![[logo] US EPA](https://webarchive.library.unt.edu/eot2008/20081106070931im_/http://www.epa.gov/epafiles/images/logo_epaseal.gif){kind=logo}
2001 Progress Report: Clinical Studies of Ultrafine Particle Exposure in Susceptible Human Subjects
EPA Grant Number: R827354C003Subproject: 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: Airborne PM - Rochester PM Center
Center Director: Oberdorster, Gunter
Title: Clinical Studies of Ultrafine Particle Exposure in Susceptible Human Subjects
Investigators: Frampton, Mark W. , Beckett, William , Cox, Christopher , Morrow, P. E. , Utell, Mark J. , Zareba, Wojciech
Current Investigators: Frampton, Mark W. , Utell, Mark J.
Institution:
Current Institution: University of Rochester
EPA Project Officer: Stacey Katz/Gail Robarge,
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
RFA: Airborne Particulate Matter (PM) Centers (1999)
Research Category: Particulate Matter
Description:
Objective:This research project is composed of a collection of studies that utilize controlled human exposures to examine, in healthy and potentially susceptible subjects, the deposition and fate of inhaled ultrafine carbon particles (UFP), and the role of UFP in inducing health effects.
Progress Summary:Subjects with asthma may represent a group with increased susceptibility to the health effects of UFP, both because of the possibility of increased airways deposition of particles, and because of underlying airway inflammation. We have completed a clinical exposure study (co-funded by the Health Effects Institute) of subjects with mild asthma. Sixteen subjects (8 male, 8 female) were exposed to air and to 10 micrograms (µg)/m3 carbon UFP for 2 hours with intermittent exercise. We measured effects on pulmonary function, symptoms, airway inflammation (exhaled nitric oxide (NO) and induced sputum), blood leukocyte activation, and cardiac electrophysiologic function. Because these studies were performed using mouthpiece exposures, we were able to measure UFP deposition during exposure, and to compare findings with our previous studies of healthy subjects.
Ultrafine Particle Deposition. In the asthmatic subjects, we found that total respiratory fractional deposition by particle number was high at rest (0.77 ± 0.05) and increased during exercise (0.86 ± 0.04). Rest deposition was significantly increased compared with our previous study in healthy subjects at rest (0.63 ± 0.03). We conclude that UFP deposition is increased in mild asthmatic subjects compared with healthy subjects (see Figure 1).
Figure 1.
Symptoms and Lung Function. There were no significant changes in respiratory symptoms or pulmonary function in response to these exposures. Subjects did not report an increase in medication use following exposures.
Blood studies revealed a particle-related increase in the total white blood cell count, with an increase in blood polymorphonuclear leukocyte (PMN) and decreases in blood lymphocytes and eosinophils. There was a reduction in expression of several adhesion molecules on circulating blood leukocytes, including intracellular adhesion molecule-1 (ICAM-1)-CD54 and L-selectin CD62L (Figure 2). These data are similar to the effects on blood cells seen in our earlier studies of healthy subjects, but appear to be present at a lower exposure concentration in asthmatic subjects, suggesting asthmatics may have heightened sensitivity for these effects. These findings are consistent with a change in vascular retention of leukocyte subsets in the hours following UFP exposure.
Figure 2.
Effects of UFP Exposure on Endothelial Function. For the last six subjects studied in this project, we examined the effects of UFP exposure on endothelial function by performing flow-mediated dilatation of the forearm circulation before exposure, and 24 and 48 hours after exposure. Figure 3 shows the change from preexposure in post-ischemic total forearm flow compared with the baseline measurement. After air exposure, flow-mediated dilation increased compared with preexposure baseline, an expected response to the exercise during the previous day’s exposure. However, this response was blunted following UFP exposure. At 48 hours, there appeared to be a rebound, with the change in total flow greater after UFP than after air.
Figure 3. Change In Flow-Mediated Dilation And Blood.
Flow-mediated dilation is mediated by endothelial NO, so we measured the plasma NO products nitrite and nitrate before and after exposure in all 16 subjects in this study. As shown in Figure 3, we found a significant increase in blood nitrates 48 hours after exposure. This finding is consistent with a rebound increase in NO production, which likely mediates the rebound seen in flow mediated dilation. These data support the hypothesis that exposure to very low concentrations of UFP alters systemic endothelial function. This is a novel finding, and we have now begun a study to determine if exposures in healthy subjects have similar effects on vascular function, and to determine the time course of the response.
In summary, our study indicates that asthmatics have increased airway deposition of UFPs, and that exposure to even low mass concentrations of UFPs alters circulating leukocyte subsets. These data are most consistent with an alteration in leukocyte retention in the pulmonary circulation. In addition, our preliminary results suggest there also are effects on systemic endothelial function.
Future Activities:We now plan to test the hypothesis that exposure to carbon UFP alters systemic endothelial function. We are initiating a new study in healthy subjects, using an exposure concentration of 50 µg/m3. Subjects will be monitored for a total of 48 hours after exposure and we will examine the time course of effects on endothelial function using the forearm flow mediated dilation test. We also will measure plasma levels of the vasoactive mediators NO and endothelins. The common blood endpoints that we have developed with the Center's inflammatory response project (R827354C002) also will be measured in this study.
Journal Articles on this Report: 5 Displayed | Download in RIS Format
| Other subproject views: | All 29 publications | 29 publications in selected types | All 26 journal articles |
| Other center views: | All 87 publications | 85 publications in selected types | All 78 journal articles |
| Type | Citation | ||
|---|---|---|---|
|
|
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) R827354 (Final) R827354C003 (2001) R827354C003 (2002) R827354C003 (Final) R826781 (2001) R826781 (Final) |
|
|
|
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) R827354 (Final) R827354C003 (1999) R827354C003 (2000) R827354C003 (2001) R827354C003 (2002) R827354C003 (2003) R827354C003 (2004) R827354C003 (Final) R827354C004 (Final) R826781 (2001) R826781 (Final) |
|
|
|
Frampton MW. Systemic and cardiovascular effects of airway injury and inflammation: ultrafine particle exposure in humans. Environmental Health Perspectives 2001;109(S4):529-532. |
R827354 (Final) R827354C003 (2001) R827354C003 (2002) R827354C003 (Final) R826781 (2001) R826781 (Final) |
|
|
|
Riesenfeld E, Chalupa D, Gibb FR, Oberdorster 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) R827354C003 (2000) R827354C003 (2001) R827354C003 (2002) R827354C003 (Final) R827354C004 (2000) R827354C004 (Final) R826781 (2000) R826781 (2001) R826781 (Final) |
|
|
|
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) R827354C003 (2001) R827354C003 (2002) R827354C003 (Final) R826781 (2001) R826781 (Final) |
|
ultrafine carbon particle, UFP, asthma, lungs, clinical exposure study, airway inflammation, blood leukocyte activation, cardiac electrophysiologic. , Air, Scientific Discipline, Health, RFA, Molecular Biology/Genetics, Risk Assessments, Health Risk Assessment, air toxics, Atmospheric Sciences, Biochemistry, particulate matter, Environmental Chemistry, aerosols, cardiopulmonary, risk assessment, susceptible populations, ultrafine particles, urban environment, aerosol, ambient air quality, cardiovascular disease, cardiovascular vulnerability, coronary artery disease, health effects, mortality, lung inflamation, carbon particles, inhalation toxicology, fine particles, environmental health effects, cardiopulmonary responses, cytokine production, particle exposure, human health effects, particulates, sensitive populations, ambient monitoring, lung, metals, ambient air monitoring, pathophysiological mechanisms, pulmonary, urban air pollution, human health, human exposure, morbidity, particle size, pulmonary disease, animal model
Progress and Final Reports:
1999 Progress Report
2000 Progress Report
Original Abstract
2002 Progress Report
2003 Progress Report
2004 Progress Report
Final Report
Main Center Abstract and Reports:
R827354 Airborne PM - 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