RFA-ES-03-001: BREAST CANCER AND THE ENVIRONMENT RESEARCH CENTERS

Department of Health
and Human Services (HHS)

NIH... Turning Discovery Into Health^®

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BREAST CANCER AND THE ENVIRONMENT RESEARCH CENTERS

RELEASE DATE: November 11, 2002 (see addenda NOT-ES-03-004, NOT-ES-03-006)

RFA: ES-03-001

Update: The following update relating to this announcement has been issued:

November 18, 2009 - See Notice NOT-ES-10-001 Clarification of Eligibility as Primary Applicant.
October 23, 2009 - This RFA has been reissued as (RFA-ES-09-008).

National Institute of Environmental Health Sciences (NIEHS)
(http://www.niehs.nih.gov)
National Cancer Institute (NCI)
(http://www.nci.nih.gov)

Letter of Intent Receipt Date: December 31, 2002

Application Receipt Date: February 11, 2003

THIS RFA CONTAINS THE FOLLOWING INFORMATION:

o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE

The National Institute of Environmental Health Sciences (NIEHS) and the
National Cancer Institute (NCI) invite applications to create a network of
research centers in which multidisciplinary teams of scientists, clinicians,
and breast cancer advocates work collaboratively on a unique set of scientific
questions that focus on how chemical, physical, biological, and social factors
in the environment work together with genetic factors to cause breast cancer.
Answering these questions will allow the translation of such findings into
information that can be applied to increase awareness of the causes of breast
cancer. This program will support a network of cooperative agreements (U01)
comprised of research teams, which will work within and across centers on
targeted biological and epidemiologic research projects. These projects will
be designed to fill specific gaps related to how environmental exposures
impact the development of the mammary gland at the cellular, molecular, organ,
and population level throughout a woman=s lifetime to influence future breast
cancer risk. The research conducted will take a unique developmental approach
to integrate time, susceptibility and exposure in order to more fully
appreciate the changes that occur in the mammary gland early in life that may
predispose the breast to cancer. These projects will help to define specific
periods of susceptibility of the breast when environmental stressors may
change the molecular architecture of the gland, conferring increased risk of
future cancer. The purpose of implementing a network of cooperative breast
cancer centers is twofold. The first goal is to integrate scientific
information on histologic, pathologic, cellular, and sub-cellular changes that
occur in normal mammary gland tissue across the lifespan and compare this to
exposure-induced changes. Discovering changes in gene and protein expression
due to agents to which young girls and women may be exposed during their
lifetime will be a primary goal. Experiments will be conducted cooperatively,
using animal models that characterize pathways related to breast and endocrine
system development during early life, puberty, pregnancy, and other time
points, which may be affected by exposures to environmental stressors
occurring at different windows of vulnerability. When clinical specimens are
available from women at risk, they will be compared to animal models. Data
from these experiments will be made available to the scientific community in
order to stimulate further investigations of mechanisms of interest. A second
goal is to conduct a focused and coordinated epidemiologic study of
determinants of puberty in girls. Attention will be paid to understanding the
shift towards earlier puberty among adolescent girls, the identification of
environmental exposures in young girls, and the interplay between genetic
polymorphisms and environmental exposures that may put them at risk of future
breast cancer. The overall goal of this network of centers is to integrate the
basic biological, toxicologic, and epidemiologic data on the development and
lifespan of the mammary gland in a way that public health messages can be
designed to educate young girls and women who are at high risk of breast
cancer on the role of specific environmental stressors in breast cancer
development and how to reduce exposure to those agents. This information will
be useful in developing clinical and public health programs that target breast
cancer prevention in young girls and women. This research program complements
other programs on breast cancer and mammary gland development being conducted
at the National Institutes of Health. The unique focus of this program
extends that research by comparing the effects of environmental stressors,
including environmental pollutants, nutritional and lifestyle factors, and
other exposures on normal mammary gland development in order to more fully
consider the multiple causes of breast cancer.

RESEARCH OBJECTIVES

Background

Breast cancer is a complex disease, the causes of which have eluded scientists
for many decades. Improvements have been made in early disease detection,
surgical and medical modalities for treatment and survival for women with
breast cancer. Although scientists and clinicians understand more today about
the process of carcinogenesis and genetic susceptibility, effective prevention
strategies targeting the causes of breast cancer remain out of reach due to
the multiplex of factors involved in breast cancer causation. Historically,
research to understand the causes of breast cancer has focused primarily on
the role of estrogen. The dose of estrogen to the mammary gland varies over
time during a woman=s life and may produce differential risks of cancer. The
need to focus on critical windows of vulnerability of the mammary gland,
especially the period of time between the onset of menarche and first
pregnancy, has been recommended by scientists as central to advancing our
knowledge. New technologies are being used to understand the molecular
aspects of cell growth and proliferation during this and other critical
windows and provide new opportunities to integrate molecular, cellular and
organ system level data. Recently, in a series of workshops and meetings
conducted by NIEHS, scientists proposed a developmental approach to
understanding the initiation of breast cancer, drawing attention to the gaps
in our knowledge concerning normal development of the mammary gland,
physiology of sexual maturation, and genetic regulation of these processes. A
major gap was the lack of data available on environmental factors that may
perturb these systems. There is a need to integrate data on the structure and
dynamics of cellular and organ system functions from experimental and clinical
models of breast development, in order to look at normal physiological
pathways and alterations that may occur from environmental stressors. This
approach may allow scientists to think about the interplay between
environmental, genetic, and physiologic causes of breast cancer in a new way.

During the past decade NIEHS has supported research that has focused on
understanding the mechanisms of selected environment agents on breast cancer
in individuals and in populations. Research programs have focused on
understanding the mechanisms of endocrine disrupting chemicals on the female
hormonal and reproductive systems, timing of exposures to environmental
toxicants and breast cancer risk, and genetic susceptibility to breast cancer.
From recent epidemiologic studies it appears that exposures to DDT and
polychlorinated biphenyls (PCBs) as measured in adulthood are not related to
breast cancer risk in women living in countries where these chemicals are
banned. There are some studies suggesting increased risk in women where
spraying with DDT continues today. There is evidence that prenatal exposures
to dioxin and soy have an effect on mammary gland development. Work has begun
to explore the perturbations in molecular mechanisms of mammary gland
development in experiments using DDT, PCBs, and polyaromatic hydrocarbons
(PAHs) as exposures. The National Toxicology Program rodent bioassay suggests
that there are about 40 chemicals that cause breast cancer. Many are
industrial exposures and are therefore difficult to study in women. Recent
evidence suggests other chemicals such as bisphenol-A, atrazine, certain
heterocyclic amines and other polyaromatic hydrocarbons may affect mammary
gland development by changing the pattern of branching in the breast affecting
primarily the terminal end buds. Scientists are also currently exploring how
chemical exposures may change the hormonal milieu and how these changes can
impact breast cancer risk. Following on the need to understand what is
happening to the mammary gland during critical windows of susceptibility,
there is strong evidence that girls less than 14 years old at the time of the
atomic bomb in Hiroshima have an increased risk of breast cancer. It has been
suggested that early cigarette smoking in adolescence may also increase risk.
Recent work in Michigan has shown that girls whose mothers were exposed to
polybrominated biphenyls (PBBs) during their pregnancy and after have an
earlier onset of menarche. Although evidence exists for selected chemicals,
most of the 70,000 chemicals in commerce today remain untested and little data
are available on human doses of exposure or cellular or physiologic effects of
these exposures on the mammary gland and female reproductive system.

During the past decade the NCI has also been actively supporting research on
the role of environmental factors on the risk of breast cancer, particularly
through epidemiological research and the development of tools such as
geographic information systems. Some of these studies have been jointly
funded with the NIEHS. NCI-supported research has led to the identification
of multiple reproductive factors that are involved in the development of
breast cancer. However, there are still significant gaps in the knowledge of
changes that occur in normal breast tissue throughout the lifespan and the
need for more research on the impact of environmental stressors on breast
tissue and pubertal development that may affect breast cancer risk.

In addition to studying traditional environmental factors such as chemicals
and physical agents, it is necessary to more completely examine the influence
of anthropometric and nutritional factors on the mammary gland during
development, puberty, pregnancy, lactation and menopause. There have been
temporal changes noted in body size, weight, and adiposity in young girls over
recent decades that may contribute to earlier age at menarche, precocious
puberty, and altered hormonal profiles. These changes in physiological
parameters may account for the rise in a woman=s risk of future breast cancer.
Social environmental factors, such as poverty, family structure and stress may
impact on nutritional choices, physical activity levels, body size and shape,
and pubertal development and translate to breast cancer risk factors. There
are many gaps in our understanding of how the growth and development of the
mammary gland and reproductive system in young girls may be influenced by
environmental factors such as changing dietary habits, lifestyle choices,
physical activity, and exposures to chemicals in products being used by young
girls. This limited evidence will provide a starting point in considering
which environmental exposures to consider for more in depth study in both the
biological and epidemiologic components of this program.

Biological data on cellular and sub-cellular outcomes should be more fully
integrated in a way that can facilitate analyses of the interplay between all
factors that may cause breast cancer. Such an effort can be useful to examine
and differentiate the multi-level interactions that impact the mammary gland
and reproductive system as they change over a woman=s lifetime. This
information will enhance our appreciation of the biological basis of sexual
maturation and allow scientists to test new hypotheses in mechanistic,
clinical and epidemiologic studies. A coordinated multi-site study of the
environmental and genetic determinants of puberty will translate the basic
information on the influence of many factors on the developing breast and
reproductive system in young girls to the population level. These two
scientific efforts will provide valuable information to the general public on
how the total environment of young girls and women impacts the health of the
breast. Components of these projects will contribute to our understanding of
the heterogeneity of the disease, susceptibility to breast cancer among
different groups of women, the development, validation and use of markers of
physiologic changes in the breast, and the mechanisms of action of chemicals
and other exposures in causing breast cancer.

Objectives

Each Breast Cancer and the Environment Research Center will be constructed in
a way to contribute to the collective effort to provide new information on the
normal growth and development of the breast and reproductive systems, provide
data at the sub-cellular, cellular, and organ system level in animal models
and human populations, evaluating the impact of environmental stressors on the
mammary gland, and explore issues related to susceptibility in developing
breast cancer. The following five scientific priority areas have been
developed after a series of workshops and meetings held on this topic attended
by scientists, representatives from breast cancer advocacy groups and health
care practitioners. They are:

o defining the molecular architecture of the developing and changing mammary
gland over the lifespan,

o timing of exposure during critical windows of vulnerability,

o creation of new and improved animal models and biomarkers to study the
impact of environmental stressors on breast cancer,

o molecular epidemiology and exposure assessment research focused on studying
important gene B environment interactions,

o inclusion of community concerns into breast cancer research projects.

More information about the workshops held can be found at
http://www.niehs.nih.gov/external/bcancer/home.htm. Gaps in our knowledge in
each of these important areas will be addressed in the collaborative projects
of the Centers.

Each Center will contain two collaborative research projects. Collaborative
Project 1 is entitled "Environmental Effects on the Molecular Architecture and
Function of the Mammary Gland across the Lifespan" and will entail the conduct
of collaborative experiments using relevant animal models on the normal
development of the mammary gland using a systems biology approach, and effects
of selected chemicals and other exposures (i.e. nutritional, social) on
endpoints such as breast pathology and gene and protein expression at critical
points in time. Collaborative Project 2 will be entitled "Environmental and
Genetic Determinants of Puberty" and will be a collaborative multi-site
epidemiologic study of sexual maturation in young girls. All study sites will
use similar methods to collect data on markers of physiologic changes during
the pubertal process, and assessment of environmental stressors of importance
to future breast cancer risk, including lifestyle behaviors, nutrition and
anthropometric markers, chemical, physical, and social exposures at home and
school. In addition, pooled analysis of genetic polymorphisms of interest
will be included to fully explore relevant gene environment interactions.
Evidence of active gene pathways from the collaborative project investigating
the molecular architecture of the breast will be considered when choosing
genetic polymorphisms for study. The study will be designed to increase our
understanding of how exposures and physiologic changes occurring during
critical windows of breast development may impact on future breast cancer
risk.

Research Scope

The Breast Cancer and the Environment Research Centers Program is intended to
create a national network that will foster interaction and collaboration
within and between centers. Each center will include the expertise of a
diverse array of individuals. Partnerships among scientists, breast cancer
advocates, community members, and health care providers will be required. The
active participation of the community and national breast cancer advocacy
groups and other community or faith based organization will be expected
throughout the Center, especially in activities which translate research
findings into useful information for the public. Evidence of such
participation in activities of the Center and especially those that are
involved with translating research findings to the public will be required and
reviewed as part of the application package. Collaborations between NIEHS
Environmental Health Sciences Centers and NCI-supported Comprehensive Cancer
Centers, NCI-supported Breast Cancer Specialized Programs of Research
Excellence (SPORE), and Department of Defense Breast Cancer Program-supported
investigators are encouraged.

Description of a Center

The Breast Cancer and the Environment Research Centers should be viewed as
formal organizational components within the institution relative to other such
existing research components at the institution. Reasonable institutional
support should be available to maintain the visibility, credibility and
promote interactions with other such units at the host institution. The
reporting, accountability, and management structure of the Center within the
institution should be equivalent to that of comparable organizations within
the institution. Cost sharing when appropriate is encouraged.

Administrative Core (approximately four to five percent of budget in years one
to seven)

Each Center will have two required core activities, an Administrative Core and
a Community Outreach and Translation Core. The Principal Investigator of the
Center will be the Administrative Core director. This core will serve as the
central coordinating body of the Center. Activities that will be directed
from the Administrative Core will include:

o Coordination of all Center research, meeting attendance, and other
activities.

o Travel support for Steering Committee, subcommittee, network and scientific
meetings.

o Support for seminars or other program enhancement activities which support
awareness and interest in topics related to breast cancer and the environment.

Community Outreach and Translation Core (approximately four to five percent of
budget in years one to seven)

The function of the Community Outreach and Translation Core (COTC) is to
develop and implement strategies to translate the scientific findings of the
center into information for the public and policy makers and to determine if
they are effective. These activities can include: developing educational
materials for children and adults about breast cancer and the environment,
conducting environmental justice related activities, conducting public
awareness forums, workshops, and meetings with stakeholders to discuss a
variety of issues, or to develop and evaluate novel approaches to disseminate
research findings to interested parties. COTC activities can also explore
areas of concern or interest to the community. For example, ethical issues
pertinent to understanding the risks of exposure to environmental pollution,
or using new early biomarkers of exposure or breast cancer risk in research.
The Center should develop a specific plan and set of integrated activities for
COTC, particularly with respect to the Center=s needs to partner with
community and target groups. COTC should be a logical outgrowth of the
scientific focus of the Center and exhibit the potential for mutual benefit
due to interactions with Center research cores and investigators. The COTC
may be useful, for example, as a means of establishing a productive
relationship with a community-based organization, which could subsequently
form the foundation of a successful implementation of the research projects
that are part of the Center. The program should not go beyond public and
community education about reducing environmental disease risk and/or hazard
exposure recognition as the COTC is not intended to give medical, legal,
political, social, or economic advice.

Collaborative Projects

Collaborative Project 1 (CP-1)(approximately 35-45 percent of budget in years
one to seven)

Collaborative Project 1 is entitled "Environmental Effects on the Molecular
Architecture and Function of the Mammary Gland across the Lifespan." The
purpose of this project is to conduct collaborative experiments using relevant
animal and cell culture models of mammary gland development over the lifespan
integrating endpoints such as gene expression, proteomics, and metabonomics,
in order to understand the effects of selected chemicals or other
environmental exposures on mammary gland pathology in these windows of time.

Two main foci guiding this program will include:

o exploration of in vitro and in vivo model systems (including cell culture
and rodent models) for understanding mammary gland development and changes
over the life span including the evaluation of critical windows of sensitivity
to environmental agents,

o evaluation and selection of potential environmental exposures for further
study in appropriate animal or other model systems, via the use of in vitro
mechanism-based screens to detect agents that possess signatures indicative of
possible mammary gland carcinogenicity.

It is anticipated that in the course of this work new and novel biomarkers of
altered structure and function will be developed. The development, validation
and integration of new and enhanced mechanism-based screening paradigms are
also encouraged. The choice and/or methods to characterize endpoints of
interest will be left to the applicant but may include breast pathology, gene
expression and protein expression profiles of relevant pathways and
metabonomic profiles (urine and serum). The goal of this work is to explore
scientific hypotheses involved in mammary gland carcinogenesis and toxicologic
responses during these windows.

Proposals should include the conceptualization of an experimental framework
and design for carrying out all aspects of this research. Key hypotheses
should be identified as well. The application should include a proposal which
defines the experimental approach and methods in the above mentioned two
areas, identify and justify choice of appropriate endpoints of interest, time
points across the lifespan, animal models and cell culture systems to be used,
and data analysis strategies and techniques.

Although the final design of the research will be agreed upon by consensus by
the Breast Biology Subcommittee of the Steering Committee, it is critical that
each applicant address both scientific foci in their application. The
Steering Committee will identify common research aims that all Centers will
participate in and those aims that may be carried out locally by individual
Centers.

Overall the key areas of expertise needed to successfully conduct this project
in a collaborative manner are: in vitro and in vivo mammary gland biology
models, toxicology, pathology, genomics, proteomics, metabonomics and
bioinformatics. All expenses to conduct such work, including the use of
appropriate facility cores, should be incorporated within the proposal for the
collaborative project. It is recognized that all areas of expertise or the
capabilities to direct and perform all areas may not be resident at a single
institution. Centers may form collaborations or consortium for the purposes
of obtaining needed expertise and capacity.

Each Center will describe their abilities in each of the areas that are
pertinent to their proposal. A description of experience in each area of
expertise delineated in the proposal, with publications to support it, should
be included in the application. It is not a requirement that any one Center
have expertise in all of these areas. After award, decisions will be made by
the Steering Committee and the Program Director with regard to which Centers
will take responsibility for specific scientific areas. These decisions will
be based on expertise and capacity to do the needed work as defined by the
Breast Biology Subcommittee. Budget adjustments may be necessary.

Collaborative Project 2 (CP-2)(approximately 35-45 percent of budget in years
one to seven)

Collaborative Project 2 will be entitled "Environmental and Genetic
Determinants of Puberty" and will be a collaborative multi-site epidemiologic
study of the young girls experiencing physiologic changes of thelarche and
sexual maturation and their exposures that can impact on their future risk of
breast cancer. All study sites will use standardized methodologies to collect
data on markers of breast development and other physiologic changes of sexual
maturation, assessment of environmental stressors of importance to future
breast cancer risk, including lifestyle behaviors, nutrition and dietary
supplements, anthropometry, chemical and physical exposures at home, and
school, and social factors. DNA specimens will be collected, stored, and
analyzed for relevant polymorphic variation related to pathways of interest in
defining susceptibility.

Each application should include a detailed study protocol with specific aims
to address leading hypotheses (to include but not limited to gene
environment interactions), sample size calculations for individual study
sites and combined analyses, definitions for enrolling study subjects and
required follow-up time (if a longitudinal design is proposed), methods for
collecting exposure data, health outcome data, and biological specimens.
Inclusion of novel biomarkers of physiological changes in hormone status,
breast development, ovarian and hormonal function, and other measures of
skeletal and sexual maturation are encouraged. After awards are made, the
Epidemiology Subcommittee of the Steering Committee will integrate all of the
meritorious study elements into one cohesive protocol that will be carried out
at each Center.

Centers should identify areas of expertise and capabilities in areas such as
epidemiology, exposure assessment of chemicals and other exposures in
biological and environmental media, biostatistics, clinical assessments,
clinical laboratory determinations, and genetics, as proposed in their
applications. All expenses to conduct such work, including the use of
appropriate facility cores, should be incorporated within the proposal for the
collaborative project. It is recognized that all areas of expertise or the
capabilities to direct and perform all areas may not be resident in each
Center. Centers may form collaborations or consortium for the purposes of
obtaining needed expertise and capacity. After award, decisions will be made
by the Steering Committee and the Program Director with regard to which
Centers will take responsibility of specific scientific areas, i.e. chemical
exposure assessment, dietary analysis, hormone analysis. A description of
such experience in each area of expertise, with publications to support it,
should be included in the application. These decisions will be based on
expertise and capacity to do the needed work. Budget adjustments may be
necessary.

Although it is unlikely that any individual study site will have enough power
to study in detail relevant gene-environment interactions, applicants are to
include and justify such hypotheses to be evaluated for the combined analyses
of data. All Centers will maintain a repository of stored biological and
environmental specimens for later analysis. Analyses may include analytical
chemistry to determine body burdens of chemical exposures. Hormone analysis,
and genetic analysis should be incorporated into the proposal study design.
The Epidemiology Subcommittee will decide over the course of the study which
analyses are necessary.

MECHANISM OF SUPPORT

This RFA will use the NIH U01 award mechanism. As an applicant you will be
solely responsible for planning, directing, and executing the proposed
project. This RFA is a one-time solicitation. The anticipated award date is
July, 2003.

The NIH U01 is a cooperative agreement award mechanism in which the Principal
Investigator retains the primary responsibility and dominant role for
planning, directing, and executing the proposed project, with NIEHS staff
being substantially involved as a partner with the Principal Investigator, as
described under the section "Cooperative Agreement Terms and Conditions of
Award." At this time, it is unknown if this RFA will be reissued after the
initial program period.

FUNDS AVAILABLE

The NIEHS and NCI intend to commit approximately up to $5 million dollars up
(total costs, including facilities and administrative costs) in Fiscal Year 03
to fund three new grants in response to this RFA. An applicant may request a
project period of up to seven years and a budget for direct costs of up to
$900,000 per year. Should an applicant plan to include subcontracts to other
institutions or organizations, only the direct costs associated with the
subcontracts will be used to tally the direct costs that apply toward the cap.
Because the nature and scope of the proposed research will vary from
application to application, it is anticipated that the size of each award may
also vary. Although the financial plans of the NIEHS and NCI include funds to
provide support for this program, awards pursuant to this RFA are contingent
upon the availability of funds and the receipt of a sufficient number of
meritorious applications.

ELIGIBLE INSTITUTIONS

You may submit an application if your institution has any of the following
characteristics:

o For-profit or non-profit organizations
o Public or private institutions, such as universities, colleges, hospitals,
and laboratories
o Units of State and local governments
o Eligible agencies of the Federal government
o Domestic institutions. Applications will not be accepted from foreign
institutions, however, foreign institutions may establish sub-contract
arrangements with domestic applicant institutions.

Partnerships between researchers and members of community based organizations,
faith based organizations and grass roots advocacy organizations that are
concerned with breast cancer are required. Applications that do not include
such partnerships will be returned as non-responsive.

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, and resources necessary to carry
out the proposed research is invited to work with his or her institution to
develop an application for support. Individuals from under represented racial
and ethnic groups as well as individuals with disabilities are always
encouraged to apply for NIH programs.

SPECIAL REQUIREMENTS

Awards made under this program must be interdisciplinary efforts bringing
together investigators from different scientific disciplines. In order to be
funded, each applicant must successfully meet the requirements as stated
below:

o Center Director should be a well-recognized scientist in the field of
mammary gland biology or environmental health sciences. The Center Director
is expected to work to provide stewardship and balance to the overall program
as it develops, conducts and reports on research conducted under the Center
umbrella.

o It is expected that a wide variety of disciplines will be represented in the
expertise of the Center. Applicants should include expertise in mammary gland
biology and carcinogenesis, environmental health sciences and toxicology,
molecular biology, epidemiology, exposure assessment, biostatistics, and
community based participatory research. Clinical expertise is also encouraged
as part of the Center.

o Proposals for two collaborative projects.

o Investigators who are named as part of the two collaborative projects will
be expected to work together with the other centers on the research. This
will entail participating in multiple planning and implementation meetings of
each collaborative project during the first year. Methods and approaches will
be decided upon by consensus. Less frequent meetings are envisioned after the
collaborative projects are launched, but there will be a minimum of two such
meetings a year for each collaborative project committee in years two to
seven.

o Each year the Centers will be involved in planning one scientific
workshop/conference on emerging issues in breast cancer and the environment.
The location of such a meeting and primary logistical support for the meeting
will rotate across the centers. A planning committee with scientific and
community members from each center will be formed each year and will be
charged with carrying out this task. NIEHS and NCI program staff will provide
assistance to this effort.

Cooperative Agreement Terms and Conditions of Award

The following terms and conditions will be incorporated into the U01 award
statement, and will be provided to the Center Director and the awardee
institutional official at the time of award.

These special Terms of Award are in addition to, and not in lieu of, otherwise
applicable OMB administrative guidelines, HHS Grant Administration Regulations
at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH Grant Administration
policy statements. [Part 92 applies when state and local governments are
eligible to apply as a "domestic organization."]

The administrative and funding instrument used for the applicants to this
program is a cooperative agreement (U01), an "assistance" mechanism (rather
than an "acquisition" mechanism) in which substantial NIH scientific and/or
programmatic involvement with the awardee is anticipated during performance
of the activity. Under the cooperative agreement, the NIH purpose is to
support and/or stimulate the recipient's activity by involvement in and
otherwise working jointly with the award recipient in a partner role, but it
is not to assume direction, prime responsibility, or a dominant role in the
activity. Consistent with this concept, the dominant role and prime
responsibility for the activity resides with the awardee for the project as a
whole, although specific tasks and activities in carrying out the studies will
be shared among the awardee and NIEHS and NCI through the Steering Committee.

1. Definitions

NETWORK: The Centers supported as a result of this RFA will form the basis of
the network of Breast Cancer and the Environment Research Centers Program.
These Centers will work collaboratively on two projects; "Defining the Effects
of Environmental Exposures on the Molecular Architecture of the Mammary Gland
over the Lifespan," and "Environmental and Genetic Determinants of Puberty."
The network will work collaboratively on holding an annual meeting on emerging
topics in breast cancer and the environment.

NATIONAL ADVISORY BOARD: A subcommittee of the National Advisory
Environmental Health Sciences Council (NAEHSC) will be established, with ad
hoc members as appropriate, to provide advice to the Director, NIEHS, related
to this program. Subcommittee members who are standing members of the NAEHSC
will also have responsibility for the second level review of all applications
for this program. The subcommittee will provide advice on the topics to be
considered at the annual workshop/conference in emerging areas in breast
cancer and the environment. This subcommittee will meet with the Steering
Committee once a year to review progress and make recommendations about future
directions for the program.

BREAST CANCER and the ENVIRONMENT TASK FORCE: A group of federal program
directors or scientists that can provide oversight and advice about the
progress of the collaborative research projects. These government scientists
may also provide liaison to other federally supported resources, such as
tissue repositories, animal model consortiums, or genomics databases. This
task force will meet with the grantees and may review materials and products
of the research as needed to provide input.

2. Awardee Rights and Responsibilities

o The Center Director will coordinate project activities scientifically and
administratively at the awardee institution and at the other sites that may be
supported by sub-contracts to this award. The Center Director of a U01 grant
will have primary authority and responsibility to define objectives and
approaches, and to plan, conduct, analyze, and publish results,
interpretations, and conclusions of studies conducted under the terms and
conditions of the cooperative agreement award.

o The Center Director will assume responsibility and accountability to the
applicant organization officials and to the NIEHS and NCI for the performance
and proper conduct of the research supported by the U01 in accordance with the
terms and conditions of the award.

o The Center Director, and a member of the Community Outreach and Translation
Core who represents the views and concerns of the breast cancer advocacy
community, will serve, as voting members of the Steering Committee, and will
attend the Steering Committee meetings and appropriate subcommittee meetings.

o The Center Director will be responsible for accepting and implementing
the goals, priorities, procedures, and policies agreed upon by the Steering
Committee.

o The Center Director of a U01 will be responsible for close coordination
and cooperation with the other components of the Network, the Steering
Committee, and with the NIEHS and NCI staff.

o The Center Director will submit periodic progress reports in a standard
format, as determined by the NIEHS and NCI.

o Awardees will retain custody of, and have primary rights to, the data
developed under these awards at their institution, subject to Government
rights of access consistent with current HHS, PHS, and NIH policies. They
will also share these data with other Centers as needed. The policy of the PHS
is to make available to the public the results and accomplishments of the
activities that it funds. The Center Director agrees to data sharing and data
pooling practices as designed by the Steering Committee and subcommittees.

o The Center Director is responsible for effective communication and
collaboration with the Network. There will be sharing of data and other
information among the Centers and between the Centers and the NIEHS and NCI.
Awardees are responsible for developing or enhancing their Internet
communication tools to ensure effective communication among the different
components that form the U01 grant (such as, sub-contracts, individual core
facilities at the institution), the other Centers, and with NIEHS and NCI.

3. Extramural Staff Responsibilities

o The NIEHS and NCI Program Directors will provide normal stewardship for the
U01 awards under this RFA. The NIEHS and NCI Program Directors will review the
scientific progress of individual U01s, and review them for compliance with
the operating policies developed by the Steering Committee. The NIEHS and NCI
Program Directors may recommend withholding support, re-allocating support
among awardees, and suspension or termination of a U01 award for lack of
scientific progress or failure to adhere to policies established by the
Steering Committee.

o The NIEHS and NCI Coordinators will have substantial scientific and
programmatic involvement to assist, guide, coordinate, and participate in the
conduct of the Network activities. The NIEHS and NCI Coordinators will
coordinate and facilitate the Network activities, will attend and participate
in all meetings of the Steering Committee and subcommittees, and will provide
liaison between the Steering Committee, the Network and the NIEHS/NCI/NIH and
other federal agencies as needed. The NIEHS and NCI Coordinators along with
supporting staff will work with the Network to facilitate one
conference/workshop per year on emerging topics in breast cancer and the
environment.

o The NIEHS and NCI Coordinators will coordinate meetings and activities that
involve the network of Centers, the Steering Committee, and the National
Advisory Environmental Health Sciences Council subcommittee on breast cancer
and the environment. The NIEHS and NCI Coordinators will regularly consult
with the Breast Cancer and the Environment Task Force on the scientific
progress of the Network. Task force members will have access to progress
reports and other relevant information submitted by the U01 awardees.

o The NIEHS and NCI Coordinators will assist the Steering Committee in
developing and drafting operating policies and policies for dealing with
recurring situations that require a coordinated action.

o Federal government staff with relevant scientific expertise or who manage
research grant programs that relate scientifically to the goals of the network
will form the Breast Cancer and the Environment Task Force. The Task Force
will meet regularly to review the progress of the Network and to recommend to
the NIEHS and NCI Program Directors scientific developments and opportunities
that may enhance the achievement of the network goals.

o The NIEHS and NCI Program Directors may also function as the NIEHS and NCI
Coordinators for this program.

4. Collaborative Responsibilities

Upon acceptance of an award, investigators agree to participate in the
cooperative nature of the Network and to work collaboratively on two research
projects. Investigators agree to exchange information freely within the
Network and publish in the scientific literature according to procedures that
the Steering Committee puts into place. Investigators agree to participate in
all meetings necessary to further the collaborative goals of the program.

5. Steering Committee

o An arbitration system, as detailed below, will be available to resolve
disagreements between the NIEHS and NCI Program Directors and the members of
the Steering Committee.

o The Steering Committee will be the main governing board of the Network. It
will function to set priorities for Centers program and its collaborative
projects.

o The Steering Committee will be composed of the director and a member of the
Community Outreach and Translation Core who represents the views and concerns
of the breast cancer advocacy community from each U01. The two
representatives from each U01 will each have one Steering Committee vote. The
chairperson, who will be someone other than an NIEHS/NCI/NIH staff member,
will be selected by the Steering Committee. The NIEHS and NCI Program
Directors are non-voting members of the Steering Committee, and will
facilitate creation of the group and will attend all meetings. NIH staff may
not serve as the Committee chair.

o The Steering Committee may, when it deems it to be necessary, invite
additional, non-voting scientific advisors to the meetings at which research
priorities and opportunities are discussed. The NIEHS and NCI reserves the
right to augment the scientific or consumer expertise of the Network when
necessary.

o There will be one Steering Committee meeting annually. The initial planning
meeting will be organized by NIEHS and NCI, but subsequent meetings will be
organized by the Steering Committee. The committee=s chair will schedule the
meetings and will be responsible for meeting agendas (in collaboration with
the Program Director), chairing the meetings, and producing Steering
Committee=s reports. The same procedure will take place for the two
subcommittees of the Steering Committee. Chairs will be selected and
responsibilities with regard to agenda planning, chairing the meetings, and
producing reports will follow the model of the Steering Committee.

o There will be two subcommittees of the Steering Committee, the Breast
Biology Subcommittee and the Epidemiology Subcommittee. Each subcommittee
will plan and implement the collaborative projects. The Breast Biology
Subcommittee will be comprised of the necessary senior investigators from CP-1
in each center, and the Epidemiology Subcommittee will be comprised of the
necessary senior investigators from CP-2 in each center. Each Center will
designate one member of the Community Outreach and Translation Core who can
represent the views and the concerns of the breast cancer advocacy community
to participate in each subcommittee. Each subcommittee will designate a
chair, who, in addition to directing the activities of the subcommittee, will
keep the NIEHS program director and Steering Committee apprised of progress of
their respective collaborative project. Each subcommittee will meet as needed
by conference call, videoconference or in person and will report to the
Steering Committee annually. It is estimated that each subcommittee will each
meet face-to-face up to four times in the first year of each collaborative
project. The initial planning meeting will take place in the Research
Triangle Park, NC, with subsequent meetings at a location that the Steering
Committee/subcommittees select and with which the NIEHS and NCI concur. The
NIEHS and NCI Program Directors or their designee(s) will attend all
subcommittee meetings. NIH representation on the Steering Committee will never
make up a majority of the total number.

o The first meeting of the Network will be a Planning Meeting, which will take
place in the Research Triangle Park, NC, very shortly after the awards are
finalized. At the Planning Meeting, the Steering Committee and subcommittees
will be formed and select chairpersons from among the members who represent
the U01 awardees. Steering Committee will also draft and agree to: the terms
of a charter to detail policies and procedures, a process for monitoring
compliance with the policies and procedures, and a process for recommending
that the NIEHS and NCI Program Directors act on evidence of non-compliance of
any Consortium component with Steering Committee policies.

o The Steering Committee will work collaboratively to hold one
workshop/conference a year, to which non-Network participants and the general
public may be invited to enable the Network to explore scientific or
technological innovations that occurs during the course of the project. These
meetings will also serve to inform the research and interested public of the
progress of the Centers. The organization of the workshops and symposia will
be the responsibility of the Network members. NIEHS and NCI may choose to
provide supplemental funds to the selected host institution, after the receipt
of an appropriate application and review by the Steering Committee.

o The Steering Committee may establish additional subcommittees. The NIEHS
and NCI Program Directors and the other NIEHS/NCI/NIH staff may serve on
subcommittees, as they deem appropriate.

5. Arbitration Process

Any disagreement that may arise on scientific/programmatic matters (within the
scope of the U01 award), between U01 awardees and the NIEHS and NCI may be
brought to arbitration. An arbitration panel will be composed of three
members: one selected by the Steering Committee (without NIH representatives
voting), or by the individual U01 awardee in the event of an individual
disagreement; a second member selected by the NIEHS and NCI; and, the third
member selected by the two prior selected members. For U01 awardees, this
special arbitration procedure in no way affects the awardees' right to appeal
an adverse action that can otherwise be appealed in accordance with the PHS
regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16.

6. Yearly Milestones and Evaluations

Awardees will finalize yearly milestones at the time of their awards. The
awardees= milestones will be provided to the Steering Committee. It is
expected that the milestones will be adjusted annually at the award
anniversary dates, both to incorporate a group=s scientific accomplishments
and progress in the field in general, as well as to reflect the
recommendations of the Steering Committee. In accord with the procedures
described above, NIH may withhold or reduce funds for projects that
substantially fail to meet their milestones or to maintain their research
activities as state-of-the-art.

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity to
answer questions from potential applicants. Inquiries may fall into three
areas: scientific/research, peer review, and financial or grants management
issues:

o Direct your questions about scientific/research issues to:

Gwen W. Collman, Ph.D.
Scientific Program Administrator
Chemical Exposures and Molecular Biology Branch
National Institute of Environmental Health Sciences
P.O. Box 12233 111 T.W. Alexander Drive (MD EC-21)
Research Triangle Park, NC 27709
Telephone: (919) 541-4980
Fax: (919) 316-4606
Email: collman@niehs.nih.gov

Kumiko Iwamoto, M.D., Dr.P.H.
Epidemiology and Genetics Research Program
National Cancer Institute
6130 Executive Boulevard, Room 5115
Bethesda, MD 20892-7324
Telephone: (301) 435-4911
Fax: (301) 402-4279
Email: iwamotok@mail.nih.gov

o Direct your questions about peer review issues to:

Sally Eckert-Tilotta, Ph.D.
Scientific Review Administrator
Scientific Review Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, MD EC-30
Research Triangle Park, NC 27709
Telephone: (919) 541-4446
Fax: (919) 541-2503
E-mail: eckertt1@niehs.nih.gov

o Direct your questions about financial or grants management matters to:

Ms. Lerlita Garcia
Grants Management Specialist
Grants Management Branch
National Institute of Environmental Health Sciences
P. O. Box 12233, MD EC-22
Research Triangle Park, NC 27709
Telephone: (919) 316-4638
Fax: (919) 541-2860
Email: garcia1@niehs.nih.gov

Ms. Crystal Wolfrey
Team Leader, DCCPS Team
Grants Administration Branch
National Cancer Institute
6120 Executive Blvd, Suite 243
Bethesda, MD 20892 (for regular mail)
Rockville, MD 20852 (for hand-delivered mail)
Telephone: (301) 496-8634
Fax: (301) 496-8601
Email: wolfreyc@gab.nci.nih.gov

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes
the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel in each collaborative project and cores
o Participating institutions
o Number and title of this RFA

Although a letter of intent is not required, is not binding, and does not
enter into the review of a subsequent application, the information that it
contains allows NIEHS staff to estimate the potential review workload and plan
the review.

The letter of intent is to be sent by the date listed at the beginning of this
document. The letter of intent should be sent to:

Sally Eckert-Tilotta, Ph.D.
Scientific Review Administrator
Scientific Review Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P. O. Box 12233, MD EC-30
Research Triangle Park, NC 27709
Telephone: (919) 541-4446
Fax: (919) 541-2503
E-mail: eckertt1@niehs.nih.gov

Courier Service Address:

Building 4401, Room 3171
79 TW Alexander Drive
Research Triangle Park, NC 27709

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application
instructions and forms (rev. 5/2001.) The PHS 398 is available at
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive
form. For further assistance contact Grants Info, telephone (301) 710-0267,
Email: GrantsInfo@nih.gov

SUPPLEMENTAL INSTRUCTIONS

The body of the scientific application will be composed of the following
sections with the appropriate page limitations:

- Introduction and organization of Center B 5 pages maximum
- Administrative Core - 15 pages maximum
- Community Outreach and Translation Core - 20 pages maximum
- Collaborative Project 1 - 25 pages maximum
- Collaborative Project 2 - 25 pages maximum
- Appendices

Human subjects and animal welfare issues should be addressed in each of the
appropriate sections. Discussions of these issues will not be subject to the
page limitations. An overall Center description, list of all performance
sites, and list of all key personnel (i.e., PHS 398 Form Page 2) should be
included at the beginning of the application. Appropriate budget pages for an
overall consolidated Center budget, including consortium or contractual
arrangements, should appear at the beginning of the application. Budget
pages, personnel descriptions and biosketches specific to the Cores and
Collaborative Projects should be incorporated in the appropriate sections.
All appendices should be labeled appropriately and should appear at the end of
the proposal, after the checklist. Applications not organized in this manner
may be returned without review.

USING THE RFA LABEL

The RFA label available in the PHS 398 (rev. 5/2001) application form must be
affixed to the bottom of the face page of the application. Type the RFA
number on the label. 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, "Breast Cancer and the
Environment Research Centers," and number, RFA ES-03-001, must be typed on
line 2 of the face page of the application form and the YES box must be
marked. The RFA label is available at:
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf

SENDING AN APPLICATION TO THE NIH

Submit a signed, typewritten original of the application, including the
checklist, and three signed 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:

Courier Service Address:

Building 4401, Room 3171
79 TW Alexander Drive
Research Triangle Park, NC 27709

APPLICATION PROCESSING

Applications must be received by the application receipt date listing in the
heading of this RFA. 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.

PEER REVIEW PROCESS

Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the NIEHS and NCI. 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, all applications will:

o Receive a written critique.

o 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 and assigned a priority score.

o Receive a second level review by the National Advisory Environmental Health
Sciences Council and National Cancer Advisory 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 your application in order to judge the likelihood that the proposed
research will have a substantial impact on the pursuit of these goals:

- Significance
- Approach
- Innovation
- Investigator
- Environment

The scientific review group will address and consider each of these criteria
in assigning your application=s overall score, weighting them as appropriate
for each application. Your 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, you may propose to carry out
important work that by its nature is not innovative but is essential to move a
field forward.

OTHER REVIEW CRITERIA

A. Overall Center

Centers must include proposals for collaborative research projects with a
conceptual theme focusing on breast cancer and the environment as outlined in
the RFA. There must be evidence of the potential for a meaningful
interdisciplinary collaboration between a multiple areas of science and
community based advocacy groups which are concerned with breast cancer.

o Evaluate the interdisciplinary nature of the proposed research activities,
integration of the projects around an overarching theme, and plans to
effectively pursue interdisciplinary research objectives.

o Evaluate the plans for active participation of breast cancer advocacy groups
and other relevant community groups in the conceptualization, planning,
implementation, and handling and dissemination of research and findings
whenever appropriate.

o Evaluate how Center scientists propose to work collaboratively within the
Center, across centers as needed for the completion of the two collaborative
projects, and across Centers to enhance research opportunities being explored
in investigator initiated activities.

B. Collaborative Projects

Environmental Effects on the Molecular Architecture of the Breast Across the
Lifespan

o Judge the innovation and appropriateness of the scientific hypotheses,
research approaches and methodology proposed to make a significant
contribution to the field of study.

o Evaluate the ability of the applicant group to contribute sufficiently to
the collaborative efforts in the each of the needed areas of expertise (ie.
animal models/pathology, genomics, proteomics, bioinformatics.) Strengths and
weaknesses in areas will be described.

o Evaluate the resources available at the institution (instrumentation, space,
capacity) to handle the work load of the collaborative project as designed by
the applicant.

o Evaluate the abilities of the investigators to contribute meaningfully to
the development and conduct of collaborative activities.

Environmental and Genetic Determinants of Puberty

o Judge the innovation and appropriateness of the scientific hypotheses and
research methods proposed to make a significant contribution to the field of
study.

o Evaluate the ability of applicant group to contribute sufficiently to the
collaborative efforts by demonstrating the capacity to recruit and follow-up
needed study subjects, design and employ appropriate exposure assessment
methodologies for all potential risk factors, and collection, banking and
analysis of biologic specimens.

o Evaluate the contribution of biostatistical expertise available to the goals
of the collaborative project.

o Evaluate the contribution of expertise in molecular epidemiology to
contribute to the collaborative efforts of studying gene-environment
interactions as part of this study.

C. Administrative Core

o Evaluate whether the lines of authority and the administrative structure
are designed for effective center management.

o Evaluate the qualifications, responsibilities, and effectiveness of
senior leaders. Identify if the percent effort is appropriate.

o Evaluate the duties and percent efforts of administrative staff of the
center in terms of their qualifications and contributions to the specialized
needs and conduct of the center's research activities.

D. Community Outreach and Translation Core (COTC)

o Evaluate the appropriateness of the proposed core activities with regard to
the potential for engaging community support for Center research projects,
adequate dissemination of study findings, and translation of research findings
to public health action.

o Evaluate the expertise of core members to fulfill the mission of the COTC.

E. Institutional Commitment

o Evaluate the effectiveness of the Center as a formal organizational
component within the institution relative to other organizational components.

o Determine whether the reporting, accountability, and management structure of
the Center within the institution are equivalent to that of comparable
organizations within the institution. Assess the adequacy of institutional
procedures and plans for monitoring, evaluating, and assuming accountability
for the general success of the Center.

o Evaluate the specific resources provided by the institution such as
personnel, appropriate facilities, financial support, and other forms of
support that reflect the level of the institution's commitment to the
functional stability, continuing development, and success of the Center.

ADDITIONAL REVIEW CRITERIA

In addition to the above criteria, your application will also be reviewed with
respect to the following:

Protections: 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.

Inclusion: The adequacy of plans to include subjects from all racial and
ethnic groups (and subgroups), and children as appropriate for the scientific
goals of the research. Plans for the recruitment and retention of subjects
will also be evaluated. (See Inclusion Criteria included in the section on
Federal Citations, below)

Data Sharing: The adequacy of the proposed plan to share data.

Budget: The reasonableness of the proposed budget and the requested period of
support in relation to the proposed research.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date: December 31, 2002
Application Receipt Date: February 11, 2003
Peer Review Date: April, 2003
Council Review: May, 2003
Earliest Anticipated Start Date: July, 2003

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.

REQUIRED FEDERAL CITATIONS

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH

It is the policy of the NIH that women and members of minority groups and
their sub-populations must be included in all NIH-supported clinical research
projects unless a clear and compelling justification is provided indicating
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 clinical research should read the AMENDMENT "NIH
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research - Amended, October, 2001," published in the NIH Guide for Grants and
Contracts on October 9, 2001
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html
The amended policy incorporates: the use of an NIH definition of clinical
research; updated racial and ethnic categories in compliance with the new OMB
standards; clarification of language governing NIH-defined Phase III clinical
trials consistent with the new PHS Form 398; and updated roles and
responsibilities of NIH staff and the extramural community. The policy
continues to require for all NIH-defined Phase III clinical trials that: a)
all applications or proposals and/or protocols must provide a description of
plans to conduct analyses, as appropriate, to address differences by
sex/gender and/or racial/ethnic groups, including subgroups if applicable; and
b) investigators must report annual accrual and progress in conducting
analyses, as appropriate, by sex/gender and/or racial/ethnic group
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

The NIH maintains a policy 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 is available at
http://grants.nih.gov/grants/funding/children/children.htm

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS

NIH policy requires education on the protection of human subject participants
for all investigators submitting NIH proposals for research involving human
subjects. You will find this policy announcement in the NIH Guide for Grants
and Contracts Announcement, dated June 5, 2000, at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT

The Office of Management and Budget (OMB) Circular A-110 has been revised to
provide public access to research data through the Freedom on 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
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm

Applicants may wish to place data collected under this RFA 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.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES

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. Furthermore, we caution reviewers that their
anonymity may be compromised when they directly access an Internet site.

HEALTHY PEOPLE 2010

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 RFA, "Breast Cancer and the
Environment Research Centers" is related to one or more of the priority areas.
Potential applicants may obtain a copy of "Healthy People 2010" at
http://www.health.gov/healthypeople

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance
No.93.113, 93.114, and 93.115, and is not subject tot he intergovernmental
review requirements of Executive Order 12372 or Health Systems Agency review.

Awards are made under authorization of Sections 301 and 405 of the Pubic
Health Service Act as amended (42 USC 241 and 284) and administered under NIH
grants policies described at http://grants.nih.gov/grants/policy/policy.htm

The PHS strongly encourages all grant recipients to provide a smoke-free
workplace and discourage the 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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices