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1 Heartlands Research Institute, Heartlands Hospital, Birmingham, UK. 2 Division of Environmental Health and Risk Management, University of Birmingham, Edgbaston, Birmingham, UK
CORRESPONDENCE: J.G. Ayres, Heartlands Hospital, Bordesley Green East, Birmingham, B9 5SS, UK. Fax: 44 1217720292
Keywords: air pollution, allergen, challenge study, particles, sulphuric acid
Received: October 16, 2000
Accepted June 11, 2001
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Abstract |
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The effect of exposure to particulate H2SO4 on the early asthmatic response to grass pollen allergen has been investigated in 13 adults with mild asthma. After establishment of the provocative dose of allergen producing a 15% fall in forced expiratory volume in one second (FEV1) (PD15) for each subject, they were exposed to air, 100 µg·m–3 or 1,000 g·m–3 H2SO4 for 1 h, double-blind in random order 
2 weeks apart, through a head dome delivery system 14 h after each exposure subject underwent a fixed-dose allergen challenge (PD15).
Ten subjects completed the study. The mean early asthmatic responses (maximum percentage change in FEV1 during the first 2 h after challenge) following air, 100 µg·m–3 H2SO4, and 1,000 µg·m–3 H2SO4, were –14.1%, –16.7%, and –18.4%, respectively. The difference between 1,000 µg·m–3 H2SO4 and air was significant (mean difference: –4.3%, 95% confidence interval (CI: –1.2––7.4%, p=0.013). The difference between air and 100 µg·m–3 H2SO4 approached significance (mean difference: –2.6%, 95% CI: 0.0––5.3%, p=0.051).
These results suggest that, at least at high mass concentration, sulphuric acid can potentiate the early asthmatic response of mild asthmatic subjects to grass pollen allergen, although the effect is limited.
Several epidemiological studies from both Europe and America have demonstrated an association between day-to-day changes in the concentration of airborne particulate matter and acute health effects 1–6. These range from increases in respiratory and cardiovascular mortality and hospital admissions, to day-to-day changes in lung function and symptoms. Groups considered to be at increased risk from particulate air pollutant exposure include those with pre-existing respiratory disease, both chronic obstructive pulmonary disease (COPD) 7 and asthma 8, although the association with asthma attacks is less consistent. This may, in part, be due to the variable metrics used to describe particulate exposure 9 and differences in the definition of "attacks" of asthma. In addition, the component(s) or characteristic(s) of the ambient aerosol responsible for health effects remain unclear, although recent interest has focused on smaller particles (<2.5 µm) 10.
Particulate sulphates are an important component of the ambient aerosol. They are principally secondary particles, formed when gas phase species react to give rise to products with low vapour pressures, which consequently condense 11. Their chief source is the atmospheric oxidation of sulphur dioxide (SO2) to sulphuric acid (H2SO4). H2SO4 exists in air in particle form; it reacts irreversibly in two stages with ammonia gas (NH3) to form ammonium bisulphate (NH4HSO4) or ammonium sulphate ((NH4)2SO4) 12.
Laboratory challenge with particulate H2SO4 in normal subjects has mostly failed to elicit any response following exposure to concentrations of ![{els]](/math/els.gif)
1,500 µg·m–3, although one study recorded an increase in nonspecific bronchial reactivity 24 h after a 4-;h long exposure to 450 µg·m–3 13. In subjects with asthma, results are conflicting, with some showing bronchoconstriction after inhalation of concentrations of H2SO4 <1,000 µg·m–3 14, 15, and in one study, with concentrations of only 100 µg·m–3 16; most studies 17–19, including the authors' own (unpublished data), have shown no significant effect on lung function.
Ambient H2SO4 levels are now, in general, low in the UK, but a recent study from CA, USA 20 has identified an association between health effects and day-to-day changes in the concentrations of this pollutant. One explanation for the differences between the epidemiological and challenge findings could be an interaction between H2SO4 and an unmeasured co-pollutant, such as an aeroallergen.
The potential for air pollutants such as ozone (O3) and nitrogen dioxide (NO2) (with or without SO2) to enhance the specific bronchial reactivity of the asthmatic airway to allergen is now well documented 21, and this has been proposed as a possible mechanistic pathway for some of their respiratory health effects in susceptible populations. There have been no previous studies in humans of the effects of H2SO4 exposure on bronchial responses to allergen. To explore this possibility further, the effect of exposure to 100 µg·m–3 and 1,000 µg·m–3 highly characterized H2SO4 aerosol (mass median diameter (MMD) 
300 nm) on the early asthmatic responses of subjects with mild asthma to inhaled grass pollen allergen was examined.
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Methods |
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). At a baseline screening visit, they underwent skin-prick testing with grass pollen (Bayer, Newbury, Berkshire, UK), positive (histamine) and negative control solutions, spirometry and bronchial challenge to grass pollen allergen (Cocksfoot and Timothy, Bayer). Only subjects that satisfied the following inclusion criteria were recruited: aged 16–60 yrs; nonsmokers; physician-diagnosed asthma taking inhaled medication only, the dose of inhaled beclomethasone or budesonide not >500 µg·24 h–1; baseline forced expiratory volume in one second (FEV1) and a ratio of FEV1 to forced vital capacity (FVC) 70% predicted 22; positive skin-prick test (mean wheal diameter >3 mm) to grass pollen; and positive early asthmatic response (>15% fall in FEV1 from baseline) to bronchial challenge with grass pollen. All subjects gave written informed consent and the project was approved by the East Birmingham Health Authority Research and Ethics Committee.
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2 weeks apart, in the presence of a stable baseline, FEV1 subjects underwent an air or H2SO4 (at 100 µg·m–3 and 1,000 µg·m–3) exposure for 1 h in a randomized, double-blind manner at 19:00 h. This was followed 14 h later by a fixed-dose allergen challenge, being the PD15 from the enrolment challenge.
Measurements
Lung function measurements, pre- and postexposure and during allergen challenge, were made using a Fleisch pneumotachograph (Vitalograph, Buckingham, UK) and the Spirotrach III system (Vitalograph) calibrated before each exposure and each bronchial challenge. The best of at least three technically acceptable blows was taken as the measured value at each point. European Community Coal and Steel predicted values were used 22. Following completion of allergen challenge, subjects were requested to record their FEV1 using a hand-held logging spirometer (Vitalograph 2110 electronic peak expiratory flow (PEF)/FEV1 diary, Vitalograph), at least hourly while awake for the remainder of the day, to detect any significant change in their lung function beyond the study period.
Bronchial challenge
Bronchial challenges were made with a breath-triggered Mefar MB3 dosimeter (Markos-Mefar, Bovezzo, Italy). They were not performed within 4 weeks of an upper respiratory tract infection. Those subjects using inhaled steroid medication discontinued them on the day of exposure (24 h prior to allergen challenge) and recommenced them at completion of their allergen challenge the following day. Antihistamine medication was discontinued for 1 week before each challenge and subjects maintained their usual daily consumption of ascorbic acid of caffeine-containing foodstuffs for the duration of the study. Dosimeter activation was set to 0.6 s during five consecutive full inspirations from functional residual capacity, followed by a 10 s breath-hold for each concentration of allergen. Each subject used the same nebulizer and their own trigger sensitivities throughout the study. At the start of each challenge, FEV1 was measured before and 1 min after diluent (phosphate buffered saline) delivery. If the values differed by <5%, the postdiluent FEV1 value was taken as baseline for that study day. If the value following diluent was 15% lower than the prediluent value, the challenge was abandoned for that day. If neither criterion was met, the procedure was repeated until one had been fulfilled. The same batch of grass pollen allergen was used throughout the study. One breath unit of allergen was defined as a single inhalation of a 50 units·mL–1 solution. All challenges were avoided during the pollen season.
On the preliminary assessment day, doubling incremental concentrations of allergen were delivered, with FEV1 measurements 3, 5, and 10 min after each five-inhalation cycle until a fall in the postdiluent FEV1 of >15% was achieved. A dose-response curve was drawn for each subject and interpolation used to establish the PD15. This cumulative dose was used in that subject's series of allergen challenges. The provocative dose was divided into two or three five-breath deliveries so that the challenge could be abandoned prematurely if necessary. On completion of allergen delivery, FEV1 measurements were made at 20, 40, and 60 min and then hourly for 7 h. If symptoms or recordings indicated a decline in FEV1, recordings were made more frequently.
The maximum reduction in FEV1 (percentage change from postdiluent FEV1) during the first 2 h after allergen inhalation was taken as the early asthmatic response. After recovery of FEV1 towards baseline, any subsequent fall in FEV1 (expressed as percentage change from postdiluent FEV1) was also recorded and defined as the late asthmatic response 24.
Exposures
Exposures were 2 weeks apart, of an hour's duration at rest and conducted at the same time of day for each individual. The pollutants were calculated to provide concentrations of 100 µg·m–3 or 1,000 µg·m–3 particulate H2SO4 (MMD 300 nm). All exposures were conducted via a purpose-built, head-only exposure system with an integral particle generator and a head dome 25 (fig. 1). Flow through the system for each exposure was maintained at 120 L·min–1 to prevent any significant re-breathing within the head dome. A technical description of the performance of the particle generator will be published elsewhere (unpublished data), but, in brief, the exposure aerosols were generated using a standard medical Micro Cirrus nebulizer (Intersurgical Ltd, Wokingham, UK) driven by bottled medical air under mass flow control and containing a dilute solution of the H2SO4. Its output was mixed with a dry, turbulent carrier stream of bottled air in a drying chamber and delivered to the breathing zone of the volunteer. The mass concentrations of the exposure aerosols were determined by the concentration of the material in the nebulizer solution and verified by sampling on a polytetrafluoroethylene filter (Whatman International Ltd, Maidstone, Kent, UK), followed by extraction into distilled deionized water and analysis of sulphates by ion chromatography. The aerosols were also characterized by electrical low pressure impaction, micro orifice uniform deposit impaction and scanning mobility particle sizing. For air (placebo) exposures, the nebulizer ran containing deionized water. For each exposure, the subject was required to sit in a comfortable chair with their head contained within a cast acrylic dome. The entry port in the wall of the dome was positioned within the breathing zone and the exit port was in the roof of the dome. A neck seal was achieved with a modified diving suit neck piece. Before each exposure, subjects brushed their teeth and gargled with an antiseptic mouth rinse to reduce the possibility of neutralization of the exposure aerosols by oral ammonia.
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Results |
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, as are their respective exposure orders and provocative doses of allergen. All exposures were well tolerated and there were no significant changes in FEV1 or FVC with any exposure (data available on request). Three subjects failed to complete the study; two due to a significant deterioration in their asthma control following their first and second fixed-dose allergen challenge, respectively. The third withdrew due to the development of another, unrelated medical condition. Their results are excluded from the data analysis.
Aerosol characteristics
Temperature and relative humidity were measured in the head dome and logged at the beginning of and at 5 min intervals during each exposure. The mean (range) temperature and relative humidity for the exposures are listed in table 2. In addition, the median mass of H2SO4 recovered from a random selection of filter trapped samples, five for each type of exposure, collected during actual exposures are displayed in table 2. There were no significant differences in temperature or relative humidity between the exposures, and the recovered median masses (107 µg·m–3 and 1,144 µg·m–3) fitted closely with those required by the authors.
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. The outputs were broadly concordant; for both mass concentrations, the MMD of the aerosols was 300 nm. The vast majority of particles were submicronic, with the count mode for each aerosol lying around 30 nm.
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) between the early asthmatic response following air and following 1,000 µg·m–2 H2SO4 exposures. The difference in early response following air and following 100 µg·m–3 H2SO4 exposures of –2.6% failed to achieve statistical significance (95% CI: 0.0––5.3%, p=0.051). There was no significant difference between the early responses following the 100 µg·m–3 and 1,000 µg·m–3 H2SO4 exposures.
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Discussion |
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Mechanisms to produce the observed changes are not clear. Theoretically they may reflect changes in the permeability of the respiratory epithelium to allergen 29, the priming or activation of cellular and/or chemical cascades involved in allergen handling 30, or even dynamic changes in the autonomic control of airway tone, in response to pollutant exposure 31. The finding that allergen responsiveness exposure is affected 14 h after H2SO4, suggests a long-lasting priming effect. This mechanistic uncertainty is further compounded by the limited understanding of the fate of exposure aerosols once they have been inhaled, despite the rigor with which the authors have attempted to characterize them. It remains unclear to what extent the aerosols will be modified by exposure to the humid environment of the human airway. Individual particles may be subject to growth and this might be expected to have significant effects on their regional deposition within the respiratory tract. Such uncertainty is mirrored by the authors' limited knowledge of the regional fate of the ambient aerosol in the normal human airway 12 and in the presence of disease states such as COPD 32.
The authors failed to detect any significant effect of particulate H2SO4 exposure on the late asthmatic responses of the volunteers. The study was not designed to test this hypothesis as subjects were recruited on the basis of their early asthmatic responses. No conclusions about the effect of H2SO4 exposure on the late asthmatic response can be drawn.
In the UK, sulphates account for 20–25% of urban, total suspended master by mass 11, of which 85% is in the fine (<2.5 µm) fraction. In the USA, sulphates comprise 20–40% of measured particles with a 50% cut-off aerodynamic diameter of 10 µm (PM10) 33. Few measurements of atmospheric H2SO4 concentrations have been made in the UK, and most were made in the 1950s and 1960s. In a more recent study from rural Essex, the peak concentration recorded over a 62 day period in 1987 was 8.7 µg·m–3 34. Data from rural sites in North America have shown higher values, with maximum daily means 15 µg·m–3 in the summer months during 1983–1986, and values of 27 µg·m–3 over shorter periods in the late 1970s 35. Maximum hourly average urban concentrations in the UK now rarely rise >50 µg·m–3, although earlier this century, hourly averages may at times have exceeded 1,000 µg·m–3.
In summary, the authors have shown potentiation of the early asthmatic response to grass pollen allergen of subjects with mild asthma by particulate sulphuric acid, and that the degree of this potentiation is similar to that previously shown for nitrogen dioxide and ozone. The reasons for this are not clear, but exploration of sulphuric acid exposures in the presence of other pollutants (including insoluble particles), and, possibly, studies of the autonomic consequences of such exposures, are needed to elucidate the likely mechanisms and to determine how these volunteer studies might relate to real-life exposures.
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), Micro Orifice Uniform Deposit Impaction (MOUDI; 
) and Scanning Mobility Particle Sizing (SMPS; —) devices. a) Low dose sulphuric acid (H2SO4) 100 µg·m–3 and b) high dose H2SO4 1,000 µg·m–3.