2014 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, 2014 through December 31,2014
RFA: Clean Air Research Centers (2009) RFA Text |  Recipients Lists
Research Category: Health Effects , Air

Objective:

This project 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 exposures to 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, sampled from the ventilation plenum of a northeastern USA highway tunnel. 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 determine which mixtures have toxicity for specific outcomes.

Progress Summary:

We continue to make progress with these studies. In the past year, we have continued analyses of our studies adding heart rate variability analyses to our previously completed exposure studies. Primary plus secondary organic aerosol (P+SOA) caused increased arterial pressure (AP) during exposure days 1, 4, and 6 (mean AP: +15 mmHg vs. control), sympathetic dominance during days 1 and 4 (standard deviation of interbeat intervals: ­‑3.4 ms), supraventricular tachycardia (heart rate: +180 beats/min for up to 5 h) between days 6 and 8 in half of animals, decreased AP on day 11 (-9 mmHg mean AP), and bradycardia in half of animals during baroreflex challenge on day 12.  Baroreflex sensitivity (BRS) increased on day 12 of exposure, indicating compensation for the hypertensive effects of P+SOA. BRS was assessed in the P+SOA and FA groups after injection of phenylephrine (10 µg/kg). To compare P+SOA to social stress, separate telemetered animals were introduced to a dominant rat for 20 min/day for 10 days.  Social stress consistently increased heart rate (+40-100 beats/min) and mean AP (+15 mmHg) while increasing a HRV measure of vagal tone (root mean square of successive differences) potentially indicating baroreflex activation.  Thus, the autonomic effects of P+SOA and social stress diverged during similar hypertensive responses.  Therefore, traffic-derived PM causes increased blood pressure, autonomic imbalance, and subsequent compensatory responses in a pattern different from acute psychological stress.

We noted recent decreases in mass concentrations of primary particulate from the tunnel which prompted us to compare outcomes over the 4 years of operation of this facility. Male Sprague-Dawley rats (250-350 g) had been exposed for 3 consecutive weeks (5 hours/day for 4 days a week) to vehicular emissions from the plenum of the traffic tunnel.  Exposures had been repeated at least once a year (as part of a larger study) from 2010 to 2013. Continuous respiratory and cardiovascular data had been collected during the exposures and analyzed as differences between exposed (n=48) and control (n=46) animals expressed as 10-minute averages over the 5-hr of exposure. Continuous exposure data also had been collected. Observed decreases in tidal volume (Tv) and peak expiratory flow (PEF) were stronger during 2011 and 2013 and were related to both total mass and particle count indicating that although total mass decreased and outcome changes lessened, there were no year to year differences on a per mass or per particle number basis.  Changes in systolic blood pressure (SBP) and Diastolic Blood Pressure (DBP) did not have a direct relationship to total mass and DBP and Mean Blood Pressure were more related to the particle count. Changes in heart rate were not consistent year to year and with the exception of those recorded in 2011, were not significant.

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 continued to implant 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 increased blood flow to the brain. In the past year, several animals were done with catheterization on the right ventricle.  In these animals, 98% of the flow went to the lungs via the pulmonary artery at baseline and in control animals. Those with exposure to traffic related aerosols had decreases in pulmonary artery perfusion such that 90% of the injected beads remained in the lung. This finding supports previous studies from our lab showing exposure to concentrated ambient particulate resulted in acute vasoconstriction of pulmonary arteries (Batalha, et al., Environmental Health Perspectives 2002;110:1191-1197). The lessened perfusion can be ascribed to this vasoconstriction and suggests that intrapulmonary right to left shunts may be opened to off-load the pressure increase related to the vasoconstriction in pulmonary arterioles. These studies when completed are expected to provide very useful information in determining mechanisms of pulmonary, cardiovascular, and central nervous system health effects related to blood flow.

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.

References:

Batalha JRF, Saldiva PHN, Clarke RW, Coull BA, Stearns RC, Lawrence J, Murthy GGK, Koutrakis P, Godleski JJ.   Concentrated ambient air particles induce vasoconstriction of small pulmonary arteries in rats.  Environmental Health Perspectives 2002;110(12):1191-1197.


Journal Articles on this Report : 10 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)
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  • 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)
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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)
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  • Journal Article Hoffmann B, Luttmann-Gibson H, Cohen A, Zanobetti A, de Souza C, Foley C, Suh HH, Coull BA, Schwartz J, Mittleman M, Stone P, Horton E, Gold DR. Opposing effects of particle pollution, ozone, and ambient temperature on arterial blood pressure. Environmental Health Perspectives 2012;120(2):241-246. R834798 (2012)
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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)
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  • Journal Article Levy JI, Diez D, Dou Y, Barr CD, Dominici F. A meta-analysis and multisite time-series analysis of the differential toxicity of major fine particulate matter constituents. American Journal of Epidemiology 2012;175(11):1091-1099. R834798 (2012)
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  • 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)
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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)
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  • Journal Article Peters JL, Kubzansky LD, Ikeda A, Spiro III A, Wright RO, Weisskopf MG, Kim D, Sparrow D, Nie LH, Hu H, Schwartz J. Childhood and adult socioeconomic position, cumulative lead levels, and pessimism in later life: the VA Normative Aging Study. American Journal of Epidemiology 2011;174(12):1345-1353. R834798 (2010)
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  • Journal Article Zanobetti A, Schwartz J. Ozone and survival in four cohorts with potentially predisposing diseases. American Journal of Respiratory and Critical Care Medicine 2011;184(7):836-841. R834798 (2010)
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  • 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
  • 2013 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 Framingharn 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