MEMORANDUM OF UNDERSTANDING
ON
High Throughput Screening, Toxicity Pathway Profiling,
and Biological Interpretation of Findings
BETWEEN THE
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES (HHS)
NATIONAL INSTITUTES OF HEALTH (NIH)
National Institute of Environmental Health Sciences (NIEHS)/
National Toxicology Program (NTP)
AND THE
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES (HHS)
NATIONAL INSTITUTES OF HEALTH (NIH)
National Human Genome Research Institute (NHGRI)
NIH Chemical Genomics Center (NCGC)
AND THE
U.S. ENVIRONMENTAL PROTECTION AGENCY (EPA)
Office of Research and Development
I. PURPOSE/OBJECTIVES/GOALS
This Tripartite Memorandum of Understanding (MOU) sets in place mechanisms to strengthen
the existing collaborations that utilize the complementary expertise and capabilities of the
NIEHS/NTP, the NCGC of the NHGRI, and the Office of Research and Development (ORD) of
the EPA in the research, development, validation, and translation of new and innovative test
methods that characterize key steps in toxicity pathways. A central component of this MOU is
the exploration of high throughput screening (HTS) assays and tests using phylogenetically
lower animal species (e.g., fish, worms), as well as high throughput whole genome analytical
methods, to evaluate mechanisms of toxicity. Ultimately, the data generated by these new tools
is to be provided to risk assessors to use in the protection of human health and the environment.
The goals of this MOU are to investigate the use of these new tools to (1) identify mechanisms of
chemically induced biological activity, (2) prioritize chemicals for more extensive toxicological
evaluation, and (3) develop more predictive models of in vivo biological response. Success in
achieving these goals is expected to result in test methods for toxicity testing that are more
scientifically and economically efficient and models for risk assessment that are more
biologically based. As a consequence, a reduction or replacement of animals in regulatory
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testing is anticipated to occur in parallel with an increased ability to evaluate the large numbers
of chemicals that currently lack adequate toxicological evaluation.
II. BACKGROUND
For several years, EPA and NIEHS have recognized the need to modify the scientific basis for
hazard identification and risk assessment by working toward partially or fully replacing current
test methods with higher throughput, mechanism-based test methods. This recognition led both
organizations to initiate programs to evaluate using in vitro biochemical- and cell-based assays
and non-rodent animal models for toxicological testing. In 2004, the NTP released its Vision
and Roadmap for the 21st Century (http://ntp.niehs.nih.gov/go/vision), which established an HTS
initiative to focus on integrating HTS and non-rodent screening assays into its testing program.
In 2005, the EPA established the National Center for Computational Toxicology (NCCT) within
ORD to bring innovative molecular biological and computational tools to the evaluation of
hazards and risks of environmental chemicals. To accomplish its mission, the NCCT works
closely with ORD鈥檚 National Health and Environmental Effects Research Laboratory
(NHEERL), which conducts related laboratory, clinical, and epidemiological research. The NTP
Vision for the 21st Century and the goal of the ORD are to support the evolution of toxicology
from a predominantly observational science at the level of disease-specific models to a
predominantly predictive science focused upon a broad inclusion of target-specific, mechanism-
based, biological observations. The NCGC, one of the centers of the Molecular Libraries
Screening Centers Network (MLSCN) within the NIH Roadmap for Medical Research
Molecular Libraries Initiative, has been a key collaborator with both the NTP and EPA in this
process. The NIH established the NCGC in 2004 as a national resource for chemical probe
development and compound profiling using industrial-scale HTS assays, informatics, and
chemistry.
In 2005, the EPA with support from the NTP funded a project at the National Research Council
(NRC) to develop a long-range vision for toxicity testing and a strategic plan for implementing
the vision. The impetus for this project was a strong commitment by both agencies that future
toxicity testing and assessment paradigms meet evolving regulatory needs (e.g., that the
paradigms readily accommodate the increasingly large numbers of substances that need to be
tested); incorporate the recent advances in molecular toxicology, computational sciences, and
information technology; and offer increased efficiency in design, costs, and animal usage. In
response, the NRC Committee on Toxicity Testing and Assessment of Environmental Agents
recently released a vision and implementation strategy titled A Vision for Toxicity Testing in the
Twenty-first Century (NRC 2007). This report is a powerful catalyst for a focused and
collaborative effort across the research community to: (1) develop a more robust scientific basis
for assessing potential adverse health effects of environmental agents; (2) provide broad
coverage of chemicals, chemical mixtures, outcomes, and life stages; (3) use population-based
and human exposure data to inform decisions regarding chemical selection and environmentally
relevant testing conditions; (4) reduce the cost and time of toxicity testing; and (5) use laboratory
animals in targeted testing where essential data are needed and cannot be appropriately obtained
in vitro or using phylogenetically lower animal species.
The convergence of science, technology, regulatory need, and public opinion has produced an
historic opportunity to transform toxicology and risk assessment into more accurate, rapid, and
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cost-effective sciences. In recognition of the need for a long-term, multiple Federal agency
commitment, this MOU is being established to guide the construction and governance of a
detailed research strategy to make the NRC Committee鈥檚 vision a reality. This MOU builds on a
number of separate and joint efforts among our three organizations that are very much aligned
with the NRC Committee鈥檚 vision. Building on the strengths of the individual organizations is
intended to facilitate the advancements necessary to move toxicology to a more predictive
science based on the most relevant and meaningful tools of modern molecular biology and
chemistry.
III. AUTHORITIES
EPA enters into this MOU pursuant to Section 103 of the Clean Air Act [42 U.S.C. 搂7403 (a)
and (b)]; Section 104 of the Clean Water Act [33 U.S.C. 搂 1254 (a) and (b)]; Section 300 j-l of
the Safe Drinking Water Act (42 U.S.C. 搂1442); Section 10 of the Toxic Substances Control Act
[15 U.S.C. 搂 2609 (a)]; and Section 20 of the Federal Insecticide, Fungicide, and Rodenticide
Act [7 U.S.C. 搂 136r (a)].
NIEHS enters into this MOU pursuant to Sections 301, 401, and 463 of the Public Health Service
Act [42 U.S.C., 搂搂 241, 281, and 285l].
NHGRI enters into this MOU pursuant to Section 301 of the Public Health Service Act [42
U.S.C. 搂 241].
IV. ROLES AND RESPONSIBILITIES
Each participant intends to implement the following provisions of this MOU, under the
responsibility of the Assistant Administrator for ORD and the Directors of the NTP and the
NCGC.
A. Toxicity Pathways: A shared focus of all participants is to identify and/or develop HTS
assays that investigate 鈥渢oxicity鈥? pathways. To this end, the three organizations agree to
collaborate to identify toxicity pathways that contribute to a variety of adverse health outcomes
(e.g., from acute oral toxicity to long-term effects like cancer) and assays that provide
information on key steps in those pathways. All participants agree that this aim will best be
accomplished through joint meetings, by seeking advice from acknowledged experts in different
disciplines in the international scientific community, and through specialized workshops. The
three organizations agree to identify data gaps where research and development are needed to
modify existing assays (e.g., incorporation of metabolic competency) or to develop new assays
designed to allow a more comprehensive evaluation of how compounds interact with key steps in
critical toxicity pathways. Once the pathways and assays are identified, the NCGC agrees to
develop suitable HTS assays, or utilize the MLSCN assay development program and/or various
government supported research and development programs (e.g., the Small Business Technology
Transfer/Small Business Innovation Research program) to do so.
B. Chemical Selection: The participants agree that large numbers of compounds with existing
toxicological data need to be identified and tested in the identified HTS assays and alternative
animal models. The NTP and the EPA have databases of toxicological information on a large
number of compounds. The EPA also has models and databases for determining whether
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exposures are likely to occur, at what level, and by what route. The EPA and NTP agree to share
toxicity and exposure information on compounds selected for testing and to collaborate, where
deemed useful, on identifying compounds for testing. The EPA and NTP also plan to make
appropriate efforts to ensure, as a means for evaluating endpoint reproducibility, some degree of
overlap between the chemical libraries under study. The EPA, NCGC, and NTP agree to jointly
determine appropriate quality assurance/quality control procedures for the compounds chosen for
testing.
C. Analysis and Bioinformatics: Analysis of individual HTS assay results (i.e., identifying
active and inactive compounds for a particular assay) and bioinformatics (i.e., evaluating sets of
data from multiple in vitro and in vivo assays while taking into account chemico-physical
properties for significant relationships) are critical to the success of the joint initiative. As a
result, the three organizations agree to: collaborate on the development of the most appropriate
tools for the analysis of HTS data, share data (both HTS as well as that generated using
traditional test methods), and work to make all the data publicly accessible. The EPA, NTP, and
NCGC agree to employ computational approaches to evaluate the information from HTS studies.
The NTP or NHEERL agree to undertake targeted in vivo follow-up studies when appropriate.
The organizations also agree to consider the use of extramural mechanisms to support these
activities. Proof-of-concept studies will be important to demonstrate the feasibility of the new
approach and their undertaking will require a critical level of effort across the institutions. It is
envisioned that these efforts will evolve towards a systems-biology approach as a foundation for
constructing and using biologically based dose-response models in risk assessment. Regulatory
acceptance of these new approaches will take considerable thought and effort. Therefore, an
important consideration will be the translation of the results of this joint research program into
testing strategies that provide data useful to risk assessors.
D. Outreach: Effective and open communication about this research program, its findings and
their use will be important to its acceptance and ultimate success. The three organizations agree
to conduct joint outreach activities related to the development and use of HTS and other
innovative approaches for assessing toxicity. Such activities might include activities:
鈥? Sponsoring relevant workshops (e.g., to identify the key toxicity pathways for various
organ systems or to develop best practices for analysis of the new data streams).
鈥? Organizing symposia that focus on advances in the area of HTS for toxicity testing and
systems-biology models for integration and interpretation of the data.
鈥? Co-sponsoring a seminar series that addresses key advancements in HTS or translation of
HTS data into phenotypic outcomes that would form the basis for more mechanistically
based risk assessment practices.
鈥? Contributing via presentations and posters to national and international meetings.
鈥? Co-authoring articles to keep the scientific community informed of progress and
advances in this research program.
鈥? Continuing to interact via joint meetings of the EPA Chemical Prioritization Community
of Practice (CPCP), the NCGC, and the NTP HTS Faculty.
鈥? Promoting the regulatory acceptance of alternative approaches when deemed
scientifically defensible.
E. Governance: The activities identified in this MOU are to be managed by a Governance
Board (GB) composed of the Director of the NCGC, the Director of the EPA/ORD National
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Center for Computational Toxicology, and the Branch Chief of the NTP Biomolecular Screening
Branch. The members of the GB, with advice from their management, are to be responsible for
developing and implementing a cross-organizational research strategy, promoting cross-
organization interactions, identifying and recommending actions to overcome barriers to success,
ensuring minimal redundancy of activities, serving as spokespersons for the tripartite effort
within and outside their respective organizations, and reporting on the overall progress of the
program to their respective organizations at periodic intervals. The GB is expected to meet by
teleconference or in person at least once every two months.
F. Scientific Review: The activities carried out by the EPA, NTP, and the NCGC in support of
this MOU will be reviewed at regular intervals (initially, approximately every six months) by
their respective review panels. For the NCGC, this is the NCGC Working Group, which reports
to the NHGRI Board of Scientific Counselors. For the NTP and the EPA, this is their respective
Boards of Scientific Counselors.
V. LIMITATIONS
All commitments made in this MOU are subject to the availability of appropriated funds and
each party鈥檚 research priorities. Nothing in this MOU, in and of itself, obligates any participant
to expend appropriations or to enter into any contract, assistance agreement, interagency
agreement, or other financial obligation.
This MOU is neither a fiscal nor a funds obligation document. Any endeavor involving
reimbursement or contribution of funds between the participants to this MOU will be handled in
accordance with applicable laws, regulations, and procedures and will be subject to separate
subsidiary agreements that will be effected in writing by representatives of the participants.
Except as provided in this Section (Section V, LIMITATION) and Section VII,
INTELLECTUAL PROPERTY, this MOU is not legally binding and does not create any right or
benefit, substantive or procedural, enforceable by law or equity against the NIH/NIEHS/NTP,
the NIH/NHGRI/NCGC, or the EPA.
VI. PROPRIETY INFORMATION
Not applicable as all participants are Federal agencies.
VII. INTELLECTUAL PROPERTY
The parties agree that inventorship of any patentable matter, created by any of the participants
pursuant to the terms of this MOU, will be determined in accordance with U.S. patent laws.
Ownership will follow inventorship and vest in the inventors or their employers as determined by
contract or law.
The participants agree to notify each other when joint-authoring a journal article that includes a
non-government employee as a co-author. In such cases, the participants should ensure that all
necessary rights under copyright are acquired to the satisfaction of all parties.
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VIII. POINTS OF CONTACT
The following individuals are designated points of contact for the MOU:
NIEHS/NTP:
Raymond Tice, Ph.D.
Acting Branch Chief
Biomolecular Screening Branch
National Toxicology Program
National Institute of Environmental Health Sciences
Mail Drop EC-17
P.O. Box 12233
Research Triangle Park, NC 27709
Tel. 919-541-4482
Fax. 919-541-0947
email: tice@niehs.nih.gov
NCGC:
Christopher P. Austin, M.D.
Director, NIH Chemical Genomics Center
National Human Genome Research Institute
National Institutes of Health
9800 Medical Center Drive, MSC 3370
Bethesda, MD 20892-3370
Tel: 301-217-5733
Fax: 301-217-5736
email: austinc@mail.nih.gov
EPA/ORD:
Robert J. Kavlock, Ph.D.
Director, National Center for Computational Toxicology
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Tel: 919-541-2326
Fax: 919-541-1194
email: kavlock.robert@epa.gov
IX. MODIFICATION/DURATION/TERMINATION
This MOU is to take effect upon signature of all participants and remain in effect for a period of
five years, unless the participants decide otherwise in writing. This MOU may be amended at
any time by the mutual written consent of the participants. Additionally, the participants agree to
review this MOU annually to determine whether it should be revised, renewed, or cancelled. A
participant may terminate its participation in this MOU by providing written notice to the other
participants at least thirty (30) days in advance of the desired termination date.
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X. APPROVALS
National Toxicology Program U.S. Environmental Protection Agency
/Samuel H. Wilson/ /George M. Gray/
Samuel H. Wilson, M.D. George M. Gray, Ph.D.
Acting Director Assistant Administrator
National Institute of Environmental Office of Research and Development
Health Sciences
National Institutes of Health
National Toxicology Program
___December 17, 2007_________________ ______Janaury 8, 2008____________________
Date Date
NIH Chemical Genomics Center
/Francis S. Collins/
Francis S. Collins, M.D., Ph.D.
Director
National Human Genome Research Institute
National Institutes of Health
_____January 30, 2008__________________
Date
/Eric D. Green/
Eric D. Green, M.D., Ph.D.
Scientific Director
Division of Intramural Research
National Human Genome Research Institute
National Institutes of Health
____Janaury 24, 2008_________________
Date
Proper Signatures
Treat as signed, 搂 1.4(d)(2)
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