2001 Progress Report: Differentiating the Roles of Particle Size, Particle Composition, and Gaseous Co-Pollutants on Cardiac IschemiaEPA Grant Number: R827353C008
Subproject: this is subproject number 008 , established and managed by the Center Director under grant R827353
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: EPA Harvard Center for Ambient Particle Health Effects
Center Director: Koutrakis, Petros
Title: Differentiating the Roles of Particle Size, Particle Composition, and Gaseous Co-Pollutants on Cardiac Ischemia
Investigators: Godleski, John J.
Current Investigators: Godleski, John J. , Gonzalez-Flecha, Beatriz , Wellenius, Gregory
Institution: Harvard University
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, 2001 through May 31, 2002
Project Amount: Refer to main center abstract for funding details.
RFA: Airborne Particulate Matter (PM) Centers (1999) RFA Text | Recipients Lists
Research Category: Air Quality and Air Toxics , Particulate Matter , Air
The objective of this research project is to investigate the effects of concomitant gaseous co-pollutants, particle size, and particle composition using a dog cardiac ischemia model and our particle concentrator technologies. To date a large number of animal exposure studies have been completed. These studies have been totally or partially funded by the Harvard Center for Ambient Particle Health Effects.
In a study recently accepted for publication (Wellenius, Coull, et al., in press), six mongrel dogs underwent thoracotomy for implantation of a vascular occluder around the left anterior descending coronary artery and tracheostomy to facilitate particulate exposure. After recovery (5 to13 weeks), pairs of subjects were exposed for 6 hours/day for 3 or 4 consecutive days. Within each pair, one subject was randomly assigned to breathe concentrated ambient particles (CAPs) on the second exposure day and filtered air otherwise. The second subject breathed CAPs on the third exposure day and filtered air otherwise. Aeorsolized CAPs were produced using the Harvard Ambient Particle Concentrator (HAPC). Immediately following each exposure, subjects underwent 5-minute coronary artery occlusion. Peak ST-segment elevation, heart rate, and arrhythmia incidence during occlusion were determined from continuous electrocardiogram (ECG) recordings. Exposure to CAPs (median: 285.7 µg/m3; range: 161.3 to 957.3 µg/m3) significantly (p < 0.01) enhanced occlusion-induced peak ST-segment elevation in lead V4 (9.4 ± 1.7 versus 6.2 ± 0.9 mm, CAPs versus filtered air, respectively) and lead V5 (9.2 ± 1.3 versus 7.5 ± 0.9 mm). We also observed enhancement of the ST-segment elevation on the day after CAPs exposure, indicating that, although transient, the effects of CAPs exposure persisted for at least 24 hours. ST-segment elevation was significantly correlated with the silicon (Si) concentration of the particles and other crustal elements possibly associated with urban street dust (p < 0.003 for Si). No associations were found with CAPs mass or number concentrations. Heart rate was not affected by CAPs exposure. These results suggest that exacerbation of myocardial ischemia during coronary artery occlusion may be an important mechanism of environmentally related acute cardiac events.
In the same group of dogs, we explored the hypothesis that inflammatory responses of the lung result in hematologic changes that influence the systemic coagulation status and cardiac microvasculature (Savage, Lawrence, et al., submitted 2002). In these studies, venipuncture was performed immediately post-occlusion for complete blood count and C-reactive protein assay. Acute decreases in platelet counts were observed on the day of exposure. Significant decreases in red cell count, hematocrit, and hemoglobin were associated with CAPs exposure, and continued for 24 hours post exposure. Increases in CRP were significantly associated with CAPs exposure, and this also continued for 24 hours post exposure. There were no aberrations in white blood cell parameters with CAPs exposures (mean 342.5 ± 194.0 µg/m3). Decreases in red cell count, hematocrit, and hemoglobin were associated with CAPs exposure, and continued for 24 hours post exposure. Increases in CRP were significantly associated with CAPs exposure, and this also continued for 24 hours post exposure. Univariate regression analysis substantiated these findings, and specifically revealed associations with tracer elements and particle mass and numbers. Platelets decreased with sulfur. Hemoglobin decreased with all tested parameters including particle mass, particle number, nickel, sulfur, black carbon, and silicon. Hematocrit followed a similar pattern, and decreased with particle mass, particle number, sulfur, and silicon. Red blood cell counts decreased with particle mass, particle number, sulfur, black carbon, and silicon. C-reactive protein was increased with particle number and nickel. Implications for these decreases in red blood cell parameters other than a localized or microvascular sequestration of red blood cells are not obvious, but have been observed in other studies.
In a recent paper by Saldiva, et al. (Saldiva, Clarke, et al., 2002) we addressed the following issues: (1) determine whether short term exposures to CAPs cause pulmonary inflammation in normal rats and rats with chronic bronchitis; (2) identify the site within the lung parenchyma where CAPs-induced inflammation occurs; and (3) characterize the component(s) of CAPs that are significantly associated with the development of the inflammatory reaction. Four groups of animals were studied: (1) air-treated, filtered air-exposed (air-sham); (2) SO2-treated (chronic bronchitis (CB)), filtered air exposed (CB-sham); (3) air-treated, CAPs-exposed (air-CAPs); and (4) SO2-treated, CAPs exposed (CB-CAPs). Sprague-Dawley male rats were exposed to CAPs, using the HAPC, or to particle-free air (sham) under identical conditions during 3 consecutive days (5 hours/day) in 6 experimental sets. CB was induced by exposure to 276 ± 9 ppm of SO2 (5 hours/day, 5 days/week, 6 weeks). Physicochemical characterization of CAPs included measurements of particle mass, size distribution, and composition. Rats were sacrificed at 24 hours after the last CAPs exposure. Pulmonary inflammation was assessed by bronchoalveolar lavage (BAL) and by measuring the numerical density of neutrophils (Nn) in the alveolar walls in the centri-acinar and in the peripheral segments of the pulmonary acinus. CAPs induced a significant increase in BAL neutrophils and in Nn in the lung tissue. Greater Nn was observed in the central compared to peripheral regions of the lung. A significant, dose-dependent association was found between V and Br concentrations and both BAL neutrophils and Nn. BAL neutrophils and protein were also correlated with Pb, SO42-, Si, organic carbon, and elemental carbon concentrations. Results demonstrate that short-term exposures to CAPs from Boston induce a significant inflammatory reaction in rat lungs, with this reaction dependent on particle composition.
In another study, using the same animals as in the study just described (Batalha, Saldiva, et al., in press) determined that short term exposures to CAPs altered the morphology of small pulmonary arteries in normal rats and rats with chronic bronchitis (CB). Histologic slides were prepared from random sections of lung lobes and coded for blinded analysis. The lumen/wall area ratio (L:W) was determined morphometrically on transverse sections of small pulmonary arteries. When all animal data (normal and CB) were analyzed together, the L:W ratios decreased as concentrations of fine particle mass, silicon, lead, sulfate, elemental carbon, and organic carbon increased. In separate univariate analyses of animal data, the association for sulfate was significant only in normal rats, whereas silicon was significantly associated in both CB and normal rats. In multivariate analyses including all particle factors, the association with silicon remained significant. Our results indicate that short-term CAPs exposures (median 182.7, ranged from 73.5 to 733.0 µg/m3) can induce vasoconstriction of small pulmonary arteries in normal and CB rats. This effect was correlated with specific particle components, and suggests that the pulmonary vasculature might be an important target for ambient air particle toxicity.
With the repeated finding in both dogs and rats of increased pathologic responses to inhalation of concentrated urban air particles and the identification of silicon (as silicate) as an element associated with some of these responses, we carried out studies to determine whether there is a change in toxicity as silicon containing particles pass through the HAPC (Savage, Lawrence, et al., submitted 2002). Using silicate rich Mt. St. Helen's volcanic ash (MSHA), we exposed three groups of Sprague-Dawley rats by inhalation for 6 hours to filtered air, MSHA, or MSHA passed though the HAPC. Twenty-four hours following exposure, BAL was performed to assess total cell count, differential cell count, and protein, lactate dehydrogenase, and n-beta glucosaminidase levels. Peripheral blood was examined for packed cell volume, total protein, total white cells, and differential cell count. No significant differences were observed among any of the groups in any parameter measured. Scanning electron microscopy and x-ray analysis was performed to identify particles in the lungs, revealing silicates typical of MSHA throughout the lung. Our findings suggest that particles passing through the HAPC have no change in their toxic potential in an exposure setting where substantial particle deposition has occurred. This study validates the use of the HAPC as a method of creating concentrated aerosol of fine urban air particles without altering their physical properties or potential for toxic insult.
In the context of this Project, we have started to support and include the innovative work of Dr. Beatriz Gonzales-Flecha's laboratory. Dr. Gonzales-Flecha's laboratory studies focus on oxidant mechanisms to explain cardiac responses. Dr. Gonzales-Flecha and her collegues have reported rapid increases in the steady-state concentration of reactive oxygen species in the lungs and heart associated with ambient particle exposures (Gurgueira, Lawrence, et al. 2002). More recently, they confirmed the role of oxidants in the inflammatory response to CAPs in adult rats. The experimental protocol included exposures to filtered air (Sham) or CAPs aerosols (CAPs, 5 hours exposure, average mass concentration: 1,100 ± 300 µg/m3) in the presence or absence of 50 mg/Kg i.p. nitrate to ammonia and ceramic (NAC). BAL, tissue, and blood samples were collected 24 hours after exposure. The results of this study suggested a dramatic increase of polymorphonuclear leukocytes (PMN) number in BAL as a result to CAPs exposures. This increase was mediated by oxidants, since pre-administration of NAC effectively prevented PMN influx into the lung. Additional recent data support our hypotheses that CAPs promotes oxidant-mediated inflammation in the lung and that sympathetic activation after CAPs deposition in the lung is critical for CAPs cardiotoxicity. Studies will continue in this important area in the coming year.
Furthermore, we have developed a rat model of acute myocardial infarction (Wellenius, Saldiva, et al., 2002) in order to study the effects of particles on ischemia-induced arrhythmias. In these studies, a myocardial infarction (MI) is surgically induced in rats. On the following day, the rats were exposed to CAPs or clean air. Specifically, a left-ventricular MI was induced in 31 Sprague-Dawley rats via thermocoagulation of a coronary artery; 32 additional rats served as sham-operated controls. Within 12 to 18 hours after surgery, diazepam-sedated animals were exposed to room air for 1 hour (baseline period), either residual oil fly ash (ROFA), carbon black, or room air for 1 hour (exposure period), and room air for an additional hour (recovery period). Lead II ECGs were recorded. In the MI group, 41percent of rats exhibited one or more premature ventricular complexes (PVCs) during the baseline period. Exposure to ROFA, but not carbon black or room air, increased arrhythmia frequency in a significant number (80 percent) of animals with pre-existing PVCs. Moreover, in MI rats, heart rate variability decreased following ROFA exposure, but increased following carbon black or room air exposure. There was no discernable difference in heart rate variability or arrhythmia frequency among sham-operated animals. These results suggest a link between acute MI and potentiation of the adverse health effects of inhaled PM. We conclude that the rat model of MI is applicable to the study of particulate-related cardiac morbidity and mortality in compromised individuals.
This appears to be a sensitive model of cardiac effects of particle exposure and we are now using this approach to study the influence of gaseous co-pollutants and CAPs. Preliminary results using carbon monoxide indicates that exposure to this gas at 35 ppm for one hour decreases arrhythmias both alone and with CAPs exposure. This rat model also appears to be useful for interventional pharmacologic experiments to determine the pathophysiologic mechanism(s) triggering the observed arrhythmias.
We will continue to assess completed experiments of CAPs exposures to determine mechanisms of vascular injury. Both collected RNA and the tissue preserved for immunocytochemical analyses from these studies are particularly valuable for determining mechanisms of vascular injury. In the coming year, we will continue to exploit this valuable resource.
Journal Articles on this Report : 2 Displayed | Download in RIS Format
|Other subproject views:||All 4 publications||4 publications in selected types||All 4 journal articles|
|Other center views:||All 200 publications||198 publications in selected types||All 197 journal articles|
||Wellenius GA, Saldiva PHN, Batalha JRF, Krishna Murthy GG, Coull BA, Verrier RL, Godleski JJ. Electrocardiographic changes during exposure to residual oil fly ash (ROFA) particles in a rat model of myocardial infarction. Toxicological Sciences 2002;66(2):327-335.||
||Wellenius GA, Coull BA, Godleski JJ, Koutrakis P, Okabe K, Savage ST, Lawrence JE, Krishna Murthy GG, Verrier RL. Inhalation of concentrated ambient air particles exacerbates myocardial ischemia in conscious dogs. Environmental Health Perspectives 2003;111(4):402-408.||
Supplemental Keywords:gaseous copollutants, particles, PM, concentrated ambient particles, CAPs, ST-segment, coronary artery occlusion, C-reactive protein, red blood cells, dog cardiac ischemia model, heart rate variability, ROFA, nickel, black carbon, silicon, cardiac ischemia., RFA, Health, Scientific Discipline, Air, Geographic Area, particulate matter, Toxicology, air toxics, Environmental Chemistry, Epidemiology, State, Risk Assessments, Microbiology, Susceptibility/Sensitive Population/Genetic Susceptibility, Environmental Microbiology, Disease & Cumulative Effects, Environmental Monitoring, Children's Health, genetic susceptability, tropospheric ozone, Atmospheric Sciences, Molecular Biology/Genetics, Biology, Environmental Engineering, ambient air quality, health effects, monitoring, particle size, risk assessment, sensitive populations, chemical exposure, interindividual variability, molecular epidemiology, particulates, Minnesota, air pollutants, exposure and effects, lung, stratospheric ozone, PM 2.5, ambient air monitoring, health risks, cardiopulmonary responses, indoor exposure, human health effects, ambient air, developmental effects, epidemelogy, respiratory disease, exposure, pulmonary disease, biological response, ambient measurement methods, Utah (UT), ambient monitoring, children, air pollution, particle exposure, biological mechanism , Human Health Risk Assessment, lung cancer, Massachusetts (MA), Washington (WA), human exposure, chronic effects, inhalation, pulmonary, ambient particle health effects, cardiopulmonary response, particulate exposure, susceptibility, assessment of exposure, Illinois (IL), elderly, inhaled, inhalation toxicology, epidemeology, environmental health hazard, human susceptibility, indoor air, Connecticut (CT), gaseous co-polutants, cardiopulmonary, human health, indoor air quality, inhaled particles, cardiac ischemia, respiratory, toxics, co-pollutants, genetic susceptibility, air quality, dosimetry, cardiovascular disease, human health risk
Progress and Final Reports:Original Abstract
Main Center Abstract and Reports:R827353 EPA Harvard Center for Ambient Particle Health Effects
Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R827353C001 Assessing Human Exposures to Particulate and Gaseous Air Pollutants
R827353C002 Quantifying Exposure Error and its Effect on Epidemiological Studies
R827353C003 St. Louis Bus, Steubenville and Atlanta Studies
R827353C004 Examining Conditions That Predispose Towards Acute Adverse Effects of Particulate Exposures
R827353C005 Assessing Life-Shortening Associated with Exposure to Particulate Matter
R827353C006 Investigating Chronic Effects of Exposure to Particulate Matter
R827353C007 Determining the Effects of Particle Characteristics on Respiratory Health of Children
R827353C008 Differentiating the Roles of Particle Size, Particle Composition, and Gaseous Co-Pollutants on Cardiac Ischemia
R827353C009 Assessing Deposition of Ambient Particles in the Lung
R827353C010 Relating Changes in Blood Viscosity, Other Clotting Parameters, Heart Rate, and Heart Rate Variability to Particulate and Criteria Gas Exposures
R827353C011 Studies of Oxidant Mechanisms
R827353C012 Modeling Relationships Between Mobile Source Particle Emissions and Population Exposures
R827353C013 Toxicological Evaluation of Realistic Emissions of Source Aerosols (TERESA) Study
R827353C014 Identifying the Physical and Chemical Properties of Particulate Matter Responsible for the Observed Adverse Health Effects
R827353C015 Research Coordination Core
R827353C016 Analytical and Facilities Core
R827353C017 Technology Development and Transfer Core