XENOBIOTICS AND NEURODEVELOPMENTAL ABNORMALITIES

Release Date:  November 25, 1998

RFA:  ES-99-002

P.T.

National Institute of Environmental Health Sciences

Letter of Intent Receipt Date:  January 20, 1999
Application Receipt Date:  February 10, 1999

PURPOSE

The National Institute of Environmental Health Sciences (NIEHS) supports research
to define the role of environmental agents in alterations of normal cellular and
physiologic processes leading to human disease.  The vulnerability of the
developing organism to environmental factors has become a major concern of the
public health community and the environmentally active general public.  The
developing nervous system is central to much of this concern.  Therefore, the
identification and understanding of the mechanisms responsible for the increased
sensitivity of the developing nervous system to environmental insult is the focus
of this initiative.

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, Xenobiotics and
Neurodevelopmental Abnormalities, 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 Summary Report: Stock No. 017-
001-00473-1) through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone: (202) 512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic, for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of State or local governments and eligible agencies of the
Federal government.  Foreign institutions and organizations are not eligible. 
Applications from minority individuals and women are encouraged.  Submission of
an application precludes concurrent submission of a regular research project
grant application (R01) containing the same research proposal.  In addition,
small grant research support may not be used to supplement research projects
currently supported by Federal or non-Federal funds or to provide interim support
for projects under review by the Public Health Service.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) Small Grants Program
(R03) awards.  Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant.  The requested costs and
project period will be $50,000 (direct cost) per year for a maximum of two years. 
Small grants are not renewable but may be extended at the discretion of the
applicant organization.

FUNDS AVAILABLE

The total estimated funds available for this small grants program is $750,000
which will support approximately ten awards.  This level of support is dependent
on the receipt of sufficient number of applications of high scientific merit. 
Although this program is provided for within the financial plans of the NIEHS,
awards pursuant to this RFA are contingent upon the availability of funds for
this purpose.

RESEARCH OBJECTIVES

Background

NIEHS has had a longstanding commitment to assessing chemicals for potential
developmental effects and for effects on the nervous system.  Much of the
previous research on the developing nervous system has focused on behavioral
alterations with limited effort directed toward the underlying biological
processes critical to the formation of the nervous system and their role in the
altered behavior.  This Request for Applications is designed specifically to
encourage exploration of the possible underlying cellular mechanisms associated
with the formation of the nervous system and the part they play in determining
alterations due to exposure to environmental agents.  These processes may
include:  the division of neural and glia precursors, the interaction of the cell
with its immediate environment by surface receptors or cell adhesion molecules,
the regulation of cytoskeletal or cell surface process that control migration of
neural cells, and/or the cell-cell interactions that underlie synaptogenesis. 
In addition, signaling molecules including growth factors, neurotransmitters,
cell adhesion molecules and components of the extracellular matrix influence the
migration, differentiation and survival of neurons and neuronal precursors.
Neurotoxicants that interfere with any of these processes and/or molecules during
a critical window in development would be expected to have serious effects on the
developing organism.  These defects may be immediately obvious as gross
malformations, but they may also be manifest as more subtle defects that may have
serious consequences as indicated by behavioral disturbances.

In order for NIEHS to successfully carry out its mission of reducing the burden
of neuronal dysfunctions due to early  perturbations from agents in the
environment, it is imperative to have information on the role of environmental
factors on a wide variety of critical mechanisms during nervous system
development.  Currently, there is good evidence from research on epidemiology and
cell biology for the role of lead in developmental impairment while the role of
pesticides and polychlorobiphenyls are far less well understood.  Studies of
other agents have been limited possibly because most developmental biologists and
neurotoxicologists have not been encouraged to explore the effect on
developmental processes with these neurotoxic agents.  The purpose of this
initiative is to foster such multidisciplinary research efforts using state-of-
the-art knowledge and techniques in cell biology and molecular biology to develop
mechanistically-based methods and models for developmental neurotoxicology.

The initiative is also intended to stimulate the development of pilot or
feasibility studies on critical target sites and biological processes susceptible
to environmental manipulation.

Research Goals

The small grants mechanism is seen as a way of encouraging both new and
established investigators to explore new areas of environmental
neurodevelopmental research that, while being of high risk, have the potential
of advancing the field.  Consequently, neurotoxicants such as lead or
methylmercury for which the link between exposure and developmental dysfunction
have been established and for which a body of research looking at molecular
mechanisms exist, would not be considered in compliance with this initiative. 
Moreover, if sufficient preliminary data are available to support an
investigator-initiated proposal, such an application would not be considered in
compliance.  By encouraging small grants to obtain preliminary data, it is the
objective of NIEHS to support investigators in both developmental neurobiology
and neurotoxicology to collaborate in examining the susceptibility of the
developing nervous system to environmental exposure.  Preliminary data are
essential to identify critical biological processes underlying developmental
neurotoxicity.  Once this information is developed, studies on the site, mode,
and mechanism of action of the environmental influences can then be generated and
prevention and intervention strategies can be developed.

It is anticipated that the preliminary information from these pilot studies will
provide the linkage of environmental exposures (under physiologically relevant
conditions of both timing and dose)  during development to subsequent
neurological disorders and will lead to the development of hypothesis-based
research to establish the cause and effect relationship in such disorders. 
Research is encouraged in but not limited to the following areas:

o  The linkage of xenobiotics with basic developmental processes such as cell
division, differentiation, cell adhesion molecules, cell-cell interactions,
growth factors, receptor activation, signal transduction activation, or apoptosis
leading to functional abnormalities.

o  The development and use of animal and human model systems including
immortalized cell lines, primary culture, and whole animals including transgenic
animals and specific mutants to identify and characterize the developmental
defect that occurs in response to a neurotoxicant.

o  Multidisciplinary studies that relate specific changes induced by xenobiotics
in neurochemical, neuroanatomical, neurophysiological and/or neurobehavioral
measurements during development with behavioral deficits.

o  The identification and validation of specific developmental milestones or
critical developmental processes (in a regional and temporal fashion) which could
be used as biomarkers of toxicity.

o  Studies to further refine and advance behavioral methodologies, particularly
the  development of behavioral test methods with direct cross--species
applicability, including tests for ontogenic development of various cognitive
functions, and for the determination of the sensitivity of neuropsychological
tests and their modulation by motivational influences.

o  To determine the role of compensation, redundancy and latency in the response
of the developing nervous system to toxic perturbation.

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
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 was 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:
https://grants.nih.gov/grants/guide/notice-files/not94-105.html.

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 the following URL address:
https://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.

LETTER OF INTENT

Prospective applicants are asked to submit, by January 20, 1999, a letter of
intent that includes a descriptive title of the proposed research, the name,
address, and telephone number of the Principal Investigator, the identities of
other key personnel and participating institutions, and the number and title of
the RFA in response to which the application may be submitted.  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 is helpful in planning
for the review of applications.  It allows NIEHS staff to estimate the potential
review work load and to avoid conflict of interest in the review.

The letter of intent is to be sent to:

Ethel B. Jackson, D.D.S.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, EC-24
111 T.W. Alexander Drive, Room 3457 East Campus (for express/courier service)
Research Triangle Park, NC  27709
Telephone:  (919) 541-7826
FAX:  (919) 541-2503
Email:  jackson4@niehs.nih.gov

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in applying
for these grants.  These forms 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)710-0267, email:
GrantsInfo@nih.gov.

SUPPLEMENTAL INSTRUCTIONS

o  The application must detail the specific budget categories and percent efforts
that will be required.  This will be a $50,000 maximum award (direct cost) per
year for two years.  The budget must be justified. Equipment will be limited to
$5,000.

o  Preliminary data are not required except to indicate the expertise of the
Principal Investigator to carry out the proposed studies.

o  The Research Plan (Specific Aims, Background and Significance, Preliminary
Studies, Research Design and Methods sections) is not to exceed ten pages. 
Tables and figures are included in the ten page limitation. Applications that
exceed page limitations or PHS 398 requirements for font size (height or
letters), type density (characters per inch), and margins (see PHS 398
directions) will be returned to the investigator.

o  Independent investigators from any scientific discipline and at any stage of
their career may apply for a small grant.

o  The Principal Investigator will be required to commit to a minimum of a 5%
effort.

o  Dependent of favorable review and contingent on the availability of funds, a
limited number of awards may be made for studies designed to develop the
preliminary data relating exposure to environmental agents with specific
dysfunctions in nervous system formation or neurological functions.

o  Participation by minority and women investigators is encouraged.

o  NIH/NIEHS has identified developmental neurotoxicology as one of its priority
areas for 1999 in its regular grants program.  Therefore, investigators who are
ready to submit an R01 application (i.e., have sufficient preliminary data, etc.)
are encouraged to do so as their applications will receive special consideration
for funding.  Also, encouraged are individual postdoctoral fellowships in this
area.

o  Appendix materials may not be used to circumvent the page limitations

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.  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.

Submit a signed, typewritten original of the application, including the
checklist, and three signed, clear, and single-sided 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, two additional copies of the application must be sent
to:

Ethel Jackson, D.D.S.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, EC-24
111 T.W. Alexander Drive, Room 3457, East Campus (for express/courier service)
Research Triangle Park, NC  27709-2233
Telephone:  (919) 541-7846
FAX:  (919) 541-2503
Email:  jackson4@niehs.nih.gov

Applications must be received by February 10, 1999.  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
responsiveness by the NIEHS.  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 the review criteria stated below.  As part of the
initial merit review, a process will be used by the initial review group in which
applications 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 the applications under review, will be discussed, assigned a priority score,
and receive a second level review by the NIEHS National Advisory Environmental
Health 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 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:

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.

The initial review group will also examine the provisions for the protection of
human subjects and the safety of the research environment.

Schedule

Letter of Intent Receipt Date:    January 20, 1999
Application Receipt Date:         February 10, 1999
Peer Review Date:                 March/April 1999
Council Review:                   May 1999
Earliest Anticipated Start Date:  August 1, 1999

AWARD CRITERIA

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

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:

Annette G. Kirshner, Ph.D.
Organs and Systems Toxicology Branch
National Institute of Environmental Health Sciences
P.O. Box 12233, EC-23
111 T.W. Alexander Drive, Room 3420A (for express/courier service)
Research Triangle Park, NC  27709-2233
Telephone:  (919) 541-0488
FAX:  (919) 541-5064
Email:  kirshner@niehs.nih.gov

Direct inquiries regarding fiscal matters to:

Mr. David L. Mineo
Office of Program Operations
National Institute of Environmental Health Sciences
P.O. Box 12233, EC-22
111 T.W. Alexander Drive, Room 3403, East Campus (for express/courier service)
Research Triangle Park, NC  27709-2233
Telephone:  (919) 541-7628
FAX: (919) 541-2860
Email:  mineo@niehs.nih.gov

The role of environmental factors may play a role in the etiology of some mental
disorders.  The NIMH welcomes secondary assignment on research ideas that address
the role of xenobiotics in abnormal brain development when they may be implicated
in the etiology of mental disorders such as schizophrenia and depression.

For questions concerning NIMH interests, contact:

Douglas L. Meinecke, Ph.D.
Division of Basic and Clinical Neuroscience Research
National Institute of Mental Health
5600 Fishers Lane, Room 11C-06
Rockville, MD  20857
Telephone:  (301) 443-5288
FAX:  (301) 443-4822
Email:  dmein@helix.nih.gov

Although NICHD is not participating in this RFA, NICHD has a long-standing
continuing commitment to research on the biological processes underlying
neurodevelopment in both humans and animal models, and on the biological and
behavioral indices that signal these developmental processes.

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 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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