[Federal Register Volume 66, Number 18 (Friday, January 26, 2001)]
[Notices]
[Pages 7894-7898]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-2371]


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DEPARTMENT OF ENERGY


Office of Science Financial Assistance Program Notice 01-18; Low 
Dose Radiation Research Program--Basic Research

AGENCY: U.S. Department of Energy.

ACTION: Notice inviting grant applications.

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SUMMARY: The Office of Biological and Environmental Research (OBER) of 
the Office of Science (SC), U.S. Department of Energy (DOE), hereby 
announces their interest in receiving grant applications for research 
that supports the DOE/OBER Low Dose Radiation Research Program.
    Research is sought by the DOE/OBER Low Dose Radiation Research 
Program for studies involving low LET radiation, in the following 
areas:
    (1) Bystander effects.
    (2) Genomic instability.
    (3) Adaptive responses.
    (4) Endogenous oxidative damage versus low dose radiation-induced 
damage.
    (5) Genetic factors that affect individual susceptibility to low 
dose radiation.
    Applications for well-justified research in other areas (see 
Supplementary Information below) will also be accepted. These Programs 
use modern molecular tools to develop a better scientific basis for 
understanding exposures and risks to humans from low doses of low LET 
radiation that can be used to achieve acceptable levels of human health 
protection at a reasonable cost.

DATES: Potential applicants should submit a one page preapplication 
referencing Program Notice 01-18 by 4:30 P.M. E.S.T., February 15, 
2001. Receipt of preapplications sent by email will be acknowledged by 
a return

[[Page 7895]]

message. An email response to preapplications discussing the potential 
program relevance of a formal application generally will be 
communicated by February 22, 2001.
    The deadline for receipt of formal applications is 4:30 P.M., 
E.D.T., May 15, 2001, in order to be accepted for merit review and to 
permit timely consideration for award in FY 2001 and FY 2002.

ADDRESSES: Preapplications referencing Program Notice 01-18, should be 
sent by E-mail to [email protected]. Preapplications will 
also be accepted if mailed to the following address: Ms. Joanne 
Corcoran, Office of Biological and Environmental Research, SC-72, U.S. 
Department of Energy, 19901 Germantown Road, Germantown, MD 20874-1290.
    Formal applications, referencing Program Notice 01-18, should be 
sent to: U.S. Department of Energy, Office of Science, Grants and 
Contracts Division, SC-64, 19901 Germantown Road, Germantown, MD 20874-
1290, ATTN: Program Notice 01-18. This address must be used when 
submitting applications by U.S. Postal Service Express, commercial mail 
delivery service, or when hand carried by the applicant.

FOR FURTHER INFORMATION CONTACT: For general information, contact Dr. 
David Thomassen, telephone: (301) 903-9817, E-mail: 
[email protected], Office of Biological and Environmental 
Research, SC-72, U.S. Department of Energy, 19901 Germantown Road, 
Germantown, MD 20874-1290.

SUPPLEMENTARY INFORMATION:

Description of Research Program Areas

    The DOE/OBER Low Dose Radiation Research Program is faced with the 
challenge of conducting research that can be used to inform the 
development of future national radiation risk policy for the public and 
the workplace. For the present solicitation, DOE/OBER is chiefly 
concerned with very low doses of low LET radiation (x and gamma rays). 
There are three biological responses of specific interest for this 
solicitation that are most likely to meet the criteria outlined below. 
These include bystander effects, induction of genomic instability, and 
adaptive responses. Applications proposing the use of additional 
biological responses will be considered only if the biological 
responses proposed for investigation can be reasonably demonstrated to 
meet the criteria outlined below. All applications focused on the 
characterization of specific biological responses, e.g., bystander 
effects, etc., should identify how the response of interest meets these 
criteria. There is also considerable interest in determining whether 
these biological responses can be extended from studies in isolated 
cells to tissues or to more complex tissue-like systems. These 
responses are discussed here:
    Bystander effects--The biological response observed in cells that 
are not directly traversed by radiation but are neighbors of an 
irradiated cell. Bystanders have been shown to respond with gene 
induction and/or production of potential genetic and carcinogenic 
changes. It is important for the DOE/OBER Low Dose program to determine 
if these so-called bystander effects can be induced by exposure to low 
LET (linear energy transfer) radiation delivered at low total doses or 
dose-rates. If such an effect is demonstrated and quantifiable, it 
could, potentially, increase estimates of risk from low dose radiation. 
This bystander effect, in essence, ``amplifies'' the biological effects 
(and the effective radiation dose) of a low dose exposure by 
effectively increasing the number of cells that experience adverse 
effects to a number greater than the number of cells directly exposed 
to radiation. Research is sought to:
     Characterize the nature of bystander effects at low doses 
of low LET radiation.
     Determine the relationship between radiation dose and the 
bystander effects at low doses of low LET radiation.
     Quantify the induction and extent of the bystander effect 
at low doses of low LET radiation.
     Determine the mechanism of the low LET radiation-induced 
bystander effect.
    Genomic Instability--The loss of genetic stability, a key event in 
the development of cancer, induced by radiation and expressed as 
genetic damage many cell divisions after the insult is administered. 
Current evidence suggests that DNA repair and processing of radiation 
damage can lead to instability in the progeny of irradiated cells and 
that susceptibility to instability is under genetic control. However, 
there is virtually no information on the underlying mechanisms and how 
the processing of damage leads to instability in the progeny of 
irradiated cells several generations later. Further, while there has 
been considerable speculation about the role of such instability in 
radiation-induced cancer, its role in this process remains to be 
determined. Research is sought to:
     Characterize the induction of genomic instability by low 
doses of low LET radiation.
     Determine the relationship between radiation dose and the 
induction of genomic instability by low doses of low LET radiation.
     Quantify the induction and extent of genomic instability 
induced by low doses of low LET radiation.
     Determine the mechanism for the induction of genomic 
instability by low LET radiation.
    Adaptive Response--The ability of a low dose of radiation to induce 
cellular changes that perturb the level of subsequent radiation-induced 
or spontaneous damage. If low doses of radiation regularly and 
predictably induce a protective response in cells to subsequent low 
doses of radiation, or to spontaneous damage, this could have a 
substantial impact on estimates of adverse health risk from low dose 
radiation. The generality and the extent of this apparent adaptive 
response in cells irradiated with small doses of ionizing radiation 
needs to be quantified. Studies of the adaptive response typically 
focus on cellular responses to high ``test'' doses of radiation 
following low ``priming'' doses. However, this solicitation is mainly 
interested in studying the lower limits for test doses and endpoints 
that show adaptive response phenomenon. Research is sought to:
     Characterize the adaptive response induced by low doses of 
low LET radiation.
     Determine the relationship between radiation dose and the 
adaptive response induced by low doses of low LET radiation.
     Quantify the induction and extent of the adaptive response 
induced by low doses of low LET radiation.
     Determine the mechanism for the induction of adaptive 
responses by low LET radiation.
    In addition to the three specific biological responses just 
described, the Program has great interest in understanding endogenous 
versus low dose radiation induced damage, and the mechanisms underlying 
individual genetic susceptibility to radiation damage.
    Endogenous versus low dose radiation induced damage. A key element 
of this research program will continue to be the development of an 
understanding of the similarities and differences between endogenous 
oxidative damage and damage induced by low levels of ionizing 
radiation, as well as an understanding of the health risks from both. 
This information will underpin our interpretation of the biological

[[Page 7896]]

effects of exposure to low doses of ionizing radiation. Although always 
needed, this information was not previously attainable because critical 
resources and technologies were not available. Today, technologies and 
resources such as those developed as part of the human genome program, 
e.g., coupled capillary electrophoresis and mass spectrometry systems 
and DNA sequence information, have the potential to detect and 
characterize small differences in damage induced by normal oxidative 
processes and low doses of radiation. A significant investment in 
technology development will be required to expand current capabilities 
for identifying and quantifying small amounts of oxidative or radiation 
induced damage. Radically new technologies are likely not needed but 
current technologies will need to be modified. Methodologies having 
high sensitivity as well as high signal-to-noise ratio will be critical 
in this effort.
    A significant research effort will be required to characterize and 
quantify normal oxidative damage in cells and the incremental increases 
induced by low doses of ionizing radiation. Preference will be given to 
the formation of partnerships between laboratories involved in 
characterization and quantification of radiation and oxidative damage 
and groups with expertise in or developing new technology to facilitate 
progress in both areas simultaneously. Although qualitative 
descriptions of differences and/or similarities between the types of 
damage induced under both conditions will be useful in the design and 
interpretation of experiments in other parts of the program, levels of 
damage induced by normal oxidative processes and incremental increases 
due to low dose radiation should be quantified.
    Genetic factors that affect individual susceptibility to low dose 
radiation. The Low Dose Radiation Research Program is interested in 
determining if genetic differences exist making some individuals more 
sensitive to radiation-induced damage since these differences could 
result in sensitive individuals or sub-populations that are at 
increased risk for radiation-induced cancer. Research should focus on:
     Identification of genes involved in the recognition, 
repair, and processing of damage induced by ionizing radiation.
     Determining the frequencies of polymorphisms in these 
genes in the population.
     Determining the biological significance of these 
polymorphisms with respect to cancer and radiation sensitivity.
    Research in these areas will strongly complement ongoing 
initiatives at the National Institutes of Health (NIH). DOE/OBER staff 
will work with staff at the NIH to ensure that research in the Low Dose 
Radiation Research Program is complementary to and not duplicative of 
research funded by NIH programs.
    The National Human Genome Research Institute (NHGRI) is funding 
research to identify common variants in the coding regions of the 
majority of human genes identified during the next five years with the 
goal of developing a catalog of all common variants. The NHGRI is also 
working to create a map of at least 100,000 single nucleotide 
polymorphisms (SNPs), the most common polymorphisms in the human genome 
representing single base-pair differences between two copies of the 
same gene. These SNPs will be a boon for mapping complex traits such as 
cancer, cancer susceptibility, and susceptibility to low dose 
radiation.
    The National Institute of Environmental Health Science (NIEHS) is 
funding research as part of its Environmental Genome Project to 
understand the impact and interaction of environmental exposures on 
human disease. The NIEHS project includes efforts to understand genetic 
susceptibility to environmental agents that will allow more precise 
identification of the environmental agents that cause disease and the 
true risks of exposures. The principal focus of NIEHS research will be 
on chemicals, so the focus on radiation in the Low Dose Radiation 
Research Program is highly complementary. Initially, the Environmental 
Genome Project will focus on categories of genes including: xenobiotic 
metabolism and detoxification genes, hormone metabolic genes, receptor 
genes, DNA repair genes, cell cycle genes, cell death control genes, 
genes mediating immune and inflammatory responses, genes mediating 
nutritional factors, genes involved in oxidative processes and genes 
for signal transduction systems.
    Identification of potential susceptibility genes and polymorphisms 
in those genes is only the first (and perhaps the easiest) step in the 
program to characterize and understand genetic susceptibility. 
Determining the biological significance of these genetic polymorphisms 
with respect to cancer and radiation sensitivity is the ultimate goal 
and the more difficult task. The international human genome project, 
structural biology research, and the NHGRI and NIEHS efforts described 
above play important roles determining which polymorphisms are most 
likely to influence gene function. Population genetics and 
computational biology approaches will be required to estimate the 
potential impact on estimates of population and individual risk. 
Genetic epidemiology approaches will also be needed to relate specific 
polymorphisms and combinations of polymorphisms with cancer risk. 
Inbred mouse strains and other model organisms with well-characterized 
differences in susceptibility to radiation-induced cancer are also 
important tools for identifying significant polymorphisms. Direct 
assessment of the biological significance of candidate ``susceptibility 
genes'' can also be undertaken using animal models such as knockout and 
knock-in mice, mice with specific genes removed or added.
    Background information on the Low Dose Radiation Research Program 
can be found in the research program plan at http://www.lowdose.org/index.html. A list of currently funded projects can be found at http://lowdose.org/research.html.
    Not all research on the biological effects of low doses of 
radiation will be equally useful for the development of radiation risk 
policy, though the path from basic radiation biology research to 
radiation risk policy is admittedly not clear at this time. It is our 
belief that the most useful research will focus on biological responses 
that:
     Are known to be induced at low doses of radiation,
     Have the potential to increase or decrease the biological 
effects of radiation if they occur at low doses of radiation,
     Have the potential to directly impact (i.e., increase or 
decrease) the subsequent development of cancer or other harmful health 
impacts,
     Are potentially quantifiable, and
     Could potentially be linked to the development of a 
biologically based model for radiation risk (see DOE Office of Science 
Program Notice 01-17).
    Alternatively, a biological response of interest could meet all of 
the above criteria only at high doses but may actually be absent (as 
opposed to simply undetectable) at low doses of radiation. Since the 
mechanisms of action may be different after high versus low doses of 
radiation, such studies would help define these mechanisms. Defining 
the unique doses where these mechanisms shift is important.
    The focus of research in the Low Dose Radiation Research Program 
should be on doses of low linear energy transfer (LET) radiation that 
are at or below current workplace exposure limits. In general, research 
in this program should focus on total radiation doses that are less 
than or equal to 10 rads. Some

[[Page 7897]]

experiments will likely involve selected exposures to higher doses of 
radiation for comparisons with previous experiments or for determining 
the validity of extrapolation methods previously used to estimate the 
effects of low doses of radiation from observations made at high doses. 
Research that principally focuses on radiation doses greater than 10 
rads, high LET radiation or non-ionizing radiation will not be 
considered without substantial justification.
    The program is currently funding a number of projects to develop 
micro-irradiation devices capable of delivering low doses of low LET 
radiation to individual cells or to specific parts of individual cells. 
For links to currently funded ``microbeam'' projects see http://lowdose.org/99meeting/abstracts/tool.html--projects 26, 28, 29 and 
http://lowdose.org/99meeting/abstracts/response.html--project 3. 
Investigators are strongly encouraged to use these or similar tools, as 
appropriate, in the design and conduct of their research. Funds are 
available to assist in the collaborative use of these or comparable 
tools or, in some cases, to provide low-cost micro-irradiation devices 
to individual investigators.

Program Funding

    It is anticipated that up to $4.0 million will be available from 
DOE/OBER for new grant awards during FY 2001 and FY 2002, contingent 
upon the availability of funds. Multiple year funding of grant awards 
is expected, and is also contingent upon the availability of 
appropriated funds, progress of the research, and continuing program 
need. It is expected that most awards will be from 1 to 5 years and 
will range from $200,000 to $400,000 per year (total costs). 
Applications requesting more than 3 years of funding will need to 
clearly justify the benefits of the additional years of research to the 
goals of the low dose radiation research program. Please note that 
funds are available from DOE to assist in the collaborative use of 
certain microbeam irradiators.

Collaboration

    Applicants are encouraged to collaborate with researchers in other 
institutions, such as universities, industry, non-profit organizations, 
federal laboratories and Federally Funded Research and Development 
Centers (FFRDCs), including the DOE National Laboratories, where 
appropriate, and to incorporate cost sharing and/or consortia wherever 
feasible.

Preapplication

    A preapplication should be submitted. The Preapplication should 
contain a title, list of investigators, address, telephone, fax and E-
mail address of the Principal Investigator, and no more than a one page 
summary of the proposed research, including project objectives and 
methods of accomplishment. Responses to the preapplications, 
encouraging or discouraging formal applications, will generally be 
communicated within 7 days of receipt. Notification of a successful 
preapplication is not an indication that an award will be made in 
response to the formal application.

Merit and Relevance Review

    Applications will be subjected to scientific merit review (peer 
review) and will be evaluated against the following evaluation criteria 
listed in descending order of importance as codified at 10 CFR 
605.10(d):
    1. Scientific and/or Technical Merit of the Project.
    2. Appropriateness of the Proposed Method or Approach.
    3. Competency of Applicant's Personnel and Adequacy of Proposed 
Resources.
    4. Reasonableness and Appropriateness of the Proposed Budget.
    The evaluation will include program policy factors such as the 
relevance of the proposed research to the terms of the announcement and 
the Department's programmatic needs. External peer reviewers are 
selected with regard to both their scientific expertise and the absence 
of conflict-of-interest issues. Non-federal reviewers may be used, and 
submission of an application constitutes agreement that this is 
acceptable to the investigator(s) and the submitting institution.

Applications

(Please Note Critical Information Below on Page Limits)

    Information about the development and submission of applications, 
eligibility, limitations, evaluation, selection process, and other 
policies and procedures may be found in the Application Guide for the 
Office of Science Financial Assistance Program and 10 CFR Part 605. 
Electronic access to the Guide and required forms is made available via 
the World Wide Web at: http://www.er.doe.gov/production/grants/grants.html. DOE is under no obligation to pay for any costs associated 
with the preparation or submission of applications if an award is not 
made.
    The Project Description must be 25 pages or less, exclusive of 
attachments. Applications with Project Descriptions longer than 25 
pages will be returned to applicants and will not be scientifically 
reviewed. The application must contain an abstract or project summary, 
letters of intent from collaborators, and short curriculum vitas 
consistent with NIH guidelines.
    Adherence to type size and line spacing requirements is necessary 
for several reasons. No applicants should have the advantage, or by 
using small type, of providing more text in their applications. Small 
type may also make it difficult for reviewers to read the application. 
Applications must have 1-inch margins at the top, bottom, and on each 
side. Type sizes must be 10 point or larger. Line spacing is at the 
discretion of the applicant but there must be no more than 6 lines per 
vertical inch of text. Pages should be standard 8\1/2\" x 11" (or 
metric A4, i.e., 210 mm x 297 mm).
    Applicants are expected to use the following ordered format to 
prepare Applications in addition to following instructions in the 
Application Guide for the Office of Science Financial Assistance 
Program. Applications must be written in English, with all budgets in 
U.S. dollars.
     Face Page (DOE F 4650.2 (10-91)).
     Project Abstract (no more than one page).
     Budgets for each year and a summary budget page for the 
entire project period (using DOE F 4620.1).
     Budget Explanation.
     Budgets and Budget explanation for each collaborative 
subproject, if any.
     Project Description (The Project Description must be 25 
pages or less, exclusive of attachments. Applications with Project 
Descriptions longer than 25 pages will be returned to applicants and 
will not be scientifically reviewed.)
     Goals.
     Background.
     Research Plan.
     Preliminary Studies and progress (if applicable).
     Research Design and Methodologies.
     Literature Cited.
     Collaborative Arrangements (if applicable).
     Biographical Sketches (limit 2 pages per senior 
investigator).
     Description of Facilities and Resources.
     Current and Pending Support for each senior investigator.
    The Office of Science, as part of its grant regulations, requires 
at 10 CFR 605.11(b) that a recipient receiving a grant to perform 
research involving

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recombinant DNA molecules and/or organisms and viruses containing 
recombinant DNA molecules shall comply with the National Institutes of 
Health ``Guidelines for Research Involving Recombinant DNA Molecules'', 
which is available via the world wide web at: http://www.niehs.nih.gov/odhsb/biosafe/nih/rdna-apr98.pdf, (59 FR 34496, July 5, 1994), or such 
later revision of those guidelines as may be published in the Federal 
Register.

(The Catalog of Federal Domestic Assistance Number for this program 
is 81.049, and the solicitation control number is ERFAP 10 CFR Part 
605)

    Dated: January 22, 2001.
John Rodney Clark,
Associate Director of Science for Resource Management.
[FR Doc. 01-2371 Filed 1-25-01; 8:45 am]
BILLING CODE 6450-01-P