Grantee Research Project Results
Final Report: Toxicology Project -- Controlled Exposure Facility
EPA Grant Number: R827355C006Subproject: this is subproject number 006 , established and managed by the Center Director under grant R827355
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Water Environment and Reuse Foundation's National Center for Resource Recovery and Nutrient Management
Center Director: Olabode, Lola
Title: Toxicology Project -- Controlled Exposure Facility
Investigators: Kaufman, Joel D. , Stewart, James A , Gemar, Kjersti A , Curtiss, Heidi M , Larson, Timothy V. , Trenga, Carol , Sands, FN , Sullivan, Jeff , Shepherd, Kristine , Jarvis, SS , Gould, Timothy
Institution: University of Washington
EPA Project Officer: Chung, Serena
Project Period: June 1, 1999 through May 31, 2004 (Extended to May 31, 2006)
RFA: Airborne Particulate Matter (PM) Centers (1999) RFA Text | Recipients Lists
Research Category: Air Quality and Air Toxics , Particulate Matter , Air
Objective:
The objective of this project is to conduct controlled exposures at the University of Washington using a delivery system that can expose human subjects to combustion-derived particles and complex air pollution mixtures such as diesel exhaust.
Summary/Accomplishments (Outputs/Outcomes):
Epidemiological studies suggest that diesel exhaust (DE) particles may be associated with increases in cardiovascular morbidity and mortality. However, the mechanism of cardiac effect remains unclear. We postulated that DE exposure would result in a concentration dependent increase in endothelial dysfunction within 24-hours of initiation of exposure.
1. Pilot Study. A secondary aim of the pilot study was to determine tolerability of exposures and blinding of exposure level. To optimize measures of exposure-effect relations for a larger planned study, we performed a double blind, randomized crossover experiment, in 9 healthy adults with 2-hour exposures to filtered air or diluted diesel exhaust at concentrations of PM2.5 equal to 50, 100, and 200 μg/m3. Each exposure was separated by a washout period of at least 2 weeks. Pilot study outcomes included reproducibility of steady-state DE exposure levels, and health measures of symptoms, blood measures of inflammation, endothelial function and oxidative stress, and microarray analysis of gene expression in peripheral blood mononuclear cells. Tolerability results indicate 97% of subjects (34 exposure sessions) responded as “willing” or “neutral” towards participating again at a given exposure level. The neutral response occurred across all levels. Symptom questionnaires ranking sixteen symptoms on a 0-5 scale were completed during and up to 22 hrs post-exposure. The highest ranking was a “2- (mild to moderate), with headache being the most common response at this level. Initial analysis of blood samples measured before, 6-hours and 22-hours post-initiation of exposure indicated consistent increases in levels of C-reactive protein, serum amyloid A and inflammatory cytokines associated with endothelial homeostasis at 22-hours post-DE exposure at the 200 μg/m3 level. Consistent changes in nitrate/nitrite or ascorbate levels were not observed. These pilot study results indicated that DE exposures were well-blinded and caused minimal symptoms in this healthy population. Although underpowered to address effect, the blood measures demonstrated reproducibility suggesting a potential to detect exposure-effect responses in a larger sample of healthy or compromised participants.
2. A Pilot Study of the Effect of Diesel Exhaust on Exhaled NO measures in Healthy Adults
A Peretz, MD, JH Sullivan, MD, MHS, CA Trenga, PhD, K Shepherd, MS, J Mieras, BA, and JD Kaufman, MD, MPH.
Community exposure and controlled exposure studies demonstrate an association between diesel exhaust (DE) and pulmonary inflammation in children and adults with asthma. However, these findings are not consistent in healthy adults. In this pilot study designed to inform a larger study of the cardiovascular effects of DE, we repeatedly measured the fractional concentrations nitric oxide in exhaled breath (FENO) as a marker of pulmonary inflammation. We hypothesized that short-term exposure to DE would result in a measurable increase in FENO post-exposure. Using a double blind, randomized crossover design, we exposed nine young healthy adults to filtered air and three levels of DE (50, 100 or 200 μg/m3) for 2 hours. Each exposure was separated by a washout period of at least 2 weeks. Online Exhaled Nitric Oxide (FENO) using a Sievers model 2801 was measured before exposure and at four time points after exposure (1, 2, 4 and 24 hours) for a total of 154 measurements. The mean levels of FENO before exposure were 39.2 ppb (± 37.5) for filtered air, and 29 ppb (± 16.6) for 200 μg/m3 DE exposure. There was no difference in the mean change in FENO levels between the 200 μg/m3 and 0 μg/m3 levels of exposure at either 1 hour post-exposure 1.67 ppb (± 3.25) or at 24 hours post-exposure 2.54 (± 7.25). Similar results were observed at two and four hours after the exposure. Conclusion: In our pilot study of healthy individuals, we found no significant association between levels of DE and change in FENO over the 24-hours post-exposure. The lack of statistical significance may be due to the small number of subjects tested.
3. Microarray Studies of Peripheral Blood Mononuclear Cells from Healthy Human Volunteers Exposed to Diesel Exhaust (DE)
EC Peck, MS, CA Trenga, PhD, RP Beyer, TK Bammler, PhD, SSrinouanprachanh, JH Sullivan, MD, MHS, FM Farin, MD, JD Kaufman, MD, MPH
Although consistent association between diesel exposure and cardiovascular effects has been demonstrated both in vitro and in human exposure studies, the mechanisms by which such events occur have yet to be elucidated. Alteration of endothelial homeostasis has been implicated in the development of cardiovascular disease. Such a disturbance may occur via mechanisms of inflammation and oxidative stress that are activated by exposure to diesel exhaust (DE). To investigate the contribution of DE exposure to the induction of such pathways, healthy human subjects were exposed to DE at concentrations of 0 and 200 micrograms per cubic meter particulate matter <2.5 microns in diameter per cubic meter (PM2.5). Peripheral blood mononuclear cells were obtained at multiple time-points (pre-exposure, 4 hr post-exposure, and 22 hr post-exposure) for the purpose of measuring changes in global gene expression. RNA was isolated using the Trizol/Qiagen method. Adequate RNA samples were obtained from six of eight subjects; from these, a subset of three subjects was selected for preliminary microarray analyses, which were conducted using the Affymetrix® platform. Two of these three subjects had paired samples for both the 0 and 200 mcg PM2.5/m3 exposure levels. Following data normalization and statistical analysis, a total of 9398 out of 54675 probe sets (Affymetrix® HG-U133 Plus 2.0 Array) were statistically significant at the α = 0.05 level. We observed a greater than 2-fold increase in expression of pro-inflammatory mediators cyclooxygenase and IL-8, in the pre to 4 hr interval and a corresponding down-regulation in the 4 hr to 22 hr interval. A similar pattern of expression was observed for superoxide dismutase (SOD2), which is increased in response to oxidative stress, and ICAM-1, a recognized vascular endothelial cell activation molecule. These data are consistent with the hypothesis that DE exerts time-dependent changes in gene expression in humans via inflammatory and oxidative stress-related mechanisms.
4. Gene Expression in peripheral blood mononuclear cells from healthy human volunteers exposed to diesel exhaust
Peck EC, Trenga CA, Beyer RP, Bammler TK, Srinouanprachabh S, Sullivan JH, Farin FM, Kaufman JD.
The mechanisms by which particulate matter (PM) may affect cardiovascular disease events have yet to be elucidated. Proposed mechanisms include endothelial dysfunction, inflammation, and oxidative stress that are activated by exposures. Using diesel exhaust (DE) as a model of exposure to investigate the induction of such pathways, healthy human subjects were exposed to DE at concentrations of 0 and 100 micrograms particulate matter <2.5 microns in diameter per cubic meter (mcg PM2.5/m3). Exposure sessions lasted for 2 hours and were conducted at least 2 weeks apart. Peripheral blood mononuclear cells were obtained at multiple time-points (pre-exposure, 4 hr post-exposure, and 22 hr post-exposure) for the purpose of measuring changes in global gene expression. RNA was isolated using the Trizol/Qiagen method. Adequate RNA samples were obtained from six of eight subjects and were arrayed using the Affymetrix® platform. Microarray analyses were conducted for five subjects whose samples met quality control criteria. Four of five subjects had paired samples for both 0 and 200 mcg PM2.5/m3 exposure levels. Following data normalization and statistical analysis, a total of 1335 out of 54675 probe sets (Affymetrix® HG-U133 Plus 2.0 Array) were significantly associated with time-dependent DE exposure effects (α = 0.01). We observed a greater than 1.5-fold change in expression of genes involved in inflammatory response (e.g., PDGF, VEGFR) when subjects were exposed to DE as compared to filtered air. These data suggest that DE exerts time-dependent changes in gene expression in humans via the above-proposed mechanisms.
Journal Articles on this Report : 1 Displayed | Download in RIS Format
| Other subproject views: | All 4 publications | 1 publications in selected types | All 1 journal articles |
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| Other center views: | All 209 publications | 113 publications in selected types | All 109 journal articles |
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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. |
R827355 (Final) R827355C006 (Final) R830954 (Final) |
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Supplemental Keywords:
air pollution, air pollutants, particulate matter, PM, diesel, diesel exhaust, diesel exhaust particles, DEP, ultrafine particles, fine particles, PM2.5, cardiovascular health effects, health effects, respiratory health effects, ambient levels, combustion products, diesel engines, occupational levels, toxicology, toxicity, exposure, controlled exposure facility, asthma, volatile organic compounds, VOCs, human exposure, animal exposure, susceptible populations,, RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, Air, ENVIRONMENTAL MANAGEMENT, particulate matter, Toxicology, air toxics, Environmental Chemistry, Health Risk Assessment, Air Pollutants, Epidemiology, Air Pollution Effects, Risk Assessments, Biochemistry, Physical Processes, Atmospheric Sciences, Risk Assessment, ambient aerosol, ambient air quality, health effects, particulates, cardiopulmonary responses, human health effects, exposure and effects, exposure, animal model, air pollution, diesel exhaust, particle exposure, human exposure, inhalation, atmospheric aerosols, ambient particle health effects, PM, aerosols, atmospheric chemistry, cardiovascular disease, exposure assessment, human health riskRelevant Websites:
http://depts.washington.edu/pmcenter/ Exit
Progress and Final Reports:
Original AbstractMain Center Abstract and Reports:
R827355 Water Environment and Reuse Foundation's National Center for Resource Recovery and Nutrient Management Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R827355C001 Epidemiologic Study of Particulate Matter and Cardiopulmonary
Mortality
R827355C002 Health Effects
R827355C003 Personal PM Exposure Assessment
R827355C004 Characterization of Fine Particulate Matter
R827355C005 Mechanisms of Toxicity of Particulate Matter Using Transgenic Mouse Strains
R827355C006 Toxicology Project -- Controlled Exposure Facility
R827355C007 Health Effects Research Core
R827355C008 Exposure Core
R827355C009 Statistics and Data Core
R827355C010 Biomarker Core
R827355C011 Oxidation Stress Makers
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
1 journal articles for this subproject
Main Center: R827355
209 publications for this center
109 journal articles for this center