2001 Progress Report: Clinical Studies of Ultrafine Particle Exposure in Susceptible Human SubjectsEPA 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. , Beckett, William , Cox, Christopher , Morrow, P. E. , Utell, Mark J. , Zareba, Wojciech
Current Investigators: Frampton, Mark W. , Utell, Mark J.
Institution: University of Rochester
Current Institution: University of Rochester
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
RFA: Airborne Particulate Matter (PM) Centers (1999) RFA Text | Recipients Lists
Research Category: Air Quality and Air Toxics , Particulate Matter , Air
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.
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).
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.
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.
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 27 publications||26 publications in selected types||All 24 journal articles|
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Supplemental Keywords:ultrafine carbon particle, UFP, asthma, lungs, clinical exposure study, airway inflammation, blood leukocyte activation, cardiac electrophysiologic., 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
Progress and Final Reports:Original Abstract
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