HUW S. JENKINS, JAGDISH L. DEVALIA, REBECCA L. MISTER, ANDREW M. BEVAN, CSABA RUSZNAK, and ROBERT J. DAVIES

Academic Department of Respiratory Medicine, St. Bartholomew's and the Royal London School of Medicine and Dentistry, London Chest Hospital, London, United Kingdom

Eleven mild atopic asthmatic patients were exposed for 6 h, in randomized order, to air, 100 ppb O3, 200 ppb NO2, and 100 ppb O3 + 200 ppb NO2, followed immediately by bronchial allergen challenge. Subsequently 10 of these patients were exposed for 3 h to air, 200 ppb O3, 400 ppb NO2, and 200 ppb O3 + 400 ppb NO2, followed immediately by bronchial allergen challenge. All exposures were carried out in an environmental chamber, with intermittent moderate exercise, and a minimal interval of 2 wk. Exposure for 6 h to 100 ppb O3, 200 ppb NO2, and 100 ppb O3 + 200 ppb NO2 did not lead to any significant increase in the airway response of these individuals to inhaled allergen, when compared with exposure for 6 h to air. In contrast, exposure for 3 h to 200 ppb O3, 400 ppb NO2, and 200 ppb O3 + 400 ppb NO2 significantly decreased the dose of allergen (in log cumulative breath units [CBU]) required to decrease FEV1 by 20% (allergen PD20FEV1), compared with exposure to air (geometric mean CBU: 3.0 for air versus 2.66 for O3 [p = 0.002]; 2.78 for NO2 [p = 0.018]; 2.65 for O3 + NO2 [p = 0.002]). These results suggest that the pollutant-induced changes in airway response of mild atopic asthmatics to allergen may be dependent on a threshold concentration rather than the total amount of pollutant inhaled over a period of time.
In recent years, there has been a progressive increase in air pollution characterized by high concentrations of atmospheric hydrocarbons, oxides of nitrogen (NOx), ozone (O3), and respirable particulate matter (particulates with a mass median diameter < 10 µm [PM10]), resulting primarily from increased use of liquid petroleum and gas in the transport and manufacturing industries and domestic settings (1, 2).
Cncern regarding the adverse health effects of ambient air pollutants has been highlighted by epidemiological studies which have shown associations between levels of these pollutants and mortality, hospital admissions, symptoms, and lung function changes in susceptible individuals with cardiorespiratory disease, including asthma (1).

Laboratory-based human exposure studies have demonstrated that ambient levels of O3 lead to small but significant changes in lung function, related to duration of exposure, concentration, and minute ventilation (9). Hence at a given concentration, greater effects are observed by increasing minute volume (i.e., with exercise) or exposure duration. Ozone also causes increased bronchial responsiveness (10), and neutrophilic airway inflammation (11, 12), in both asthmatics and normals. In contrast, studies of NO2 exposure have demonstrated inconsistent effects on lung function (5), but have suggested that this pollutant may also cause an increase in bronchial responsiveness in asthmatics (13). However, several studies have suggested that the effect on lung function of combined exposures to pollutant gases may be more harmful (14, 15).
More recent studies have demonstrated that exposure to pollutants may lead to increased airway response to inhaled allergen in asthmatic individuals, thereby providing an explanation for the increased morbidity from asthma as shown in epidemiological studies. Molfino and coworkers (16) demonstrated that exposure to 120 ppb ozone for as little as 1 h increased bronchial sensitivity of asthmatics to ragweed allergen, although these findings were not confirmed by Ball and colleagues (17). Subsequently Jörres and coworkers (18) showed that exposure to 250 ppb ozone for 3 h with exercise in mild asthmatics causes a highly significant increase in responsiveness to inhaled allergen, as measured by the dose of allergen required to cause a 20% reduction in FEV1 (PD20FEV1). Similar interactions have been observed for exposure to NO2 by Tunnicliffe and colleagues (19) (400 ppb NO2 for 1 h), and Strand and colleagues (20) (260 ppb NO2 for 30 min), using different experimental protocols.
We have previously shown that exposure for 6 h to a combination of 400 ppb NO2 and 200 ppb sulfur dioxide, but not to the individual gases alone, caused a significant fall in PD20FEV1 for Dermatophagoides pteronyssinus allergen in mild asthmatics, when compared with air exposure (21). Subsequently this effect was found to persist over a 48-h period and to be maximal at 24 h (22).
In the present study, we hypothesized that exposure of mild atopic asthmatics to O3 and NO2 in combination rather than individually would cause greater impairment in lung function and increased airway responsiveness to inhaled allergen. Furthermore, we hypothesized that a short exposure to high concentrations of pollutants would have a similar effect to a longer exposure to low concentrations, when both exposures delivered the same total dose of these gases. In order to test these hypotheses, we aimed to examine the effects of exposure to O3 and NO2, both individually and in combination, and the relationship between concentration and exposure duration, on the response to inhaled allergen in exercising mild atopic asthmatics. The effects of prolonged exposure (6 h) to low concentrations (100 ppb O3 and 200 ppb NO2) were compared with exposure for half the time to double the concentration, to assess whether adverse effects were dependent upon inhaled concentration or total inhaled dose.

Subjects

Eleven nonsmoking mild atopic asthmatic patient volunteers were studied. At the baseline screening visit, patients performed spirometry; skin prick testing with dust mite, grass pollen, cat and dog allergens (ALK [UK] Ltd, Reading, UK); bicycle ergometry; and histamine challenge. Only patients satisfying the following inclusion criteria were recruited: nonsmokers; age 18 to 45; mild asthma well controlled with inhaled 2-agonists only (less than 14 inhalations of albuterol [100 µg per actuation] per week); not on regular inhaled corticosteroids or other anti-inflammatory therapy (inhaled sodium cromoglycate, nedocromil sodium, or oral theophyllines); FEV1 greater than 70% predicted; provocative concentration of histamine causing a 20% reduction in FEV1 (PC20) < 2 mg/ml; documented allergy to house dust mite as shown by a weal greater than 3 mm after skin prick testing with D. pteronyssinus allergen. All patients gave written consent, and approval for the study was granted by East London and the City Health Authority Research Ethics Committee.
Baseline characteristics and clinical data of patients are shown in Table 1.
BASELINE CHARACTERISTICS OF STUDY PATIENTS

The patients underwent two study protocols, each involving four exposures to pollutant gases and allergen challenge, in randomized, single-blinded manner, in that the investigator but not the patient was aware of the exposure atmosphere (Table 2). All exposures were separated by an interval of at least 2 wk. In study protocol 1 (long exposures, low concentrations), the 11 patients were exposed for 6 h to air, 100 ppb O3, 200 ppb NO2, and the combination of 100 ppb O3 and 200 ppb NO2. Spirometry was performed before and after exposure. Bronchial challenge with increasing doses of D. pteronyssinus allergen was performed immediately after exposure, until the FEV1 fell by at least 20% from baseline. In study protocol 2 (short exposures, high concentrations), 10 of the 11 patients underwent subsequent exposure for 3 h, in randomized, single-blinded manner to air, 200 ppb O3, 400 ppb NO2, and the combination of 200 ppb O3 and 400 ppb NO2. Spirometry and bronchial allergen challenge were performed as described for protocol 1.

Exposure Chamber
Exposures were performed in a specially designed sealed exposure chamber (with dimensions 12 × 8 × 6 feet) into which pollutant gases were fed via Teflon tubing, dispersed with a fan, and then removed slowly by an exhaust system. Ozone was supplied at the desired concentration by a Static 300 ozone generator (Ambiox Ltd, Gwent, UK), using filtered room air. Nitrogen dioxide was supplied from cylinders containing 500 ppm NO2/air mixture (BOC Special Gases, London, UK) and before entry into the chamber was diluted with air to the desired concentration using a gas blender. Concentrations of O3 and NO2 in the chamber were monitored continuously by a Dasibi model 1180 ozone analyzer and a Dasibi model 2108 chemiluminescent NOx analyzer (both Quantitech Ltd, Milton Keynes, UK), fed by Teflon tubing sampling at head height.

Exposure Protocol
Prior to exposure the volunteer was asked about any recent symptoms and potential exposures to allergens. Exposures were cancelled in the event of symptoms of allergic rhinitis or upper respiratory tract infection within the previous 14 d. Pollen-allergic patients were studied outside the relevant pollen season, and animal-allergic patients were not studied in the event of recent animal exposure. Exposures were cancelled if ambient morning O3 and NO2 concentrations were above 25 ppb and 100 ppb, respectively.
Spirometry was performed immediately prior to exposure. A dry bellows spirometer (Vitalograph Ltd, Buckingham, UK), which was calibrated weekly, was used, according to American Thoracic Society (ATS) guidelines. During exposure patients were asked to perform moderate exercise on a bicycle ergometer according to a predetermined program (to achieve approximate minute ventilation of 32 L/ min) for 10 min every 40 min. Compliance with exercise program was confirmed by printer output from the ergometer. Peak flow readings were also recorded every 40 min as a safety measure. Temperature and relative humidity in the chamber were recorded by means of a wet and dry thermometer. After exposure, spirometry was repeated, and after 10 min bronchial allergen challenge was performed by a separate investigator blinded to the exposure protocol.

 
Bronchial Allergen Challenge
A DeVilbiss 646 nebulizer (DeVilbiss Healthcare U.K. Ltd., Feltham Middlesex, UK) fitted with a Rosenthal-French dosimeter (Johns Hopkins University, Baltimore, MD) using a triggering air pressure of 20 pounds per square inch (psi) and an opening time of 0.6 s, was used. Increasing concentrations of D. pteronyssinus allergen were inhaled until a fall in FEV1 of greater than 20% of the postsaline control value was observed. Two inhalations of albuterol (100 µg per actuation) were then given to reverse bronchospasm, and two inhalations of beclamethasone dipropionate (100 µg per actuation) to reduce any late-phase reactions.
The PD20FEV1, the dose (in cumulative breath units [CBU]) of allergen required to cause a 20% decrease in FEV1, was calculated by linear interpolation of the last two points on a log dose-response curve (1 CBU equivalent to one breath of a 1 in 5,000 allergen solution).

Statistics

The number of individuals required to detect a significant change in PD20FEV1 as a result of pollutant exposure was calculated on the basis of our previous study (21), which demonstrated a 65% reduction in PD20FEV1 after exposure to 400 ppb NO2 + 200 ppb SO2. Standard power calculations to a level of power of 90% gave a figure of 10 patients for investigation.
All data were tested for normal distribution prior to further analysis. FEV1 and forced vital capacity (FVC) measured before and after exposures were analyzed both in terms of actual and percentage change. Repeated-measures analysis of variance (ANOVA) was used for the four exposures in both protocols, and the effect of each pollutant exposure was compared with the effect of air exposure alone by paired Student's t test.
PD20FEV1 data were log-transformed, and the four exposures in each experimental protocol were assessed by repeated-measures ANOVA. Subsequently the effect of each pollutant exposure was compared to that of air exposure alone by paired Student's t test.
Temperature and relative humidity recorded inside the exposure chamber varied between 25 and 28° C and 40 and 50%, respectively. No significant differences were observed between the different pollutant exposures.
Table 3 shows the values for measurement of FEV1 before and after exposure to the different air and pollutant atmospheres for either 6 h or 3 h, and mean percentage change in FEV1. Corresponding values for mean percentage change in FVC were (1) 3.77, 1.79, 2.09, and 2.96 for air, 100 ppb O3, 200 ppb NO2, and 100 ppb O3 + 200 ppb NO2, respectively, in protocol 1; and (2) 2.3, 3.87, 2.06, and 4.74 for air, 200 ppb O3, 400 ppb NO2, and 200 ppb O3 + 400 ppb NO2, respectively, in protocol 2. Analysis by repeated-measures ANOVA showed no significant differences in changes in FEV1 (p = 0.381) and FVC (p = 0.538) between the four 6-h exposures. Analysis for data obtained after exposure for 3 h showed that although repeated-measures ANOVA was not significant for change in FEV1 (p = 0.115), this was significant for percent change in FEV1 for exposure to 200 ppb O3 (p = 0.013) and to 200 ppb O3 plus 400 ppb NO2 (p = 0.050) compared with exposure to air. In contrast, neither change in FVC (p = 0.381) nor percent change in FVC (p = 0.308) was significant. Analysis of peak expiratory flow rate (PEFR) data showed no evidence of adaptation (i.e., short-term decline followed by recovery) occurring during 6-h exposures. Despite the large number of exposures, there was no evidence of decline in lung function over the course of the study (mean preexposure FEV1 3.7 L for first and final exposures).

INDIVIDUAL FEV1 VALUES (L) BEFORE AND AFTER EXPOSURE TO AIR AND POLLUTANT GASES, AND MEAN % CHANGE IN FEV1
The results for bronchial responsiveness to inhaled allergen for the 6-h exposures are shown in Table 4 and Figure 1. Individual PD20FEV1 data are shown in Table 5. Geometric mean (95% confidence interval [CI]) PD20FEV1 (log CBU) values were calculated as 2.94 (2.68 to 3.20) for air, 2.91 (2.61 to 3.21) for O3, 2.77 (2.41 to 3.13) for NO2, and 2.69 (2.35 to 3.03) for O3 + NO2. Analysis of log-transformed values by repeated-measures ANOVA showed no significant differences among the four exposures. Although all three pollutant exposures caused small reductions in PD20FEV1 in comparison with 6 h exposure to air, none was statistically significant. A trend toward significance, however, was observed for the combination of 100 ppb O3 + 200 ppb NO2 (p = 0.067).

BRONCHIAL ALLERGEN SENSITIVITY AFTER EXPOSURE TO AIR AND POLLUTANT GASES, EXPRESSED AS ALLERGEN PD20FEV1
The effect of 6 h exposure to 100 ppb O3, 200 ppb NO2, and 100 ppb O3 + 200 ppb NO2, compared with air, on allergen PD20FEV1 in mild asthmatics. Squares represent geometric means.

INDIVIDUAL DATA FOR ALLERGEN PD20FEV1 (CBU) PRIOR TO LOG TRANSFORMATION
In contrast to 6-h exposure to low concentrations of pollutants, highly significant reductions in PD20FEV1 were observed for all the 3-h pollutant exposures (at double the concentrations for half the exposure period), in comparison to 3 h exposure to air (Table 4 and Figure 2). Analysis by repeated-measures ANOVA showed a strongly significant effect (p = 0.002). Geometric mean (95% CI) PD20FEV1 (log CBU) values were calculated as 3.0 (2.58 to 3.43) for air, 2.66 (2.31 to 3.01) for O3 (p = 0.02), 2.78 (2.32 to 3.23) for NO2 (p = 0.018), and 2.65 (2.30 to 3.00) for O3 + NO2 (p = 0.002).
The effect of 3 h exposure to 200 ppb O3, 400 ppb NO2, and 200 ppb O3 + 400 ppb NO2, compared with air, on allergen PD20FEV1 in mild asthmatics. Squares represent geometric means.

For the two exposures for which significant effects were seen, in comparison to air exposure, on both PD20FEV1 and percent change in FEV1, (i.e., 200 ppb O3 for 3 h, and 200 ppb O3 + 400 ppb NO2 for 3 h) we measured correlations between these two effects. No significant correlations were observed between individual pollutant-induced changes in PD20FEV1 and differences between percent change in FEV1 after pollutant exposure and that after air exposure (for 200 ppb O3 for 3 h, r = 0.427, p = 0.219; for 200 ppb O3 + 400 ppb NO2 for 3 h, r = 0.235, p = 0.513).

In this study we have shown that exposure for 3 h, with intermittent moderate exercise, to 200 ppb O3 and 400 ppb NO2, both individually and in combination, significantly increased the airway response to inhaled allergen in mild atopic asthmatics. Additionally, exposure to 200 ppb O3 and 200 ppb O3 + 400 ppb NO2 significantly decreased the FEV1 in these individuals. In contrast, exposure for 6 h to half the concentrations, namely 100 ppb O3 and 200 ppb NO2, either alone or in combination, did not significantly affect the lung function nor the airway response to inhaled allergen in the same patients.
Because the magnitude of the effect of exposure to the combination of the two pollutants at the higher concentrations of 200 ppb O3 and 400 ppb NO2, respectively, was not significantly greater than the effect of either pollutant individually, this study suggests that there is no significant interaction between O3 and NO2, and also that the detrimental effects of these pollutants on airway function and caliber may become manifest at threshold concentrations of between 100 and 200 ppb for O3 and between 200 and 400 ppb for NO2. Indeed, the lack of any significant effects after exposure for even a doubly prolonged period of 6 h to lower concentrations of pollutants, theoretically delivering the same total dose as the shorter exposure to higher concentrations of these pollutants, lends further support to the hypothesis that inhaled concentration rather than total dose determines changes in allergen sensitivity.

The spirometry results from these studies should be interpreted with caution. The aims, and thus power calculations, were directed primarily toward changes in PD20FEV1. In general, larger numbers are required in studies of lung function changes after pollutant exposure. Nevertheless, our findings are broadly in agreement with previous studies (1, 3, 5). No changes were seen after NO2 at either concentration, and a significant reduction in percentage FEV1 was observed after 3-h exposure to 200 ppb O3, with or without 400 ppb NO2.

Although some recent studies have also demonstrated that prior exposure to either O3 (16, 18) or NO2 (19, 20) can sensitize the airways of asthmatics and rhinitics to inhaled allergen, and sulfur dioxide (15), to our knowledge this is the first study to investigate the effects of O3 and NO2 in combination. Unlike the effect of O3 on lung function parameters such as FEV1 and FVC, in which the effects of concentration, exposure duration, and minute ventilation have been studied extensively (9), there is no information on such interactions for the effect of O3 or other pollutants on bronchial allergen sensitivity. Accordingly, this is also the first study to investigate both the concentration- and time-dependent effects of these pollutants, either individually or in combination, in the same individuals.

 
The overall findings from the present study for O3-induced changes in the airway response of asthmatics, however, are in accordance with those of others. Jörres and coworkers (18) investigated the effects of exposure for 3 h to air or 250 ppb O3 on the airway response of intermittently exercising mild allergic asthmatics and allergic rhinitics to inhaled allergen and methacholine. These investigators have shown that exposure to O3 both significantly decreased the lung function and increased the bronchial responsiveness to allergen in both groups of individuals, as indicated by significant decreases in the amounts of allergen required to reduce the mean FEV1 by 20% from baseline, compared with preexposure for 3 h to filtered air. Furthermore, preexposure to O3 significantly increased the airway responsiveness to methacholine in the asthmatics but not the rhinitics. Ball and colleagues (17) exposed nonexercising asthmatic patients for 1 h to either air or half the concentration, namely 120 ppb O3, and demonstrated that this did not significantly alter the airway response of these individuals to inhaled allergen, compared with exposure to air.

Our findings for NO2-induced effects on the airway response of asthmatics to inhaled allergen observed after exposure for 3 h are in accordance with the findings of others. Tunnicliffe and colleagues (19) investigated the effect of exposure at rest for 1 h to air, 100 ppb NO2 or 400 ppb NO2 on the airway response to subsequent allergen inhalation in mild asthmatics and demonstrated that although exposure to 400 ppb NO2 did not significantly alter the baseline FEV1 in these individuals, this concentration significantly increased the airway response during both the immediate and late phase after inhaled allergen, when compared with exposure to air. Similarly, Strand and colleagues (20) investigated the effect of exposure for 30 min to 260 ppb NO2 and demonstrated that this concentration enhanced the airway response of asthmatics during the late phase after allergen inhalation. More recently, these investigators reported that repeated exposure of asthmatic patients over a period of four consecutive days, for 30 min to 260 ppb NO2 at the same time each day, led to a small but significant increase in the airway response of these individuals to doses of allergen which when given as a single dose had no significant effects (23).
Our findings for the effect of exposure to 400 ppb NO2, however, are contrary to our previous findings which demonstrated that this pollutant significantly enhanced the airway response of asthmatic individuals to inhaled allergen only when used in combination with 200 ppb SO2, but not used alone (21). It is likely that this disparity is a consequence of the slightly different study designs employed in the two studies. In the present study an intermittent moderate exercising schedule, which can theoretically accentuate the effects of NO2 through increased minute volume and delivery to the distal airways (24), was employed unlike in the previous study. Also, unlike our previous study which demonstrated an additive effect of NO2 and SO2, no significant additive effects of NO2 and O3 were observed on bronchial sensitivity to inhaled allergen, at either high or low concentrations. These findings, however, are analogous to those of Hackney and colleagues who demonstrated that exposure to O3 in combination with NO2 had the same effect on lung function as exposure to O3 alone (25). A possible explanation for this observation may be that because both O3 and NO2 are thought to exert their harmful effects through a similar mechanism of oxidative stress (3, 5, 26), then once a state of saturation is attained during exposure to either the combination or the individual pollutants, additional effects are unlikely to be seen. In contrast, the additive effects observed after exposure to NO2 and SO2 may be a result of the different underlying mechanisms of action for these two pollutants (4, 5). Another possible explanation is that SO2 elicits a spirometric response very rapidly, in minutes, whereas ozone is known to require a longer duration (3, 4). Thus spirometry performed immediately after exposure may have been too early to catch a combination effect.

 
The possibility of a type 2 error occurring in the studies investigating the lower concentrations of these pollutants (the first study protocol), however, should not be overlooked, especially as exposure to 100 ppb O3 for 6.6 h has been shown to cause significant neutrophilic inflammation (27). A smaller effect to that seen after exposure to the higher concentrations of the pollutants (the second study protocol) may have been missed by the use of insufficient numbers of study patients. Also the use of allergen PD20FEV1, a more stringent and therefore a relatively less sensitive measure of bronchial hyperreactivity, compared with changes in the early and late phase after allergen challenge, as used by Tunnicliffe and colleagues (19) and Strand and colleagues (20, 23), may be important. Furthermore, in the present study allergen challenge was performed immediately after exposure and it is possible that a significant time-lagged effect, maximal after 24 to 48 h, could have been observed as we have demonstrated previously with NO2 and SO2 (22). One of the universal limitations of in vivo chamber studies of the effects of pollutants is that the effect of background exposures to air pollutants, other irritants, and allergens cannot be accounted for entirely, and is of particular relevance when studies are carried out in major cities of the world where ambient pollutant levels are high. In addition, chamber studies can never completely re-create natural conditions, where it is likely that more complex pollutant mixtures are involved, together with chronic exposure to smaller allergen doses.

The most likely mechanism for O3- and NO2-induced increases in bronchial sensitivity to inhaled allergens is through epithelial dysfunction, mediated by oxidant damage due to lipid peroxidation in epithelial lining fluid and formation of free radicals (26). Both O3 and NO2 have been shown to increase epithelial permeability (28, 29), thus potentially increasing the access of allergen to the immunocompetent and inflammatory cells underlying the lamina propria and involved in the allergic reaction. Additionally, NO2 has been shown to reduce mucociliary activity of the airways in vivo (30) and in vitro (29), and thus has the potential of enhancing the accessibility of allergen to the subepithelial cells, owing to its decreased clearance from the airways. Several studies have demonstrated that both O3 and NO2 lead to airway inflammation in humans, as indicated by increased numbers of neutrophils, eosinophils, mast cells, and lymphocytes in nasal (31) and bronchoalveolar lavages (11, 12, 32). Studies by Peden and colleagues (31) and Wang and colleagues (33) have further demonstrated that prior exposure to O3 and to NO2 "primes" eosinophils for subsequent activation by allergen in the nasal mucosa of perennially allergic asthmatics and seasonal allergic rhinitics, respectively. The fact that spirometric changes after O3 exposure are not correlated with bronchial reactivity (34) or airway inflammation (35) suggests that more than one mechanism is likely to be involved in pollution-induced airway disease.
In conclusion, exposure of mild atopic asthmatics for 3 h to 200 ppb O3 and 400 ppb NO2, alone and in combination significantly increased sensitivity to inhaled allergen as compared with exposure to air, without additive effects. Exposure for 6 h in the same subjects to 100 ppb O3 and 200 ppb NO2, alone or in combination, did not have significant effects. Further studies are required at intermediate concentrations to determine accurate threshold levels for these allergen-enhancing effects.
Correspondence and requests for reprints should be addressed to Dr. H. S. Jenkins, Academic Department of Respiratory Medicine, St. Bartholomew's and the Royal London School of Medicine and Dentistry, London Chest Hospital, Bonner Road, London E2 9JX, UK.
(Received in original form August 24, 1998 and in revised form December 22, 1998).Acknowledgments: The authors thank those involved for their commitment to this project. They also thank Ms. L. Paul for her help with statistical analysis.
Supported by a joint initiative by the United Kingdom Departments of Health and Transport. The grant was administered by the Institute for Environment and Health, at the University of Leicester, UK, which also provided helpful support. Dr. Devalia was supported by the National Asthma Campaign.


INTRODUCTION

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