Airborne Particulate Matter Health Effects: Cardiovascular Mechanisms
Science to Achieve Results (STAR) Program

Opening Date: January 25, 2002
Closing Date: April 30, 2002

Summary of Program Requirements
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Program Title:  Airborne Particulate Matter Health Effects: Cardiovascular Mechanisms

Synopsis of Program:

The Environmental Protection Agency (EPA) invites research grant applications to conduct studies on the role of particulate matter (PM) air pollution in cardiovascular illness and mortality.  A potentially important role of PM has been suggested by epidemiology studies showing increased cardiopulmonary-related mortality and hospital admissions for cardiovascular disease associated with increases in exposure to PM.  The objective of this program is to encourage in vitro and in vivo research in laboratory animals and humans on the specific cellular, molecular, and physiologic mechanisms by which ambient air PM, alone or in combination with gaseous co-pollutants, mediates adverse cardiovascular effects.  A sub-objective is to encourage involvement of cardiovascular experts in research efforts to address the adverse health effects associated with PM exposure.

Contact Persons:
 Stacey Katz,  Phone: 202-564-8201; email
 Gail Robarge, Phone: 202-564-8301; email

Applicable Catalog of Federal Domestic Assistance (CFDA) Number(s): 66.500

Eligibility Information:
Academic and not-for-profit institutions located in the U.S., and state or local governments are eligible to apply for assistance under this program.

Award Information:
Anticipated Type of Award: Grant
Estimated Number of Awards: Approximately 5-6
Anticipated Funding Amount: Approximately $5 million
Potential Funding per Grant per Year: Up to $350,000 per year for a total of up to three years

Sorting Code:
The sorting code for applications submitted in response to this solicitation is

Deadline/Target Dates:
Letter of Intent Due Date(s): None
Application Proposal Due Date(s): No later than 4:00 P.M., ET, April 30, 2002


The U.S. Environmental Protection Agency (EPA), Office of Research and Development (ORD), National Center for Environmental Research (NCER), as part of its Science to Achieve Results (STAR) program, is seeking grant applications for research on cardiovascular mechanisms of particulate matter health effects. As stated by the National Research Council in its report, Research Priorities for Airborne Particulate Matter, Volume I (1), key research questions include:

1. What are the underlying mechanisms that can explain the epidemiological findings of mortality/morbidity associated with exposure to ambient PM?

2. What subpopulations are at increased risk of adverse health outcomes from particulate matter?

Cardiovascular Disease and Air Pollution

Heart disease is the leading cause of death for all Americans.  Death rates for heart disease and stroke rise significantly for those above 65 years of age, accounting for more than 40% of all deaths among persons 65-74, and almost 60% of those aged 85 years and older.  Although overall death rates from heart disease and stroke declined in the 1980s and 1990s, heart failure emerged as a major chronic disease for older adults (2).

Established cardiovascular risk factors such as high blood cholesterol, smoking, diabetes, and hypertension do not fully explain the etiology or incidence of coronary heart disease. Such findings suggest that additional, less substantiated risk factors may contribute significantly to cardiovascular pathogenesis.

Increases in outdoor PM air pollution levels have been associated with a number of adverse health outcomes including increased hospitalization for cardiopulmonary diseases, premature (excess) mortality, exacerbation of asthma and other respiratory-tract diseases, and decreased lung function  (3, 4).  Epidemiologic studies reporting these findings have identified several susceptible subpopulations – individuals with cardiovascular and respiratory diseases, the elderly, and children – as being at greater risk for adverse effects from PM exposure.  Although research on respiratory health endpoints associated with PM exposure has been very active, it is only in recent years that cardiovascular endpoints have come to command a more urgent focus.

A number of epidemiologic studies published in the last few years examined the relationship between acute PM exposures and cardiovascular disease-related hospital admissions and deaths (3).  The results were generally consistent across studies, indicating that increases in ambient levels of PM were associated with increases in adverse cardiovascular events.

In addition, controlled human exposure studies and several panel studies of human subjects have examined the relationship between heart and blood measurements and PM exposure.  Effects observed in such studies have demonstrated correlations between increases in PM and changes in factors related to inflammatory processes and heart disease, including decreases in heart rate variability in the elderly and increased levels of blood factors involved in coagulation, clotting, and the acute phase response (5, 6, 7, 8, 9, 10).

Studies of laboratory animals exposed to concentrated airborne particulates and other types of PM have found these exposures to be associated with changes in ECG patterns, including elevation of the S-T segment, arrhythmia, increased pulmonary artery systolic pressure, decreased cardiac output, decreased stroke volume, and shortened activation recovery interval (11,12,13, 14).

A number of animal models of susceptible populations have been used in toxicology studies examining PM.  The studies have shown that animals with compromised health, either genetic or induced, are more susceptible to instilled or inhaled particles, although there is increased animal-to-animal variability in these models (15, 16).

Overall, the number of cardiovascular studies in both humans and laboratory animals is fairly small (17). Nevertheless, they provide some support for hypotheses regarding possible mechanisms by which PM exposure may be linked with adverse cardiac outcomes.

Characterization of Airborne PM

Air pollution is a widespread problem in the United States, with over 130 million individuals exposed to levels of air pollution that exceed one or more health-based ambient standards.

One of the major air pollutants of concern, PM represents a broad class of chemically and physically diverse substances.  Particles can be described by size, formation mechanism, origin, chemical composition, atmospheric behavior and method of measurement.  The concentration of particles in the air varies across space and time, and is related to the source of the particles and the transformations that occur in the atmosphere.

PM can be principally characterized as discrete particles spanning several orders of magnitude in size, with inhalable particles falling into the following general size fractions:

  • PM10  (generally defined as all particles equal to and less than 10 microns in aerodynamic diameter; particles larger than this are not generally deposited in the lung);
  • PM2.5, also known as fine fraction particles (generally defined as those particles with an aerodynamic diameter of 2.5 microns or less)
  • PM10-2.5, also known as coarse fraction particles (generally defined as those particles with an aerodynamic diameter greater than 2.5 microns, but equal to or less than a nominal 10 microns); and
  • Ultrafine particles generally defined as those less than 0.1 microns.
Fine and coarse particles are distinct in terms of the emission sources, formation processes, chemical composition, atmospheric residence times, transport distances and other parameters.  Fine particles are directly emitted from combustion sources and are also formed secondarily from gaseous precursors such as sulfur dioxide, nitrogen oxides, or organic compounds.  Fine particles are generally composed of sulfate, nitrate, chloride and ammonium compounds, organic and elemental carbon, and metals.  Combustion of coal, oil, diesel, gasoline, and wood, as well as high temperature process sources such as smelters and steel mills, produce emissions that contribute to fine particle formation.  In contrast, coarse particles are typically mechanically generated by crushing or grinding and are often dominated by resuspended dusts and crustal material from paved or unpaved roads or from construction, farming, and mining activities.  Fine particles can remain in the atmosphere for days to weeks and travel through the atmosphere hundreds to thousands of kilometers, while most coarse particles typically deposit to the earth within minutes to hours and within tens of kilometers from the emission source.  Some scientists have postulated that ultrafine particles, by virtue of their small size and large surface area to mass ratio may be especially toxic.  There are studies which suggest that these particles may leave the lung and travel through the blood to other organs, including the heart.


Research is needed to understand the cardiovascular mechanisms of action of PM, acting alone or in combination with co-pollutants, from a variety of sources, including coal burning combustion systems, diesel and gasoline engines, residential wood combustion and biomass burning. Particles representing PM from an airshed (e.g., collected on filters or concentrated from ambient air) also need to be studied to elucidate mechanisms of toxicity of ambient air constituents.

Since it is likely that short term and long term PM exposure may cause adverse health effects by different mechanisms, proposals may focus on examining mechanisms that underlie acute effects following short term exposure to PM and/or effects of long-term PM exposure.  Substantial efforts are now underway at EPA and elsewhere to explore potential pulmonary mechanisms of PM toxicity.  Through this RFA, EPA hopes to expand the body of research exploring potential cardiovascular mechanisms through which PM exposures may adversely affect health.  This RFA provides a new opportunity for cardiac and vascular researchers, and others not traditionally involved in air pollution research, to bring their expertise to this field.  EPA strongly encourages collaboration between cardiovascular and environmental health scientists to merge cardiovascular expertise with knowledge of particles, air pollution exposures and health effects.

Areas of research that would be considered responsive to the RFA include:

Mechanisms of Pathogenesis: Humans and/or Laboratory Animals:

In vitro and in vivo research to develop and evaluate novel hypotheses addressing specific mechanisms by which PM may affect the cardiovascular system.  These could include, but are not limited to, factors affecting the electrical activity of the heart, processes which damage cardiac cells, cause endothelial cell dysfunction, or alterations in blood viscosity or clotting.  Proposals which address these issues in an integrated manner applying both cellular and molecular approaches in either laboratory animals or humans are encouraged.
Models of Susceptibility:
Epidemiology studies suggest that elderly people with cardiovascular disease are particularly susceptible to the effects of PM.  Therefore, proposals are encouraged which use animal models of cardiovascular disease to study the effects of PM, especially newer genetic models that target specific cellular pathways.  Specific aims should include studies elucidating the underlying mechanism of PM effects in these models.  If development of a new animal model is proposed, the proposal should include plans to disseminate the model and willingness to share the model with the scientific community.
Controlled Exposure Studies in Humans or Animals:
Studies which demonstrate whether and how inhaled PM directly affects the heart (e.g., through uptake of particles into the circulatory system or through release of soluble substances into the circulatory system) or whether and how PM affects autonomic control of the heart and cardiovascular system.

Studies which demonstrate whether and how lung inflammation caused by PM exposure leads to cardiovascular-related morbidity (e.g., lung inflammation and cytokine production cause adverse systemic hemodynamic effects; lung inflammation from inhaled PM causes increased blood coagulability; lung injury from inhaled PM causes impairment of oxygenation in individuals with cardiac disease).  Proposals with a primary emphasis on the pulmonary effects of PM rather than on how pulmonary factors interact with the cardiovascular system will not be considered responsive.

Particles that are not considered environmentally relevant or which are not generally found in the air in urban areas should not be proposed for study, nor should particles whose exposure is primarily in occupational settings.  Applications proposing to study the effects of silica or asbestos will not be considered.


1. National Research Council. 1998. Research Priorities for Airborne Particulate Matter. Volume I.  Immediate Prioriies and Long-Range Research Portfolio. National Academy Press. Washington, D.C.

2 .U.S. Department of Health and Human Services. January 2000.  Healthy People 2010. Washington, DC.

3. Samet JM, Zeger SL, Dominici F, Curriero F, Coursac I, Dockery DW, Schwartz J, Zanobetti A. 2000. National morbidity, mortality, and air pollution study. Part II: morbidity and mortality from air pollution in the United States. Cambridge, MA: Health Effects Institute; research report no. 94.

4. U.S. Environmental Protection Agency. 1996. Air quality criteria for particulate matter. Research Triangle Park, NC: National Center for Environmental Assessment-RTP Office; report nos. EPA/600/P-95/001aF-cF.

5. Dockery DW, Pope CA III, Kanner RE, Villegas GM, Schwartz J. 1999. Daily changes in oxygen saturation and pulse rate associated with particulate air pollution and barometric pressure. Cambridge, MA Health Effects Institute; research report no. 83.

6. Liao D, Creason J, Shy C, Williams R, Watts R, Zweidinger R. 1999. Daily variation of particulate air pollution and poor cardiac autonomic control in the elderly. Environ. Health Perspect. 107:521-525.

7. Peters A, Doring A, Wichmann HE, Koenig W. 1997. Increased plasma viscosity during air pollution episode: a link to mortality? Lancet 349:1582-1587.

8. Peters A, Frohlich M, Doring A, Immervoll T, Wichmann HE, Hutchinson W, Pepys MB, Koenig W. 2001. Particulate air pollution is associated with an acute phase response in men: results from the MONICA-Augsburg Study. Eur. Heart J.:22:1198-1204.

9. Pope CA III, Dockery DW, Kanner RE, Vollegas GM, Schwartz J. 1999. Oxygen saturation, pulse rate, and particulate air pollution: a daily time-series panel study. Am J. Respir. Crit. Care Med. 159: 365-372.

10. Pope CA III, Verrier RL, Lovett EG, Larson AC, Raizenne ME, Kanner RE, Schwartz J, Villegas GM, Gold DR, Dockery DW. 1999. Heart rate variability associated with particulate air pollution. Am. Heart J. 138:890-899.

11. Godleski JJ, Verrier RL, Koutrakis P, Catalano P. 2000. Mechanisms of Morbidity and Mortality from Exposure to Ambient Air Particles. Cambridge, MA: Health Effects Institute; research report no. 91.

12. Watkinson WP, Campen MJ, Costa DL. 1998. Cardiac arrhythmia induction after exposure to residual oil fly ash particles in a rodent model of pulmonary hypertension. Toxicol. Sci. 41(2):209-16.

13. Devlin RB, Johnson TA, Ghio A, Huang YC, Costa DL, Bromberg P, Cascio W. 2001. Pulmonary and cardiac changes in pigs exposed to residual oil fly ash. Amer. J. Respir. and Critical Care Med. 163:A311.

14. Nadziejko C, Chen LC, Fang K, Gordon T. March 2001. Comparison of acute cardiovascular effects of concentrated ambient particulate matter and tobacco smoke in hypertensive rats. Toxicol. Sci. 60:162 2001. Presented at Society of Toxicology Annual Meeting, San Francisco CA.

15. Kodavanti UP, Costa DL, Bromberg PA. 1998. Rodent models of cardiopulmonary disease: their potential applicability in studies of air pollutant susceptibility. Environ. Health Perspect. 106 Suppl1:111-30 Review.

16. Kodavanti UP, Costa DL. 2001. Rodent models of susceptibility: what is their place in inhalation toxicology? Respir. Physiol. 128(1):57-70 Review.

17. U.S. Environmental Protection Agency. 2001. Air Quality Criteria Document for Particulate Matter (Second External Review Draft. Key sections include: 6.31 Cardiovascular Effects Associated with Acute Ambient Particulate Matter Exposure; Systemic Effects Secondary to Lung Injury, Cardiovascular Effects of Ambient Particulate Matter Exposures.


 It is anticipated that a total of approximately $5 million, including direct and indirect costs, will be awarded, depending on the availability of funds. Proposals may request funding for projects with a total cost up to $350,000/year with a duration of up to 3 years.


Academic and not-for-profit institutions located in the U.S., and state or local governments, are eligible under all existing authorizations.  Profit-making firms are not eligible to receive grants from EPA under this program.  Federal agencies and national laboratories funded by federal agencies (Federally-funded Research and Development Centers, FFRDCs) may not apply.

Federal employees are not eligible to serve in a principal leadership role on a grant. FFRDC employees may cooperate or collaborate with eligible applicants within the limits imposed by applicable legislation and regulations.  They may participate in planning, conducting, and analyzing the research directed by the principal investigator, but may not direct projects on behalf of the applicant organization or principal investigator.  The principal investigator's institution may provide funds through its grant from EPA to a FFRDC for research personnel, supplies, equipment, and other expenses directly related to the research.  However, salaries for permanent FFRDC employees may not be provided through this mechanism.

Federal employees may not receive salaries or in other ways augment their agency's appropriations through grants made by this program.  However, federal employees may interact with grantees so long as their involvement is not essential to achieving the basic goals of the grant.1 The principal investigator’s institution may also enter into an agreement with a federal agency to purchase or utilize unique supplies or services unavailable in the private sector. Examples are purchase of satellite data, census data tapes, chemical reference standards, analyses, or use of instrumentation or other facilities not available elsewhere, etc.  A written justification for federal involvement must be included in the application, along with an assurance from the federal agency involved which commits it to supply the specified service.

1. EPA encourages interaction between its own laboratory scientists and grant principal investigators for the sole purpose of exchanging information in research areas of common interest that may add value to their respective research activities. However, this interaction must be incidental to achieving the goals of the research under a grant. Interaction that is “incidental” is not reflected in a research proposal and involves no resource commitments.

Potential applicants who are uncertain of their eligibility should contact Jack Puzak in NCER, phone (202) 564-6825, email:

A set of special instructions on how applicants should apply for an NCER grant is found on the NCER web site Standard Instructions for Submitting a STAR Application. The necessary forms for submitting an application will be found on this web site.

The need for a sorting code to be used in the application and for mailing is described in the Standard Instructions for Submitting a STAR Application. The sorting code for applications submitted in response to this solicitation is  2002-STAR-G1.

The deadlines for receipt of the applications by NCER are no later than 4:00 p.m. ET, April 30, 2002.

Further information, if needed, may be obtained from the EPA officials indicated below.  Email inquiries are preferred.
Stacey Katz
Phone: 202-564-8201

Gail Robarge
Phone: 202-564-8301