CHEMICAL MIXTURES IN ENVIRONMENTAL HEALTH

NIH Guide, Volume 26, Number 38, November 21, 1997

RFA: ES-98-002

P.T.

National Institute of Environmental Health Sciences
U.S. Environmental Protection Agency

Letter of Intent Receipt Date:  January 10, 1998
Application Receipt Date:  February 10, 1998

PURPOSE

The National Institute of Environmental Health Sciences (NIEHS) and the U.S.
Environmental Protection Agency (EPA) share the common goal of promoting research
that will ultimately reduce the extent of adverse human health effects occurring
as a consequence of exposure to hazardous environmental agents.  Historically,
research on individual environmental agents has been critical in providing the
mechanistic information necessary to begin unraveling the relationship=s between
human illness and dysfunction and  environmental exposure, the timing of exposure
and individual susceptibility.  The protection of human health relies on setting
standards for single substances that are based on the mechanistic knowledge
gained from the integration of available data from all relevant research
disciplines such as toxicology, molecular biology, biochemistry and epidemiology.
Yet in our society, human exposure to chemicals, be it environmental or
occupational, is rarely limited to a single chemical; rather, people are exposed 
to a myriad of chemicals throughout their lifetime.  Unfortunately, not only is
there a lack of knowledge concerning the characterization of real-life mixtures
based on human exposure or human body burden but there are limited experimental
strategies available that focus on understanding the mechanisms of action of
chemical mixtures as it relates to human health.  As a consequence, there is
limited knowledge of the underlying biological and  pathobiological processes
associated with how living systems handle chemical mixtures and are affected by
them.  Moreover, we have limited abilities to predict how chemicals in a mixture
interact with each other or biological systems.  Accordingly, the objective of
this Request For Application (RFA)  is to encourage innovative experimental
approaches and/or computational, statistical or predictive strategies for
chemical mixtures that focus on the mechanistic basis for chemical interactions
and related health effects.  It is anticipated that research projects generated
as a result of this RFA will provide the scientific foundation necessary to
develop biologically relevant risk assessment models for human exposure to
chemical mixtures.  The issuance of this RFA is a joint announcement by NIEHS and
EPA and reflects our common research interests.  The program will be managed by
both agencies to ensure complementary balance of the research portfolio.

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, "Chemical Mixtures@ 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 and foreign, not-for-profit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, and units of State or local governments. Minority individuals,
persons with disabilities, and women are encouraged to apply as Principal
Investigators.

MECHANISM OF SUPPORT

The funding mechanisms to be used to assist the scientific community in
participating in this grant program will be those of: 1) the National Institutes
of Health (NIH) investigator-initiated research project grant (R01); or 2) the
Environmental Protection Agency's Office of Research and Development,
administered in accordance with 40 CFR Part 30 and 40.  Policies that govern
grant award programs of each agency will prevail for respective sources of
support.  Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant. The requested direct costs
for an application submitted in response to this RFA may not exceed $250,000 per
year.

FUNDS AVAILABLE

The total estimated funds available for the first year of support for this
program (including direct and indirect costs) is expected to be up to $4.5
million in fiscal year 1998.  NIEHS is designating $1.5 million in the first year
and EPA is designating at least $3.0 million in total funds with grant support
not to exceed 5 years.  It is anticipated that most EPA awards will be for 3
years. The anticipated number of awards is eight to twelve,  although the actual
number may vary.  The level of support is dependent on the receipt of sufficient
number of applications of high scientific merit.  Although this program is
provided for within the financial plans of the NIEHS and EPA, awards pursuant to
this RFA are contingent upon the availability of funds for this purpose.

RESEARCH OBJECTIVES

Background

The U.S. EPA mission is to protect environmental quality and human health through
effective regulations, policy decisions and outreach programs supported by sound
science through research and development activities. Complementary to this
mission is the goal of the NIEHS to support research that examines human health
consequences of exposure to physical and chemical toxicants in the environment
as well as the underlying mechanisms involved in environmentally related disease
and dysfunction.  Understanding what mixtures of chemicals the public is exposed
to as well as the mechanisms involved in the interaction of these mixtures and
subsequent health effects is a priority research area.  Considering the
approximate 80,000 chemicals in commerce, the task of testing these chemicals on
an individual basis, let alone as a mixture is not feasible.

Chemical mixtures vary significantly in their composition.  Simple mixtures may
contain two or three chemicals whereas complex mixtures, such as those found at
some hazardous waste sites, contain hundreds of chemicals, representing a variety
of organic and inorganic classes of chemicals, with varying degrees of toxicity
and different modes of toxic action.  Clearly, toxicological evaluation of these
complex mixtures is difficult but important for hazard assessment and assessment
of risk to human health.  This assessment, however, is made more challenging in
that the behavior of chemicals in mixtures cannot necessarily be inferred from
the behavior ascribed to a single pure chemical.  For example, several outcomes
have been observed as a result of chemical interactions in a mixture: (1)
chemicals act independently, and thus the chemicals in the mixture are
qualitatively and quantitatively similar to their separate effects; (2) they
demonstrate additive effects, simple summing of the toxicity of the chemicals in
a mixture describes the total toxicity; (3) there are antagonistic effects,
resulting in toxicity being reduced to a greater extent than would have been
predicted; and (4) chemicals demonstrate synergism, resulting in toxicity that
is greater than additive.

From a public health perspective, our inability to predict whether agents act in
an additive, synergistic, or antagonistic fashion at concentrations encountered
in the environment creates real problems for human health risk assessment.  Many
examples exist where the interactions of chemicals with each other or other
physical or biological agents affect health to a greater extent than would have
been predicted based on toxicity of the individual components.  A mixture of
ozone and aldehydes, which are components of smog, causes more severe effects
than expected from the additive effects.  A much greater risk of developing lung
cancer is observed in smokers who are also exposed to radon or asbestos.  People
infected with hepatitis B are at greater risk for developing aflatoxin-induced
liver cancer.  Experimental studies in hens suggest that some of the reported
illnesses described for the veterans of the Persian Gulf War might have resulted
from interactions between immunization shots, anti-nerve gas prophylaxis,
insecticides and insect repellents.  This concept has been recently endorsed by
Haley and Kurt in a cross-sectional epidemiological study in Gulf War veterans
on their neurotoxicological health effects.

Some of the mechanisms involved in alterations in toxicity have been studied and
have been shown to be a consequence of changes in the toxicokinetics and/or
toxicodynamics of one chemical by another. Toxicokinetic changes affect the
absorption, distribution, metabolism and/or excretion of a chemical and can have
profound effects on dose-response relationships.  Changes at the toxicodynamic
level might involve a competition between chemicals for binding to a target site,
such as a receptor or alter the susceptibility of target cells to the effects of
another agent.  This could also include changes in signal transduction pathways
and cell cycle control.  Though some of these alterations have been described for
simple mixtures of two components, unraveling the effects of complex mixtures
with up to hundreds of chemicals has not been attempted to an appreciable extent.

It has been estimated that to design a full factorial study to examine the
interaction(s) of three chemicals at five different dose levels requires 125
treatment groups and 750 animals if six animals are included in each treatment
group.  The end result of such a large expenditure of time and funds would be
information on one temporal sequence of exposures at one time point post-
exposure.  Clearly, the information gained would be of limited value.  Therefore
a rational approach to studying mixtures includes  prioritizing and identifying
chemical mixtures that are based on known human exposures, and applying
innovative experimental and computational strategies to dissect the mechanistic
basis for interactions of chemicals in a mixture.

Research Goals

The goals and scope of this RFA are to encourage and support research on chemical
mixtures that will take advantage of the latest advances in computational and
information technologies and molecular biology techniques to focus on the
mechanistic basis for chemical interactions in biological systems and related
health effects and to develop better mathematical tools for risk assessment.  In
addition, since there is a general lack of knowledge concerning the
characterization of real-life mixtures based on human exposure and body burden,
research will be supported that focuses on exposure assessment, including
environmental transport and fate.

Understanding the mechanistic basis for interactions at a quantitative level is
necessary before confidence can be gained to provide realistic risk assessments
for chemical mixtures.  For example, using physiologically-based
pharmacokinetics/pharmacodynamic (PBPK/PD) modeling and innovative experimental
approaches, the mechanism for non-additive interactions of multiple chemicals
could be discerned and applied to environmentally relevant concentrations of
chemicals. Research on the mechanistic basis for cellular and/or molecular
perturbations and associated health effects by mixtures of chemicals is
encouraged in this RFA.  Research on chemical interactions that exacerbate both
cancer and non-cancer effects is strongly encouraged. For example, the toxic
effects of chemical mixtures on liver have been extensively studied, but it also
has been observed that opposing effects for different organs can occur.

"Mixtures" for the purposes of this RFA is defined as two or more agents in
combination.  This could include but not be limited to chemical-chemical,
chemical-biological or chemical-physical agent interactions.  Some examples of
mixtures that could be considered for study include, air pollutants, solvents,
volatile organics, pesticides, PAHs, metals or some combination of these.

The following areas of research interest are not intended to be complete, and
investigators may study these and other topics that meet the objectives of this
RFA:

o  Developing innovative experimental strategies to elucidate the mechanism for
interactive effects of chemical mixtures using animal models, in vitro cell
systems and gene expression systems.  Chemical mixtures at environmentally
relevant concentrations should be considered for these mechanistic studies. 
Dose-response, temporal effects and multiple target endpoints should be taken
into consideration.

o  Understanding the molecular and/or cellular perturbations associated with
exposure to simple or complex mixtures.  This could include cellular responses
such as effects on receptor systems, changes in gene expression associated with
xenobiotic metabolism, signal transduction, or cell cycle control.  Such research 
could lead to eventual development of mechanistically-based biomarkers.

o  Investigating the effects of metal mixtures on molecular and cellular
functions.  Mixtures  can include metal/metal, metal/metalloid, metal/organics. 
In addition speciation of metallic elements could also be considered.

o  Developing and assessing novel methods for measuring and characterizing
chemical mixtures in human populations and the environment, including the use of
feral animals as models and/or sentinel species.

o  Developing novel statistical and mathematical strategies to interpret results
and provide better models for predictive toxicology.  Some promising approaches
include QSAR (quantitative structure activity relationships), PBPK/PD modeling
and fractional factorial designs.

SPECIAL REQUIREMENTS

Applicants should request funds for one trip/year for an annual meeting of
grantees to be held either at NIEHS in Research Triangle Park, North Carolina or
at the U.S. EPA in Washington D.C.

QUALITY ASSURANCE NARRATIVE STATEMENT

EPA regulations as stated in 40CFR30.54 require the inclusion of a Quality
Assurance Narrative Statement (QANS, OMB # 2080-0033, approved 8/14/97) for any
project application involving data collection or processing, environmental
measurements, and/or modeling.  The QANS provides information on how quality
processes or products will be assured. While applications to NIEHS/NIH cannot be
considered incomplete without this statement, EPA cannot fund any application
without a reviewed QANS; therefore it is requested that the QANS be included with
all applications.  This statement should not exceed two consecutively numbered,
8.5x11-inch pages of single-spaced standard 12-point type with 1-inch margins. 
This statement is to be considered as additional information and is not counted
against the 25 pages permitted for the Research Plan.  The Quality Assurance
Narrative Statement should, for each item listed below, either present the
required information or provide a brief justification as to why the item does not
apply to the proposed research.  For awards that involve environmentally related
measurements or data generation, a quality system that complies with the
requirements of ANSI/ASQC E4, "Specifications and Guidelines for Quality Systems
for Environmental Data Collection and Environmental Technology Programs," must
be in place.

1.  The activities to be performed(reference may be made to the specific page and
paragraph number in the application where this  information may be found);
criteria for determining the acceptability of data quality in terms of precision,
accuracy, representativeness, completeness, comparability.

2.  The study design including sample type and location requirements and any
statistical analyses that were used to estimate the types and numbers of samples
required for physical samples or similar information for studies using survey and
interview techniques.

3.  The procedures for the handling and custody of samples, including sample
identification, preservation, transportation, and storage.

4.  The methods that will be used to analyze samples or data collected, including
a description of the sampling and/or analytical instruments required.

5.  The procedures that will be used in the calibration and performance
evaluation of the sampling and analytical methods used during the project.

6.  The procedures for data reduction and reporting, including a description of
statistical analyses to be used and of any computer models to be designed or
utilized associated with verification and validation techniques.

7.  The intended use of the data as they relate to the study objectives or
hypotheses.

8.  The quantitative and or qualitative procedures that will be used to evaluate
the success of the project.

9.  Any plans for peer or other reviews of the study design or analytical methods
prior to data collection.

If the application is exempt from the Quality Assurance statement a brief
justification (3-4 sentences) needs to be included.

ANSI/ASQC E4, "Specifications and Guidelines for Quality Systems for
Environmental Data Collection and Environmental Technology Programs" is available
for purchase from the American Society for Quality Control, phone 1-800-248-1946,
item T55.  Only in exceptional circumstances should it be necessary to consult
this document.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and their
sub-populations must be included in all NIH supported 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
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513), and in the NIH GUIDE FOR GRANTS AND CONTRACTS, Volume 23,
Number 11, March 18, 1994.

Investigators may also obtain copies from these sources or from the program staff
or contact person listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by January 10, 1998, a letter of
intent that includes a descriptive title of the proposed research, the name,
address and telephone number of the principal investigator, the identities of
other key personnel and consultants, the participating institutions, and the
number and title of the RFA in response to which the application may be
submitted.  It is important to consider during the planning phase of the
application that the requested direct costs for the applications submitted in
response to this RFA may not exceed $250,000 per year.

Although a letter of intent is not required, is not binding, and does not enter
into the review of the subsequent application, the information that it contains
is helpful in planning for the review of applications. It allows review staff to
estimate the potential review work load and to avoid conflicts 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
111 T. W. Alexander Drive, EC-24
Research Triangle Park, NC 27709
Telephone: (919) 541-7826
FAX: (191) 541-2503

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 Division of Extramural Outreach
and Information Resources, National Institutes of Health, 6701 Rockledge Drive,
MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email: 
ASKNIH@od.nih.gov.

The RFA label available in the PHS 398 application form must be affixed to the
bottom of the face page of the application.  Failure to use this label could
result in delayed processing of the application such that it may not reach the
review committee in time for review.  In addition, the RFA title and number must
be typed on line 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:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040-MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)

At the time of submission, two additional copies of the application must also 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
111 T. W. Alexander Drive, EC-24
Research Triangle Park, NC 27709

Applications must be received by February 10, 1998.  If an application is
received after that date, the Center for Scientific Review (CSR) will contact the
applicant to determine whether it will be returned to the applicant or be
reviewed with unsolicited applications for the next regular receipt date.  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. In addition, 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.

REVIEW CONSIDERATIONS

Because the scope of the research proposed in response to this RFA encompasses
the interest of several NIH institutes and centers, applications might receive
dual assignments based on the established PHS referral guidelines.  Applications
will be administratively reviewed by NIH staff for completeness and
responsiveness to this RFA.  Applications found to be incomplete or non-
responsive to this RFA will be inactivated and returned to the applicant without
further consideration.  Those 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 NIEHS and EPA in accordance with NIH peer
review procedures.  As part of the initial merit review, all applications will
receive a written critique.  Those applications judged by the study section panel
to be non-competitive will be administratively withdrawn from competition.  Those
applications judged to be competitive, deemed to have the highest scientific
merit, generally the top half of the applications under review, will be discussed
at the study section meeting, assigned a priority score, and receive a second
level review by the EHS advisory council.

Review Criteria

The following criteria will be considered:

(1) 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
field?

(2) 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?

(3) 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?

(4) 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 (if any)?

(5) 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?

AWARD CRITERIA

The anticipated date of award is July 1, 1998.  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.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.  The
opportunity to clarify any issues or questions from potential applicants is
welcomed.

Direct inquiries regarding programmatic issues to:

Claudia Thompson, Ph.D.
Chemical Exposures and Molecular Biology Branch
National Institute of Environmental Health Sciences
P.O. Box 12233, 104 Alexander Drive, MD-3-04
Research Triangle Park, NC  27709
Telephone:  (919) 541-4638
FAX:  (919) 541-4937
Email:  thompso1@niehs.nih.gov

Chris Saint, Ph.D.
National Center for Environmental Research and Quality Assurance
U.S. Environmental Protection Agency
401 M Street, S.W.
Washington, DC  20460
Telephone:  (202) 564-6909
FAX:  (202) 565-2448
Email:  saint.chris@epamail.epa.gov

Thomas Veirs
National Center for Environmental Research and Quality Assurance
U.S. Environmental Protection Agency
401 M Street, S.W.
Washington, DC  20460
Telephone:  (202) 564-6831
FAX:  (202) 565-2447
Email:  veirs.thomas@epamail.epa.gov

Direct inquiries regarding fiscal matters to:

Mr. David L. Mineo
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-7628
FAX:  (919) 541-2860
Email:  mineo@niehs.nih.gov

Mr. Jack Puzak
National Center for Environmental Research and Quality Assurance
U.S. Environmental Protection Agency
401 M Street, S.W. (8701R)
Washington, DC  20460
Telephone:  (202) 564-6825
FAX:  (202) 565-2444
Email:  puzak.jack@epamail.epa.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance
No.93.113, 93.114 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.  EPA awards are made under
authority of 40 CFR Part 30 and 40. This program is not subject to the
intergovernmental review requirements of executive order 12372 or Health Systems
Agency Review.

The Public Health Service (PHS) and EPA 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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