2012 Progress Report: Relative Toxicity of Air Pollution Mixtures

EPA Grant Number: R834798C001
Subproject: this is subproject number 001 , established and managed by the Center Director under grant R834798
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Air Pollution Mixtures: Health Effects across Life Stages
Center Director: Koutrakis, Petros
Title: Relative Toxicity of Air Pollution Mixtures
Investigators: Godleski, John J. , Diaz, Edgar , Koutrakis, Petros , Lawrence, Joy , Wolfson, Mike
Current Investigators: Godleski, John J. , Koutrakis, Petros
Institution: Harvard University
EPA Project Officer: Ilacqua, Vito
Project Period: January 1, 2011 through December 31, 2015 (Extended to December 31, 2016)
Project Period Covered by this Report: August 1, 2011 through July 31,2012
RFA: Clean Air Research Centers (2009) RFA Text |  Recipients Lists
Research Category: Health Effects , Air

Objective:

Project 1 is an inhalation toxicological animal exposure study that investigates the relative toxicity of different component concentration combinations of air pollution mixtures. These components include both particles and gases that are emitted directly from sources (primary species) or are formed in the atmosphere through a series of reactions that are predominantly photochemical (secondary species). The project uses source-specific emissions as well as ambient air or concentrated ambient particles and our photochemical chamber technologies to generate realistic mixtures. We are testing the biological responses of exposure to fresh, aged primary, and secondary pollutants (both gas and particle phase) formed from the photochemical oxidation of traffic emissions or Boston ambient air. We will investigate whether the toxicological effects of exposure to aged primary or secondary particles. Toxicity is assessed in Sprague-Dawley rats by changes in 1) in vivo oxidant response, 2) blood pressure, 3) measures of inflammation, and 4) vascular blood flow/resistance. 

Progress Summary:

During the reporting period, we have completed three papers which are in press in the Journal Air Quality, Atmosphere, and Health. These papers describe the reaction chamber and exposure system used for studying the effects of primary and secondary particles derived from a traffic tunnel on respiratory, cardiovascular and systemic outcomes.

The Toxicological Evaluation of Realistic Emissions of Source Aerosols approach was adapted to investigate the health effects of fresh and aged vehicular particulate (PM) emissions. A ventilation stack of a large urban highway tunnel in the northeastern United States was used as the source of primary vehicular emissions. The system used to prepare aerosols for inhalation toxicology studies consists of: 1) a sampling system to extract the effluent from the plenum of the ventilation stack; 2) a photochemical chamber to simulate atmospheric aging; and 3) a countercurrent parallel-plate membrane diffusion denuder that efficiently and non-selectively removes gaseous pollutants. To form secondary organic aerosol (SOA), direct plenum primary vehicular emissions were diluted with clean air inside the chamber. O3 was added to titrate the baseline NO in the chamber to enhance photochemical reactions. Our methods made it possible to generate reproducible exposures.

These investigations examine the relative toxicity of these air pollution mixtures, focusing on source-specific emissions, secondary particles derived from these, and combinations of primary and secondary particles from traffic-derived particles. All exposures were done at a target dose of 50 micrograms per cubic meter. Sprague Dawley rats were repeatedly exposed to primary only (P), secondary organic aerosol only (SOA), a combination of the two (P+SOA) or filtered air for 5-hours/day for 3 weeks. Blood pressure (BP) was measured continuously using implanted telemetry. Mixed effects models were used to compare responses of systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR).

Exposure to P increased and maintained an effect on SBP and DBP across weeks showing a significant dose response. SOA exposure on the first day resulted in a significant increase in both SBP and DBP (p=0.001, p=0.0003), becoming strongly negative by week 3. With P+SOA, significant increases in SBP and DBP of 13 mmHg were observed on the first day of exposure (p=0.04, p=0.0015), which were maintained through week 1 for SBP and through week 2 for DBP. Sham exposures in the SOA and P+SOA groups after 3 weeks showed compensatory decreases in both SBP and DBP. No exposure had a significant effect on HR. Both primary and secondary traffic-derived aerosols can substantially increase SBP and DBP but these increases are eventually lost.

Effects resulting from these low levels of exposure are remarkable, because humans may be acutely exposed to such levels near highways and are likely to be exposed to higher concentrations for longer durations over a lifetime. Significant changes in blood pressure are demonstrated here as a result of exposure to relatively small yet stable concentrations of pollutants. Sustained increases in blood pressure were observed and were able to be maintained not only across entire days of exposure, but over weeks of exposure. In addition, an unexpected but highly significant compensatory response causing a dramatic decrease in both systolic and diastolic blood pressures also was seen after previously exposed animals were exposed to filtered air. This suggests a biological protective effect with repeated exposures that cannot be explained by simple autonomic nervous system activation. These results confirm the adverse health effects associated with inhalation of fine particles and give insight into a potential biological adaptation to repeated and anticipated pollutant exposure to maintain blood pressure.

We also examined how exposure to primary and secondary traffic-related particles affect a number of blood pressure control mechanisms, including DNA methylation of the promoter of endothelial nitric oxide synthase (eNOS), a gene implicated in vasoconstriction. Overall trends indicate a decrease in DNA methylation with exposure. Although this is a cross-sectional sample, the decrease in DNA methylation in the eNOS promoter suggests activation of the gene. This may result in a more rapid vasodilatory effect that supports the development of a compensatory response. Manuscripts from this study currently are in preparation.

The studies of respiratory outcomes, including breathing pattern, in-vivo chemi-luminescence (IVCL), broncho-alveolar lavage, and complete blood count, were equally different among the three exposures. Although all produced decreases in tidal/minute volumes and inspiratory/expiratory flows, there were differences in inflammatory changes in BAL, with increased neutrophils for SOA and for P+SOA and increased lymphocytes for P and P+SOA, without changes in total protein, ß-NAG or IVCL.

Both primary and secondary particles derived from the tunnel resulted in adverse respiratory, inflammatory and cardiovascular responses. A pattern of adaptation to the exposure was found with subchronic exposures. Irradiation of the primary particles and gases enhanced the toxicity of the traffic emissions producing inflammatory changes in BAL, decreasing flows and volumes in breathing pattern and increasing diastolic blood pressure. Respiratory changes were augmented with repeated exposure to the SOA and P+SOA scenarios, suggesting a cumulative effect and a central response to the pollutants manifested by a decrease in tidal volume. P+SOA had a greater overall response than SOA only; suggesting that the particles and the more complex agglomerates formed in this multi-pollutant scenario greatly enhanced the toxicity of primary traffic-derived particles.

We are adding a rat model of vascular flow and resistance to our exposures, with progress in the development of the preparation of rats with implanted hardware for these microsphere studies. Specifically, this includes catheterizing the left ventricle for perfusion and the thoracic aorta for sampling, and connecting these catheters to access ports implanted subcutaneously in the posterior intra-scapular area. In this year, we have changed from a thoracic approach to implant the cardiac hardware to an abdominal approach and for the aortic sampling we have changed to an approach using the external carotid. These changes should have less surgical morbidity. In addition, studies were started to investigate the pathophysiological mechanisms by which these exposures resulted in the blood pressure changes observed.

Future Activities:

We will continue with our investigations as described above. Exposures to fresh and photochemically aged source emissions/CAPs, with and without ozone and other secondary gases, will be conducted. Toxicity of exposures will be assessed in rats using a variety of outcomes, as described above including changes in INCL, blood pressure, inflammation, and vascular flow/resistance. This will make it possible to determine the contribution of different components of the exposure mixture to observed biological effects.


Journal Articles on this Report : 4 Displayed | Download in RIS Format

Other subproject views: All 36 publications 14 publications in selected types All 14 journal articles
Other center views: All 410 publications 347 publications in selected types All 347 journal articles
Type Citation Sub Project Document Sources
Journal Article Diaz EA, Chung Y, Papapostolou V, Lawrence J, Long MS, Hatakeyama V, Gomes B, Calil Y, Sato R, Koutrakis P, Godleski JJ. Effects of fresh and aged vehicular exhaust emissions on breathing pattern and cellular responses – pilot single vehicle study. Inhalation Toxicology 2012;24(5):288-295. R834798 (2012)
R834798 (2013)
R834798 (2014)
R834798 (2015)
R834798 (Final)
R834798C001 (2012)
R834798C001 (2014)
R834798C001 (Final)
R832416 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: ResearchGate-Abstract & Full Text PDF
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  • Abstract: Taylor and Francis-Abstract
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  • Journal Article Diaz EA, Chung Y, Lamoureux DP, Papapostolou V, Lawrence J, Long MS, Mazzaro V, Buonfiglio H, Sato R, Koutrakis P, Godleski JJ. Effects of fresh and aged traffic-related particles on breathing pattern, cellular responses, and oxidative stress. Air Quality, Atmosphere & Health 2013;6(2):431-444. R834798 (2012)
    R834798 (2013)
    R834798 (2014)
    R834798 (2015)
    R834798 (Final)
    R834798C001 (2012)
    R834798C001 (2013)
    R834798C001 (2014)
    R834798C001 (Final)
    R832416 (Final)
  • Full-text: ResearchGate-Abstract & Full Text PDF
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  • Abstract: Springer-Abstract
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  • Journal Article Lamoureux DP, Diaz EA, Chung Y, Coull BA, Papapostolou V, Lawrence J, Sato R, Godleski JJ. Effects of fresh and aged vehicular particulate emissions on blood pressure in normal adult male rats. Air Quality, Atmosphere & Health 2013;6(2):407-418. R834798 (2012)
    R834798 (2013)
    R834798 (2014)
    R834798 (2015)
    R834798 (Final)
    R834798C001 (2012)
    R834798C001 (2013)
    R834798C001 (2014)
    R834798C001 (Final)
    R832416 (Final)
  • Full-text: ProQuest-Full Text PDF
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  • Abstract: Springer-Abstract
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  • Journal Article Papapostolou V, Lawrence JE, Ferguson ST, Wolfson JM, Diaz EA, Godleski JJ, Koutrakis P. Development and characterization of an exposure generation system to investigate the health effects of particles from fresh and aged traffic emissions. Air Quality, Atmosphere & Health 2013;6(2):419-429. R834798 (2012)
    R834798 (2013)
    R834798 (2014)
    R834798 (2015)
    R834798 (Final)
    R834798C001 (2012)
    R834798C001 (2013)
    R834798C001 (2014)
    R834798C001 (Final)
    R832416 (Final)
  • Abstract: Springer-Abstract
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  • Other: ResearchGate-Abstract
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  • Supplemental Keywords:

    pollution, particles, mixtures, oxidative stress, inflammation, vascular flow, blood pressure, epigenetics, pulmonary inflammation, vehicular emissions, secondary aerosols, Scientific Discipline, Air, air toxics, Environmental Chemistry, Health Risk Assessment, Air Pollution Effects, Biochemistry, Environmental Monitoring, ambient air quality, children's health, complex mixtures, health effects, particulates, sensitive populations, air pollutants, aerosol particles, biological sensitivities, exposure and effects, lung epithelial cells, susceptible populations, chemical composition, neurotoxicity, human exposure, toxicity, coronary artery disease, cardiopulmonary, cardiotoxicity, environmental effects, human health, mortality

    Relevant Websites:

    http://www.hsph.harvard.edu/clarc/ Exit EPA Disclaimer

    Progress and Final Reports:

    Original Abstract
  • 2010 Progress Report
  • 2011 Progress Report
  • 2013 Progress Report
  • 2014 Progress Report
  • Final Report

  • Main Center Abstract and Reports:

    R834798    Air Pollution Mixtures: Health Effects across Life Stages

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R834798C001 Relative Toxicity of Air Pollution Mixtures
    R834798C002 Cognitive Decline, Cardiovascular Changes, and Biological Aging in Response to Air Pollution
    R834798C003 Identifying the Cognitive and Vascular Effects of Air Pollution Sources and Mixtures in the Framingham Offspring and Third Generation Cohorts
    R834798C004 Longitudinal Effects of Multiple Pollutants on Child Growth, Blood Pressure and Cognition
    R834798C005 A National Study to Assess Susceptibility, Vulnerability, and Effect Modification of Air Pollution Health Risks