2010 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. , Koutrakis, Petros
Institution: Harvard University
EPA Project Officer: Chung, Serena
Project Period: January 1, 2011 through December 31, 2015 (Extended to December 31, 2016)
Project Period Covered by this Report: January 1, 2010 through December 31,2010
RFA: Clean Air Research Centers (2009) RFA Text |  Recipients Lists
Research Category: Health Effects , Air


Project 1, an inhalation toxicological animal exposure study, 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 particulate and our photochemical chamber technologies to generate realistic mixtures.  We are testing these specific hypotheses: (i) secondary gaseous pollutants formed from the photochemical oxidation of traffic emissions or Boston ambient gases can induce biological responses; (ii) aging Boston concentrated ambient particles (CAPs)  or source specific primary particles in the photochemical chamber enhances their toxicity; (iii) toxicological effects of photochemically aged source emissions, ambient air, or CAPs are exacerbated by co-exposure to ozone and other secondary gases; and (iv) mixture composition and toxicity exhibit inter- and intra-seasonal variability due to changes in source emissions and weather conditions.  Toxicity will be 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. Three concurrent exposures groups (Sham, Control Exposure and Exposure) will allow us to control for the variability in CAPs composition. With this design, there can always be a direct comparison between two exposure mixtures on every exposure day, making it possible to determine which mixture is more toxic.

Progress Summary:

During the reporting period, we have completed a group of 8 papers all dealing with primary and secondary emissions from power plant, studies that were funded by the previous Harvard EPA PM Center and the Electric Power Research Institute. These papers have all been accepted for publication and will be published in a special issue of the journal, Inhalation Toxicology.  We have also completed similar studies on emissions derived from traffic using a northeastern traffic tunnel as the source of mixed vehicular emissions, and compared the effects of the emissions with or without simulation of atmospheric aging by photochemistry and formation of secondary particles.

Both Primary (P) 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 sub-chronic 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 (secondary particles only) and P+SOA (aged primary plus secondary particles) 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 multipollutant scenario greatly enhanced the toxicity of primary traffic derived particles. 
Blood Pressure data showed an increase in systolic, diastolic and mean pressure for P, increased diastolic and decreased pulse pressure for P+SOA and increases in systolic, diastolic and pulse pressure for SOA. These changes decreased with repeated exposures overtime. Sham exposures after the last test exposure showed a sharp decrease in systolic and diastolic blood pressure in those animals previously exposed to SOA.  This pattern of decreasing changes in blood pressure during repeated exposures indicates development of a compensatory response.  We also examined how exposure to primary and secondary traffic-related particles affect 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; though the data is a cross-sectional sample, the decrease in DNA methylation in the eNOS promoter suggests activation of the gene, which may result in a more rapid vasodilatory effect supports the development of a compensatory response.  Several manuscripts from this study are currently in preparation.
These investigations are continuing in the new CLARC, as we examine the relative toxicity of different components of air pollution mixtures, focusing on source-specific emissions and ambient particles and gases.  In the new CLARC, we are adding a rat model of vascular flow and resistance to our exposures, with excellent progress to report in techniques to prepare 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 intrascapular area.
Exposures conducted at our tunnel site in support of the new CLARC to date have included primary emissions, with some preliminary secondary exposures scheduled for August 2011.

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 vivo chemiluminescence, blood pressure, inflammation, and vascular flow/resistance), to determine the contribution of different components of the exposure mixture to observed biological effects.

Journal Articles on this Report : 1 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 Papapostolou V, Lawrence JE, Diaz EA, Wolfson JM, Ferguson ST, Long MS, Godleski JJ, Koutrakis P. Laboratory evaluation of a prototype photochemical chamber designed to investigate the health effects of fresh and aged vehicular exhaust emissions. Inhalation Toxicology 2011;23(8):495-505. R834798 (2010)
R834798 (2011)
R834798 (2013)
R834798 (2014)
R834798 (2015)
R834798 (Final)
R834798C001 (2010)
R834798C001 (2011)
R834798C001 (2014)
R834798C001 (Final)
R834798C005 (Final)
R832416 (Final)
R832416C005 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: ResearchGate-Abstract & Full Text PDF
  • Abstract: Informa-Abstract
  • 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, complex mixtures, health effects, particulates, sensitive populations, children's health, air pollutants, biological sensitivities, aerosol particles, exposure and effects, lung epithelial cells, susceptible populations, chemical composition, neurotoxicity, human exposure, toxicity, coronary artery disease, cardiopulmonary, cardiotoxicity, environmental effects, mortality, human health

    Relevant Websites:

    http://www.hsph.harvard.edu/clarc/index.html Exit

    Progress and Final Reports:

    Original Abstract
  • 2011 Progress Report
  • 2012 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