2013 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: Ilacqua, Vito
Project Period: January 1, 2011 through December 31, 2015 (Extended to December 31, 2016)
Project Period Covered by this Report: January 1, 2013 through December 31,2013
RFA: Clean Air Research Centers (2009) RFA Text |  Recipients Lists
Research Category: Health Effects , Air

Objective:

This is an inhalation toxicological animal exposure study which investigates the relative toxicity of air pollution mixtures. These mixtures 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 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. Toxicity is assessed in Sprague-Dawley rats by changes in: 1) in vivo chemiluminescence (IVCL) as a measure of oxidant response; 2) blood pressure (BP); 3) measures of pulmonary and systemic inflammation; and 4) vascular blood flow/resistance. Comparisons among exposures groups will determine which mixtures have toxicity for specific outcomes.

Progress Summary:

During the reporting period, we published three papers in one issue of the Journal Air Quality, Atmosphere, and Health which discuss our present work on the toxicity of primary and secondary pollutants related to traffic. Specifically, these papers described the reaction chamber and exposure system used to study emissions from a northeastern traffic tunnel. Three types of exposures were generated: primary (P), secondary organic aerosols (SOA), and primary plus secondary (PA+SOA). All exposures were generated at a target dose of 50 µg/m3. Exposure to primary or secondary particles initially increases blood pressure. However, only primary particles have a sustained response while secondary particles increase then subsequently decrease blood pressure. Combined primary and secondary exposures increased blood pressure over the first two weeks, but during the third week the increase was not sustained. Respiratory responses differed among the three exposures types. Although all produced decreases in tidal/minute volumes and inspirato­ry/expiratory flows, there were differences in inflammatory changes in BAL. Specifically, we observed an increase in neutrophils for SOA and P+SOA and an increase in lymphocytes for P and P+SOA.

Mechanisms responsible for the association PM2.5 exposures and increases in blood pressure have yet to be elucidated. We measured effects of primary and secondary components of traffic-derived PM2.5 on baroreceptor reflex sensitivity (BRS) and gene expression of 84 blood pressure related genes using Quigen® Rat Hypertension RNA expression microarrays, and RT-PCR of endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) primary mediators of blood pressure on heart and lung tissues. Rats were exposed to P, SOA, P+SOA, or filtered air (FA) for five hours/day, four days/week for three consecutive weeks. Gene expression was measured through real-time PCR of heart and lung tissue mRNA after two and four days of exposure. BRS was assessed in the P+SOA and FA groups after injection of phenylephrine (10µg/kg).

In all mechanistic studies PM2.5 exposures were targeted to be about 50 µg/m3. Mass measurements for all exposures averaged 49.1±2.9 µg/m3. A 2-fold decrease in eNOS was seen in heart tissue for P and P+SOA exposures after two days. A 3.5-fold decrease in ET-1 was seen in lung for P exposures after four days. For P+SOA, a 3-fold increase in ET-1 was seen in heart tissue after two days with a 12-fold increase after four days. In the microarray studies, SOA exposure had the greatest response with both increasing and decreasing blood pressure response and control systems. P and P+SOA exposures activated or inactivated fewer genes, but the findings are consistent with increases in blood pressure with some evidence of changes showing control mechanisms.

Suggestive trends showed both traffic related particle exposed rats and sham exposed rats responded with a normal BRS gain after exposure indicating a compensatory response. Exposed animals showed a diminished response, or possible resetting, in week one which returned to normal by weeks two and three. The trends in BRS and gene expression of eNOS and ET-1 explain the initial increase in BP (↓ eNOS, ↑ ET-1 and no change in BRS). The subsequent lack of increase in BP in some exposure groups with continued exposure correlated with the changes in gene expression of numerous blood pressure control mechanisms to limit increases in blood pressure.

A major goal of this project was to measure changes in vascular flow and resistance in all vital organs after exposure to traffic related aerosols or filtered air. These experiments are challenging because they require preparation of rats with implanted hardware for repeated injections of fluorescent microspheres.  Specifically, this procedure 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 implanted the cardiac hardware via an abdominal approach with less morbidity. Preliminary studies showed that exposures to traffic-related particles at an exposure dose in the range of only 30 µg/m3 decrease blood flow to the heart and the brain. These studies should provide useful information in determining the mechanisms of both cardiovascular and central nervous system health effects. 

Future Activities:

We will continue with our investigations as described above. Exposures to fresh and photochemically aged traffic particles with and without ozone and other secondary gases will be conducted. Toxicity of exposures will be assessed in rats using a variety of outcome 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 : 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 Breysse PN, Delfino RJ, Dominici F, Elder ACP, Frampton MW, Froines JR, Geyh AS, Godleski JJ, Gold DR, Hopke PK, Koutrakis P, Li N, Oberdorster G, Pinkerton KE, Samet JM, Utell MJ, Wexler AS. US EPA particulate matter research centers: summary of research results for 2005–2011. Air Quality, Atmosphere & Health 2013;6(2):333-355. R834798 (2013)
R834798 (2014)
R834798 (2015)
R834798 (Final)
R834798C001 (2013)
R834798C001 (2014)
R832413 (Final)
R832414 (Final)
R832415 (Final)
R832416 (Final)
  • Abstract: Springer-Abstract
    Exit
  • Other: ResearchGate-Abstract
    Exit
  • 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
    Exit
  • Abstract: Springer-Abstract
    Exit
  • 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
    Exit
  • Abstract: Springer-Abstract
    Exit
  • 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
    Exit
  • Other: ResearchGate-Abstract
    Exit
  • Supplemental Keywords:

    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

    Progress and Final Reports:

    Original Abstract
  • 2010 Progress Report
  • 2011 Progress Report
  • 2012 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