Introduction

1. OVERALL GOALS AND OBJECTIVES

The fundamental objective of the proposed Center is to understand how specific PM characteristics and sources impact inflammation, autonomic responses, and vascular dysfunction (Figure 1). To meet this objective, the Center, through its five proposed Projects, will systematically address the following four key scientific questions:

I) What types of pathophysiological effects are produced by PM exposures and how do these effects relate to specific particle composition, size, formation processes and origin (toxic components)?
II) What are the effects of gaseous co-pollutants on the observed PM exposure-response relationships?
III) What are the biological mechanisms whereby PM exposures can induce inflammation and autonomic responses that lead to pulmonary and/or cardiac dysfunction?
IV) Are certain individuals more susceptible to PM due to their health condition, age, genetic characteristics and/or nutritional factors?

figure 1
Figure 1: Linking inflammation, autonomic effects and vascular dysfunction to PM sources

2. EXISTING EPA PM CENTER

Over the last five years the existing EPA PM Center has supported a large interdisciplinary research group that has collaborated intensively to investigate the health effects of ambient PM, in accordance with the National Research Council's research priorities for ambient particle research. To date, Center research has produced over 70 peer-reviewed publications (1-70). Some of our major accomplishments are in the key areas of exposure, susceptibility, biological mechanisms, toxic components, and methodological issues, which are briefly presented below.

2.1 Exposure relationships: A large data set on personal exposures and indoor and outdoor concentrations was collected for panels of susceptible individuals across the US (46-48). These investigations suggest that personal exposures to PM2.5 of ambient origin are highly correlated with outdoor concentrations. However, the regression slopes of personal exposures on outdoor concentrations, which are usually less than one, vary substantially depending on house characteristics, season, and city climatic conditions. The strong correlations between personal and ambient concentrations were unique to PM2.5, as personal exposures to O3, SO2 and NO2 were substantially lower than, and weakly correlated with, corresponding outdoor con-centrations (49).

2.2 Susceptible populations: Our epidemiological studies have provided strong evidence that individuals with congestive heart failure, COPD, and diabetes are at higher risk than healthy individuals (4, 22, 30, 59, 60, 68, 69, 70). In an effort to understand why individuals with certain diseases are at greater risk than others, Center researchers exposed animals with cardiopulmonary diseases such as COPD and myocardial infarction to Concentrated Ambient Particles (CAPs)(2,10,24). The findings of these toxicological studies support those of the epidemiological studies and provide insight about possible mechanisms responsible for the observed PM effects.

2.3 Toxic components: Many of our CAPs animal toxicology and human panel studies have linked pulmonary and cardiovascular health outcomes to different PM components such as trace metals, elemental carbon, sulfates and silicon (2,10,45). 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 (32).

2.4 Biological mechanisms: We have conducted exposure studies designed to elucidate the biological mechanisms whereby PM can induce adverse health effects. Results from a series of human and animal studies showed that exposures were linked to changes in heart rate variability (HRV), arrhythmias, pulmonary inflammation and vascular dysfunction (1,9,10,26,42).

2.5 Methodological issues: New statistical and epidemiological methods were developed to provide the necessary tools to address challenging PM issues such as: harvesting (54,65,67); confounding (58); dose-exposure relationships (51,53,54,56); gaseous co-pollutants , and; weather confounding (6,7,26,38,39,40,41). Many new exposure and monitoring particle technologies were also developed under the aegis of our Center and are currently used worldwide. These include the ultrafine particle concentrator, the toxicological samplers, the miniature multi-pollutant sampler, the personal cascade impactor, and the membrane diffusion denuder (12,13,14,15, 16,17,18,19,20,21).

3. PROPOSED EPA PM CENTER: APPROACH

3.1 Center Strategy: The cornerstone of the proposed Center is a multi-faceted exposure approach encompassing ambient, CAPs, and specific-source exposures. These novel exposure approaches will be used to elicit a large array of biological responses, in humans and animals, focusing primarily on pulmonary and cardiovascular outcomes. This will make it possible to investigate the effects of toxic PM components (size, number and composition -- elemental and organic carbon, black carbon, trace elements, organics and sulfates) and gaseous co-pollutants (CO, NO2, SO2, O3 and VOCs) and explore biological mechanisms and susceptibility (Figure 1).

3.2. Center Research: As outlined above, the proposed Center includes five highly interdisciplinary and integrated projects (see Table 1) that collectively will address the four scientific questions.

Project 1 [NAS study] will examine the association between subject-specific PM exposures and intermediate markers of autonomic dysfunction, systemic inflammation, endothelial activation and oxidative stress in participants of the Normative Aging Study, a large, ongoing prospective cohort study in Eastern Massachusetts. Electrocardiograms, blood samples, food frequency questionnaires, medication use, genetic data and one-week integrated indoor PM samples for each study participant will be collected. These data together with subject-specific data on medical and behavioral characteristics will be used in structural equation models to examine the effects of particle composition, (black carbon, sulfate), genetic phenotypes (GSTM1, HO-long), medication use (beta and calcium blockers, statins) and dietary intake (vitamin C and omega fatty acids), on the observed associations between exposures and biological outcomes. [Scientific Questions I, III and IV]

table 1

Project 2 [Bus Study] will use a cross-over exposure design to examine the inflammatory and autonomic effects of traffic-related PM and gases in 36 older adults. Subjects will be exposed to either PM plus its gaseous co-pollutants or gases alone. For both exposure scenarios, participants will be exposed to the pollutants during 5-hour long field trips via diesel-powered buses in Boston, MA. This Project will examine whether mobile source-related pollution (particles and gases) is associated with autonomic dysfunction, HRV, pulmonary and systemic inflammation (eNO, CRP, IL?6, fibrinogen, WBC) and endothelial activation (ICAM-1). [Scientific Questions I, II and III]

Project 3 [Human CAPs Study] will examine the cardiovascular effects of fine, coarse and ultrafine CAPs. This will be a randomized block design, double-blinded study that will expose 50 healthy adults to fine, ultrafine, and coarse CAPs, in Toronto. Each participant will receive 4 exposures in random sequence with each exposure session separated by at least two weeks. Vascular function and inflammatory examinations will afford pre- and post-exposure measurements of brachial artery diameter, flow-mediated dilatation and nitroglycerin-mediated dilatation. In addition, measurements of HRV, BP, cardiac output, stroke volume and systemic vascular resistance will be performed during exposure sessions. [Scientific Questions I and III]

Project 4 [Animal CAPs Study] will investigate the relationship between particle composition and vascular response. Sprague Dawley rats and spontaneously hypersensitive rats will be exposed to fine CAPs in Boston. Exposures will be administrated during two distinct daytime periods to capture different PM source contributions: i) early morning exposures which are comprised of mostly local emissions rich in carbonaceous particles and; ii) mid-day exposures which are comprised of mostly transported particles rich in sulfates. Biological outcomes to be measured will include pulmonary and systemic inflammation, blood pressure by telemetry, endothelin-1, endothelial nitric oxide synthase (eNOS), atrial naturetic peptide (ANP), oxidant response in the heart and lung by in vivo chemiluminescence, and vascular morphometry of lung and cardiac vessels. [Scientific Questions I, III and IV]

Project 5, the Toxicological Evaluation of Realistic Emission Source Aerosol [TERESA study], will investigate the relative toxicity of primary and secondary vehicular emissions. Exhaust emissions from a tunnel in Boston will be introduced into a photochemical reaction chamber, where secondary PM will be formed. Normal and hypertensive rats will be exposed to the primary and secondary PM, and will be evaluated for pulmonary, systemic, and cardiovascular effects. Project 5 will examine whether atmospheric photochemical processes enhance the toxicity of gases and PM emitted from vehicles and will determine whether susceptible animal models will have greater biological responses to PM than the corresponding healthy animal model. [Scientific Questions I, III and IV]

In addition to the five projects the Center will encompass three Cores: i) The Administration and Research Coordination Core will be responsible for research coordination and prioritization, data management, human and animal subject research protocols and, quality assurance (directed by Koutrakis and Dockery); ii) The Particle Technology and Monitoring Core will be responsible for the development, evaluation and application of particle collection and exposure devices as well as exposure monitoring (led by Demokritou and Koutrakis) and: iii) The Biostatistical Core will provide support for statistical analysis for all projects, including substantial design consultation and analytical work (directed by Coull and Schwartz).

3.3. Center Participants: The Center will involve researchers from the following institutions i) Harvard School of Public Health; ii) St. Michael's Hospital, University of Toronto; iii) University of Michigan; iv) Veterans Administration Boston Hospital and; v) Brigham and Women's Hospital, Harvard Medical School.

3.4. Center Infrastructure: Our proposed research portfolio builds upon the existing Center infrastructure developed over the past five years, including an inter-disciplinary research group of faculty, research staff and students as well as the already available cohorts, animal models, standard and innovative biological assessments, statistical tools and particle technologies. More specifically, we will use a large existing cohort, NAS, already developed exposure technologies, such as the fine, ultrafine and coarse concentrators and, a mobile photochemical chamber with a mobile exposure toxicology unit as the basis for the projects. As a result, the ambitious research portfolio outlined in this Center proposal will be timely and cost-effective.

3.5. Center Expertise: The proposed research program includes projects that span several disciplines in which our investigators have expertise, including: Exposure Assessment (Koutrakis, Suh, JR Brook, Urch, Silverman), PM Physics and Chemistry (Koutrakis, Demokritou, Lawrence, JR Brook and Wolfson), Epidemiology (Dockery, Gold, Schwartz and Speizer), Cardiology (RD Brook, Vokonas and Stone), Pulmonary Health (Gold, Silverman and Speizer), Toxicology (Godleski, Gonzalez-Flecha, Silverman, Urch and Wellenius) and Biostatistics (Coull, Corey, Schwartz and Zanobetti). This group of investigators has been collaborating on particle health effects research for more than a decade. Also many other faculty members from our Department who are not included in the budget will be available as needed, including: Drs. Christiani (Occupational Medicine), Spengler (Indoor Air), Milton (Aerobiology), Kelsey (Toxicology), Verrier (Cardiology), Smith (Biomarkers), Brain (Physiology) and Levy (Risk).

3.6. Center Administration: The Center Director will be Petros Koutrakis, who is the Director of the existing EPA PM Center. He is a Professor of Environmental Sciences and the Director of the Exposure, Epidemiology & Risk (EER) Program at Harvard. He will be assisted by Deputy Center Director Douglas Dockery, Professor of Environmental Epidemiology at EER.

3.7. Expected Benefits: The proposed research will address important scientific issues relating to PM health effects. It will generate critical information on the PM toxic components (Projects 1 and 4), the toxicity of primary and secondary traffic PM (Project 5), the role of gaseous co-pollutants (Project 2), and, the toxicity of fine, coarse and ultrafine PM (Project 3). All five Projects will measure a large array of exposure characteristics (physico-chemical particle parameters and gaseous co-pollutants) and biologic outcomes (pathologic, functional, and molecular parameters of cardiovascular response). This combination of detailed exposure and biological assessments will make it possible to examine the effects of specific PM sources or components (Hazardous Components) on specific mechanistic pathways by which PM cause adverse health effects (Biological Mechanisms) on individuals with cardiovascular diseases (Susceptibility). Thus, the proposed research program will provide important information that is critical for the development of Air Quality Standards and their Implementation.

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