Grantee Research Project Results

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

EPA Grant Number: R828112C078
Subproject: this is subproject number 078 , established and managed by the Center Director under grant R828112
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Health Effects Institute (2000 — 2005)
Center Director: Greenbaum, Daniel S.
Title: Effects of Ozone on Pulmonary Function and Airway Inflammation in Normal and Potentially Sensitive Human Subjects
Investigators: Balmes, John R. , Tager, Ira , Whitin, John C. , Ferrando, Ronald E , Finkbeiner, Walter E , Morrow, P. E. , Utell, Mark J. , Chen, Lisa L. , Speers, Donna M. , Krein, Peter M. , Aris, Robert M. , Hearne, Patrick Q. , Frampton, Mark W. , Voter, Karen Z. , Torres, Alfonso , Welch, Barbara , Cox, Christopher , Scannell, Cornelius , Christian, Dorothy , Kelly, Thomas , Tsai, Ying
Institution: University of California - San Francisco , University of Rochester School of Medicine and Dentistry , University of California - Berkeley
Current Institution: University of California - San Francisco , University of California - Berkeley , University of Rochester School of Medicine and Dentistry
EPA Project Officer: Chung, Serena
Project Period: April 1, 2000 through March 31, 2005
RFA: Health Effects Institute (1996) RFA Text |  Recipients Lists
Research Category: Air , Human Health

Objective:

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.

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.

Summary/Accomplishments (Outputs/Outcomes):

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.

Supplemental Keywords:

Air, ambient air quality, air toxics, epidemiology, health effects, particulate matter, ozone, inhalation studies, human exposure, disease, biochemistry, susceptibility., RFA, Health, Scientific Discipline, Air, particulate matter, air toxics, Environmental Chemistry, Health Risk Assessment, Epidemiology, Risk Assessments, Susceptibility/Sensitive Population/Genetic Susceptibility, mobile sources, Biochemistry, indoor air, genetic susceptability, ambient air quality, particulates, lung injury, motor vehicles, sensitive populations, exposure and effects, human health effects, inhalability, air pollutants, lung, pulmonary function, engines, epithelial cells, ozone, animal model, epidemelogy, ambient air, airway disease, exposure, air pollution, environmental health effects, automobiles, emissions, human exposure, inhalation, carcinogens, ambient particle health effects, particulate exposure, lung inflammation, sensitive subjects, inhalation toxicology, ozone monitoring, inhaled, environmentally caused disease, indoor air quality, human health, human health risk, air quality, sensitive human subjects

Progress and Final Reports:

Original Abstract

2000

2001

2002

2003

Main Center Abstract and Reports:

R828112    Health Effects Institute (2000 — 2005)

Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R828112C042 Does Inhalation of Methanol Vapor Affect Human Neurobehavior?
R828112C043 Human Responses to Nitrogen Dioxide
R828112C044 The Role of Inflammation in Ozone-Induced Lung Injury
R828112C045 How Does Exercise Affect the Dose of Inhaled Air Pollutants?
R828112C046 How Do Chemicals in Diesel Engine Exhaust Damage DNA?
R828112C047 Effect of Nitrogen Dioxide on Bacterial Respiratory infectionin Mice
R828112C048 Effects of Ozone Exposure on Airway Epithelium
R828112C049 Inhalation of Aldehydes and Effects on Breathing
R828112C050 Does Ozone Cause Precancerous Changes in Cells?
R828112C051 Effects of Formaldehyde on Human Airway Epithelial Cells Exposed in a Novel Culture System
R828112C052 Carbon Monoxide and Cardiac Arrhythmias
R828112C053 Effects of Formaldehyde and Particle-Bound Formaldehyde on Lung Macrophage Functions
R828112C054 Mechanisms for Protecting Lung Epithelial Cells Against Oxidant Injury
R828112C055 Relationship of Nitropyrene-Derived DNA Adducts to Carcinogenesis
R828112C056 Particle Trap Effects on Heavy-Duty Diesel Engine Emissions
R828112C057 Carbon Monoxide and Atherosclerosis
R828112C058 Nitrogen Dioxide and Respiratory Illness in Children
R828112C059 Noninvasive Methods for Measuring Ventilation in Mobile Subjects
R828112C060 Oxidant Air Pollutants and Lung Cancer: An Animal Model
R828112C061 Detection of Carcinogen-DNA Adducts: Development of New Methods
R828112C062 Effects of Carbon Monoxide on Heart Muscle Cells
R828112C063 Development of Personal Ozone Samplers: Three Approaches
R828112C064 Development of Biomarkers to Monitor Carcinogen Exposure
R828112C065 Effects of Prolonged Ozone Inhalation on Collagen Structure and Content in Rat Lungs
R828112C065II Prolonged Ozone Exposure and the Contractile Properties of Isolated Rat Airways
R828112C065III Changes in Complex Carbohydrate Content and Structure in Rat Lungs Caused by Prolonged Ozone Inhalation
R828112C065IV Genetic Control of Connective Tissue Protein Synthesis After Prolonged Ozone Inhalation
R828112C065V Pulmonary Function Alterations in Rats After Chronic Ozone Inhalation
R828112C065VII Prolonged Ozone Exposure Leads to Functional and Structural Changes in the Rat Nose
R828112C065VIII - IX Studies of Changes in Lung Structure and Enzyme Activitiesin Rats After Prolonged Exposure to Ozone
R828112C065X An Innovative Approach to Analyzing Multiple Experimental Outcomes: A Case Study of Rats Exposed to Ozone
R828112C065XI The Consequences of Prolonged Inhalation of Ozone on Rats: An Integrative Summary of the Results of Eight Collaborative Studies
R828112C066 Interactive Effects of Nitropyrenes in Diesel Exhaust
R828112C067 Detection of Formaldehyde–DNA Adducts: Development of New Methods
R828112C068I Comparison of the Carcinogenicity of Diesel Exhaust and Carbon Black in Rat Lungs
R828112C068II An Investigation of DNA Damage in the Lungs of Rats Exposed to Diesel Exhaust
R828112C068III No Evidence For Genetic Mutations Found In Lung Tumors From Rats Exposed To Diesel Exhaust or Carbon Black
R828112C069 Noninvasive Determination of Respiratory Ozone Absorption: The Bolus-Response Method
R828112C070 The Effects of Inhaled Oxidants and Acid Aerosols on Pulmonary Function
R828112C071 Biochemical Consequences of Ozone Reacting with Membrane Fatty Acids
R828112C072 DNA Mutations in Rats Treated with a Carcinogen Present in Diesel Exhaust
R828112C073 Developmental Neurotoxicity of Inhaled Methanol in Rats
R828112C074 Methanol Distribution in Non Pregnant and Pregnant Rodents
R828112C075 Is Increased Mortality Associated with Ozone Exposure in Mexico City?
R828112C076 Effects of Fuel Modification and Emission Control Devices on Heavy-Duty Diesel Engine Emissions
R828112C077 Metabolic Studies in Monkeys Exposed to Methanol Vapors
R828112C078 Effects of Ozone on Pulmonary Function and Airway Inflammation in Normal and Potentially Sensitive Human Subjects
R828112C079 Improvement of a Respiratory Ozone Analyzer
R828112C080 Mechanism of Oxidative Stress from Low Levels of Carbon Monoxide
R828112C081 Long-Term Exposure to Ozone: Development of Methods to Estimate Past Exposures and Health Outcomes
R828112C082 Effects of Ambient Ozone on Healthy, Wheezy, and Asthmatic Children
R828112C083 Daily Changes in Oxygen Saturation and Pulse Rate Associated with Particulate Air Pollution and Barometric Pressure
R828112C084 Evaluation of The Potential Health Effects of the Atmospheric Reaction Products of Polycyclic Aromatic Hydrocarbons
R828112C085 Mechanisms of Response to Ozone Exposure: The Role of Mast Cells in Mice
R828112C086 Statistical Methods for Epidemiologic Studies of the Health Effects of Air Pollution
R828112C087 Development of New Methods to Measure Benzene Biomarkers
R828112C088 Alveolar Changes in Rat Lungs After Long-Term Exposure to Nitric Oxide
R828112C089 Effects of Prenatal Exposure to Inhaled Methanol on Nonhuman Primates and Their Infant Offspring
R828112C090 A Pilot Study of Potential Biomarkers of Ozone Exposure
R828112C091 Effects of Concentrated Ambient Particles on the Cardiac and Pulmonary Systems of Dogs
R828112C092 Cancer, Mutations, and Adducts in Rats and Mice Exposed to Butadiene and Its Metabolites
R828112C093 Effects of Concentrated Ambient Particles in Rats and Hamsters: An Exploratory Study
R828112C094I The National Morbidity, Mortality, and Air Pollution Study: Methods and Methodologic Issues
R828112C094II The National Morbidity, Mortality, and Air Pollution Study: Morbidity and Mortality from Air Pollution in the United States
R828112C095 Association of Particulate Matter Components with Daily Mortality and Morbidity in Urban Populations
R828112C096 Acute Pulmonary Effects of Ultrafine Particles in Rats and Mice
R828112C097 Identifying Subgroups of the General Population That May Be Susceptible to Short-Term Increases in Particulate Air Pollution
R828112C098 Daily Mortality and Fine and Ultrafine Particles in Erfurt, Germany
R828112C099 A Case-Crossover Analysis of Fine Particulate Matter Air Pollution and Out-of-Hospital Sudden Cardiac Arrest
R828112C100 Effects of Mexico City Air on Rat Nose
R828112C101 Penetration of Lung Lining and Clearance of Particles Containing Benzo[a]pyrene
R828112C102 Metabolism of Ether Oxygenates Added to Gasoline
R828112C103 Characterization and Mechanisms of Chromosomal Alterations Induced by Benzene in Mice and Humans
R828112C104 Acute Cardiovascular Effects in Rats from Exposure to Urban Ambient Particles
R828112C105 Genetic Differences in Induction of Acute Lung Injury and Inflammation in Mice
R828112C106 Effects on Mice of Exposure to Ozone and Ambient Particle Pollution
R828112C107 Emissions from Diesel and Gasoline Engines Measured in Highway Tunnels
R828112C108 Case-Cohort Study of Styrene Exposure and Ischemic Heart Disease Investigators
R828112C110 Effects of Metals Bound to Particulate Matter on Human Lung Epithelial Cells
R828112C111 Effect of Concentrated Ambient Particulate Matter on Blood Coagulation Parameters in Rats
R828112C112 Health Effects of Acute Exposure to Air Pollution
R828112C113 Benzene Metabolism in Rodents at Doses Relevant to Human Exposure from Urban Air
R828112C114 A Personal Particle Speciation Sampler
R828112C115 Validation and Evaluation of Biomarkers in Workers Exposed to Benzene in China
R828112C116 Biomarkers in Czech Workers Exposed to 1,3-Butadiene: A Transitional Epidemiologic Study
R828112C117 Peroxides and Macrophages in the Toxicity of Fine Particulate Matter in Rats
R828112C118 Controlled Exposures of Healthy and Asthmatic Volunteers to Concentrated Ambient Particles in Metropolitan Los Angeles
R828112C119 Manganese Toxicokinetics at the Blood-Brain Barrier
R828112C120 Effects of Exposure to Concentrated Ambient Particles from Detroit Air on Healthy Rats and Rats with Features of Asthma or Mild Bronchitis
R828112C121 Field Evaluation of Nanofilm Detectors for Measuring Acidic Particles in Indoor and Outdoor Air
R828112C123 Time-Series Analysis of Air Pollution and Mortality: A Statistical Review
R828112C126 Effects of Exposure to Ultrafine Carbon Particles in Healthy Subjects and Subjects with Asthma
R828112C128 Neurogenic Responses of Rat Lung to Diesel Exhaust
R828112C130-I Relationships of Indoor, Outdoor, and Personal Air (RIOPA). Part I. Collection Methods and Descriptive Analyses
R828112C132 An Updated Study of Mortality Among North American Synthetic Rubber Industry Workers