Release Date:  November 7, 2000

RFA:  ES-01-002

National Institute of Environmental Health Sciences

Letter of Intent Receipt Date:  February 15, 2001
Application Receipt Date:       March 15, 2001


The mission of the National Institute of Environmental Health Science (NIEHS) 
is to reduce the burden of environmentally associated diseases and 
dysfunctions by defining how environmental agents affect our health, 
individuals differ in their susceptibility to these agents, and how these 
susceptibilities change over time.  Recent advances in gene expression 
analysis using microarray technology have made the assessment of effects of 
environmental agents on global gene expression possible.  The emerging 
potential of this pioneering technology has clearly shown a capability for 
revolutionizing the way experiments are conducted and interpreted in the 
frontier areas of environmental health sciences research.  Advancing 
environmental health sciences research is of enormous importance to NIEHS and, 
thus, the NIEHS has initiated a national program to develop and accelerate 
research using microarray technology to assess global gene expression profiles 
and characteristics associated with physiological mechanisms linking 
environmental agent exposures to environmental diseases and dysfunctions. The 
overall NIEHS program has as its goal a coordinated effort to define how the 
entire genetic complement of an organism responds to environmental agents, 
including chemicals, physical agents, and physiological stresses.

The present Request for Application (RFA) initiative is to develop a national 
Toxicogenomics Research Consortium (TRC) that will increase the capacity of 
the extramural research community to apply microarray gene expression 
profiling to the understanding of biological responses to environmental stress 
by: 1) accelerating research in the broad area of environmental stress 
responses using microarray gene expression profiling, 2) developing standards 
and practices that will allow analysis of gene expression data across 
platforms and provide intra- and inter- laboratory validations, and 3)  
contributing to the development of a relational database for gene expression 
data. It is anticipated that the research outcomes discovered by the TRC will 
substantially contribute to advancing the development of new approaches for 
the therapeutic intervention or the prevention of environmental diseases and 


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 Request for Applications, 
Toxicogenomics Research Consortium, is related to the priority area of 
environmental health.  Potential applicants may obtain a copy of Healthy 
People 2010 at 


Applications may be submitted by domestic non-profit and for-profit 
organizations, private and public, such as universities, colleges, private 
companies, hospitals, laboratories, units of state or local governments, and 
eligible agencies of the Federal government. Applications from foreign 
institutions will not be accepted, however research projects from
investigators from foreign institutions can be included as sub-contracts in 
the proposal submitted by the domestic institution. Racial/ethnic minority 
individuals, women, and persons with disabilities are encouraged to apply as 
Principal Investigators. Applicants should take note that there are special 
requirements for responsiveness to this RFA (see Special Instructions for All 
Applicants), and the criteria for receiving award consideration by the NIEHS 
(see Review Criteria).


The administrative and funding instrument to be used for awards resulting from 
this RFA will be the National Institutes of Health (NIH) U19 Cooperative 
Agreement.  The total project period requested for applications responding to 
this RFA is five years.  A U19 mechanism provides support for both research 
project components and core facilities.  A cooperative agreement is an  
assistance mechanism (rather than an acquisition mechanism) in which 
substantial NIH scientific or programmatic involvement with the awardee is 
anticipated during the performance of the activity.  Under the cooperative 
agreement, the NIEHS=s role is to support and/or stimulate the recipient=s 
activity by working jointly with the award recipient as a partner, but it is 
not to assume direction, prime responsibility, or a dominant role in the 
activity.  Details of the responsibilities, relationships and governance of 
the studies to be funded under a cooperative agreement are discussed later in 
this document under the section Terms and Conditions of Award.  There is no 
intent, real or implied, for the NIEHS staff to direct awardee activities or 
to limit the freedom of awardee investigators in this regard.  Assistance via 
a cooperative agreement differs from the NIH research project grant in that 
the government component (NIEHS) awarding the cooperative agreement 
anticipates a partnership relationship that will enhance the efficiency and 
effectiveness of an awardee=s efforts.


The NIEHS has budgeted up to $5.5 million in estimated total costs to support 
the first year of all five to six awards made in response to this RFA and $7.5 
million is estimated for each of the subsequent four years of awarded support 
for this program.  The NIEHS expects to make at least five to six awards as a 
result of this RFA.  Because the nature and scope of the research posed in 
applications may vary, it is anticipated that the size of the awards will 
vary.  The number of awards and the level of awarded support depend on the 
receipt of a sufficient number of applications of high scientific merit.  
Although this RFA 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.  Unless otherwise noted, all NIH grant policies apply.  This RFA 
is a one-time solicitation.  The NIEHS has not yet determined whether this or 
a related RFA will be issued in the future to continue the program described 
in this RFA.  The anticipated award date is September, 2001.



Toxicogenomics is defined as a scientific field that studies how genomes 
respond to environmental stressors/toxicants.  Toxicogenomics combines genome-
wide mRNA expression profiling with protein expression patterns using 
bioinformatics to understand the role of gene-environment interactions in 
disease and dysfunction.

The use of DNA micro-array technologies to assess changes in gene expression 
is a rapidly growing research area that will have a large impact on many 
fields, including the environmental health sciences.  This technology will 
allow a paradigm shift in biology and toxicology as it allows a global 
perspective on how an organism responds to a specific stress, drug, or 
toxicant. Data generated in toxicogenomic studies will provide information on 
cellular networks of responding genes that will help define important target 
molecules associated with the toxicity mechanism, provide biomarkers for 
epidemiological studies, intensify research on alternative model testing 
procedures and support the development of new toxicity screening processes.  
Specifically, experiments using micro-array technology will help define the 
complex regulatory circuitry within a cell, tissue and organ that is 
responding to specific stressors.  This technology is particularly important 
because it may be able to help pinpoint locations and time points to 
effectively intercede in the cascade of biochemical and molecular events 
perturbed by environmental stressors and, thus, positively modulate the 
cellular response in a manner reducing or preventing adverse effects.  DNA 
micro-array technology will undoubtedly become a major tool in environmental 
medicine, for both diagnosis/prognosis determinations for specific diseases or 
dysfunctions and the examination of interacting drug sensitivities and 

It is envisioned that DNA microarray technologies will permit the design and 
execution of research in the environmental sciences that will clarify whether:
o  specific toxicants have unique gene expression profiling signatures,
o  different cells in different tissues have profoundly different responses to 
and signatures for a toxicant,
o  different animal species show similar, overlapping or distinct patterns of 
gene responses to a toxicant,
o  a specific toxicant signature is altered depending upon the stage in the 
developmental process or defined health conditions,
o  responses to complex mixtures can be more easily elucidated and defined by 
their gene expression profiling signatures,
o  response(s) to chronic low doses of (a) toxicant(s) or environmental 
pollutant(s) can be defined by gene expression profiling, and
o  specific gene polymorphisms can be defined that are characteristic of an 
increased susceptibility to the pathology leading to the morbidity and/or 
mortality of environmental health diseases or disorders.


The main objective of the Toxicogenomics Research Consortium (TRC) program is 
to establish a consortium of five or six Cooperative Research Members (CRMs), 
each with an established research infrastructure and research excellence in 
gene expression profiling technologies, that will conduct research within the 
mission responsibilities of the NIEHS as requested in this RFA.  The CRMs, 
operating within the Consortium program will address three main goals:
o  the enhancement of research in the broad area of global gene expression 
profiling as it relates to environmental stress responses,
o  the development of standards and practices which will allow validated data 
generation and management for inclusion in a public data base, and
o  contributions of data and expertise toward  the development of a robust 
relational data base of microarray gene expression data.

These CRMs will employ gene expression profiling for conducting studies that 
will elucidate basic biological pathways and their interactions with toxicant 
exposures, as well as defining how the entire genetic complement of an 
organism responds to environmental stressors/ toxicants.  Environmental 
stressors/toxicants include: chemicals, physical agents, and physiological 
stresses. The TRC will also directly contribute to the establishment of common 
guidelines for proper protocols and practice standards for the analysis of 
gene expression profiling data across different microarray platforms by 
contributing samples and data to a centralized resource contractor who will 
provide RNA analysis and bioinformatics support.  NIEHS will support through a 
Resource Contractor the RNA analysis and bioinformatics support activities 
associated with the development of the logistics for CRMs contributing to and 
accessing the relational database envisioned for the overall NIEHS 
toxicogenomics program.  These support activities will be independently put in 
place by the NIEHS for the benefit and use of the CRMs of the TRC.

Research Scope

The research scope of this TRC program broadly includes both basic and 
toxicological research activities.

Basic Research:
The Consortium members must have a very strong scientific presence in basic 
research utilizing gene expression profiling technologies and scientific 
expertise in one of the following basic science areas: cell cycle regulation, 
signal transduction, biological damage/stress response, cell death control, 
and developmental/differentiation mechanisms.  The research scope of each CRM 
must be broad enough to span work in two or more of the following organisms: 
yeast, Drosophilia, mouse, rat, and/or human.

Toxicological Research:
The scope of the research to be performed by the Consortium members must 
include a strong presence in an area of toxicological research exploring the 
mechanism of action of environmental agents that can be investigated using 
gene expression profiling technologies.

the Cooperative Research Member (CRM) described in this RFA are as follows 
(see also Review Criteria and Procedures below):
o  Competent and experienced principal investigator who is committed to and 
directly involved in using gene expression profiling in his or her research.
o  Availability of competent and experienced project leaders to direct 
individual research projects associated with the proposed CRM.
o  Availability of the fully operational technical resources and facilities 
necessary (core laboratories) for the conduct of the experiments.
o  Access to properly managed animal facilities for projects conducting animal 
o  Substantive evidence of departmental and institutional support for and 
commitment to the proposed Research Member.
o  Documented willingness to cooperate in a coordinated manner within the 
Toxicogenomics Research Consortium (TRC).
o  Documented willingness to carry out experimental toxicological studies 
designed by the consensus process of the TRC Steering Committee to be 
performed by members of the TRC, including providing materials and data from 
such toxicological research to the participating TRC members and, as deemed 
appropriate, to the NIEHS contracted gene expression analysis/bioinformatics 
support resource. 
o  Documented willingness to deposit toxicologically relevant data into public 
databases following procedures developed by the consortium in accord with the 
Steering Committee consensus process and extant applicable NIH grant policies 
in this regard.
o  A proposed overall CRM project structure consisting of:
(1) a minimum of two basic research projects with a minimum of one aim in each 
related to toxicology as described in this RFA, and

(2) core components representing at a minimum the administrative core, 
technical facility(ies) core(s) and toxicology research core as described in 
this RFA. 


I.  Definitions

COOPERATIVE RESEARCH MEMBER (CRM): The organized awardee infrastructure 
supporting a coordinated U19 program of NIEHS mission relevant research being 
conducted by an organized group of scientists.  CRMs consist of three 
components: basic research projects, a toxicology research core and facilities 
cores. In addition to the requisite toxicology research core and 
administrative core, a CRM has technical facilities cores (including a 
bioinformatics component).

TOXICOGENOMICS RESEARCH CONSORTIUM: An interacting consortium group comprised 
of the five or six U19 Cooperative Research Members awarded as a result of 
this RFA.

COOPERATIVE AGREEMENT: An assistance mechanism in which there is anticipated 
to be substantial programmatic involvement by NIEHS scientific program staff 
with the recipient organization during the performance of the planned 

AWARDEE: The institution to which the cooperative agreement is awarded.

PRINCIPAL INVESTIGATOR: The person who assembles the program, is responsible 
for submitting the application in response to this RFA, and is responsible for 
the administrative and scientific performance of the program.  The Principal 
Investigator will also oversee the progress on each of the basic and 
toxicological research projects, and will coordinate the activities of the 
projects and cores.

program staff scientist who coordinates the programmatic involvement of the 
NIEHS with the CRMs of the TRC.  The ETRC is a voting partnership member of 
the TRC Steering Committee.

ARBITRATION PANEL: A panel that is formed to review scientific or programmatic
disagreement(within the scope of the award) that may arise between award 
recipients and NIEHS.  It will be composed of three members: (i) a designee of 
the Steering Committee chosen without NIEHS staff voting, (ii) one NIEHS 
designee, and (iii) a third designee with relevant expertise who is chosen by 
the other two (in the case of an individual disagreement, the first member may 
be chosen by the individual awardee).  The Arbitration Panel will help resolve 
both scientific and programmatic issues that develop during the course of work 
and that restrict progress.

of Extramural Research and Training (DERT) is the extramural program component 
of the NIEHS that supports extramural research.  The DERT Working Group (DWG) 
is composed of program scientists from the NIEHS extramural program staff.  
The DWG membership consists of the NIEHS Toxicogenomics Consortium Research 
Coordinator, and four NIEHS Program Administrators, who have substantial 
scientific/programming advisory involvement regarding the conduct of the TRC 
activities.  The DWG is chaired by the NIEHS Toxicogenomics Research 
Coordinator (ETRC) member of the TRC Steering Committee.

committee of the TRC.  The TRC Steering Committee consists of the principal 
investigators and Toxicology Research Core Directors of each of the funded 
cooperative agreements, the NIEHS Extramural Toxicogenomics Research 
Consortium Coordinator, one science program staff representative of the NIEHS 
DERT Working Group (DWG), and one representative of the NIEHS Resource 
Contractor.  Each Steering Committee membership identified in this definition 
has one vote in the deliberations and actions of the Steering Committee.  The 
Steering Committee will meet on a bi-annual basis to set TRC performance 
priorities, evaluate performance milestones, and plan for the future 
coordinated experimental studies of the TRC.  The Steering Committee may add 
non-voting scientific advisors to provide expert opinions on specific subject 
areas as deemed necessary by its deliberations.

II.  Terms and Conditions of Award

The following terms and conditions will be incorporated into the U19 award 
statement, and will be provided to the Principal Investigator, as well as the 
appropriate institutional official, at the time of award.  Failure to abide by 
any of the TERMS AND CONDITIONS OF AWARD pertaining to awardee 
responsibilities as stipulated, may result in reduction of funding, 
withholding of support, or suspension or termination of award.

These special TERMS AND CONDITIONS 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 [Part 92 is applicable 
when State and local Governments are eligible to apply], and other HHS, NIH, 
and NIH grant administration policies.

A.  The administrative and funding instrument used for this program will be 
the Cooperative Agreement (U19).  The cooperative agreement is an assistance 
mechanism (rather than an acquisition mechanism), in which substantial NIH 
scientific and/or programmatic involvement with the awardee is anticipated 
during the 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 supported by a cooperative 
agreement resides with the awardee for the project as a whole, although 
specific tasks and activities in carrying out the study will be shared among 
the awardee(s) and the NIEHS.

B.  Awardee Rights and Responsibilities:

1.  The Principal Investigator is the scientist who is designated by the 
awardee institution to direct the CRM project.  The Principal Investigator 
will have primary authority and responsibility to define objectives and 
approaches, and to plan and conduct the proposed research.  The Principal 
Investigator will assume responsibility and accountability to the applicant 
institution and to the NIEHS for the performance and proper conduct of the 
research in accordance with the TERMS AND CONDITIONS OF AWARD.

The Principal Investigator of each Cooperative Research Member (CRM) will:
o  Manage the integration of the specific scientific projects.
o  Provide leadership for conducting the toxicology research core studies.
o  Oversee the management of the administrative and facilities core 
o  Provide yearly summaries of progress during the bi-annual Consortium 

2.  The Principal Investigator or designated representative will serve as a 
voting member of the TRC Steering Committee and will attend meetings as 

3.  As stated in the RFA, the Principal Investigator will be responsible for 
accepting the NIEHS TRC general and targeted goals, procedures, and policies. 
 Included, but not limited to, would be the transfer of gene expression 
profiling data to a third party, such as a NIEHS contract-based resource, for 
the purpose of developing and/or utilizing a public gene expression profiling 
relational database.  The TRC Steering Committee will set and evaluate 
specific yearly milestones for each Cooperative Research Member (CRM) 
Toxicology Research Core for their generation of data pertaining to the 
consortium conducted toxicology studies described under the special 
requirements section of this RFA.

4.  Awardees will retain custody of, and have primary rights to data developed 
under awards, subject to Government rights of access consistent with HHS, PHS, 
and NIH policies.  Under the terms of OMB circular A-110, data generated by 
grantees is now subject to the Freedom of Information Act.  Data and 
procedures for its use developed under the U19 may be considered unique 
research resources.  The policy of the PHS is to make available to the public 
results and accomplishments of activities that it funds.  All awardees must 
adhere to PHS policy for distribution of unique research resources produced 
with PHS funding, which was published at: 
Publication or oral presentation of work done under this agreement will 
require appropriate acknowledgment of NIEHS support: see Acknowledgment of 
Federal Funding (Section 507) in the Notice of Legislative Mandates Contained 
in the FY2000 Omnibus Appropriations at:
Dissemination of information, data or substances supplied by NIEHS will 
require clearance by NIEHS to assure conformity with any existing 
confidentiality agreements with the primary suppliers of such information, 
data or substances to the NIEHS.

5.  Possessory rights of physical materials acquired during the course of 
research rests with the applicant.  Prior to award, the applicant must 
formulate a policy for final disposition of such physical materials and 
ownership rights in the event that such physical materials are transferred to 
other parties who use them to make discoveries.

6.  The NIEHS recognizes that most countries retain interests in physical 
materials developed during the course of research within their domains.  In 
the event that an applicant includes a foreign project collaboration as a sub-
contract in the proposed CRM application, a formal statement of agreement, 
prior to an award, must be provided to the NIEHS, signed by an authorized 
representative of the applicant institution and that of the collaborators, if 
any, for equitable return of any profits or royalties derived from discoveries 
supported by the CRM award to indigenous peoples, research collaborators, 
cooperating institutions or governmental entities in the country of origin, as 
appropriate to their contributions.

C.  NIEHS Extramural Staff Responsibilities

1.  The NIEHS will select one extramural program staff scientist with 
appropriate expertise to serve as the NIEHS Extramural TRC Research 
Coordinator (ETRC) for the TRC.  During the performance of the award, through 
the ETRC, the NIEHS will participate in the TRC as a partner in the planning, 
prioritization, implementation, and technical scientific guidance of the 
tasked activities developed by the Steering Committee. The ETRC will have one 
independent vote on the TRC Steering Committee.  The ETRC is responsible for 
providing appropriate scientific and scientific program management assistance 
to the CRMs in support of and in accord with the tasked activities established 
by the TRC Steering Committee in its pursuit of fullfilling the obligations of 
the Terms and Conditions of Award established for each CRM.  The ETRC serves 
as the primary liaison for the TRC with the contracted support services and 
materials to be independently provided by the NIEHS.  It all cases the role of 
the ETRC will be to provide advisory scientific expertise and scientific 
program coordination of TRC research activities to assist and facilitate, but 
not to direct, these research activities.

2.  The NIEHS Extramural TRC Research Coordinator, as well as any other TRC 
group member, may assist in research planning, may suggest studies within the 
approved scope of the TRC objectives and research activities, may present to 
the TRC experimental findings from published sources or from contract projects 
in support of these suggestions, may participate in the design of experiments 
agreed to by the TRC, may advise on the selection and accessing of sources for 
resources, may advise in the scientific management and technical performance 
of the TRC research activities, and participate in the analysis of results 
achieved by these research activities.  The ETRC will not, however, directly 
conduct laboratory studies in the research activities being performed by the 

3.  Upon recommendation of the NIEHS Extramural TRC Research Coordinator, 
NIEHS may provide a CRM access to physical and/or intellectual resources from 
NIEHS contracted resources to support appropriate TRC activities when such 
resources are required to meet the Terms and Conditions for Award for a CRM.  

The following is a list of resources that may be supplied:
a.  Reference materials for standardization of analytical systems, as 
analytical standards, and for related purposes.
b.  Needed resources to ensure CRM data validation, such as test materials and 
c.  Data from testing/analyses conducted in the resource contract 
d.  Laboratory testing capacity in an NIEHS contract-based resource.
e.  Searches of computer files of materials, gene or gene expression 
profiling, or biological activity in an NIEHS contract supported database in 
accord with any confidentiality agreement between the Government and the 
supplier of such material or information.

4.  The ETRC will serve as the TRC liaison to the NIEHS= National Center for 
Toxicogenomics (NCT) Coordination Panel.  In this capacity, the ETRC 
represents and makes presentations on behalf of the TRC to a committee of 
NIEHS scientists that evaluates the overall effectiveness and achievements of 
the combined extramural, intramural and contract laboratories contributing to 
the overall national toxicogenomics program of the NIEHS.  The NCT 
Coordination Panel provides, through appropriate channels, recommendations to 
the Director, NIEHS, for evaluating future national directions and needs in 
Toxicogenomics research.  The NIEHS reviews such recommendations for a 
determination for NIEHS actions using a Toxicogenomics Advisory Committee of 
20-25 senior extramural scientists with relevant expertise in the fields of
toxicogenomics, proteomics, bioinformatics and toxicology, who are not 
Principal Investigators of a cooperative agreement involved in the 
Toxicogenomics Research Consortium supported as a result of this RFA.

5.  The NIEHS will select one Program Administrator from the NIEHS extramural 
program staff to administer the cooperative agreement awards for the CRMs of 
the TRC.  The TRC/CRM PA, who is separate and distinct from the ETRC, will 
provide the NIEHS stewardship of the cooperative agreement awards during the 
performance of the awarded research activities.  The Program Administrator 
will monitor the adequacy of each individual CRM awards progress annually and 
provide the usual grant stewardship and administrative assistance for each 
individual cooperative agreement.

The NIEHS retains the option for the TRC/CRM Program Administrator to 
recommend to the NIEHS Director the withholding or reduction of support or 
suspension or termination of funding for any project within a CRM of the 
Toxicogenomics Research Consortium that substantially fails to achieve its 
gene expression profile milestone goals. The NIEHS also retains the option for 
withholding or reduction of support or suspension or termination of funding 
for any CRM cooperative agreement that materially fails to comply with the 
Terms and Conditions of the award.

6.  The NIEHS Division of Extramural Research and Training (DERT) will form a 
DERT Working Group (DWG) with the following responsibilities.  The DERT 
working group will have substantial scientific and/or programmatic involvement 
with TRC during the conduct of this activity through technical assistance and 
technical coordination facilitation of collaborations with the DWG members 
administered resource sponsored or cosponsored programs of the NIEHS, 
including the NIEHS Environmental Genome Program, the Mouse Genome Project, 
the Pharmacogenetics Project and the Metabolic Toxicology Program.  
However, the role of the NIEHS will be strictly to assist and facilitate and 
not to direct the activities of the TRC or its CRMs.  It is anticipated for 
the TRC that decisions in all of its coordinated activities will be reached by 
consensus of the Toxicogenomics Research Consortium Steering Committee and 
that NIEHS will be given the opportunity to offer input to this process 
through the Extramural Toxicogenomics Research Coordinator and the DWG.  The 
DWG will be chaired by the NIEHS Extramural Toxicogenomics Research 
Coordinator and have four other NIEHS staff scientists as members appointed by 
the Director, DERT, NIEHS.  A representative member of the DWG shall 
participate in the TRC Steering Committee and will hold one vote on behalf of 
the DWG in the consensus deciding activities of that committee.  This vote is 
independent of the vote of the ETRC described in item number one above.  NIEHS 
staff will not have a majority of the votes in the TRC voting processes.  

The TCR DERT Working Group will:
o  Participate through its representative on the Steering Committee with the 
other Steering Committee members in the group process of setting research 
priorities, for the prescribed toxicological experiments, deciding optimal 
research approaches and protocol designs, and contributing to the adjustment 
of research protocols or approaches as warranted. The DWG participation will 
assist and facilitate the group consensus process and not direct it.
o  Attend all Steering Committee meetings with representation as a voting 
member and assist in developing research priorities, operating guidelines, 
quality control procedures, and consistent policies for dealing with recurrent 
situations that require coordinated actions by a the CRMs comprising a multi-
component, highly complex national cooperative research program.
o  Serve on subcommittees of the Steering Committee, as appropriate.
o  Assist in promoting the availability of the toxicogenomics data and related 
resources developed in the course of this project to the scientific community 
at large.

D.  Collaborative Responsibilities

The Principle Investigators and Toxicology Research Core Directors for the U19 
Toxicogenomic Research Consortium (TRC) cooperative agreement awards, the 
NIEHS Extramural TRC Research Coordinator, one representative of the TRC/DWG, 
and one scientist representative of the NIEHS Resource Contract will form a 
Togicogenomics Research Consortium Steering Committee.  A chairperson, not 
from the NIEHS, will be selected by majority vote of the TRC Steering 
Committee members.  The Steering Committee may, when deemed to be necessary, 
invite additional, ad hoc, non-voting advisors to the meetings.  Other NIEHS 
program staff, as appropriate, may attend the TRC Steering Committee meeting. 
 The TRC Steering Committee may, as deemed necessary, establish tasked 
subcommittees.  NIEHS program staff may serve on these subcommittees.  The TRC 
Steering Committee will meet at least twice annually. One meeting will be at 
the NIEHS in Research Triangle Park, NC and the second at a time and place 
agreed upon by the TRC Steering Committee.  The TRC Steering Committee will 
serve as the main governing board of the Toxicogenomics Research Consortium. 
An arbitration process will be established, as detailed further below, to 
resolve any disagreement that may arise between NIEHS program scientists and 
the non-government membership of the TRC Steering Committee.  The Steering 
Committee will be responsible for evaluating tasked activities progress within 
the Toxicogenomics Research Consortium, overseeing the toxicology research 
core studies, and monitoring CRM compliance with the Terms and Conditions of 
Award pertaining to these tasks.  The Steering Committee, as a group, will 
evaluate the data presented by individual Principal Investigators for the 
tasked activities of their CRM program.  The Steering Committee will assist 
and facilitate the development of uniform procedures for data quality 
assessment.  All CRMs will be required to accept and implement the common 
guidelines, procedures and standards approved by the Steering Committee in 
this regard.  Members of the Steering Committee will:
o  accept and participate in the cooperative nature of the group, and
o  attend bi-annual Steering Committee meetings to review results, evaluate 
data, check progress toward milestones, and conduct planning and prioritizing 
activities of the Toxicogenomics Research Consortium.

A planning meeting of the TRC Steering Committee will be convened by the NIEHS 
extramural program staff shortly after the U19 awards have been made.  At this 
meeting, a Chair will be selected and the group may:
o  draft a charter/operations manual that details policies and procedures and 
agree on the terms of this charter/operations manual,
o  determine a plan for scheduling the time and place of future meetings, and
o  review criteria for the validation of gene expression profile data for 
contributing data for inclusion in the NIEHS sponsored gene expression 
profiling relational database.  Subsequent meetings will conduct the Steering 
Committee functions described earlier in this section.

In summary, the purpose of the Toxicogenomics Research Consortium (TRC) 
Steering Committee is to apply its collective knowledge to accelerate the pace 
of discovery and characterization of gene expression profiles providing an 
identification of toxicant induced gene signatures associated with 
environmental disease or disorders.  Members of the TRC Steering Committee and 
their collaborators will participate in recommending guidelines and standards 
for the discovery and validation of global gene expression profiles of 
critical importance to environmental health sciences research.  Members of the 
TRC Steering Committee will have the advantage of access to resources, 
information, technologies, ideas, and expertise in multi-disciplinary areas to 
facilitate their research.  As validated data on global gene expression 
profiling is acquired, the NIEHS will provide a mechanism to ensure the 
dissemination of such information to the research community, with appropriate 
safeguards for the protection of intellectual property.  Ideally, the best-
case expected outcome from these cooperative, coordinated efforts would be the 
discovery of toxicant exposure gene signatures useful for designing 
therapeutic intervention or prevention strategies for reducing or eliminating 
an environmental disease or disorder.

E. Arbitration Panel

Any disagreement that may arise on scientific/programmatic matters (within the 
scope of the U19 award), between award recipients and the NIEHS Extramural 
Program staff may be brought to arbitration.  An Arbitration Panel will be 
convened composed of three members: one selected by the Toxicogenomics 
Research Consortium Steering Committee without NIEHS staff voting, a second 
member selected by the NIEHS, and a third member agreed upon by the other two. 
For U19 awardees, this special arbitration procedure in no way affects the 
awardee=s right to appeal an adverse action that is otherwise appealable in 
accordance with NIH regulations 42 CFR Part 50, Subpart D and HHS regulation 
at 45 CFR Part 16.


It is the policy of the NIH that women and members of minority groups and 
their subpopulations must be included in all NIH supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification is provided that inclusion is 
inappropriate with respect to the health of the subjects or the purpose of the 
research. This policy results from the NIH Revitalization Act of 1993 (Section 
492B of Public Law 103-43).

All investigators proposing research involving human subjects should read the 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research" published in the NIH Guide for Grants and Contracts on 
August 2, 2000 
A complete copy of the updated guidelines are available at  The 
revisions relate to NIH defined Phase III clinical trials and require: a) all 
applications or proposals and/or protocols to 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) all 
investigators to report accrual and to conduct and report analyses, as 
appropriate by sex/gender and/or racial/ethnic group differences.


It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects" research, conducted or supported by 
the NIH, unless there are scientific and ethical reasons not to include them. 
This policy applies to all initial (Type 1) applications submitted for receipt 
dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
NIH Policy and Guidelines on the Inclusion of Children as Participants in 
Research Involving Human Subjects that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 

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


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.  Reviewers are cautioned that their anonymity may be compromised when 
they directly access an Internet site.


The NIEHS strongly encourages all potential applicants to attend a pre-
application Technical Assistance Workshop (TAW) which will be held at the 
NIEHS in Research Triangle Park, NC. Since the concept of a cooperative 
Toxicogenomic Research Consortium is an entirely new concept for the NIEHS and 
the applicant population, this workshop will provide NIEHS staff the 
opportunity to clarify any perceived ambiguities in the RFA and, thereby, 
enable applicants to present their strongest case for support.  NIEHS 
encourages potential applicants to check its web site for future information:


Prospective applicants are asked to submit, by February 15, 2001, a letter of 
intent that includes a descriptive title of the proposed research, the name, 
address, and telephone number of the Principal Investigator, the identities of 
other key personnel and participating institutions, and the number and title 
of the RFA in response to which the application may be submitted.

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

The letter of intent should be sent to:

Linda K. Bass, Ph.D.
Scientific Review Administrator
Scientific Review Branch
Division of Extramural Research and Training
111 Alexander Drive
P.O. Box 12233
Research Triangle Park, NC 27709
Phone (919) 541-1307
Fax (919) 541-2503


The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for the U19 grants described in this RFA. These forms are available 
at most institutional offices of sponsored research and may be obtained from 
the Division of Extramural Outreach and Information Resources, National 
Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD
20892-7910, telephone 301/710-0267, E-mail:

The RFA label available in the PHS 398 (Rev 4/98) application form must be 
affixed to the bottom of the face page of the application.  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 (TOXICOGENOMICS RESEARCH 
CONSORTIUM) and number (ES-01-002) must be typed on line 2 of the face page of 
the application form and the YES box must be marked.   

The sample RFA label available at:
has been modified to allow for this change. Please note this is in pdf format.

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

BETHESDA, MD 20892-7710
or BETHESDA, MD 20817 (for express/courier service)

At the time of submission, two additional copies of the application and all 
the APPENDIX material must also be sent to:

Linda K. Bass, Ph.D.
Scientific Review Administrator
Scientific Review Branch (EC-30)
Division of Extramural Research and Training
111 Alexander Drive
P.O. Box 12233
Research Triangle Park, NC 27709
Phone (919) 541-1307
Fax (919) 541-2503

Applications must be postmarked by March 15, 2001.  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.


Applicants must consider and address the following in the preparation of 
applications called for in this RFA:

1.  Specific issues related to cooperative agreements must be addressed as 

a.  Special budget considerations.

Applicants must budget (i.e., based on a city centrally located in the USA) 
for travel and per diem expenses for the TRC Steering Committee meetings.  In 
the first year, applicants should plan for the Principal Investigator, two 
project investigators, and the director of the Toxicology Research Core to 
attend two TRC Steering Committee meetings.  In the second and subsequent 
years, applicants should plan for the Principal Investigator to attend two TRC 
Steering Committee meetings per year.

It is anticipated that the coordinated Toxicology Research Core activity will 
be at a basal level during the first year.  Applicants should budget 
proportionally more funding to the basic research projects and facilities 
cores in the first year and budget a 25 percent effort of a core director and 
one FTE technical support position for the Toxicology Research Core Facility 
in the first year.  Applicants should budget proportionally more of the 
increase from the first year to the second and subsequent years to increase 
the Toxicology Research Core budget to not less than $100,000 direct cost in 
years two through five.

b.  Special research considerations

Basic research projects included in the application for a CRM must have AT 
EXPOSURE TO A TOXICANT within the research scope described in this RFA (see 
also item 2b, 2b(i) and 2b(ii) below).

Applicants must include their specific plans for responding to the Terms and 
Conditions of Award section.  Applicants should state their willingness to 
collaborate and share data freely with the other TRC awardees, to participate 
in planning and to serve on the TRC Steering Committee and be bound by its 
decisions for setting the standards and guidelines for characterization and 
validation of global gene expression profiling results, and to be able and 
willing to share data and communicate with each other and the NIEHS in an 
internet environment.  Applicants should also describe how they would comply 
with the involvement of an NIEHS Extramural TRC Research Coordinator.

2.  Application format to follow

a.  The format outlined in the form PHS 398 kit should be followed except for 
the additional materials listed below which should be included in the 
indicated order after the LITERATURE CITED section.

i.  An overview of the CRM concept proposed

The Principal Investigator should provide a brief discussion (not to exceed 
two pages) of the functionally integrated concept for the CRM program proposed 
and how it will be responsive to the goals and objectives stated in this RFA 
for the Toxicogenomic Research Consortium.

ii. Documentation of gene expression profiling accomplishments.

The application must contain clear documentation of the applicant=s capacity 
to successfully and productively perform gene expression profiling 
technologies.  The total length for the presentation of this documentation 
should not exceed five pages.  Brief, concise statements are encouraged.  
Please focus these statements on past accomplishments, rather than future 
plans except as noted.  For the purposes of this RFA, completed data is 
defined as gene expression profile data produced in and by the research group 
included in the CRM application.  It is suggested that the following question 
regarding GENE EXPRESSION PROFILE PRODUCTION be considered in your response.  
 How does your group=s past effort support its ability/capacity to 
successfully accommodate this toxicogenomics project?  Discussion should 
include, but is not limited to:
o  Prior experience in hybridization and increasing throughput.
o  Prior experience in attaining milestones with regard to DNA microarray 
development (for example chip printing, hybridization schedules, and data 
analysis throughput).
o  Cost analysis of DNA microarrays, hybridization, and data analysis in terms 
of personnel and materials cost on a per unit chip cost.
It is suggested that graphical and tabular material may be the best means of 
presenting some of the relevant information, e.g.,
-  a graph indicating, for the past year (per month), the number and type of 
chips produced.

-  a graph indicating, for the past year (per month), the number and type of 
hybridizations attempted.
- a graph for the number and type of analyses performed.

iii. A statement of acceptance of NIEHS staff participation as described in 
NIEHS Extramural Staff Responsibilities.

iv. A statement by the Principal Investigator accepting participation on the 
TRC Steering Committee and implementing, if applicable, the goals, procedures 
and policies agreed upon by the TRC Steering Committee.

b.  Format for the CRM

The format outlined in the form PHS 398 kit should be followed.  The 
formatting of the application should take into consideration the expectation 
that a Cooperative Research Member should be structured to include:
o  Basic Research Projects (two to three minimum).
o  A Toxicology Research Core (one only)
o  An Administrative Core (one only).
o  Facility Cores (as required).

i.  Basic Research Projects should be organized in the standard PHS 398 format 
of an R01 proposal with sections for an abstract, specific aims, background 
and significance, preliminary results, experimental design and methods and 
references.  It is IMPORTANT to note that each Basic Research Project must 
have one Specific Aim that is directly related to research involving a 
toxicant exposure that is within the scope of this RFA.

ii. The Toxicology Research Core should be organized in the standard PHS 398 
format of an R01 proposal.  It is IMPORTANT to note that the research to be 
actually conducted by the Toxicology Research Core will be determined by the 
consensus process of the TRC Steering Committee during the first year of the 
awarded CRM.  The proposal for the Toxicology Research Core should therefor 
present a theoretical demonstration project that displays the potential of the 
research core.  The proposal should present a novel research idea to be 
investigated via a global toxicological gene expression profiling research 
project and should be organized in the standard PHS 398 format of an R01 
proposal with sections for an abstract, specific aims, background and 
significance, preliminary results, experimental design and methods and 


Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the program staff in the Division of Extramural Research and 
Training (DERT), NIEHS.  Incomplete and/or non-responsive applications will be 
returned to the applicant without further consideration.  As part of the 
initial merit review, a process may be used by the initial review group in 
which applications receive a written critique and undergo a process in which 
only those applications deemed to have the highest scientific merit, generally 
the top half of the applications under review, will be discussed and assigned 
a priority score.  The scored applications will receive a second level review 
by the National Advisory Environmental Health Sciences Council.

The specific points of consideration for completeness and responsiveness to 
the RFA are: (1) the appropriateness of the science proposed in regard to the 
mission of the NIEHS, and (2) the general completeness of the application 
including responsiveness to programmatic requirements and the organizational 
adequacy for review (this includes both scientific and budgetary 
considerations). The specific points of programmatic responsiveness to this 
RFA include: (1) documentation as requested in this RFA that investigators or 
groups of investigators in the application have performed and appropriately 
documented the performance of not less than 75 hybridizations using microarray 
gene expression profiling technology prior to the submission date for the 
application,(2) a proposed overall CRM project structure that includes a 
minimum of two basic research projects with a minimum of at least one specific 
aim in each project having a translational component to toxicological research 
(for example, a focus on the mechanism of action of one or more environmental 
agents), an administrative core that provides administrative services for the 
CRM, (a)technical facility core(s) providing instrumentation, bioinformatics 
and statistical support for the research, and a toxicology research core that 
supports the conduct of TRC coordinated toxicology research projects.  To 
ensure the goals of this RFA can be met, applications not containing the 
indicated hybridization documentation and/or overall CRM project structure 
described above will not be accepted by the NIEHS.
Applications that are complete and responsive to this RFA will be evaluated 
for scientific and technical merit by an appropriate peer review group 
convened by the Division of Extramural Research and Training of the NIEHS in 
accordance with the review criteria stated below.


The overall program application is evaluated by considering the research 
projects, supporting cores, and the administrative structure, and how these 
multi-disciplinary components function together to achieve the goals of the 
TRC program.  For the application to receive an overall priority score, it 
must consist of at least two approved research projects, each of which has 
multiple specific aims with at least one specific aim addressing a 
toxicological research issue and one Toxicology Research Core (found to have 
significant and substantial merit) for the full five year duration of the 
project period.

Specific scientific consideration factors to be evaluated in the consideration 
of the program are as follows:
o  Scientific merit of the program as a whole, as well as that of the 
individual parts.
o  Significance of the overall program goals.  This includes the significance 
and importance of the research program to furthering knowledge of gene 
expression profiling in environmental health sciences.
o  Scientific gain of combining the component parts into a CRM.  The 
appropriateness of the size of the program is an important consideration.
o  Cohesiveness and multidisciplinary scope of the program and the 
coordination and interrelationships of all individual research projects and 
cores to the common theme of using and improving gene expression profiling for 
biology and toxicology research via advances using applied microarray 
o  Leadership and scientific ability of the principal investigator and his or 
her commitment and ability to develop a well-defined central research focus 
and to devote adequate time and effort to work within the parameters of the 
TRC consortia.
o  Past accomplishments of the research team (Principal Investigator, Project 
and Core Leaders)in the proposed, including demonstrable experience of not 
less than 75 hybridizations for the application of gene array profiling to 
address biological issues.
o  Environment and resources in which the research will be conducted, 
including availability of space, equipment, human subjects, animals, or other 
resources as required, and the potential for interaction with scientists from 
other departments.

o  Institutional commitment to the requirements of the program, including 
fiscal responsibility and management capability of the institution to assist 
the Principal Investigator and his or her staff in following DHHS, PHS, and 
NIH policy.


The review of the individual Research Projects is similar to the review of 
individual project grant applications (RO1).  Accordingly, these projects must 
have substantial scientific merit.  The review criteria (Significance, 
Approach, Innovation and Environment) are intended to encourage reviewers to 
focus on the global impacts of each project and the program overall, rather 
than concentrating on the experimental details and their critiques.  

The review criteria are as follows:
o  Significance: Does this study address an important problem?  If the aims of 
the application are achieved, how will scientific knowledge be advanced?  What 
will be the effect of these studies on the concepts or methods that drive this 
o  Approach: Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of the 
project?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics? Does the project make maximal use of microarray 
technology to achieve its goals?
o  Innovation: Does the project employ novel concepts, approaches or method?  
Are the aims original and innovative?  Does the project challenge existing 
paradigms or develop new, methodologies or technologies?
o  Investigator: Is the investigator appropriately trained and well suited to 
carry out this work? Is the work proposed appropriate to the experience level 
of the principal investigator and other researchers?
o  Environment: Does the scientific environment in which the work will be done 
contribute to the probability of success?  Do the proposed experiments take 
advantage of unique features of the scientific environment or employ useful 
collaborative arrangements?  Is there evidence of institutional support?
o  When human subjects are involved, the adequacy of plans to include women 
and minorities in the study design and the potential of that design to address 
scientific question(s) proposed must be addressed.


o  Utility of the core to the CRM, each core should provide essential 
facilities or service for two or more projects judged to have substantial 
merit (e.g., the number of projects that will benefit from centralized 
administrative and research services, the economy of effort that will be 
realized through use of shared services, etc.)
o  Quality of the facilities or services provided by this core (including 
procedures, techniques, and quality control) and criteria for prioritization 
of usage.
o  Qualifications, experience and commitment of the personnel involved in the 
o  Appropriateness of the budget.


o  The general criteria for a technical facility core (immediately above) 
apply.  In addition, the following specific criterion also applies.
o   The scientific merit of a hypothetical prospectus project constructed to 
demonstrate how this toxicology research core would conduct a toxicological 
research project using gene expression profiling to investigate the 
environmental stress effects expressed in a biological system exposed to a 
defined toxicant.


For all applications, in addition to evaluating the scientific components, the 
review will also assess:
o  Administrative planning and leadership capability to provide for internal 
quality control of ongoing research, the research needs of the consortia, 
allocation of funds, enhancement of internal communication and cooperation 
among the investigators involved in the program, communication with the 
consortia, and replacement if the principal investigator if required on an 
interim or permanent basis.
o  Appropriateness of the budget in relation to the proposed core.
o  The decision making process within the proposed program for the evaluation 
of research productivity, allocation of funds, and management of the 
o  Whether the administrative core promotes joint planning and evaluation 
activities as well as collaborations and interactions among different research 
cores of the program.


Letter of Intent Receipt Date:  February 15, 2001
Application Receipt Date:       March 15, 2001
Peer Review Date:               June/July, 2001
Council Date:                   September, 2001
Earliest Anticipated Award:     September, 2001


Award criteria that will be used to make award decisions include:
o  scientific merit (as determined by peer review),
o  programmatic priorities, and
o  availability of funds.

An award will not be able to be offered for applications that do not have the 
following approved application components as a result of the peer review 
o  a minimum of two approved basic research projects, and
o  an approved Toxicology Research Core.
It should also be noted that Facilities Cores that do not serve at least two 
approved research projects will not be able to be funded as independent cores.


Inquiries are encouraged.  The opportunity to clarify any issues or questions 
from potential applicants is welcome.  Direct inquiries regarding programmatic 
issues to:

Michael E. McClure, Ph.D.
Chief, Organs and Systems Toxicology Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, MD EC-23
Research Triangle Park, NC 27709
Telephone:  (919) 541-5327
Fax:  (919) 541-5064

Direct inquiries regarding fiscal matters to:

Ms. Jackie Russell
Grants Management Specialist 
Grants Management Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, MD EC-22
Research Triangle Park, NC 27709
Telephone:  (919) 541-0751
Fax:  (919) 541-2860


This program is described in the Catalog of Federal Domestic Assistance No. 
93.113 and 93.866.  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, 42 USC 241 and 285) and administered under NIH grants policies and 
Federal Regulations 42 CFR 52 and 45 CFR Part 74 and 92.  This program is not 
subject to the intergovernmental review requirements of Executive Order 12372 
or Health Systems Agency review.

The PHS encourages all grant and contract recipients to provide a smoke-free 
workplace and promote the non-use of tobacco products.  In addition, Public 
law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain 
facilities (or in some cases, a 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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Bethesda, Maryland 20892
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