Full Text ES-96-003

ENDOCRINE DISRUPTING CHEMICALS AND WOMEN'S HEALTH OUTCOMES

NIH GUIDE, Volume 24, Number 38, October 27, 1995

RFA:  ES-96-003

P.T. 34

Keywords: 
  Endocrinology 
  Hormones 
  Toxicology 
  Epidemiology 


National Institute of Environmental Health Sciences
Office of Research on Women's Health

Letter of Intent Receipt Date:  December 1, 1995
Application Receipt Date:  January 18, 1996

PURPOSE

Research on the health effects of chemicals and other exposures that
are suspected to disrupt the normal activity of the endocrine system
is a high priority of the National Institute of Environmental Health
Sciences (NIEHS) and the Office of Research on Women's Health (ORWH)
of the National Institutes of Health.  Exposure to these chemicals
may have broad based systemic effects and alter reproductive,
neurologic, and/or immunologic function and may increase a human risk
of hormonal cancers.  Accordingly, the goal of this Request for
Applications (RFA) is to encourage toxicologic, basic science, and
epidemiologic research on the human health effects of exposure to
chemicals that mimic, antagonize, or indirectly alter the activity of
hormones.  Of particular interest are the health effects on women,
since these affect both the woman herself and may affect future
offspring.  Research is encouraged to determine the endocrine
affecting potential of a variety of chemicals, understand their
biological activity, and understand the biologic consequences of
exposure during early development, the reproductive period, and later
life.  Research on the offspring of women who have been exposed is
also needed to understand the transgenerational effects of exposures
to environmental chemicals that affect endocrine.

The NIEHS is the principal Federal funding agency to support research
examining human health consequences of exposure to physical and
chemical toxicants in the environment.  Research supported by NIEHS
spans many disciplines, including toxicology, molecular and cellular
biology, epidemiology, and clinical research.

The Office of Research on Women's Health (ORWH) of the National
Institutes of Health (NIH) supports research on diseases, disorders,
and conditions that affect women and ensure that research conducted
and supported by NIH adequately addresses issues regarding women's
health.  Research on environmental influences on women's health has
been designated as a priority area of ORWH.

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,
Endocrine Disrupting Chemicals and Women's Health Outcomes, is
related to the priority areas of environmental health and women's
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 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 of the Federal government.  Foreign
institutions are not eligible for First Independent Research Support
and Transition (FIRST) (R29) awards.  Applications from minority
individuals and women are encouraged.

MECHANISM OF SUPPORT

This RFA will use the NIH individual research project grant (R01),
and FIRST (R29) award.  Responsibility for the planning, direction,
and execution of the proposed project will be solely that of the
applicant.  The requested costs and project period for an R01
application submitted in response to the present RFA may not exceed
$100,000 (direct costs)/per year; R29 applications must be for five
years.

FUNDS AVAILABLE

The total estimated funds available for the first year of support for
the entire program is $1.5 million.  All awards will be made directly
by NIEHS in conjunction with ORWH sponsorship.  The ORWH will
contribute funds to NIEHS to co-fund projects.  The expected range of
number of awards is 8 to 10.

The 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 and ORWH, awards
pursuant to this RFA are continent upon the availability of funds for
this purpose.

RESEARCH OBJECTIVES

Background

Many industrial and environmental chemicals mimic, antagonize, or
indirectly alter the activity of hormones, particularly steroid
hormones.  These chemicals have been classified as "endocrine
disruptors" because they may bind to the estrogen and/or other
hormone receptors, either imitating the action of the hormone or
blocking its activity.  These chemicals impact endocrine glands and
other target organs that depend on the endocrine system for
regulation.  Endocrine disruptors that have been identified are
commonly found in the environment include a variety of herbicides,
fungicides, insecticides, nematocides and industrial chemicals such
as dioxin, polychlorinated biphenyls (PCBs), and other chlorinated
compounds.  Some of these chemicals have been shown to be weakly
estrogenic, antiestrogenic, antiandrogenic, or effect thyroid hormone
function.  Exposure to these compounds prenatally or in early
postnatal life can disturb the development of the endocrine system
and organs that respond to hormonal signals in animals.  Women, who
were exposed to these chemicals during early development, neonatally,
or later in life may have increased risk of endocrine dysfunction
leading to infertility, fibroids, endometriosis, early menopause,
osteoporosis, autoimmune diseases, and breast and other cancers.
Exposure to exogenous sources of estrogens and other endocrine
altering chemicals may also occur during critical biological periods,
such as puberty and the childbearing years.  Exposures at these times
may be related to changes in reproductive capacity and an increase in
adverse women's health conditions in later life.  Untangling issues
related to the timing of exposure are especially important to
understand the mechanism of action of these compounds and their
cellular effects during critical periods of a female's development.

Women may be exposed to exogenous sources of estrogens through the
use of pharmaceuticals containing synthetic estrogens, in the
workplace, through environmental contamination from industrial or
agricultural processes, and dietary exposures from consuming
contaminated fish or vegetable sources of phytoestrogens.
Organochlorine compounds are ubiquitous in the environment and their
biologically persistent nature makes their presence a potential
hazard for a long time period.  Body stores of compounds such as DDT
and dioxins accumulate in adipose tissue, have long biological half
lives and may be active in the body for more than 20 years.

In the exposed pregnant woman, endocrine disrupting chemicals can be
passed through the placenta, exposing the fetus, or may be expressed
in human milk through breast feeding, exposing the neonate to
significant levels of these chemicals.  National surveys of
pollutants in human milk document the presence of pesticides and
chemicals such as dioxins.  Exposures to certain pesticides have been
shown to shorten the period a woman is able to lactate.  Exposures
during critical developmental periods during gestation may affect the
development of the nervous, endocrine and immunologic systems in the
fetus and may impact on the regulation of various physiologic
processes within the neuro endocrine axis.

Birth defects such as cleft palate and malformations in genitalia may
be more common after exposures during gestation to these agents.
Abnormalities of growth and development have been reported in cohorts
of children accidentally exposed in utero to endocrine disrupting
chemicals in Japan and Taiwan.  It is not clear whether these
chemicals are exhibiting direct neurotoxic and immunotoxic effects or
whether these effects are mediated by alterations in the endocrine
system.  More research is clearly needed to clarify these pathways.

In certain ethnic groups, such as some Native American populations
where fish eating predominates, pregnant women consuming contaminated
fish have substantial exposures to organochlorine compounds that they
pass on to the fetus.  It will be important to determine the health
status of women and their offspring ingesting these contaminants and
to follow up the children for future disease risk.

Research Goals

The goals and scope of this initiative are twofold.  The first is to
encourage and support mechanistically based research on the health
effects of endocrine disruptor concentrations that are commonly found
in the environment.  Research would be encouraged to define the
action of these chemicals on the reproductive, immune, and nervous
systems during critical periods of exposure (in utero, neonatal,
pubertal, reproductive aged adult, post menopausal) concentrating
primarily on women's health.  Experimental work on the cellular,
molecular, genetic, and systemic effects of exposures are
appropriate.  The second area of emphasis is to examine emerging
hypotheses in human populations that complement the recent findings
in the laboratory and in wildlife.  Emphasis should be placed on
development and validation of methods to precisely measure these
exposures in human populations.

For the purpose of this RFA, endocrine disruptors are defined as
those chemicals that mimic or antagonize directly or indirectly an
endocrine system.  Examples include, but are not limited to,
estrogenic pesticides, naturally occurring phytoestrogens, and
pesticides or industrial chemicals with antiestrogenic or
antiandrogenic activity.  This RFA is not intended to support
research that primarily focuses on the health effects of the use of
oral contraceptives or menopausal replacement hormones.

Toxicologic testing of endocrine disruptors using bioassays or
alternative methods, which are necessary for regulatory purposes,
will be considered nonresponsive to this RFA.  Research on the role
of endocrine disruptors in breast cancer development is also not a
focus of research in this RFA.  Support for research on breast cancer
is being provided under the National Action Plan for Breast Cancer,
grants from the Department of Defense and other National Cancer
Institute and NIEHS initiatives.

Areas of research that are encouraged include, but are not limited
to:

o  Studies of the effects of endocrine disrupting chemicals on the
following health endpoints.  Health effects pertinent to reproduction
would include endocrine dysfunction, infertility, endometriosis,
pregnancy outcomes, and lactation.  Health effects pertinent to
women's health would include fibroids, early menopause, osteoporosis,
autoimmune diseases, and gynecologic cancers.  Of particular interest
are studies that focus on exposures during critical periods of
development.  The development and validation of biomarkers of
endocrine disrupting exposure and early health effects are
encouraged.

o  Research that clarifies the transgenerational effects of in utero
and neonatal/early postnatal effects of endocrine disrupting
chemicals.  This would include the occurrence of birth defects,
perturbations of growth and development, precocious puberty in young
offspring and functional changes that are detected in later life.

SPECIAL REQUIREMENTS

Applicants should request funds for one trip in years 1 and 3 to the
NIEHS in Research Triangle Park, North Carolina for a program
meeting.

Animal Welfare Considerations

Investigators are encouraged to consider alternative methods and
approaches in their research applications that do not require the use
of whole animals, that use alternative species such as nonmammals or
invertebrates, that reduce the number of animals required, and that
incorporate refinements to procedures that will result in the
elimination of further minimization of pain and distress to animals.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECT

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 58 14508-14513) and reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.

Investigators also 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 December 1, 1995, 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 consultants,
the 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
111 T.W. Alexander Drive, Building 17, Room 1716
Research Triangle Park, NC  27709
Telephone:  (919) 541 7826
FAX:  (919) 541 2503

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) 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 Office of Grants Information, Division of Research Grants,
National Institutes of Health, 6701 Rockledge Drive, Room 3034, MSC
7762, Bethesda, MD 20892 7762, telephone 301/710-0267, Email:
girg@drgpo.drg.nih.gov.

The RFA label available in the PHS 398 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.

FIRST award applications must include at least three sealed letters
of reference attached to the face page of the original application.
FIRST applications submitted without the required number of reference
letters will be considered incomplete and will be returned without
review.

Submit a signed, typewritten original of the application, including
the checklist, and three signed, clear, and single sided photocopies
in one package to:

DIVISION OF RESEARCH GRANTS
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 also be sent to:

Ethel Jackson, D.D.S.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233
111 T.W. Alexander Drive, Building 17, Room 1716
Research Triangle Park, NC  27709

Applications must be received by January 18, 1996.  If an application
is received after that date, the DRG may contact the applicant to
determine whether it will be returned to the applicant or be reviewed
with unsolicited applications for the next regular receipt date.  The
Division of Research Grants (DRG) 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 DRG will not accept any application that is
essentially the same as one already reviewed.  This does not include
the submission of substantial revisions of applications already
reviewed, but such applications must include an introduction
addressing the previous critique.

REVIEW CONSIDERATIONS

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 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

o  scientific, technical, or medical significance and originality of
proposed research as it relates to contributions to knowledge of
health outcomes in women as a result of exposure to environmentally
derived endocrine disruptors.

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; and

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

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

AWARD CRITERIA

The anticipated date of award is June 1996. The following will be
considered in making funding decisions:

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

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcomed.

Direct inquiries regarding programmatic issues to:

For Human Studies:
Gwen W. Collman, Ph.D.
Chemical Exposures and Molecular Biology Branch
National Institute of Environmental Health Sciences
P.O. Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-4500
FAX:  (919) 541-2843
Email:  collman@niehs.nih.gov

For Animal Studies:
Jerrold Heindel, Ph.D.
Organ and Systems Toxicology Branch
National Institute of Environmental Health Sciences
P.O. Box 12233
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
Research Triangle Park, NC  27709
Telephone:  (919) 541-1373

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 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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