Abstract  The objective of this study was to predict the lung burden of diesel exhaust particles (DEPs) from automobile emissions in rats and humans by means of a mathematical model. We previously developed a model to predict the deposition of DEPs in the lungs of these species. In this study, the clearance and retention of deposited DEPs in the lung are examined. A diesel particle is composed of a carbonaceous core (soot) and the adsorbed organics. These materials can be removed from the lung after deposition by two mechanisms: (a) mechanical clearance, provided by mucociliary transport in the ciliated airways as well as macrophage phagocytosis and migration in the non-ciliated airways, and (b) clearance by dissolution. We used a compartmental model consisting of four anatomical compartments to study the clearance of DEPs from the lung: nasopharyngeal, tracheobronchial, alveolar, and the lung-associated lymph node compartments. We also assumed a particle model made up of material components according to the characteristics of clearance: (1) a carbonaceous core of about 80 percent of particle mass, (2) slowly cleared organics of about 10 percent of particle mass, and (3) fast cleared organics accounting for the remaining 10 percent of particle mass. The kinetic equations of the retention model were first developed for Fischer 344 rats. The transport rates of each material component of DEPs (soot, slowly cleared organics, fast cleared organics) were derived using available experimental data and several mathematical approximations. The lung burden results calculated from the model showed that while the organics were cleared at nearly constant rates, the alveolar clearance rate of diesel soot decreased with increasing lung burden. This is consistent with existing experimental observations. At low lung burdens, the alveolar clearance rate of diesel soot was a constant, equal to the normal clearance rate controlled by macrophage migration to the mucociliary escalator, whereas at high lung burdens, the clearance rate was determined principally by transport to the lymphatic system. The retention model of DEPs for rats was extrapolated to humans of different age groups from birth to adulthood. To derive the transport rates for the human model, the mechanical clearance from the alveolar region of the lung was assumed to be dependent on the specific particulate burden on the alveolar surface. The reduction in the mechanical clearance in adult humans due to high concentration exposure was found to be much less than that observed in rats. The reduction in children was greater than that in adults. For clearance by dissolution, the transport rates were assumed to be the same for humans and rats. We combined the retention model of DEPs and the deposition model for these particles to compute the accumulated mass of diesel soot and the associated organics in various compartments of the human lung under different exposure conditions. It was found that the lung burdens of both diesel soot and the associated organics were much higher in humans than in rats for the same period of exposure because of the higher particle intake and slower clearance rate in humans. The reduction in clearance caused by excessive lung burdens would not occur in human if the exposure concentration was kept below 0.05 mg/m3. Also, it was found that for the same exposure,the lung burden per unit lung weight was higher in children and reached a maximum at about 5 years of age. These results are of use in health risk assessment due to DEP exposure.

Abstract  The biological effects of inhaled aerosols are often related to their site(s) of deposition within the respiratory tract. However, deposition patterns may differ between humans and those experimental animals commonly used in inhalation toxicology studies, making cross-species risk extrapolations difficult. This paper reviews the factors that control deposition and synthesizes much of the available data on comparative regional deposition.

Abstract  National Institutes of Helath; National Institute of Environmental Health Sciences; Veterans Administration.

Abstract  Theoretical particle deposition studies for children and youths in practical health physics or medical aerosol therapy require detailed information on alterations of anatomical as well as physiological parameters during postnatal growth. Based on the commonly used anatomical model A of Weibel, assuming regular dichotomy, for an adult human lung, a mathematical model was developed for the calculation of airway parameters, such as geometrical dimensions and number of airways as functions of age. Sometimes widely scattered experimental data obtained by different authors were fitted to analytical functions by a multiregressional procedure. Due to the lack of these data for most of the generations of the anatomical model, theoretical considerations had to be applied. For changes of respiration parameters with progressing age, e.g., tidal volume or respiratory frequency, also experimental data were used. The results of these calculations can then serve as a base for the determination of deposition probabilities in different regions of the human respiratory tract.

Abstract  Determinations were made of respiratory tract deposition and gastrointestinal tract burdens following whole body inhalation exposures, typical of those used in many chronic exposures; these were compared to values obtained in nose-only exposures. Fischer-344 rats were exposed in large volume chambers, in a whole body mode, to 0.1 μm volume median diameter (VMD) 67Ga2O3 particles 5 hrs/day. Deposition per unit of exposure time and retention were essentially identical following either 1 or 3 day exposures. The lung deposition of particles was 2.8 units/hr for males and 2.2 units/hr for females if the exposure concentration was expressed as 1 unit/L. These values represent a deposition of approximately 15% of the inhaled particles, similar to values obtained for nose-only exposures. Aerosol deposition per kgm body weight was 24% higher in females than males. Passage of material into the gastrointestinal tract was 1.6-fold greater for these whole body exposures as compared to nose-only exposures to the same aerosol mainly resulting from extra material ingested by grooming of the pelt. Approximately 60% of the pelt burden was calculated to be ingested following whole body exposures.

Abstract  The materials studied were atomized glycerol and dusts of methylene blue, bismuth subcarbonate, glycerol, Na2SO4 and tyrosine. The per cent of penetration of the various participates were measured through the human nose, by using a quantity called the equivalent impaction diameter. Removal of nasal hairs increased the per cent of penetration.

Abstract  Mathematical dosimetry models should improve the accuracy of various extrapolations required in dose-response assessment because they include explicit descriptions of the major mechanistic determinants of the exposure-dose-response continuum. The availability of these anatomic and physiologic parameters for different mammalian species (including humans) and the physicochemical parameters for individual chemicals is an important consideration in the formulation of model structures and the application of simplifying assumptions to develop default models. A framework is presented that includes iterative development of model structures as more data become available. Development of the default dosimetry adjustments for interspecies extrapolation used in the inhalation reference concentration (RfC) methods of the U.S. Environmental Protection Agency (EPA) is discussed as an example of iterative model development, a process intended to ensure that model structures are commensurate with available data. The framework also aids evaluation of different model structures and can be applied to identify key parameters. Examples are provided to illustrate how insight on the key mechanistic determinants of exposure-dose-response can guide interpretation of data in the absence of comprehensive model structures, identify gaps in the database for a given chemical, or direct data gathering for chemicals that are yet to enter production.

Abstract  A pathway through the system of branching in the respiratory region of the lung is modelled by a circular cylinder, closed at one end, with partitions which define the component respiratory units. In this model the transport of O2 during inspiration, generated by diffusion is compared with that produced by diffusion together with convection and the importance of convection in the respiratory region in promoting oxygen uptake at the alveolar wall is discussed. For this discussion it is only necessary to consider inspiration. The equations are solved numerically for flow rates of 10, 85 and 200 liters/min. O2 uptake at the wall and curves of constant O2 concentration are shown to illustrate the influence of convection. It is found that after a 2 sec inspiration from an O2 tension of 98 mm Hg and a lung volume of 2300 ml, convection is about 12 per cent as important as diffusion at a flow rate of 85 liters/min, whereas at 10 liters/min convection is only about 0.4 per cent as important as diffusion.

Abstract  The distribution of the various epithelial types lining the nasal cavity in normal 7 and 16 weeks old male Fischer-344 rats and male B6C3F1 mice has been mapped at the light microscopic level. Photographs of transverse sections of the nose were analysed using a Zeiss Videoplan computerized image analysis system programmed for measurement and evaluation of count, area, perimeter and length. In rats, the volumes of the nasal cavity at 7 and 16 weeks are 156 and 257 mm3 respectively; while in mice the nasal cavity volume is essentially the same (32 . 5 and 31 . 5 mm3) at the same two ages. Total surface areas of the nasal cavity in rats at 7 and 16 weeks are 799 and 1344 mm2 respectively; and in mice 278 and 289 mm2. The percentages of the nasal cavity surface lined by squamous, respiratory and olfactory epithelium are similar at both ages in both species. Applications and significance of these data are discussed.

Abstract  U.S. Department of Energy.

Abstract  The effect of particle size on the regional deposition of aerosols inhaled through the mouth was determined in 93 studies on 34 subjects. The test aerosols were spherical monodisperse insoluble iron oxide particles (specific gravity 2.5) containing radioactive tags, ranging in median unit density diameter from 2.1 to 12.5-microns (σ ≅ 1.08). Particles deposited on the bronchial tree were translocated to the stomach by mucociliary clearance which was essentially complete within the first day. The proportion of the initial lung burden of radioactive particles removed during the first 24 hours provided a functional measure of tracheo-bronchial deposition. A portion of the inhaled aerosol was deposited in the head by impaction. As an impactor, the tracheobronchial tree is more efficient. For each individual subject, head and tracheobronchial deposition increased with increasing particle size. Alveolar depositions decreased with size for particles larger than 4-microns.

Abstract  Experiments examining the dosimetry of inhaled manganese generally focus on pulmonary deposition and subsequent delivery of manganese in arterial blood to the brain. Growing evidence suggests that nasal deposition and transport along olfactory neurons represents another route by which inhaled manganese is delivered to certain regions of the rat brain. The purpose of this study was to evaluate the olfactory uptake and direct brain delivery of inhaled manganese phosphate ((54)MnHPO(4)). Male, 8-wk-old, CD rats with either both nostrils patent or the right nostril occluded underwent a single, 90-min, nose-only exposure to a (54)MnHPO(4) aerosol (0.39 mg (54)Mn/m(3); MMAD 1.68 Ám, "small letter sigma"(g) 1.42). The left and right sides of the nose, olfactory pathway, striatum, cerebellum, and rest of the brain were evaluated immediately after the end of the (54)MnHPO(4) exposure and at 1, 2, 4, 8, and 21 d postexposure with gamma spectrometry and autoradiography. Rats with two patent nostrils had equivalent (54)Mn concentrations on both sides of the nose, olfactory bulb, and striatum, while asymmetrical (54)Mn delivery occurred in rats with one occluded nostril. High levels of (54)Mn activity were observed in the olfactory bulb and tubercle on the same side (i.e., ipsilateral) to the open nostril within 1-2 d following (54)MnHPO(4) exposure, while brain and nose samples on the side ipsilateral to the nostril occlusion had negligible levels of (54)Mn activity. Our results demonstrate that the olfactory route contributes to (54)Mn delivery to the rat olfactory bulb and tubercle. However, this pathway does not significantly contribute to striatal (54)Mn concentrations following a single, short-term inhalation exposure to (54)Mn HPO(4).

Abstract  This work was performed to verify whether or not the inhalation response to cigarette smoke in animal species for assessing carcinogenic potential in humans reflects the strong epidemiological evidence in human smokers. Significant increases in the numbers of malignant tumors of the respiratory tract were not seen in rats, mice, hamsters, dogs, or nonhuman primates exposed for long periods of time to very high concentrations of mainstream cigarette smoke. The results are clearly at variance with the epidemiological evidence in smokers, and it is difficult to reconcile this major difference between observational studies in humans and controlled laboratory studies.

Abstract  National Institutes of Health. #We conducted a series of experiments with ultrafine particles (~20 nm) and larger particles (< 200 nm) of "nuisance" dusts to evaluate the involvement of alveolar macrophages (AM) in particle-induced lung injury and particle translocation in rats. After intratracheal instillation of both ultrafine particles and larger particles of TiO2, we found a highly increased interstitial access of the ultrafine particles combined with a large acute inflammatory reaction as determined by lung lavage parameters. An additional experiment revealed that intratracheal instillation of phagocytized ultrafine TiO2 particles (inside AM) prevented both the pulmonary inflammatory reaction and the interstitial access of the ultrafine particles. Another experiment shoved that the influx of polymorphonuclear cells (PMN) into the alveolar space unexpectedly decreased with higher doses of ultrafine particles, wheras alveolar epithelial permeability (protein leakage) increased. The divergence between PMN influx into the alveolar space and changes in alveolar epithelial permeability implies that they are separate events. Pulmonary inflammatory parameters determined by lung lavage analysis correlated best with the surface area of the retained particles rather than with their mass, volume, or numbers. Because higher doses resulted in an increased interstitialized fraction of particles, we suggest that inflammatory events induced by particles in the interstitial space can modify the inflammation in the alveolar space detectable by lung lavage. Our results demonstrate the dual role of AM for modifying particle-induced lung injury, i.e., both preventing such injury and contributing to it. We conclude that the increased pulmonary toxicity of ultrafine particles is related to their larger surface area and to their increased interstitial access. Further, we suggest that the interstitialization of particles is important for induction of pulmonary fibrotic reactions and that ultrafine particles of nuisance dusts should have different threshold limit values for occupational exposure because of their increased pulmonary toxicity.

Abstract  U.S. Department of Energy. #An aerosol Conditioner (wetted wall reactor) was modified to mimic the conditions inside the human respiratory tract, i.e., relative humidity > 99% and 37CC. By combining the wetted wall reactory with tandem differential mobility analyzer, a system was developed to study the hygroscopic properties of' aerosols in submicrometer range. This paper describes the system, and the results of system tests using three com- pounds of known composition, NaCI, (NH4)2SO4, and (NH4)HSO4, are presented.

Abstract  Although children are an important human population, dosimetry models for gases have been used to predict absorption mainly in laboratory animals and adult humans. To correct this omission, we have used several sources of data on age-dependent lower respiratory tract (LRT) volumes, age-dependent airway dimensions, a model of the adult tracheobronchial region, and a model of the adult acinus to construct theoretical LRT lung models for humans from birth to adulthood. An ozone (O3) dosimetry model was then used to estimate the regional and local uptake of O3 in the (theoretical) LRT of children and adults. For sedentary or quiet breathing, the LRT distribution of absorbed O3, the percent uptake (84 to 88%) and the centriacinar O3 tissue dose are not very sensitive to age. For maximal work during exercise, predicted LRT uptakes range from 87 to 93%, and the regional percent uptakes are more dependent on age than during quiet breathing. In general, the total quantity of O3 absorbed per minute increases with age. Regardless of age and state of breathing, the largest tissue dose of O3 is predicted to occur in the centriacinar region, where many animal studies show the maximal morphological damage from O3.

Abstract  Acidic sulfate is the most toxicologically important sulfur oxide which exists in the ambient air. To determine if particle size influences toxic effects of sulfuric acid, we investigated the effects of sulfuric acid aerosols of two different sizes on biochemical and cellular parameters of bronchoalveolar lavage fluid from exposed guinea pigs. Guinea pigs were exposed to fine (mass median diameter, 0.3 Ám), and ultrafine (mass median diameter, 0.04 Ám) sulfuric acid aerosols at 300 Ág/m3 for 3 hr/day. The animals were euthanized immediately and 24 hr after 1 and 4 days of exposure and lungs were lavaged. Elevated ▀-glucuronidase, lactate dehydrogenase activities, and total protein concentration as well as decreased cell viability were observed in the lavage after a single exposure to sulfuric acid aerosols of both sizes. These alterations were small, though statistically significant, and transient. No alteration in these parameters was observed after 4 days of exposure to acid aerosols. In contrast, sulfuric acid-induced alterations in alveolar macrophage function were more pronounced and longer lasting. Immediately after a single exposure to fine acid, there was a 2.7-fold increase in the spontaneous tumor necrosis factor (TNF) release over that in the control group while endotoxin-stimulated TNF release was increased by 2.2-fold. In addition, acid aerosols of both sizes increased the TNF release from macrophages after 4 days of exposure, although there was no clear temporal pattern of induction or recovery. Furthermore, immediately after 4 days of exposure to either fine or ultrafine acid, the amount of H202 that could be induced from baseline production by alveolar macrophages was 2.2-fold higher than that of the controls. The phagocytic function of macrophages was also altered by exposure to sulfuric acid aerosols. Twenty-four hours after single or multiple exposure, fine acid enhanced (as high as 78% above control) the in vitro phagocytic activity of alveolar macrophages while ultrafine acid depressed the phagocytic capacity (as much as 50% below that in the control). In addition to these biochemical parameters and cellular functions, we also measured the intracellular pH (pHi) of macrophages harvested after exposures to these acid aerosols using a pH-sensitive fluorescent dye. The resting pH, was depressed after a single exposure to both acid aerosols. The depression in pH, persisted 24 hr after ultrafine acid exposure. A similar depression of resting pH, was observed 24 hr after 4 days of exposure to ultrafine acid while the resting pHi of the groups of animals that were exposed to fine acid was not affected. We conclude that exposure to sulfuric acid can produce pronounced alterations in cellular function and intracellular pH of alveolar macrophages and that sulfuric acid of different particle size produces different patterns of changes in alveolar macrophages.

Abstract  Experimental data are reported on total deposition of a solid monodisperse aerosol along the human respiratory tract in a study with 25 healthy adults of both sexes. The test aerosol was generated by condensation of carnauba wax vapor onto suitable condensation nuclei. The particles were solid spheres at body temperature and ranged from 0.2 to 2 µm diameter, with a geometric standard deviation of less than 1.1. The deposition efficiency was assessed by photometric measurement of light scattering at 90° in the inhaled and the exhaled air. On each exposure subject the relevant spiro-metric parameters were assessed in order to correlate these with the deposition data. Measurements were made at constant respiratory frequency and tidal volume, and at spontaneous respiration conditions.

Abstract  The xanthine oxidase catalyzed oxidations of a series of aliphatic aldehydes and 2- and 4-pyridinecarboxaldehydes were studied in phosphate buffers by monitoring the reduction of ferricytochrome c at 25.0° In aqueous solutions, these aldehydes exist in equilibrium with their hydrated forms. In order to clearly establish the relationship between the acid-base-catalyzed hydration of the aldehydes and the enzymatically catalyzed oxidation of the aldehyde-hydrate system, detailed kinetic analyses of both processes were carried out separately. Enzymatic catalysis was studied as a function of pH and of acetaldehyde concentration, and the catalytic components associated with the acid-base-catalyzed hydration of acetaldehyde in phosphate buffers were evaluated. These data, taken together, show not only that the unhydrated aldehyde is the substrate for xanthine oxidase action but also suggest that substantial enzymatic inhibition arises from the formation of the hydrate. The involvement of the unhydrated aldehyde as the preferential substrate is commnn for the aldehydes studied and in the evaluation of their respective Michaelis constants, Km: acetaldehyde, 0.0058 m; propionaldehyde, 0.014 μ; n-butyraldehyde, 0.048 m; 2-pyridinecarboxaldehyde, 0.0061 m; and 4-pyridinecarboxaldehyde, 0.002 m; correction was made to compensate for respective fractions of hydration. © 1972, American Chemical Society. All rights reserved.

Abstract  It is difficult to extrapolate observations and results from one species to another and from animals to humans because of interspecies differences. A complete and systematic description of such differences among commonly used laboratory animals is lacking. We have reviewed the relevance of deposition, clearance, and the type and magnitude of biological response to inhaled aerosols. Current predictions on the probability of deposition of inhaled aerosols differ, but the fraction of aerosol that is actually deposited in the respiratory tract appears independent of body size. Different species of animals breathing the same aerosol do not receive identical lung doses, and thus exposure concentration is not an adequate description of lung dose. Parameters that affect the magnitude of local doses include changes in ventilation, collection efficiency, lung anatomy, and clearance mechanisms. Apart from these variations, the interspecies differences in substance metabolism and innate biological responsiveness make it unlikely that the extent of lung damage will be identical even in cases where lung doses are equal. We need a comprehensive view of species differences with predictive power.