The Health Effects Institute

Synopsis
Research Report Number 78

Effects of Ozone on Pulmonary Function and Airway Inflammation in Normal and Potentially Sensitive Human Subjects

Part I: Airway Inflammation and Responsiveness to Ozonein Normal and Asthmatic Subjects
John R. Balmes, Robert M. Aris, Lisa L. Chen, Cornelius Scannell, Ira B. Tager,Walter Finkbeiner, Dorothy Christian, Thomas Kelly, Patrick Q. Hearne, Ronald Ferrando, and Barbara Welch
Departments of Medicine and Pathology, University of California, San Francisco, CA, and the Division of Public Health Biology and Epidemiology, School of Public Health, University of California, Berkeley, CA
Part II: Airway Inflammation and Responsiveness to Ozone in Nonsmokers and Smokers
Mark W. Frampton, Paul E. Morrow, Alfonso Torres, Karen Z. Voter, John C. Whitin, Christopher Cox, Donna M. Speers, Ying Tsai, and Mark J. Utell
Departments of Medicine, Environmental Medicine, Pediatrics, and Biostatistics, University of Rochester School of Medicine and Dentistry, Rochester, NY
Part III: Mediators of Inflammation in Bronchoalveolar Lavage Fluid from Nonsmokers, Smokers, and Asthmatic Subjects Exposed to Ozone: A Collaborative Study
Mark W. Frampton, John R. Balmes, Christopher Cox, Peter M. Krein, Donna M. Speers, Ying Tsai, and Mark J. Utell

BACKGROUND

Ozone is a common air pollutant and a major component of smog. The current National Ambient Air Quality Standard (which is currently being revised) is 0.12 parts per million (ppm), a level not to be exceeded for more than one hour, once per year. This standard is based largely on evidence that, in sensitive individuals, short-term exposure to ozone causes symptoms such as cough and shortness of breath, and reversible changes in some tests of lung function.

A procedure called spirometry is commonly used to measure lung function, particularly the measurement of forced expiratory volume in one second (FEV1), which is the volume of air a subject can forcibly exhale in the first second following maximal inhalation. Exposure to ozone causes a transient decrease in FEV1 in many people. This response is highly reproducible within an individual; however, there are marked differences among individuals in their sensitivities to ozone. Ozone also can cause the airways to become hyperresponsive to inhaled substances (such as the drug methacholine) that constrict the large airways or bronchi; this response is reflected in the airways becoming increasingly resistant to air flow. Finally, inhaling ozone can produce airway inflammation and cell injury, as evidenced by the appearance of cellular and biochemical markers of these reactions in airway fluids.

This report describes the results of two independent studies that were designed to (1) evaluate the range of ozone-induced responses in the general population, (2) study the effects of short-term exposure to ozone in populations with underlying airway inflammation (smokers and people with asthma), and (3) compare the responses in sensitive populations with those in normal subjects. A common goal of both studies was to characterize ozone-induced responses in populations thought to be most sensitive to ozone so that appropriate standards can be set to protect human health.

STUDY DESIGN

The studies described in this report were conducted by two investigator groups: Dr. John Balmes and colleagues of the University of California, San Francisco, and Dr. Mark Frampton and associates of the University of Rochester. Drs. Balmes and Frampton used similar ozone exposure regimens but different study populations: normal and asthmatic men and women exposed to 0.2 ppm ozone or clean air for four hours in the Balmes study, and male and female nonsmokers and smokers exposed to 0.22 ppm ozone or clean air for four hours in the Frampton study. In both studies subjects performed moderate exercise during the exposures. The investigators made a number of pulmonary function measurements and used a procedure called bronchoscopy to collect fluids and tissue samples from the subjects' airways. They analyzed these samples for indicators of inflammation and lung damage.

Balmes separated subjects into two categories on the basis of how much their FEV1 response decreased after exposure to ozone: those least sensitive (smallest decrease) or most sensitive (greatest decrease) to ozone. The investigators addressed three issues: (1) Is an individual's reactivity to inhaled methacholine predictive of how his or her lung function would change after exposure to ozone? (2) What is the relation between ozone-induced airway inflammation (measured 18 hours after exposure) and changes in lung function (measured during and immediately after exposure)? and (3) Do the changes in lung function and markers of inflammation in response to ozone exposure differ between normal people and people with asthma?

Dr. Frampton's overall objectives were similar to those of the Balmes study, except that Dr. Frampton studied smokers as a potentially susceptible population. Because he was able to identify only a few smokers as sensitive to ozone (on the basis of their FEV1 responses), all smokers were grouped together for further study. Dr. Frampton measured pulmonary function and markers of inflammation immediately after air or ozone exposure and 18 hours later, thus allowing examination of the time course of these two responses in the same subject. The two investigator groups collaborated to compare the levels of three markers of airway inflammation among the normal, asthmatic, and smoker groups.

RESULTS AND IMPLICATIONS

These studies produced both confirmatory and new information about the responses of normal and potentially susceptible people to environmentally relevant concentrations of ozone. Both investigators confirmed findings from other laboratories. Namely, that exposure to ozone at levels that occur in ambient settings results in reversible changes in FEV1. Also, many people develop an inflammatory response in their airways (as determined by the appearance of markers of inflammation and cell injury in their lung fluids) after being exposed to ozone. Furthermore, they found no correlation among ozone-induced respiratory symptoms, changes in pulmonary function (as measured by FEV1), and markers of airway inflammation.

Both Balmes and Frampton found that a subject's airway responsiveness to methacholine did not correlate with the reduction in FEV1 observed after ozone exposure. Moreover, normal subjects who were characterized as being most sensitive or least sensitive to ozone (by measurements of FEV1) did not differ in their ozone-induced inflammatory responses. This implies that even if pulmonary function does not change, other potentially harmful effects of ozone, such as airway inflammation, may occur. Balmes found that breathing ozone caused similar changes in FEV1 in normal and asthmatic subjects. However, 18 hours after exposure to 0.02 ppm ozone for four hours, the levels of some markers of inflammation in lung fluids from asthmatic subjects were higher than the levels observed in normal subjects. Although this suggests that when people with asthma are exposed to ozone, they may develop more intense respiratory tract inflammation than healthy people, further studies are needed at multiple time points after exposure.

Dr. Frampton and colleagues found that although smokers have a greater degree of underlying airway inflammation than nonsmokers, they actually had smaller ozone-induced decrements in FEV1 than nonsmokers. The magnitude of the inflammatory response to ozone was similar in smokers and nonsmokers. It was also the same in subjects characterized as most sensitive and least sensitive to ozone on the basis of their FEV1 responses. The investigators found that some compounds (called cytokines) that are known to be important mediators of inflammation were present immediately after exposure to ozone. However, the overall inflammatory response was greater 18 hours after ozone exposure (when lung function had returned toward normal levels) than immediately after exposure.

An unexpected finding of the collaborative study was that the effects of the bronchoscopic procedures used to obtain the airway fluids and biopsy specimens may persist for many weeks in some subjects. This has critical implications for studies involving repeated invasive procedures.

The results of the studies reported here suggest that measuring symptoms and pulmonary function (using standard measurements of air flow) may not be sufficient to evaluate the potential risks associated with ozone exposure. Many individuals experience airway inflammation after being exposed to ozone, and this response is not reflected in the FEV1 response. The significance of ozone-induced inflammation in terms of subsequent airway disease has not been determined. More attention needs to be directed toward assessing the effects of ozone on small airway function and toward developing noninvasive measurements of airway inflammation.

CODE:BALMES/FRAMPTON 78

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