Grantee Research Project Results
Final Report: Identifying the Physical and Chemical Properties of Particulate Matter Responsible for the Observed Adverse Health Effects
EPA Grant Number: R827353C014Subproject: this is subproject number 014 , established and managed by the Center Director under grant R827353
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Health Effects Institute (2015 - 2020)
Center Director: Greenbaum, Daniel S.
Title: Identifying the Physical and Chemical Properties of Particulate Matter Responsible for the Observed Adverse Health Effects
Investigators: Koutrakis, Petros , Godleski, John J. , Coull, Brent , Lawrence, Joy
Institution: Harvard University
EPA Project Officer: Chung, Serena
Project Period: June 1, 1999 through May 31, 2005 (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:
Theme III: Biological Mechanisms/Dosimetry: Theme III focused upon mechanisms of cardiac vulnerability as a result of air pollution exposure. Many of our concentrated ambient particles (CAPs) animal toxicology and human panel studies have linked pulmonary and cardiovascular health outcomes to different particulate matter (PM) components such as trace metals, elemental carbon (EC), sulfates and silicon (Batalha, et al., 2002; Clarke, et al., 2000; Saldiva, et al., 2002). Reanalysis of the Harvard Six Cities study provided strong evidence of increased toxicity associated with combustion-related PM from traffic and power plants compared to soil dust (Laden, et al., 2000).
The objectives of Theme III were to identify the particulate and gaseous air pollutants responsible for increased cardiac vulnerability as an adverse health effect and to define the biological mechanisms that lead to this outcome. As part of this theme, we specifically worked to: (1) identify the physical and chemical properties of particulate matter responsible for the observed adverse health effects; (2) determine whether gaseous co-pollutants exacerbate the effects of particles; (3) investigate the biological mechanisms by which particulate matter produces mortality and acute or chronic morbidity; and (4) examine particle deposition patterns and fate in the respiratory tract. These objectives were addressed in several areas of research that explored the components of air pollution that cause adverse health effects and the biological mechanisms that may lead to fatal outcomes. The projects under this theme built upon the findings from a number of our previous animal studies, which made it possible to explore and define both cardiac and pulmonary responses to inhaled fly ash and concentrated ambient particles (Killingsworth, et al., 1997).
Although many of the individual toxicological studies described here were done with support of other grants, the final analyses were done with support from our Environmental Protection Agency (EPA) PM Center. The primary objectives of the analyses conducted for this project were: to characterize the components of CAPs that are significantly associated with the development of pulmonary inflammation; to determine whether short term exposures to CAPs alter the morphology of small pulmonary arteries; and to determine if increased pathologic responses may have similarly resulted from concentrated exposures to what may be considered non-toxic silicate particles. These analyses have resulted in a number of publications, several of which are described below (Batalha, et al., 2002; Saldiva, et al., 2002; Godleski, et al., 2002).
To characterize the components of CAPs that are significantly associated with the development of pulmonary inflammation, mature male rats were exposed to CAPs using the Harvard/EPA Ambient Particle Concentrator (HAPC) to determine if pulmonary inflammation was affected in a dose-dependent manner. Chronic bronchitic (CB) rats were employed as a model of pulmonary disease (250 ppm SO2 x 5 days/week for 6 weeks). Age-matched, room air-exposed rats were used as a normal control group. For urban particle exposures, normal or CB animals were exposed by inhalation for 6 hours/day for three consecutive days to CAPs or filtered air. In all, we had six complete studies as outlined in Table 1 below. This number of experimental exposures allowed us to relate CAPs composition to animal responses. Before the first day of exposure, and after the last day of exposure, animals in each group had breathing pattern studies using the BUXCO analysis system. On the day after the last exposure, animals were sacrificed and studied by bronchoalveolar lavage (BAL), collection of BAL cellular RNA, total lung RNA and collection of lung and heart tissues for morphologic studies.
Table 1. Experimental Design
Date |
Total # of Animals |
Number of animals for BAL Studies |
No. of Animals for Histology Studies |
No. of Animals for BUXCO Studies |
Three-Day Mean CAPs (μg/m3) |
Conc. Factor |
|||
|
|
Air |
CB |
|
|
|
|
||
|
|
Sham |
CAPs |
Sham |
Caps |
|
|
|
|
Mar. 1997 |
40 |
8 |
8 |
8 |
8 |
2 |
none |
170.7 |
19.9 |
June 1997 |
40 |
8 |
8 |
8 |
8 |
2 |
6-8 |
481.0 |
29.9 |
Sept 1997 |
48 |
10 |
10 |
10 |
10 |
2 |
15-21 |
187.1 |
12.1 |
Jan 1998 |
47 |
8 |
8 |
8 |
8 |
3-4 |
9-12 |
126.1 |
18.2 |
Mar. 1998 |
40 |
8 |
8 |
7 |
8 |
2-3 |
6-12 |
267.3 |
35.1 |
June 1998 |
44 |
7 |
8 |
8 |
8 |
2-4 |
8-12 |
300.7 |
38.2 |
Summary/Accomplishments (Outputs/Outcomes):
In the assessment of pulmonary inflammation, BAL was conducted on the animals. The numerical density of neutrophils (Nn) in two areas of the alveolar walls was assessed. CAPs and several PM components induced a significant increase in BAL neutrophils in normal animals. Among components, lead (Pb) had the most significant association. No other cell type had any significant change. In rats with chronic bronchitis, significant increases in BAL neutrophils were associated with all components except chlorine (representing sea salt aerosols). In addition, in bronchitic rats, lymphocytes were also significantly increased in association with vanadium (p< 0.01) as well as traffic related factors Br, Pb, EC, and organic carbon (OC) (p< 0.05). Of BAL fluid components, Pb, SO42-, EC, OC and Si were associated with increases in protein. Greater Nn was observed in the central compared to peripheral regions of the lung. When responses were assessed in relationship to component concentrations in the exposures, robust, significant, and dose-dependent associations between Nn and the concentrations of V, Br, Pb, EC and OC were found. Thus, short-term exposures of rats to CAPs from Boston induce a significant inflammatory reaction in the lungs dependent upon the concentration of airborne components. Results of the BAL studies show that significant increases in neutrophils were found in normal rats, and rats with chronic bronchitis had an enhanced response. Increases in lymphocytes and protein in BAL fluid were also observed in the chronic bronchitic animals. In the tissue studies, Nn was significantly increased in normal animals, but a significant change was not detected in the chronic bronchitic animals. Given the BAL results, it is likely that the difference may have been more difficult to detect morphologically with the presence of chronic bronchitis. Nevertheless it is clear that CAPs exposure increases pulmonary inflammation (Saldiva, et al., 2002).
We also studied the pulmonary response to CAPs using normal animals from which we have collected total lung RNA (Godleski, et al., 2002). The RNA was pooled, labeled, and hybridized to multiple Affymetrix rat micro-array chips (A-chips) to explore the range of responses to CAPs exposure. Using the A-chip results, data from the sham-exposed group was subtracted from the CAPs group. Since these chips typically include multiple measurements of the same gene, cluster analyses of the results as well as biologic responder cluster assessments of these micro-array studies strongly support the pro-inflammatory potential of CAPs. An overall increase in pro-inflammatory mediators such as C-C chemokines, IL-1, IL-6 and TNF is illustrated with an overall decrease in immune enhancers such as IL-2 and interferon.
To determine whether short term exposures to CAPs alter the morphology of small pulmonary arteries in normal rats and rats with chronic bronchitis, Sprague-Dawley male rats were exposed to CAPs using the HAPC, or to particle-free air (sham) under identical conditions during three consecutive days (5h/day) in six experimental sets (Batalha, et al., 2002). Histological slides were prepared from random sections of lung lobes and coded for blinded analysis. The lumen/wall area ratio (L/W) was determined morphometrically on transverse sections of small pulmonary arteries. When all animal data (normal and CB) were analyzed together, the L/W ratios decreased as concentrations of PM2.5, Si, Pb, SO42-, EC and OC increased. In separate univariate analyses of animal data, the association for sulfate was significant only in normal rats, whereas silicon was significantly associated in both CB and normal rats. In multivariate analyses including all particle factors, the association with silicon remained significant. Our results indicate that short-term CAPs exposures (median 182.75, range 73.50-733.00 μg/m3) can induce vasoconstriction of small pulmonary arteries in normal and CB rats. This effect was correlated with specific particle components, and suggests that the pulmonary vasculature might be an important target for ambient air particle toxicity
Since our group utilizes the HAPC to generate concentrated aerosols of outdoor air particles for experimental exposures, and since we have reported increased pathologic responses to inhalation of concentrated urban air particles and identified silicon (as silicate) as an element associated with many of these responses, we sought to determine whether the HAPC may have had some effect on what may be considered non-toxic silicate particles. Using silicate rich Mt. St. Helen’s volcanic ash (MSHA), we exposed three groups of Sprague-Dawley rats by inhalation for 6 hours to filtered air, MSHA, or MSHA passed though the HAPC (Savage, et al., 2003). Twenty-four hours following exposure, BAL was performed to assess total cell count, differential cell count, protein, lactate dehydrogenase, and n-beta glucosaminidase levels. Peripheral blood was examined for packed cell volume, total protein, total white cells, and differential cell count. Morphologic studies localized particles in the lung and assessed pulmonary vasculature. No significant differences were observed among any of the groups in any parameter measured including morphometric analysis of pulmonary vasoconstriction. Scanning electron microscopy and x-ray analysis identified particles as silicates typical of MSHA throughout the lung. Our findings suggest that particles passing through the HAPC have no change in their toxic potential in an exposure setting where particle deposition in the lung has occurred.
Conclusions:
Data from our animal studies suggest that short-term exposures to CAPs from Boston induce a significant inflammatory reaction in rat lungs, with this reaction influenced by particle composition. Our results also demonstrate that the short-term CAPs exposures can induce vasoconstriction of small pulmonary arteries in normal and CB rats. The magnitude of the observed vasoconstrictive response to CAPs exposure is related to CAPs mass and specific particle constituent concentrations. Thus, vasoconstriction of pulmonary vessels associated with CAPs exposures may be the result of an effect at the level of the pulmonary vascular endothelial cells with an abnormal balance between releasing of endothelium-derived constricting factors and endothelium-derived relaxing factors. We speculate that the resultant pulmonary endothelial dysfunction with predominant release of mediators that constrict vessels could lead to a dominant vasoconstrictive status in the lungs and possibly in the heart. There is also evidence in the microarray studies for increases in reactive oxygen species (ROS) activity, as well as evidence for activation of organic chemical metabolism and detoxification mechanisms.
References:
Batalha JRF, Saldiva PHN, Clarke RW, Coull BA, Stearns RC, Lawrence J, Krishna Murthy GG, Koutrakis P, Godleski JJ. Concentrated ambient air particles induce vasoconstriction of small pulmonary arteries in rats. Environmental Health Perspectives 2002;110(12):1191-1197.
Clarke RW, Coull BA, Reinisch U, Catalano P, Killingsworth CR, Koutrakis P, Kavouras I, Krishna Murthy GG, Lawrence J, Lovett EG, Wolfson JM, Verrier RL, Godleski JJ. Inhaled concentrated ambient particles are associated with hematologic and bronchoalveolar lavage changes in canines. Environmental Health Perspectives 2000;108(12):1179-1187.
Godleski J, Clark R, Coull B, Saldiva P, Jiang N, Lawrence J, Koutrakis P. Composition of inhaled urban air particles determines acute pulmonary responses. Annals of Occupational Hygiene 2002;46(Suppl. 1):419-424.
Killingsworth C, Alessandrini F, Murthy G, Catalano P, Paulauskis J, Godleski J. Inflammation, chemokine expression, and death in monocrotaline-treated rats following fuel oil fly ash inhalation. Inhalation Toxicology 1997;9:541-565.
Laden F, Neas L, Dockery D, Schwartz J. Association of fine particulate matter from different sources with daily mortality in six U.S. cities. Environmental Health Perspectives 2000;108(10):941-947.
Saldiva PH, Clarke RW, Coull BA, Stearns RC, Lawrence J, Koutrakis P, Suh H, Tsuda A, Godleski JJ. Acute pulmonary inflammation induced by concentrated ambient air particles is related to particle composition. American Journal of Respiratory and Critical Care Medicine 2002;165(12):1610-1617.
Savage ST, Lawrence J, Katz T, Stearns RC, Coull BA, Godleski JJ. Does the Harvard/U.S. Environmental Protection Agency ambient particle concentrator change the toxic potential of particles? Journal of the Air & Waste Management Association 2003;53(9):1088-1097.
Journal Articles on this Report : 5 Displayed | Download in RIS Format
| Other subproject views: | All 5 publications | 5 publications in selected types | All 5 journal articles |
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| Other center views: | All 207 publications | 205 publications in selected types | All 204 journal articles |
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Batalha JRF, Saldiva PHN, Clarke RW, Coull BA, Stearns RC, Lawrence J, Krishna Murthy GG, Koutrakis P, Godleski JJ. Concentrated ambient air particles induce vasoconstriction of small pulmonary arteries in rats. Environmental Health Perspectives 2002;110(12):1191-1197. |
R827353 (Final) R827353C014 (Final) R825242 (Final) R832416 (2008) |
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Clarke RW, Coull B, Reinisch U, Catalano P, Killingsworth CR, Koutrakis P, Kavouras I, Murthy GGK, Lawrence J, Lovett E, Wolfson JM, Verrier RL, Godleski JJ. Inhaled concentrated ambient particles are associated with hematologic and bronchoalveolar lavage changes in canines. Environmental Health Perspectives 2000;108(12):1179-1187. |
R827353 (Final) R827353C014 (Final) |
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Hamada K, Goldsmith C-A, Suzaki Y, Goldman A, Kobzik L. Airway hyperresponsiveness caused by aerosol exposure to residual oil fly ash leachate in mice. Journal of Toxicology and Environmental Health-Part A 2002;65(18):1351-1365. |
R827353 (Final) R827353C014 (Final) R825702 (Final) R826779 (Final) |
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Saldiva PHN, Clarke RW, Coull BA, Stearns RC, Lawrence J, Krishna Murthy GG, Diaz E, Koutrakis P, Suh H, Tsuda A, Godleski JJ. Lung inflammation induced by concentrated ambient air particles is related to particle composition. American Journal of Respiratory and Critical Care Medicine 2002;165(12):1610-1617. |
R827353 (Final) R827353C014 (Final) R825242 (Final) |
Exit Exit Exit |
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Savage ST, Lawrence J, Katz T, Stearns RC, Coull BA, Godleski JJ. Does the Harvard/U.S. Environmental Protection Agency Ambient Particle Concentrator change the toxic potential of particles? Journal of the Air & Waste Management Association 2003;53(9):1088-1097. |
R827353 (Final) R827353C014 (Final) R827353C017 (Final) |
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Supplemental Keywords:
RFA, Scientific Discipline, Health, PHYSICAL ASPECTS, Air, ENVIRONMENTAL MANAGEMENT, HUMAN HEALTH, Air Pollution Monitoring, particulate matter, Toxicology, air toxics, Environmental Chemistry, Epidemiology, Air Pollution Effects, Risk Assessments, Microbiology, Susceptibility/Sensitive Population/Genetic Susceptibility, Environmental Microbiology, Environmental Monitoring, Health Effects, Physical Processes, Children's Health, genetic susceptability, indoor air, Atmospheric Sciences, Molecular Biology/Genetics, Biology, Risk Assessment, ambient air quality, interindividual variability, molecular epidemiology, monitoring, particulates, sensitive populations, chemical exposure, air pollutants, cardiopulmonary responses, health risks, human health effects, indoor exposure, PM 2.5, ambient air monitoring, exposure and effects, ambient air, ambient measurement methods, exposure, lead, pulmonary disease, developmental effects, epidemelogy, biological response, respiratory disease, air pollution, ambient monitoring, children, Human Health Risk Assessment, particle exposure, biological mechanism , cardiopulmonary response, human exposure, inhalation, pulmonary, susceptibility, particulate exposure, assessment of exposure, ambient particle health effects, human susceptibility, environmental health hazard, inhalation toxicology, cardiopulmonary, indoor air quality, inhaled particles, air quality, cardiovascular disease, dosimetry, exposure assessment, human health risk, respiratoryRelevant Websites:
http://www.hsph.harvard.edu/epacenter/epa_center_99-05/index.html Exit
Progress and Final Reports:
Original AbstractMain Center Abstract and Reports:
R827353 Health Effects Institute (2015 - 2020) Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R827353C001 Assessing Human Exposures to Particulate and Gaseous Air Pollutants
R827353C002 Quantifying Exposure Error and its Effect on Epidemiological
Studies
R827353C003 St. Louis Bus, Steubenville and Atlanta Studies
R827353C004 Examining Conditions That Predispose Towards
Acute Adverse Effects of Particulate Exposures
R827353C005 Assessing Life-Shortening Associated with Exposure to
Particulate Matter
R827353C006 Investigating Chronic Effects of Exposure to Particulate
Matter
R827353C007 Determining the Effects of Particle Characteristics on Respiratory Health of Children
R827353C008 Differentiating the Roles of Particle Size, Particle Composition,
and Gaseous Co-Pollutants on Cardiac Ischemia
R827353C009 Assessing Deposition of Ambient Particles in the Lung
R827353C010 Relating Changes in Blood Viscosity, Other Clotting Parameters,
Heart Rate, and Heart Rate Variability to Particulate and Criteria Gas Exposures
R827353C011 Studies of Oxidant Mechanisms
R827353C012 Modeling Relationships Between Mobile Source Particle Emissions and Population Exposures
R827353C013 Toxicological Evaluation of Realistic Emissions of Source Aerosols (TERESA) Study
R827353C014 Identifying the Physical and Chemical Properties of Particulate Matter Responsible for the Observed Adverse Health Effects
R827353C015 Research Coordination Core
R827353C016 Analytical and Facilities Core
R827353C017 Technology Development and Transfer Core
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
5 journal articles for this subproject
Main Center: R827353
207 publications for this center
204 journal articles for this center