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Biomedical subjects

G C Smaldone

Publications and source records attributed to G C Smaldone.

At least 19 recordsLinked to original sources

Nebulizer function during mechanical ventilation.

In the setting of mechanical ventilation, recent studies have cast doubt on the ability of nebulizer systems to deliver adequate amounts of medication. We therefore studied ventilator-related and nebulizer-related factors that could potentially affect the amount of aerosol inhaled by an intubated subject. Utilizing two separate protocols, we used a bench model of a ventilator circuit, radiolabeled (technetium pertechnetate, 99mTc) saline droplets and a filter technique to measure the percentage of radioaerosol delivered. First, we compared four commercially available jet nebulizers and found that there were significant differences in rate of aerosol production between systems, ranging from 3 to 37%. Delivered aerosol was measured at different ventilator settings, and it was found that the duty cycle can potentially influence output by sevenfold. Some nebulizers were also sensitive to changes in the initial volume of solution placed in the nebulizer. The inclusion of a humidification device significantly reduced output by a mean of 41 +/- 3.5%, but it did not affect particle distribution. Endotracheal tube diameter was not an important variable. Then, with the effects of the above variables established, a separate series of experiments was performed to test whether the use of different radiolabeling compounds can confound the measurement of inhaled drugs. Two nebulizers (AeroTech II and Twin Jet) and pentamidine as the test drug were studied with fixed ventilator settings, treatment time, endotracheal tube size, and volume fill. No humidification was used. The nebulizer solution was labeled with 99mTc, which was bound to either human serum albumin (HSA) or sulfur colloid (SC).(ABSTRACT TRUNCATED AT 250 WORDS)

Aerosols

Mucociliary clearance in adult asthma.

Severe impairment of mucociliary clearance (MC) in hospitalized asthmatics has recently been demonstrated in peripheral and central airways. MC was also shown to improve with clinical recovery and hospital discharge (2). In the present study, we measure MC in chronic, stable asthma in subjects with a wide range of obstruction to see if MC was related to the severity of chronic disease. We separated the subjects into those with severe obstruction with expiratory flow limitation during tidal breathing (FL subjects) and those without tidal flow limitation (NFL subjects) to see if the presence of chronic flow limitation was associated with regional MC abnormalities. Seventeen asthmatic patients were studied. Mucociliary clearance was assessed using inhaled radioaerosol and serial measurements of the retention of radioactivity over 2 h. By controlling breathing pattern, the initial pattern of deposition in the lungs was matched, with all subjects having a predominance of particles in the central airways. This pattern was normalized for regional lung volume using a xenon equilibrium scan and expressed as a specific central to peripheral (sC/P) ratio. The percentage retention of deposited radioactivity at 120 min ranged from 19 to 83% (mean, 52%). FL subjects had a mean retention at 120 min of 66% (range, 55 to 83%). The NFL subjects had a mean retention at 120 min of 33% (range, 19 to 51%). Throughout the 2-h study period, retention by the FL group was significantly greater than that of the NFL group with separation of 95% confidence intervals.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult

Deposition of aerosolized pentamidine and failure of pneumocystis prophylaxis.

OBJECTIVE: To determine if outcome of Pneumocystis carinii prophylaxis is related to total lung dose of aerosolized pentamidine. SETTING: AIDS treatment centers at a VA and University Hospital. PATIENTS: Fifty-eight HIV-infected patients receiving P carinii prophylaxis with aerosolized pentamidine using a nebulizer (CIS-US AeroTech II) were followed up over a 90-week period. Treatment consisted of 60 to 90 mg every two weeks. MEASUREMENTS: In all patients, deposition of pentamidine aerosol was measured using a radioaerosol filter technique. Factors thought to be important in deposition, nebulizer output and breathing pattern were also measured. Six months later, repeated deposition studies were performed in 20 patients. Pentamidine dose to the lung was related to occurrence of P carinii pneumonia and correlated with nebulizer function and breathing parameters. Outcome was assessed in terms of pentamidine deposition and patient characteristics, including demographic, immunologic, physiologic, and medical variables. RESULTS: Ten patients (17.2 percent) had development of P carinii pneumonia. However, pentamidine deposited in the failures (8.18 +/- 4.74 mg) was no different than deposition in protected patients (6.39 +/- 3.07 mg, p = NS). Most of the variability in deposition was accounted for by variability in nebulizer output (r = 0.919, p less than 0.001). Deposition did not significantly correlate with any of the measured breathing parameters. Serial deposition measurements were not significantly different by paired analysis. The incidence of P carinii pneumonia did not correlate with any measured patient characteristic. CONCLUSIONS: Failure of aerosolized pentamidine prophylaxis is not related to total lung dose of pentamidine. Other factors such as inadequate microscopic deposition between alveoli, pentamidine clearance, or drug resistance may be important. In HIV-infected patients, interpatient variability in aerosol deposition can be reduced by reducing variability in nebulizer output rather than control of breathing pattern.

Aerosols

Exposure of health care workers to aerosolized pentamidine.

In patients, urinary levels of pentamidine have been shown to reflect pulmonary deposition of aerosolized drug. Using urinary levels and air filter samples, we assessed factors responsible for health care worker (HCW) exposure. We measured serial urine samples in HCWs who administered aerosol pentamidine over an 11-month period and compared them with serial urine levels measured over 30 days in a normal volunteer in whose lungs a known amount of pentamidine (3.39 mg) had been deposited. Ambient exposure to pentamidine was determined by continuous high volume air sampling in the treatment room during routine therapy. In addition, the amount of pentamidine released by six HIV-positive subjects, performing tidal breathing with a Respirgard II nebulizer in an airtight booth, was measured by extracting air from the booth through a filter. The effect of adding noseclips, of coughing (with nebulizer shut down), and of removing the nebulizer from the patient's mouth without turning it off, were determined. Pentamidine in the urine of the normal volunteer reached a peak concentration of 9.5 ng/mg creatinine/ml and was detectable for 30 days following the exposure. In HCWs, pentamidine was detected intermittently in four of five individuals with levels as high as 18.2 ng/mg creatinine/ml. Samples of ambient treatment room air indicated small daily releases of pentamidine (0.013 +/- 0.02 mg per patient treated), but simultaneous urine levels in HCWs were negative. The data from the airtight booth revealed that removing the nebulizer from a patient's mouth without turning it off caused a 360-fold increased in pentamidine release compared to tidal breathing. Coughing resulted in a 6.9 (range 0.9-14.2)-fold increase in release, while the addition of noseclips had no significant effect. The pattern of intermittently positive urine tests and the low levels of ambient pentamidine detected in the air of the treatment room suggest that HCWs are being exposed to episodic but high concentrations of pentamidine. High level exposure is most likely to occur during treatment interruptions which are usually precipitated by coughing episodes. Because of the intermittent pattern of exposure and slow clearance of pentamidine, urine assay is useful for detecting high intermittent exposure. Random air sampling is a sensitive indicator of low level exposures but may not detect episodic high level releases.

Aerosols

Factors determining pulmonary deposition of aerosolized pentamidine in patients with human immunodeficiency virus infection.

Although aerosolized pentamidine (AP) has recently been approved for prophylaxis and is undergoing clinical trials for treatment of pneumocystis, pneumonia (PCP), factors important in the deposition of AP have not been described. Using radioaerosol techniques, deposition was measured in 22 patients receiving AP for prophylaxis or treatment of PCP. In all patients total and regional deposition of pentamidine, breathing pattern, pulmonary function (PFT), regional ventilation, and type of nebulizer were analyzed. Bronchoalveolar lavage (BAL) was performed 24 h after inhalation to assess the relationship between pentamidine levels in BAL fluid and measured aerosol deposition. The nebulizers tested were the Marquest Respirgard II and the Cadema AeroTech II, both previously characterized in our laboratory. The aerosol particles consist of water droplets containing dissolved pentamidine and technetium 99m bound to albumin. Analysis of particles sampled during inhalation via cascade impaction confirmed a close relationship between radioactivity in the droplets and the concentration of pentamidine as measured by HPLC (r = 0.971, p less than 0.0001; n = 18). Deposition was measured by capturing inhaled and exhaled particles on absolute filters and measuring radioactivity. This technique allows the determination of the deposition fraction (DF, the fraction of the amount inhaled that is deposited), which provides information on factors strictly related to the patient. To confirm the filter measurements, pentamidine deposition was also measured by gamma camera. The camera measurement was possible because each patient's thoracic attenuation of radioactivity was determined by a quantitative perfusion scan (mg pentamidine deposited via both techniques, r = 0.949, p less than 0.0001; n = 26). Regional lung volume and ventilation were determined by xenon 133 equilibrium scan and washout. Pentamidine deposition varied markedly between patients, but BAL levels of pentamidine significantly correlated with measured deposition (r = 0.819, p less than 0.01; n = 9). DF averaged 0.621 +/- 0.027 (SEM) and did not correlate with any measured lung parameter, including breathing pattern and PFT. Regional deposition did not correlate with regional ventilation. The major factor influencing pentamidine deposition was aerosol delivery (mg deposited versus mg inhaled; r = 0.963, p less than 0.0001; n = 26). The nebulizer was an important determinant of aerosol delivery, with the AeroTech delivering between 2.5 and 5 times more drug than the Respirgard. These observations are important in assessing treatment failure and cost of therapy.

Aerosols

Changes in mucociliary clearance during acute exacerbations of asthma.

Previous studies have suggested that mucociliary clearance (MC) is impaired in asthmatic subjects. If so, impaired clearance may be an important factor in acute exacerbation. We proposed that if MC plays a significant role in acute illness, MC should be impaired during the exacerbation but improve after recovery. To test this hypothesis, five asthmatic patients with attacks requiring hospitalization underwent measurement of MC using radiolabeled aerosol and a gamma camera. They were studied on the second or third day after admission with repeat measurements after discharge. Spirometry was performed before all studies. After an equilibrium xenon scan (133Xe), which defined lung borders and measured regional volume, radiolabeled saline particles containing technetium-labeled (99mTC) sulfur colloid were deposited and used to label airway mucus. Deposition patterns were matched by regulating particle distribution and breathing pattern. MC was then measured as percentage retention of radioactivity at 10-min intervals for 2 h. When hospitalized, 96.0 +/- 2.06% (SEM) of the initial radioactivity was retained in the lung after 2 h, indicating little clearance of mucus from the lung. In fact, no significant changes were detected when activity at 120 min was compared with measurements at 10 min (99.2 +/- 0.22%, NS). After discharge clearance was markedly enhanced. That is, retention of lung activity was significantly lower at all time intervals from 10 min onward, with only 70.9 +/- 3.86% retained at 120 min (p = 0.008). During an asthmatic attack warranting hospital admission, MC is significantly impaired, with marked improvement following recovery.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease

Urine pentamidine as an indicator of lung pentamidine in patients receiving aerosol therapy.

To determine if urine pentamidine was reflective of lung pentamidine, we compared levels of the drug in bronchoalveolar lavage fluid and simultaneously obtained urine. Thirty-one patients who were receiving aerosolized pentamidine either as treatment or as prophylaxis underwent BAL and submitted urine samples for pentamidine analysis. Pentamidine was analyzed in both phases of BAL fluid (supernatant and cell pellet) and in urine using high performance liquid chromatography. Urine results were normalized for creatinine. Patients were categorized as prophylaxis failures (active Pneumocystis carinii pneumonia on prophylaxis), electives (free from PCP on prophylaxis), treatment (daily AP in treatment doses for active PCP, or miscellaneous (single dose of AP). Levels in BAL fluid and urine varied widely over several orders of magnitude. However, for all patients, we found a highly significant relationship between BAL supernatant and urine (r = 0.97, p less than 0.0001). No statistical differences were found when comparing levels of pentamidine between failures and electives; however, the number of failures was small. We conclude that urine pentamidine is related to lung pentamidine and can be used as a clinical indicator in patients receiving aerosolized therapy.

Administration, Inhalation

Use of aerosols to estimate mean air-space size in chronic obstructive pulmonary disease.

Using in vivo measures of aerosol recovery (RC) as a function of breath-hold time (t) (Gebhart et al. J. Appl. Physiol. 51: 465-476, 1981), we estimated the mean diameter (D) of the pulmonary air spaces in subjects diagnosed with chronic obstructive pulmonary disease (COPD) (n = 8) and in subjects with normal pulmonary function (n = 10). For each subject, RC (aerosol expired/aerosol inspired) decreased exponentially with t. Based on a model of the lung as a system of randomly oriented cylindrical tubes, the half time (t1/2) (i.e., the breath-hold time to reach 50% of RC with no breath hold) is proportional to a mean diameter (D) of air spaces filled with aerosol. Subjects with normal pulmonary function had a mean t1/2 = 6.5 +/- 0.8 s, corresponding to a mean D = 0.36 +/- 0.05 mm. On the other hand, subjects with COPD had a mean t1/2 = 12.7 +/- 3.2 s, corresponding to a mean D = 0.70 +/- 0.18 mm [i.e., twice as large (P less than 0.01) as normal subjects]. Furthermore, D correlated significantly with diffusing capacity in the patients with COPD (r = -0.95, P less than 0.001 for D vs. percent predicted diffusing capacity of CO) but not with any other measure of pulmonary function. In contrast, D varied only slightly in normals and did not correlate with any measure of pulmonary function. We conclude that in vivo measures of RC vs. t, in conjunction with other pulmonary function tests, may be a useful tool for identifying actual changes in pulmonary air-space sizes associated with pulmonary disease.

Aerosols

Human variation in the peripheral air-space deposition of inhaled particles.

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)

Aerosols

Quantitative deposition of aerosolized gentamicin in cystic fibrosis.

In cystic fibrosis (CF), the clinical effectiveness of aerosolized antibiotics is controversial. Previous investigators have not considered the type of nebulizer, droplet size, and dose to the lung in assessing the results of aerosol therapy. The present study tests the importance of these factors by standardizing an aerosol system for delivery of antibiotics and other agents to patients with CF. Particle size, distribution, and output from a commercially available nebulizer were measured. Thirteen patients with CF inhaled aerosol (MMAD = 1.1 micron) containing gentamicin (160 mg in nebulizer) and 99mTc-labeled human serum albumin. Patients' sputum and serum were analyzed for gentamicin levels by immunoenzymatic assay (Emit; Syva Corp., Palo Alto, CA). Using a gamma camera and suitable filters, central versus peripheral deposition (C/P ratio) and whole lung deposition were measured and related to sputum gentamicin levels. Gentamicin deposit averaged 12.3 mg +/- 5.9 (SD) or 7.69% of the original amount placed in the nebulizer. Peak sputum levels averaged 376.6 micrograms/ml +/- 275, whereas serum levels were undetectable in all patients. When peak sputum levels were normalized for the amount deposited, a close correlation with C/P ratio was obtained (r = 0.88, p less than 0.05). Furthermore, an inverse relationship was found between the C/P ratio and the %FEV1 (r = 0.76, p less than 0.05). Finally, a bell-shaped relationship between deposited dose and minute ventilation was seen in the patients (r = 0.88, p less than 0.05), i.e., an optimal minute ventilation was shown. These relationships may be important when designing future clinical studies.

Aerosols

Evaluation of quantitative aerosol techniques for use in bronchoprovocation studies.

To investigate airway physiology by use of inhaled aerosols, it is frequently necessary to measure the actual amount of material deposited on the airway wall as well as the site of particle deposition. To satisfy these needs, radiolabeled aerosols and gamma camera techniques have been used to measure regional deposition of inhaled particles. To make quantitative measurements of the amount deposited, previous investigators have used a "phantom" technique to indirectly calibrate the gamma camera for the attenuation of gamma rays through the lungs and chest wall. For this calibration, the phantom is a simulated lung containing a known amount of radioactivity. Radioactive counts emitted from the phantom are assumed to be attenuated in the same manner as the intact human lung. The present article describes a technique to determine directly the amount of inhaled aerosol deposited in the lung and simultaneously to calibrate the gamma camera for each individual subject. We used right angle light scattering and a gamma camera to measure individual values of the deposition fraction (DF) of inhaled aerosol deposited in the lung and the coefficient of attenuation (AC) of gamma rays in normal and obstructed lungs of human subjects. Radiolabeled monodisperse aerosols 1 and 2 microns in diameter were used. Knowledge of the activity of the inhaled aerosol (microcurie per liter), the volume inhaled, and the measured DF determined each subject's AC (counts per minute per microcurie). DF varied by an order of magnitude in normal (0.04 to 0.48) and obstructed (0.16 to 0.75) of subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent

Quantitative assays of pharmacologic aerosols used in studying asthma.

To more nearly accurately quantitate the dose of pharmacologic agents delivered to human and animal airways via aerosols, we have developed a monodisperse aerosol containing either methacholine or histamine that permits a light scattering device (tyndallometry) to measure accurately the quantity of inspired and expired particles. These aerosols (described in previous studies) are simultaneously tagged with a radioactive label (technetium 99m) to permit the use of external gamma camera imaging. Present work focuses on the development of assay techniques to measure the quantity of methacholine delivered in these aerosols. The lack of specific radioimmune or radioenzyme assays coupled with the cross-reaction of organic contaminants with conventional chemical reagents for measuring methacholine required the development of separative techniques to isolate the methacholine from the organic aerosol contaminants. With aqueous extraction and column separation we have been able to completely isolate the methacholine from these contaminants. This allows the application of standard spectrophotometric assays for methacholine to quantitate the methacholine in the resulting solution. These separative techniques will permit the use of these aerosols in quantitative studies of airway reactivity.

Aerosols

Location of flow-limiting segments via airway catheters near residual volume in humans.

Previous studies have demonstrated sites of flow limitation in the central airways of dogs and humans. At low lung volumes, however, during a forced expiration, it is not clear whether flow-limiting segments (FLS) move into the lung periphery. Using intrabronchial lateral pressure catheters, we located FLS in human subjects at all lung volumes between functional residual capacity (FRC) and residual volume (RV). Three individuals with severe intracranial hemorrhage maintained on ventilators were studied. Partial maximal flow-volume curves were generated from 1 liter above FRC to RV by lowering downstream pressure and using the interrupter technique. Sites of FLS were defined as the most downstream points where lateral pressure did not change with driving pressure. FLS were found in all subjects in the central airways. In one subject, FLS moved from segmental bronchi to the first subsegmental bronchus as RV was approached but not beyond. In the other two subjects, FLS remained fixed in location at all measured lung volumes. At constant volume, multiple FLS were located, all in parallel, e.g., fixed in left upper, left lower, and right middle lobar bronchi. In conclusion, sites of flow limitation remain in the central airways as lung volume approaches RV. FLS may move peripherally within the central airways but not beyond proximal subsegmental bronchi.

Aged

Enhancement of particle deposition by flow-limiting segments in humans.

Severe chronic obstructive pulmonary disease is associated with central deposition of inhaled aerosols. This pattern may be due to functional narrowing of the large airways during expiration at flow-limiting segments (FLS). Using a gamma camera and 2.5-micron particles, we compared the pattern of aerosol deposition following quiet breathing with that after a controlled forced expiration (cough) when FLS are known to form in central airways. Lung size measurement by 133Xe allowed construction of regions of interest over the central airways and lung periphery. Deposition in these regions was normalized for area and lung thickness and expressed as a central-to-peripheral (C/P) ratio. In addition, using right-angle light scattering, the fraction of inhaled particles deposited with each breath (DF) was determined. During control studies, airflow and tidal volume were continuously monitored to insure that tidal loops were well below the maximum expiratory flow-volume (MEFV) curve. To create dynamic compression, cough was used to generate a partial MEFV curve, while inspiratory flow, tidal volume, and functional residual capacity were maintained close to quiet breathing. With cough, C/P ratios increased markedly from 1.04 +/- 0.18 to 2.21 +/- 0.61 (P less than 0.01, n = 6). DF for the lung and airways did not significantly change (0.43 +/- 0.11 to 0.45 +/- 0.09, P = NS). The greater enhancement of regional deposition in the central airways with deposition unchanged over the whole lung demonstrates that, during cough, peripheral deposition is actually reduced when compared with quiet breathing. We conclude that dynamic compression at FLS can be an important factor in the central deposition of inhaled particles.

Humans

Flow limitation, cough, and patterns of aerosol deposition in humans.

We studied deposition of radioactive monodisperse 1.5-micron aerosol in humans following inhalation during quiet breathing. Two groups were studied: normal, defined by tidal loops below the maximum expiratory flow-volume (MEFV) envelope [forced expiratory volume at 1 s at percent of forced vital capacity (FEV1%) 62-78]; and flow-limited, with tidal loops superimposed on MEFV relationship (FEV1% 21-57) and flow-limiting segments (FLS) known to exist in central airways. During simultaneous imaging with a gamma camera, fraction of inhaled aerosol deposited in the lung (DF) was determined by right-angle light scattering. With regions of interest defined by an equilibrium image of 133Xe, regional deposition was normalized for area and lung thickness and expressed as a central-to-peripheral (C/P) ratio. Deposition was uniform throughout the lung in normal subjects [C/P 1.02 +/- 0.07 (SD), n = 6]. In flow-limited group, central deposition predominated (C/P 1.98 +/- 0.64, n = 6, P less than 0.05). Tidal volume and inspiratory flow, forces thought to influence deposition during inspiration, were not different between groups. Spontaneous cough occurred in five flow-limited subjects during aerosol inhalation, with further increase in central deposition when compared with quiet breathing (C/P 1.85 +/- 0.60 to 2.69 +/- 0.600, P less than 0.01). During cough, tidal volume (ml) was reduced significantly (576 +/- 151 to 364 +/- 117, P less than 0.01) with no change in inspiratory flow (l/s) (1.37 +/- 0.23 to 1.38 +/- 0.40, P = NS). DF, however, was unaffected by cough (0.34 +/- 0.13 to 0.61 +/- 0.12, P = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Aerosols

Effect of exercise on deposition and subsequent retention of inhaled particles.

To investigate the effect of exercise and its associated increase in ventilation on the deposition and subsequent retention of inhaled particles, we measured the fractional and regional lung deposition of a radioactively tagged (99mTc) monodisperse aerosol (2.6 microns mass median aerodynamic diam) in normal human subjects at rest and while exercising on a bicycle ergometer. Breath-by-breath deposition fraction (DF) was measured throughout the aerosol exposures by Tyndallometry. Following each exposure gamma camera analysis was used to 1) determine the regional distribution of deposited particles and 2) monitor lung retention for 2.5 h and again at 24 h. We found that DF was unchanged between ventilation at rest (6-10 l/min) and exercise (32-46 l/min). Even though mouth deposition was enhanced with exercise, it was not large enough to produce a significant difference in the deposition fraction of the lung (DFL) between resting and exercise exposures. The central-to-peripheral distribution of deposited aerosol was larger for the exercise vs. resting exposure, reflecting a shift of particle deposition to more central bronchial airways. Apical-to-basal distribution was not different for the two exposures. Retention at 2.5 h and 24 h (R24) was reduced following the exercise vs. the resting exposure, consistent with greater bronchial deposition during exercise. The product of DFL and R24 gave a measure of fractional burden at 24 h (B24), i.e., the fraction of inhaled aerosol residing in the lungs 24 h after exposure. B24 was not significantly different between rest and exercise exposures.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult