Grantee Research Project Results
2003 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: Rochester PM Center
Center Director: Oberdörster, Günter
Title: Clinical Studies of Ultrafine Particle Exposure in Susceptible Human Subjects
Investigators: Frampton, Mark W. , Zareba, Wojciech , Morrow, P. E. , Utell, Mark J. , Cox, Christopher , Beckett, William
Current 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)
Project Period Covered by this Report: June 1, 2003 through May 31, 2004
RFA: Airborne Particulate Matter (PM) Centers (1999) RFA Text | Recipients Lists
Research Category: Air Quality and Air Toxics , Particulate Matter , Air
Objective:
The objectives of the research project are to develop a facility for human studies of ultrafine particles and to utilize controlled human exposures to examine, in healthy and potentially susceptible subjects, the deposition of inhaled ultrafine carbon particles (UFP) and the role of UFP in inducing respiratory and cardiovascular health effects.
This is one of the projects of the Rochester PM Center. The progress for the other projects is reported separately (see reports for R827354 C001, R827352C002, R827354C004 and R827352C005).
Progress Summary:
In our previous Progress Reports, we described the development of an ultrafine particle exposure system for use in human studies: particle generation and characterization; measurements of ultrafine particle deposition in healthy subjects at rest and exercise; and effects on induced sputum cellularity, alterations in blood leukocytes, and heart rate variability and repolarization. The findings were consistent with the hypothesis that inhalation of ultrafine carbon particles at low mass concentrations have the potential to elicit cardiovascular effects. Confirmation of these findings would represent the most convincing support for the ultrafine hypothesis to date.
We designed 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, circulating leukocyte activation, 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.
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 measured the pulmonary diffusing capacity for carbon monoxide, which is affected by changes in 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 have now completed the control and particle exposures for all 16 subjects in this study. Results have been presented at the American Thoracic Society International Conference in Orlando, FL, and a manuscript is in press. The results of this study confirmed our previous observations of UFP effects on leukocyte expression of adhesion molecules. Monocyte expression was decreased significantly for CD18, CD11b, and CD54. We also observed a significant reduction in the pulmonary diffusing capacity for carbon monoxide (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 DLCO is a function of the diffusing capacity of the pulmonary “membrane”, Dm, and the pulmonary capillary blood volume, Vc. 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.
We did not see any significant effect of UFP exposure on total forearm blood flow, either before or after ischemia. UFP exposure appeared, however, to cause a blunting of the increase in peak flow in response to exercise. Forearm blood flow following ischemia was measured 3.5 hours after exposure. The values represent change from the pre-exposure measurement. 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. The difference in peak flows at 3.5 hours after exposure was significant by paired t-test, but not by analysis of variance. Minimal vascular resistance, which is the mean arterial pressure divided by the peak flow, was significantly increased compared with air exposure at this time point. Mean arterial pressure did not change significantly. 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.
Significance
The findings from this study provide confirmation of our previous observations of changes in blood leukocyte adhesion molecule expression. The reduction in diffusing capacity and changes in forearm flow-mediated vascular dilatation suggest that inhalation of low mass concentrations of ultrafine carbon particles cause subtle changes in both pulmonary and systemic endothelial function.
Summary of Human Clinical Studies of UFP Exposure
Our initial hypotheses that inhalation of ultrafine carbon particles would cause pulmonary inflammation and an acute phase response have not been confirmed. We observed subtle changes, however, in blood leukocyte subsets and adhesion molecule expression that suggest there may be effects on endothelial function. Findings from our study of exposure to 50 µg/m3 appear to confirm these observations. The finding that these very low mass concentrations of particles have vascular effects have important implications for future particulate matter regulatory strategies. Further studies are needed to confirm our observations and to determine effects in people with underlying vascular dysfunction.
Future Activities:
The mechanism by which UFP mediate vascular effects is unknown. We hypothesized that the effect on pulmonary diffusing capacity is mediated by alterations in pulmonary endothelial function as a consequence of an increased burden of reactive oxygen species carried into the deep lung on the surface of the ultrafine particles. We further hypothesize that this burden of reactive oxygen species is a consequence of the high surface area of ultrafine particles and that these effects will not be seen with exposure to a similar mass concentration of larger (fine) carbon particles with a lower surface area. We have therefore initiated a study to test the following hypothesis: The reduction in diffusing capacity for carbon monoxide following inhalation of carbon particles is proportional to the surface area of the deposited aerosol. In this study, healthy subjects will be exposed to purified air and two different aerosols, at equivalent lung deposition by mass, but differing in surface area. Sixteen healthy never-smokers, with normal pulmonary function, aged 18 to 40 years will be studied. Each subject will have three exposures separated by at least 2 weeks, and a total of 10 visits will be required for each subject.
If our hypothesis is confirmed, these studies will demonstrate that UFP inhalation has a greater effect on vascular function than fine particles at a similar mass concentration. They will also set the stage for future studies to determine whether reactive oxygen species mediate the vascular effects of UFP.
Journal Articles on this Report : 2 Displayed | Download in RIS Format
Other subproject views: | All 27 publications | 26 publications in selected types | All 24 journal articles |
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Other center views: | All 106 publications | 99 publications in selected types | All 91 journal articles |
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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) R832415 (2010) R832415 (2011) R832415 (Final) R832415C003 (2011) R832415C004 (2011) |
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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) R827354C003 (2003) R827354C003 (Final) R827354C004 (Final) R826781 (Final) R832415 (2010) R832415 (2011) R832415 (Final) R832415C003 (2011) R832415C004 (2011) |
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Supplemental Keywords:
pollution prevention, urban air pollution, atmosphere, metals, air, health, waste, atmospheric sciences, biochemistry, children’s health, environmental chemistry, epidemiology, genetics, virology, molecular biology, health risk assessment, risk assessments, incineration, combustion, combustion engines, air toxics, tropospheric ozone, PM2.5, particulates, ultrafine particles, particulate matter, particle exposure, particle size, aerosol, aerosols, ambient air, ambient air monitoring, ambient air quality, animal model, atmospheric, cardiopulmonary, cardiopulmonary responses, cardiovascular disease, cardiovascular vulnerability, coronary artery disease, cytokine production, fine particles, human exposure, human health, human health effects, environmental health effects, inhalation toxicology, lead, lung, lung inflammation, metals, morbidity, mortality, pathophysiological mechanisms, pulmonary, pulmonary disease, stratospheric ozone, sensitive populations, susceptible populations,, 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 mechanismsRelevant Websites:
http://www2.envmed.rochester.edu/envmed/PMC/ Exit
Progress and Final Reports:
Original AbstractMain 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
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.
Project Research Results
- Final Report
- 2004 Progress Report
- 2002 Progress Report
- 2001 Progress Report
- 2000 Progress Report
- 1999 Progress Report
- Original Abstract
24 journal articles for this subproject
Main Center: R827354
106 publications for this center
91 journal articles for this center