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Biomedical subjects

Y S Cheng

Publications and source records attributed to Y S Cheng.

At least 91 records · Page 5Linked to original sources
PubMed1989

Effect of four-week repeated inhalation exposure to unconjugated azodicarbonamide on specific and non-specific airway sensitivity of the guinea pig.

Reports of respiratory problems among industrial workers exposed repeatedly by inhalation to azodicarbonamide (ADA) raised concern that ADA might be a pulmonary sensitizer. We used a non-invasive method for measuring specific airway conductance to evaluate the potential for repeated inhalation of unconjugated ADA to cause specific or non-specific pulmonary sensitization in the guinea pig. Two groups of male Hartley guinea pigs were exposed 6 h/day, 5 days/week for 4 weeks to aerosolized ADA at 51 or 200 mg/m3, or to filtered air as controls. One group was tested for specific sensitization to ADA by measuring specific airway conductance during inhalation challenge with ADA before and on the third day after the 4-week ADA exposure. The ADA concentrations for the challenges were identical to the repeated exposure concentrations (51 or 200 mg/m3, 200 mg/m3 for controls). The other group was tested for non-specific airway sensitization by inhalation challenge with aerosolized histamine before and after the 4-week ADA exposure. Histamine was administered in stepwise increasing concentrations to elicit an airway response in each guinea pig. Skin tests for immunological responses to ADA, body weight and histopathology of the respiratory tract and skin test sites were also evaluated. The 4-week exposure to ADA did not result in either specific or non-specific airway sensitization. The ADA exposure did not induce positive skin reactions, influence body weight or cause histopathological responses. These results indicate that ADA, acting alone (i.e. not conjugated to a protein), is not a pulmonary sensitizer in the guinea pig exposed repeatedly for 4 weeks and challenged to simulate a 'Monday morning' exposure.

Administration, Inhalation↗
PubMed1989

Lung toxicity after 13-week inhalation exposure to nickel oxide, nickel subsulfide, or nickel sulfate hexahydrate in F344/N rats and B6C3F1 mice.

The relative toxicity of nickel oxide (NiO), nickel sulfate hexahydrate (NiSO4.6H2O), and nickel subsulfide (Ni3S2) was studied in F344/N rats and B6C3F1 mice after inhalation exposure for 6 hr/day, 5 days/week, for 13 weeks. Exposure concentrations used (as mg Ni/m3) were 0.4-7.9 for NiO, 0.02-0.4 for NiSO4.6H2O, and 0.11-1.8 for Ni3S2. No exposure-related effects on mortality and only minor effects on body weight gain were seen in rats or mice. The most sensitive parameter for nickel toxicity was histopathologic change in the lungs of exposed animals were chronic active inflammation, fibrosis, and alveolar macrophage hyperplasia were associated with nickel exposure. There was an exposure-related increase in lung weight in rats and mice. Equilibrium levels of nickel in the lung were reached by 13 weeks of nickel sulfate and nickel subsulfide exposure, whereas lung levels of nickel continued to increase throughout exposure to nickel oxide. Additional exposure-related histopathologic lesions in treated animals included atrophy of the olfactory epithelium after nickel sulfate and nickel subsulfide exposure. No nasal lesions were seen after nickel oxide exposure. Lymphoid hyperplasia of the bronchial lymph nodes developed in animals exposed to all three nickel compounds. The order of toxicity corresponded to the water solubility of the nickel compounds, with nickel sulfate being most toxic, followed by nickel subsulfide and nickel oxide.

Administration, Inhalation↗
PubMed1989

Biochemical responses of rat and mouse lung to inhaled nickel compounds.

Nickel subsulfide (Ni3S2), nickel sulfate (NiSO4), and nickel oxide (NiO) are encountered occupationally in the nickel refining and electroplating industries, with inhalation being a common route of exposure. The purposes of this study were to evaluate the biochemical responses of lungs of rats and mice exposed for 13 weeks to occupationally relevant aerosol concentrations of Ni3S2, NiSO4, and NiO, to correlate biochemical responses with histopathologic changes, and to rank the compounds by toxicity. Biochemical responses were measured in bronchoalveolar lavage fluid (BALF) recovered from lungs of exposed animals. Parameters evaluated in BALF were lactate dehydrogenase (LDH), beta-glucuronidase (BG), and total protein (TP). Total and differential cell counts were performed on cells recovered in BALF. All compounds produced an increase in LDH, BG, TP, and total nucleated cells, and an influx of neutrophils, indicating the presence of a cytotoxic and inflammatory response in the lungs of exposed rats and mice. Increases in BG were greater than increases in LDH and TP for both rats and mice. Chronic active inflammation, macrophage hyperplasia, and interstitial phagocytic cell infiltrates were observed histologically in rats and mice exposed to all compounds. Statistically significant increases in BG, TP, neutrophils, and macrophages correlated well with the degree of chronic active inflammation. Results indicated a toxicity ranking of NiSO4 greater than Ni3S2 greater than NiO, based on toxicities of the compounds at equivalent mg Ni/m3 exposure concentrations.

Aerosols↗
PubMed1989

Experimental measurements of the diffusion coefficient of 212Pb.

Knowledge of the diffusion coefficient of Rn progeny is necessary for assessing the radiation exposure resulting from exposure to Rn and its progeny. The diffusion coefficient for 220Rn progeny was determined in ambient air by two independent methods, measuring deposition using a cylindrical tube or screens. A sampling train consisting of a diffusion tube and a screen-type diffusion battery was used for the experimental study. A range of flow rates and relative humidities was investigated. For 35% less than or equal to RH less than or equal to 85%, results from the two systems agree with each other. The diffusion coefficient of 212Pb was 0.036 +/- 0.002 cm2 s-1 and 0.037 +/- 0.004 cm2 s-1 for the tube and screen penetration methods, respectively. In low humidity air (RH less than 30%), a linear relationship between the diffusion coefficient of 212Pb and relative humidity was observed. The observed diffusion coefficient is strongly affected by the amount of material agglomerated onto the 212Pb atom. Further studies on the effects of trace gases and organics are required to fully understand the results.

Bismuth↗
PubMed1989

Azodicarbonamide: methods for the analysis in tissues of rats and inhalation disposition.

1. A method has been developed for measuring azodicarbonamide (ADA) and its metabolite biurea in tissues of rat. The method is based on the reaction of ADA with triphenylphosphine; the derivative so formed was isolated and quantified using reversed-phase h.p.l.c. Quantification was by u.v. detection with 14C-ADA as internal standard. Biurea was measured by oxidation to ADA, followed by treatment as described above. 2. When biurea was added to tissues at 100-400 micrograms, recoveries of 92-125% were observed. In contrast, recoveries of ADA added to tissues were generally much less than 100% and could not be reliably determined. The inability to quantify ADA added to tissues was ascribed to its rapid and facile reduction by tissue sulphydryl groups. 3. When rats were exposed to ADA aerosol concentrations of 200, 100, 50 and 0 mg/m3 for 13 weeks by inhalation, a non-linear dose-dependent accumulation of biurea was observed in lungs. No ADA was detected in lungs. Neither biurea nor ADA could be detected in kidneys.

Administration, Inhalation↗
PubMed1989

Influence of experimental pulmonary emphysema on the toxicological effects from inhaled nitrogen dioxide and diesel exhaust.

This project examined the influence of preexisting, experimentally induced pulmonary emphysema on the adverse health effects in rats of chronic inhalation exposure to either nitrogen dioxide or automotive diesel-engine exhaust. Previous reports indicated that humans with chronic lung disease were among those most severely affected by episodic exposures to high concentrations of airborne toxicants. There were no previous reports comparing the effects of chronic inhalation exposure to components of automotive emissions in emphysematous and normal animals. The hypothesis tested in this project was that rats with preexisting pulmonary emphysema were more susceptible than rats with normal lungs to the adverse effects of the toxicant exposures. Young adult rats were housed continuously in inhalation exposure chambers and exposed seven hours per day, five days per week, for 24 months to nitrogen dioxide at 9.5 parts per million (ppm)2, or to diesel exhaust at 3.5 mg soot/m3, or to clean air as control animals. These concentrations were selected to produce mild, but distinct, effects in rats with normal lungs. Pulmonary emphysema was induced in one-half of the rats by intratracheal instillation of the proteolytic enzyme elastase six weeks before the toxicant exposures began. Health effects were evaluated after 12, 18, and 24 months of exposure. The measurements included respiratory function, clearance of inhaled radiolabeled particles, pulmonary immune responses to instilled antigen, biochemistry and cytology of airway fluid, total lung collagen, histopathology, lung morphometry, and lung burdens of diesel soot. The significance of influences of emphysema and toxicant exposure, and interactions between influences of the two treatments, were evaluated by analysis of variance. The elastase treatment resulted in pulmonary emphysema that was manifested by enlarged alveoli and alveolar ducts, and by ruptured alveolar septa. There was no accompanying inflammation and no alterations of bronchioles. The emphysema persisted throughout the study period, with little evidence of progression. Lung weight was increased, physiological lung volumes were enlarged, lung compliance was increased, and airflow was obstructed. Nitrogen dioxide exposure of normal rats caused mild epithelial hyperplasia and a thickening of the walls of terminal bronchioles, an extension of bronchiolar epithelium into proximal alveoli, and inflammation in proximal alveoli. Lung volume and weight and the lung collagen content were increased. Airway fluid indicators of cell damage and oxidant protective mechanisms were increased. Similar effects of nitrogen dioxide exposure were superimposed over the effects of emphysema in emphysematous nitrogen dioxide-exposed rats. Several parameters were affected similarly by nitrogen dioxide exposure and emphysema (for example, increased lung volume), and the combined effects tended to be additive.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Characterization and chemical properties of phosphoribosylamine, an unstable intermediate in the de novo purine biosynthetic pathway.

Incubation of [1-13C]-5-phosphoribosyl pyrophosphate ([1-13C]PRPP) and glutamine with PRPP amidotransferase results in rapid production and disappearance of two new resonances at 89.3 and 85.9 ppm. These resonances coincide with two of the products produced upon incubation of [1-13C]ribose 5-phosphate with NH3. Extensive NMR studies (15N and 1H-13C chemical shift correlation spectra) have allowed assignment of these resonances to beta- and alpha-phosphoribosylamine. These studies represent the first spectral observations of this chemically reactive intermediate. The rate of interconversion of alpha- to beta-phosphoribosylamine as a function of pH has been determined by saturation and inversion-transfer NMR methods. The rate of formation of 5-phosphoribosylamine (PRA) from ribose 5-phosphate and NH3 and its rate of decomposition as a function of pH have been determined with a glycinamide ribonucleotide synthetase trapping system fashioned after earlier studies of Nierlich and Magasanik [Nierlich, D. P., & Magasanik, B. (1965) J. Biol. Chem. 240, 366]. Phosphoribosylamine has a t1/2 = 38 s at 37 degrees C and pH 7.5. The pH-independent equilibrium constant for ribose 5-phosphate and NH3 with phosphoribosylamine has been established, 2.5 M-1, by use of these rate constants as well as by NMR methods. This equilibrium constant and the rates of nonenzymatic interconversion of alpha- and beta-PRA provide essential background for studying the mechanism of glycinamide ribonucleotide synthetase and investigating the possibility of channeling phosphoribosylamine between this enzyme and the first enzyme in the purine pathway.

Amidophosphoribosyltransferase↗
PubMed1988

Evaluation of a real-time aerosol monitor (RAM-S) for inhalation studies.

Measurement of the aerosol concentration in inhalation toxicology studies is generally done by gravimetric and/or chemical analysis of filter samples taken over a known period of time at a fixed sampling flow rate. The value obtained represents the time-averaged concentration in an exposure chamber. However, the filter method does not provide information as to the stability of aerosol concentration in "real-time" nor as to the time required for the aerosol concentration to reach the target value during the start-up of exposures. In order to accomplish evaluation of aerosol stability and chamber rise and fall times, a direct measurement device is required. An available real-time aerosol monitor (RAM-S, GCA Corp., Bedford, MA) is a photometer which collects scattered light from an aerosol cloud at a 70 +/- 25 degrees angle. The output signal is 0 to 10 volt with three ranges corresponding to maximum aerosol concentrations of 200, 20, and 2 mg/m3. The performance of the RAM-S was evaluated in inhalation studies involving nickel sulfate hexahydrate, nickel oxide, nickel subsulfide, and azodicarbonamide. Several RAM-S units were calibrated by obtaining both filter samples and voltage readings of a RAM-S simultaneously. Results indicated that the response of the RAM-S instruments was linear. However, the voltage output per given aerosol concentration was different for each compound used. Furthermore, there was interinstrument variability in the voltage response to aerosol concentration of a given compound. At concentrations higher than 100 mg/m3, modification of the flow system in the RAM-S was made to increase the sheath air around the optical system and also to dilute the aerosol concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1988

Comparative toxicity of nickel oxide, nickel sulfate hexahydrate, and nickel subsulfide after 12 days of inhalation exposure to F344/N rats and B6C3F1 mice.

The relative toxicity of nickel oxide (NiO), nickel sulfate hexahydrate. (NiSO4.6H2O), and nickel subsulfide (Ni3S2) was studied in F344/N rats and B6C3F1 mice after inhalation exposure for 6 h/day, 5 days/week for 12 exposure days. Exposure concentrations used (as mg Ni/m3) were 0.9-23.6 for NiO; 0.8-13.3 for NiSO4.6H2O, and 0.4-7.3 for Ni3S2. For each compound there were 5 exposure groups plus a control group. NiSO4.6H2O was the most toxic compound with exposure related mortality seen at exposure concentrations of 13.3 mg/m3 in rats and 1.6 mg/m3 and above in mice. For Ni3S2, mortality was seen in mice (but not in rats) at the highest exposure concentration (7.3 mg/m3). No mortality was seen after NiO exposure. Lesions of the lung and nasal cavity were seen in both rats and mice after exposure to NiSO4.6H2O and Ni3S2 at the 4 highest exposure concentrations. Lesions of the lung were seen primarily at the highest exposure concentrations after NiO exposure. The amount of nickel in the lungs at the end of exposure varied in relation to the water solubility of the compounds. Based on these 2-week studies, the toxicity ranking was NiSO4.6H2O greater than Ni3S2 much greater than NiO. Additional studies are in progress to assess the relative toxicities of these three nickel compounds after 90-day exposures.

Administration, Inhalation↗
PubMed1988

Accumulation of guanylate binding proteins in patients treated with interferons.

We have previously described an interferon (IFN)-induced protein with a molecular weight of 67,000. This protein has an affinity to guanylates and is thus called guanylate binding protein (GBP). The synthesis of GBP is inducible by IFNs in all human diploid fibroblast cell lines that we studied. To determine whether or not the GBP synthesis is IFN-inducible in humans as well as in cultured cells, we have studied the levels of GBP in the peripheral blood leukocytes (PBL) of patients treated with either type I or type II IFN. An increased GBP level was found the day immediately after treatment with either type of IFN, and the elevated GBP levels were maintained for at least 8 days. Among the patients studied, we found a higher level GBP accumulation (2.3x) in patients treated with IFN-beta than in those treated with IFN-gamma (1.6x). The increase of GBP in patients receiving IFN-gamma correlated with increases in class II histocompatibility antigens, HLA-DR and HLA-DQ in monocytes. Thus, the levels of GBP in peripheral blood leukocytes may be used as a parameter for the study of IFN responses in patients.

Cells, Cultured↗
PubMed1987

Self-assembly of a high molecular weight basement membrane heparan sulfate proteoglycan into dimers and oligomers.

A high molecular weight basement membrane heparan sulfate proteoglycan, isolated from murine Englebreth-Holm-Swarm tumor, is seen in platinum replicas as an elongated flexible core (Mr = 450,000) consisting of a series of tandem globular domains from which extend, at one end, two to three heparan sulfate chains (average Mr = 80,000 each). This macromolecule will self-assemble into dimers and lesser amounts of oligomers when incubated in neutral isotonic buffer. These molecular species can be separated by zonal velocity sedimentation and assembly is seen to be time- and concentration-dependent. In rotary-shadowed platinum replicas the binding region is found at or near the end of the core at the pole opposite the origin of the heparan sulfate chains. Dimers are double-length structures and oligomers are seen as stellate clusters: in both, the heparan sulfate chains appear peripherally oriented. While isolated cores self-assemble, isolated heparan sulfate chains do not bind intact proteoglycans. Furthermore, proteolytic removal of a non-heparan sulfate containing core moiety destroys the ability of the proteoglycan monomer to form larger species or bind intact proteoglycan, further supporting the binding topography determined morphologically. These negatively charged macromolecular complexes may be important contributors to basement membrane structure and function.

Animals↗
PubMed1987

Metalloproteinases in endochondral bone formation: appearance of tissue inhibitor-resistant metalloproteinases.

Dissected embryonic chick limbs release neutral metalloproteinases during endochondral bone development. These enzymes degrade cartilage proteoglycan and gelatin in culture medium. We found the enzymes active in the medium conditioned by explants of the region adjacent to the bone marrow cavity (cavity-surround). These enzymes degrade proteoglycan (PG) and/or gelatin. These spontaneously active enzymes are resistant to serum and tissue proteinase inhibitors, alpha 2-macroglobulin, and cartilage metalloproteinase inhibitor (TIMP). The other enzymes secreted from tarsus and bone marrow explants are mostly latent in the culture medium. Activated tarsus enzymes (PG degrading and gelatinolytic) are blocked by the above inhibitors. Activated marrow enzyme does not degrade PG but is resistant to those inhibitors. Cavity-surround enzymes may play an important role in embryonic osteogenesis of long bones because of their resistance to tissue and serum inhibitors. The in vivo mechanisms by which cavity-surround enzymes are activated are yet to be determined.

Animals↗
PubMed1987

Chemical characterization of phosphoribosylamine, a substrate for newly discovered trifunctional protein containing glycineamide ribonucleotide synthetase activity.

PRA has been characterized for the first time using 13C-NMR spectroscopy. Incubation of [1-13C]ribose-5-phosphate with NH3 results in the production of 38:62 alpha:beta anomeric mixture of PRA, alpha,beta ribose-5-phosphate and variable amounts of dimeric materials. NMR studies at various pHs allowed determination of the pH independent Kequi = 0.95 +/- 0.14 M-1 for this reaction. In addition, using magnetization transfer NMR methodology the rate of conversion of alpha to beta PRA was determined to be 44 sec-1 at 37 degrees C (pH 8.0). The rates of formation (from ribose-5-phosphate and NH3) and degradation of PRA were also measured using E. coli GAR synthetase (recently cloned, overproduced and purified to homogeneity) as a trap. Determination of these rates allowed an independent and accurate measurement of Kequi = 2.7 M-1. In addition, in close agreement with early studies of Nierlich and Magasanik, the half life of PRA at 37 degrees C and pH 7.5 was determined to be 35 sec. Characterization of the chemical stability of PRA and Kequi for ribose-5-phosphate, NH3 with PRA will now allow detailed kinetic analysis of the newly discovered trifunctional protein containing GAR synthetase activity in addition to AIR synthetase and GAR transformylase activities. Comparison of the properties of the 110 kd GAR synthetase and an independently isolated 54 kd GAR synthetase are reported. Experiments are underway to investigate the possibility that unstable intermediates such as PRA are not released into solution, but that the transfer is mediated by specific protein-protein interactions between GAR synthetase and PRPP amidotransferase.

Ammonia↗
PubMed1987

The inhalation toxicity of two commercial dyes: solvent yellow 33 and solvent green 3.

The quinoline dye 2-(2'-quinolyl)-1,3-indandione or Solvent Yellow 33 (SY) and the anthraquinone dye 1,4-di-p-toluidinoanthraquinone or Solvent Green 3 (SG) are used in many manufactured products including military smoke grenades. During manufacturing, SY or a combination of both SY and SG can be released into the air, exposing factory workers by inhalation to these dye compounds. The potential inhalation toxicity of these compounds was tested by exposing F344/N rats to different concentrations of SY or SY/SG dye mixture (30:70 w/w) for 6 hr/day, 5 days/week for 4 or 13 weeks. In the 4-week studies, rats were exposed to SY aerosols at average concentrations of 10 +/- 5, 51 +/- 10, or 230 +/- 30 mg/m3 (means +/- SD) or SY/SG aerosols at average concentrations of 11 +/- 5, 49 +/- 11, or 210 +/- 50 mg/m3 (means +/- SD). Rats exposed to the highest concentration of SY or SY/SG had body weights that were approximately 8% or 7% less, respectively, than their controls after exposure. Rats exposed to the highest concentration of SY/SG for 4 weeks also had reduced pulmonary gas exchange efficiency, airflow obstruction, mild pulmonary inflammation, slight Type II pulmonary epithelial cell hyperplasia, and proliferation of vacuolated alveolar macrophages. In the 13-week studies, rats were exposed to SY aerosols at average concentrations of 1.0 +/- 0.2, 10.8 +/- 1.8, or 100 +/- 17 mg/m3 (means +/- SD) or SY/SG aerosols at average concentrations of 1.1 +/- 0.5, 10.2 +/- 3.1, or 101 +/- 23 mg/m3 (means +/- SD). Animals exposed to the highest concentration of SY or SY/SG for 13 weeks had body weights that were approximately 5 or 9% less, respectively, than their controls after exposure and had accumulation of vacuolated alveolar macrophages in lungs. Rats exposed to the highest concentration of SY/SG dye mixture for 13 weeks also had indications of mild pulmonary inflammation and slight Type II pulmonary epithelial cell hyperplasia. Very little SY was found in lungs after any exposures, indicating its clearance from lungs was at a rapid rate. However, significant amounts of the SG component of the SY/SG mixture were detected in lungs after each exposure. Lung clearance half-times of SG from the 13-week exposure were estimated to be approximately 280 days. In summary, neither test material appeared to be highly toxic following inhalation. However, the slightly higher toxicity observed for SY/SG over SY alone is probably related to the longer lung retention of the SG component of the dye mixture.

Administration, Inhalation↗
PubMed1987

The fate of inhaled azodicarbonamide in rats.

Azodicarbonamide (ADA) is widely used as a blowing agent in the manufacture of expanded foam plastics, as an aging and bleaching agent in flour, and as a bread dough conditioner. Human exposures have been reported during manufacture as well as during use. Groups of male F344/N rats were administered ADA by gavage, by intratracheal instillation, and by inhalation exposure to determine the disposition and modes of excretion of ADA and its metabolites. At 72 hr following gavage, 30% of the administered ADA was absorbed whereas following intratracheal instillation, absorption was 90%. Comparison between groups of rats exposed by inhalation to ADA to achieve body burdens of 24 or 1230 micrograms showed no significant differences in modes or rates of excretion of [14C]ADA equivalents. ADA was readily converted to biurea under physiological conditions and biurea was the only 14C-labeled compound present in excreta. [14C]ADA equivalents were present in all examined tissues immediately after inhalation exposure, and clearance half-times on the order of 1 day were evident for all tissues investigated. Storage depots for [14C]ADA equivalents were not observed. The rate of buildup of [14C]ADA equivalents in blood was linearly related to the lung content as measured from rats withdrawn at selected times during a 6-hr inhalation exposure at an aerosol concentration of 25 micrograms ADA/liter. In a study extending 102 days after exposure, retention of [14C]ADA equivalents in tissues was described by a two-component negative exponential function. The results from this study indicate that upon inhalation, ADA is rapidly converted to biurea and that biurea is then eliminated rapidly from all tissues with the majority of the elimination via the urine.

Administration, Inhalation↗
PubMed1987

Acute inhalation exposure of azodicarbonamide in the guinea pig.

Humans have been exposed to azodicarbonamide (ADA) by inhalation where bulk quantities of ADA are handled in the workplace. Responses of some workers have led to concern for the potential irritant and sensitizing properties of inhaled ADA. This study examined the effects of inhaling ADA on lung structure and function of guinea pigs during and after an acute exposure. Groups of 20 guinea pigs were exposed to each of 3 concentrations of ADA (19, 58, and 97 mg/m3), plus air as a control, for 1 hr. Pulmonary function was measured before exposure (baseline), during exposure, immediately after exposure and 24 hr after exposure. Dynamic compliance (Cdyn), total pulmonary resistance (RL), tidal volume (VT), respiratory frequency and minute volume were measured. In addition, gross necropsies and histological examinations of respiratory tract tissues were done either immediately following the exposure or 24 hr after exposure. There were no effects of ADA exposure on gross necropsy, histology, Cdyn, or RL. Some significant, concentration-related decreases in VT, respiratory frequency and minute volume were seen. The magnitudes of these changes were small: the largest change was seen in minute volume, amounting to a 24% decrease in the high concentration group. Inhalation exposure of guinea pigs to ADA at concentrations of up to 97 mg/m3 resulted in minor changes in pulmonary function without any changes in lung histology.

Air Pollutants↗