Full Text ES-97-003
 
CANCER AND TEFS FOR DIOXIN AND DIOXIN-LIKE CHEMICALS
 
NIH GUIDE, Volume 26, Number 13, April 25, 1997
 
RFA: ES-97-003
 
P.T. 34

Keywords: 
  Toxicology 
  Cancer/Carcinogenesis 
  0705048 

 
National Institute of Environmental Health Sciences
 
Letter of Intent Receipt Date: June 6, 1997
Application Receipt Date:  July 9, 1997
 
PURPOSE
 
Environmental health research carried out by the National Institute
of Environmental Health Sciences (NIEHS) provides a solid scientific
foundation for understanding interrelationships between the
environment, genetics and temporal factors as they relate to human
disease and dysfunction.  The NIEHS Division of Extramural Research
and Training is responsible for developing and directing the
investigator-initiated hypothesis-driven mechanistically-based
research related to the NIEHS mission. Research conducted by the
National Toxicology Program (NTP), centered at the NIEHS, focuses on
the evaluation of environmental/industrial agents for their toxic
effects using a broad array of test systems and generates data to
strengthen the scientific foundations for risk assessment.
 
The goal of this Request for Applications (RFA) is to provide data to
aid the NIEHS in defining the mechanisms of action of agents under
study by the NTP to improve the risk assessment process, and,
thereby, better protect the public health.
 
Therefore, the NTP and the Division of Extramural Research and
Training, have designed a program to improve collaboration between
government and non-government scientists, thereby providing
broad-based input into this process.
 
This program, as outlined in this RFA, utilizes the R03 Small Grants
Program to encourage investigator-initiated applications that will
utilize animals/tissues/cells or sera from an NTP study involving
exposure to dioxin-like chemicals.  It is anticipated that this
investigator-initiated research will complement the NTP study on
dioxin and dioxin-like compounds by providing additional information
on their mechanism(s) of action.
 
HEALTHY PEOPLE 2000
 
The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This RFA,
Cancer and TEFs for Dioxin and Dioxin-like Chemicals is related to
the priority area of environmental health.  Potential applicants may
obtain a copy of "Healthy People 2000" (Full Report: Stock no.
017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through
the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone: (202) 512-1800).
 
ELIGIBILITY REQUIREMENTS
 
Applications may be submitted by domestic, for-profit and non-profit
organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State or local governments and
eligible agencies of the Federal government.  Foreign institutions
and organizations are not eligible.  Applications from minority
individuals and women are encouraged.  Submission of an application
precludes concurrent submission of a regular research grant
application (R01 or R29) containing the same research proposal.  In
addition, small grant research support may not be used to supplement
research projects currently supported by Federal or non-Federal funds
or to provide interim support for projects under review by the Public
Health Service.
 
MECHANISM OF SUPPORT
 
This RFA will use the NIH Small Grants Program (R03) awards.
Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant.  The requested
costs and project period will be a maximum of $50,000 (direct cost)
for a maximum of one year.  Small grants are not renewable but may be
extended for an additional year with no additional funds at the
discretion of the applicant organization.
 
FUNDS AVAILABLE
 
The total estimated funds available for this small grants program is
$400,000 which will support approximately six (6) to eight (8)
awards. This level of support is dependent on the receipt of a
sufficient number of applications of high scientific merit.  Although
this program is provided for within the financial plans of the
NIEHS/NTP, awards pursuant to this RFA are contingent upon the
availability of funds for this purpose.
 
RESEARCH OBJECTIVES
 
Background
 
The delineation of human cancer risk following exposure to mixtures
of chemicals have been difficult to quantify due to the lack of
validated models.  One methodology used is the Toxic Equivalency
Factor (TEFs). The TEF methodology is a relative potency scheme for a
strictly defined class of chemicals, namely the 2, 3, 7, 8-chlorine
substituted dibenzo-p-dioxin and dibenzofurans.  These chemicals are
structurally-related and produce the same spectrum of toxic effects
in animals.  These chemicals bind to the aryl hydrocarbon (Ah)
receptor and the subsequent activation of this receptor leads to a
cascade of biochemical and toxic effects.  There are limited data on
the relative carcinogenic potency of almost all of these chemicals
since only dioxin and a mixture of  hexachlorodibenzo-p-dioxins have
been tested.  Hence the ability of these relative potency factors to
predict the cancer risk of mixtures of these chemicals has been
questioned.
 
The TEF methodology does not include the interactions of dioxin-like
chemicals with nondioxin-like chemicals.  Since human exposures are
to mixtures containing both dioxin-like and nondioxin-like chemicals,
in order for the TEF methodology to accurately predict the risk of
cancer or other endpoints, it must be expanded to include both
dioxin-like and nondioxin-like chemicals, singly and in mixtures.
 
Research Goals
 
In order to determine whether the TEFs currently used for dioxin and
dioxin-like chemicals are valid for the chemicals tested singly or in
mixtures, the NTP proposes to test the following chemicals/mixtures
in a two year bioassay:
 
o  2,3,7,8 tetrachlorodibenzo-p-dioxin (cas#74601-6)
o  1,2,3,7,8 pentachlorodibenzo-p-dioxin (cas#40321-76-4)
o  2,3,4,7,8 pentachlorodibenzofuran (cas#57117-31-4)
o  3,31,4,41,5 pentachlorobiphenyl(PCB126) (cas#57465-28-8)
o  2,21,4,41,5,51 hexachlorobiphenyl (PCB153)(cas#35065-27-1)
 
Each chemical will be tested individually.  A mixture containing all
four chemicals and a binary mixture of dioxin and PCB153 will also be
tested.
 
The objective of these NTP studies is to test the following
hypotheses:
 
o  The USEPA interim TEFs for dioxins, dibenzofurans and PCBs can
predict the relative carcinogenic potency of single congeners in
female Sprague-Dawley rats.
 
o  The USEPA interim TEFs for dioxins, dibenzofurans, and planar PCBs
can predict the relative carcinogenic potency of an environmentally
relevant mixture of these chemicals in the female Sprague-Dawley rat.
 
o  The carcinogenicity of a dioxin is not altered by the presence of
a nondioxin-like PCB.
 
o  The relative potencies for biochemical endpoints, such as CYP1A1
induction, in the two-year studies are equivalent to the relative
potency for carcinogenesis when estimated based on administered dose.
 
o  The relative carcinogenic potencies of the individual congeners,
based on target tissue dose, are the same as the relative potencies
based on CYP1A1 induction using the same-target tissues.
 
o  The relative carcinogenic/biochemical potencies based on
administered dose are the same as those based on tissue dose.
 
o  The relative potencies based on serum or whole blood
concentrations are equivalent to administered dose and target tissue
dose.
 
To aid the NTP in developing the scientific data set necessary to
substantiate these hypotheses and to provide additional information
on the mechanism of tumor development by these agents or on the sites
or mechanisms of additional toxicities of these chemicals/mixtures,
the NTP, in coordination with the Division of Extramural Research and
Training,  proposes to add additional investigator-initiated studies
from this RFA to these studies.
 
Projects that will provide additional support for these hypotheses
are requested.  They include but are not limited to proposals that
will:
 
o Establish the relationship between changes in tissue receptor
levels for estrogen, epidermal growth factor or glucocorticoids and
time, dose, chemical/mixture and TEF of chemicals.
 
o Establish the relationship between measurements of tissue oxidative
stress, tissue vitamin A metabolism, liver induction of porphyrins or
other aspects of the pleotrophic action of dioxin-like chemicals and
time, dose, chemical/mixture and TEF of chemical.
 
o Establish the relationship between changes in the activity of cell
cycle regulatory proteins like CDC2 or the protooncogene SRC and
time, chemical/mixture and TEF of chemical.
 
o Characterize the immunotoxicity of these chemicals singularly or in
mixtures proposed and its relation to time, dose, carcinogenicity and
TEF.
 
o Characterize the reproductive, neuro- and other non-cancer organ
toxicity of these chemicals/mixtures and their relationship to
carcinogenicity and the TEFs.
 
Research proposed needs to be hypothesis driven,
mechanistically-based and must be justified as to how the animals
from this NTP study are unique in providing tissues needed for the
studies proposed and how the studies can be accomplished within the
budget and personnel proposed.
 
Study Design Considerations
 
A detailed statement of work, including test doses and tissues that
will be analyzed by the NTP as well as special groups of animals
available for investigator-initiated studies under this RFA, may be
obtained from the NIEHS home page at the following address:
http://www.niehs.nih.gov/dert/dioxin.htm
 
The following additional information is intended to complement the
information found on the web-site.
 
o Tissues and sera from the "grantee" animals will be shared by those
successful applicants to this RFA.  Applicants should check with NTP
(see inquiries section) for tissue/sera availability before
finalizing their proposals and also take into account sharing
tissues/sera with the NTP and other investigators.
 
o Investigators must, in their proposal, be specific as to number of
animals/tissues/cells/sera needed, preparation of tissues needed,
doses needed, shipping requirements and ages (104 weeks or interim).
Investigators requiring fresh tissues should fully define the tissue
and shipping requirements.  Attendance to the necropsy may be
impractical depending on the extent of the study proposed.
 
o Since these seven (7) studies will probably start one or more
months apart, it will take a minimum of 18 months for the conclusion
of the 52-week necropsies.  Investigators must state in the
application how they will account for this time factor in their study
design and explain how they will analyze and control for variability
of time (fresh or frozen) of samples, i.e., show a time-line of
tissue availability and analysis with proper controls (will samples
be collected and analyzed together or monthly?).
 
o Because of the nature of the R03 Program (i.e., two-year maximum
time frame; one year grant with one year no-cost extension) it will
not be practical to design a study that encompasses the 13, 30, 52
and 104 week necropsies.  Thus, investigators should concentrate on
the 13, 30 and 52 week times or specify other times points needed.
 
o Proposals need not cover all seven (7) studies or all time points
or all dose levels.  Investigators should carefully examine the
protocol and design a proposal to specifically address a particular
question related to the hypothesis being tested using the minimum
number of animals, chemicals and necropsy times needed.
 
Investigators are requested to set aside funds for a trip to NIEHS to
discuss their results and to be prepared to integrate their results
into an NTP final report.  Inclusion of data in the NTP final report
would not preclude independent publication.  The
investigator-initiated work may be published independently at the
discretion of the investigators. Investigators may also have access
to NTP data on, for example, blood, tissue, adipose tissue levels of
chemicals which may be needed for analysis and interpretation of
their data.
 
SPECIAL REQUIREMENTS
 
LETTER OF INTENT
 
Prospective applicants are asked to submit, by June 6, 1997, 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,  participating institutions,
and the number and title of the RFA in response to which the
application may be submitted.  Although a letter of intent is not
required, is not binding, and does not enter into the review of
subsequent application, the information that it contains is helpful
in planning for the review of applications.  It allows NIEHS staff to
estimate the potential review work load and to avoid conflict of
interest in the review.
 
The letter of intent is to be sent to:
 
Ethel B. Jackson, D.D.S.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, MD 17-09
111 T.W. Alexander Drive
Research Triangle Park, NC 27709
Telephone: (919) 541-7826
FAX: (919) 541-2503
EMAIL: jackson4@niehs.nih.gov
 
APPLICATION PROCEDURES
 
The research grant application form PHS 398 (rev. 5/95) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research and may be obtained from
the Office of Grants Information, Division of Research Grants,
National Institutes of Health, 6701 Rockledge Drive, Room 3034, MSC
7762, Bethesda, MD 20892-7762, telephone 301/435-0714, EMAIL:
girg@drgpo.drg.nih.gov.
 
THE FOLLOWING ARE SUPPLEMENTAL INSTRUCTIONS:
 
o  The application must detail the specific budget categories and
percent efforts that will be required.  This will be a $50,000
maximum award - direct cost.  The budget must be justified. Equipment
will be limited to $5,000.
 
o  The applicant must be explicit in describing the proposed
interface between the NTP study design and the proposed project.
 
o  Preliminary data are not required except to indicate the expertise
of the Principal Investigator to carry out the proposed studies.
 
o  The Research Plan (Specific Aims, Background and Significance,
Preliminary Studies, Research Design and Methods sections) is not to
exceed Ten (10) pages.  Tables and figures are included in the
Ten-page limitation.  Applications that exceed page limitations or
PHS 398 requirements for font size (height or letters), type density
(characters per inch), and margins (see PHS 398 directions) will be
returned to the investigator.
 
o  Do not submit an appendix.
 
The RFA Label available in the PHS 398 (rev. 5/95) application form
must be affixed to the bottom of the face page of the application.
Failure to use this label could result in delayed processing of the
application such that it may not reach the review committee in time
for review.  In addition, the RFA title and number must be typed on
Line 2 of the face page of the application form and the YES box must
be marked.
 
Submit a signed, typewritten original of the application, including
the checklist, and three signed, clear, and single-sided photocopies
in one package to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)
 
At the time of submission, two additional copies of the application
must be sent to Dr. Ethel Jackson, Chief, Scientific Review Branch
(see address below). If these two additional copies are not forwarded
to Dr. Jackson, it will adversely affect the review of the grant
application.
 
Ethel Jackson, D.D.S.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, MD 17-09
111 T.W. Alexander Drive
Research Triangle Park, NC 27709-2233
Telephone: (919) 541-7846
FAX: (919) 541-2503
EMAIL: jackson4@niehs.nih.gov
 
Applications must be received by July 9, 1997.  If an application is
received after that date, it will be returned to the applicant
without review.  The Division of Research Grants (DRG) will not
accept any application in response to this RFA that is essentially
the same as one currently pending initial review, unless the
applicant withdraws the pending application.  The DRG will not accept
any application that is essentially the same as one already reviewed.
 
This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an
introduction addressing the previous critique.
 
REVIEW CONSIDERATIONS
 
Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the NIEHS in accordance with NIH peer review
procedures.  As part of the initial merit review, all applications
will receive a written critique and undergo a process in which only
those applications deemed to have the highest scientific merit,
generally the top half of applications under review, will be
discussed and assigned a priority score.
 
Review Criteria
 
The following criteria will be considered:
 
o  Hypothesis driven, mechanistically-based nature of the study with
justification as to how the animals are unique in providing tissues
needed for the proposed studies.
 
o  Focus of the study on the relationship among exposure, toxicity
endpoint, time and the TEFs of the chemical/mixtures.
 
o  Scientific, technical, or medical significance of the proposed
research.
 
o  Efficiency of study design: Is this the best use of the tissues?
 
o  Appropriateness and adequacy of the experimental design and
methods proposed to carry out the research;
 
o  Innovativeness or promise of the research idea;
 
o  Qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;
 
o  Reasonableness/appropriateness of the requested budget in relation
to the proposed research; and
 
o  Availability of the investigators resources necessary to perform
the research.
 
NOTE: If the project can be completed without the aid of this NTP
study, the proposal will not qualify under this RFA.
 
AWARD CRITERIA
 
The anticipated date of award is December 1997 pending availability
of funds.  The following will be considered in making funding
decisions:
 
o  quality of the proposed project as determined by peer review;
 
o  availability of funds; and
 
o  program balance among research areas of the announcement.
 
Because of the nature of the NTP studies actual funding of these
projects may not all be made at the same time.  Awards will be made
so that the proposed project can be completed within the time frame
of the award.
 
INQUIRIES
 
Written, telephone or Email inquiries concerning this RFA are
encouraged.  The opportunity to clarify any issues or questions from
potential applicants is welcome.
 
Direct inquiries regarding programmatic issues to:
 
Jerrold J. Heindel, Ph.D.
Organs and Systems Toxicology Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, MD 3-02
111 T.W. Alexander Drive (Fed-x addr)
Research Triangle Park, NC  27709-2233
Telephone:  (919) 541-0781
FAX:  (919) 541-2843
EMAIL: heindelj@niehs.nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Mr. David L. Mineo
Chief, Grants Management Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, MD 2-01.
111 T.W. Alexander Drive (Fed-x addr)
Research Triangle Park, NC  27709-2233
Telephone:  (919) 541-7628
FAX: (919) 541-2860
EMAIL: mineo@niehs.nih.gov
 
For clarification of NTP study design or for information on tissue
availability contact:
 
John R. Bucher, Ph.D.
Environmental Toxicology Program
National Institute of Environmental Health Sciences
P.O. Box 12233, MD A2-08
111 T.W. Alexander Dr., Bldg. 101, Rm A222
Research Triangle Park, NC  27709-2233
Telephone:  (919) 541-4532
FAX: (919) 541-0295
EMAIL: bucher@niehs.nih.gov
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance No. 93.113 and 93.115. Awards are made under authorization
of the Public Health Service Act, Title IV, Part A (Public Law
78-410, as amended by Public Law 99-158, 43 USC 241 and 285) and
administered under PHS grants policies and Federal Regulations 42 CFR
52 and 45 CFR Part 74.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.
 
The Public Health Service (PHS) strongly encourages all grant and
contract recipients to provide a smoke-free workplace and promote the
non-use of all tobacco products.  In addition, Public Law 103-227,
the Pro Children Act of 1994, prohibits smoking in certain facilities
(or in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care or early childhood
development services are provided to children.  This is consistent
with the PHS mission to protect and advance the physical and mental
health of the American people.
 
.

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