Full Text ES-94-001


NIH GUIDE, Volume 22, Number 38, October 22, 1993

RFA:  ES-94-001

P.T. 34

  Health, Radiation Effects 
  Environmental Effects 
  Biology, Cellular 

National Institute of Environmental Health Sciences

Letter of Intent Receipt Date:  December 15, 1993
Application Receipt Date:  February 16, 1994


Human health and human disease result from three interactive
elements:  environmental factors, genetic susceptibility, and age.
The mission of the National Institute of Environmental Health
Sciences (NIEHS) is to reduce the burden of human illness and
dysfunction from environmental causes by further understanding each
of these elements and how they interrelate.  The NIEHS achieves its
mission through a multidisciplinary biomedical research program,
prevention and intervention efforts, and a communication strategy
that encompasses training, education, technology transfer, and
community outreach.  The ultimate goal of the NIEHS activities is to
define and understand the mechanism of action of environmental agents
on human health and to transfer this knowledge to the public benefit.

The Energy Policy Act that was signed into law in October 1992,
authorizes a five year Electromagnetic Fields (EMF) research and
public information dissemination program.  The Department of Energy,
the NIEHS, and other Federal agencies will be coordinating EMF
research and public information dissemination activities.  In this
Act, NIEHS is designated as the lead agency for coordinating and
conducting the health effects studies and communicating the results
to policy makers and the general public on the possible adverse
effects, if any, of EMFs by the generation, transport and use of

To accomplish the goals established in the Act, the NIEHS plans to
initiate a number of targeted research efforts addressing specific
effects of EMF that have been identified in the literature.  The aims
for these efforts will be to define both the robustness of any EMF
effects and to determine the biological significance of such effects,
if any.

The current Request for Applications (RFA) is for the establishment
of a research effort that addresses the effects of EMF on cells
particularly on gene expression.  In addition, the research to be
supported in this RFA is limited to topics for which 60 Hz EMF
effects have been previously reported.


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,
Cellular Effects of Low Frequency Electromagnetic Fields, 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 "Healthy People 2000" (Summary Report: Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington DC 20402-9325 (telephone 202-783-3238).


Applications may be submitted by domestic and foreign for- profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of state or local
governments, and eligible agencies in the Federal government.
Applications from minority individuals and women are encouraged.


This RFA will use the National Institutes of Health (NIH) individual
research grant (R01) only.  Responsibility for planning, direction,
and execution of the proposed project will be solely that of the
applicant.  The total project period for applications submitted in
response to the present RFA may not exceed four years.

This RFA is a onetime solicitation.  Future unsolicited and competing
continuation applications will compete with all
investigator-initiated applications and be reviewed according to the
customary peer review procedures.


The estimated funds (total costs) available for the first year of
support for the entire program are anticipated to be $1,500,000.  It
is expected that six to eight awards will be possible.  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 in the financial plans of the NIEHS, awards pursuant to
this RFA are contingent upon the transfer of funds for this purpose
from the Department of Energy.



As a result of electrification of our homes and work places, people
from all walks of life and of all ages are now exposed to power
frequency (60 Hz) electric and magnetic fields.  Increasingly
scientists, regulators, and lay people are asking whether human
exposure to these fields involves risks to human health.  Such
questions are based in part on the results of epidemiologic studies,
which have raised the possibility that exposure to power line
frequency electric and magnetic fields (EMF) increases risk for
certain forms of cancer.  In addition other studies have shown that
certain types of EMF exposure can cause minor variations in heart
rate and reaction times in humans.  There have also been some reports
of individuals with unusual sensitivity or adverse symptoms when
exposed to fields from power lines.  However, the biological
significance of these and other non-cancer studies is uncertain, and
it is unclear if these effects are predictors of adverse health
effects in humans.  Thus, there is a need for additional research on
the biological effects of EMF exposure particularly at the power line
frequencies (60 Hz).

Despite the number of studies on the biological effects of EMF, there
remains considerable controversy concerning the health effects of
EMF.  One reason for the controversy is the finding of both positive
and negative effects in some similar studies.  Another reason is that
many of the studies examining the biological effects of EMF have not
been replicated.  Also, there are scientists who believe that power
frequency fields contain too little energy to cause biological
effects.  First, the energy of a 60 Hz electromagnetic wave is too
weak to break chemical bonds, and second, natural electric fields in
the body are greater than those that can be induced by common EMF
exposure.  Thus, there is not as yet a consensus on the biological
effects of EMF or the human health consequences for any such effects.

One of the highly cited and studied areas is effects of EMF on the
behavior of cells exposed to electric and/or magnetic fields.
Studies have examined a wide range of endpoints.  For example, in
vitro studies report effects on cell membranes, RNA transcription,
ornithine decarboxylase activity, calcium-ion efflux, and cellular
response to hormones.  These responses to EMF at the cellular level
display a considerable complexity, including resonant responses in
frequency and field strength, complex time dependencies, and
dependence on the ambient DC magnetic field created by the earth.

There have been a number of studies that observe changes in the gene
expression of cells exposed to EMF.  For example, Henderson and
Goodman have reported gene expression changes in HL60 cells after 20
minutes of exposure to 5.7 or 8 micro tesla 60 and 72 Hz fields.
Specifically, the transcripts of the genes c-myc, B-actin, c-src etc
are reported to be increased in such experiments (Goodman et al,
Electro and Magnetobiology 11:19-28, 1992, Goodman et al,
Bioelectromagnetics 7:23-29, 1986,).  There have been a number of
studies initiated to replicate these and earlier results, but they
have not obtained similar results.

Therefore, there continues to be a controversy in the literature
because many of the reported findings have not been observed by
investigators attempting to replicate reported findings.  However, in
most instances, investigators have not completely replicated exposure
conditions and assays, and therefore, the lack of response reported
by other investigators may be due to differences in the protocols.

Research Goals and Scopes

The focus of this RFA is on the assessment of previously reported
effects of 60 Hz EMF on cellular processes.  It is important that
applications which address this question consider not only new
directions for research, but also include experiments which replicate
the previously reported effects.  One review criterion for this RFA
will be the fidelity of the replication experiments.  In addition, it
is important that any biological findings be related to human health
risks.  Thus, research approaches which may initially identify
biological effects should be broad enough to enable the investigator
to assess the biological significance of such effects, if any.

The following list provides examples of areas of research interest,
but it is not intended to be complete. Investigators are encouraged
to study these or other topics that have been reported in the peer
reviewed literature.

o  Effects on calcium and calcium mediated processes;
o  Effects on gene expression, particularly genes which may be
involved in cancer;
o  Effects on signal transduction;
o  Effects on protooncogenes such as c-myc, c-jun and c-fos in human
o  Effects on activity of protein kinase.

EMF Exposure Conditions

One of the complicating factors for understanding the biological
effects of EMF is the wide variety of exposure systems and conditions
used to assess EMF effects.  While the NIEHS recognizes that a varied
approach to research questions is necessary and useful, the
complexity of the EMF exposure parameters limits the number of
approaches the NIEHS can realistically support.  Therefore, this RFA
will only support research that is done at 60 and/or 50 Hz.

For example, projects that propose to study the effects of 60 Hz EMF
on genes should include as an initial study, a replication of the
cellular experiments of Henderson and Goodman to establish the
laboratory baseline.  While additional details of the experiments may
be needed, the key exposure features of the experiments were:  8 and
80 micro Tesla magnetic fields, 5 to 30 minute exposure (at 20
minutes maximum effects were measured) of HL60, HeLa, and HAL
(fibroblastic) cells.  The media for the HL60 cells was RPMI from
GIBCO and the cells were exposed in T-25 flasks in 15 ml medium.  The
long axis of the flasks was oriented parallel to the magnetic field,
i.e., the magnetic field passed from the bottom of the flask through
the cap.  The flasks were positioned in the center of the Helmholtz
coil, which resulted the maximum electric field at the wide bottom of
the flask where the cells are concentrated.  For other replicate
experiments, the investigator is reminded that the application must
include a detailed description of experiments to be replicated.
Descriptions that are primarily citations of the literature are not
considered adequate, but details of the experimental protocol can be
provided in an appendix.  However, all critical information for the
review of the application must be included in the application as the
appendix is not a part of the application.


Applicants should request funds for one trip annually to the National
Institute of Environmental Health Sciences for an EMF Program


Prospective applicants are asked to submit, by December 15, 1993, a
letter of intent that includes a descriptive title of the proposed
project, 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 (CELLULAR EFFECTS

Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, the information
that it contains is helpful in planning for the review of
applications.  It allows NIEHS staff to estimate the potential review
workload and to avoid conflict of interest in the review.

The letter of intent is to be sent to Dr. Michael J. Galvin, Jr. at
the address listed under INQUIRIES.


The research grant application form PHS 398 (rev.9/91) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research and from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD  20892,
telephone (301) 594-7378.

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 2a 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, photocopies, in one package to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, the investigator must also send two
additional copies of the application to:

Mr. David Mineo
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
104 T.W. Alexander Drive
P.O. Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-1373

Applications must be received by February 16, 1994.  If an
application is received after that date, it will be returned to the
applicant or will be placed in the pool of applications for the next
regular receipt date.


Applications will be administratively reviewed by NIH staff for
completeness and responsiveness to this announcement.  Applications
found to be incomplete or nonresponsive will be returned to the
applicant without further consideration. Those applications that are
complete and responsive may be subjected to triage to determine their
scientific merit relative to other applications received in response
to this RFA.  The NIH/NIEHS will administratively withdraw from
competition those applications judged to be noncompetitive and so
notify the applicant and institutional official.  Those applications
judged to be competitive will undergo further scientific merit
review.  These applications will be evaluated in accordance with the
criteria stated in the RFA for scientific/technical merit by an
appropriate peer review group convened by NIH.  The second level of
review will be provided by the National Advisory Environmental Health
Sciences Council.

The subject of this RFA may overlap interests of other Institutes,
Centers and Divisions (ICDs).  Applications will, therefore, be
assigned according to extant Referral Guidelines.

Review criteria for RFAs are generally the same as those for
unsolicited research grant applications.

o  Availability of resources necessary to perform project objectives.

o  Appropriateness of the proposed budget and duration in relation to
proposed objectives.

o  Strength of institutional commitment as evidenced by provision of
appropriate resources, services, technical support, and allocation of

o  Inclusion of accurately and completely described replicate
experiments of the appropriate studies for biological endpoints
previously reported to be affected by 60 Hz fields.  For example
investigators proposing gene expression studies may want to include
replicate experiments of the Henderson and Goodman findings.

o  The approach of the investigator to assess not only the biological
effects of the 60 Hz fields but also the significance, if any, to
human health risk.

o  Adequacy of the exposure system to provide accurate and
reproducible exposures.  In addition, all the components of the
system must be available to other researchers. Therefore the local
manufacture of coils is discouraged, and the use of equipment which
is also available to other researchers and is well characterized is
encouraged.  One source for an EMF in vitro exposure system is
Batelle Pacific Northwest Laboratory, Richland, Washington from Dr.
Barry Wilson.  Other comparable systems would be acceptable if
components of such systems are available to other researchers.

o  Experimental approaches to determining the biological significance
of any findings.


The anticipated date of award is September 30, 1994.

The following will be considered in making funding decisions:

o  Quality of the proposed project as determined by peer review
o  Availability of funds
o  Program balance and relevance to mission of NIEHS
o  Balance of the replication studies


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

Direct inquiries regarding programmatic issues and address the letter
of intent to:

Michael J. Galvin, Jr., Ph.D.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-7825

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) 541-1373


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.


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