2000 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, 2000 through May 31, 2001
RFA: Airborne Particulate Matter (PM) Centers (1999) RFA Text | Recipients Lists
Research Category: Air Quality and Air Toxics , Particulate Matter , Air
These studies 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 and ultrafine carbon particles containing trace metals (UMP) in inducing health effects.
We have 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. Because our initial exposure mass concentrations are within the range of PM measurements outdoors, it was important to know numbers and mass concentrations of particles within the Clinical Research Center and the Environmental Chamber where the facility is located, as well as in the intake air for the exposure facility. These measurements were performed, and represent the first report of ultrafine particle number within an acute health care facility (Reisenfeld, et al., 2000).
For our initial studies, exposures were conducted at rest with a relatively low concentration of pure carbon UFP (~10 µg/m3, ~2 x 106 particles/cm3, count median diameter 26.4 nm, GSD 2.3). Twelve healthy nonsmoking subjects (6 female) inhaled either filtered air or UFP by mouthpiece for 2 hours at rest, with a 10 minute break after the first hour. Exposures were double blinded, randomized, and separated by at least 2 weeks. The total respiratory tract deposition fraction (DF) was determined for six different particle size fractions after correction for system losses, and the overall DF was calculated for both number and mass for each subject. Respiratory symptoms, spirometry, blood pressure, pulse-oximetry, and exhaled NO were assessed before and at intervals after the exposure. Sputum induction was performed 18 hours after exposure. Continuous 24-hour, 12-lead Holter monitoring was performed on the day of the exposure and analyzed for changes in heart rate variability and repolarization phenomena.
The results of this initial exposure study have been presented in abstract form (Frampton, Chalupa, Morrow, Gibb, Oberdörster, Speers, et al., 2000; Boscia, et al., 2000; Frampton, Chalupa, Morrow, Gibb, Oberdorster, Boscia, et al., 2000). The overall DF was 0.66 ± 0.12 (mean ± SD) by number, and 0.58 ± 0.14 by mass. Analysis of variance indicated no significant 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. However, significant "carry-over" effects were found for some endpoints. Analysis of heart rate variability (HRV) also showed evidence for occasional "carry-over" effects. Overall, we concluded that exposure to 10 g/m3 carbonaceous UFP at rest did not cause significant respiratory or cardiac effects in healthy nonsmokers.
We subsequently studied healthy subjects exposed for 2 hours to air and to two concentrations of carbonaceous UFP, 10 µg/m3 and 25 µg/m3, with intermittent exercise. Each of the three exposures was separated by at least 2 weeks, and a total of seven visits were required for each subject. Monitoring and measurements were identical to those for the resting exposures.
The planned 12 subjects (6 male and 6 female) completed all phases of the study. Analysis of variance currently is in progress by Dr. Cox, from the Biostatistical Core. Preliminary 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; mean ± SD). There were no obvious particle-related effects on symptoms, spirometry, pulse oximetry, airway nitric oxide production, or sputum cell differential counts. In addition, no effects were seen on blood concentrations of fibrinogen, von Willebrandt factor, or clotting factor VII. HRV data from this protocol currently are being analyzed. Interestingly, polymorphonuclear leukocyte (PMN) expression of CD54 (ICAM-1) and CD11a (LFA-1), as measured by immunofluorescence and flow cytometry, showed significant differences between UFP and air exposure. For ICAM-1, expression decreased after both particle and air exposures, but the reduction was to a greater degree after UFP than after air exposure, with a dose-response relationship. Our findings suggest that UFP exposure may enhance exercise effects on PMN adhesion molecule expression or vascular distribution in healthy subjects.
We also found a statistically significant increase in the expression of CD25 (the IL-2 receptor) on circulating T lymphocytes after exposure to 25 µg/m3 UFP (p=0.025). For all of these surface markers, the magnitude of change was small, and unlikely to be clinically important. However, they are consistent with our hypothesis that UFP exposure may alter the activation state of circulating leukocytes.
Data from this study are currently being submitted to Dr. Christopher Cox for formal analysis of variance. Preliminary analyses of the Holter monitor data are in progress. An abstract has been accepted for presentation at the ATS International Conference in San Francisco, May 20, 2001 (Frampton, et al., in press).
We conclude that exercise increases the already high respiratory deposition of UFP, and our data suggest that exposure to 10-25 µg/m3 UFP is associated with effects on circulating leukocytes. We have now initiated studies of UFP exposure in subjects with asthma. Because of the possibility of "carry-over" effects suggested by the analysis of variance, we have increased the interval between exposures to 3 weeks. In addition, subjects now return 48 hours after exposure for additional studies, including cardiac monitoring, to determine if there are delayed effects.
Future studies are planned in elderly healthy subjects, and in subjects with chronic obstructive pulmonary disease (COPD) and coronary artery disease.
Journal Articles on this Report : 2 Displayed | Download in RIS Format
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Supplemental Keywords:pollution prevention, atmosphere, particulates, metals, sensitive population., 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