Final Report: Studies of Changes in Lung Structure and Enzyme Activitiesin Rats After Prolonged Exposure to Ozone

EPA Grant Number: R828112C065VIII - IX
Subproject: this is subproject number 065VIII - IX , 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: Studies of Changes in Lung Structure and Enzyme Activitiesin Rats After Prolonged Exposure to Ozone
Investigators:
Institution: Duke University Medical Center , University of California - Davis
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 , Health Effects

Objective:

Ozone is a major pollutant in smog. It is formed by complex photochemical reactions between nitrogen oxides and volatile organic compounds in the presence of sunlight. Motor vehicle and industrial emissions are prominent sources of these compounds. Peak atmospheric ozone concentrations generally occur during the summer months because the photochemical reactions that produce ozone are enhanced by sunlight and high temperature. The standard currently set by the U.S. Environmental Protection Agency for ozone exposure is 0.12 parts per million (ppm), a level that is not to be exceeded for more than one hour once a year.

Exposure to ozone as part of photochemical smog is known to have acute health effects in humans. There is also concern that prolonged exposure may lead to chronic lung damage. The National Toxicology Program (NTP) conducted a series of tests to evaluate ozone's carcinogenicity in rats and mice after prolonged exposure to this pollutant. The NTP study presented a unique opportunity to study ozone's noncancerous effects as well; therefore, the NTP and the HEI entered into a collaboration. The studies discussed in this Commentary, which were two of eight studies and a biostatistical analysis in the NTP/HEI Collaborative Ozone Project, were conducted to determine whether prolonged inhalation of ozone produces lasting effects on lung structure, potentially contributing to or aggravating chronic lung disease.

Summary/Accomplishments (Outputs/Outcomes):

Healthy male and female F344/N rats were exposed to either 0.12, 0.5, or 1.0 ppm ozone for six hours/day, five days/week, for 20 months; control animals breathed filtered air. In two independent studies, Drs. Chang and Pinkerton and their colleagues investigated the effects of this prolonged ozone exposure on respiratory tract structure. They used light and electron microscopy to measure site-specific changes in cell and tissue characteristics. The Pinkerton group also studied the activity levels of antioxidant enzymes, which protect tissues against the potentially harmful effects of oxidants such as ozone. The investigators' goals were to characterize the nature and magnitude of the alterations in the tissue and cellular structure in the respiratory tract and the changes in enzyme activities.

The investigators focused most of their analyses on the regions of the lung that are known to be targets for damage induced by ozone. Dr. Chang and colleagues found that in rats exposed to 0.5 or 1.0 ppm ozone, cellular reorganization occurred in the smallest airways of the lungs, known as bronchioles and alveolar ducts, when compared with control animals. All changes observed were localized to the centriacinar region, which is the anatomical site that is the junction of the conducting airways and the gas-exchange region of the lung. In a process known as bronchiolarization, the thinner cells normally lining these regions were replaced by thicker cells that are more characteristic of the small bronchioles. Thickening of the interstitium, which is the supporting tissue for cells, also was seen in the alveolar ducts of rats exposed to 0.5 or 1.0 ppm ozone. These changes were specific to the centriacinar region and were not seen in randomly chosen sections from other regions of the lung. In this study, no structural effects were observed in rats exposed to 0.12 ppm ozone.

Dr. Pinkerton and colleagues did not find any cellular reorganization in the trachea and bronchi (the larger airways of the lung), but did report some changes in the amount of mucus and an increase in the activities of antioxidant enzymes. In agreement with Dr. Chang's findings, Dr. Pinkerton and colleagues observed cellular reorganization and bronchiolarization in the centriacinar region of the lungs of rats exposed to 0.5 or 1.0 ppm ozone. Dr. Pinkerton also reported increases in some indices of bronchiolarization at the exposure level of 0.12 ppm ozone. However, these latter results may not be statistically significant. Also, both the cellular reorganization and the bronchiolarization varied by region, depended on gender, and had weak statistical support. Thus, the question of whether prolonged exposure to 0.12 ppm ozone affects the structure of rat lungs requires further study.

Overall, the results of these studies confirm earlier reports that cellular reorganization occurs in specific regions of the small airways of rats exposed to concentrations of ozone equal to or greater than 0.5 ppm. The cellular reorganization observed in these two studies was confined to the centriacinar region of the lungs and consisted of cells that are sensitive to ozone being replaced by types of cells that are more resistant. The protective response of the lung is also illustrated by the fact that antioxidant enzyme activities increased in response to ozone exposure in these small airways. There were no signs of airway inflammation in rats exposed to ozone in either study. Because the structural changes observed in these studies, even at the highest ozone exposure concentrations, were relatively mild and did not cause changes in lung function, the implications of these studies for human health must be evaluated with caution.

Supplemental Keywords:

Air, ambient air quality, air toxics, epidemiology, health effects, particulate matter, human health risk assessment, mobile sources, ozone, inhalation studies, animal models, disease, cumulative effects., RFA, Health, Scientific Discipline, Air, particulate matter, Toxicology, air toxics, Environmental Chemistry, Health Risk Assessment, Risk Assessments, mobile sources, Disease & Cumulative Effects, Biochemistry, ambient air quality, lung injury, particulates, motor vehicles, carbohydrate content of lungs, air pollutants, human health effects, inhalability, lung, lung disease, exposure and effects, airway disease, ambient air, engines, ozone, animal model, chronic ozone inhalation, air pollution, automobiles, emissions, environmental health effects, human exposure, inhalation, lung inflammation, particulate exposure, ambient particle health effects, inhaled, inhalation toxicology, effects of ozone in the lung, human health, lung content, human health risk

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 infection in 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