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CARDIOVASCULAR TOXICITY OF CONCENTRATED AMBIENT FINE, ULTRAFINE AND COARSE PARTICLES IN CONTROLLED HUMAN EXPOSURES

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Impact/Purpose:

Using our controlled particle exposure facility, we have demonstrated that short-term exposure to fine Concentrated Ambient Particles (CAPs) + ozone (O3) causes acute conduit artery vasoconstriction and is associated with increased diastolic blood pressure in healthy adults. Both of these findings were associated with the organic carbon component of the particulate matter (PM).

This proposal aims to further examine the components and sources of PM responsible for these cardiovascular physiologic responses. A new state-of-the-art ambient PM exposure facility (to be built at the University of Toronto in collaboration with Harvard School of Public Health) will allow us to examine responses to fine, ultrafine and coarse CAPs, in downtown Toronto, Canada. To gain insight into these responses, cardiovascular outcomes in the proposed study will include not only our more established physiologic outcomes (brachial artery diameter and blood pressure), but also complementary measurements including cardiovascular hemodynamics, autonomic function (e.g., HRV), markers of systemic inflammation (e.g., CBCs, IL-6, CRP) and endothelial dysfunction (endothelins).

Using our controlled particle exposure facility, we have demonstrated that short-term exposure to fine Concentrated Ambient Particles (CAPs) + ozone (O3) causes acute conduit artery vasoconstriction and is associated with increased diastolic blood pressure in healthy adults. Both of these findings were associated with the organic carbon component of the particulate matter (PM).

This proposal aims to further examine the components and sources of PM responsible for these cardiovascular physiologic responses. A new state-of-the-art ambient PM exposure facility (to be built at the University of Toronto in collaboration with Harvard School of Public Health) will allow us to examine responses to fine, ultrafine and coarse CAPs, in downtown Toronto, Canada. To gain insight into these responses, cardiovascular outcomes in the proposed study will include not only our more established physiologic outcomes (brachial artery diameter and blood pressure), but also complementary measurements including cardiovascular hemodynamics, autonomic function (e.g., HRV), markers of systemic inflammation (e.g., CBCs, IL-6, CRP) and endothelial dysfunction (endothelins).

Description:

Overview:  We recently completed the 141 exposures of 34 subjects. We are continuing testing of an additional 25 subjects through funding from Health Canada and support from Harvard University. These subjects will have three exposures including HFMA and two coarse CAPs. When completed in March 2012, in total we will have data for 100 coarse CAPs and 30 fine CAPs. In addition, we will include data from a previous study of 30 subjects (Brook, et al., 2009; Urch, 2010a) each receiving fine CAPs alone and fine CAPs+O3 at a lower CAPs level of 150 µg/m3. With this larger data set, we will have similar numbers of coarse (100 exposures) and fine (90 exposures) CAPs to compare cardiopulmonary responses. We also will examine dose-response associations between mass concentration and cardiopulmonary responses for each size fraction.
 
Statistical analyses were carried out at various stages throughout the exposures/data collection, and the results are summarized below. A number of significant collaborations were established as a result of the research project and our partnership with Harvard, leading to further studies, support of students/fellows and joint manuscripts. Below we present the findings to date:
 
Induced Sputum: Induced sputum is a non-invasive test used to collect cells from lung airways for examining acute lung inflammation. We previously have used this test to demonstrate adverse effects of controlled O3 exposures. Neutrophils, which are a gross marker of inflammation, are recruited from the blood into the lungs after an injury such as PM inhalation. We observed that sputum neutrophil counts were higher the morning after exposure for coarse CAPs compared to fine CAPs and both filtered air exposures. The results (Speck, et al., 2009) suggest a greater inflammatory response to coarse vs. fine CAPs, even though the mass concentration was lower for coarse CAPs (200 vs. 250 µg/m3). With the larger data set we will be able to examine differences in PM composition, which may explain the findings. Finally, we observed a stronger association between neutrophil levels and β-(1,3)-D-glucan concentration for coarse vs. fine CAPs suggesting that the biologic component of PM may be important, as described below.
 
Inflammatory Exposure Data: Currently, we are examining CBCs and blood IL-6/CRP as well as health effect associations with endotoxin and β-(1,3)-D-glucan for coarse and fine PM size fractions.
 
CAP and O3 Exposure and Blood IL-6: A retrospective analysis was carried out on blood IL-6, an acute phase protein and inflammatory marker, measured before and after controlled exposures to fine CAP and O3 (Urch, et al., 2010b). Blood IL-6 increased 3 hours after fine CAP exposure, but not as anticipated after CAP+O3 exposure. A possible explanation for the lack of IL-6 increase after CAP+O3 exposure was that some individuals switched to shallow breathing during CAP+O3 exposure, reducing their inhaled dose and resulting in a weakened IL-6 response. These findings highlight the importance of research examining co-pollutant mixtures vs. single pollutant exposures.
 
Ambient Air Pollution Effects on Blood IL-6 and Fibrinogen Levels: We were interested in assessing the effects of prior ambient exposures on baseline inflammatory measures from controlled exposure studies. This was a retrospective analysis using repeated-measures data in 45 non-smoking sub­jects (Thompson, et al., 2010). Hourly and daily moving averages were calculated for O3, NO2, SO2, and PM2.5. The association between pollutant exposure and baseline IL-6 and fibrinogen were assessed using up to 7-day moving averages. A significant association was observed for O3 as well as SO2 and IL-6 with similar trends for NO2 and PM2.5. These findings highlight the importance of considering the subject’s ambient pollution exposure before chamber exposures and suggest that the ambient pre-exposure data should be included in analyses of controlled exposure effects in order to control for potential baseline and carry-over effects during and after exposures.
 
Inflammation and Oxidative Stress: Health Canada supported measures of inflammation and oxidative stress in blood (IL-6, CRP, endothlin-1, vascular endothelial growth factor [VEGF]) and in urine (8-hydroxy-2-deoxyguanosine [8-OHdG], thiobarbituric acid reactive substances [TBARS] and VEGF). Results of the urine biomarkers showed elevated levels of VEGF at 3 hours (p=0.078) and 24 hours (p=0.040) following fine CAPs exposures. TBARS also increased at 24 hours after (p=0.075) exposures. Exposure to coarse CAP showed a similar but non-significant pattern for urine VEGF and TBARS. VEGF is a vascular permeability-inducing agent and an important stimulator of angiogenesis. TBARS is a biomarker of lipid peroxidation caused by oxidative stress. The results were presented in a meeting abstract and as an extended abstract published by the Air & Waste Management Association as conference proceedings (Liu, et al., 2011).
 
Blood Pressure and Brachial Artery Changes: We previously have shown significant increases in diastolic BP (DBP) during fine CAPs+O3 vs. filtered air exposures, as well as decreases in flow-mediated dilation (FMD) after exposure (Brook, et al., 2009). Our results showed increases in systolic BP (SBP) during CAPs exposures, with responses greater for fine CAPs as compared to coarse CAPs and smaller increases for both HEPA-filtered medical air (HFMA) and HEPA-filtered ambient air (HFAA) exposures. However, the increases in SBP did not reach statistical significance vs. either filtered air (FA) response. DBP also increased during CAPs, but no more so than during FA. Brachial artery diameter and FMD responses were not different from those of FA. As with all our outcome measures, we plan to examine dose-response associations with PM composition to determine whether this affects the level and variability of response. These results were presented at a meeting and reported in abstracts (Urch, et al., 2010c; Urch, et al., 2011).
 
Epigenetic Changes: As a pilot study, we examined the epigenetic effects of coarse and fine CAPS, and their bioaerosol components LPS and glucan in a subgroup of 11 study participants. In preliminary analyses, we found that fine particles induced Alu and IL-12 hypomethylation, and that coarse particles, endotoxin and glucan induced TLR-4 hypomethylation. Moreover, mediation analyses showed that DNA methylation changes might be on the pathway to elevated systemic white blood cells (WBCs) and elevated SBP and DBP.
 
Filtered Air Exposures: Early in the study, we observed a pattern of similar changes in outcome measures (e.g., BP, blood neutrophils) for HEPA filtered ambient air (HFAA) and CAPs exposures. The HFAA changes were larger than the changes observed in previous studies. The facemask delivery system was the same for the new facility and the CAP facility used in the prior studies, ruling this out as a factor. The two main differences in the facilities were: 1) the inlet for the older facility was on the second floor compared to ground-level for the new facility; and 2) the dilution air for the older facility included a charcoal pre-filter, while the new facility uses only a HEPA filter. We hypothesized that in our study ambient VOCs may have contributed to the HFAA responses. In order to explore this possibility, we added a second filtered air exposure that contained no particles or ambient gases—HEPA-filtered medical air (HFMA), using humidified gas cylinder medical air as the inlet air to the exposure chamber. Subsequent results revealed an apparent difference in responses between the HFAA and HFMA, with the HFMA showing the smallest changes in most response variables. Thus, the medical air may be a more appropriate control, although the filtered ambient air response does suggest some effect of the ambient gases and volatiles that can pass through the HEPA filter. We have measured VOC exposure levels and gaseous pollutants and will explore potential associations.
 
Biologic Components of PM: Innate immunity and inflammatory pathways have been shown to involve molecular structures called pathogen-associated molecular patterns, such as endotoxin and β-(1,3)-D-glucan that are important components of coarse PM. Few studies have considered that biologic components may contribute to respiratory and cardiovascular effects. Our study showed that ambient and exposure levels of endotoxin and β-(1,3)-D-glucan were highly correlated. Exposure levels of endotoxin and β-(1,3)-D-glucan were ~6-fold greater than respective ambient levels. Exposure levels of β-(1,3)-D-glucan were positively associated with lung and systemic neutrophil counts. Associations were stronger for individuals with atopy (positive skin tests) and for coarse CAP exposures. Associations with neutrophil counts were weaker but positive between exposure endotoxin levels and lung/systemic neutrophils.
 
Traffic Density: As a major source of air pollution, traffic-related emissions, commonly referred to as traffic-related air pollution (TRAP), are particularly important. Of note, diesel engine exhaust emissions produce nearly 100 times more PM compared to petroleum engines. In order to investigate the TRAP contribution to our exposures and to the cardiopulmonary responses, we set up a video camera to record traffic flow on the street adjacent to the CAP inlet. College Street is a four-lane street with two eastbound and two westbound lanes as well as streetcar tracks in the middle lanes. Although the streetcars are electric, they generate PM due to their brakes. Detailed data were obtained for traffic during exposures, including minute-by-minute eastbound and westbound counts, separately for cars, trucks (diesel) and streetcars. Total vehicle counts over the 130 minute-exposure period range from 2,300 to 2,700 vehicles of which 8-10% were diesel and ~2-3% were streetcars.
 
Heart Rate Vari­ability (HRV) Changes: A proposed mechanism of PM-induced cardiovascular effects is autonomic dysfunction, or an imbalance between the sympathetic and parasympathetic nervous systems. HRV has been used as a surrogate for autonomic tone in exposure stud­ies. In a retrospective analysis of controlled exposures to fine CAPs, O3, fine CAPs+O3 and filtered air, we assessed the impact of exposure on HRV (Fakhri, et al., 2009). We observed a dose-response association between CAPs mass concentration and HRV measures that differed for exposures with O3 versus without O3. The HRV data for the current coarse and fine CAPs exposures will be analyzed in 2012.
 
Cardiac Electrophysiology Changes: Cardiovascular mortality associated with air pollution exposure may be sudden or arrhythmic in nature. Changes in cardiac repolarization have been linked to an increased risk of arrhythmias. A retrospective analysis of 12-lead ECG recordings obtained from a previous CAP study was carried out (Sivagangabalan, et al., 2011). We examined the T-wave interval from the peak to the end (Tp-e), an estimate of repolarization time that relates to repolarization dispersion and arrhythmogenesis. Results showed a significant increase in the Tp-e interval from the start to the end of CAP+O3 exposure compared to filtered air. We also examined T-wave alternans (TWA), which are beat-to-beat fluctuation in the magnitude and shape of the T-wave. However, no significant exposure-induced changes were observed. A manuscript on the TWA results has been resubmitted to Environmental Health Perspectives and currently is under review (Kusha, et al., in review). A review paper on air pollution and arrhythmic risk was submitted to the Canadian Journal of Cardiology and is undergoing revision for resubmission (Watkins, et al., 2011). We plan to further study Tp-e and TWA in subjects with implanted defibrillators exposed to fine CAPs and O3, in single and co-pollutant mixtures.
 
Ultrafine CAPs: Health Canada also has funded studies using the ultrafine concentrator, initially for setup/characterization and then to carry out human exposures following the same protocol and outcome measures as the coarse and fine CAPs. Initial results have shown increases in blood pressure during ultrafine CAPs exposure as we previously reported for fine CAPs (Urch, 2010a; Fakhri, et al., 2009; Brook, et al., 2009). Ultrafine CAPs exposures studies on 20 subjects will be completed by March 2013.
 

Record Details:

Record Type:PROJECT( ABSTRACT )
Start Date:10/01/2005
Completion Date:09/30/2010
Record ID: 200623