2011 Progress Report: Human Clinical Studies of Concentrated Ambient Ultrafine and Fine Particles

EPA Grant Number: R832415C003
Subproject: this is subproject number 003 , established and managed by the Center Director under grant R832415
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Rochester PM Center
Center Director: Oberdörster, Günter
Title: Human Clinical Studies of Concentrated Ambient Ultrafine and Fine Particles
Investigators: Frampton, Mark W. , Gelein, Robert , Oakes, David , Phipps, Richard , Utell, Mark J. , Zareba, Wojciech
Institution: University of Rochester
EPA Project Officer: Chung, Serena
Project Period: October 1, 2005 through September 30, 2010 (Extended to September 30, 2012)
Project Period Covered by this Report: July 1, 2010 through June 30,2011
RFA: Particulate Matter Research Centers (2004) RFA Text |  Recipients Lists
Research Category: Health Effects , Air

Objective:

The overall objective of our current and planned studies is to determine the pulmonary and cardiovascular effects of exposure to ultrafine and fine particulate matter (PM). The clinical studies in healthy humans and susceptible individuals proposed in this research core focus on the effects of ambient ultrafine and fine particles on three major determinants of adverse cardiac events: 1) blood coagulation induced by effects on platelets and circulating microparticles; 2) cardiac output; and 3) cardiac rhythm and repolarization.

Our overall hypothesis is that inhalation of ambient PM causes small but measurable changes in coagulation and cardiovascular function that help explain the cardiovascular effects of PM exposure. We further hypothesize that the cardiovascular effects are determined by the ability of PM to generate reactive oxygen and nitrogen species, and are more pronounced in subjects with genetically determined reduced antioxidant defenses. Inhaled ultrafine particles increase the burden of reactive oxygen species (ROS) to the endothelium. Endothelial activation and vasoconstriction increase platelet adherence and release of thromboxane, activate and prolong the transit time of blood leukocytes, and deplete vascular nitric oxide (NO). Particles also may have direct effects on platelets and leukocytes. Vascular injury triggers release of procoagulant microparticles into the blood, and initiation of coagulation. In collaboration with the Vascular and Inflammation Facility Core, we measure the effects of inhaled ambient fine PM on platelet number, phenotype, and function, and quantitate intravascular microparticles derived from platelets and endothelial cells.

Progress Summary:

Cardiovascular Effects of Ultrafine Particles in Genetically Susceptible Subjects (CUSP)

Our human clinical studies of UFP inhalation have shown evidence for acute effects on vascular function.  We hypothesize that the acute vascular effects of UFP exposure are a consequence of reduced NO bioavailability. We have developed a new approach to test this hypothesis, involving the measurement of nitric oxide metabolites in both arterial and venous blood.  Specifically, we hypothesize that exposure to ultrafine particles will deliver a burden of reactive oxygen species to the pulmonary vascular endothelium, altering the delivery of NO, specifically as nitrite, to the systemic vasculature.  We expect that UFP exposure will alter the artery-to-vein nitrite gradient that is normally present.

This study is jointly funded by this center and by the NIH, to test this hypothesis in healthy subjects. For the EPA-funded part of this study, we added a new, separate set of analyses that was not part of the NIH application, but is highly relevant to the whole issue of PM effects on vascular function and NO bioavailability. We have done a set of analyses to detect subtle effects on the membrane of circulating red blood cells. Our hypothesis is that inhaled UFP or their products cause subtle alterations in the red blood cell (RBC) membrane that shift the dynamics of RBC transport and storage of nitrite and other NO metabolites.

We presented preliminary findings (11 subjects, 4 of which were GSTM1 null) at the ATS International Conference, May 2011. Exposure to concentrated UFP did not cause symptoms or changes in heart rate or blood pressure.  Arterial punctures were well tolerated, and no subject withdrew from the study because of discomfort.  Of a total of 66 arterial puncture attempts, 88% were successful.  The arterial-venous gradient for nitrite increased 3 hours after UFP relative to air exposure (air, 13.96 vs. UFP, 190.39 nm, p=0.06 by paired t- test), driven by an increase in arterial nitrite concentrations after UFP but not air exposure. There were no significant effects on the reactive hyperemia index. Thus, exposure to UFP non-significantly increased nitrite arterial-venous gradients 3 hours after exposure, without effects on vascular function.

We now have completed subject exposures for this study. Data analysis is in progress.

Significance to the Field:

These studies will provide important new information about the cardiac and vascular effects of exposure to UFP, and will test specific mechanisms for these effects. In addition, we will test the hypothesis that specific genetic polymorphisms confer increased susceptibility to UFP effects.

Relationship to the Overall Center Goals:

These studies are highly relevant to the overall Center goal of understanding the cardiovascular effects of UFP exposure.

Relevance to the Agency’s Mission:

Findings from these studies will improve our understanding of the health effects of breeding ambient UFP, and will help to inform the development of rational ambient air quality standards.


Journal Articles on this Report : 41 Displayed | Download in RIS Format

Other subproject views: All 57 publications 44 publications in selected types All 41 journal articles
Other center views: All 190 publications 156 publications in selected types All 143 journal articles
Type Citation Sub Project Document Sources
Journal Article Azadniv M, Torres A, Boscia J, Speers DM, Frasier LM, Utell MJ, Frampton MW. Neutrophils in lung inflammation: which reactive oxygen species are being measured? Inhalation Toxicology 2001;13(6):485-495. R832415 (2010)
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  • Journal Article Beckett WS, Chalupa DF, Pauly-Brown A, Speers DM, Stewart JC, Frampton MW, Utell MJ, Huang L-S, Cox C, Zareba W, Oberdorster G. Comparing inhaled ultrafine versus fine zinc oxide particles in healthy adults:a human inhalation study. American Journal of Respiratory and Critical Care Medicine 2005;171(10):1129-1135. R832415 (2010)
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  • Journal Article Berger A, Zareba W, Schneider A, Ruckerl R, Ibald-Mulli A, Cyrys J, Wichmann HE, Peters A. Runs of ventricular and supraventricular tachycardia triggered by air pollution in patients with coronary heart disease. Journal of Occupational and Environmental Medicine 2006;48(11):1149-1158. R832415 (2010)
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  • Journal Article Chalupa DC, Morrow PE, Oberdorster G, Utell MJ, Frampton MW. Ultrafine particle deposition in subjects with asthma. Environmental Health Perspectives 2004;112(8):879-882. R832415 (2010)
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  • Journal Article Daigle CC, Chalupa DC, Gibb FR, Morrow PE, Oberdorster G, Utell MJ, Frampton MW. Ultrafine particle deposition in humans during rest and exercise. Inhalation Toxicology 2003;15(6):539-552. R832415 (2010)
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  • Journal Article Elder ACP, Gelein R, Azadniv M, Frampton M, Finkelstein J, Oberdorster G. Systemic interactions between inhaled ultrafine particles and endotoxin. Annals of Occupational Hygiene 2002;46(Suppl 1):231-234. R832415 (2011)
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  • Journal Article Elder ACP, Gelein R, Azadniv M, Frampton M, Finkelstein J, Oberdorster G. Systemic effects of inhaled ultrafine particles in two compromised, aged rat strains. Inhalation Toxicology 2004;16(6-7):461-471. R832415 (2010)
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  • Journal Article Elder A, Gelein R, Finkelstein J, Phipps R, Frampton M, Utell M, Kittelson DB, Watts WF, Hopke P, Jeong C-H, Kim E, Liu W, Zhao W, Zhuo L, Vincent R, Kumarathasan P, Oberdorster G. On-road exposure to highway aerosols. 2. Exposures of aged, compromised rats. Inhalation Toxicology 2004;16(Suppl 1):41-53. R832415 (2010)
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  • Journal Article Elder A, Couderc J-P, Gelein R, Eberly S, Cox C, Xia X, Zareba W, Hopke P, Watts W, Kittelson D, Frampton M, Utell M, Oberdorster G. Effects of on-road highway aerosol exposures on autonomic responses in aged, spontaneously hypertensive rats. Inhalation Toxicology 2007;19(1):1-12. R832415 (2010)
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  • Journal Article Fanning EW, Froines JR, Utell MJ, Lippmann M, Oberdorster G, Frampton M, Godleski J, Larson TV. Particulate Matter (PM) Research Centers (1999-2005) and the role of interdisciplinary center-based research. Environmental Health Perspectives 2009;117(2):167-174. R832415 (2010)
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  • Journal Article Frampton MW. Systemic and cardiovascular effects of airway injury and inflammation: ultrafine particle exposure in humans. Environmental Health Perspectives 2001;109(Suppl 4):529-532. R832415 (2010)
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  • Journal Article Frampton MW, Stewart JC, Oberdorster G, Morrow PE, Chalupa D, Pietropaoli AP, Frasier LM, Speers DM, Cox C, Huang L-S, Utell MJ. Inhalation of ultrafine particles alters blood leukocyte expression of adhesion molecules in humans. Environmental Health Perspectives 2006;114(1):51-58. R832415 (2010)
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  • Journal Article Frampton MW. Does inhalation of ultrafine particles cause pulmonary vascular effects in humans? Inhalation Toxicology 2007;19(Suppl 1):75-79. R832415 (2010)
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  • Journal Article Hampel R, Breitner S, Ruckerl R, Frampton MW, Koenig W, Phipps RP, Wichmann HE, Peters A, Schneider A. Air temperature and inflammatory and coagulation responses in men with coronary or pulmonary disease during the winter season. Occupational & Environmental Medicine 2010;67(6):408-416. R832415 (2010)
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  • Journal Article Hildebrandt K, Ruckerl R, Koenig W, Schneider A, Pitz M, Heinrich J, Marder V, Frampton M, Oberdorster G, Wichmann HE, Peters A. Short-term effects of air pollution: a panel study of blood markers in patients with chronic pulmonary disease. Particle and Fibre Toxicology 2009;6:25. R832415 (2009)
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  • Journal Article Jeong C-H, Hopke PK, Chalupa D, Utell M. Characteristics of nucleation and growth events of ultrafine particles measured in Rochester, NY. Environmental Science & Technology 2004;38(7):1933-1940. R832415 (2010)
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  • Journal Article Jeong C-H, Evans GJ, Hopke PK, Chalupa D, Utell MJ. Influence of atmospheric dispersion and new particle formation events on ambient particle number concentration in Rochester, United States, and Toronto, Canada. Journal of the Air & Waste Management Association 2006;56(4):431-443. R832415 (2010)
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  • Journal Article Lagudu UR, Raja S, Hopke PK, Chalupa DC, Utell MJ, Casuccio G, Lersch TL, West RR. Heterogeneity of coarse particles in an urban area. Environmental Science & Technology 2011;45(8):3288-3296. R832415 (2011)
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  • Journal Article Lippmann M, Frampton M, Schwartz J, Dockery D, Schlesinger R, Koutrakis P, Froines J, Nel A, Finkelstein J, Godleski J, Kaufman J, Koenig J, Larson T, Luchtel D, Liu L-JS, Oberdorster G, Peters A, Sarnat J, Sioutas C, Suh H, Sullivan J, Utell M, Wichmann E, Zelikoff J. The U.S. Environmental Protection Agency Particulate Matter Health Effects Research Centers Program: a midcourse report of status, progress, and plans. Environmental Health Perspectives 2003;111(8):1074-1092. R832415 (2010)
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  • Journal Article Oberdorster G, Utell MJ. Ultrafine particles in the urban air:to the respiratory tract—and beyond? Environmental Health Perspectives 2002;110(8):A440-A441. R832415 (2010)
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  • Journal Article Ogulei D, Hopke PK, Chalupa DC, Utell MJ. Modeling source contributions to submicron particle number concentrations measured in Rochester, New York. Aerosol Science and Technology 2007;41(2):179-201. R832415 (2010)
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  • Journal Article Pietropaoli AP, Frampton MW, Hyde RW, Morrow PE, Oberdorster G, Cox C, Speers DM, Frasier LM, Chalupa DC, Huang L-S, Utell MJ. Pulmonary function, diffusing capacity, and inflammation in healthy and asthmatic subjects exposed to ultrafine particles. Inhalation Toxicology 2004;16(Suppl 1):59-72. R832415 (2010)
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  • Journal Article Riesenfeld E, Chalupa D, Gibb FR, Oberdo G, Gelein R, Morrow PE, Utell MJ, Frampton MW. Ultrafine particle concentrations in a hospital. Inhalation Toxicology 2000;12(Suppl 2):83-94. R832415 (2010)
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  • Journal Article Ruckerl R, Ibald-Mulli A, Koenig W, Schneider A, Woelke G, Cyrys J, Heinrich J, Marder V, Frampton M, Wichmann HE, Peters A. Air pollution and markers of inflammation and coagulation in patients with coronary heart disease. American Journal of Respiratory and Critical Care Medicine 2006;173(4):432-441. R832415 (2010)
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  • Journal Article Ruckerl R, Phipps RP, Schneider A, Frampton M, Cyrys J, Oberdorster G, Wichmann HE, Peters A. Ultrafine particles and platelet activation in patients with coronary heart disease – results from a prospective panel study. Particle and Fibre Toxicology 2007;4:1. R832415 (2010)
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  • Journal Article Shah AP, Pietropaoli AP, Frasier LM, Speers DM, Chalupa DC, Delehanty JM, Huang L-S, Utell MJ, Frampton MW. Effect of inhaled carbon ultrafine particles on reactive hyperemia in healthy human subjects. Environmental Health Perspectives 2008;116(3):375-380. R832415 (2007)
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  • Journal Article Stewart JC, Villasmil ML, Frampton MW. Changes in fluorescence intensity of selected leukocyte surface markers following fixation. Cytometry Part A 2007;71A(6):379-385. R832415 (2007)
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  • Journal Article Stewart JC, Chalupa DC, Devlin RB, Frasier LM, Huang LS, Little EL, Lee SM, Phipps RP, Pietropaoli AP, Taubman MB, Utell MJ, Frampton MW. Vascular effects of ultrafine particles in persons with type 2 diabetes. Environmental Health Perspectives 2010;118(12):1692-1698. R832415 (2011)
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  • Journal Article Su Y, Sipin MF, Spencer MT, Qin X, Moffet RC, Shields LG, Prather KA, Venkatachari P, Jeong C-H, Kim E, Hopke PK, Gelein RM, Utell MJ, Oberdorster G, Berntsen J, Devlin RB, Chen LC. Real-time characterization of the composition of individual particles emitted from ultrafine particle concentrators. Aerosol Science and Technology 2006;40(6):437-455. R832415 (2010)
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  • Journal Article Thurston GD, Bekkedal MY, Roberts EM, Ito K, Pope III CA, Glenn BS, Ozkaynak H, Utell MJ. Use of health information in air pollution health research:past successes and emerging needs. Journal of Exposure Science and Environmental Epidemiology 2009;19(1):45-58. R832415 (2010)
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  • Journal Article Utell MJ, Frampton MW. Toxicologic methods: controlled human exposures. Environmental Health Perspectives 2000;108(Suppl 4):605-613. R832415 (2010)
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  • Journal Article Utell MJ, Frampton MW, Zareba W, Devlin RB, Cascio WE. Cardiovascular effects associated with air pollution:potential mechanisms and methods of testing. Inhalation Toxicology 2002;14(12):1231-1247. R832415 (2010)
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  • Journal Article Wang Y, Hopke PK, Sun L, Chalupa DC, Utell MJ. Laboratory and field testing of an automated atmospheric particle-bound reactive oxygen species sampling-analysis system. Journal of Toxicology 2011;2011:419476 (9 pp). R832415 (2011)
    R832415 (Final)
    R832415C003 (2011)
    R831078 (Final)
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  • Abstract from PubMed
  • Associated PubMed link
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  • Journal Article Wang Y, Hopke PK, Chalupa DC, Utell MJ. Effect of the shutdown of a coal-fired power plant on urban ultrafine particles and other pollutants. Aerosol Science and Techology 2011;45(10):1245-1249. R832415 (2011)
    R832415 (Final)
    R832415C001 (2011)
    R832415C003 (2011)
  • Full-text: Taylor & Francis-Full Text HTML
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  • Abstract: Taylor & Francis-Abstract
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  • Other: Taylor & Francis-Full Text PDF
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  • Journal Article Wang Y, Hopke PK, Utell MJ. Urban-scale spatial-temporal variability of black carbon and winter residential wood combustion particles. Aerosol and Air Quality Research 2011;11(5):473-481. R832415 (2011)
    R832415 (Final)
    R832415C003 (2011)
    R831078 (Final)
  • Full-text: AAQR-Full Text PDF
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  • Abstract: AAQR-Abstract
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  • Journal Article Wang Y, Hopke PK, Rattigan OV, Xia X, Chalupa DC, Utell MJ. Characterization of residential wood combustion particles using the two-wavelength aethalometer. Environmental Science & Technology 2011;45(17):7387-7393. R832415 (2011)
    R832415 (Final)
    R832415C001 (2011)
    R832415C003 (2011)
  • Abstract from PubMed
  • Full-text: ACS-Full Text HTML
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  • Abstract: ACS-Abstract
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  • Other: ACS-Full Text PDF
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  • Journal Article Yue W, Schneider A, Stolzel M, Ruckerl R, Cyrys J, Pan X, Zareba W, Koenig W, Wichmann H-E, Peters A. Ambient source-specific particles are associated with prolonged repolarization and increased levels of inflammation in male coronary artery disease patients. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 2007;621(1-2):50-60. R832415 (2010)
    R832415 (2011)
    R832415 (Final)
    R832415C003 (2011)
    R832415C004 (2011)
    R827354 (Final)
  • Abstract from PubMed
  • Full-text: ScienceDirect-Full Text HTML
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  • Abstract: ScienceDirect-Abstract
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  • Other: ScienceDirect-Full Text PDF
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  • Journal Article Yue W, Schneider A, Ruckerl R, Koenig W, Marder V, Wang S, Wichmann H-E, Peters A, Zareba W. Relationship between electrocardiographic and biochemical variables in coronary artery disease. International Journal of Cardiology 2007;119(2):185-191. R832415 (2010)
    R832415 (2011)
    R832415 (Final)
    R832415C003 (2011)
    R832415C004 (2011)
    R827354 (Final)
  • Abstract from PubMed
  • Abstract: Elsevier-Abstract
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  • Journal Article Zareba W, Nomura A, Couderc JP. Cardiovascular effects of air pollution:what to measure in ECG? Environmental Health Perspectives 2001;109(Suppl 4):533-538. R832415 (2010)
    R832415 (2011)
    R832415 (Final)
    R832415C003 (2011)
    R832415C004 (2011)
    R827354 (Final)
    R827354C003 (Final)
    R827354C004 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: JSTOR - Full Text PDF
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  • Journal Article Zareba W, Couderc JP, Oberdorster G, Chalupa D, Cox C, Huang L-S, Peters A, Utell MJ, Frampton MW. ECG parameters and exposure to carbon ultrafine particles in young healthy subjects. Inhalation Toxicology 2009;21(3):223-233. R832415 (2008)
    R832415 (2009)
    R832415 (2010)
    R832415 (2011)
    R832415 (Final)
    R832415C002 (2010)
    R832415C002 (2011)
    R832415C003 (2010)
    R832415C003 (2011)
    R832415C004 (2009)
    R832415C004 (2010)
    R832415C004 (2011)
    R827354 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Abstract: Taylor and Francis-Abstract
    Exit
  • Supplemental Keywords:

    RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, Air, particulate matter, Health Risk Assessment, Risk Assessments, Physical Processes, atmospheric particulate matter, acute cardiovascular effects, long term exposure, atmospheric particles, airway disease, exposure, ambient particle health effects, human exposure, ultrafine particulate matter, atmospheric aerosol particles, PM, aersol particles, cardiovascular disease

    Progress and Final Reports:

    Original Abstract
  • 2006 Progress Report
  • 2007 Progress Report
  • 2008 Progress Report
  • 2009 Progress Report
  • 2010 Progress Report
  • Final Report

  • Main Center Abstract and Reports:

    R832415    Rochester PM Center

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R832415C001 Characterization and Source Apportionment
    R832415C002 Epidemiological Studies on Extra Pulmonary Effects of Fresh and Aged Urban Aerosols from Different Sources
    R832415C003 Human Clinical Studies of Concentrated Ambient Ultrafine and Fine Particles
    R832415C004 Animal models: Cardiovascular Disease, CNS Injury and Ultrafine Particle Biokinetics
    R832415C005 Ultrafine Particle Cell Interactions In Vitro: Molecular Mechanisms Leading To Altered Gene Expression in Relation to Particle Composition