Final Report: Acute Pulmonary Effects of Ultrafine Particles in Rats and MiceEPA Grant Number: R828112C096
Subproject: this is subproject number 096 , 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: Acute Pulmonary Effects of Ultrafine Particles in Rats and Mice
Investigators: Oberdörster, Günter
Institution: 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: Health Effects , Air
Objective:Many epidemiologic studies, carried out in diverse locations with varying levels and composition of ambient particulate matter and other air pollutants, have reported associations between small increases in the level of particulate matter and increases in daily morbidity and mortality. The strongest associations appear to be in the elderly and in individuals with cardiopulmonary conditions such as chronic obstructive pulmonary disease (COPD). However, a biological mechanism linking low-level particle exposure and pathophysiologic effects has not been established. Assessing the effects of inhaled particulate matter in appropriate animal models is critical to learning how such pollutants may exert adverse health effects.
Ambient particulate matter varies in size and chemical composition. Some scientists have hypothesized that very small particles (less than 100 nm in diameter) are particularly toxic. Although they constitute only about 1% to 8% of the mass of particulate matter in ambient air, these ultrafine particles are present in very high numbers, have greater total surface area than larger particles, and may deposit in greater numbers in the lungs. The Health Effects Institute funded the animal study described in this report to address whether and how ultrafine particles might exert effects in the airways.
Summary/Accomplishments (Outputs/Outcomes):Dr Gunter Oberdorster, from the University of Rochester School of Medicine and Dentistry, and his colleagues hypothesized that inhaled ultrafine particles induce an inflammatory response in the airways of mice and rats and that animals with preexisting airway inflammatory conditions may be particularly vulnerable. The investigators focused on inhaled carbon and platinum particles because these elements are constituents of particles found in urban atmospheres. They also evaluated the effects of Teflon fumes containing ultrafine Teflon particles, which are not representative of ambient particles but have been shown to induce a potent inflammatory response leading to severe physiologic effects in rats. They exposed animals to 100 mg/m 3 carbon and platinum particles for 6 hours and to 40 mg/m 3 Teflon particles for 15 minutes. These concentrations are much higher than those of ultrafine particles in ambient air. The investigators also evaluated the effects of intratracheal instillation of ultrafine titanium dioxide particles and, in separate experiments, the effects of coexposure to ultrafine carbon particles and ozone, a gaseous environmental pollutant that can induce inflammation.
The investigators tested small numbers of young and old mice and rats that were healthy or had pulmonary conditions. They used mice injected with elastase to model humans with emphysema; old Tsk mice, a strain with a genetic defect in lung development, to model the effects of chronic emphysema and age; and mice and rats pretreated with the bacterial product endotoxin to model humans who have a bacterial airway infection. Pulmonary inflammation was evaluated by measurement of cellular and biochemical parameters in bronchoalveolar lavage fluid, focusing on increases in the percentage of neutrophils and production of reactive oxygen species, which appeared to be the most sensitive indicators of a response. Measurements of cytokine and chemokine messenger RNA levels in tissue extracts as well as histologic assessments were performed.
Inhalation of ultrafine carbon or platinum particles, or Teflon particles in the absence of Teflon-generated gaseous components, did not induce an inflammatory response in either young or old healthy mice and rats. Ultrafine particle exposures had limited effects in some of the animal models of pulmonary dysfunction tested and no effect in others. For example, ultrafine carbon and platinum particles induced small inflammatory responses in both young and old elastase-treated mice, but ultrafine carbon particles had no effect in the old Tsk mice used to model chronic emphysema, either with or without endotoxin pretreatment. In rats preexposed to endotoxin, ultrafine carbon particles induced a small inflammatory response over background airway inflammation in young but not old animals. By contrast, a complex statistical analysis of their results led the investigators to conclude that older age and a compromised or sensitized respiratory tract increased sensitivity to ultrafine particle effects in mice and rats. These conclusions are overstated, however, given that the responses to ultrafine particles were small and occurred only in some animal models and certain end points.
Instilling ultrafine titanium dioxide particles directly into the trachea of mice, a technique that bypasses the nasal filtering mechanisms and delivers a much higher concentration to the lungs than inhalation, induced a strong inflammatory response. Inhalation of ultrafine Teflon fumes in rats also induced a strong inflammatory response, but only if the fumes contained both ultrafine Teflon particles and gaseous components. Coexposure to ultrafine carbon particles and ozone induced responses that appeared to be additive, less than additive, or more than additive compared with responses to the separate components, depending on the model and end point tested. These results suggest that ultrafine particles may induce inflammatory responses in the airways in some circumstances: for example, when high doses are deposited in the lower respiratory tract by intratracheal instillation or when the particles are combined with potentially toxic gases.
In conclusion, the investigators conducted an interesting study in healthy mice and rats and in mice and rats with preexisting airway conditions to address the important issue of whether ultrafine particles induce an inflammatory response in the airways. The findings provide little evidence that inhaled ultrafine particles cause inflammation, however. This may be due to limitations in the study?s design, which include small numbers of animals and experiments, uncertainties about the susceptibility of the animal models used to the effects of ultrafine particles, and the relative toxicity of the particles studied compared to particles of different chemical composition. These uncertainties make it difficult to extrapolate the results of this study to possible effects of ultrafine particles on humans. Additional research in humans and in a variety of animal models evaluating multiple endpoints and particles is required to evaluate further whether ultrafine particles induce inflammatory or other adverse health effects.
Supplemental Keywords:Air, ambient air quality, air toxics, epidemiology, health effects, particulate matter, biochemistry, motor vehicle emissions, diesel exhaust, animal models, mobile sources, disease., RFA, Scientific Discipline, Health, Air, Toxicology, particulate matter, air toxics, Environmental Chemistry, Health Risk Assessment, Risk Assessments, mobile sources, ambient air quality, lung injury, particulates, motor vehicles, exposure and effects, carbon, human health effects, inhalability, air pollutants, lung, carbon balck, animal model, engines, diesel exhaust, carbon black, air pollution, environmental health effects, lung cancer, automobiles, emissions, human exposure, ambient particle health effects, inhalation, particulate exposure, lung inflammation, inhaled, PM, human health, ultrafine particles, platinum
Progress and Final Reports:Original Abstract
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 FormaldehydeDNA 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