This Program Announcement expires on July 31, 2004, unless reissued.


Release Date:  July 27, 2001

PA NUMBER:  PA-01-121
National Institute of Dental and Craniofacial Research


The National Institute of Dental and Craniofacial Research (NIDCR) 
invites research grant applications to support research leading to an 
increase in knowledge about the use of fluorides for improving oral 
health.  Special emphasis is sought in the areas of the overall 
metabolism of fluoride, effects of fluoride on bone and teeth, the 
development of “gold standard” methods for fluoride analysis of a wide 
variety of sample types, the influence of environmental factors on the 
effectiveness of fluoride, including temperature, altitude, food 
components, nutrients, and food additives, and the development of 
biomarkers for monitoring body fluoride burden and noninvasive methods 
to quantify fluorosis in vivo.  In relation to the first of these 
areas, a comprehensive approach is intended in order to address 
bioavailability, intake and excretion and the influence of environment, 
genetics, nutrition, physiology and socio-economic and cultural 
diversity on the uptake, metabolism and biological and cosmetic effects 
of fluoride.  The second area includes recognition of the need for 
practical epidemiologic studies of the current impact of water 
fluoridation and other fluoride modalities on dental caries and dental 


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 Program 
to several priority areas.  Potential applicants may obtain a copy of 
"Healthy People 2010" at


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.  
Domestic applications may include international components.  The NIDCR 
encourages applications that include investigators who are 
racial/ethnic minority individuals, women and persons with 
disabilities.  Although an application must be submitted from a single 
institution, collaborative arrangements with other institutions are 
strongly encouraged.  Also, applications are not restricted to 
traditional dental, oral and craniofacial research settings.


The mechanism of support will be the individual research project grant 
(R01) or the exploratory/developmental grant (R21).  Responsibility for 
the planning, direction, and execution of the proposed project will be 
solely that of the applicant.  

The objective of the exploratory/developmental mechanism (R21) is to 
encourage applications to explore the feasibility of an innovative 
research question or approach, which may not be justifiable through 
extant research, or competitive as a standard research project grant 
(R01).  These are short-term awards (up to two years) with limited 
funding (up to $100,000 per year for direct costs). 

Fluoride has been recognized as the central component in strategies to 
prevent dental caries, a disease that has had major health, economic 
and social effects on communities worldwide.  The use of fluorides in 
the prevention of dental caries has been demonstrated to be one of the 
most successful public health promotion measures in history.  Dramatic 
reductions in dental caries in children have been experienced where 
fluoride has been made available through sources such as fluoridated 
water, salt, toothpastes, topical rinses, gels, and dietary 
supplements.  Savings of approximately $40 billion have been estimated 
in oral health care delivery in the USA alone in the past 40 years, 
primarily as a result of the use of fluoride. 

Although the incidence of caries has dramatically decreased since water 
fluoridation and fluoride toothpastes have been widely applied as a 
preventive measure, dental caries remains widespread and severely 
affects a large segment of the population in the world.  Fluoride has 
shown to be effective as an anti-caries and anti-osteoporosis element.  
However, the following critical issues related to its action in bone 
and teeth remain unclear.  1) The minimal effective fluoride level in 
human body to prevent and control dental caries without increasing the 
risk of dental fluorosis is still not established.  2) The cellular and 
molecular mechanism mediating anti-caries and -osteoporosis effects is 
unclear. 3) The interactions between fluoride and other food components 
remain undefined; for example, it has been implicated that some food 
preservatives such as benzoate can potentiate fluoride effects, but its 
underlying mechanism has not been fully studied.  4) Fluoride 
monitoring needs more convenient and accurate “gold standard 
measurement” of body fluoride burden, which can be used to determine 
fluoride in environment, foods, and body fluids and tissues.  This 
measurement method is critical for sample analysis, real-time and 
pharmacokinetic measurements.  It is critical to fully understand the 
mechanisms by which fluoride prevents dental caries and osteoporosis, 
and to improve routines, materials and schemes of fluoride 
administration.  Therefore, further investigation of these issues is of 
great significance.

In 1999, the NIDCR held two workshops to bring together fluoride 
researchers from various fields including biochemistry, nutrition, 
environment, epidemiology and behavioral science, to discuss the 
current scientific knowledge and to propose direction for future 
fluoride research.  On February 1, 1999, a group of experts was 
convened to develop a research agenda related to recent fluoridation 
interventions that have been introduced within the U.S.  A second 
workshop identified research needs for international collaborative 
research on fluoride.  This workshop was co-sponsored with 10 partners, 
including other NIH components, the Centers for Disease Control and 
Prevention (CDC), private corporations, and the International 
Association for Dental Research.  Research recommendations from both 
workshops form the basis of this announcement.


The purpose of this PA is to encourage research leading to an increase 
in knowledge about the use of fluorides for improving oral health.  
Appropriate topics for investigation under this PA include, but are not 
limited to studies:
1. To elucidate the molecular mechanisms of the action of fluoride on 
tooth and bone cells.  These investigations might include the 
effects of fluoride on:

o Expression of genes that play a critical role in tooth and bone 
development and mineralization;

o Proteins and other factors participating in tooth and bone 
development and mineralization;

o Intracellular signaling systems regulating tooth and bone 

2. To determine the relative contribution of pre-eruptive and post-
eruptive effects of fluoride on prevention of dental caries.

3. To determine the target concentration of fluoride in the oral 
environment to optimize the local action of fluoride for caries 

4. To develop new generations of fluoride therapeutics, local delivery 
systems or devices to produce long-lasting and appropriate 
concentration of active fluoride compounds which provide better 
efficacies, better cost-effectiveness, and an improved safety 
profile.  These new therapeutics will be specific for target 
tissues, and present in low levels in non-target tissues.

5. To investigate the interactions between fluorides and food 
components, nutrients and additives, and to develop methods to 
enhance the beneficial effect of fluoride. 

6. To investigate the influence of environmental factors including 
temperature and altitude on the effectiveness of fluoride.  

7. To develop simple global “gold standard” measurements, which are 
more accurate, rapid and convenient analyses for monitoring of 
fluoride levels such as screening, pharmacokinetics, time course 
determination, and other purposes in body fluids and other specimens 
including blood, saliva, urine and hair.

8. To ascertain the relative contribution of currently available 
fluoride modalities on dental caries prevention and control and on 
dental fluorosis in populations.

9. To investigate skeletal fluorosis and other fluoride effects on bone 
in areas with high concentrations of natural fluoride, including 
identification of environmental, cultural and social factors 
associated with excessive fluoride exposure, the pathogenesis of 
skeletal fluorosis, and development of valid and noninvasive methods 
to quantify fluorosis in vivo and to identify risk indicators or 
markers for dental fluorosis. 

10. To measure the public health cosmetic significance of enamel 
opacities/fluorosis across cultures, and to explore preventive and 
therapeutic interventions for both enamel and skeletal fluorosis.


It is the policy of the NIH that women and members of minority groups 
and their subpopulations must be included in all NIH supported 
biomedical and behavioral research projects involving human subjects, 
unless a clear and compelling rationale and justification is provided 
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 "NIH Guidelines For Inclusion of Women and Minorities as 
Subjects in Clinical Research," which have been published in the 
Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH 
Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994 
available on the web at the following URL address:

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 the following URL address:

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.


All investigators proposing research involving human subjects should 
read the policy that was published in the NIH Guide for Grants an 
Contracts, June 5, 2000 (Revised August 25, 2000), available at: 


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

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


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.


The PHS 398 research grant application instructions and forms (rev. 
5/2001) at are 
to be used in applying for these grants and will be accepted at the 
standard application deadlines ( 
as indicated in the application kit.  This version of the PHS 398 is 
available in an interactive, searchable PDF format. Although applicants 
are encouraged to begin using the 5/2001 revision of the PHS 398 as 
soon as possible, the NIH will continue to accept applications prepared 
using the 4/1998 revision until January 9, 2002. Beginning January 10, 
2002, however, the NIH will return applications that are not submitted 
on the 5/2001 version.  For further assistance contact GrantsInfo, 
Telephone 301/710-0267, Email:

Applicants planning to submit an investigator-initiated new (type 1), 
competing continuation (type 2), competing supplement, or any 
amended/revised version of the preceding grant application types 
requesting $500,000 or more in direct costs for any year are advised 
that he or she must contact the Institute or Center (IC) program staff 
before submitting the application, i.e., as plans for the study are 
being developed.  Furthermore, the application must obtain agreement 
from the IC staff that the IC will accept the application for 
consideration for award.  Finally, the applicant must identify, in a 
cover letter sent with the application, the staff member and Institute 
or Center who agreed to accept assignment of the application.  

This policy requires an applicant to obtain agreement for acceptance of 
the original application as well as any subsequent revisions.  Refer to 
the NIH Guide for Grants and Contracts, March 20, 1998 at 


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 NIH staff.  The research grant 
application form PHS 398 (rev. 5/2001) at is to be used 
in applying for these grants, with modular budget instructions provided 
in Section C of the application instructions.  Applicants are 
permitted, however, to use the 4/1998 revision of the PHS 398 for 
scheduled application receipt dates until January 9, 2002.  If you are 
preparing an application using the 4/1998 version, please refer to the 
step-by-step instructions for Modular Grants available at  Additional 
information about Modular Grants is also available on this site.

The title and number of the program announcement must be typed on line 
2 of the face page of the application form and the YES box must be 

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

BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)


Applications will be assigned on the basis of established PHS referral 
guidelines.  Applications will be evaluated for scientific and 
technical merit by an appropriate scientific review group convened in 
accordance with the standard NIH peer review procedures.  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 review by the appropriate national 
advisory council or board.

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 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 assigning 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 
method? Are the aims original and innovative?  Does the project 
challenge existing paradigms or develop new methodologies or 

(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:

o  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.

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

o  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.


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.

Applications will compete for available funds with all other favorably 
recommended applications.  For those applications assigned to NIDCR, 
applicants should be aware that, in addition to scientific merit, 
program priorities and program balance, the total cost of the proposed 
project and the availability of funds will be considered by the NIDCR 
staff and the National Advisory Dental Research Council in making 
funding recommendations. In addition, the NIDCR values complementary 
funding from other public and private sources including foundations and 
industrial concerns.  In circumstances in which applications have 
similar scientific merit, but vary in cost-competitiveness, the NIDCR 
is likely to select the more cost-competitive application for funding.
Written, email and telephone inquiries concerning this PA are 
encouraged.  The opportunity to clarify any issues or questions from 
potential applicants is welcome.
Direct inquiries regarding programmatic issues to:
Guo H. Zhang, Ph.D., M.Sc.
Program Director 
Chronic Diseases Branch
Division of Extramural Research, 
National Institute of Dental Research
National Institutes of Health
Building 45 (Natcher), Room 4An.18B
Bethesda, MD 20892-6402
Telephone: 301 594-0618
Fax: 301 480-8318

Direct inquiries regarding grants management issues to:
Mr. Martin R. Rubinstein
Chief, Grants Management Section
Division of Extramural Research
National Institute of Dental Research
National Institutes of Health
Building 45 (Natcher), Room 4AN-44A
Bethesda, MD 20892-6402
Telephone:  301-594-4800
This program is described in the Catalog of Federal Domestic Assistance 
No. 93.121.  Awards are made under authorization of the Public Health 
Service Act, Title IV, Part A (Public Law 78-410, as amended by Public 
Law 99-158, 42 USC 241 and 285) and administered under PHS grants 
policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74.  This 
program is not subject to the intergovernmental review requirements of 
Executive Order 12372 or Health Systems Agency review.
The 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 

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