The Role of Air Pollutants in Cardiovascular Disease

RELEASE DATE: September 12, 2003

RFA Number: RFA-ES-03-010

Department of Health and Human Services (DHHS)
Environmental Protection Agency (EPA)


National Institutes of Health (NIH)
EPA’s Office of Research and Development (EPA)


National Institute of Environmental Health Sciences (NIEHS)
National Center for Environmental Research (EPA)





- Synopsis of Program
- Purpose of this RFA
- Research Objectives
- Mechanism(s) of Support
- Funds Available
- Eligible Institutions
- Individuals Eligible to Become Principal Investigators
- Special Requirements
- Where to Send Inquiries
- Letter of Intent
- Submitting an Application
- Supplementary Instructions
- Peer Review Process
- Review Criteria
- Receipt and Review Schedule
- Award Criteria
- Required Federal Citations


The National Institute of Environmental Health Sciences (NIEHS) and the US Environmental Protection Agency (EPA), as part of its Science to Achieve Results (STAR) program, invite research grant applications to conduct studies on the role of air pollutants, especially particulate matter (PM), in cardiovascular illness and mortality. A potentially important role of PM has been suggested in epidemiology studies showing increased cardiopulmonary-related mortality and hospital admissions for cardiovascular disease associated with increases in exposure to PM. The mechanisms by which PM, or other air pollutants, cause these toxic effects are not adequately understood. It is likely that different mechanisms are responsible for acute and chronic effects.

The objectives of this program are three fold. The first is to encourage innovative, multidisciplinary in vitro and in vivo research, in laboratory animals and humans, on the specific cellular, molecular and physiologic mechanisms by which air pollutants mediate adverse cardiovascular effects. Another key objective is to identify and investigate factors that make individuals more susceptible to the cardiovascular effects of air pollutants. In addition, the intent is to encourage collaboration between investigators with expertise in environmental health science and those with expertise in state-of-the-art techniques and methodologies used in cardiology and/or cardiovascular research.

This RFA will use NIH R01 and R21 (Exploratory/Developmental) award mechanisms and EPA’s STAR program, administered in accordance with 40 CFR Part 30 and 40. Funding to an individual grantee will be provided by a single award from either NIH or EPA.


The National Institute of Environmental Health Sciences (NIEHS) and the US Environmental Protection Agency (EPA) invite research applications to address the mechanisms by which air pollutants, especially particulate matter, contribute to the development, progression, or exacerbation of cardiovascular disease. The major purposes of this initiative are to:

  • support innovative, multidisciplinary in vitro and in vivo research, in laboratory animals and humans, on the specific cellular, molecular, and physiologic mechanisms by which air pollutants mediate adverse cardiovascular effects;
  • identify and investigate factors, such as age, pre-existing disease, and genetics, that make individuals more susceptible to the cardiovascular effects of air pollutants; and
  • encourage collaboration between cardiovascular researchers and environmental health researchers in the application of the state-of-the-art tools and models to the problem of environmentally related cardiovascular disease.


Cardiovascular disease (CVD) is the leading cause of death in the U.S. According to the American Heart Association’s “Heart Disease and Stroke Statistics -- 2003 Update,” in 2000 CVD caused nearly 40% of all deaths, and was listed as primary or contributing cause in about 60 percent. Furthermore, 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. In addition to age, “traditional” risk factors for CVD include lifestyle (such as smoking, physical inactivity, and diet), serum lipids, gender, race, and family history (genetics). However, these risk factors do not fully explain the etiology or incidence of CVD, and recent data have indicated that exposure to air pollutants is also a risk factor.

The strongest and most consistent association between air pollution exposure and cardiovascular morbidity and mortality has been seen for ambient particulate matter. Particulate matter (PM) is a mixture of solid particles and liquid droplets that vary in size and origin. It represents a broad class of chemically and physically diverse substances. The concentration of PM in air varies across space and time and is related to the source of the PM and the transformations that occur in the atmosphere. Particles are generally classified into three aerodynamic categories: Coarse PM (between 2.5 and 10 microns) is typically derived from attrition, erosion, or dispersion of soil, road dust and construction debris or agglomeration of smaller combustion particles. Ultrafine (smaller than 0.1 micrometers in diameter) and fine PM (less than 2.5 micrometers) are emitted or formed from combustion products of fossil fuels (e.g., from vehicle engines, power plants, and refineries) and contain sulfate, nitrate, chloride and ammonium compounds, carbon (soot), a spectrum of organic compounds, and metals.

Large prospective epidemiologic studies have shown that living in areas with higher levels of ambient particulate matter (PM) is associated with an increased risk of premature cardiopulmonary death. For example, the Harvard Six-Cities study followed 8111 subjects from six cities with varying levels of air pollution for 6 years, and reported a significant difference in the adjusted mortality-rate ratios for all-cause and cardiopulmonary deaths between the most and least polluted cities in the study. Likewise, the American Cancer Society study followed over 500,000 individuals from all 50 states and reported a 6% increase in cardiopulmonary deaths for every 10 micrograms/m3 elevation in PM. Time series and panel studies of daily mortality and hospital admissions have also found a significant association with daily fluctuations in ambient particulate matter concentrations.

Improved air quality appears to correlate with a decrease in cardiopulmonary mortality. A ban on coal sales in Dublin in 1990 resulted in a 35.6 microgram/m3 (70%) average reduction in PM. Adjusted death rates for respiratory and cardiovascular deaths over the 6-year period after the ban declined by 15.5% and 10.3%, respectively, as compared to the 6-year period before the ban.

The mechanisms by which PM, or other air pollutants, cause these toxic effects are not adequately understood, and it is likely that different mechanisms are responsible for acute and chronic effects. In addition, PM consists of many different components, and different components may affect cardiovascular disease by different mechanisms. Anomalous stimulation of the autonomic nervous system, perhaps via stimulation of afferent nerve endings in the lung, has been proposed as one mechanism by which PM acutely affects cardiac physiology. Cardiac responses to PM that have been reported in humans include increased heart rate, decreased heart rate variability, increased ST-segment depression greater than 0.1 mV during mild exercise among subjects with established coronary heart disease, and increased discharge of implanted cardiac-defibrillators. Studies of laboratory animals exposed to concentrated ambient particulate matter and other types of PM have found acute changes in cardiac function, including elevation of the S-T segment, arrhythmia, increased pulmonary artery systolic pressure, decreased cardiac output, decreased stroke volume, and shortened refractory period.

Other mechanisms may also play a role in PM-induced adverse cardiovascular outcomes. For instance, inflammatory and pro-inflammatory changes in the lung have been suggested as contributing to PM-related CVD. It has been proposed that reactive oxygen species (ROS) and other active compounds such as inflammatory cytokines, which are produced in the lung after exposure to PM, might be transported to the heart and vascular tissues and exert detrimental effects there or might stimulate other organs such as the liver to produce compounds that affect the cardiovascular system. For example, elevated levels of C-reactive protein, an inflammatory protein associated with risk of CVD, have been associated with exposure to increased levels of PM in humans. Likewise, exposure of humans and laboratory animals to particulate material resulted in changes in blood coagulation proteins (e.g., fibrinogen) and platelets that may lead to a hypercoagulable state. Recent progress also indicates that thrombosis and inflammation are closely related and interactive processes, and one may influence the other.

Atherosclerosis is a common pathologic condition in most adults that underlies many other cardiovascular diseases. There is evidence that PM exposure might hasten the development of this condition. For instance, in atherosclerosis-prone Watanabe rabbits, instillation of suspended PM collected from the ambient environment enhanced the progression of atherosclerosis. Likewise, polycyclic aromatic hydrocarbons (PAHs), such as benzo(a)pyrene, which are components of indoor and outdoor air pollution, have been shown in vitro to alter the redox environment in vascular walls, activating signaling pathways that can lead to proliferation of vascular smooth muscle cells, one of the hallmarks of atherosclerotic changes in the vessel wall. In addition, certain aldehydes, such as acrolein and butadiene, are cardiovascular toxicants and have been shown to induce proliferation of vascular smooth muscle cells as well. These aldehydes are present in some work environments and in ambient air, and several are listed as hazardous air pollutants in the Clean Air Act Amendments of 1990 (section 112(b)).

Research has also indicated that some individuals and groups are more susceptible to the effects of PM than others. Epidemiologic studies have identified individuals with cardiovascular and respiratory diseases, elderly individuals, and children as being at greater risk for adverse effects from PM exposure. For instance, a recent study showed a higher risk of PM-related cardiovascular mortality in elderly patients with pulmonary disease than in those without pulmonary disease. Studies have also shown that animals with compromised health, either genetically or experimentally induced, are more susceptible to instilled or inhaled particles.

Inhalation of air pollutants and their impact on the lung has long been a concern and the subject of intensive research. The effects of air pollutants beyond the lung have not been readily appreciated. It is only in recent years that cardiovascular endpoints have come to command a more urgent focus, and clearly many questions remain as to the role that these environmental agents play in CVD. Epidemiology and clinical studies have indicated that exposure to air pollutants can increase the risk for cardiovascular disease; however, despite these compelling associations, relatively little data exist on the mechanisms of action of these pollutants.

The primary objectives of this research program are to support research that will better elucidate the mechanisms by which air pollutants affect the cardiovascular system, resulting in increased morbidity and mortality, and to define factors which lead to differential susceptibility for certain groups and individuals. The research should use appropriate, innovative models and model systems and state-of-the-art technologies. In addition, because of the complex nature of this area, development of multidisciplinary collaborations is a second important objective. Therefore this RFA is designed to foster collaborations of environmental health and cardiovascular researchers, in order to promote the use of the most relevant, state-of-the-art cardiovascular models and methodologies, in combination with validated exposure methods to relevant air pollutants. The use of laboratory animal models and techniques that have been used successfully in cardiovascular research, but that may not have been applied to environmentally related CVD, is encouraged. These might include genetically manipulated rodent strains that are inherently susceptible or resistant to pollutants, as well as large animal models that more closely model the human cardiovascular system. Also, the use of state-of-the-art cellular and molecular biology, genetic and genomic, proteomic, and metabolic profiling technologies is encouraged.

This RFA is designed to solicit proposals that would address one or both of the following key questions:

  • What are the physiological, cellular, biochemical, molecular mechanisms by which air pollutants adversely affect the cardiovascular system, resulting in increased morbidity and mortality?
  • Who are the populations most susceptible to air pollutant-induced cardiovascular effects and what are the underlying mechanisms of this susceptibility?

The RFA solicits proposals on basic in vitro, animal, and controlled human exposure studies, and small clinical studies. Studies should be hypothesis driven and designed to identify or understand mechanisms by which air pollutants adversely affect the cardiovascular system. Proposals to screen chemicals for cardiovascular toxicity will only be considered responsive if they are designed to better understand how different PM components or their mixtures affect the cardiovascular system. Proposals to study acute or chronic effects of PM are both responsive. In addition, proposed air pollutant exposures are expected to be environmentally relevant. An example of an environmentally relevant exposure is ambient particulate matter. Use of laboratory-generated particles would require a strong rationale as to its scientific and environmental relevance. Similarly, studies proposing extremely high doses, or use of instillation rather than inhalation, require justification.

Examples of research that would be responsive to this RFA would include, but not be limited to the following, as they relate to air pollution exposure:

  • role of genetic background and gene polymorphisms in susceptibility
  • role of underlying health in susceptibility to pollutants
  • identification of cellular targets of air pollutants
  • alterations of cell function, such as cell signaling, signal transduction pathways, cell proliferation, and alterations in ion channel function
  • changes in protein and gene expression and post-translational modifications of proteins
  • pollutant-related alterations in endothelial cell function
  • mechanisms of electrophysiologic changes related to pollutant exposure: e.g., alterations in autonomic signaling
  • role of inflammation (e.g., inflammatory cells and mediators, cytokines, adhesion molecules)
  • role of oxidative stress (e.g., the roles of reactive oxygen and nitrogen species, enzymes such as NAD(P)H oxidase and the cyclooxygenases, and antioxidants)
  • immune function alterations that may be associated with CVD
  • role of changes in blood parameters, e.g., coagulation
  • mechanisms of pollutant-induced alterations in atherosclerosis progression
  • physiologic mechanisms that may induce cardiac changes from neural networks in the pulmonary system -- either locally or via the central nervous system
  • secondary effects of air pollutants (through lung and blood) on the cardiovascular system

The novel application of appropriate animal models, such as large animals, naturally susceptible models (e.g., ApoE, LDL-R, spontaneously hypertensive rats, and hyperlipidemic rabbits), and genetically or pharmacologically manipulated or disease-induced models is encouraged. The innovative use of in vitro models (e.g., isolated-perfused hearts and cultured myocardial cells) is also encouraged.

To ensure that proposals address priority areas of research, studies will be considered non-responsive if they include a large population-based study design. Additionally, any of the following proposed air pollutant exposures will be considered non-responsive:

  • substances primarily found in occupational settings, including silica, asbestos, carbon disulfide
  • environmental tobacco smoke
  • carbon monoxide as the only toxic inhalant


This RFA will use NIH R01 and R21 (Exploratory / Developmental) ( award mechanisms and the Environmental Protection Agency’s Science to Achieve Results (STAR) program, administered in accordance with 40 CFR Part 30 and 40. The application procedures described in this RFA have been designed to meet the needs of both NIEHS and EPA.

Applications will be evaluated by an NIH-convened peer review panel. Subsequent to peer review, meritorious applications will be considered for funding by either EPA or NIEHS. Policies that govern grant award programs of each agency will prevail for respective sources of support. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is August 2004. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application.

This RFA uses just-in-time concepts. It also uses the modular budgeting formats (see This program does not require cost sharing as defined in the current NIH Grants Policy Statement at


NIEHS and EPA intend to commit $2 million each in FY 2004 to fund the first budget year of 10–15 new grants. Funding to an individual grantee will be provided by a single award from either NIH or the EPA STAR program. Applicants for R01 grants may request up to four years of support and up to $250,000 per year in direct costs. Applicants for R21 (Exploratory / Developmental) applications are limited to two years of support and $150,000 per year in direct costs. Should an applicant plan to include subcontracts to other institutions or organizations, only the direct costs associated with the subcontracts will be used to tally the direct costs that apply toward the cap. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of NIEHS and EPA provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.


You may submit (an) application(s) if your institution has any of the following characteristics:

  • Non-profit organizations. Applications will not be accepted from for-profit organizations; however, organizations may establish subcontract arrangements with for-profit organizations.
  • Public or private institutions, such as universities, colleges, hospitals, and laboratories.
  • Domestic institutions. Applications will not be accepted from foreign institutions; however, foreign institutions may establish sub-contract arrangements with domestic applicant institutions.
  • Units of State and local governments.
  • Eligible agencies of the Federal government.
  • Non-profit faith-based or community-based organizations.


Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with his or her institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH and EPA programs.


Applications for R21 grants should be for new, highly innovative research using models and technologies that have not been previously applied to the field of environmentally related CVD.

Applications for R01 grants must be for collaborative research between at least one investigator with expertise in environmental health science and one investigator with demonstrated expertise in state-of-the-art techniques and methodologies used in cardiology and/or cardiovascular research. Applications not proposing such a collaboration will be returned to the applicant.

All applicants should request funds for travel to attend a grantees’ meeting approximately two years after the award of the grants. In addition, applicants for R01 grants should request funds to attend a second meeting approximately four years after the award of the grants.

Quality Assurance Statement: A Quality Assurance Statement (QAS) must be submitted for each project proposed in any application submitted in response to this RFA. This requirement results from implementation of ANSI/ASOC E4, Specifications and Guidelines for Quality Systems for Environmental Data Collection and Environmental Technology Programs, and is available for purchase from the American Society for Quality. Each QAS should not exceed two pages. This Statement should, for each item listed below, present the required information, reference the specific page and paragraph number containing the information, or provide a justification of why the item does not apply to the proposed research.

  1. Identify the individual who will be responsible for the quality assurance and quality control aspects of the research. (Quality assurance (QA) is an integrated system of management activities involving planning, implementation, documentation, assessment, and improvement to ensure that a process, or item is of the type and quality needed for the project. Quality control (QC) is the system of technical activities that measures the attributes and performance of a process or item against defined standards, to verify that they meet the stated requirements.)
  2. Discuss the activities to be performed or the hypothesis to be tested and criteria for determining acceptable data quality. (Note: Such criteria may be expressed in terms of precision, accuracy, representativeness, completeness, and comparability or in terms of data quality objectives or acceptance and evaluation criteria.) Also, these criteria must be applied to determine the acceptability of existing, or "secondary," data to be used in the project. (In this context, secondary data may be defined as data previously collected for other purposes or from other sources.)
  3. Describe the study design. Include sample type(s) and location requirements, all statistical analyses that were or will be used to estimate the types and numbers of physical samples required, or equivalent information for studies using survey and interview techniques.
  4. Describe the procedures that will be used in the calibration and performance evaluation of all analytical instrumentation and all methods of analysis to be used during the project. Explain how the effectiveness of any new technology will be measured.
  5. Describe the procedures for the handling and custody of samples, including sample collection, identification, preservation, transportation, and storage, or how the accuracy of test measurements will be verified.
  6. Discuss the procedures for data reduction and reporting, including a description of all statistical methods to make inferences and conclusions, with identification of any statistical software to be used; discuss any computer models to be designed or utilized and describe the associated verification and validation techniques.
  7. Describe the quantitative and/or qualitative procedures that will be used to evaluate the success of the project, including any plans for peer or other reviews of the study design or analytical methods prior to data collection.


We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

  • Direct your questions about scientific/research issues to:

    J. Patrick Mastin, PhD
    Division of Extramural Research and Training
    National Institute of Environmental Health Sciences
    111 T. W. Alexander Drive
    P.O. Box 12233, MD EC-23
    Research Triangle Park, NC 27709
    Telephone: 919-541-3289
    Fax: (919) 541-5064

    Stacey A. Katz, MPH
    US Environmental Protection Agency
    National Center for Environmental Research (8723R)
    1200 Pennsylvania Ave., N.W.
    Washington, DC 20460
    Telephone: (202) 564-8201
    FAX: (202) 565-2448

    Gail Robarge, MS
    US Environmental Protection Agency
    National Center for Environmental Research (8723R)
    1200 Pennsylvania Ave., N.W.
    Washington, DC 20460
    Telephone: (202) 564-8301
    FAX: (202) 565-2448

  • Direct your questions about peer review issues to:

    Linda K. Bass, PhD
    Scientific Review Administrator
    Scientific Review Branch
    Division of Extramural Research and Training
    National Institute of Environmental Health Sciences
    P.O. Box 12233, MD EC-30
    Research Triangle Park, NC 27709
    Telephone: (919) 541-1307
    Fax: (919) 541-2503

  • Direct your questions about financial or grants management matters to:

    Ms. Lisa Archer
    Grants Management Specialist
    Grants Management Branch
    National Institute of Environmental Health Sciences
    P. O. Box 12233, MD EC-22
    Research Triangle Park, NC 27709
    Telephone: (919) 541-0751
    Fax: (919) 541-2860

    Mr. Jack Puzak
    Acting Director
    National Center for Environmental Research (8701R)
    US Environmental Protection Agency
    1200 Pennsylvania Ave., NW
    Washington, DC 20460
    Telephone: (202) 564-6825
    Fax: (202) 565-2444


Prospective applicants are asked to submit a letter of intent that includes the following information:

  • Descriptive title of the proposed research
  • Name, address, and telephone number of the Principal Investigator
  • Names of other key personnel
  • Participating institutions
  • Number and title of this RFA

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows staff at NIEHS and EPA to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to:

Linda K. Bass, PhD
Scientific Review Administrator
Scientific Review Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, MD EC-30
Research Triangle Park, NC 27709
Telephone: (919) 541-1307
Fax: (919) 541-2503


Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001) and submitted to the Center for Scientific Review, NIH. Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at . The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email:


Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at


The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at:


Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to:

Center For Scientific Review
National Institutes Of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710
Bethesda, MD 20817 (for express/courier service)

At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to:

Linda K. Bass, PhD
Scientific Review Administrator
Scientific Review Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, MD EC-30
79 T.W. Alexander Drive, 3rd Floor, Room 3167 (courier/express)
Research Triangle Park, NC 27709
Telephone: (919) 541-1307
Fax: (919) 541-2503


Applications must be received on or before the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review.

Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks.

The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is, the application for the RFA must not include an Introduction describing the changes from the previous unfunded version of the application.


Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIEHS and EPA. Incomplete applications will not be reviewed.

If the application is not responsive to the RFA, NIH staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle.

Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIEHS in accordance with the review criteria stated below. As part of the initial merit review, all applications will:

  • Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score
  • Receive a written critique
  • Receive a second level review by the NIEHS National Advisory Council or by EPA’s National Center for Environmental Research.


The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to evaluate the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of the following criteria in assigning the application’s overall score, weighting them as appropriate for each application.

  • Significance
  • Approach
  • Innovation
  • Investigator
  • Environment

The application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.


Does this study address important research objectives related to the impact of air pollutants on cardiovascular disease? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field?


Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Is there clear evidence of significant interdisciplinary interactions in the conception, design, and proposed implementation of the project?


Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies?


Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)?


Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support?


In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score:

For R01 grant applications: Are both environmental health science and cardiovascular researchers included in the application, and is there adequate evidence that a productive collaboration is likely?


The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below).


The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below).


If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed.


Sharing Research Data

Applicants requesting more than $500,000 in direct costs in any year of the proposed research are expected to include a data sharing plan in their application. The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or priority score.


The reasonableness of the proposed budget and the requested period of support in relation to the proposed research.


Letter of Intent Receipt Date: November 19, 2003
Application Receipt Date: December 19, 2003
Peer Review Date: February 2004
Council and EPA Review: May 2004
Earliest Anticipated Start Date: August 2004


Award criteria that will be used to make award decisions include:

  • Scientific merit (as determined by peer review)
  • Availability of funds
  • Programmatic priorities.

Funding will be provided by a single award from either NIH or EPA.

EPA Programmatic Review: Applications that are considered meritorious by the peer reviewers are subjected to a programmatic review within the EPA to assure a balanced research portfolio for the Agency. Applications are then recommended for funding to the NCER Director who makes funding decisions. Applications are selected for an award based on consideration of the scientific quality of proposals and relevance to EPA program research priorities, program balance, budget, and available funds.



Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained.


Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose-finding studies (phase I); efficacy studies (phase II); efficacy, effectiveness and comparative trials (phase III). The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risk to the participants. (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998:


Starting with the October 1, 2003 receipt date, investigators submitting an NIH application seeking more than $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible. Investigators should seek guidance from their institutions, on issues related to institutional policies, local IRB rules, as well as local, state and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.


It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43).

All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (; a complete copy of the updated Guidelines are available at The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.


The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at


NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at


Criteria for federal funding of research on hESCs can be found at and at Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see It is the responsibility of the applicant to provide, in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review.


The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at

Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.


The Department of Health and Human Services (DHHS) issued final modification to the “Standards for Privacy of Individually Identifiable Health Information”, the “Privacy Rule,” on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule (classified under the Rule as “covered entities”) must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website ( information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on “Am I a covered entity?” Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at


All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.


The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at


This program is described in the Catalog of Federal Domestic Assistance at and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. Awards by EPA are made under the authority of 40 CFR Part 30 and 40 and are subject to terms and conditions and other considerations. All awards made by NIEHS are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at

The PHS and EPA strongly encourage all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.