DEVELOPMENTAL TOXICOLOGY EXPLORATORY (R21) RESEARCH GRANTS
 
Release Date:  June 14, 2001

RFA:  RFA-ES-01-006

National Institute of Environmental Health Sciences
 (http://www.niehs.nih.gov)
The American Chemistry Council
 (http://www.americanchemistry.com)

Letter of Intent Date:     July 17, 2001
Application Receipt Date:  August 17, 2001
 
THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  IT INCLUDES 
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED 
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA.

PURPOSE

Recent advances in developmental biology, molecular biology and genomics 
present unique and timely opportunities to examine the site and mechanism of 
action of potential environmental developmental toxicants and to thereby set 
the stage for intervention and prevention strategies. The overall objective 
of this Request for Applications (RFA) is therefore to stimulate research on 
the mechanism of action of developmental toxicants using the state of the art 
tools of genomics, proteomics and model organisms including transgenic and 
gene knock out genetic animal models. This objective will be achieved by 
stimulating the interaction/collaboration of developmental toxicologists with 
developmental biologists, molecular biologists and geneticists in order to 
fully integrate these new research directions and to expand our knowledge on 
the mode of action of developmental toxicants.  The new information obtained 
from these interactions will be used to accelerate research in developmental 
toxicology, advance new approaches in molecular epidemiology and improve 
qualitative and quantitative risk assessment processes for evaluating the 
potential for exposure induced developmental defects.

This RFA is jointly supported by the National Institute of Environmental 
Health Sciences (NIEHS) and the American Chemistry Council (ACC).  The NIEHS 
supports research into the role of environmental agents in the etiology of 
disease and dysfunction.  The ACC is a not-for-profit organization 
established with the funding support of member companies of the U.S. chemical 
industry.  The ACC has affirmed its commitment to Responsible Care ® and the 
American Public’s right to know by initiating a Long-Range Research 
Initiative (LRI) program support by $100 million over a five-year period.  
The LRI seeks to increase the knowledge of the potential risks that chemicals 
have on human health and the environment.  Thus, this RFA is a unique 
collaboration of Government and Industry interested in improving the health 
of the American people by improving the quantity and the quality of the data 
on potential developmental toxicants that is available for use in the risk 
assessment process.

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: “Developmental 
Toxicology Exploratory (R21) Research Grants," is related to several areas of 
emphasis in the disease prevention objectives.  Potential applicants may 
obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and non-
profit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and eligible 
agencies of the Federal government.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as Principal 
Investigators. 

SPECIAL REQUIREMENTS

Letter of Authorization

Because the domestic applications will be co-funded by the National 
Institutes of Health (NIH) and the American Chemistry Council (ACC), all 
applicants should submit a brief letter to the NIH indicating that the 
application and the summary statements for such applications can be shared 
with the ACC.  Letters of authorization should be prepared by the Principal 
Investigator and co-signed by the official for the applicant organization.  
This letter should be submitted as a cover letter accompanying the 
application.

Periodic Meetings

Upon initiation of this program, the NIH and the American Chemistry Council 
plans to sponsor periodic meetings to encourage exchange of information among 
investigators, to foster collaborative efforts among program grantees, and to 
identify resources that would enhance the productivity of grantees.  For this 
purpose, applicants should request travel funds for a two-day meeting each 
year, the timing and location of which will be announced. Applicants should 
include in their applications a statement indicating their willingness to 
participate in such meetings and, as appropriate, to cooperate with other 
researchers.

MECHANISM OF SUPPORT

This RFA will use the NIH R21 Exploratory/Developmental award mechanism.  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 RFA 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.

Specific application instructions have been modified to reflect the purpose 
and nature of this mechanism, as well as to accommodate the "Modular Grant" 
and "Just-In-Time" streamlining efforts being implemented by the NIH.  
Complete and detailed instructions and information on Modular Grant 
applications can be found at the website 
http://grants.nih.gov/grants/funding/modular/modular.htm.

FUNDS AVAILABLE
The total estimated funds available for this RFA is approximately $2 million 
that will support up to 15 awards.  The annual funding plans of the NIEHS and 
the ACC have included, respectively, $1.5 million and $500,000 for each of 
two years to fund applications awarded in response to this RFA.  This level 
of support is dependent on the receipt of a sufficient number of applications 
of high scientific merit.  Awards will be for up to $100,000 per year (direct 
costs) for up to two years. The amount and time must be justified in the 
application.

BACKGROUND

This RFA is jointly supported by the National Institute of Environmental 
Health Sciences (NIEHS) and the American Chemistry Council (ACC), U.S.A.  The 
NIEHS supports research into the role of environmental agents in the etiology 
of disease and dysfunction.  The support of research on reproductive and 
developmental toxicology is a primary area of interest to the mission of the 
NIEHS. The ACC is an independent, not-for-profit organization established 
with the funding support of member companies of the U.S. chemical industry.  
The ACC has affirmed its commitment to Responsible Care? and the American 
Public’s right to know by initiating a Long-Range Research Initiative (LRI) 
program supported by $100 million over a five-year period.  The LRI seeks to 
increase the knowledge of the potential risks that chemicals have on human 
health and the environment.  The present initiative RFA addresses the mutual 
research goals of the NIEHS and the ACC to improve the quantity, quality, and 
timeliness of data from investigations on the mechanisms of developmental 
toxicants. Thus, this jointly sponsored RFA represents a unique collaboration 
of Government and Industry to support novel, high potential research that 
will contribute to the improvement of the health of the American people by 
improving the quantity and quality of the data on developmental toxicants 
that is available for use in the risk assessment process.

A number of developmental components and processes involved in the 
organization of a metazoan body plan are shared between invertebrates and 
vertebrates, as described in a recent review (Scientific Frontiers in 
Developmental Toxicity and Risk Assessment: National Academy Press, 
Washington, D.C., 2000).  Genes are shared across phyla that control 
processes such as dorsoventral dimension; organogenesis of limbs, eyes, 
heart, visceral mesoderm, and gut; cytodifferentiation in neurogenesis and 
myogenesis; and segmentation.  There are approximately 17 cell signaling 
pathways identified that operate in early, mid, and late development in 
diverse species.  In invertebrates such as the fruitfly (Drosophilia sp.) and 
the nematode worm (C. elegans), null (functional deletion) mutations in these 
morphogenetic and signaling pathways are often lethal.  In mammals (mice), 
the genes encoding most components of these pathways have undergone 
duplication and slight diversification, leading to redundancy in the 
pathways.  Null mutants are not always lethal, and may result in specific 
local losses that closely resemble those associated with human developmental 
defects.  These defects reflect those times and places in development where a 
deleted component is not overlapped by a redundant component.  It is 
anticipated that many of the kinds of defects that occur in developmental 
programs might arise from altered cell signaling pathways leading to 
alterations in selective gene expression, cell secretion, cell proliferation, 
and/or cell migration.

Recent technological advances in genomics, including the recent sequencing of 
the genome of the human and a number of other species, have provided valuable 
information on the similarities and differences in the number and 
organization of genes amongst species.  The new knowledge now in hand will 
allow the investigation of gene expression during development using RNA 
isolated from the specific organs of embryos and fetuses of the various 
species amenable to laboratory modeling.  The use of DNA micro-array 
technologies to assess changes in gene expression is a rapidly growing 
research area that will have a large impact on many fields, including 
developmental toxicology. This technology will allow a global 
genomic/proteomic assessment of how an organism responds to a specific 
stress, drug, or toxicant. Data generated in these experiments will provide 
information on cellular networks of responding genes, help define important 
target molecules and pathways for toxicity investigations, as well as 
providing information on future biomarkers of toxic exposure and/or effect. 
Experiments using micro-array technology will help define the complex genomic 
regulatory circuitry and metabolic pathways within a cell, tissue and organ 
that respond to specific stressors. This technology may be able to help 
define the cascade of biochemical and molecular events that define pathways 
that lead to modulation and repair of a prenatal insult, thus preventing the 
occurrence of developmental toxicity.  

The science of proteomics promises to take over where genomics leaves off and 
provide data on tissue and time specific protein expression as well as post 
translational modifications altering protein activity. Indeed, it is feasible 
that the integration of functional genomics and proteomics in the discipline 
of metabonomics will soon provide global profiles and signatures of cellular 
metabolism for advancing new approaches to metabolic toxicology, in general, 
and developmental toxicology, in particular.  The use of these new 
technologies (genomics and proteomics) and new surrogate humanized model 
systems in developmental toxicology will undoubtedly have a major impact on 
toxicology research within next decade and beyond.  They offer the 
opportunity to markedly expand on our ability to develop a thorough 
understanding of the basic mechanisms of development as well as an improved 
knowledge of species differences which will undoubtedly and significantly 
contribute to improved public health via protective intervention and 
prevention strategies. 

RESEARCH OBJECTIVES

The objectives of this RFA are to use the new technologies described in this 
RFA and appropriate model organisms to develop a more complete description of 
the mechanism of action of specific toxicants.  This includes the toxicants’ 
interaction with specific molecular components of cellular or developmental 
processes in the conceptus and the consequences of those interactions for the 
function of the cellular or developmental process and the outcome, namely the 
developmental defect, recognized as either a structural malformation or 
functional deficit.  It is anticipated that accomplishment of this goal will 
require the interaction and collaboration of developmental biologists, 
molecular biologists and developmental toxicologists. These multi-, intra- 
and inter- disciplinary collaborations are strongly encouraged by this RFA.

The research objectives of the R21 mechanism used in this RFA are to support: 
1) innovative, high-risk research, requiring preliminary testing or 
development; 2) exploration of new approaches or concepts to a particular 
substantive area; 3) research and development of new technologies, techniques 
or methods; or 4) initial research and development of data upon which 
significant future research may be built, i.e., the data should have a high 
level of impact on the field. The project research and/or development aims 
and scope can be relevant to any of the developmental toxicology science 
areas relevant to the mission areas supported by the research agenda of the 
NIEHS and the ACC as described below. 

In general, it is expected that the new approaches proposed for this RFA will 
consider the use of candidate chemicals that have been well characterized in 
vivo with respect to their sites of toxicity and dose responses.  This RFA, 
in particular, seeks to explore a diversity of proposed modes of action and 
chemical classes in order to evaluate the broadest possible range of effects 
on developing embryos.  The well-studied dioxin and dioxin-like substances 
will not receive priority consideration in this regard.  The molecular 
approaches proposed should be related to survival (viability) or to a 
structural or functional defect in the embryo or fetus in order to determine 
exposures that lead to adaptation or repair verses those that lead to toxic 
manifestations. Relatively few toxicants have been sufficiently evaluated for 
effects on signaling pathway effects during development in mammals (e.g., 
cyclopamine and retinoic acid), but the potential for interference in these 
key cell signaling pathways is considered to be highly feasible.  Such 
interference should be evaluated for impact on functional tissue or organ 
physiology or morphogenesis in the fetus, neonate, adolescent or adult 
individual. It is considered highly important that consideration be given to 
whether or not the observed effects on genes or gene activity occur similarly 
across species and are manifest as developmental defects. It is also 
important that consideration be given to understanding the time course and 
dose-response relationships between genetic, functional and morphogenetic 
effects across species since these data are critically important to risk 
assessment applications.  To enhance the applicability to risk assessment, 
study designs that use environmentally relevant doses of test chemicals are 
encouraged, especially those that will provide sound data extending into the 
low dose portion of the dose response curve, i.e., in the region beneath 
traditionally observed NOAELs (No Observed Adverse Effect Levels) or LOAELs 
(Lowest Observed Adverse Effect Levels).  It is anticipated that proposals 
using chemicals that have supportive data on developmental toxicity in rodent 
models and/or humans will be of compelling interest in this regard.  
Experimental models may include laboratory models studied for the 
conservation of the cell signaling transduction pathways (Drosophilia, C. 
elegans, zebrafish, etc.), species and strains normally used in toxicolology 
studies, and genetically sensitized/transgenic models with altered signal 
transduction pathways.  In any event, any application that is submitted in 
response to this RFA should include appropriate justification(s) for the 
selection of chemical(s), dose(s) and experimental model(s).

Applications are solicited in, but not limited to, the following areas. 

o  Characterization of global gene expression profiles in specific 
organs/tissues 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 proteomic approaches to understand the effects of 
developmental toxicants on growth factor signaling and cross talk between and 
among signaling pathways.

o  Evaluation of specific signal transduction pathways and the associated 
genetic regulatory circuits as sites of action of developmental toxicants 
using model organisms and/or genomics, and the development of causal 
relationships to the developmental lesion(s).

o  Characterization of molecular stress and checkpoint pathways as sites of 
action of developmental toxicants and the elucidation of causal relationships 
between pathway alterations and dysmorphogenesis.

o  Use of genomic and proteomic profiling to show species and tissue specific 
toxicity of developmental toxicants that do not translate across species.

o  Application of genomic and proteomic technologies to examine the role and 
mechanism of oxidative damage from chemical exposure in the etiology of 
dysmorphogenesis or embryo lethality.

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

o  Use of genetically sensitized models, including transgenic and gene knock-
out animal models, to determine the potential for interactions between 
chemical exposures and genetic susceptibility that increase the risk for 
developmental toxicity.

o  Use of microarray and proteomic analysis to examine the effects of 
mixtures of toxicants with similar or different mechanisms of action and to 
compare the molecular results with dysmorphogenesis caused by the mixtures 
and individual components. 

o  Analysis of systems responsible for the metabolism and transport of 
chemicals to the fetal compartment and their relationship to differences in 
embryonic survival, morphogenesis, or functional defects leading to 
morbidity.

o  The use of genomic approaches to examine fetal programming of  
modifications associated with exposure(s) to (an) environmental agent(s) 
during development that may result in functional changes later in life.

It should be noted that for the purpose of this RFA research is limited to 
animal models and in vitro approaches that will provide mechanistic 
information on exposure to environmental agents during development and how 
that leads to lethality or dysmorphogenesis.  Proposals to screen chemicals 
without regard to related studies on the specific mechanism of actions of the 
chemical(s) studied are not responsive to this RFA and will not be accepted.  
Epidemiological and clinical studies are considered non-responsive to this 
specific RFA.  It is anticipated that such research may be the focus of 
future RFA initiatives. 

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

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 biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification are 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 research involving human subjects should read the 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); 
a complete copy of the updated Guidelines is available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm
The revisions relate to NIH defined Phase III clinical trials and require: a) 
all applications or proposals and/or protocols to 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) all investigators to report accrual, and to conduct and report 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH 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 was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at: 
http://grants.nih.gov/grants/guide/notice-files/not98-024.html

Investigators also may obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.

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.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.

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 RFA (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.

LETTER OF INTENT

Prospective applicants are asked to submit, by July 6, 2001, a letter of 
intent that includes a descriptive title of the proposed project, the name, 
address, and telephone number of the Principal Investigator, the identities 
of other key personnel and participating institutions if planned 
collaborations are known, and the 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 subsequent application, the information that it contains allows 
NIEHS staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent to:

Ethel B. Jackson, D.D.S.
Chief, Scientific Review Branch (EC-30) 
Division of Extramural Research and Training
Office of Program Operations
National Institute of Environmental Health Sciences 
P.O. Box 12233, 111 T.W. Alexander Drive
Research Triangle Park, NC  27709 
Telephone:  (919) 541-7846 
FAX:  (919) 541-2503 
Email: jackson4@niehs.nih.gov

APPLICATION PROCEDURES

Applicants are strongly encouraged to contact the program contacts listed 
under INQUIRIES with any questions regarding their proposed project.

The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants with the modifications noted below.  Application 
kits are available at most institutional offices of sponsored research and 
may be obtained from the Division of Extramural Outreach and Information 
Resources, National Institutes of Health, 6701 Rockledge Drive, MSC-7910, 
Bethesda, MD 20892-7910, telephone 301/435-0714, email GrantsInfo@nih.gov. 
Applications are also available on the World Wide Web at: 
http://grants.nih.gov/grants/forms.htm

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets.  Only 
limited budgetary information is required under this approach.  The just-in-
time concept allows applicants to submit certain information only when there 
is a possibility for an award.  It is anticipated that these changes will 
reduce the administrative burden for the applicants, reviewers, and Institute 
staff.
  
The following instructions are to be used in conjunction with the information 
accompanying application form PHS 398 (rev. 4/98); they refer only to 
selected items in the application form.  All PHS 398 requirements should be 
followed, with the exception of those items affected by the following 
instructions.  Applications not conforming to the requested format will be 
returned to the applicant without review.

FACE  PAGE 

Item 2, Check the box marked “Yes” and type the RFA code number (RFA ES-01-
006) and title ( Developmental. Toxicology Exploratory Grants (R21) Program) 
on this line.

Item 6:  Up to a total of two years of support may be requested.

Items 7a and 7b:  These items should be completed indicating Direct Costs 
($100,000) and Total Costs [$100,000 plus Facilities and Administrative (F&A) 
costs] for the initial budget period.

Items 8a and 8b:  These items should be completed indicating the Direct 
(i.e., $200,000) and Total Costs (i.e., $200,000 plus F&A) for the entire 
proposed period of support.

DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD

Do not complete Form Page 4 of the PHS 398.  It is not required and will not 
be accepted with the application.

BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT

Do not complete the categorical budget table on Form Page 5 of the PHS 398.  
It is not required and will not be accepted with the application.

NARRATIVE BUDGET JUSTIFICATION

Prepare a Modular Grant Budget Narrative page. (See 
http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) 
At the top of the page, enter the total direct costs requested for each year. 
This is not a Form page.

Under Personnel, list all project personnel, including their names, percent 
of effort, and roles on the project. No individual salary information should 
be provided. However, the applicant should use the NIH appropriation language 
salary cap and the NIH policy for graduate student compensation in developing 
the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct 
plus facilities and administrative) for each year, each rounded to the 
nearest $1,000.  List the individuals/organizations with whom consortium or 
contractual arrangements have been made, the percent effort of all personnel, 
and the role on the project. Indicate whether the collaborating institution 
is foreign or domestic.  The total cost for a consortium/contractual 
arrangement is included in the overall requested modular direct cost amount.  
Include the Letter of Intent to establish a consortium.

BIOGRAPHICAL SKETCH 

The Biographical Sketch provides information used by reviewers in the 
assessment of each individual's qualifications for a specific role in the 
proposed project, as well as to evaluate the overall qualifications of the 
research team.  A biographical sketch is required for all key personnel, 
following the instructions below. No more than three pages may be used for 
each person. A sample biographical sketch may be viewed at: 
http://grants.nih.gov/grants/funding/modular/modular.htm.

- Complete the educational block at the top of the form page;
-  List position(s) and any honors; 
-  Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years;
-  List selected peer-reviewed publications, with full citations

CHECKLIST
 
This page should be completed and submitted with the application.  If the F&A 
rate agreement has been established, indicate the type of agreement and the 
date.  All appropriate exclusions must be applied in the calculation of the 
F&A costs for the initial budget period and all future budget years. The 
applicant should provide the name and phone number of the individual to 
contact concerning fiscal and administrative issues if additional information 
is necessary following the initial review.

OTHER SUPPORT

Do not complete this section.  It is not required and will not be accepted 
with the application.

RESEARCH PLAN

Do not exceed a total of 10 pages inclusive of the following sections:  
Specific Aims; Background and Significance; Preliminary Studies/Progress 
Report (evidence of feasibility); and Research Design and Methods.  Pertinent 
subject selection and recruitment information (e.g., inclusion of women, 
minorities, children), as it impacts on study design, should also be 
included.  Tables, figures and photographs are included in the 10 page 
limitation.

Item a, SPECIFIC AIMS

The applicant should begin with a statement that justifies the designation of  
the application as an Exploratory/Developmental Research Grant as defined 
under the PURPOSE section of this program announcement.

The instructions for this section suggest that the applicant state “the 
hypotheses to be tested.”  Since some applications submitted in response to 
this RFA may also be design- or problem-driven (e.g., development of novel 
technologies), or need-driven (initial research to develop a body of data 
upon which future research will build), hypothesis testing per se may not be 
the driving force in developing such a proposal and, therefore, may not be 
applicable.  Thus, the application should state the hypotheses, design, 
problem and/or need which will drive the proposed research. Submission of an 
application under this RFA precludes concurrent submission to the NIH of 
another application containing substantially the same research plan.

Item b, BACKGROUND AND SIGNIFICANCE

In this section it is important to identify clearly how the application 
addresses the specific objectives of this program announcement. For example, 
identify briefly how this application relates to the purpose of the R21 
mechanism as stated in this RFA  (i.e., highly innovative, high risk/high 
impact research; 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 a body of data 
upon which significant future research may be built).

Item c, PRELIMINARY STUDIES/PROGRESS REPORT

Minimal preliminary data are expected for an Exploratory/Developmental Grant 
application.

Item d, RESEARCH DESIGN AND METHODS

Fully describe the research design and methods. In many cases, an 
Exploratory/Developmental Grant mechanism will support novel research in an 
area or the research and development of new technologies.  Where appropriate, 
specific criteria by which to judge the feasibility of novel approaches 
(including milestones that will mark progress) should be explicitly described 
in this section.

LITERATURE CITED

APPENDIX

Appendix materials may not be used to circumvent the page limitations.  
Letters of support are not part of the appendix.  However, letters of support 
may be used to establish the Principal Investigator's research as separate 
and distinct from those of a former mentor or to denote collaborative or 
consultant relationships.  Up to three publications, submitted manuscripts or 
abstracts may also be included.  Five copies of appendix materials should be 
submitted.  (Refer to PHS 398 application for additional Appendix 
guidelines.)

The RFA label available in the PHS 398 (rev 4/98) 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 sample RFA label available at:  
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf
has been modified to allow for this change.  Please note this is in pdf form.

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, please send two additional copies of the 
application to:

Ethel B. Jackson, D.D.S.
Chief, Scientific Review Branch (EC-30) 
Division of Extramural Research and Training
Office of Program Operations
National Institute of Environmental Health Sciences 
P.O. Box 12233, 111 T.W. Alexander Drive
Research Triangle Park, NC  27709 
Telephone:  (919) 541-7846 
FAX:  (919) 541-2503 
Email: jackson4@niehs.nih.gov

Applications must be received by 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.

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.  The 
CSR will not accept any application that is essentially the same as one 
already reviewed.  This does not preclude the submission of substantial 
revisions of applications already reviewed, but such applications must 
include an introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and 
for responsiveness to this RFA by NIEHS and ACC staff.  Incomplete and/or 
non-responsive applications will be returned to the applicant without further 
consideration.  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 review criteria stated below.  
As part of the initial merit review, all applications will receive a written 
critique and undergo a process in which only those applications deemed to 
have the highest scientific merit, generally the top-half of applications 
under review, will be discussed, assigned a priority score, and receive a 
second level of review by the National Advisory Environmental Health Sciences 
(NAEHS) Council.

Review Criteria

The goals of NIH-supported research are to advance the 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 the application in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals.  Each 
of these criteria will be addressed and considered in the assignment of the 
overall score, weighting them as appropriate for each application.  Note that 
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.

(1) Significance.  Does this study address an important problem?  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?

(2) 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?

(3) 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?

(4) Investigator.  Is the investigator 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)?

(5) 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?

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

- The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also 
be evaluated.

- The reasonableness of the proposed budget and duration in relation to the 
proposed research.

- 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.

SCHEDULE 

Letter of Intent:        July 17, 2001
Application Receipt:     August 17, 2001
NIEHS Committee Review:  October/November, 2001
Council Review:          February 11-12, 2001	
Earliest Funding:        April 1, 2002

AWARD CRITERIA
 
Applications will compete with all other approved applications submitted in 
response to this RFA for the available funds provided by the NIEHS and the 
ACC.  The following will be considered in making funding decisions: the 
quality of the proposed project as determined by peer review; program 
priority and balance among research areas solicited by this RFA and the 
availability of funds.
 
In addition, the following factors will also be considered for applications 
assigned to the NIEHS in response to this jointly sponsored NIEHS/ACC program 
RFA:

o  potential for ground-breaking, precedent setting significance of the 
proposed research, with particular emphasis on novel and innovative 
approaches that clearly require additional preliminary data for their value 
to be established;

o  potential to stimulate new research concepts or directions of high 
importance  to biomedical/behavioral problems, or providing a 
technique/system of wide applicability to developmental toxicology research. 

INQUIRIES
 
Potential applicants are encouraged to call the NIEHS staff members listed in 
the program announcement regarding the areas of science relevant to this RFA 
that the NIEHS/ACC program supports. The opportunity to clarify any issues or 
questions from potential applicants is welcome.              

Direct inquiries regarding programmatic issues to:

Michael E. McClure, Ph.D. or Jerry Heindel, Ph.D.
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) 541-1442  or (919) 541-0781
FAX:  (919) 541-5064 
Email:  mm461n@nih.gov or heindelj@niehs.nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Jackie Russell 
Grants Management Specialist
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) 541-0751 
FAX:  (919) 541-2860  
Email:  russell@niehs.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.113 and 93.115. 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 and Federal Regulations 42 CFR 52 and 
45 CFR Part 74 and 92.  This program is not subject to the intergovernmental 
review requirements of Executive Order 12372 or Health Systems Agency review.

The Public Health Service (PHS) strongly encourages all grant and contract 
recipients to provide a smoke-free workplace and promote the non-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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	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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