Full Text ES-94-009

MECHANISTICALLY-BASED ALTERNATIVE METHODS IN TOXICOLOGY

NIH GUIDE, Volume 23, Number 35, September 30, 1994

RFA:  ES-94-009

P.T. 34

Keywords: 
  Toxicology 


National Institute of Environmental Health Sciences

Letter of Intent Receipt Date:  November 15, 1994
Application Receipt Date:  December 20, 1994

PURPOSE

The National Institute of Environmental Health Sciences (NIEHS) invites
applications to conduct research to develop mechanistically-based
alternative methods and models for toxicology research and testing.

Assessment of the potential adverse health effects of chemicals is
currently accomplished largely by tests utilizing laboratory animals.
While such traditional tests have provided information useful for human
health risk assessment, improved test methods are needed that are more
predictive, that provide information more supportive of quantitative
risk assessment, can be achieved in a shorter time frame, and are more
cost-effective.

This RFA is issued to foster the development, validation, and use of
improved testing and research methods that either do not require the
use of animals, reduce the number of animals, or involve the use of
alternatives such as non-mammalian species.  This NIEHS initiative will
facilitate the integration of recent advances in molecular and cellular
biology and new research technologies into alternative toxicology
testing methodologies that will provide improved human health hazard
identification and improved dose-response relationships, thereby
contributing to improved risk assessment.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This RFA,
Mechanistically-Based Alternative Methods in Toxicology, is related to
the priority area of Environmental Health.  Potential applicants may
obtain a copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00474-0) or "Healthy People 2000" (Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington DC 20402-9325 (telephone 202-783-3238).

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 or local governments,
and eligible agencies in the Federal government.  Applications from
minority individuals and women are encouraged.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) individual
research project grant (R01).  Responsibility for planning, direction,
and execution of the proposed project will be solely that of the
applicant.  The total project period requested in and application may
not exceed three years.

FUNDS AVAILABLE

The estimated funds (total costs) available for the first year of
support for the entire program is $1.5 million.  The expected number of
awards is eight to ten.

This level of support is dependent on the receipt of a sufficient
number of applications of high scientific merit.   Support will not be
provided under this RFA for research activities focussed on clinical
trials or the initiation of large-scope epidemiologic studies.

RESEARCH OBJECTIVES

The NIEHS proposes to expand research efforts to develop
mechanistically-based alternative methods and test systems for
toxicological research and testing.  The development of alternative
testing methods that incorporate new knowledge regarding the molecular
and cellular mechanisms of toxicity will be encouraged, as well as the
refinement of existing test methods/models by utilizing new scientific
information and techniques such as characterization of the similarities
and differences at the cellular and molecular level of test models with
humans.

Toxicological test methods and systems are encouraged in the  priority
areas of carcinogenicity, neurotoxicity, and developmental toxicity,
but will be considered in any area of toxicity testing.

Examples of alternative test methods and models that may be appropriate
for development under each of these priority areas include:

o  Development of cell cultures or genetically engineered cell lines
that can be used to characterize the biological activity and toxicity
profiles of chemicals and classes of chemicals at the molecular and
cellular level, and that are predictive of the toxic effects of
chemicals in existing test species or humans.  Such systems might
incorporate reporter constructs that allow for the automated
quantification of response.  Note that cytotoxicity assays are not
responsive to this RFA.

o  Development and utilization of transgenic animals that more closely
model the human response to toxic substances and that can detect
toxicant effects using fewer animals and shorter time frames.

o  Development and characterization of systems for toxicity testing
that utilize non-mammalian or invertebrate species that are predictive
of the toxic effects of chemicals in existing test species or humans.

o  Development and utilization of improved computer-based prediction
and modeling systems for specific toxicologic endpoints.  These might
include physiologically-based pharmacokinetic (PBPK) models,
toxicokinetic models, and biologically-based structure-activity
relationship modeling/prediction system.  These should include not only
the design of the model, but also the design and implementation of the
experiments to be conducted utilizing the model.

It is anticipated that new methods/test systems worthy of further
evaluation in detailed validation studies will result from the research
supported by the RFA.  Thus, applications submitted under this RFA must
develop both a mechanistically based alternative model or test system
(for example a tiered multiple system approach) and also provide
sufficient evaluation to show its utility as a test/model.  Thus,
studies designed to simply explore the mechanism of action of a single
toxicant in an alternative test/model will not be considered responsive
to this RFA.

SPECIAL REQUIREMENTS

Applicants may request funds for one trip annually to the National
Institute of Environmental Health Sciences for a meeting to discuss
important new findings and a sharing of research progress.

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 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 new policy results from
the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43)
and supersedes and strengthens the previous policies (Concerning the
Inclusion of Women in Study Populations, and Concerning the Inclusion
of Minorities in Study Populations), which have been in effect since
1990. The new policy contains some provisions that are substantially
different from the 1990 policies.

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 reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March
18, 1994.

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

LETTER OF INTENT

Prospective applicants are asked to submit, by November 15, 1994, a
letter of intent that includes the title of the proposed project, a
short descriptive abstract, the name, address, and telephone number of
the Principal Investigator, and RFA title and number.

Although a letter of intent is not required, is not binding, and does
not enter into the review of the subsequent application, the
information that it contains is helpful in planning for the review of
applications.  It allows the NIEHS staff to estimate the potential
review workload and to avoid conflict of interest in the review.

The letter of intent is to be sent:

Dr. Ethel Jackson
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233
Building 17, Room 1717
104 TW Alexander Drive
Research Triangle Park, NC  27709
Telephone:  (919) 541-7826
FAX:  (919) 541-2503

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research and from the Office of
Grants Information, Division of Research Grants, National Institutes of
Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone
(301) 594-7378.  Applications must be received by December 20, 1994.
If an application is received after that date, it will be returned to
the applicant.

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

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, two additional copies of the application
must also be sent to Dr. Ethel Jackson at the address listed under
LETTER OF INTENT.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by NIH staff for
completeness and responsiveness.  Incomplete applications will be
returned to the applicant without further consideration.  If the
application is not responsive to the RFA, NIEHS staff will contact the
applicant to determine whether to return the application to the
applicant or submit it for review in competition with unsolicited
applications at the next review cycle.

Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the NIEHS in accordance with the review
criteria stated below.  As part of the initial merit review, a process
(triage) may be used by the initial review group in which applications
will be determined to be competitive or non-competitive based on their
scientific merit relative to other applications received in response to
the RFA.  Applications judged to be competitive will be discussed and
be assigned a priority score.  Applications determined to be
non-competitive will be withdrawn from further consideration and the
Principal Investigator and the official signing for the applicant
organization will be notified.  The second level of review will be
provided by the National Advisory Environmental Health Sciences
Council.

Review criteria for RFAs are generally the same as those for
unsolicited research grant applications.

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal Investigator
and staff, particularly but not exclusively in the area of the proposed
research;

o  availability of resources necessary to perform the research;

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

The subject of this RFA may overlap interests of other Institutes,
Centers and Divisions (ICDs).  Applications will, therefore, be
assigned according to extant Referral Guidelines.

AWARD CRITERIA

This anticipated date of award is July 1, 1994.  The following will be
considered in making funding decisions.

o  quality of proposed programs as determined by peer review,
o  availability of funds; and
o  program balance among research areas of the RFA.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Jerrold J. Heindel, Ph.D.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, 104 T.W. Alexander Drive
Research Triangle Park, NC  27709
Telephone:  (919) 541-0781
FAX:  (919) 541-2843
Email:  Heindel_J@NIEHS.NIH.GOV

Direct inquiries regarding fiscal matters to:

Mr. David L. Mineo
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233
104 T.W. Alexander Drive
Research Triangle Park, NC  27709
Telephone:  (919) 541-1371

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 the
Public Health Service Act, Title IV, Part A (Public Law 78-410, as
amended by Public Law 99-158, 43 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 Public Health Service (PHS) strongly encourages all grant
recipients to provide a smoke-free workplace and promote the non-use of
all tobacco products.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American
people.

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