Three-dimensional computational fluid dynamics simulations of particle deposition in the tracheobronchial tree.

Simulation of the dynamics and disposition of inhaled particles within human lungs is an invaluable tool in both the development of inhaled pharmacologic drugs and the risk assessment of environmental particulate matter (PM). The goal of the present focused study was to assess the utility of three-dimensional computational fluid dynamics (CFD) models in studying the local deposition patterns of PM in respiratory airways. CFD models were validated using data from published experimental studies in human lung casts. The ability of CFD to appropriately simulate trends in deposition patterns due to changing ventilatory conditions was specifically addressed. CFD simulations of airflow and particle motion were performed in a model of the trachea and main bronchi using Fluent Inc.'s FIDAP CFD software. Particle diameters of 8 microm were considered for input flow rates of 15 and 60 L/min. CFD was able to reproduce the observed spatial heterogeneities of deposition within the modeled bifurcations, and correctly predicted the "hot-spots" of particle deposition on carinal ridges. The CFD methods also predicted observed differences in deposition for high-versus-low flow rates. CFD models may provide an efficient means of studying the complex effects of airway geometry, particle characteristics, and ventilatory parameters on particle deposition and therefore aid in the design of human subject experiments.

The health relevance of ambient particulate matter characteristics: coherence of toxicological and epidemiological inferences.

The aim of this article is to review progress toward integration of toxicological and epidemiological research results concerning the role of specific physicochemical properties, and associated sources, in the adverse impact of ambient particulate matter (PM) on public health. Contemporary knowledge about atmospheric aerosols indicates their complex and variable nature. This knowledge has influenced toxicological assessments, pointing to several possible properties of concern, including particle size and specific inorganic and organic chemical constituents. However, results from controlled exposure laboratory studies are difficult to relate to actual community health results because of ambiguities in simulated PM mixtures, inconsistent concentration measurements, and the wide range of different biological endpoints. The use of concentrated ambient particulates (CAPs) coupled with factor analysis has provided an improved understanding of biological effects from more realistic laboratory-based exposure studies. Epidemiological studies have provided information concerning sources of potentially toxic particles or components, adding insight into the significance of exposure to secondary particles, such as sulfate, compared with primary emissions, such as elemental and organic carbon from transportation sources. Recent epidemiological approaches incorporate experimental designs that take advantage of broadened speciation monitoring, multiple monitoring stations, source proximity designs, and emission intervention. However, there continue to be major gaps in knowledge about the relative toxicity of particles from various sources, and the relationship between toxicity and particle physicochemical properties. Advancing knowledge could be facilitated with cooperative toxicological and epidemiological study designs, with the support of findings from atmospheric chemistry.

Ozone-induced modulation of cell-mediated immune responses in the lungs.

Most pulmonary immunotoxicology studies of ambient pollutants have been broadly designed to discern if overall humoral or cell-mediated immunity (CMI) was altered; few have assessed effects on particular aspects of immune function. We hypothesized that effects from ozone (O3) exposure on pulmonary CMI are linked in part to changes in local immune cell capacities to form and/or to interact with immunoregulatory cytokines. Rats exposed to 0.1 or 0.3 ppm O3 4 h/day 5 days/week, for 1 or 3 weeks were assessed for resistance to, and pulmonary clearance of, a subsequent Listeria monocytogenes challenge. In situ cytokine release and immune cell profiles were also analyzed at different stages of the antilisterial response. Although O3 exposure modulated CMI, effects were not consistently concentration- or duration-dependent. Exposure did not effect cumulative mortality from infection, but induced concentration-related effects upon morbidity onset and persistence. All 1-week exposed rats had listeric burdens trending higher than controls; 0.3 ppm rats displayed continual burden increases rather than any onset of resolution. Rats exposed for 3 weeks had no O3-related changes in clearance. No exposure-related effect on neutrophil or pulmonary macrophage (PAM) numbers or percentages was noted. Bacterial burden analyses with respect to cell type showed that Listeria:PAM ratios in 0.3 ppm rats ultimately became greatest compared to all other rats. In situ IL-1alpha and TNFalpha levels were consistently higher in O3-exposed rats. All rats displayed increasing in situ IFNgamma levels as infection progressed, but no constant relationship was evident between IFNgamma and initial IL-1alpha/TNFalpha levels in O3-exposed hosts. It seems that short-term (i.e., 1 week) repeated O3 exposures imparted more effects upon CMI than a more prolonged (i.e., 3 week) regimen, with effects manifesting at the level of the PAM and in the cytokine network responsible for immunoactivation.

Clearance and translocation of aluminum oxide (alumina) from the lungs.

Significant respiratory-tract exposure to insoluble aluminum compounds, such as alumina (aluminum oxide, Al(2)O(3)), can occur in occupational settings, yet little is known about the temporal pattern of pulmonary clearance of these materials from the lungs with repeated exposures, and potential subsequent translocation to other organs. This study evaluated the clearance pattern of alumina from the lungs of rats, and burdens in selected extrapulmonary organs (brain, bone, liver, spleen, kidney). Rats were instilled with alumina once weekly for 20 wk. Quantification of retention was performed by measuring aluminum burdens in the lungs and extrapulmonary organs during the exposure period, and then weekly for an additional 19 wk after the exposures ended. Lung burdens of aluminum were found to steadily increase during exposure. Clearance of the material following the end of the exposure regime was extremely slow; only approximately 9% of the amount in the lungs following the 20 weekly exposures was cleared by the end of the postexposure period. This study supports the concept of gradual accumulation and long-term retention of aluminum within the respiratory tract of individuals repeatedly exposed to alumina in occupational settings.

Toxicological bases for the setting of health-related air pollution standards.

The development of air pollution standards ideally involves the integration of data from the disciplines of epidemiology, controlled clinical studies, and animal toxicology. Epidemiological studies show statistical associations between health outcomes and exposure; they cannot establish a definite cause-effect relationship. The utility of toxicological studies is to establish this relationship. Recently, there was simultaneous promulgation of a new National Ambient Air Quality Standard (NAAQS) for particulate matter < 2.5 microns in aerodynamic diameter (PM2.5) and a revised NAAQS for ozone (O3). The O3 NAAQS was based, in part, on a sound foundation of toxicological data from controlled exposure studies in humans and animals. It also relied on epidemiological studies of hospital admissions for respiratory diseases. Such studies also served as important bases for the new PM2.5 NAAQS. However, the most influential bases for the PM NAAQS were the numerous and generally consistent epidemiological studies that associated exposure with premature mortality in susceptible subpopulations and the inability of numerous hypothesized confounding factors to negate the associations. Using ozone and PM as examples, this paper discusses the scientific basis for NAAQS promulgations in situations in which the underlying database differed greatly in the extent of toxicological support.

Intratracheal instillation as an exposure technique for the evaluation of respiratory tract toxicity: uses and limitations.

The evaluation of respiratory tract toxicity from airborne materials frequently involves exposure of animals via inhalation. This provides a natural route of entry into the host and, as such, is the preferred method for the introduction of toxicants into the lungs. However, for various reasons, this technique cannot always be used, and the direct instillation of a test material into the lungs via the trachea has been employed in many studies as an alternative exposure procedure. Intratracheal instillation has become sufficiently widely used that the Inhalation Specialty Section of the Society of Toxicology elected to develop this document to summarize some key issues concerning the use of this exposure procedure. Although there are distinct differences in the distribution, clearance, and retention of materials when administered by instillation compared to inhalation, the former can be a useful and cost-effective procedure for addressing specific questions regarding the respiratory toxicity of chemicals, as long as certain caveats are clearly understood and certain guidelines are carefully followed.

Immunotoxicologic effects of inhaled chromium: role of particle solubility and co-exposure to ozone.

Soluble and insoluble hexavalent chromium (Cr6+) agents are concomitantly released with ozone (O3) during welding. Although pulmonary/immunologic implications from exposure to each agent individually have been investigated, the effects from simultaneous exposure, as occurs under actual working conditions, are unclear. To investigate immunomodulatory effects of inhaled Cr6+, F-344 rats were exposed for 5 h/day, 5 days/week for 2 or 4 weeks to atmospheres containing soluble potassium chromate (K2CrO4) or insoluble barium chromate (BaCrO4), each alone at 360 micrograms Cr/m3 or in combination with 0.3 ppm O3. One day after the final exposure, rats were euthanized, their lungs were lavaged, and pulmonary macrophages (PAM) were recovered for assessment of basal and inducible functions. Rats inhaling K2CrO4-containing atmospheres had greater levels of total recoverable cells, neutrophils, and monocytes in bronchopulmonary lavage compared to rats exposed to insoluble Cr6+ atmospheres, O3 alone, or air; these rats also had a reduced percentage of PAM, although total PAM levels remained unaffected. Although Cr exposure-related changes in PAM functionality were evident, any dependence upon Cr solubility was variable. K2CrO4-containing atmospheres modulated PAM-inducible interleukins-1 and -6, and tumor necrosis factor-alpha production to a greater degree than those containing BaCrO4. Conversely, BaCrO4-containing atmospheres affected PAM basal nitric oxide production and interferon-gamma-primed/zymosan-stimulated reactive oxygen intermediate production to a greater extent than did those containing K2CrO4. In none of the PAM assays did co-inhalation of O3 result in a modulation of the effects obtained with either Cr6+ compound itself. The results indicate that, while immunomodulatory effects of inhaled Cr6+ upon PAM are related to particle solubility, the co-inhalation of O3 apparently does not cause further modifications of the metal-induced effects.

Effects of vanadium upon polyl:C-induced responses in rat lung and alveolar macrophages.

Hosts exposed to vanadium (V) display a subsequent decrease in their resistance to infectious microorganisms. Our earlier studies with rats inhaling occupationally relevant levels of V (as, ammonium metavanadate, NH4VO3) indicated that several nascent/inducible functions of pulmonary macrophages (PAM) were reduced. In the present study, V-exposed rats were examined to determine whether some of the same effects might also occur in situ. Rats were exposed nose-only to air or 2 mg V/m3 (as NH4VO3) for 8 h/d for 4 d, followed, 24 h later, by intratracheal (it) instillation of polyinosinic:polycytidilic acid (polyl:C) or saline. Analysis of lavaged lung cells/fluids after polyl:C instillation indicated that total lavageable cell/neutrophil numbers and protein levels, while significantly elevated in both exposure groups (as well as in saline-treated V-exposed rats), were always greater in V-exposed hosts. Exposure to V also affected the inducible production of interleukin 6 (IL-6) and interferon gamma (IFN gamma), but apparently not that of tumor necrosis factor-alpha (TNF alpha) or IL-1. Although polyl:C induced significant increases in lavage fluid IL-6 and IFN gamma levels in both exposure groups, levels were greater in V-exposed rats. If calculated with respect to total lavaged protein, however, V-exposed rats produced significantly less cytokine. Following polyl:C instillation, there were no marked exposure-related differences in basal or stimulated superoxide anion production by pooled lavaged cells or PAM specifically. With V-exposed rats, pooled cells recovered 24 h after saline instillation displayed reduced production (in both cases) compared to the air control cells; PAM-specific production was affected only after stimulation. In both exposure groups, polyl:C caused decreased superoxide production in recovered cells. Though less apparent with pooled cells, there was a time post polyl:C instillation-dependent decrease in stimulated PAM-specific superoxide production; this effect was greater in PAM from V-exposed rats than in PAM from air controls. Phagocytic activity of PAM from rats in both exposure groups was significantly increased by polyl:C instillation, although total activity in cells obtained from V-exposed rats was always significantly lower compared to air control cells. Our results indicate that short-term, repeated inhalation of occupationally relevant levels of V by rats modulates pulmonary immunocompetence. Modified cytokine production and PAM functionality in response to biological response modifiers (such as lipopolysaccharide, IFN gamma, or polyl:C) may be, at least in part, responsible for the increases in bronchopulmonary disease in humans occupationally exposed to V.

Effects of ozone upon macrophage-interferon interactions.

Lung cell populations may be directly exposed to environmental airbone toxicants such as ozone (O3). Since pulmonary macrophages (M phi) play a pivotal role in host pulmonary immunocompetence, their function in this regard may be compromised by pollutant exposure thereby giving rise to an increased incidence of pulmonary disease. The current in vitro study was designed to provide some insight into possible mechanisms by which O3 induces decreased host pulmonary resistance against microbial pathogens. Specifically, this study investigated the impact of an acute O3 exposure upon the ability of a cultured mouse M phi cell line (WEHI-3) to interact with, and respond to, the major M phi-activating cytokine, interferon-gamma (IFN gamma). The results of this study indicate that WEHI-3 exposure to 1 ppm O3 for 4 h reduced both the binding of, and responsivity to, IFN gamma. Among the functional parameters affected by this inability to properly bind/respond to IFN gamma were: reactive oxygen intermediate production, phagocytic activity, and cellular calcium ion elevation; IFN gamma-enhanced expression of surface histocompatibility antigens was unaffected by O3 exposure. The reduced activity of any one of these critical M phi functions could provide a basis for previously-documented increases in microbial pathogen survival in the lungs, and overall compromise of host health following O3 exposure.

Pulmonary immunotoxicity of inhaled ammonium metavanadate in Fisher 344 rats.

Male Fisher 344 rats were exposed to 2 mg vanadium(V)/m3 (as ammonium metavanadate NH4VO3, 0.32 micron MMD) atmospheres for 8 hr/day for 4 days in a nose-only exposure system. In exposed rats, lung V burdens increased in a time-dependent fashion. Analysis of lung cells and lavage fluid 24 hr after the final exposure suggested that tissue damage and a strong inflammatory response was elicited; numbers of neutrophil and small macrophages (Mø), as well as levels of lavageable protein and lactate dehydrogenase, were significantly elevated as compared with levels observed with air-exposed rats. Vanadium also affected pulmonary alveolar Mø (PAM) capacities to produce and respond to immunoregulating cytokines. Inducible PAM production of tumor necrosis factor-alpha was significantly inhibited, as was the ability to increase cell surface Class II/I-A molecule expression in response to interferon-gamma (IFN gamma). PAM from V-exposed hosts were also inhibited in their ability to be primed by IFN gamma to produce superoxide anion and hydrogen peroxide in response to stimulation with opsonized zymosan. These studies indicate that short-term repeated exposure of rats to atmospheric V, at levels encountered in an occupational setting, can alter host pulmonary immunomocompetence, with one major effect occurring at the level of cytokine-related functions. These alterations may be underlying mechanisms for the well-documented increases in bronchopulmonary infections and cancers in workers chronically exposed to V-containing atmospheres.

Vanadium affects macrophage interferon-gamma-binding and -inducible responses.

Mouse WEHI-3 cells were exposed overnight to vanadium [V; ammonium metavanadate (NH4VO3) or vanadium pentoxide (V2O5)] to determine whether documented V-induced immunomodulation might arise from altered macrophage (M phi) interactions with interferon-gamma (IFN gamma) or altered IFN gamma-inducible responses. Binding studies performed at 22 degrees C indicated that although NH4VO3-pretreated cells had approximately 48% fewer actively-binding Class I IFN gamma receptors, binding affinities were 1.5-fold greater than that of control cell receptors; Class II expression was unaffected but affinities were reduced 2-fold. Postbinding IFN gamma-receptor complex internalization was unaffected by V pretreatment. Spontaneous production of both hydrogen peroxide and superoxide anion was significantly increased by treatment with both V compounds. Total hydrogen peroxide and superoxide production was increased by stimulation of IFN gamma-primed cells with zymosan, but relative increases in primed V-treated cells were lower than that in controls. Vanadium-treated cells also displayed decreased rates of IFN gamma-induced changes in [Ca2+]i levels secondary to increased resting [Ca2+]i levels. Although V-treated cells did not display significant increases in I-A expression after IFN gamma treatment, increased numbers of I-A+ cells (irrespective of priming) and lower maximal antigen densities than observed on I-A+ control cells were evident. Results from this study show that V exposure may produce alterations in M phi-mediated functions, in part, by modifying cell interactions with IFN gamma and subsequent IFN gamma-dependent functional parameters.

Ozone-induced alteration in beta-adrenergic pharmacological modulation of pulmonary macrophages.

Ozone is a ubiquitous air pollutant which can affect numerous function s of the respiratory system. However, previous work has not provided any information concerning its ability to modulate pharmacological receptors of pulmonary macrophages. This study examined, using a chemiluminescence assay, the beta-adrenergic modulation of pulmonary macrophages harvested from rabbits exposed for 3 hr/day for 5 days to 0.1, 0.3 or 0.6 ppm ozone (O3) or to 3 hr/day for 20 days to 0.1 or 0.3 ppm. Receptor activity was monitored using release of reactive oxygen species (ROS) following administration to the cells of the beta2-receptor agonist, isoproterenol. An O3-exposure concentration-dependent response was observed for isoproterenol efficacy following 5-day exposures, in that 0.1 ppm O3 induced a significant enhancement of beta-adrenergic inhibition of ROS production, 0.3 ppm ozone produced no significant change from control, and 0.6 ppm decreased inhibition. No significant effects on beta-adrenergic modulation were noted following the 20-day exposures. The results of this study suggest that short-term repeated exposures to O3 are capable of inducing alterations in the pharmacological functioning of pulmonary macrophages, while longer term exposures may result in adaptation. Alterations in receptor function have implications in terms of pulmonary defense and disease.

Interaction of gaseous and particulate pollutants in the respiratory tract: mechanisms and modulators.

Human contact with air pollution usually involves exposure to more than one chemical, and biological responses to the inhalation of polluted atmospheres likely depend upon the interplay between individual materials. Thus, characterizing effects from exposures to mixtures of air pollutants is necessary for adequate quantitation of health risks. Exposure to gas/particle mixtures may result in respiratory tract responses which are additive, or reflect synergistic or antagonistic interactions. The occurrence and type of interaction depends upon numerous factors, including the biological endpoint being examined and the specific exposure conditions, such as concentration, duration, and the physicochemical characteristics of the exposure atmosphere. It is, therefore, not always possible to predict solely from the presence of certain pollutants in a complex atmosphere exactly whether there will be an interaction and, if so, what type it will be. This complicates attempts to relate responses observed in laboratory studies of mixtures to those which may occur under ambient patterns of exposure, an extrapolation needed for human risk assessment.

Empirical modeling of particle deposition in the alveolar region of the lungs: a basis for interspecies extrapolation.

Different species exposed to the same particle atmosphere may not receive identical initial doses in comparable respiratory tract regions, and the selection of a certain species for toxicologic evaluation of inhaled particles may, thus, influence the estimated human lung, or systemic, dose, as well as its relationship to potential adverse health effects. Estimating regional particle deposition patterns is important for establishing the comparability of animal models, for understanding interspecies differences in the expression of chemical toxicities, and, ultimately, for the human risk assessment process. A method is described which offers a strategy for summarizing published data on regional deposition of particles of different diameters and calculating a deposited fraction for a particular particle size distribution. This involved the construction of nomograms to allow estimation of alveolar deposition fractions in three species, namely the human, monkey, and rat. A regression model was then developed to permit the calculation of more exact deposition fractions. Although this paper describes the procedure for one region of the lungs, the same technique can be applied to other regions of the respiratory tract or to the total system for which deposition data are available. While this technique may facilitate the interpretation of available experimental results and their application to human health risk assessment, appropriate caution should be exercised in applying the developed nomograms given limitations of the deposition database upon which it is based.

Alteration of pulmonary macrophage intracellular pH following inhalation exposure to sulfuric acid/ozone mixtures.

Recent studies have demonstrated that additive and synergistic effects on rabbit pulmonary macrophages (PM phi) function can occur after combined exposures to acid aerosols and ozone. This study investigated intracellular pH (pHi) homeostasis and H+ extrusion mechanisms of PM phi from rabbits exposed to sulfuric acid, ozone, and their mixtures. Animals were exposed for 3 h to 125 micrograms/m3 sulfuric acid, 0.1, 0.3, 0.6 ppm ozone, or combinations of acid with each concentration of ozone, and the pHi was determined by a fluorescent dye ratioing technique. Exposure to 125 micrograms/m3 acid reduced pHi and exposure to ozone resulted in a concentration-dependent reduction in pHi. Ozone generally tended to mitigate the effect of the acid aerosol on pHi. Other groups of rabbits were exposed to 50 micrograms/m3 sulfuric acid, 0.6 ppm ozone, or their mixture, for 3 h, and PM phi were again harvested. The pHi of PM phi following exposure to each of the pollutant atmospheres was not different from control. However, H+ extrusion with an imposed internal acid load was found to be significantly depressed following exposure to either sulfuric acid or ozone alone, while the mixture produced a significant interaction.

Nonspecific bronchial responsiveness assessed in vitro following acute inhalation exposure to ozone and ozone/sulfuric acid mixtures.

Air pollution may play some role in the recent increase in severity and prevalence of asthma, but the specific chemical components with the ambient pollutant mix that may be responsible have not been delineated. Since ambient exposures involve mixtures, it is essential to examine airway responses to realistic pollutant mixtures. This study examined the ability of single (3-h) inhalation exposures to ozone and to mixtures of ozone plus sulfuric acid to induce nonspecific airway hyperresponsiveness in healthy rabbits. Airway responsiveness was assessed using an in vitro assay involving administration of increasing doses of acetylcholine to bronchial rings obtained from animals exposed to 0.1-0.6 ppm ozone or to mixtures of ozone and 50-125 micrograms/m3 sulfuric acid aerosol; results were compared to those reported previously for sulfuric acid alone. Bronchial hyperresponsiveness to ozone was noted following exposure at all concentrations, but the combination of pollutants results in antagonism. The results support the potential for ozone to induce airway hyperresponsiveness in healthy animals and suggest that interaction with sulfuric acid may reduce the effectiveness of both pollutants.

Immunotoxicity of sulfuric acid aerosol: effects on pulmonary macrophage effector and functional activities critical for maintaining host resistance against infectious diseases.

Despite the widespread occurrence of acidic sulfur oxides in the ambient environment and their potential risks to human health, effects associated with pulmonary immune defenses have been poorly studied. The current in vivo study was designed to provide some insight into this relatively unexplored area by investigating the impact of inhaled sulfuric acid on immune defense mechanisms critical for maintaining pulmonary resistance against infectious diseases. Results of this study demonstrate that repeated inhalation of sulfuric acid reduces the uptake and intracellular killing of pathogenic bacteria by exposed pulmonary macrophages, and depresses the activity/production of important biological modifiers critical for maintaining pulmonary immunocompetence. These findings have important implications for human health, and may contribute to a better understanding of the possible mechanism(s) underlying the epidemiological evidence which suggests an association between total sulfates in the ambient air and increased incidence of acute bronchitis and lower respiratory illness in school-age children.

Comparative biological potency of acidic sulfate aerosols: implications for the interpretation of laboratory and field studies.

Biological responses to inhaled acid sulfates result from the deposition of hydrogen ion (H+) on airway surfaces. Thus, effects from sulfuric acid and ammonium bisulfate, the two major ambient species, have been assumed to be the same for a given H+ concentration within the exposure atmosphere, assuming similar respiratory tract deposition patterns. However, recent inhalation studies have indicated that sulfuric acid is disproportionately potent compared to ammonium bisulfate when the H+ content of the exposure atmosphere is considered, suggesting that some factors following inhalation affect the amount of H+ contacting airway surfaces. This study assessed a mechanism potentially underlying this phenomenon, namely, the extent of neutralization by respiratory tract ammonia. This was evaluated using a physical model system designed to mimic transit of these aerosols in the upper respiratory tract of the animal model used in this laboratory, the rabbit. The results suggest that for equal exposure quantities of H+, more acid would be deposited when sulfuric acid is inhaled than when ammonium bisulfate is inhaled. Furthermore, results from a series of in vitro exposures of tracheal epithelial cells to sulfuric acid and ammonium bisulfate aerosols indicated that the biological response is a function of the total mass (ionic) concentration of H+ deliverable to the cells or the total extractable H+ per particle. The results of this study have possible implications for ambient monitoring of particulate-associated strong acidity, suggesting that it may be necessary to specilate such measures into the relative amounts of H+ as sulfuric acid or ammonium bisulfate in order to most accurately relate atmospheric acid levels to observed health effects. In addition, since much of the ambient particulate-associated H+ exists as sulfuric acid/ammonium bisulfate mixtures rather than pure compounds, H(+)-associated health effects from controlled exposure studies of sulfuric acid may not be transferable to ambient population situations on a 1:1 basis. Since any such errors in exposure assessment will necessarily bias downward the strength of H(+)-related health effects associations found via epidemiological studies, failure to address the specification of H+ may cause such studies to underestimate the human health effects of strong acids.

Nonspecific airway hyperresponsiveness induced by inhalation exposure to sulfuric acid aerosol: an in vitro assessment.

Air pollution may be a factor in the recent increase in severity and prevalence of asthma, but the specific chemical components within the ambient pollutant mix which may be responsible have not been delineated. Acid sulfate aerosols, such as sulfuric acid, have been associated with exacerbation of symptoms in asthmatics and induction of nonspecific airway hyperresponsiveness in normal laboratory animals. This study examined the ability of single (3 hr) inhalation exposures to sulfuric acid to induce nonspecific airway hyperresponsiveness in healthy rabbits. Responsiveness was assessed using an in vitro assay involving administration of increasing doses of acetylcholine or histamine to bronchial and tracheal rings obtained from animals exposed to 50-500 micrograms/m3 sulfuric acid aerosol. Bronchial hyperresponsiveness to both agonists was noted following exposures at > or = 75 micrograms/m3. In addition, sulfuric acid altered the normal response pattern of trachea to histamine. The results provide further support for a role of acid sulfates in the induction of airway hyperresponsiveness, and suggest that effects may be due to modulation of pharmacological receptors involved in maintaining airway tone.

Inhalation of particulate lead oxide disrupts pulmonary macrophage-mediated functions important for host defense and tumor surveillance in the lung.

Lead, an immunomodulator and potential human carcinogen, is a major airborne pollutant in industrial environments which poses a serious threat to human health. Despite the wide-spread occurrence of respirable lead particles in the air, and the potential human health risks, effects associated with inhalation of particulate lead on the the lung have been poorly studied. This study was performed to determine whether inhalation of particulate lead oxide (PbO), at a concentration below the currently acceptable air lead standard for occupational exposure, disrupts macrophage (M phi) functions important for maintaining pulmonary immunocompetence. These functions include phagocytosis, production of reactive oxygen intermediates, and the biological activity of tumor necrosis factor-alpha (TNF-alpha). Rabbits exposed to PbO at 30 micrograms/m3 for 4 days (3 hr/day) were sacrificed and their lungs lavaged immediately, 24 hr, and 72 hr after the final exposure. Lactate dehydrogenase (a marker of lung cell damage) and lysozyme activity (a marker of lysosome permeability), measured in the lavage fluid, were significantly increased 24 and 72 hr after exposure. PbO produced neutrophil infiltration nor effects on M phi viability or total numbers. Effects on M phi functions were as follows. Phagocytic uptake of latex particles was reduced with increasing post-exposure time reaching a maximum inhibition at 72 hr. Inhalation of PbO enhanced hydrogen peroxide (H2O2) and superoxide anion radical (O2-) production in a time-dependent manner; effects on H2O2 began at 24 hr and were persistent up to 72 hr. Effects on TNF-alpha release/activity appeared earliest and were persistent up to 72 hr. Immediately and 24 hr after exposure, lipopolysaccharide-stimulated activity of TNF-alpha was depressed by 62 and 50%, respectively; after 72 hr, TNF-alpha release was significantly enhanced compared to control levels. Results demonstrate that the lung is a sensitive target for the toxic effects of inhaled lead. This study provides the first evidence that inhalation of particulate lead, at an occupationally relevant concentration, and in the absence of elevated blood lead levels, alters pulmonary M phi functions critical for lung defense against inhaled antigens. Our findings may have important implications for human health and should be considered when evaluating the health risks associated with inhaled lead.