ENVIRONMENTALLY INDUCED CARDIOVASCULAR MALFORMATIONS

RELEASE DATE:  April 3, 2002

PA NUMBER:  PA-02-093 (see NOT-ES-04-004)

EXPIRATION DATE:  June 1, 2004, unless reissued

National Institute of Environmental Health Sciences (NIEHS) 
 (http://www.niehs.nih.gov)

THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanism(s) of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS PA

The National Institute of Environmental Health Sciences (NIEHS) invites 
applications to study environmental agents that cause cardiovascular 
malformations (CVMs). The purposes of this Program Announcement (PA) are to 
stimulate research to characterize environmental agents that cause alterations 
in the development of the cardiovascular system and thereby lead to 
cardiovascular malformations, and to investigate the cellular and molecular 
mechanisms involved in the development of these malformations. The use of 
mammalian and non-mammalian animal models, including transgenic and gene 
knock-out animal models, and of state-of-the-art molecular biology techniques 
such as genomics and proteomics is encouraged, as well as collaborations 
between environmental health scientists and developmental biologists, to 
develop research programs to address the high rate of cardiovascular 
malformations.

RESEARCH OBJECTIVES

Background

Cardiovascular malformations (CVMs) are the most common type of birth defect 
among live births in the US, occurring in approximately 0.8 percent of live 
births. The most common types of CVMs include atrial or ventricular septal 
defects, transposition of the great vessels, persistent truncus arteriosus, 
teratology of Fallot, and coarctations. Despite the importance of these in 
malformations, both in terms of human suffering and cost to the healthcare 
system, the causes of most cases of CVMs are not known. Etiologic factors that 
have been identified include genetics; maternal diseases, such as diabetes; 
certain drugs, such as phenytoin and cocaine; and dietary factors, such as 
folic acid deficiency, vitamin A excess, and copper deficiency. In addition, 
certain environmental chemicals have been shown to be associated with cardiac 
malformations. For instance, in one large epidemiological study of cardiac 
malformations, the Baltimore-Washington Infant Study, exposure to such 
environmental factors as paints, solvents and degreasers, and pesticides, were 
associated with increased cardiac malformations. Epidemiological studies have 
also reported CVM associations with air pollutants (ozone and carbon monoxide) 
and trichloroethylene (TCE). In addition, environmental contaminants such as 
TCE, bis-diamine, and dioxin have been shown to be cardiac teratogens in 
animal studies. Despite the evidence for an environmental role in CVMs, the 
list of environmental agents tested for teratogenic effects on the heart is 
limited and relatively little research has been done on the cellular and 
molecular basis of the teratogenic effects of environmental agents or on the 
possible interactions between environmental exposures and other factors such 
diet and genetics. Recent advances in genomic and molecular biology technology 
and in the understanding of the development of the fetal heart, make this an 
opportune time to initiate such studies.

General considerations:

o Chemicals to be studied can represent known teratogens, such as 
trichloroethylene, or suspected teratogens, such as components of air 
pollution. Studies of mixtures are also acceptable.

o In characterizing the actions of known or potential cardioteratogens, 
dose-response curves should be determined, and the dose ranges should include 
environmentally relevant doses.

o The use of state-of-the-art technologies, such as genomic and proteomic 
technologies, is encouraged.

o Studies to determine interactions between environmental exposures and 
genetics and/or nutritional factors are highly encouraged.

o The use of genetically altered model organisms, such as transgenic animals 
and non-mammalian species, is encouraged.

o Proposals should take into consideration the metabolism of environmental 
chemicals and the proximal metabolite to which the fetus is exposed.

o In general in vivo and organ cultures procedures should be used, except in 
studies in which the ultimate CVM is known and in vitro experiments are 
proposed to examine responses of specific fetal cell types, to determine 
cellular and/or molecular mechanisms.

Specific areas of interest to NIEHS include, but are not limited to the 
following:

o Characterization of new potential environmental cardioteratogens. This 
characterization would include the types of CVMs induced, dose-response 
evaluation, identification of specific windows of vulnerability to the agent, 
and development of preliminary data for further mechanistic studies.

o Use of forward and reverse mutagenesis studies in model organisms to 
determine the genes altered by specific cardiovascular developmental toxicants 
and the relationship of the altered gene activity to dysmorphogenesis.

o Characterization of global gene expression profiles in the developing heart 
of model organisms associated with the normal range of development and after a 
developmentally toxic exposure. The relationship between the changes in gene 
expression and the developmental lesion should be assessed.

o Use of genomic and/or proteomic profiling to determine how well data on 
toxicant-induced malformations can be extrapolated across species.

o Identification and evaluation of specific signal transduction pathways and 
the associated genetic regulatory circuits that might be sites of action of 
developmental cardiovascular toxicants. The causal relationships between 
exposure and the CVMs should be developed.

o Determination of the potential for interactions between exposures to 
environmental agents and genetic susceptibility that increase the risk for 
cardiovascular developmental toxicity.

Special Requirements

o This initiative focuses on mechanisms of development of CVMs. Therefore, 
proposals dealing with human epidemiological or clinical studies will not be 
considered as responsive. In some cases, use of human tissues in mechanistic 
studies could be considered responsive.

o Proposals solely designed to screen a large number of agents will not be 
considered responsive. Screening of members of specific classes of agents is 
responsive as long as follow-up mechanistic studies of these agents are 
included.

o Proposals should focus only on malformations of the heart and major vessels, 
e.g., the aorta, vena cavae, pulmonary artery, and pulmonary vein.

o For this PA, diet will not be considered an environmental agent, and can 
only be considered in the context of interactions with environmental agents

MECHANISM(S) OF SUPPORT 

This PA will use the NIH R21 and R01 award mechanism(s). As an applicant, you 
will be solely responsible for planning, directing, and executing the proposed 
project.  The total project period of an R21 proposal may not exceed two years,
and the total direct costs, including third party facilities and administrative
costs, may not exceed $100,000 per year.

The objective of the Exploratory/Developmental Grant (R21) mechanism is to 
encourage applications for one-time grants to support innovative, 
high-risk/high-impact research requiring preliminary testing or development; 
exploration of the use of approaches and concepts new to a particular 
substantive area; research and development of new technologies, techniques, or 
methods; or initial research and development of data upon which significant 
future research may be built. Applications will be considered as high impact 
if they demonstrate the potential for ground-breaking, precedent-setting 
significance, and high risk because they either lack sufficient preliminary 
data to ensure their feasibility, or involve using a new model system or 
technique. While this PA is intended to encourage innovation and high impact 
research, and while minimal preliminary data are expected to be described in 
the application, applications should clearly indicate that the proposed 
research and/or development is scientifically sound, that the qualifications 
of the investigators are appropriate, and that resources available to the 
investigators are adequate. As the R21 grant project cannot be renewed; if 
sufficient data are generated during the term of the award, investigators 
could then apply for further funding through regular research grant, e.g., the 
research project grant (R01) mechanism.

On the other hand, R01 grant applications should be grounded in more 
established model systems and methodologies with which the investigators have 
experience, as evidenced by preliminary data in the application and/or 
publications in peer-reviewed literature, while at the same time being 
innovative and moving the field forward. 

This PA uses just-in-time concepts.  It also uses the modular as well as the 
non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm
Specifically, if you are submitting an application with direct costs in each 
year of $250,000 or less, use the modular format. Otherwise follow the 
standard instructions for grant applications.

ELIGIBLE INSTITUTIONS 

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

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign

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 their 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 programs.

WHERE TO SEND INQUIRIES

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

o Direct your questions about scientific/research issues to:

J. Patrick Mastin, Ph.D.
Scientific Program Administrator
Organs and Systems Toxicology Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, EC-23 
111 T.W. Alexander Drive (for express/courier service) 
Research Triangle Park, NC 27709
Telephone: 919-541-3289
FAX: 919-541-5064
Email: mastin@niehs.nih.gov

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

Ms. Carolyn Mason
Grants Management Official
Grants Management Branch
Office of Program Operations
Division of Extramural Research and Training 
National Institute of Environmental Health Sciences 
P.O. Box 12233, EC-22 
111 T.W. Alexander Drive, (for express/courier service) 
Research Triangle Park, NC  27709 
Telephone:  (919) 541-1373
FAX:  (919) 541-2860  
Email: mason6@niehs.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001). The PHS 398 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

APPLICATION RECEIPT DATES 

Applications submitted in response to this program announcement will be 
accepted at the standard application deadlines, which are available at 
http://grants.nih.gov/grants/dates.htm. Application deadlines are also 
indicated in the PHS 398 application kit.

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

SPECIFIC INSTRUCTIONS FOR APPLICATIONS THAT REQUEST $500,000 OR MORE PER YEAR

Applications requesting $500,000 or more in direct costs for any year must 
include a cover letter identifying the NIH staff member within one of NIH 
institutes or centers who has agreed to accept assignment of the application.

Applicants requesting more than $500,000 must carry out the following steps:

1) Contact the NIEHS program staff at least six weeks before submitting the 
application, i.e., as you are developing plans for the study;

2) Obtain agreement from the NIEHS staff that the NIEHS will accept your 
application for consideration for award; and,

3) Identify, in a cover letter sent with the application, the staff member and 
IC who agreed to accept assignment of the application.

This policy applies to all investigator-initiated new (type 1), competing 
continuation (type 2), competing supplement, or any amended or revised version 
of these grant application types. Additional information on this policy is 
available in the NIH Guide for Grants and Contracts, October 19, 2001 at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html.

SENDING AN APPLICATION TO THE NIH 

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

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

APPLICATION PROCESSING

Applications must be received by or mailed on or before the receipt dates 
described at http://grants.nih.gov/grants/funding/submissionschedule.htm
The CSR will not accept any application in response to this PA that is 
essentially the same as one currently pending initial review unless the 
applicant withdraws the pending application. The CSR will not accept any 
application that is essentially the same as one already reviewed. This does 
not preclude the submission of a substantial revision of an application 
already reviewed, but such application must include an Introduction addressing 
the previous critique.

PEER REVIEW PROCESS

Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines. An appropriate scientific review group 
convened in accordance with the standard NIH peer review procedures 
http://www.csr.nih.gov/refrev.htm will evaluate applications for scientific 
and technical merit.  

As part of the initial merit review, all applications will:

o Receive a written critique.
o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score.
o Receive a second level review by the appropriate national advisory council 
or board.

REVIEW CRITERIA

Note that the page limit for the Research Plan in R21 applications under this 
Program Announcement is 15 pages, as opposed to 25 pages for R01 applications.

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 discuss the following aspects of 
your application in order to judge the likelihood that the proposed research 
will have a substantial impact on the pursuit of these goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The scientific review group will address and consider each of these criteria 
in assigning your application=s overall score, weighting them as appropriate 
for each application. Your 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, you may propose to carry out 
important work that by its nature is not innovative but is essential to move a 
field forward.
  
(1) SIGNIFICANCE: Does your study address an important problem? If the aims of 
your application are achieved, how do they advance scientific knowledge? What 
will be the effect of these studies on the concepts or methods that drive this 
field?

(2) APPROACH: Are the conceptual framework, design, methods, and analyses 
adequately developed, well integrated, and appropriate to the aims of the 
project? Do you acknowledge potential problem areas and consider alternative 
tactics?

(3) INNOVATION: Does your project employ novel concepts, approaches or 
methods? Are the aims original and innovative? Does your project challenge 
existing paradigms or develop new methodologies or technologies?

(4) INVESTIGATOR: Are you appropriately trained and well suited to carry out 
this work? Is the work proposed appropriate to your experience level as the 
principal investigator and to that of other researchers (if any)?

(5) ENVIRONMENT: Does the scientific environment in which your 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?

For R21 applications, the above stated criteria will be reviewed, but it will 
be noted that the R21 is a developmental/exploratory grant mechanism that is 
used for high risk/high impact projects to generate preliminary data to 
develop novel hypotheses. Therefore, review standards for preliminary data and 
past performances are not applicable for this mechanism.

ADDITIONAL REVIEW CRITERIA

In addition to the above criteria, your application will also be reviewed with 
respect to the following:

PROTECTIONS: The adequacy of the proposed protection for humans, animals, or 
the environment, to the extent they may be adversely affected by the project 
proposed in the application.

INCLUSION: 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 included in the 
section on Federal Citations, below.)

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

AWARD CRITERIA

Applications submitted in response to a PA will compete for available funds 
with all other recommended applications. The following will be considered in 
making funding decisions:  

o Scientific merit of the proposed project as determined by peer review.
o Availability of funds. 
o Relevance to program priorities.

REQUIRED FEDERAL CITATIONS 

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 AMENDMENT "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://grants.nih.gov/grants/stem_cells.htm and   
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 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.

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 PA 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 No. 
93.3113 and is not subject to the intergovernmental review requirements of 
Executive Order 12372 or Health Systems Agency review. Awards are made under 
authorization of Sections 301 and 405 of the Public Health Service Act as 
amended (42 USC 241 and 284 and administered under NIH grants policies 
described at http://grants.nih.gov/grants/policy/policy.htm

The PHS strongly encourages 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.

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