2003 Progress Report: Effects of Particle-Associated Irritants on the Cardiovascular System

EPA Grant Number: R827351C006
Subproject: this is subproject number 006 , established and managed by the Center Director under grant R827351
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: EPA NYU PM Center: Health Risks of PM Components
Center Director: N/A
Title: Effects of Particle-Associated Irritants on the Cardiovascular System
Investigators: Nadziejko, Christine
Institution: New York University School of Medicine
EPA Project Officer: Chung, Serena
Project Period: June 1, 1999 through May 31, 2005 (Extended to May 31, 2006)
Project Period Covered by this Report: June 1, 2002 through May 31, 2003
RFA: Airborne Particulate Matter (PM) Centers (1999) RFA Text |  Recipients Lists
Research Category: Air Quality and Air Toxics , Particulate Matter , Air

Objective:

The effect of particulate matter (PM) on the cardiovascular system is an increasingly important public health issue. However, the physical and/or chemical properties of PM responsible for these serious health effects currently are unknown. Any hypothesis about a mechanism of cardiovascular effects rests on some assumptions that certain types of PM constituents are culprits.

This research project has focused on particle-associated irritants based in part on the time course of effects reported in recent epidemiological studies. There is consistent evidence from times-series studies that the lag time between elevated levels of PM2.5 and increases in cardiovascular-related hospital admissions and death is very short (i.e. one day or less). There is one well-studied physiological mechanism that is consistent with rapid effects of PM on both cardiovascular and pulmonary function, namely stimulation of irritant receptors in the respiratory tract. Irritant receptor activation involves a bimolecular reaction between a protein receptor in the lung and an agonist, which triggers a rapid increase in intracellular calcium (Ca++) leading to activation of nerve fibers that send impulses to the central nervous system. Signals from the central nervous system then cause slowing of respiration and changes in blood pressure and heart rate via neural reflex pathways. The stereotypical response to an inhaled irritant is an immediate change in respiratory rate and heart rate, which returns to normal soon after exposure stops.

This is one of the projects funded by the New York University (NYU) PM Center. The progress for the other projects is reported separately (see reports for R827351C001 through R827351C005, and R827351C007 through R827351C016).

Progress Summary:

Progress Years 1-4

Over the course of the first 3 years of this project, we did more than 50 experiments exposing rats to concentrated ambient PM (CAPS), irritant aerosols, PM surrogates, and even some irritant gases. Every experiment involved monitoring of cardiovascular functional data in air-exposed and pollutant-exposed rat models of human disease before exposure, during exposure, and for 48-72 hours after exposure. We did extensive exploratory data analysis while experiments were being performed and solved a number of issues related to the quantification of telemetric data. However, it was apparent that there was no suitable statistical method for determining whether there was a significant difference between the treated and control groups because the onset and duration of the effects were unknown. In the fourth year, Dr. Nadziejko collaborated with Dr. Jing-Shiang Hwang, a visiting scientist (and statistician) in the PM Center, and Dr. Arthur Nádas, a mathematical statistician in the Department of Environmental Medicine. This collaboration resulted in a simple but powerful method of analyzing repeated measures data when the time course of the effect is not known a priori. This method, which is called the Fishing License method, was used to analyze all of the telemetry data from the last few years.

In addition to the studies examining cardiovascular physiological responses, we also found that rats exposed to CAPs had a significant increase in the frequency of supraventricular arrhythmias. Epidemiology studies suggest that exposure to air pollution increases the frequency of cardiac arrhythmias. A limitation of these studies is that it is difficult to link an increased risk of arrhythmias to a specific air pollutant. Animal exposure studies offer the opportunity to examine the effects of concentrated ambient fine PM, ultrafine PM, and copollutant gases separately. Male Fischer 344 rats, aged 18 months, with implanted ECG transmitters were used to determine the effects of PM on the frequency of arrhythmias. We found that old F 344 rats had many spontaneous arrhythmias. An arrhythmia classification system was developed to quantify arrhythmia frequency. Arrhythmias were broadly grouped into two categories, premature beats and delayed beats. The rats were exposed to CAPS or air for 4 hours. The rats were exposed twice with a crossover design so each rat could serve as its own control. The CAPS concentrations were 160 µg/m3 and 200 µg/m3 for the first and second exposures, respectively. There was a significant increase in the frequency of irregular and delayed beats after exposure to CAPS. The same rats were subsequently exposed to laboratory-generated ultrafine carbon particles, to SO2, or to air with a repeated-crossover design. In these experiments, there was no significant change in the frequency of any category of spontaneous arrhythmia following exposure to ultrafine carbon or SO2. Thus, this series of experiments adds supporting evidence that ambient PM increases the frequency of cardiac arrhythmias.

Progress Year 5

During the past year, we have started studies to examine the role of the vanillinoid receptor (also known as the capsaicin receptor, irritant receptor, or TRPV1 receptor) in the acute response to inhaled irritant particulates. This project is funded in part by the Health Effects Institute (in collaboration with Dr. Barbara Turpin, Rutgers University) and is closely related to the goals of this PM Center project. Using TRPV1 knock out mice and normal C57BL/6 control mice, we found that the characteristic acute change in breathing pattern caused by inhaling an irritant aerosol is abolished in TRPV1 knock out mice. Thus, the well-studied respiratory irritant reflex response can now be linked to a specific receptor that is located in the respiratory tract. As part of this PM Center project, we are using a sensitive immunohistochemical method and the newly available antibody against rodent TRPV1 receptors to determine where these receptors are located in the respiratory tract.


Journal Articles on this Report : 5 Displayed | Download in RIS Format

Other subproject views: All 5 publications 5 publications in selected types All 5 journal articles
Other center views: All 111 publications 100 publications in selected types All 88 journal articles
Type Citation Sub Project Document Sources
Journal Article Nadziejko C, Fang K, Nadziejko E, Narciso SP, Zhong M, Chen LC. Immediate effects of particulate air pollutants on heart rate and respiratory rate in hypertensive rats. Cardiovascular Toxicology 2002;2(4):245-252. R827351 (2003)
R827351 (Final)
R827351C005 (2001)
R827351C005 (2002)
R827351C005 (Final)
R827351C006 (2003)
R827351C006 (Final)
  • Abstract from PubMed
  • Abstract: SpringerLink-Abstract
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  • Journal Article Nadziejko C, Fang K, Chen LC, Gordon T, Nadas A. Quantitative analysis of cardiac data from rats monitored by telemetry: reducing within-and between-animal variability. Cardiovascular Toxicology 2002;2(4):237-244. R827351 (2003)
    R827351 (Final)
    R827351C005 (2002)
    R827351C005 (Final)
    R827351C006 (2003)
    R827351C006 (Final)
  • Abstract from PubMed
  • Abstract: SpringerLink-Abstract
    Exit
  • Journal Article Nadziejko C, Fang K, Narciso S, Zhong M, Su WC, Gordon T, Nadas A, Chen LC. Effect of particulate and gaseous pollutants on spontaneous arrhythmias in aged rats. Inhalation Toxicology 2004;16(6-7):373-380. R827351 (2003)
    R827351 (Final)
    R827351C005 (Final)
    R827351C006 (2003)
    R827351C006 (Final)
  • Abstract from PubMed
  • Abstract: Taylor and Francis-Abstract
    Exit
  • Journal Article Nadziejko C, Chen LC, Nadas A, Hwang JS. The 'Fishing License' method for analysing the time course of effects in repeated measurements. Statistics in Medicine 2004;23(9):1399-1411. R827351 (2003)
    R827351 (Final)
    R827351C005 (Final)
    R827351C006 (2003)
    R827351C006 (Final)
  • Abstract from PubMed
  • Abstract: Wiley Online - Abstract
    Exit
  • Journal Article Narciso SP, Nadziejko E, Chen LC, Gordon T, Nadziejko C. Adaptation to stress induced by restraining rats and mice in nose-only inhalation holders. Inhalation Toxicology 2003;15(11):1133-1143. R827351 (2001)
    R827351 (Final)
    R827351C005 (2002)
    R827351C005 (Final)
    R827351C006 (2003)
    R827351C006 (Final)
  • Abstract from PubMed
  • Abstract: Taylor and Francis-Abstract
    Exit
  • Supplemental Keywords:

    thoracic particles, PM10, fine particles, PM2.5, ultrafine particles, PM0.1, lung dosimetry models, human exposure models, pulmonary responses, cardiovascular responses, immunological responses, criteria air pollutants, concentrated ambient aerosols, aerosol, air pollutants, air pollution, airborne pollutants, airway disease, airway inflammation, airway variability, allergen, ambient air, ambient air quality, analytical chemistry, assessment of exposure, asthma, asthma morbidity, atmospheric monitoring, biological markers, childhood respiratory disease, children, combustion, combustion contaminants, combustion emissions, compliance monitoring, dosimetry, epidemiology, exposure, exposure and effects, health effects, heart rate variability, human exposure, human health, human health effects, incineration, lead, lung, mercury, morbidity, particulates, pulmonary, pulmonary disease, respiratory,, RFA, Health, PHYSICAL ASPECTS, Scientific Discipline, Air, ENVIRONMENTAL MANAGEMENT, particulate matter, Environmental Chemistry, Health Risk Assessment, air toxics, Risk Assessments, Physical Processes, Environmental Monitoring, Atmospheric Sciences, Risk Assessment, ambient air quality, atmospheric particulate matter, particulates, atmospheric particles, chemical characteristics, toxicology, ambient air monitoring, acute cardiovascular effects, airborne particulate matter, environmental risks, exposure, epidemelogy, Sulfur dioxide, air pollution, aerosol composition, atmospheric aerosol particles, human exposure, PM, exposure assessment

    Relevant Websites:

    http://www.med.nyu.edu/environmental/centers/epa/ Exit

    Progress and Final Reports:

    Original Abstract
  • 1999
  • 2000 Progress Report
  • 2001
  • 2002
  • 2004
  • Final Report

  • Main Center Abstract and Reports:

    R827351    EPA NYU PM Center: Health Risks of PM Components

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R827351C001 Exposure Characterization Error
    R827351C002 X-ray CT-based Assessment of Variations in Human Airway Geometry: Implications for Evaluation of Particle Deposition and Dose to Different Populations
    R827351C003 Asthma Susceptibility to PM2.5
    R827351C004 Health Effects of Ambient Air PM in Controlled Human Exposures
    R827351C005 Physicochemical Parameters of Combustion Generated Atmospheres as Determinants of PM Toxicity
    R827351C006 Effects of Particle-Associated Irritants on the Cardiovascular System
    R827351C007 Role of PM-Associated Transition Metals in Exacerbating Infectious Pneumoniae in Exposed Rats
    R827351C008 Immunomodulation by PM: Role of Metal Composition and Pulmonary Phagocyte Iron Status
    R827351C009 Health Risks of Particulate Matter Components: Center Service Core
    R827351C010 Lung Hypoxia as Potential Mechanisms for PM-Induced Health Effects
    R827351C011 Urban PM2.5 Surface Chemistry and Interactions with Bronchoalveolar Lavage Fluid (BALF)
    R827351C012 Subchronic PM2.5 Exposure Study at the NYU PM Center
    R827351C013 Long Term Health Effects of Concentrated Ambient PM2.5
    R827351C014 PM Components and NYC Respiratory and Cardiovascular Morbidity
    R827351C015 Development of a Real-Time Monitoring System for Acidity and Soluble Components in Airborne Particulate Matter
    R827351C016 Automated Real-Time Ambient Fine PM Monitoring System