Full Text ES-94-004


NIH GUIDE, Volume 23, Number 1, January 7, 1994

RFA:  ES-94-004

P.T. 34

  Environmental Effects 

National Institute of Environmental Health Sciences

Letter of Intent Receipt Date:  March 8, 1994
Application Receipt Date:  April 8, 1994


Research on environmentally related causes of breast cancer and its
prevention is a priority of the National Institute of Environmental
Health Sciences (NIEHS).  Accordingly, the goal of this Request for
Applications (RFA) is to stimulate research on the role of
environmental factors in the etiology of breast cancer.  Of
particular interest are aspects related to the timing of the
exposures to harmful environmental agents and the subsequent cellular
and genetic changes that may lead to breast cancer.  Another equally
important area of research is to develop a better understanding of
what effects environmental agents have on the normal growth and
development of mammary gland tissues.  In vitro and in vivo studies
that further our understanding of the influence of environmental
factors on sex steroid hormones, growth factors, and receptors in
cellular and genetic processes are encouraged.

Much is still unknown regarding the etiology and underlying
mechanisms resulting in breast cancer.  The objective of this RFA is
to enhance our understanding of environmental influences on cellular,
genetic, and hormonal mechanisms that are responsible for normal
growth and development of breast tissue and how chemical and physical
agents influence that development, which may lead to carcinogenesis.
The timing of exposures to those agents with respect to specific
windows of susceptibility may be critical for defining risk periods
in a woman's lifetime and may provide new insight into breast cancer


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,
Timing of Environmental Exposures in Breast Cancer, is related to the
priority areas of environmental health and cancer.  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).


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 Awards (FIRST) (R29) awards.  Applications
from minority individuals and women are encouraged.


This RFA will use the National Institutes of Health (NIH) individual
research 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 total project period for R01
applications submitted in response to the present RFA may not exceed
four years; R29 applications must be for five years.

This RFA is a one-time solicitation for applications for new awards.
Future unsolicited competing continuation applications will compete
with all investigator-initiated applications and be reviewed
according to the customary peer review procedures.


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

This level of support is dependent on the receipt of a sufficient
number of applications of high scientific merit.  Although this
program is provided for in the financial plans of the NIEHS, awards
pursuant to this RFA are contingent upon the availability of funds
for this purpose.



Although there is convincing evidence that some environmental and
industrial chemicals produce mammary tumors in experimental animals,
such evidence is lacking for human breast cancer.  Most epidemiologic
studies of breast cancer risk have focused on reproductive factors
and have found factors such as late age at first birth, early age at
menarche, late age at menopause, to be associated with breast cancer
risk.  Several environmental factors such as ionizing radiation,
electromagnetic radiation, exposure to tobacco smoke, alcohol,
caffeine, and organochlorine pesticides have been suggested to
increase breast cancer risk in human populations.  The timing of
exposure to these or other environmental agents would also be
critical for developing future cancers.

Endogenous sex steroid hormones are of primary importance in the
growth and development of mammary gland tissue and pertubations in
the regulation of these hormones may be related to breast cancer
risk.  Environmental agents that may influence endogenous levels or
activity of steroid hormones have not been carefully studied.  It is
important to determine if exposure to chemicals or other agents that
may act as environmental estrogens influence the endogenous levels or
activity of all relevant steroid hormones.  Research that explores
the biologic mechanism of these environmental effects on cell growth
and development, genetic regulation of cellular processes, and
hormone synthesis and regulation focusing on the timing of these
actions will help to better understand the action of these agents.

It is important to identify and understand the critical time periods
in life at which environmental agents may effect growth and
development of the mammary gland and which may ultimately increase
the risk of breast cancer.  Critical periods of time in ductal
morphogenesis are usually considered to be puberty and pregnancy when
rapid cell proliferation and differentiation is occurring.  Other
critical periods of time should be studied in relation to cancer
development and latency.

Some evidence does exist that suggests that the timing of exposure to
selected environmental agents may play a crucial role in determining
whether or not cancer occurs.  The increased risk seems to be time
dependent in these cases such that exposure to these agents during
other time periods does not impart as high a risk of breast cancer.
In atomic bomb survivors, early studies indicated an increased risk
of breast cancer in those exposed before 20 years of age (Tokunaga et
al. 1987).  This was also true for women irradiated during childhood
for a variety of medical conditions (Hrubec et al. 1989, Hildreth et
al. 1989).  Radiation exposure to young girls during puberty may be
critical due to susceptibility of the rapidly growing breast tissue
mediated by vast hormonal changes during this time.  Later studies
with latency periods of 35 years suggest that the a nine-fold risk of
breast cancer is found in the subgroup of women who were newborn to
four years of age during exposure (Tokunaga et al. 1987).  Cigarette
smoking and heavy drinking during the prepubertal time period has
also been suggested to be related to developing future breast
cancers.  Palmer et al. (1991) has shown that the risk ratio for
heavy smoking was 1.8 among those who started smoking before 16 years
and 2.4 if smoking began before age 14.  The risk was attributed to
the age when the girls began smoking rather than the duration of
smoking, suggesting that there may be critical periods during breast
development that are more highly susceptible to carcinogenic insults.
The induction of DMBA-induced mammary gland tumors has been shown to
be dependent on the age of the experimental animal and the extent of
cellular differentiation in the mammary gland during that time (Russo
and Russo 1978, Russo et al. 1978).  Pregnancy, a period of time of
extensive cellular proliferation and differentiation, may also be
considered a relevant period of susceptibility for environmentally
induced damage to breast tissue.  Women taking DES during pregnancy
to prevent miscarriages have an increased relative risk of 2.5 of
developing breast cancer 30 years after taking the drug (Greenberg et
al. 1984).

Research goals

This research program is designed to stimulate experimental work in
three important areas to enhance our understanding of environmental
influences on normal breast development and breast cancer.  These are
to understand the cellular and genetic effects of environmental
agents on the normal growth and development of the mammary gland,
study the role of environmental factors in the development of breast
cancer, and explore the role of timing of these agents during
critical developmental periods as it pertains to future risk of
abnormal development and carcinogenesis.  Research into how exposures
during these periods effect the latency of the disease is also
desirable.  It should be noted that research that explores the
cellular, genetic, and hormonal aspects of normal and abnormal breast
development, without regard to the role of environmental factors will
not be considered responsive to this RFA.  Population-based studies
on the relationship between environmental factors and breast cancer
risk are not included in this RFA.

Studies should identify chemical and physical agents that affect
normal cell growth and development and may act as initiating or
promoting carcinogens.  These agents could include, but are not
limited to, chemicals such as pesticides or industrial products,
environmental estrogens, ionizing and electromagnetic radiation,
exposure to contaminated drinking water, indoor and ambient air
pollution, tobacco smoke products, caffeine, and alcohol.
Interaction of these agents and steroid hormones, such as estrogen,
progesterone, and prolactin in the regulation of cellular and genetic
mechanisms in mammary glands, should also be explored.

Periods of time of interest may include the fetal period, the window
from birth to puberty, puberty, the window from puberty to first
pregnancy, pregnancy, lactation, surgical and natural menopause, and
the postmenopausal period.  Cellular processes that may be involved
include, but are not limited to, cell proliferation, apoptosis,
ovarian and pituitary steroid metabolism and bioavailability, growth
factor production and activity, estrogen receptor activity, gene
mutation and regulation, ductal morphogenesis and mammary gland cell
differentiation.  Research is encouraged using animal model systems,
human cell lines, and tumor and normal breast tissue samples from
animals or humans.


Applicant should request funds for one trip annually to the National
Institute of Environmental Health Sciences 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.



NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be required to include minorities and
women in study populations so that research findings can be of
benefit to all persons at risk of the disease, disorder or condition
under study; special emphasis should be placed on the need for
inclusion of minorities and women in studies of diseases, disorders
and conditions which disproportionately affect them.  This policy is
intended to apply to males and females of all ages.  If women or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed population-based studies, a clear
compelling rationale should be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group, together with a rationale
for its choice.  In addition, general and racial/ethnic issues should
be addressed in developing a research design and sample size
appropriate for the scientific objectives of the study.  This
information should be included in the form PHS 398 in Sections 1-4 of
the Research Plan AND summarized in Section 5, Human Subjects.
Applicants are urged to assess carefully the feasibility of including
the broadest possible representation of minority groups.  The NIH
recognizes that it may not be feasible or appropriate in all research
projects to include representation of the full array of United States
racial/ethnic minority populations (i.e., Native Americans (including
American Indians or Alaskan Natives), Asian/Pacific Islanders,
Blacks, Hispanics).

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment of
diseases, disorders or conditions, including, but not limited to,
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed and the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and will be
reflected in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these


Prospective applications are asked to submit, by March 8, 1994, 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
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
Research Triangle Park, NC  27709
Telephone:  (919) 541-7826
FAX:  (919) 541-2503


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) 710-0267.

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 2A of the face page of the application form and the YES box must
be marked.

FIRST 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

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:

Ethel Jackson, D.D.S.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233
104 T.W. Alexander Drive, Building 17, Room 1716
Research Triangle Park, NC  27709
Telephone:  (919) 541-7826

Applications must be received by April 8, 1994.  If an application is
received after that date, it will be returned to the applicant or
will be placed in the pool of applications for the next regular
receipt date.  The Division of Research Grants (DRG) will not accept
any application in response to this announcement 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 preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an
introduction addressing the previous critique.

The subject of this RFA may overlap interests of other Institutes,
Centers and Divisions (ICDs).  It should be noted that the National
Cancer Institute has an interest in the subject matter of this RFA.
Applications will be given an Institute assignment based on current
referral guidelines for funding components of PHS.


Applications will be administratively reviewed by NIH staff for
completeness and responsiveness to this announcement. Applications
found to be incomplete or nonresponsive will be returned to the
applicant without further consideration. Those applications that are
complete and responsive may be subjected to triage to determine their
scientific merit relative to other applications received in response
to this RFA.  The NIEHS will administratively withdraw from
competition those applications judged to be noncompetitive and so
notify the applicant and institutional official.  Those applications
judged to be competitive will undergo further scientific merit
review.  These applications will be evaluated in accordance with the
criteria stated in the RFA for scientific/technical merit by an
appropriate peer review group convened by the NIEHS.  The second
level of review will be provided by the National Advisory
Environmental Health Sciences Council.

Review criteria for this RFA 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; and

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


The anticipated date of award is September 30, 1994.

Applications assigned to ICDs other than NIEHS will compete for
available funds with all other approved applications assigned to that
ICD.  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.


Written and telephone 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:

Gwen W. Collman, Ph.D.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-4980
FAX:  (919) 541-2843

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


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.


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