Final Report: Effect of Diesel Exhaust Particulate Exposures on Endothelial Function in Humans: The Role of Oxidative Stress

EPA Grant Number: R830954
Title: Effect of Diesel Exhaust Particulate Exposures on Endothelial Function in Humans: The Role of Oxidative Stress
Investigators: Kaufman, Joel D. , Chandler, Wayne , Gill, Edward , Koenig, Jane Q. , Larson, Timothy V. , Leotta, Daniel , Sheppard, Lianne (Elizabeth) A. , Sullivan, Jeff , Trenga, Carol , Yost, Michael
Institution: University of Washington
EPA Project Officer: Chung, Serena
Project Period: August 15, 2003 through August 14, 2006 (Extended to August 14, 2008)
Project Amount: $1,036,972
RFA: Airborne Particulate Matter Health Effects: Cardiovascular Mechanisms (2002) RFA Text |  Recipients Lists
Research Category: Air Quality and Air Toxics , Particulate Matter , Air , Health Effects

Objective:

Diesel exhaust particulate is a substantial and biologically active fraction of urban ambient fine particulate air pollution, which is associated with increases in cardiovascular morbidity and mortality. This project addresses the overall hypothesis that ambient fine particulate matter exerts cardiovascular health effects via alteration of endothelial homeostasis, through a mechanism mediated by oxidative stress. These studies use a controlled human inhalation exposure to diesel exhaust as an experimental model exposure for ambient fine particulate, to address the following objectives: 1) Determine whether exposure to inhaled diesel exhaust (DE) is associated with endothelial dysfunction in a concentration-related manner; 2) Determine whether exposure to inhaled DE is associated with evidence of systemic oxidative stress; and 3) Determine whether antioxidant supplementation blunts the DE effect on endothelial function.

Summary/Accomplishments (Outputs/Outcomes):

We conducted a pilot study and three experiments to address our specific objectives. From the pilot study, exposures at 0, 50, 100, and 200 μg/m3 of PM2.5 proved safe, and exposure concentrations were successfully administered as planned. We were able to conclude that subjects cannot reliably determine the level of exposure they experience; hence, we felt comfortable proceeding under the assumption that our subsequent experiments can be considered double-blind.

Experiments 1 and 2, conducted to address the first two primary aims of the study, called for random-order exposures at three different nominal concentrations: 0, 100, and 200 μg/m3 of PM2.5 and to collect ultrasound images of the brachial artery diameter, and blood samples analyzed for markers of endothelial homeostasis, thrombosis, inflammation, and oxidative stress [D-dimer, C-reactive protein, PAI-1, von Willebrand’s Factor (VWF), endothelin-1, and multiple cytokines (e.g., IL-2, IL-6, TNF-alpha)]. Microarray studies of peripheral blood mononuclear cells were also conducted, and urine samples were measured for F2-alpha isoprostane and 8-OHdG. Postexposure we also assessed endothelium-dependent flow-mediated dilation.

The results of these experiments demonstrated that short-term exposure to diesel exhaust is associated with acute endothelial response and vasoconstriction of a conductance artery. They also demonstrated differential gene expression between healthy participants exposed to filtered air and diesel exhaust. However, consistent effects of diesel exhaust on either the autonomic control of the heart as measured by heart rate variability or on pro-thrmobotic endpoints as measured by several plasma markers (D-dimer, platelet number, VWF, PAI-1 and CRP) were not seen. We also did not detect significant changes in oxidative stress or systemic antioxidant responses (as measured by plasma levels of ascorbic acid, or urinary levels of F2-isosprostances or 8-OHdG) in subjects with metabolic syndrome.

The purpose of Experiment 3 was to determine whether antioxidant supplementation blunts the DE effect on endothelial function. Participants were exposed to diesel exhaust at nominal concentrations of 0 and 200 μg/m. Although the project’s time and funding were exhausted prior to completing the required sample size for Experiment 3, our research to this point has been successful and played a large role in funding of a new NIH-sponsored Disease Investigation through Specialized Clinically-Oriented Ventures in Environmental Research (DISCOVER) Center: Cardiovascular Disease and Traffic-Related Air Pollution (1P50ES015915-01), funding period: June 1, 2008 through May 31, 2013. This new funding will allow us to complete Experiment 3.

Conclusions:

We have observed forearm vascular changes following controlled exposure to air pollutants. Brook and colleagues exposed subjects to concentrated ambient particles plus ozone, while Mills (like our group) used diluted fresh diesel exhaust for the exposure situation. Mills’ study differs from ours and Brook’s in studying forearm blood flow via arterial catheterization, injection of vasoactive compounds, and plethysmography. In addition to being less feasible in this country due to human subjects constraints, their method is more likely to assess blood flow in resistance than in conductive vessels, and thus be less analogous to coronary artery behavior. The consistency in the findings provides reassurance that this likely represents a real effect. Neither we nor Brook observed the expected decrease in endogeneous NO-mediated vasodilation seen in typical pathological situations (diabetes, hyperlipidemia), which has been typically operationalized as "endothelial dysfunction" by most investigators. Instead, we--like Brook--have observed brachial artery vasoconstriction acutely, following exposure to air pollutants. When coupled with animal studies by Sun, Campen, and our group, these findings represent the most consistent physiological changes observed with PM exposures thus far in clinical studies. We believe these changes are significant and can form an important basis for further work regarding the mechanism of air pollution’s effect on the cardiovascular system.


Journal Articles on this Report : 10 Displayed | Download in RIS Format

Other project views: All 33 publications 10 publications in selected types All 10 journal articles
Type Citation Project Document Sources
Journal Article Allen J, Trenga CA, Peretz A, Sullivan JH, Carlsten CC, Kaufman JD. Effect of diesel exhaust inhalation on antioxidant and oxidative stress responses in adults with metabolic syndrome. Inhalation Toxicology 2009;21(13):1061-1067. R830954 (Final)
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  • Journal Article Carlsten C, Kaufman JD, Peretz A, Trenga CA, Sheppard L, Sullivan JH. Coagulation markers in healthy human subjects exposed to diesel exhaust. Thrombosis Research 2007;120(6):849-855. R830954 (2007)
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  • Journal Article Carlsten C, Kaufman JD, Trenga CA, Allen J, Peretz A, Sullivan JH. Thrombotic markers in metabolic syndrome subjects exposed to diesel exhaust. Inhalation Toxicology 2008;20(10):917-921. R830954 (Final)
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  • Journal Article Cosselman KE, Krishnan RM, Oron AP, Jansen K, Peretz A, Sullivan JH, Larson TV, Kaufman JD. Blood pressure response to controlled diesel exhaust exposure in human subjects. Hypertension 2012;59(5):943-948. R830954 (Final)
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  • Journal Article Gould T, Larson T, Stewart J, Kaufman JD, Slater D, McEwen N. A controlled inhalation diesel exhaust exposure facility with dynamic feedback control of PM concentration. Inhalation Toxicology 2008;20(1):49-52. R830954 (Final)
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  • Journal Article Krishnan RM, Sullivan JH, Carlsten C, Wilkerson HW, Beyer RP, Bammler T, Farin F, Peretz A, Kaufman JD. A randomized cross-over study of inhalation of diesel exhaust, hematological indices, and endothelial markers in humans. Particle and Fibre Toxicology 2013;10:7 (10 pp.). R830954 (Final)
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  • Journal Article Peretz A, Leotta DF, Sullivan JH, Trenga CA, Sands FN, Aulet MR, Paun M, Gill EA, Kaufman JD. Flow mediated dilation of the brachial artery: an investigation of methods requiring further standardization. BMC Cardiovascular Disorders 2007;7:11 (8 pp.). R830954 (2007)
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  • Journal Article Peretz A, Peck EC, Bammler TK, Beyer RP, Sullivan JH, Trenga CA, Srinouanprachnah S, Farin FM, Kaufman JD. Diesel exhaust inhalation and assessment of peripheral blood mononuclear cell gene transcription effects: an exploratory study of healthy human volunteers. Inhalation Toxicology 2007;19(14):1107-1119. R830954 (2007)
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  • Journal Article Peretz A, Sullivan JH, Leotta DF, Trenga CA, Sands FN, Allen J, Carlsten C, Wilkinson CW, Gill EA, Kaufman JD. Diesel exhaust inhalation elicits acute vasoconstriction in vivo. Environmental Health Perspectives 2008;116(7):937-942. R830954 (Final)
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  • Journal Article Peretz A, Kaufman JD, Trenga CA, Allen J, Carlsten C, Aulet MR, Adar SD, Sullivan JH. Effects of diesel exhaust inhalation on heart rate variability in human volunteers. Environmental Research 2008;107(2):178-184. R830954 (Final)
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  • Supplemental Keywords:

    RFA, Health, Scientific Discipline, Air, HUMAN HEALTH, particulate matter, air toxics, Environmental Chemistry, Health Risk Assessment, Exposure, Risk Assessments, Susceptibility/Sensitive Population/Genetic Susceptibility, mobile sources, genetic susceptability, Biology, copollutant exposures, sensitive populations, atmospheric particulate matter, engine exhaust, airway epithelial cells, cardiopulmonary responses, fine particles, PM 2.5, inhaled pollutants, acute lung injury, morbidity, diesel engines, air pollution, susceptible subpopulations, endothelial function, diesel exhaust, automotive exhaust, chronic health effects, lung inflammation, oxidant gas, particulate exposure, cardiopulmonary response, heart rate, ambient particle pollution, Acute health effects, inhaled, chronic obstructive pulmonary disease, highrisk groups, human susceptibility, diesel exhaust particles, diesel exhaust particulate, cardiotoxicity, cardiopulmonary, mortality, DEP, concentrated particulate matter, air contaminant exposure, air quality, co-pollutants, environmental hazard exposures, toxics, airborne urban contaminants, biomarker, cardiovascular disease

    Relevant Websites:

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    Progress and Final Reports:

    Original Abstract
  • 2004 Progress Report
  • 2005 Progress Report
  • 2006 Progress Report
  • 2007 Progress Report