Final Report: Acute Cardiovascular Effects in Rats from Exposure to Urban Ambient Particles

EPA Grant Number: R828112C104
Subproject: this is subproject number 104 , 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 Cardiovascular Effects in Rats from Exposure to Urban Ambient Particles
Investigators: Vincent, Renaud
Institution: Safe Environments Programme
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


Particulate matter (PM) in ambient air is a complex mixture containing particles of different sizes and chemical composition. Short-term increases in ambient PM levels have been associated with shortterm increases in morbidity and mortality from cardiovascular causes. However, the biologic mechanism by which PM may affect cardiovascular events and the roles of particle size and composition are not well understood. One hypothesis is that particle deposition in the lung induces the release of factors that affect blood cells and vessels throughout the body. The Health Effects Institute funded the study described in this report to address this hypothesis and to elucidate how the chemical composition of the particles could change the effects of PM on the cardiovascular system.

Summary/Accomplishments (Outputs/Outcomes):

Dr Renaud Vincent and his colleagues of Health Canada, Ottawa, hypothesized that ambient PM would cause changes in certain cardiovascular parameters; for example, heart rate and blood pressure or the concentration of compounds that regulate the constriction and dilation of blood vessels. The investigators implanted rats with radiotransmitters (to collect continuous data on heart rate, blood pressure, and body temperature) and indwelling catheters for repeated blood sampling. The animals were exposed for 4 hours to clean air or one of four types of resuspended particles: ambient particles (Ottawa dust), ambient particles that had been washed in water to remove soluble components, diesel soot, or carbon black. The investigators used stored resuspended particles rather than fresh particles to ensure that particle concentration and chemical composition were identical among experiments. The investigators measured several endpoints in the rats? blood and plasma (endothelins, nitric oxide products, and catecholamines), changes in heart rate, blood pressure, and general activity, and injury to lung tissue.

The investigators found that exposure to urban PM, washed urban PM, and diesel soot (but not carbon black) caused an increase in endothelin-3 and to a lesser extent endothelin-1. This is important because endothelins help to regulate normal cardiovascular homeostasis between vasoconstriction and vasodilation. Elevation of endothelin-1 is an indicator of the severity of congestive heart failure in some patients and may predict cardiac death, whereas its decrease may herald an improvement in symptoms; elevation of endothelin-3 may be associated with systemic vasoconstriction in cardiac patients.

Urban PM also caused an increase in blood pressure; the effect disappeared when washed particles were used. The increase in blood pressure was not observed with diesel soot or carbon black. This indicates that one or more of the soluble components in the unwashed urban particles may be responsible for the blood pressure effects of urban PM. The investigators suggested that soluble metals may have been responsible for this adverse effect; among other candidates, zinc may be important because zinc-dependent enzymes are involved in the regulation of endothelins, which may then impact blood pressure. Whether this is indeed the case remains to be determined.

The increase in blood pressure after exposure to urban PM was small, however, and its significance is unclear because the stress caused in the animals by handling and surgery was substantial; this was reflected in the variability of the baseline physiologic parameters (ie, heart rate, blood pressure, and body temperature) and blood catecholamine measurements. The study could have benefitted from additional analyses of changes in electrocardiogram or in the daily rhythm variations in heart rate and blood pressure. Additional short-term and transient changes in these physiologic parameters at different time points after exposure to the particles, if present, would strengthen the argument that PM may have adverse effects on the cardiovascular system.

The investigators found no evidence of damage to lung epithelial cells from exposure to any of the particles by using an assay that measured lung cell proliferation several days after exposure. These findings confirm previous studies with the same urban particles in the same laboratory. In those studies, however, urban PM did increase other indices of lung injury, ie, levels of inflammatory markers in lung lavage fluid. It is possible that exposure to washed urban particles, diesel soot, or carbon black might also have affected those markers of lung inflammation.

The use of resuspended particles rather than fresh particles was a valid choice to ensure the stability of the administered concentration and the chemical composition of the particles among experiments. The relevance of the effects of resuspended particles to those observed with fresh particles is in question, however, because they likely underwent chemical and physical changes during storage. Due to aggregation, these particles are presumably larger than fresh particles and it is unclear whether larger particles penetrate the deep lung. Nevertheless, the finding that both resuspended ambient particles and diesel soot affected the same endothelins strengthens the confidence in these data.

Main strengths of this study were that the investigators compared several classes of particles and measured diverse endpoints. The finding that urban PM changed endothelin levels might be strengthened by future research using several PM concentrations and by reconstituting the urban PM from the washed PM, which would show whether or not adding the soluble components to the washed particles would restore the biologic effects.

In conclusion, the investigators found effects on endothelins after exposure to resuspended urban PM, washed particles, and diesel soot, and effects on blood pressure after exposure to urban PM. Although extrapolating results from animal studies to humans and from the high levels used in this study to ambient levels always involves uncertainties, these findings open interesting avenues to further explore the possible mechanisms by which inhaled PM may cause adverse cardiovascular events. More research is needed to assess whether changes in endothelin levels would occur in humans exposed to ambient levels of particulate matter, and whether these changes may contribute to the adverse cardiovascular events that have been associated with air pollution episodes in epidemiology studies.

Supplemental Keywords:

Air, ambient air quality, air toxics, epidemiology, health effects, particulate matter, biochemistry, motor vehicle emissions, diesel exhaust, animal model, Mortality, disease., RFA, Scientific Discipline, Health, Air, Toxicology, particulate matter, air toxics, Health Risk Assessment, Environmental Chemistry, Risk Assessments, mobile sources, Biochemistry, ambient air quality, lung injury, particulates, urban air quality, motor vehicles, exposure and effects, human health effects, inhalability, air pollutants, lung, acute cardiovascular effects, animal model, engines, urban ambient particles, diesel exhaust, air pollution, environmental health effects, automobiles, urban air pollutants, emissions, human exposure, ambient particle health effects, inhalation, particulate exposure, lung inflammation, acute cardiovascualr effects, PM, coronary artery disease, inhalation toxicology, inhaled, urban air pollution, rats, Acute health effects, human health, urban environment, cardiovascular disease

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