shielded from other objects or molecules. We apply this alternative interpretation to in vitro measurements of macrophage uptake of 26-nm-diameter fluorescent beads and to in vivo data presented in a classic inhalation toxicology paper on nano-sized TiO2 particles. In their paper, Oberdörster et al. (Environ. Health Perspect. 102[suppl. 5]:173-179, 1994) reported that following inhalation exposure to 20-nm or 250-nm TiO2 particles, the half-times for alveolar clearance of polystyrene test particles were proportional to square centimeters of TiO2 particle surface per million macrophages; macrophage toxicity from TiO2 particle surface was assumed to be the cause of the decrease in the clearance rate of polystyrene test particles. When TiO2 particle projected area was incorporated into the in vivo macrophage dosimetry calculations, particle projected areas ranged in value from covering only a fraction (0.1) of the macrophage surface to covering the cell surface 4 times over. The observed decrease in macrophage mediated alveolar clearance of polystyrene test particles was directly related to the potential for TiO2 particles to mask the surface of the macrophage-a possibility that was visualized in vitro with confocal laser scanning microscopy.

Abstract  The experimental techniques and the results of inhalation studies with radioaerosols on normal non-smokers for mouth-breathing are described and discussed. Monodisperse iron oxide particles tagged with 198Au are produced with a spinning top generator in the aerodynamic size range between 1 to 10 micrometers. An aerosol inhalation apparatus enables the subjects to breathe under standardized conditions with respect to tidal volume and breathing frequency. The calculation of total deposition is based upon measurements of the number of in- and exhaled particles per breath by means of photometric methods and pneumotachography. The retention of the radioactive particles present in the body after aerosol administration is measured with a body counter designed and constructed for these experiments. Retention measurements as functions of time after inhalation are carried out in extrathoracic-, chest- and stomach-position. The body counter consists of four shielded NaF(TI)-detectors. The geometrical arrangement, the collimation and the shielding of the four detectors have been optimized by computer calculations in such a way that the response of the counter is independent of the distribution of activity within the chest. Another characteristic feature of the body counter is its low sensitivity to neighboring organs and to neighboring regions within the respiratory tract. For the evaluation of extrathoracic deposition, the activity measured in the stomach immediately after inhalation is added to extrathoracic activity. The elimination of material from the chest (intrathoracic airways) is found to be much slower for the material deposited in the alveolar region (non-ciliated air spaces) than for the amount deposited in the tracheobronchial tree (ciliated airways). This allows the intrathoracic deposition to be divided into tracheobronchial and alveolar deposition by means of the different slopes of the normalized chest retention function. Different normalized chest retention functions are presented and analysed with respect to their different elimination rates belonging to the tracheobronchial and alveolar region. Total, tracheobronchial, alveolar and extrathoracic deposition data are reported in the aerodynamic diameter range between 1 and 10 micrometers.

Abstract  The respiratory frequency, tidal volume, minute volume, oxygen uptake and carbon dioxide output of unsedated hamsters, rats, guinea pigs and rabbits were measured to obtain comparative data and to evaluate the performance of those species as unsedated subjects. The animals were trained to remain stationary and breathe through nonrebreathing valves while expired gas was collected and respiratory frequency was monitored. Measurements of dogs also were conducted to obtained comparative data by similar methods. Hamsters were readily trained and performed reliably during repeated trials. Rats and guinea pigs were more difficult to train and performed erratically. The rabbits' performance was intermediate between that of hamsters and the other species. The back pressures caused by the small animal nonrebreathing valves at estimated peak flow rates were either similar to or less than those encountered by dogs. Measured respiratory values were compared to values predicted by published equations based on body weight. Data from this study generally reflected species differences related to body weight and metabolic rate similar to those predicted by the equations, but values from the four smaller species also may have reflected differences related to behavior.

Abstract  We measured the single-breath diffusing capacity for carbon monoxide (DLCO), total lung capacity (TLC), functional residual capacity (FRC), and residual volume (RV) in anesthetized male hamsters, rats, guinea pigs, and rabbits whose weights varied from 40 to 3,500 g. TLC (defined as an airway pressure of 25 cmH2O) was calculated by neon dilution. The DLCO was estimated by a modification of the single-breath method. There was a high correlation between body weight and our measurement of both the diffusing capacity and the lung volumes. No significant difference in DLCO was observed in rats when measured in different body positions, at airway pressures of 10 or 20 cmH2O, from FRC or RV, in male or female rats, or following hyperventilation.

Abstract  The emphasis in this chapter is going to be primarily on measurement of particle retention in the respiratory tract, although many of the same considerations apply to gas uptake. Inhaled air, unless it has been previously filtered, contains airborne dust. Figure 1 shows the size range of some aerosols typically encountered in natural and occupational settings. In the process of respiration, air flows into the lungs where it is brought in close proximity to lung surfaces for the purpose of oxygen and carbon dioxide exchange. This same process also makes the lungs an excellent filter of the particles present in inhaled air, and a significant fraction do not exit upon exhalation. The total mass of air breathed daily can range from 10 to 25 kg. Even rural “clean” air has a particulate concentration of about 0.05 ppm (by weight). Hence, even if only half of these particles are deposited in the lung, this amounts to a daily accumulation of 0.5–1.25 mg potentially toxic material on delicate lung surfaces. During smog episodes, particulate concentrations have been measured to be as high as 3–4 ppm (Goldsmith and Friberg 1977), resulting in a daily accumulation of about 60 mg. The correlation between air pollution indices and chronic pulmonary disease has been examined (Lave and Seskin 1970; Ferris 1978, and considerable attention is currently focused on the health effects of indoor air pollution (Spengler and Sexton 1983).Types of inhaled particles for which measurement of retained dose is of major interest are briefly described in the following sections.

Abstract  Intersubject variability in both peripheral air-space dimensions and breathing pattern [tidal volume (VT) and respiratory frequency (f)] may play a role in determining intersubject variation in the fractional deposition of inhaled particles that primarily deposit in the lung periphery (i.e., distal to conducting airways). In healthy subjects breathing spontaneously at rest, we measured the deposition fraction (DF) of a 2.6-microns monodisperse aerosol by Tyndallometry while simultaneous measurement of VT and f were made. Under these conditions particle deposition occurs primarily in the peripheral air spaces of the lung. As an index of peripheral air-space size, we used measurements of aerosol recovery (RC) as a function of breath-hold time (t) (Gebhart et al. J. Appl. Physiol. 51: 465-476, 1981). In each subject, we measured RC (aerosol expired/aerosol inspired) of a 1.0-micron monodisperse aerosol as a function of breath-hold time for inspiratory capacity breaths of aerosol. The half time (t1/2) (the breath-hold time to reach 50% RC with no breath hold) is proportional to a mean diameter (D) of air spaces filled with aerosol. In the 10 subjects studied, we found a variable DF, range 0.04-0.44 [0.25 +/- 0.12 (SD)]. DF correlated most closely with 1/f, or the period of breathing (r = 0.96, P less than 0.01). There was no significant correlation between DF and t1/2 as an index of peripheral air-space size. In fact there was little deviation in t1/2 in these normal subjects [coefficient of variation (CV) = 0.12].(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract  The deposition efficiency of an aerosol in oral airways was studied in three human male subjects (aged 25, 29, and 50 years) during oronasal breathing while engaged in moderate and heavy exercise. An aerosol of monodisperse spherical oil droplets containing a core of sodium-fluorescein (uranine) was generated by condensing di-2-ethylhexyl-sebacate onto uranine nuclei. Particle size was monitored by an optical counter and pulse height analyzer. The aerosol was delivered through an oronasal mask connected to a pneumotachograph to monitor nasal air flow. Exercise conditions were simulated by controlling respiratory rate and tidal volume. Oral airway deposition of uranine was measured by filter fluorometry of gargle rinsings. Technetium-99 (Tc-99) was added to the aerosol to facilitate identification of deposition sites by radiation scanner. Deposition efficiency was measured 70 times under moderate exercise, and 21 times under heavy exercise conditions. Deposition fraction (DF) was dependent on particle size, as 36, 58, and 79 percent of the 5, 10, and 15 micron diameter particles, respectively, deposited in the oral airway during moderate exercise. During heavy exercise, 19, 36, and 52 percent of the 5, 10, and 15 micron diameter particles were deposited. Site of deposition depended on oral airway size, with anterior airway regions demonstrating less deposition with large fixed mouthpieces and heavy exercise.

Abstract  Thoracic airway calibers were estimated in 15 healthy subjects from gravitational losses during respiratory pauses of particles inhaled as aerosol boluses to different volumetric depths in the respiratory tract. Intersubject variability of thoracic airway dimensions and particle deposition for controlled and spontaneous mouth-breathing were correlated by Spearman's rank correlation analysis. The correlations between deposition of particles in the diameter range 1 - 5 μm and aerosol derived lung morphology suggest that the intersubject variability of particle deposition is primarily due to morphological differences between individuals. They also confirm the current understanding of behavior in the human respiratory tract of particles larger than 1 μm in diameter: with increasing particle size, the site of deposition is shifted proximally in the lungs.

Abstract  The deposition of particles in replicate cast models of the human nasal cavity has been measured in three different laboratories for a range of particle sizes from 0.6 to 200 nm. The results of these measurements on four different casts can be fit by a single equation of the form eta = 1 -exp [-bQ-1/8 D1/2], where eta is the fraction of particles deposited in the nasal cavity, Q is the volumetric flow rate (1 min-1), D is the particle diffusion coefficient (cm2s-1), and b is found to be 12.65 +/- 0.17. The measurements were conducted over a range of flow rates from 1.4 to 28.7 1 min-1 (50 1 min-1 for sizes from 4.6 to 200 nm) using radon and thoron decay product aerosols as well as larger ultrafine particles. These results thus represent a current best estimate of the diffusional deposition of ultrafine particles in the human nasal cavity.