THE ROLE OF AIR POLLUTANTS IN CARDIOVASCULAR DISEASE
 
RELEASE DATE:  September 10, 2003
 
RFA Number:  RFA-ES-03-010

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

PARTICIPATING ORGANIZATIONS:

National Institutes of Health (NIH) 
 (http://www.nih.gov)
EPA's Office of Research and Development (EPA)
 (http://www.epa.gov/ord)

COMPONENTS OF PARTICIPATING ORGANIZATIONS:

National Institute of Environmental Health Sciences (NIEHS)
 (http://www.niehs.nih.gov)
National Center for Environmental Research (EPA)
 (http://www.epa.gov/ncer)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.113, 93.837, 
66.509 

LETTER OF INTENT RECEIPT DATE:  November 19, 2003

APPLICATION RECEIPT DATE:  December 19, 2003
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

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

PURPOSE OF THIS RFA

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:

o 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;

o 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

o 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.
 
RESEARCH OBJECTIVES

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.  (For additional information on ambient PM, go to 
http://www.epa.gov/oar/aqtrnd97/brochure/pm10.html.)

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:

o What are the physiological, cellular, biochemical, molecular 
mechanisms by which air pollutants adversely affect the cardiovascular 
system, resulting in increased morbidity and mortality?

o 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:

o role of genetic background and gene polymorphisms in susceptibility
o role of underlying health in susceptibility to pollutants
o identification of cellular targets of air pollutants
o alterations of cell function, such as cell signaling, signal 
transduction pathways, cell proliferation, and alterations in ion 
channel function
o changes in protein and gene expression and post-translational 
modifications of proteins
o pollutant-related alterations in endothelial cell function 
o mechanisms of electrophysiologic changes related to pollutant 
exposure: e.g., alterations in autonomic signaling
o role of inflammation (e.g., inflammatory cells and mediators, 
cytokines, adhesion molecules)
o 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)
o immune function alterations that may be associated with CVD
o role of changes in blood parameters, e.g., coagulation
o mechanisms of pollutant-induced alterations in atherosclerosis 
progression
o physiologic mechanisms that may induce cardiac changes from neural 
networks in the pulmonary system -- either locally or via the central 
nervous system
o 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:

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

MECHANISM OF SUPPORT

This RFA will use NIH R01 and R21 (Exploratory / Developmental) 
(http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html) award 
mechanisms and the Environmental Protection Agency's Science to Achieve 
Results (STAR) program (http://es.epa.gov/ncer/rfa/#2004), 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 
http://grants.nih.gov/grants/funding/modular/modular.htm).  This 
program does not require cost sharing as defined in the current NIH 
Grants Policy Statement at 
http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm

FUNDS AVAILABLE
 
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.
 
ELIGIBLE INSTITUTIONS 
 
You may submit (an) application(s) if your institution has any of the 
following characteristics:

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

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.
 
SPECIAL REQUIREMENTS

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.
 
WHERE TO SEND INQUIRIES

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:

o 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
Email:  mastin@niehs.nih.gov

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
Email:  katz.stacey@epa.gov

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
Email:  robarge.gail@epa.gov

o 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 
E-mail:  bass@niehs.nih.gov 

o 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
Email:  archer@niehs.nih.gov

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
Email: puzak.jack@epa.gov
 
LETTER OF INTENT
 
Prospective applicants are asked to submit a letter of intent that 
includes the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o 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 
E-mail:  bass@niehs.nih.gov

SUBMITTING AN APPLICATION

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 http://www.dunandbradstreet.com . 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 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an 
interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS:  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 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-
by-step guidance for preparing modular grants.  Additional information 
on modular grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

USING THE RFA LABEL: 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: 
http://grants.nih.gov/grants/funding/phs398/labels.pdf.
 
SENDING AN APPLICATION TO THE NIH: 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 
E-mail:  bass@niehs.nih.gov
 
APPLICATION PROCESSING: 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.  

PEER REVIEW PROCESS  
 
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:

o 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
o Receive a written critique
o Receive a second level review by the NIEHS National Advisory Council 
or by EPA's National Center for Environmental Research.
 
REVIEW CRITERIA

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. 

o Significance 
o Approach 
o Innovation
o Investigator
o 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.

SIGNIFICANCE: 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?

APPROACH: 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?

INNOVATION: 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?

INVESTIGATOR(S): 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)?

ENVIRONMENT: 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?  

ADDITIONAL REVIEW CRITERIA: 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?

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: 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).
 
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: 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).

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: 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.
  
ADDITIONAL REVIEW CONSIDERATIONS

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.

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

RECEIPT AND REVIEW SCHEDULE

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

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

o Scientific merit (as determined by peer review)
o Availability of funds
o 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.
 
REQUIRED FEDERAL CITATIONS 

HUMAN SUBJECTS PROTECTION: 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.
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm 

DATA AND SAFETY MONITORING PLAN: 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: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

SHARING RESEARCH DATA: 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. 
http://grants.nih.gov/grants/policy/data_sharing  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.

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH:  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 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
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.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS: 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 
http://grants.nih.gov/grants/funding/children/children.htm

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: 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 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of 
research on hESCs can be found at http://stemcells.nih.gov/index.asp and 
at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  
Only research using hESC lines that are registered in the NIH Human 
Embryonic Stem Cell Registry will be eligible for Federal funding (see 
http://escr.nih.gov).   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. 

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: 
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 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

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.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:  
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 
(http://www.hhs.gov/ocr/) provides 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 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: 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.

HEALTHY PEOPLE 2010: 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 
http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at http://www.cfda.gov/ 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 that can be found at 
http://es.epa.gov/ncer/guidance/.  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 
http://grants.nih.gov/grants/policy/policy.htm.

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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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