Fluoride Action Network

NIDCR program announcement: Research on Fluorides to Improve Oral Health

Source: National Institute of Dental and Craniofacial Research | July 27th, 2001
Industry type: NIDCR

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 http://www.health.gov/healthypeople/.


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



  1. To determine the relative contribution of pre-eruptive and post-

eruptive effects of fluoride on prevention of dental caries.


  1. To determine the target concentration of fluoride in the oral

environment to optimize the local action of fluoride for caries



  1. 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.


  1. To investigate the interactions between fluorides and food

components, nutrients and additives, and to develop methods to

enhance the beneficial effect of fluoride.


  1. To investigate the influence of environmental factors including

temperature and altitude on the effectiveness of fluoride.


  1. 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.


  1. To ascertain the relative contribution of currently available

fluoride modalities on dental caries prevention and control and on

dental fluorosis in populations.


  1. 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.


  1. 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 https://grants.nih.gov/grants/funding/phs398/phs398.html are

to be used in applying for these grants and will be accepted at the

standard application deadlines (https://grants.nih.gov/grants/dates.htm)

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: GrantsInfo@nih.gov.


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

https://grants.nih.gov/grants/funding/phs398/phs398.html 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

https://grants.nih.gov/grants/funding/modular/modular.htm.  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

Email: guo.zhang@nih.gov


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

Email:  Martin.Rubinstein@nih.gov




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


*Original online at https://grants.nih.gov/grants/guide/pa-files/PA-01-121.html