Quantitative exposure of humans to an octamethylcyclotetrasiloxane (D4) vapor.

There is potential for human exposure to cyclic siloxanes by the respiratory route. To determine the pharmacokinetics of octamethylcyclotetrasiloxane (D4), a material commonly found in personal care products, the respiratory intake and uptake of D4 were measured in 12 healthy volunteers (25-49 years) on two occasions. Subjects inhaled 10 ppm D4 (122 micrograms/liter) or air (control) during a 1-h exposure via a mouthpiece in a double-blind, randomized fashion. Inspiratory and expiratory D4 concentrations were continuously measured. Exhaled air and plasma D4 levels were measured before, during, and after exposures. Individual D4 uptakes were measured under steady-state conditions during three rest periods (10, 20, and 10 min, respectively) alternating with two 10-min exercise periods. Mean D4 intake was 137 +/- 25 mg (SD) and the mean deposition efficiency was equivalent to 0.74/(1 + 0.45 VE), where VE is the minute ventilation. No changes in lung function were induced by the D4 vapor. Plasma measurements of D4 gave a mean peak value of 79 +/- 5 ng/g (SEM) and indicated a rapid nonlinear blood clearance. Using lung volume and respiratory surface area estimates based on functional residual capacity measurements, we developed a model and determined that the effective mass transfer coefficient for D4 was 5.7 x 10(-5) cm/s from lung air to blood. In an additional eight subjects, we compared D4 deposition with mouthpiece and nasal breathing at resting ventilations. For these individuals, mean deposition was similar for the two exposure protocols, averaging 12% after correction for exposure system losses. These are the first data describing the intake and absorption of D4 and they should contribute to a meaningful safety assessment of the compound.

Acute respiratory exposure of human volunteers to octamethylcyclotetrasiloxane (D4): absence of immunological effects.

Humans are exposed to silicones in a number of commercial and consumer products. Some of these silicones, including octamethylcyclotetrasiloxane (D4), are volatile. Therefore, there is a potential for respiratory exposure. A pharmacokinetic analysis of respiratory exposure to D4 is presented in the accompanying paper (M. J. Utell et al., 1998, Toxicol. Sci. 44, 206-213). Possible immune effects of respiratory exposure to D4 are investigated in this paper. Normal volunteers were exposed to 10 ppm D4 or air for 1 h via a mouthpiece using a double-blind, crossover study design. Assays were chosen to screen for immunotoxicity or a systemic inflammatory response. Assessment of immunotoxicity included enumeration of peripheral lymphocyte subsets and functional assays using peripheral blood mononuclear cells. Because in humans there is no direct test for adjuvant effect of respiratory exposure, we analyzed proinflammatory cytokines and acute-phase reactants in peripheral blood, markers for a systemic inflammatory response, as surrogate markers for adjuvancy. These tests were repeated when the volunteers were reexposed to D4 approximately 3 months after this initial exposure. Blood was obtained prior to exposure, immediately postexposure, and 6 and 24 h postexposure. In these short-term, controlled human exposures, no immunotoxic or proinflammatory effects of respiratory exposure to D4 were found.

Evaluation of early airway disease in smokers: cost effectiveness of pulmonary function testing.

We studied 73 young adults who were presently cigarette smokers to evaluate whether the identification of abnormalities in pulmonary function tests had a detectable influence on modification of smoking habits. Utilizing rate schedules for these tests presently applicable in Rochester, New York, we determined the potential cost to these subjects and community relative to the number of subjects who stopped smoking as a result of test findings. Subjects were evaluated by questionnaire and function testing including spirometry, flow-volume curves, body plethysmography and single breath nitrogen washout test (SBN2). Functional abnormalities were present in 75% of subjects screened. The SBN2 test was most sensitive, identifying 97% of subjects with any abnormality. The presence of common respiratory symptoms was found to be highly predictive of test abnormalities. Subjects were informed of results and counseled. At six-month follow-up, 7% of subjects with abnormal test results had stopped smoking. Utilizing even our most cost-effective test, the SBN2, it would cost +1,392 for each "benefit" defined as one subject not smoking for six months. Application of these screening techniques is unlikely to be effective in altering smoking habits in the absence of continued physician support.

Effects of ozone on normal and potentially sensitive human subjects. Part II: Airway inflammation and responsiveness to ozone in nonsmokers and smokers.

Exposure to ozone at levels near the National Ambient Air Quality Standard causes respiratory symptoms, changes in lung function, and airway inflammation. Although ozone-induced changes in lung function have been well characterized in healthy individuals, the relationship between airway inflammation and changes in pulmonary function have not been prospectively examined. The purpose of this study was to determine whether individuals who differ in, lung function responsiveness to ozone also differ in susceptibility to airway inflammation and injury. A secondary goal was to determine whether ozone exposure induces airway inflammation in smokers, a population known to have airway inflammation and an increased burden of toxic oxygen species. Healthy nonsmokers (n = 56) and smokers (n = 34) were exposed to 0.22 parts per million (ppm)* ozone for 4 hours, with intermittent exercise, for the purpose of selecting ozone "responders" (decrement in forced expiratory volume in 1 second [FEV1] > 15%) and "nonresponders" (decrement in FEV1 < 5%). Selected subjects then were exposed twice to ozone (0.22 ppm for 4 hours with exercise) and once to air (with the same exposure protocol), each pair of exposures separated by at least 3 weeks, in a randomized, double-blind fashion. Nasal lavage (NL) and bronchoalveolar lavage (BAL) were performed immediately after one ozone exposure and 18 hours after the other, and either immediately or 18 hours after the air exposure. Indicators of airway effects in lavage fluid included changes in inflammatory cells, proinflammatory cytokines, protein markers of epithelial injury and repair, and generation of toxic oxygen species. In the classification exposure, fewer smokers than nonsmokers were responsive to ozone (11.8% vs. 28.6%, respectively); an insufficient number of smoker-responders were identified to study as a separate group. In the BAL study, all groups developed a similar degree of airway inflammation, consisting of increases in interleukins 6 and 8 (maximal immediately after exposure), and increases in polymorphonuclear leukocytes (PMNs), lymphocytes, and mast cells (maximal 18 hours after exposure). The increase in PMNs was inversely correlated with age (p = 0.013), but gender, nonspecific airway responsiveness, and allergy history were not predictive of inflammation. Alveolar macrophage production of toxic oxygen species decreased after ozone exposure in nonsmokers; however, not in smokers. Findings from nasal lavage did not mirror lower airway inflammatory responses in these studies. We conclude that, in response to ozone exposure, smokers experienced smaller decrements in lung function and fewer symptoms than nonsmokers; however, the intensity of the airway inflammatory response was independent of smoking status or airway responsiveness to ozone. Furthermore, the burden of toxic oxygen species following ozone exposure was greater for smokers than for nonsmokers. Subjects were young, healthy, and able to sustain exercise; the results may not be representative of nonsmokers or smokers in general. Nevertheless, the findings indicate that measuring symptoms and spirometric changes is not sufficient to assess the potential risks associated with ozone exposure.

Effects of ozone on normal and potentially sensitive human subjects. Part III: Mediators of inflammation in bronchoalveolar lavage fluid from nonsmokers, smokers, and asthmatic subjects exposed to ozone: a collaborative study.

To provide bases of comparison between the studies described in Parts I and II of this Research Report, concentrations of interleukin 6 (IL-6)*, interleukin 8 (IL-8), and alpha 2-macroglobulin (a2M) were measured in airway lavage fluids obtained in the Balmes study (Part I) and compared with the same measurements in the Frampton study (Part II). For healthy subjects in the Balmes study, IL-6 and a2M, but not IL-8, increased in association with ozone exposure. Statistical analyses suggested that effects of ozone on IL-8 levels observed in the first exposure and bronchoscopy may have carried over to the second exposure and bronchoscopy, which may have obscured an effect of ozone on IL-8 after the second exposure. For asthmatic subjects in the Balmes study, IL-6 and IL-8 increased in both bronchial and alveolar lavage fluid, but not in proximal airway lavage fluid. The mean interval between exposures was longer for asthmatic subjects than for healthy subjects, and no carryover effects were seen. When the Balmes and Frampton data were analyzed together, subject groups in the two studies (nonsmokers, smokers, and subjects without and with asthma) did not differ significantly in the response of cytokines to ozone exposure. The finding of possible carryover effects in one group suggests that subtle effects of ozone exposure, or bronchoscopy including proximal airway lavage and biopsy, or both, may persist for three weeks in some subjects.

Oxidant and acid aerosol exposure in healthy subjects and subjects with asthma. Part II: Effects of sequential sulfuric acid and ozone exposures on the pulmonary function of healthy subjects and subjects with asthma.

These studies were undertaken to evaluate pulmonary responses of humans sequentially exposed to acidic aerosols and ozone at levels that could reasonably be encountered in actual environmental exposures. Subjects first were exposed to sulfuric acid (H2SO4) aerosol to sensitize the airways to ozone. The exposure protocols were designed to provide more quantitative information about the threshold levels of ozone that produce adverse biological effects and to provide exposure-response data on ozone. Two groups of 30 nonsmoking volunteers of both sexes, between the ages of 18 and 45 years, were recruited. The healthy study population comprised 16 men and 14 women with an average age of 28 years and no airway hyperreactivity. The second group comprised 10 men and 20 women comparable in age to the control group, but with allergic asthma and positive skin tests. The study examined an exposure-response relationship using three levels of ozone ranging from below the current standard to one and one-half times the ambient air quality standard (0.08, 0.12, and 0.18 ppm* [parts per million]) with preexposure 24 hours earlier to H2SO4 (100 micrograms/m3) or sodium chloride (NaCl) (control) aerosol in a 45-m3 environmental chamber. The study used an incomplete block design in which each subject was exposed to four of the six paired experimental atmospheres. Both the selection of paired exposures and the order in which they were presented were randomized. The exposure protocol required nine days: Day 1, training and baseline preexposure measurements; Day 2, the first of the three-hour particle (H2SO4 or NaCl) exposures; Day 3 (24 hours after Day 2), ozone exposure at 0.08, 0.12, or 0.18 ppm for three hours; Day 4 (two to four weeks later), exposure to the same ozone concentration as on Day 4. After at least another two weeks, Days 6, 7, 8, and 9 repeated Days 2, 3, 4, and 5 using a second ozone concentration. All three-hour exposures included several predetermined periods of exercise and pulmonary function measurements. To examine for delayed effects, pulmonary function tests were measured two and four hours after exposure on the ozone days. Data were analyzed over the time course of exposure and by exposure level of ozone at each time point to reveal dose-response relationships more closely. The main findings of the study are as follows. No significant symptomatic or physiologic effects of exposure to either aerosol or ozone on lung function were found for the healthy group.(ABSTRACT TRUNCATED AT 400 WORDS)

Respiratory syncytial virus infection in adults: clinical, virologic, and serial pulmonary function studies.

We prospectively studied 10 previously healthy adults who developed an acute respiratory illness while working in an infants' ward during a community outbreak of respiratory syncytial virus infection. In addition to clinical and viral evaluation, total respiratory resistance before and after carbachol aerosol inhalation was measured. All 10 subjects had respiratory syncytial virus infection documented by viral isolation, and all developed pronounced cough, nasal congestion, and fever. Eight subjects missed work for an average of 6 days. In all 10 patients, the total respiratory resistance was significantly elevated through 8 weeks. Altered airway reactivity, characterized by exaggerated responses of pulmonary resistance to carbachol challenge, was also observed through the first 8 weeks of evaluation. In this group, respiratory syncytial virus produced a protracted illness associated with appreciable morbidity. The pathophysiologic mechanism of this illness in part appeared to arise from altered airway reactivity.

Clinical and physiological manifestations of bronchiolitis and pneumonia. Outcome of respiratory syncytial virus.

The physiological abnormalities and clinical correlates of 32 infants consecutively hospitalized with lower respiratory tract disease from respiratory syncytial virus (RSV) were studied in an attempt to characterized the infant most at risk for the acute and long-term complications of RSV infection. Arterial oxygen saturation (Sao2) determinations were obtained daily by means of an ear oximeter. On admission all infants were hypoxemic with a mean Sao2 of 87% (range, 74% to 95%). The mean of the lowest Soa2 recorded during their hospitalization was 85.5% (range, 53% to 96%). The hypoxemia improved little during hospitalization but showed improvement three to seven weeks later. The severity of the hypoxemia correlated significantly with the duration of viral shedding, occurrence of apnea, respiratory rate, age, and percentage of immature neutrophils. Clinical severity did not correlate with the degree of hypoxemia.

Airway responses to sulfate and sulfuric acid aerosols in asthmatics. An exposure-response relationship.

Epidemiologic studies support an association between elevated levels of sulfates and increased symptoms in asthmatics. To determine if these pollutants produce airway responses, 17 asthmatics inhaled the following sulfates: sodium bisulfate, ammonium sulfate, ammonium bisulfate (NH4HSO4), or sulfuric acid (H2SO4) aerosols with an aerodynamic diameter of 0.80 micron at concentrations of 100 micrograms/m3, 450 micrograms/m3, and 1,000 micrograms/m3. A sodium chloride (NaCl) aerosol of similar characteristics, administered by double-blind randomization, served as a control. Subjects breathed these aerosols for a 16-minute period via a mouthpiece. Deposition studies showed 54 to 65% retention of the inhaled aerosols. At the 1,000 micrograms/m3 concentration, the Threshold Limit Value for occupational exposure, H2SO4 and NH4HSO4 inhalation produced significant reductions in specific airway conductance (SGaw) (p less than 0.05) and forced expiratory volume in one second (p less than 0.01) compared with NaCl or pre-exposure values. At the 450 micrograms/m3 concentration, only H2SO4 inhalation produced a significant reduction in SGaw (p less than 0.01). At 100 micrograms/m3, a level 3 to 5 times greater than peak urban levels, no significant change in airway function occurred after any sulfate exposure. These data indicate that asthmatics demonstrate bronchoconstriction after brief exposure to common acidic sulfate pollutants.

Frequency dependence of total respiratory resistance in early airway disease.

Patients who develop frequency dependence of lung compliance will theoretically have frequency dependence of pulmonary resistance. We investigated the ability of the simpler, noninvasive measurement of frequency dependence of total respiratory resistance to identify subjects with frequency dependence of compliance. Ten healthy nonsmokers, 14 asymptomatic smokers, and 6 patients with obstructive airway disease were studied. Frequency dependence of total respiratory resistance was determined by the superimposed oscillating airflow technique at 3 to 9 cycles per sec, and frequency dependence of lung compliance was determined by measurements at 10 to 80 breaths per min. Spirometry, airway resistance, closing volume, and closing capacity were also measured. Frequency dependence of lung compliance and total respiratory resistance were closely correlated (P less than 0.001, r = 0.82), but closing volume, closing capacity, spirometry, and airway resistance could not be used to identify subjects with abnormal frequency dependence of lung compliance. Measurements of frequency dependence of total respiratory resistance and lung compliance, total respiratory resistance at 3 cycles per sec, and closing volume minus expiratory reserve volume were able to distinguish significantly between the smokers and the nonsmokers, but spirometry, closing volume, closing capacity, and airway resistance could not. These data indicate that in asymptomatic smokers and subjects with obstructive airway disease, frequency dependence of lung compliance can be predicted from measurements of frequency dependence of total respiratory resistance. These two tests appear to have equivalent sensitivity and selectivity in detecting the uneven time constants in the airways of asymptomatic smokers.

Amantadine aerosols in normal volunteers: pharmacology and safety testing.

The acceptability and pharmacology of intermittent aerosol administration of amantadine was assessed in healthy volunteers. Amantadine solutions of 2.5, 1.5, or 1.0 g/100 ml were used for 12 30-min, twice-daily aerosol treatments in 15 subjects. Overall, the aerosol treatments were well tolerated. During and up to 1 h after aerosol exposures, nasal irritation, rhinorrhea, dysgeusia, or a combination of symptoms was experienced by some of the subjects receiving either of the two higher amantadine concentrations. Aerosol treatments were associated with small but statistically significant decreases in maximal expiratory flow rates. One hour after aerosol treatments with the 1.0-g/100 ml solution, amantadine levels in nasal wash samples (mean, 30.3 micrograms/ml; range, 1.7 to 108 micrograms/ml) greatly exceeded blood and nasal wash levels reported after oral administration. Amantadine can be administered safely by small-particle aerosol to humans in doses that could be expected to exert an antiviral effect in influenza A virus infections.

Amantadine effect on peripheral airways abnormalities in influenza. A study in 15 students with natural influenza A infection.

Amantadine HCl administration has resulted in accelerated resolution of influenza A illness. Prolonged abnormalities in pulmonary function have been described in uncomplicated influenza A. To study the effect of amantadine on these changes, we evaluated young adults with documented natural influenza A with clear chest examinations and X rays. Subjects received placebo or amantadine in random, double-blind fashion. Physiologic studies included maximal expiratory flow volume curves with air and helium-oxygen mixtures. Air flow rates were unchanged in all subjects throughout. Initially, both groups showed comparable decreases in mean helium-oxygen maximal expiratory flow rates. The amantadine group showed accelerated physiologic improvement: significant increase in helium-oxygen flow rates occurred within 7 days (P less than 0.05). The rate of improvement in the helium-oxygen flow rates in the placebo group was not statistically significant. These studies confirm peripheral airways dysfunction after uncomplicated influenza A and suggest that amantadine is associated with accelerated resolution of this dysfunction.

Pulmonary mechanics after uncomplicated influenza A infection.

Pulmonary mechanics were evaluated in 13 nonsmoking adults with acute, uncomplicated influenza A/Port Chalmers/73(H3N2) virus infection. Subjects had no evidence of lower respiratory tract involvement on physical examination. Viral and/or scrologic evidence of influenza infection was established for all subjects. Physiologic measurements included forced expiratory rates by spirometry and total pulmonary resistance (RT) measured at 3, 5, 7, and 9 cycles per sec by the oscillometric technique. Subjects were studied at time of acute illness and at 1, 3, and 5 weeks thereafter. Spirometric measurements were initially normal in all subjects and did not change significantly throughout the study. Elevated RT measured at 3 cycles per sec and an abnormal degree of frequency dependence of RT, determined by comparing RT at 3 cycles per sec to RT at 9 cycles per sec, were initially present in 10 of 13 subjects. All 7 of these subjects initially abnormal who were tested 7 days after the onset of illness had abnormal frequency dependence. At 3 weeks, 7 of the 10 subjects initially abnormal continued to have frequency dependence of RT. All but 2 subjects reverted to normal levels by 5 weeks. Frequency dependence of RT indicates that acute influenza infection produces uneven time constants in the airways. A generalized increase in peripheral airway resistance or localized compliance changes could account for these abnormalities. Because these abnormalities persisted well beyond the period of clinical illness, these data imply that asymptomatic mechanical dysfunction of the lungs is a frequent sequela to acute influenza A virus infection. RT measured by the oscillometric method was a suitable noninvasive method for detecting abnormal airway time constants in these subjects with acute upper respiratory diseases.

Effects of nitrogen dioxide exposure on pulmonary function and airway reactivity in normal humans.

Nitrogen dioxide (NO2) is a product of combustion that has become recognized as a significant component of indoor air in some homes. Despite extensive study, it remains unresolved whether exposures to low levels of NO2 affect airway function or reactivity. These studies were designed to assess effects of various levels and patterns of NO2 exposure on pulmonary function and airway reactivity in normal humans. Normal volunteers screened for the absence of airway hyperreactivity were exposed for 3 h in an environmental chamber to purified air or NO2, separated by at least 2 wk, according to three protocols: (1) continuous 0.60 ppm NO2, (2) baseline 0.05 ppm NO2 with intermittent peaks of 2.0 ppm, and (3) continuous 1.5 ppm NO2. Subjects exercised for 10 min of each 30 min at a level sufficient to result in a minute ventilation near 40 L/min. Pulmonary function was measured before, during, and after exposure. Airway reactivity to increasing doses of carbachol was assessed 30 min after exposure. NO2 did not directly alter pulmonary function in any of the exposure protocols. In addition, airway reactivity was not altered by continuous exposure to 0.60 ppm or intermittent peaks of 2.0 ppm NO2. In contrast, continuous exposure to 1.5 ppm NO2 resulted in a greater fall in FVC and FEV1 in response to carbachol than after exposure to air (percent decrease in FVC: 1.5% after air, 3.9% after NO2, p less than 0.01). We conclude that for subjects without airway hyperreactivity, exposure to 1.5 ppm NO2 for 3 h increases airway reactivity, whereas repeated 15-min exposures to 2.0 ppm NO2 do not alter airway reactivity.

Airway hyperreactivity and peripheral airway dysfunction in influenza A infection.

We studied 39 consecutive college students with documented nonpneumonitic influenza A/Victoria/3/75/H3N2 infection to examine alterations in pulmonary mechanics and airway reactivity to cholinergic challenge, and to assess the effect of the antiviral agent amantadine on these changes. Thirty-six of the 39 subjects (92 per cent) demonstrated diminished forced flow rates and decreased density-dependent forced flow rates while breathing a helium-O2 mixture as compared to an air mixture. On initial evaluation, there was no significant difference in forced flow rates or density dependence between a group of 18 subjects treated with amantadine and 21 subjects given a placebo. However, the placebo group demonstrated further decreases in density dependence 7 days after initial presentation, whereas the amantadine group demonstrated a significant increase in density dependence (P less than 0.05), which suggested an accelerated improvement in peripheral airway dysfunction in the treated group. After inhalation of carbachol aerosol, 25 subjects showed a significant (P less than 0.05) increase in total respiratory resistance that was prolonged and independent of hay fever history. Airway hyperreactivity gradually diminished during a 7-week period in both groups. There was no significant difference in the initial degree of hyperreactivity or in the rate of improvement between groups. These data suggest that nonpneumonitic influenza infection may be associated with both an inflammatory response predominantly in the peripheral airways and transient bronchial hyperreactivity. By means of its antiviral effect, amantadine may arrest the proliferation of virus and associated inflammatory response in peripheral airways, but airway hyperreactivity presumably related to initially damaged airway depithelium is not attenuated by inhibition of viral replication after infection has been established.

Airway reactivity to nitrates in normal and mild asthmatic subjects.

Epidemiologic studies have reported increased symptoms in young asthmatics when atmospheric pollutants containing nitrates and sulfates are elevated. To determine if inorganic nitrate pollutants cause increased airway reactivity in humans, 10 normal volunteers and 11 mild asthmatics inhaled a sodium nitrate (NaNO3) aerosol with an aerodynamic diameter of 0.46 micron at a concentration of 7,000 microgram/m3, a level 100--1,000 times greater than reported urban levels for nitrates. A sodium chloride (NaCl) aerosol of similar characteristics served as a control. By double-blind randomization, each subject breathed NaCl or NaNO3 for a 16-min period and again 2--4 h later. Deposition studies showed 32--78% retention of the inhaled aerosol. Functional residual capacity, airway resistance, forced vital capacity, 1-s forced expiratory volume, and maximum and partial expiratory flow rates at 60 and 40% of total lung capacity did not significantly change during or after exposure. All subjects remained asymptomatic. To establish if aerosol exposure increased reactivity to a known bronchoconstrictor, subjects inhaled 0.025--1.0% carbachol following the 16-min exposure. Although prior inhalation of NaNO3 or NaCl aerosols did not significantly alter the effect of carbachol on pulmonary function, two asthmatics demonstrated mild potentiation of the carbachol bronchoconstrictor response after nitrate exposure. These results suggest that in normal subjects and mild asthmatics short-term NaNO3 exposure does not alter pulmonary function.

Neutrophils in lung inflammation: Which reactive oxygen species are being measured?

The oxidative burst in circulating polymorphonuclear leukocytes (PMN) plays a fundamental role in pulmonary defense and injury. Flow cytometric techniques have been developed for quantitation of oxidative burst activity at the single cell level using 2',7'-dichlorofluorescin (DCFH). However, the specific reactive oxidant species being measured using this method are not clearly defined. Isolated human PMN were loaded with DCFH diacetate, stimulated with phorbol myristate acetate (PMA) in the presence or absence of specific reagents, and analyzed using flow cytometry. Addition of PMA resulted in a 90-fold increase in the fluorescence intensity of DCFH-loaded neutrophils (p <.01). Inhibition of NADPH oxidase activity using a calmodulin antagonist (W-13) decreased PMA-induced DCFH oxidation by 70% (p <.05). Inhibition of nitric oxide synthase using N(G)-monomethyl-L-arginine (NMMA) did not significantly reduce DCFH oxidation, and did not alter the action of W-13. Addition of superoxide dismutase (SOD) had no effect, but catalase, with or without SOD, suppressed DCFH oxidation by 90% (p <.01). These data suggest that hydrogen peroxide, and not NO, is primarily responsible for the PMA-induced oxidation of DCFH in human PMN under these conditions.

Inhalation of 0.30 ppm nitrogen dioxide potentiates exercise-induced bronchospasm in asthmatics.

Epidemiologic studies support an association among elevated levels of nitrogen dioxide (NO2), increased respiratory symptoms, and alterations in lung function. To determine if low level NO2 inhalation potentiates exercise-induced bronchospasm, 15 asthmatic subjects, defined by airway constriction with cold air provocation, inhaled 0.30 ppm (560 micrograms/m3) NO2 for 30 min. All asthmatics inhaled either air or 0.30 ppm NO2 via a mouthpiece for 20 min at rest followed by 10 min of exercise on a bicycle ergometer at a workload of 300 kpm/min, producing a 3-fold or greater increase in minute ventilation. Our studies showed 72 +/- 2 (SE)% deposition of inhaled NO2 at rest and 87 +/- 1% deposition with exercise (p less than 0.001). Nitrogen dioxide inhalation at rest resulted in no significant change in pulmonary function. Nitrogen dioxide inhalation plus exercise compared to control (air) exposure plus exercise produced significantly greater reductions in FEV (p less than 0.01) and partial expiratory flow rates at 60% of total lung capacity (p less than 0.05). One hour after completion of NO2 exposure and exercise, pulmonary function had returned to baseline values. To determine if NO2 exposure caused increased reactivity to a known bronchoconstrictor, asthmatic subjects inhaled cold air (range: -11 +/- 2 degrees C) at 3 successive rates of isocapnic ventilation. The response to cold air was expressed as the respiratory heat exchange required to reduce the FEV by 10% (PD10RHE). Prior NO2 exposure potentiated the fall in FEV, PD10RHE, and specific airway conductance (p less than 0.05) after isocapnic cold air hyperventilation, compared to the control exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary performance of elderly normal subjects and subjects with chronic obstructive pulmonary disease exposed to 0.3 ppm nitrogen dioxide.

Symptoms and changes in pulmonary function of subjects with chronic obstructive pulmonary disease (COPD) and elderly normal subjects, induced by a 4-h exposure to 0.3 ppm NO2, were investigated using a double-blind, crossover design with purified air. The 5-day experimental protocol required approximately 2 wk with at least a 5-day separation between randomized 4-h exposures to either NO2 or air which included several periods of exercise. Over a 2-yr period, COPD subjects, all with a history of smoking, consisting of 13 men and 7 women (mean age of 60.0 yr) and 20 elderly normal subjects of comparable age and sex were evaluated. During intermittent light exercise, COPD subjects demonstrated progressive decrements in FVC and FEV1 compared with baseline with 0.3 ppm NO2, but not with air. Differences in percent changes from baseline data (air-NO2) showed an equivocal reduction in FVC by repeated measures of analysis of variance and cross-over t tests (p less than 0.10). Subgroup analyses suggested that responsiveness to NO2 decreased with severity of COPD; in elderly normal subjects, NO2-induced reduction in FEV1 was greater among smokers than never-smokers. A comparison of COPD and elderly normal subjects also revealed distinctions in NO2-induced responsiveness.

The prevalence of alpha-antitrypsin heterozygotes (Pi MZ) in patients with obstructive pulmonary disease.

An increased incidence of intermediate deficiency of serum alpha1-antitrypsin resulting from Pi phenotype MZ has been reported in patients with chronic obstructive pulmonary disease (COPD) by some laboratories but not confirmed by others. Prevalence of Pi MZ was determined in patients with COPD among 502 subjects referred to a pulmonary function testing laboratory in a region with low concentrations of air pollutants. Control prevalences were obtained from 930 randomly selected subjects in the same community as well as from patients without COPD referred to the laboratory. Depending on criteria used to define COPD, 155 to 306 subjects had COPD. Pi MZ prevalence in subjects with COPD varied from 1.5 to 4 times the prevalence in the community control group and in the patients without COPD. This difference approached significance or was significant. Because Pi MZ was present in only 3.5 to 4.5 per cent of patients with COPD, Pi MZ is not a major factor in the etiology of COPD in this community. The higher incidence of Pi MZ inpatients with COPD reported by other investigators may be explained by small sample size, bias in selection of study or control population groups, or the development of COPD from interaction between Pi MZ and air pollutants or other factors not present in this community.