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2003 Progress Report: Asthma Susceptibility to PM2.5
EPA Grant Number: R827351C003Subproject: this is subproject number 003 , established and managed by the Center Director under grant R827351
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: EPA NYU PM Center: Health Risks of PM Components
Center Director: Lippmann, Morton
Title: Asthma Susceptibility to PM2.5
Investigators: Thurston, George D. , Reibman, Joan
Institution: NYU School of Medicine
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, 2003 through May 31, 2004
RFA: Airborne Particulate Matter (PM) Centers (1999)
Research Category: Particulate Matter
Description:
Objective:The objectives of this research project are to investigate which particulate matter (PM) component(s) and PM mechanisms affect asthmatics most strongly and to prospectively follow a cohort of non-smoker asthmatics and evaluate PM effects on their health status. The ultimate goals are to establish technical and operational feasibility for a combined epidemiological/clinical research study; demonstrate associations between specific PM components and commonly occurring asthma exacerbations attributable to air pollution; and develop hypotheses regarding the mechanisms of the PM-health effects association that can be tested via toxicological studies by other researchers in the New York University (NYU) U.S. Environmental Protection Agency (EPA) PM Research Center (e.g., via controlled exposure studies). Moreover, the results of this study may be used as preliminary results for a follow-up study in this already characterized population.
This is one of the projects funded by the New York University (NYU) PM Center. The progress for the other projects is reported separately (see reports for R827351C001, R827351C002, and R827351C004 through R827351C016).
Progress Summary:Progress Years 1-4
We originally recruited patients during 1999-2000 for our cohort of adult non-smoking asthmatic subjects willing to be followed by prospective monitoring, on days following low versus high PM2.5 concentrations. Because of difficulties in the first summer (of 1999) in inducing sputum in asthma patients, we thought we needed to improve our induced sputum technique. Approval was obtained to induce sputum from normal volunteers, and 10 subjects were recruited and duplicate procedures performed on these subjects.
Subjects with asthma were recruited from the previous summer cohort, clinics, and local advertisements. Participants were asked to be “on call” for 1 day notice to come for 4 visits—2 “High” and 2 “Low” visits. These correspond to 2-day lag visits from the defined day. Subjects then underwent pulmonary function testing (PFT), blood draw, and premedication with bronchodilator followed by sputum induction. “High” and “Low” PM days were defined based on analysis of previous data: “High” = PM10 ≥ 40 µg/m3; “Low” = PM 10 ≤ 20 µg/m3.
Sputum induction was performed by use of increasing concentrations of hypertonic saline (3 percent, 4 percent, 5 percent) via an ultrasonic nebulizer that were inhaled for 7 minutes. Subjects underwent spirometry for measurement of FEV1 at the start of the procedure, and after each period of saline inhalation. If the FEV1 dropped 20 percent, the procedure was terminated. After each saline inhalation, subjects coughed into a sterile container. Sputum plugs were separated from saliva and examined within 2 hours. After weighing, sputum plugs were dissolved in dithiothreitol (0.1 percent) and phosphate buffered saline. The suspension then was filtered and a total nonsquamous cell count performed. Cell viability was determined by trypan blue exclusion. Cytospins were prepared, stained with Wright’s stain, and a differential cell count of nonsquamous cells types performed. Metachromatic cells were detected in preparations stained with toluidine blue. Cell pellets also were prepared for RNA analysis.
At that time, sputum samples were collected successfully on both normal subjects (n = 10) and from subjects with asthma (n = 11). In addition, some 44 blood serum samples were collected. Although this did not provide a database sufficient for the originally envisioned “high” versus “low” PM day comparisons, these samples did provide a basis for evaluating which biomarkers can be successfully used to assess PM-induced effects. For example, preliminary findings from several of these samples already have demonstrated the ability to detect and measure inflammatory cells in sputum samples, as well as the presence of elevated levels of eosinophils. In addition, sputum samples were analyzed for the presence of dendritic cells (CD1a+), and the quality of mRNA was tested in sputum cell pellets.
Overall, progress was made toward our study goals, but practical problems arose. The number of subjects that reliably participated was too limited, and only 2 days in the summer of 2000 met the “high” pollution day criteria, as opposed to an expected 18 days. Furthermore, only 50 percent of our previous subjects agreed to return for the study. Forty subjects were screened by PFT and clinical parameters. Twenty of these subjects failed screening on PFT criteria, even after modification of exclusion criteria; 13 patients agreed to participate in the screening. These factors conspired to significantly reduce the number of sample-days that could be collected.
The limitations in our ability to collect and analyze samples forced us to re-examine and to adjust our approach to better work towards achieving our planned goals. Based upon the above-discussed prior findings from the already collected samples, new subject blood samples were collected biweekly on 17 asthma subjects during the summer of 2001. This scheduled design avoided past problems experienced in trying to bring in subjects on short notice.
Our methods involved monitoring subjects with asthma over a 3-month period in the summer of 2001 for spirometry (every 2 weeks), AM and PM peak flow measurements (daily), symptom questionnaire (severity scale, albuterol use), and serum samples (every 2 weeks). We also collected PM and other pollution data continuously over this 3-month period. Our goal was to determine whether there is an association between PM levels and these defined health outcomes. In particular, we aimed to test the hypothesis that increases in plasma levels of specific chemokines related to asthma (i.e., involved in eosinophil recruitment and Th2 responses) are associated with elevations in ambient PM. Thus, blood samples and PFT measurements were collected during subject visits over 12 weeks during July-September 2001 (total = 6 samples/subject).
There was a wide range of PM2.5 levels experienced over the summer of 2001 in the New York area, with levels ranging from below 10 µg/m3 to nearly 60 µg/m3. This provided a range of exposures with which to look for variations in biomarkers during this period. We analyzed the daily PM samples collected near the NYU School of Medicine (at Hunter College) for trace elemental composition (using our PM Center Resource x-ray fluorescence analyzer), allowing us to examine our health effects data relative to exposures to various PM components over time.
We finished analyzing our serum plasma samples for key inflammatory cytokines and chemokines. These samples were collected from individuals with asthma repeatedly throughout the summer of 2001. Cytokines that could be meaningfully evaluated in these samples, and are indicative of changes in immune cellular responses, were determined in serum media; specifically: Eotaxin, RANTES, IL-5, and IP-10 (a Th1 control). Such markers recently have been shown to be measurable at very low levels in plasma by Campbell, et al. (2001). Of these biomarkers, we found that blood RANTES levels increased with increasing PM2.5 during the summer of 2001. In these data, PM2.5 is a significant predictor of RANTES in a one-way test (t = 1.73), and when the one apparent outlier (i.e., a very low value from one patient) is excluded, the significance of this association is further increased (to t = 3.32) (see Figure 1). Overall, the results of this study suggest that chemokines involved in airway inflammation in asthmatics, such as RANTES, can increase in response to short-term elevations in ambient PM2.5 levels and may offer one reason why asthma exacerbations occur during episodes of increased ambient PM levels.
Progress Year 5
Given our RANTES results from the summer of 2001, we now have similarly analyzed the previous years’ (1999 and 2000) blood samples collected in this population for chemokines to test the consistency of this relationship across years. Although fewer in number (a total of 21 samples collected in those two campaigns versus 60 in the summer of 2001), this analysis will provide an independent test of the relationship, as well as increase the number of samples that are analyzed, providing greater statistical power with which to consider possible other pollutant interactions in our model. Genotype evaluation of all patients also is being conducted.
References:
Campbell JD, Stinson MJ, Simons FER, Rector ES, Hay Glass GT. In-vivo stability human chemokine and chemokine receptor. Human Immunology 2001;62(7):668-678.
Future Activities:A manuscript of results is being prepared for submission to a medical journal. Using biomarker data, as well as the other health data collected for each subject, we will look at comparisons of PM mass/component responses in this group of asthmatics.
Journal Articles on this Report: 1 Displayed | Download in RIS Format
| Other subproject views: | All 4 publications | 2 publications in selected types | All 2 journal articles |
| Other center views: | All 95 publications | 86 publications in selected types | All 74 journal articles |
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Reibman J, Hsu Y, Chen LC, Bleck B, Gordon T. Airway epithelial cells release MIP-3α/CCL20 in response to cytokines and ambient particulate matter. American Journal of Respiratory Cell and Molecular Biology 2003;28(6):648-654. |
R827351 (2003) R827351 (Final) R827351C003 (2003) R827351C003 (Final) R827351C004 (2002) R827351C004 (Final) |
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thoracic particles, PM10, fine particles, PM2.5, ultrafine particles, PM 0.1, lung dosimetry models, human exposure models, pulmonary responses, cardiovascular responses, immunological responses, criteria air pollutants, concentrated ambient aerosols, aerosol, air pollutants, air pollution, airborne pollutants, airway disease, airway inflammation, airway variability, allergen, ambient air, ambient air quality, analytical chemistry, assessment of exposure, asthma, asthma morbidity, atmospheric monitoring, biological markers, childhood respiratory disease, children, combustion, combustion contaminants, combustion emissions, compliance monitoring, dosimetry, epidemiology, exposure, exposure and effects, health effects, heart rate variability, human exposure, human health, human health effects, incineration, lead, lung, mercury, morbidity, particulates, pulmonary, pulmonary disease, respiratory,
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HUMAN HEALTH, ENVIRONMENTAL MANAGEMENT, Air, Scientific Discipline, Health, RFA, PHYSICAL ASPECTS, Susceptibility/Sensitive Population/Genetic Susceptibility, Health Effects, Risk Assessment, Risk Assessments, genetic susceptability, Health Risk Assessment, Physical Processes, Atmosphere, particulate matter, Environmental Chemistry, Allergens/Asthma, Environmental Monitoring, exposure assessment, asthma indices, ambient air quality, chemical characteristics, inhalation, ozone, second hand smoke, human health risk, air toxics, particulates, sensitive populations, toxicology, atmospheric particles, ozone monitoring, air pollution, airborne pollutants, airway disease, environmental risks, tobacco smoke, ambient air monitoring, atmospheric particulate matter, exposure, human susceptibility, asthma triggers, allergic response, atmospheric aerosol particles, airborne particulate matter, asthma, health risks, human exposure, airway inflammation
Relevant Websites:
http://www.med.nyu.edu/environmental/centers/epa/
Progress and Final Reports:
1999 Progress Report
2000 Progress Report
2001 Progress Report
2002 Progress Report
Original Abstract
Final Report
Main Center Abstract and Reports:
R827351 EPA NYU PM Center: Health Risks of PM Components
Subprojects under this Center:
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R827351C001 Exposure Characterization Error
R827351C002 X-ray CT-based Assessment of Variations in Human Airway Geometry: Implications for Evaluation of Particle Deposition and Dose to Different Populations
R827351C003 Asthma Susceptibility to PM2.5
R827351C004 Health Effects of Ambient Air PM in Controlled Human Exposures
R827351C005 Physicochemical Parameters of Combustion Generated Atmospheres as Determinants of PM Toxicity
R827351C006 Effects of Particle-Associated Irritants on the Cardiovascular System
R827351C007 Role of PM-Associated Transition Metals in Exacerbating Infectious Pneumoniae in Exposed Rats
R827351C008 Immunomodulation by PM: Role of Metal Composition and Pulmonary Phagocyte Iron Status
R827351C009 Health Risks of Particulate Matter Components: Center Service Core
R827351C010 Lung Hypoxia as Potential Mechanisms for PM-Induced Health Effects
R827351C011 Urban PM2.5 Surface Chemistry and Interactions with Bronchoalveolar Lavage Fluid (BALF)
R827351C012 Subchronic PM2.5 Exposure Study at the NYU PM Center
R827351C013 Long Term Health Effects of Concentrated Ambient PM2.5
R827351C014 PM Components and NYC Respiratory and Cardiovascular Morbidity
R827351C015 Development of a Real-Time Monitoring System for Acidity and Soluble Components in Airborne Particulate Matter
R827351C016 Automated Real-Time Ambient Fine PM Monitoring System