Grantee Research Project Results
2004 Progress Report: Air Pollution and Human Vascular Dysfunction: Mechanism and Mediators
EPA Grant Number: CR830837Title: Air Pollution and Human Vascular Dysfunction: Mechanism and Mediators
Investigators: Brook, Robert D. , Keeler, Gerald J. , Brook, Jeffrey R. , Dvonch, Joseph T. , Silverman, Frances , Vincent, Renaud , Rajagopalan, Sanjay
Institution: University of Michigan , Health Canada - Ottawa , Environment Canada , University of Toronto
Current Institution: University of Michigan , Health Canada - Ottawa , University of Toronto
EPA Project Officer: Chung, Serena
Project Period: May 1, 2003 through April 30, 2006 (Extended to April 30, 2008)
Project Period Covered by this Report: May 1, 2004 through April 30, 2005
Project Amount: $1,050,000
RFA: Airborne Particulate Matter Health Effects: Cardiovascular Mechanisms (2002) RFA Text | Recipients Lists
Research Category: Human Health , Particulate Matter , Air
Objective:
Short-term exposure to concentrated ambient fine particulate air pollution (PM2.5) and ozone (O3) causes acute conduit artery vasoconstriction and increases the risk for acute myocardial infarction. This abrupt alteration in vascular tone likely is an important biological mechanism linking air pollution exposure with acute cardiovascular events. The objectives of this research project are to: (1) elucidate the underlying patho-physiological mechanisms linking air pollution with impaired arterial reactivity; (2) determine the significance of the air pollution-mediated arterial vasoconstriction on systemic hemodynamics and blood pressure; and (3) identify the specific air pollution components responsible for the detrimental impact on human vascular function.
Progress Summary:
This research project, hereafter referred to as CLEANAIR (Cardiovascular Linkage between Endothelial dysfunction ANd AIR pollution), is composed of two major components. Project 1, at the University of Michigan, is investigating the mechanisms of arterial vasoconstriction related to concentrated ambient PM2.5 (CAP) exposure. Project 2 (sub-study), at the University of Toronto, is investigating the CAP and gaseous components responsible for eliciting the biological responses in a human exposure model.
Project 1 Status
Overall, Project 1 continues to meet anticipated timelines. Because of limitations in availability of the human exposure chamber during Year 1 of the project, we began exposures in February 2004 (6-8 months late) and continued through June 2004. Exposures for Year 2 of the project began in February 2005 and continued through June 2005. It is anticipated that exposures will resume in fall 2005 and continue through June 2006 (extra 3-5 months) to complete the project on time.
In Year 1, all necessary equipment was purchased, and engineering projects were completed. Year 2 of the project was on schedule for completing human exposures.
Table 1. Project 1 Completed Human Exposures (Years 1 and 2, End: June 2005)
Exposure |
Placebo (n) |
Bosentan (n) |
Vitamin C (n) |
Total Exposures Complete |
CAP + O3 |
25 |
25 |
25 |
75 |
n= number of patients exposed |
Project 1 will require a total of 150 exposures (i.e., 50 patients, 3 exposures each) during 3 years (16-17 patients per year). For the final year, we will need to complete 25 patients (75 total exposures). To complete this project, we anticipate performing exposures beginning in fall 2005 and continuing through June 2006 (study completion). Based upon enrollment success to date and availability of the exposure chamber (AirCare-1), we should be able to meet these timelines.
Project 2 Status
Overall, this project is slightly behind schedule. A major reason for the delay was the addition of a fourth (filtered air/placebo) exposure per subject, which was recommended by both internal and external reviews of the project. Exposures began in November 2003 and continue on an ongoing basis without interruption (approximately 1-2 exposure per week). This project has enrolled 10 subjects thus far. The plan is to enroll 50 subjects (4 exposures each), for a total of 200 exposures during 3 years. Table 2 demonstrates the status of exposures as of June 2005.
Table 2. Project 2 Enrollment Status (End: June 2005)
Filtered Air (n) |
CAP (n) |
CAP + O3 (n) |
O3 (n) |
Total (n) |
16 |
16 |
16 |
16 |
64 |
n= number of patients exposed |
Exposures for Year 1 of this project began 6 months after grant activation because of the time required to set up the subcontract with the University of Toronto. During this period, the purchase of equipment (Terason ultrasound) and training of ultrasound technicians took place.
All data on human outcomes from both project sites (i.e., blood pressure, blood biomarkers, platelet aggregation, endothelial function, arterial compliance, and 24-hour blood pressure) have been successfully collected and analyzed and are stored on our computer databases at the University of Michigan and backed up on CDs. Additional blood aliquots are being archived in a -70oC freezer at the University General Clinical Research Center. Blood for plasma endothelins has been sent to the University of Ottawa (Dr. Vincent) and is being analyzed by high performance liquid chromatography (HPLC). All data from both sites currently are archived in a coded, randomized fashion. No analyses are planned to be performed until completion of the entire project; therefore, there are no preliminary data to report. There have been no changes to the aims of both projects.
Exposure Estimation, Air Pollution Measurement and Characterization
Air pollution exposure measurements and characterizations have been collected at both project sites. Both projects monitor continuous CAP PM2.5 (TEOM, light scatter) and ozone levels during actual exposures. Characterizations of collected filters are being performed in the laboratories of co-principal investigators Dr. Gerald Keeler (metals from both project sites) and Dr. Jeffrey Brook (organic carbon/elemental carbon from both project sites). Sulfates and nitrates are being characterized at each site respectively.
As part of this project, the University of Michigan Air Quality Laboratory (UMAQL) is performing the physical and chemical characterization of pollutants in support of the exposure studies taking place in Ann Arbor, Michigan. The measurements performed include, the gaseous pollutants ozone, SO2, CO, NOx, acid gases, and characterization of particulate matter (PM), including the particle size and number, as well as the PM composition, which includes organic and elemental carbon, a suite of trace elements, and sulfate and nitrate.
Design, Construction, Implementation, and Evaluation of Equipment and Supplies for Human Exposure Chamber and Exposure Characterization. During Year 1 of the project, an enclosed chamber for use in human exposure studies was obtained, modified, and installed in the mobile atmospheric research laboratory, AirCARE1. A system was designed, field-evaluated, and implemented, which would allow generation and controlled delivery of ozone to human exposure subjects. Likewise, an integrated system also was designed and field-tested for the controlled delivery of CAPs. After evaluation of the results, which showed that the system would deliver 120 ppb continuously of ozone and 150 µg/m3 of CAPs, as per study protocol, the exposure studies began.
Table 3 details the pollutant measurement performed during each 2-hour human-exposure period. Mass concentration of CAPs was determined by placing 37-mm Teflon filters (Gelman Science) in the air stream of CAPs at a flow rate of 7 L/min. In addition, a Rupprecht and Patashnick Series 1400a TEOM was placed to monitor the CAPs continuously during the exposure periods. An identical TEOM also was run continuously to measure ambient PM2.5 concentrations.
To characterize size distribution of CAPs, Scanning Mobility Particle Sizer (SMPS) (TSI, model 3936), and Aerodynamic Particle Sizer (APS) (TSI, model 3321) were operated during the 2-hour periods. Ozone is monitored using the Thermo Electron Model 49 analyzer.
During each exposure period, CAPs also were sampled on pre-baked Quartz filters (Gelman Science), and 47-mm Teflon filters were collected at a flow rate of 7 L/min. An Aethalometer™ also was used to obtain a real-time measurement of the aerosol black carbon concentration. Furthermore, meteorological parameters, including temperature, relative humidity, precipitation, and wind speed and direction, were monitored to assess the day-to-day variability in local transport pathways and source influences.
As of June 2005, a total of 75 human exposure periods were completed successfully using the AirCARE1 facility in Ann Arbor.
Table 3. Measurements During Each Exposure Period
Measurement |
Measurement Method |
Measurement Frequency |
Mass |
TEOM |
Continuous |
Ozone (O3) |
TEI Model 49 O3 Analyzer |
Continuous |
Black Carbon |
Aethalometer |
Continuous |
Particle Size (0.5 to 20 μm) |
Aerodynamic Particle Sizer |
Continuous |
Particle Size (10 nm to 500 nm) |
Scanning Mobility Particle Sizer Model TSI 3936 |
Continuous |
Post-Exposure Analysis |
||
Trace Metals |
Open Face Filter Packs Sampler |
2-hour Integrated Samples |
Organic/ |
Open Face Filter Packs Sampler |
2-hour Integrated Samples |
Major Ions |
Open Face Filter Packs Sampler |
2-hour Integrated Samples |
Meteorological Measurements |
||
Temperature |
R.M. Young Temp/RH Probe |
Continuous |
Relative Humidity |
R.M. Young Temp/RH Probe |
Continuous |
Wind Direction |
R.M Young Wind Monitor-RE |
Continuous |
Wind Speed |
R.M Young Wind Monitor-RE |
Continuous |
Figure 1 shows an example of the temporal variations of CAPs mass and ozone concentration achieved by the AirCARE1 concentrator and ozone generation and delivery system during the 2-hour human-exposure period on April 14, 2004. As shown in this figure, the levels of CAPs and ozone were produced and maintained very close to the proposed target values, 150 μg/m3 and 120 ppb, respectively. It should be noted, however, that under exposure periods of very low ambient PM concentrations, a level of 150 µg/m3 typically cannot be maintained, but this has occurred only for a small number of the human-exposure periods. Although not unexpected, this is a limitation of most concentrators, including the one in the AirCARE1, for days with ambient concentrations of PM2.5 less than 5 µg/m3. In addition to the continuous monitoring of CAPs and ozone, levels of EC and particle number concentration as well as meteorological condition have been monitored continuously during each exposure period. Figure 2 illustrates temporal variations of EC and ultrafine particle number concentration during the 2-hour exposure period. This continuous monitoring enables us to identify any short-term air pollution episode at the site.
Figure 1. Temporal Variations of CAPs and Ozone Concentration During a 2-Hour Exposure Period on April 14, 2004
Figure 2. Temporal Variations of CAPs, EC, and Ultrafine Particle Concentrations During a 2-Hour Exposure Period on March 17, 2004
At the University of Michigan, laboratory analysis and data processing have been conducted in accordance with the protocols outlined by the quality assurance program plan developed for this project. We have completed gravimetric analysis of CAPs samples collected on Teflon filters from 55 exposure studies. Those Teflon filters, as well as 30 CAPs samples collected at the University of Toronto site, were extracted in 8 mL of 10 percent HNO3. The extraction solution was sonicated for 48 hours in an ultrasonic bath, and then was acid-digested passively for a 2-week duration. The extracts are being analyzed for a suite of elements by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Another set of Teflon filter CAPs samples was extracted with 7 mL of ultra pure MQ water for anions and cations by ion chromatography.
Results to Date
As discussed earlier, all data from both sites on human outcomes and measures of environmental exposures are data-based and stored in a randomized, coded fashion. No analyses are expected to be performed until completion of both projects. No results, therefore, are reported here.
Future Activities:
We plan to continue human exposures in both Projects 1 and 2 throughout Year 3 of the grant. The equipment, experimental techniques, study subjects, methods for evaluating biological outcomes, and characterizations of pollutants will not change from those used in Years 1 and 2. We anticipate completing a total of 150 exposures by June 2006 for Project 1 (on schedule). This target will be met by performing exposures during fall 2005 and continuing through June 2006. If, for unforeseen reasons, AirCare1 is not available for human exposures in fall 2005, a no-cost extension request, will be submitted to the EPA Project Officer during Year 3 to give us time to complete Project 1. At the present rate of enrollment, we will complete approximately 15 x 3 additional exposures (45 total) during Year 3, if Project 1 can do exposures only during January-June 2006. We would fall approximately 30 exposures (i.e., 10 patients) short of schedule in this case. In this event, the additional 10 subjects would be enrolled and completed by fall 2006.
Journal Articles:
No journal articles submitted with this report: View all 5 publications for this projectSupplemental Keywords:
endothelium, atherosclerosis, concentrated ambient air pollution,, RFA, Scientific Discipline, Health, Air, particulate matter, Health Risk Assessment, Risk Assessments, Biochemistry, atmospheric particulate matter, particulates, human health effects, PM 2.5, airway disease, ozone, airborne particulate matter, cardiovascular vulnerability, air pollution, human exposure, vascular dysfunction, cardiovascular diseaseProgress and Final Reports:
Original AbstractThe 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.