Time course of response to ozone exposure in healthy adult females.

Ozone exposure causes acute decrements in pulmonary function, increases airway responsiveness, and changes the breathing pattern. We examined these responses in 19 ozone-responsive (DeltaFEV(1) > 5%) young females exposed to both air and 0.35 ppm ozone. The randomized 75-min exposures included two 30-min exercise periods at V(E) approximately 40 L/min. Responses were measured before, during, and after exposure and at 18 and 42 h postexposure. FVC, FEV(1), and FIV(0.5) decreased (p <.01) immediately postexposure by 13.2%, 19.9%, and 20.8%, respectively, and the airway responsiveness was significantly increased. Raw increased (p <.05), while TGV remained essentially unchanged. At 18 h postexposure, the airways were still hyperresponsive and FEV(1) and FIV(0.5) were still 5% below the preexposure levels. There were no residual effects in any of the variables at 42 h postexposure. During exercise in ozone the tidal volume was decreased (-14%) and respiratory frequency increased (+15%). The changes in airway responsiveness were not related to changes in spirometric measurements. We found no significant differences between postair and postozone mouth occlusion pressure (Pm(0.1)) and the hypercapnic response to CO(2) rebreathing. We conclude that ozone induced typical acute changes in airway responsiveness and that ventilatory (exercise), spirometric (inspiratory and expiratory), and plethysmographic pulmonary function may show some residual effects for up to 18 h after exposure. The ozone-induced alteration in breathing pattern during exercise does not appear to be related to a change in ventilatory drive.

Increased specific airway reactivity of persons with mild allergic asthma after 7.6 hours of exposure to 0.16 ppm ozone.

BACKGROUND: Exposure to ozone causes decrements in lung function, increased airway reactivity to nonspecific bronchoconstrictors, and lung inflammation. Epidemiology studies show an association between ambient oxidant levels and increased asthma attacks and hospital admissions. OBJECTIVE: The purpose of our study was to evaluate the response of persons with mild asthma to inhaled allergen after ozone exposure conditions similar to those observed in urban areas of the United States. METHODS: Using a double-blind, counter-balanced design, we exposed 9 (5 women and 4 men) subjects with mild atopic asthma (house dust mite sensitive) to clean air and to 0.16 ppm ozone for 7.6 hours; exposures were separated by a minimum of 4 weeks. During exposure, subjects performed light exercise (ventilation = 24 L/min) for 50 minutes of each hour, and pulmonary function was evaluated before and after exposures. The morning after exposure, subjects underwent bronchial challenge with inhaled house dust mite allergen (Dermatophagoides farinae). Using a series of doubling allergen concentrations, subjects inhaled 5 breaths of nebulized allergen (0.06 to 500 AU/mL) at 10-minute intervals until a minimum of a 20% decrement in FEV(1) was elicited. RESULTS: Compared with the change in FEV(1) during air exposure, there was a mean 9.1% +/- 2.5% (SEM) decrement in FEV(1) observed because of ozone (P <.01). Seven of the 9 subjects required less allergen after ozone exposure than after air exposure; there was a 0.58 mean dose shift in the doubling concentration of allergen attributable to the ozone exposure (P =.03). CONCLUSION: These findings indicate that exposure of subjects with mild atopic asthma to ozone at levels sufficient to cause modest decrements in lung function also increases the reactivity to allergen. To the extent that this effect occurs in response to ambient exposures, ozone may be contributing to the aggravation of asthma.

Nociceptive mechanisms modulate ozone-induced human lung function decrements.

We have previously suggested that ozone (O3)-induced pain-related symptoms and inhibition of maximal inspiration are due to stimulation of airway C fibers (M. J. Hazucha, D. V. Bates, and P. A. Bromberg. J. Appl. Physiol. 67: 1535-1541, 1989). If this were so, pain suppression or inhibition by opioid-receptor agonists should partially or fully reverse O3-induced symptomatic and lung functional responses. The objectives of this study were to determine whether O3-induced pain limits maximal inspiration and whether endogenous opioids contribute to modulation of the effects of inhaled O3 on lung function. The participants in this double-blind crossover study were healthy volunteers (18-59 yr) known to be "weak" (WR; n = 20) and "strong" O3 responders (SR; n = 42). They underwent either two 2-h exposures to air or two 2-h exposures to 0. 42 parts/million O3 with moderate intermittent exercise. Immediately after post-O3 spirometry, the WR were randomly given either naloxone (0.15 mg/kg iv) or saline, whereas SR randomly received either sufentanil (0.2 microgram/kg iv) or saline. O3 exposure significantly (P < 0.001) impaired lung function. In SR, sufentanil rapidly, although not completely, reversed both the chest pain and spirometric effects (forced expiratory volume in 1 s; P < 0.0001) compared with saline. Immediate postexposure administration of saline or naloxone had no significant effect on WR. Plasma beta-endorphin levels were not related to an individual's O3 responsiveness. Cutaneous pain variables showed a nonsignificant weak association with O3 responsiveness. These observations demonstrate that nociceptive mechanisms play a key role in modulating O3-induced inhibition of inspiration but not in causing lack of spirometric response to O3 exposure in WR.

Prediction of ozone-induced FEV1 changes. Effects of concentration, duration, and ventilation.

The purpose of this analysis of previously published data was to identify a model that accurately predicts the mean ozone-induced FEV1 response of humans as a function of concentration (C), minute ventilation (VE), duration of exposure (T), and age. Healthy young adults (n = 485) were exposed for 2 h to one of six ozone concentrations while exercising at one of three levels. Candidate models were fitted to portions of the data and evaluated on the basis of their ability to predict the mean response of independent samples. A sigmoid-shaped model that is consistent with previous observations of ozone exposure-response (E-R) characteristics was identified and found to accurately predict the mean response with independent data. This model in a more general form may allow the prediction of responses under conditions of changing C and VE. We did not find that response was more sensitive to changes in C than in VE, nor did we find convincing evidence of an effect of body size upon response. We did find that response to ozone decreases with age. In summary, we have identified a biologically plausible, predictive model that quantifies the relationship between the ozone-induced change in FEV1, and C, VE, T, and age.

Allergen bronchoprovocation of patients with mild allergic asthma after ozone exposure.

BACKGROUND: Clinical and epidemiologic studies suggest that ambient ozone exposure may increase the response of patients with asthma to inhaled allergen. OBJECTIVES: The study was designed to evaluate whether a resting 1-hour exposure to 0.12 ppm ozone increases the sensitivity of patients with atopic asthma to inhaled allergen. METHODS: Outside of their allergen season, 15 patients with mild atopic asthma (5 women and 10 men) were exposed, on separate occasions, for 1 hour at rest to clean air and 0.12 ppm ozone. Exposures were separated by a minimum of 4 weeks in a counterbalanced, double-blind design. After exposure, subjects underwent inhalation challenge with doubling doses of aerosolized allergen (0.05 to a maximum of 1600 protein nitrogen units/ml) until we elicited a 20% FEV1 decrement (PC20). RESULTS: Baseline symptoms, spirometry, and histamine bronchoreactivity were similar for the two exposures. Neither spirometry results nor symptoms were significantly changed after either exposure. The mean difference in response to allergen challenge on the air and ozone days, for the 12 subjects who attained a PC20 was not significant (p = 0.124). Three subjects required the same allergen dose to reach PC20 for both exposures, five required less allergen after ozone exposure, and four required more. There was no order effect for the acute response to allergen challenges (p = 0.325). However, 20 hours after allergen challenge, histamine bronchoreactivity was increased (p < 0.05) to a similar degree for both air and ozone. CONCLUSIONS: A resting exposure for 1 hour to 0.12 ppm ozone did not potentiate an immediate bronchoconstrictive response to grass allergen in this group of patients with mild atopic asthma.

Comparison of pulmonary responses of asthmatic and nonasthmatic subjects performing light exercise while exposed to a low level of ozone.

To determine if asthmatic subjects (ASTH, n = 17) experience greater O3-induced pulmonary decrements than nonasthmatic subjects (NONA, n = 13), both groups were exposed for 7.6 h to both clean air and 0.16 ppm O3. Exposures consisted of seven 50-min periods of light exercise (VE = 14.2 and 15.3 l/min/m2 for ASTH and NONA, respectively), each followed by 10 min rest. A 35-min lunch period followed the third exercise. Following O3 exposure, decrements in forced expiratory volume in one second (FEV1) and FEV1 divided by forced vital capacity (FVC), corrected for air exposure, for ASTH (-19.4 +/- 3.1% and -6.2 +/- 2%, respectively) were significantly greater (p = 0.04 and 0.02) than for NONA (-9.8 +/- 1.9% and -1 +/- 1%, respectively). There was no difference (p = 0.33) for decrements in FVC between ASTH (-11.8 +/- 1.9%) and NONA (-8.8 +/- 2.1%). Nine of 17 ASTH experienced wheezing with O3, while only one experienced wheezing with air (p = 0.004); no NONA experienced wheezing. Six of 17 ASTH requested inhaled beta-agonist bronchodilator prior to and/or during O3 exposure and experienced some temporary alleviation of decrements. At end exposure, however, ASTH who were medicated had greater O3-induced decrements than those who were not medicated. ASTH who had the larger O3-induced decrements had lower baseline FEV1/FVC and lower baseline %predicted FEV1. These data indicate that in ASTH, unlike NONA, some portion of O3-induced pulmonary decrements experienced was related to bronchoconstriction, and that O3-responsiveness for ASTH depended upon baseline airway status.

Lung function response of healthy women after sequential exposures to NO2 and O3.

Since NOx emissions bear a precursor-product relation with ambient ozone (O3) levels, the sequence of peak ambient concentrations is first nitrogen dioxide (NO2) followed later in the day by ozone (O3). We ascertained whether preliminary exposure to 0.6 parts per million (ppm) NO2 would affect the lung function response to subsequent exposure to 0.3 ppm O3. Twenty-one healthy young nonsmoking women (18 to 35 yr of age) underwent two sets of exposures on two different days separated by a minimum of 2 wk. On one day, subjects were exposed to air for 2 h followed 3 h later by a 2-h exposure to O3. On the other day, the first exposure was to NO2; order of the days was randomized. During each exposure subjects intermittently exercised, alternating 15 min of rest with 15 min of exercise (Ve approximately 40 L/min). Spirometry was performed before the first exposure and at 1-h intervals until the end of the 2-h (O3) exposure. Plethysmography measurements were made before and after NO2 and O3 exposures. Nonspecific airway reactivity (AR) was determined at least 1 wk prior to the first exposure and following each O3 exposure. AR to methacholine (MCh) was expressed as dose required to decrease FEV1 by 10% (PD10FEV1). Nitrogen dioxide exposure alone did not reduce FEV1 but did significantly enhance O3-induced spirometric changes. No significant effects were observed in plethysmography. On both exposure days, the median PD10FEV1 was significantly reduced (p < 0.05) from control PD10FEV1 (14.3 mg/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Respiratory responses to repeated prolonged exposure to 0.12 ppm ozone.

Repeated exposure to high concentrations of ozone results first in augmentation (typically on the second day) and then attenuation of pulmonary response in humans. To determine the effects of repeated prolonged low-concentration ozone exposure, we exposed 17 healthy nonsmoking male subjects to 0.12 ppm ozone for 6.6 h on 5 consecutive days. Subjects were also exposed once to filtered air. Volunteers exercised at a ventilation of approximately 39 L/min for 50 min of each hour during the exposure. Spirometry, plethysmography, and symptom responses were obtained before, during, and after each exposure. Nasal lavage and aerosol bolus dispersion were obtained before and after exposure. Spirometry decreased and symptoms increased on the first day. Responses were less on the second day compared with those on the first day, and they were absent compared with control values on the subsequent 3 days of ozone exposure. Percent change in FEV1 after ozone exposure compared with that after air exposure averaged -12.79, -8.73, -2.54, -0.6, +0.18% for Days 1 to 5 of ozone exposure, respectively. FEV1 responses ranged from a zero to 34% decrease on Days 1 and 2. After each exposure, we determined the ratio of SRaw after inhaling a fixed dose of methacholine to SRaw after inhaling saline aerosol, as an index of airway responsiveness. Airway responsiveness was significantly increased after each ozone exposure. The mean ratios were 2.22, 3.67, 4.55, 3.99, 3.24, and 3.74 for filtered air and ozone Days 1 to 5, respectively. Symptoms of cough and pain on deep inspiration increased significantly on ozone Day 1 only.(ABSTRACT TRUNCATED AT 250 WORDS)

Human health effects of air pollution.

Over the past three or four decades, there have been important advances in the understanding of the actions, exposure-response characteristics, and mechanisms of action of many common air pollutants. A multidisciplinary approach using epidemiology, animal toxicology, and controlled human exposure studies has contributed to the database. This review will emphasize studies of humans but will also draw on findings from the other disciplines. Air pollutants have been shown to cause responses ranging from reversible changes in respiratory symptoms and lung function, changes in airway reactivity and inflammation, structural remodeling of pulmonary airways, and impairment of pulmonary host defenses, to increased respiratory morbidity and mortality. Quantitative and qualitative understanding of the effects of a small group of air pollutants has advanced considerably, but the understanding is by no means complete, and the breadth of effects of all air pollutants is only partially understood.

Effects of steady-state and variable ozone concentration profiles on pulmonary function.

Measurements of ambient ozone (O2) concentration during daylight hours have shown a spectrum of concentration profiles, from a relatively stable to a variable pattern usually reaching a peak level in the early afternoon. Several recent studies have suggested that in estimating exposure dose (O3 concentration [C] x exposure time [T] x ventilation [V]), O3 concentration needs to be weighted more heavily than either ventilation or duration of exposure in the estimates. In this study we tested the hypothesis that regardless of concentration pattern and exposure rate the same exposure dose of O3 will induce the same spirometric response. We exposed 23 healthy male volunteers (20 to 35 yr of age) for 8 h to air, 0.12 ppm O3 (steady-state), and a triangular exposure pattern (concentration increased steadily from zero to 0.24 ppm over the first 4 h and decreased back to zero by 8 h). During the first 30 min of each hour, subjects exercised for 30 min at minute ventilation (VE) approximately 40 L/min. The order of the exposures was randomized, and the exposures were separated by at least 7 days. The response patterns over the 8-h periods for spirometric variables in both O3 exposures were statistically different from air exposure changes and from each other. For FEV1 the p values were 0.017 between air and steady-state profile, 0.002 between air and triangular profile, and 0.037 between steady-state and triangular profiles. Although in the triangular pattern of exposure the maximal O3 concentration was reached at 4 h, the maximum FEV1 decrement (10.2%) was observed at 6 h of exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Does nitrogen dioxide exposure increase airways responsiveness?

A number of reports have suggested that exposure to nitrogen dioxide (NO2) may cause increased airways responsiveness (AR). Twenty studies of asthmatics and five studies of healthy subjects exposed to NO2 were used to test this hypothesis using a simple method of meta-analysis. Individual data were obtained for the above studies and the direction of change in AR was determined for each subject. Only studies with available individual data were used. Subjects from these studies whose directional change in AR could not be determined were excluded. The fraction of positive responses (i.e. increased AR) was determined for all subjects within a group and tested for significance using a sign test. Data were also grouped according to NO2 concentration and by whether the exposure included exercise. There was an overall trend among asthmatics for AR to increase (60%) but this was primarily due to increased AR seen in resting exposures (70%). Among healthy subjects AR also increased with NO2 exposure but only at concentrations above 1.0 ppm. This analysis suggests that NO2 exposure causes increased airway responsiveness in healthy and asthmatic subjects but that exercise during exposure may modify this response in asthmatics.

Respiratory response of humans exposed to low levels of ozone for 6.6 hours.

Recent evidence suggests that prolonged exposures of exercising men to 0.08 ppm ozone (O3) result in significant decrements in lung function, induction of respiratory symptoms, and increases in nonspecific airway reactivity. The purpose of this study was to confirm or refute these findings by exposing 38 healthy young men to 0.08 ppm O3 for 6.6 h. During exposure, subjects performed exercise for a total of 5 h, which required a minute ventilation of 40 l/min. Significant O3-induced decrements were observed for forced vital capacity (FVC, -0.25 l), forced expiratory volume in 1 s (FEV1.0, -0.35 l), and mean expiratory flow rate between 25% and 75% of FVC (FEF25-75, -0.57 l/s), and significant increases were observed in airway reactivity (35%), specific airway resistance (0.77 cm H2O/s), and respiratory symptoms. These results essentially confirm previous findings. A large range in individual responses was noted (e.g., percentage change in FEV1.0; 4% increase to 38% decrease). Responses also appeared to be nonlinear in time under these experimental conditions.

An air quality data analysis system for interrelating effects, standards, and needed source reductions: Part 11. A lognormal model relating human lung function decrease to O3 exposure.

Forced expiratory volume in 1 second (FEV1) was measured in 21 men exercising while exposed to four O3 concentrations (0.0, 0.08, 0.10, and 0.12 ppm). A lognormal multiple linear regression model was fitted to their mean FEV1 measurements to predict FEV1 percent decrease as a function of O3 concentration and exposure duration. The exercise level used was probably comparable to heavy manual labor. The longest O3 exposure studied was 6 h. Extrapolating cautiously to an 8-h workday of heavy manual labor, the model predicts that O3 concentrations of 0.08, 0.10, and 0.12 ppm would decrease FEV1 by 9, 15, and 20 percent, respectively.

Ozone concentration and pulmonary response relationships for 6.6-hour exposures with five hours of moderate exercise to 0.08, 0.10, and 0.12 ppm.

The magnitudes of pulmonary responses we previously observed (1) following 6.6-h exposures to 0.12 ppm ozone (O3) suggested that responses would also occur with similar exposures at lower O3 concentrations. The objective of this study was to determine the extent of pulmonary function decrements, respiratory discomfort, and increased airway reactivity to methacholine induced by exposure to O3 below 0.12 ppm. Separate 6.6-h chamber exposures to 0.00, 0.08, 0.10, and 0.12 ppm O3 included six 50-min periods of moderate exercise (VE approximately equal to 39 L/min, HR approximately equal to 115 bpm, and VO2 approximately equal to 1.5 L/min). Each exercise period was followed by 10 min of rest. A 35-min lunch break was included midway through the exposure. Although not intended as an exact simulation, the overall duration, intensity, and metabolic requirements of the exercise performed were representative of a day of moderate to heavy work or play. Preexposure FEV1 averaged 4.39 L, and essentially no change (+0.03 L) occurred with exposure to 0.00 ppm O3. Significant decreases (p less than 0.01) of -0.31, -0.30, and -0.54 L were observed with exposures to 0.08, 0.10, and 0.12 ppm, respectively. The provocative dose of methacholine required to increase airway resistance by 100% (PD100) was 58 cumulative inhalation units (CIU) following exposure to 0.00 ppm and was significantly reduced (p less than 0.01) to 37 CIU at 0.08, 31 CIU at 0.10, and 26 CIU at 0.12 ppm O3; reductions in PD100 are considered indicative of increases in nonspecific airway responsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)

Human health effects of exposure to airborne acid.

This paper summarizes and critiques a series of reports on the health effects of acid aerosol exposure, presented at the Symposium on the Health Effects of Acid Aerosols and compares these data to selected previous studies. The role of the two major defenses against acid aerosols, the conversion of acid to the ammonium salts by respiratory ammonia and buffering of acid by airway surface liquid are discussed in relation to airway acid burdens expected from typical inhalation exposures. The roles of particle size and hygroscopicity on airway deposition of aerosol are also included. The major health effects studied were the effects of acid aerosol on mucociliary clearance in healthy individuals and changes in lung function in asthmatics, an important sensitive subpopulation. The broad range of response in asthmatics suggests the need for further study.

The relationship between exposure duration and sulfur dioxide-induced bronchoconstriction in asthmatic subjects.

The purpose of this study was to determine the shortest duration of exposure to 1.0 ppm sulfur dioxide (SO2) sufficient to induce bronchoconstriction significantly greater than that observed with exposure to clean air (CA) in exercising SO2-sensitive asthmatics. Asymptomatic, nonmedicated, male asthmatics (n = 12) with airway hyperresponsiveness to both methacholine and SO2 were exposed in a chamber (20 degrees C, 40% relative humidity) for 0.0, 0.5, 1.0, 2.0 and 5.0 min to both CA and 1.0 ppm SO2 on separate days (10 exposures). Just prior to each exposure, subjects walked on a treadmill in CA for 5 min at a predetermined speed/elevation to elicit a target ventilation of about 40 L/min, i.e., a brisk pace up a slight incline. After this walk, subjects rapidly entered an adjoining exposure chamber containing either CA or SO2 and immediately walked at the same speed/elevation for the specified exposure duration. Subjects then rapidly exited the chamber. Specific airway resistance (SRaw) and ratings of respiratory symptoms associated with asthma [shortness of breath/chest discomfort (SB/CD) and wheezing (WHZ)] were measured prior to any exercise and following each exposure. Postexposure SRaw and symptom ratings increased with increased exposure duration in SO2; postexposure SRaw also was increased with increased exposure duration in CA but to a lesser extent. After adjusting for the CA response, significantly greater SO2-induced bronchoconstriction was observed for the 2.0 and 5.0 min exposures as indicated by substantially greater increases in SRaw and substantially higher ratings of respiratory symptoms. The authors conclude that with the above exposure conditions, on average, SO2-sensitive asthmatics exhibit significant bronchoconstriction at exposure durations of 2.0 min or more.