Final Report: Clinical Studies of Ultrafine Particle Exposure in Susceptible Human Subjects

EPA Grant Number: R827354C003
Subproject: this is subproject number 003 , established and managed by the Center Director under grant R827354
(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: Clinical Studies of Ultrafine Particle Exposure in Susceptible Human Subjects
Investigators: Frampton, Mark W. , Utell, Mark J.
Institution: University of Rochester
EPA Project Officer: Chung, Serena
Project Period: June 1, 1999 through May 31, 2005 (Extended to May 31, 2006)
RFA: Airborne Particulate Matter (PM) Centers (1999) RFA Text |  Recipients Lists
Research Category: Air Quality and Air Toxics , Particulate Matter , Air

Objective:

Our overall objectives were to utilize controlled human exposures to examine, in healthy and potentially susceptible subjects, the role of ultrafine particles (UFP) in inducing respiratory and cardiovascular health effects. We developed a facility for experimental exposure of humans to ultrafine particles, which permits the quantitative determination of the exposure levels, respiratory intakes, and depositions of the aerosol. Our hypothesis was that inhalation of UFP alters pulmonary vascular function, circulating leukocyte activation, coagulation, and cardiac repolarization. We speculated that these alterations reflect mechanisms involved in the observed increase in cardiovascular morbidity and mortality associated with particulate air pollution.

Summary/Accomplishments (Outputs/Outcomes):

For our initial studies, exposures were conducted in healthy subjects at rest with a relatively low concentration of elemental carbon UFP (~10 μg/m3, ~2 x 106 particles/cm3, count median diameter [CMD] 26.4 nm, GSD 2.3). The overall deposition fraction (DF) was 0.66 ± 0.12 (mean ± SD) by number, and 0.58 ± 0.14 by mass. We found no differences in respiratory symptoms, blood pressure, pulse-oximetry, spirometry, exhaled NO, blood markers of coagulation and endothelial activation, leukocyte activation, or sputum cell differential counts. There was no convincing evidence for significant effects on heart rate variability, repolarization, or arrhythmias. We concluded that exposure to 10 μg/m3 elemental carbon UFP for 2 hours at rest does not cause significant respiratory or cardiac effects in healthy nonsmokers.

We then initiated studies to examine concentration-response effects, and to incorporate exercise. Subjects received each of three exposures (air, 10, and 25 μg/m3 UFP). Analyses indicated that exercise further increased the relatively high resting deposition of UFP (number deposition fraction at rest: 0.63 ± 0.04; exercise: 0.76 ± 0.06; means ± SD). There was evidence for a concentration-related effect of UFP exposure on the percentage of blood monocytes. In addition, monocyte expression of CD54 (ICAM-1) decreased after exposure in a concentration-response pattern (p=0.001), with the greatest effect occurring at 0 and 3.5 hours after exposure, and the differences resolved at 21 hours after exposure. Overall, the findings provided evidence for effects of UFP exposure, with exercise, on blood monocyte number and leukocyte expression of surface markers. In general, surface marker expression decreased in association with UFP exposure, consistent with retention of higher expressing cells within the capillary bed. ECG recording analyses showed that the response of the parasympathetic system (measured by normalized units of high-frequency [HF] components) was blunted during recovery from exercise immediately after exposure to UFP in comparison to air exposure. These findings suggested that inhalation of UFP at both concentrations altered myocardial repolarization in healthy subjects.

We next initiated a study to confirm and extend these observations in a larger group of healthy men and women, using a higher, yet still environmentally relevant, concentration of UFP. Our hypothesis was that inhalation of UFP alters pulmonary vascular function and circulating leukocyte activation. In order to test our hypothesis, and to determine concentration-response relationships, we initiated exposures of healthy subjects to a higher concentration, 50 μg/m3 UFP, using the same protocol. In these studies, we also measured the pulmonary diffusing capacity for carbon monoxide (DLCO), which is affected by changes in pulmonary capillary blood volume in 16 subjects. We observed a significant reduction in the DLCO, 21 hours after exposure to 50 μg/m3 UFP when compared with air. There was also a significant reduction in blood NO products throughout the post-exposure period. The reduction in DLCO in these studies may be caused by mild pulmonary vasoconstriction, as a consequence of reduced NO availability, leading to a reduction in the pulmonary capillary blood volume.

In addition, we measured flow-mediated vascular dilatation of the forearm (FMD), before and at intervals up to 48 hours after exposure, using forearm plethysmography before and after ischemia, which measures the response in resistance vessels to the post ischemic increase in flow. FMD is mediated in part by endothelial NO action on vascular smooth muscle, and we hypothesized that UFP-induced reductions in vascular responsiveness would be accompanied by reduction in plasma NO reaction products. We therefore measured changes in the products of NO metabolism, nitrite, and nitrate. We did not see any significant effect of UFP exposure on total forearm blood flow, either before or after ischemia. However, UFP exposure appeared to cause a blunting of the increase in peak flow in response to exercise. Peak flow (0 minutes) after air exposure increased, representing increased flow-mediated dilatation in response to exercise, which is an expected change. However, peak flow did not increase with UFP exposure. These findings suggest that exposure to UFP reduced or delayed the exercise-induced increase in flow-mediated dilatation. Thus, inhalation of ultrafine carbon particles may have subtle vasoconstrictive effects in both the pulmonary and systemic vasculature.

Subjects with asthma may represent a group with increased susceptibility to the ultrafine particles. In asthmatics, we found that total respiratory deposition was significantly increased compared to healthy subjects at rest. Blood studies revealed a particle-related decrease in blood eosinophils, basophils, and CD4+ T-lymphocytes. Blood monocytes showed a significant reduction in CD11b expression after exposure. Exposure to even low mass concentrations of ultrafine particles altered circulating leukocyte subsets. These data are most consistent with an alteration in leukocyte retention in the pulmonary circulation.

Patients with diabetes have been identified in recent epidemiological studies as being particularly susceptible to the effects of PM exposure. We hypothesize that patients with diabetes, who are known to have underlying endothelial dysfunction, will show enhanced vascular responses to particle inhalation. Preliminary analysis showed significant reductions in forearm flow-mediated vascular dilatation in comparison with healthy subjects.

In summary, we found high deposition of UFP with vasoconstrictive effects in both the pulmonary and systemic circulations. Future studies will examine these effects in subjects with diabetes using ambient particles. Our data demonstrate that UFP contribute to PM-induced adverse cardiovascular responses.

Technical Report:

Full Final Technical Report (PDF, 8pp., 127KB, about PDF)


Journal Articles on this Report : 24 Displayed | Download in RIS Format

Other subproject views: All 27 publications 26 publications in selected types All 24 journal articles
Other center views: All 104 publications 98 publications in selected types All 90 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. R827354 (2004)
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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. R827354 (2004)
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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. R827354 (Final)
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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. R827354 (2004)
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  • Journal Article Cyrys J, Heinrich J, Peters A, Kreyling W, Wichmann HE. Emission, immission und messung feiner und ultrafeiner partikel (Emission, immission and measurement of fine and ultrafine particles). Umweltmedizin Forschung Und Praxis 2002;7(2):67-77. R827354 (2004)
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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. R827354 (2004)
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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. R827354 (Final)
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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. R827354 (Final)
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  • Journal Article Elder ACP, Gelein R, Oberdorster G, Finkelstein J, Notter R, Wang Z. Efficient depletion of alveolar macrophages using intratracheally inhaled aerosols of liposome-encapsulated clodronate. Experimental Lung Research 2004;30(2):105-120. R827354 (Final)
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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. R827354 (Final)
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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. R827354 (Final)
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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. R827354 (Final)
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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. R827354 (Final)
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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. R827354 (Final)
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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. R827354 (Final)
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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. R827354 (Final)
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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. R827354 (Final)
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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. R827354 (Final)
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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. R827354 (Final)
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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. R827354 (Final)
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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. R827354 (Final)
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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. R827354 (Final)
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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. R827354 (Final)
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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. R827354 (Final)
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  • Supplemental Keywords:

    RFA, Health, Scientific Discipline, Air, particulate matter, air toxics, Environmental Chemistry, Health Risk Assessment, Risk Assessments, Biochemistry, Atmospheric Sciences, Molecular Biology/Genetics, ambient air quality, cytokine production, particle size, particulates, sensitive populations, health effects, risk assessment, cardiopulmonary responses, fine particles, human health effects, morbidity, ambient air monitoring, lung, cardiovascular vulnerability, pulmonary disease, susceptible populations, animal model, carbon particles, environmental health effects, particle exposure, ambient monitoring, human exposure, particulate exposure, lung inflamation, pulmonary, coronary artery disease, inhalation toxicology, urban air pollution, mortality, urban environment, aerosol, cardiopulmonary, human health, aerosols, cardiovascular disease, ultrafine particles, pathophysiological mechanisms

    Relevant Websites:

    Full Final Technical Report (PDF, 8pp., 127KB, about PDF)
    http://www2.envmed.rochester.edu/envmed/PMC/indexPMC.html Exit

    Progress and Final Reports:

    Original Abstract
  • 1999 Progress Report
  • 2000 Progress Report
  • 2001 Progress Report
  • 2002 Progress Report
  • 2003 Progress Report
  • 2004 Progress Report

  • Main Center Abstract and Reports:

    R827354    Rochester PM Center

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R827354C001 Characterization of the Chemical Composition of Atmospheric Ultrafine Particles
    R827354C002 Inflammatory Responses and Cardiovascular Risk Factors in Susceptible Populations
    R827354C003 Clinical Studies of Ultrafine Particle Exposure in Susceptible Human Subjects
    R827354C004 Animal Models: Dosimetry, and Pulmonary and Cardiovascular Events
    R827354C005 Ultrafine Particle Cell Interactions: Molecular Mechanisms Leading to Altered Gene Expression
    R827354C006 Development of an Electrodynamic Quadrupole Aerosol Concentrator
    R827354C007 Kinetics of Clearance and Relocation of Insoluble Ultrafine Iridium Particles From the Rat Lung Epithelium to Extrapulmonary Organs and Tissues (Pilot Project)
    R827354C008 Ultrafine Oil Aerosol Generation for Inhalation Studies