RADIATION RESEARCH 163, 115–123 (2005)
? 2005 by Radiation Research Society.
All rights of reproduction in any form reserved.
Priority List of Research Areas for Radiological Nuclear
Terry C. Pellmar,a,1Sara Rockwellband the Radiological/Nuclear Threat Countermeasures Working Group2
aArmed Forces Radiobiology Research Institute (AFRRI), Uniformed Services University, Bethesda, Maryland 20889-5603; andbYale University
School of Medicine, Department of Therapeutic Radiology, New Haven, Connecticut 06520-8040
Pellmar, T. C., Rockwell, S. and the Radiological/Nuclear
Threat Countermeasures Working Group. Priority List of Re-
search Areas for Radiological Nuclear Threat Countermea-
sures. Radiat. Res. 163, 115–123 (2005).
To help the nation prepare for the possibility of a terrorist
attack using radiological and nuclear devices, the Office of
Science and Technology Policy and the Homeland Security
Council established an interagency working group. The work-
ing group deliberated on the research needs for radiological/
nuclear threat countermeasures and identified and prioritized
18 areas for further attention. The highest priorities were giv-
en to research on (1) radioprotectors for use prior to expo-
sure; (2) therapeutic agents for postexposure treatment; (3)
antimicrobial therapy for infections associated with radiation
exposure; (4) cytokines and growth factors; (5) mechanisms
of radiation injury at the molecular, cellular, tissue and or-
ganism levels; and (6) automation of biodosimetric assays.
High priority was given to (1) developing biomarkers for bio-
1Address for correspondence: Armed Forces Radiobiology Research
Institute (AFRRI), Uniformed Service University, 8901 Wisconsin Ave-
nue, Bldg. 42, Bethesda, Maryland 20889-5603; e-mail: pellmar@afrri.
2Richard Hatchett, Department of Health and Human Service (working
group co-chair); David G. Jarrett, AFRRI (working group co-chair); Terry
C. Pellmar, AFRRI (working group co-chair); George Alexander, National
Institutes of Health; William F. Blakely, AFRRI; Itzhak Brook, AFRRI;
Robert Claypool, Department of Veterans Affairs; Norman Coleman, Na-
tional Institutes of Health; Ronald E. Goans, Tulane University; Joseph
Gootenberg, Food and Drug Administration; Earl Hughes, Department of
Energy; Kristi Koenig, Department of Veterans Affairs; Brad Leissa,
Food and Drug Administration; Patrick Lowry, REAC/TS; Fred Mettler,
University of New Mexico, Department of Veterans Affairs; Patricia Mil-
ligan, Nuclear Regulatory Commission; Michael A. Noska, Food and
Drug Administration; Nicki Pesik, Centers for Disease Control and Pre-
vention; Robert C. Ricks, REAC/TS; Sara Rockwell, Yale University
School of Medicine; Walter Schimmerling, NASA; Thomas M. Seed,
AFRRI; Tom Sizemore, Department of Veterans Affairs; James M. Smith,
Centers for Disease Control and Prevention; Katherine Swartsel, Depart-
ment of Veterans Affairs; Horace Tsu, AFRRI; Joseph Weiss, Department
of Energy; Kevin Yeskey, Department of Homeland Security; William
Dickerson and Pataje G. S. Prasanna, AFRRI (consultants to Research
Subgroup of Working Group).
dosimetry; (2) enhancing training in the radiation sciences;
(3) exploring the consequences of combined injury; (4) estab-
lishing a repository of information regarding investigational
countermeasures; and (5) following the health of an exposed
population to better prepare for subsequent events. The re-
search areas that the committee felt required the attention of
the radiation research community are described in this report
in an effort to inform this community about the needs of the
nation and to encourage researchers to address these critical
? 2005 by Radiation Research Society
To help the nation prepare for the eventuality of a ter-
rorist attack using weapons of mass destruction, the Office
of Science and Technology Policy and the Homeland Se-
curity Council established the Weapons of Mass Destruc-
tion Medical Countermeasures Subcommittee in the Spring
of 2003. Their mission was the ‘‘identification, coordination
and prioritization of research, development and acquisition
of medical countermeasures for biological threat agents that
may be used against United States civilian population, mil-
itary forces and those of our friends and allies.’’ In support
of that mission, an interagency working group was estab-
lished to address radiological and nuclear threat counter-
measures. The working group (see footnote 2) consisted of
representatives from a broad range of federal agencies and
included a few key individuals from academia. From this
larger group, a subgroup was assembled to consider the
research needs of the nation to address radiological/nuclear
threat countermeasures. Described in this report are the re-
search areas that the committee felt required the attention
of the radiation research community. They are presented
here in an effort to inform this community about the needs
of the nation and to encourage researchers to address these
critical issues. Table 1 provides a summary list of these
The research subgroup identified 18 key research areas
relevant to the development of medical countermeasures
against radiological and nuclear threats. Each area was as-
Report Documentation Page
OMB No. 0704-0188
Public reporting burden for the collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and
maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information,
including suggestions for reducing this burden, to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington
VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to a penalty for failing to comply with a collection of information if it
does not display a currently valid OMB control number.
1. REPORT DATE
2. REPORT TYPE
3. DATES COVERED
00-00-2005 to 00-00-2005
4. TITLE AND SUBTITLE
Meeting Report. Priority List of Research Areas for Radiological Nuclear
5a. CONTRACT NUMBER
5b. GRANT NUMBER
5c. PROGRAM ELEMENT NUMBER
5d. PROJECT NUMBER
5e. TASK NUMBER
5f. WORK UNIT NUMBER
7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)
Armed Forces Radiobiology Research Institute (AFRRI),Uniformed
8. PERFORMING ORGANIZATION
9. SPONSORING/MONITORING AGENCY NAME(S) AND ADDRESS(ES)
10. SPONSOR/MONITOR’S ACRONYM(S)
11. SPONSOR/MONITOR’S REPORT
12. DISTRIBUTION/AVAILABILITY STATEMENT
Approved for public release; distribution unlimited
13. SUPPLEMENTARY NOTES
15. SUBJECT TERMS
16. SECURITY CLASSIFICATION OF:
17. LIMITATION OF
19a. NAME OF
c. THIS PAGE
Standard Form 298 (Rev. 8-98)
Prescribed by ANSI Std Z39-18
Priority List of Research Areas for Radiological
Nuclear Threat Countermeasures
Priority Area of research
Radioprotector: Pre-exposure agents
Therapeutic agents: Postexposure treatment
Cytokines and growth factors
Mechanisms of radiation-induced injury
Biodosimetry assay automation
Biomarkers and devices for biodosimetry
Training in the radiation sciences
Information repository of investigational countermeasures
Medical follow-up of exposed populations
Risk communication and psychological consequences
Development of animal models
Mechanisms of radiation-induced carcinogenesis
Teratogenesis and hereditary effects
signed one of four priorities: top, high, medium or low as
judged by their relevance to this mission. The top priority
was given to areas in which research is urgently needed to
provide the best opportunities for life-saving interventions
in the event of a radiological or nuclear attack. In general,
higher priority was given to areas focusing on immediate,
rather than delayed, consequences of radiation exposure.
The priorities reflect the perceived relevance to the terrorist
threat but do not represent a judgment on the intrinsic value
of the research; all areas listed were deemed important to
our long-term understanding of radiation injury and coun-
termeasures. Furthermore, many research areas in radiation
sciences that are not critical to radiological/nuclear threat
countermeasures are and will continue to be important to
the advancement of medical care and the science of the
nation. The effort of the research subgroup built on the
meetings and documents (1–4) produced by several previ-
ous working groups and committees.3The 18 key research
areas identified by the committee are discussed below.
1. To develop new agents to prevent the adverse biomed-
ical consequences of exposure to ionizing radiation.
2. To provide strategies in conjunction with the U.S. Food
and Drug Administration’s (FDA) regulatory require-
ments to facilitate preclinical development and clinical
implementation of new agents and regimens.
In the event of a radiological/nuclear terrorist attack, it
will be important to provide first responders, remediation
workers and, if there is advance warning, the resident pop-
ulation with a radioprotector that would mitigate the effects
3Radiobiology Research Review Meeting, held in Bethesda, MD on
February 26, 2003, sponsored by the National Institute of Allergy and
Infectious Diseases of NIH; Molecular and Cellular Biology of Moderate
Dose Radiation and Potential Mechanisms of Radiation Protection Work-
shop, held in Bethesda, MD on December 17–18, 2001, sponsored by the
National Cancer Institute, NIH; Education and Training for Radiation
Scientists Workshop, held in Bethesda, MD May 12–14, 2003, sponsored
by American Society of Therapeutic Radiology and Oncology and Ra-
diation Research Program, National Cancer Institute, NIH; Report of the
Medical Preparedness and Response Subgroup of the Working Group on
Radiological Dispersal Device (RDD) Preparedness, Department of
Homeland Security, May 2003; Report of the Medical Preparedness and
Response Subgroup of the Working Group on Radiological Dispersal De-
vice (RDD) Preparedness, Department of Homeland Security, May 2003;
Animal Experimentation at the Frontiers of Molecular, Cellular, Tissue
Radiobiology, 1996, sponsored by NASA; Modifying Normal Tissue
Damage Postirradiation; Report of a workshop held in Bethesda, MD on
September 6–8, 2000, sponsored by the Radiation Research Program,
National Cancer Institute, NIH; and Basic Research Needs for Countering
Terrorism, based on a workshop held in Gaithersburg, MD on February
28 to March 1, 2002, sponsored by the Department of Energy, http://
of exposure to ionizing radiation. Ideally this agent would
be long-lasting, would be easily administered, preferably
orally, and would have low toxicity. Amifostine, shown in
animal studies to be a radioprotector, is FDA-approved for
specific consequences of radiation therapy, but it has sig-
nificant side effects and a limited window of effectiveness
(5). Other agents are in preclinical phases of development.
For example, the steroid 5-androstenediol has been shown
to provide moderate protection against certain radiation ef-
fects in rodents (6, 7). The soy isoflavone genistein and
nutraceuticals including vitamin E analogs are also under
investigation as possible radioprotectors (8–10). Much
more research needs to be done. Appropriate expertise and
resources must be available to conduct radiation toxicity
and radiation protection experiments including concept de-
velopment, drug development, long-term toxicity studies,
and translation to clinical testing and application. Of sig-
nificance, this area of research is applicable to oncology
and to accidental occupational exposures as well as to gen-
eral population exposures.
THERAPEUTIC AGENTS (POSTEXPOSURE
To develop new therapeutic agents that can be used to
treat people who have been exposed to ionizing radiation.
In the event of a terrorist attack with a radiological or
nuclear device, treatment of the exposed population will be
a very high priority. Treatment of minor casualties as out-
patients will be necessary to ensure adequate hospital fa-
cilities. Casualties with life-threatening infection, bleeding
and gastrointestinal symptoms will require in-patient med-
ical attention. However, people with lower exposures, of
which there may be many, could receive therapeutic agents
in the outpatient setting. Currently, available treatments are
not optimal for administration to mass casualties, requiring
intravenous administration and monitoring for severe side
effects. The therapeutic armamentarium needs to be ex-
Some classes of agents are discussed separately in this
document because of the maturity of their development.
However, development of new therapeutic agents need not
be constrained to these categories. Possibilities exist in fla-
vonoids, prostaglandins, steroids and nitroxides, among
others (1, 3, 11, 12). New agents may be identified as we
learn more about the mechanisms of radiation injury (12).
Novel combinations of therapeutic agents might provide
synergism, allow use of lower doses, and thereby limit side
effects and/or facilitate achieving effective treatment. Com-
bined therapies may be necessary to treat all aspects of the
injury, but the interactions of the drugs must be assessed.
ANTIMICROBIAL AGENTS AFTER RADIATION
1. To optimize protocols for antimicrobial therapy for in-
fections associated with radiation exposure.
2. To evaluate the physiological and cellular mechanisms
that lead to infection with the goal of developing new
Infection is a primary medical complication and major
cause of mortality after exposure to ionizing radiation. An-
timicrobial defenses are compromised by exposure to ra-
diation. The normal barriers to infection in the skin, air-
ways and gastrointestinal tract are compromised, and the
immune response to pathogens is reduced. The microbial
flora in the gut is disrupted, local toxins are released, and
pathogens can cross from the intestine into the body (trans-
location), leading to systemic infection that can result in
shock and death.
Mortality often can be averted by administering antimi-
crobials to prevent or treat the infection. However, accepted
antimicrobial strategies for minimizing disease in individ-
uals with an intact immune system often are inadequate
when host immune defenses and tissue integrity have been
compromised by exposure to radiation (13, 14). The guide-
lines for antimicrobial therapy in febrile neutropenic pa-
tients do not apply to radiation casualties. Additional data
in animals and humans are required to determine optimal
therapy for radiation-related infections. Research on the
physiological and cellular mechanisms that lead to infection
also are necessary for the development of interventions to
prevent and attenuate infections.
CYTOKINES AND GROWTH FACTORS
1. To obtain an FDA-approved indication for currently
marketed cytokines to be used for radiation injury.
2. To develop additional cytokines and growth factors for
treatment of radiation injury
Exposure to radiation at moderate doses causes a pro-
found decrease in cells in the bone marrow and places pa-
tients at risk of death from infection (secondary to neutro-
penia) or bleeding (secondary to thrombocytopenia). By
stimulating the repopulation of neutrophils and thrombo-
cytes in the bone marrow, some cytokines have been found
to promote recovery in animal models (1, 4, 15). G-CSF
(Filgrastim, Neupogen?), pegylated G-CSF (pegfilgrastim,
Neulasta?), GM-CSF (sargramostim, Leukine?), and IL11
(oprelvekin, Neumega?) are now FDA-approved for the
profound neutropenia and thrombocytopenia that can occur
with cancer chemotherapy. An FDA indication for radiation
injury does not yet exist, although many animal efficacy
studies have been completed.
A limitation of G-CSF and IL11 is that they need to be
administered by daily injection for an extended period. In
addition, IL11 has severe toxicity. New formulations that
have a prolonged effect (e.g. pegfilgrastim, which requires
only one or two injections) would simplify the logistics of
administration and reduce the requirement for patient fol-
low-up in a mass casualty situation.
As demonstrated by G-CSF and IL11, cytokines and
growth factors are very promising classes of compounds.
Additional research is needed to advance this area and to
optimize the use of cytokines and growth factors for treat-
ment of radiation injury. Thrombopoietin (TPO), stem cell
factor (SCF), and megakaryocyte growth and development
factor (MDF) are currently under investigation (1, 16–19).
Keratinocyte growth factor (KGF) shows promise for treat-
ment of the gastrointestinal syndrome that follows radiation
exposure as well as for prevention of some of the late se-
quelae (1, 20, 21). These and other agents need to be further
explored, tested and developed.
MECHANISMS OF RADIATION-INDUCED INJURY
1. To understand the mechanisms of radiation injury at the
molecular, cellular, tissue and organism levels as a basis
for development of preventative, therapeutic and diag-
2. To develop new medical interventions and diagnostics
for radiation injury.
To prevent, treat or ameliorate radiation injury to tissue
requires an understanding of the basic mechanisms of in-
jury at the molecular, cellular, tissue and organism level.
Radiation injury can manifest itself early or years after the
exposure (12, 22). In either case, the initiating biological
events that trigger the pathology and the biological events
that sustain the progression must be understood. For ex-
ample, understanding the biological basis for the loss of
immune progenitor cells in the bone marrow will allow the
logical development of interventions to mitigate the adverse
effects. Increasing evidence suggests the involvement of the
renin-angiotensin system in radiation nephropathy; capto-
pril, an angiotensin-converting enzyme (ACE) inhibitor,
and angiotensin II (AII) blockers show promise for treat-
ment (11, 23). Pentoxifylline and tocopherol have been
shown to induce regression of superficial radiation-induced
fibrosis (24). Late-developing scarring of lung and other
tissue has been untreatable, but new knowledge of the
mechanisms of the development of this damage could lead
to new interventions.
Only by understanding the progression from the initial
radiation injury and its secondary effects to the late func-
tional manifestations of tissue damage will effective ther-
apeutic agents be developed (12). Mechanistic studies will
provide new concepts about how to intervene, which could
lead to more effective, less toxic interventions.
The injuries considered in this requirement include late
effects of radiation that cause functional damage to tissues
such as the lungs and kidneys and specifically exclude car-
cinogenesis, which is addressed in a separate section.
BIODOSIMETRY ASSAY AUTOMATION
To improve, through automation, the speed and efficien-
cy of biodosimetric assays for triage and therapy.
If there is a radiological or nuclear incident, medical fa-
cilities will be severely burdened with people worried about
their radiation exposures. Some will have received medi-
cally significant doses of radiation; others will not. All will
require assessment. To handle this situation, biodosimetric
systems must be rapid and efficient.
A multifaceted and integrated biodosimetry system using
early physical assessments, bioindicators and biological
dose assessments to aid clinical management can provide
the dose estimates necessary for triage. However, despite
the robustness and adaptability of existing biodosimetric
approaches, the process is tedious and time-consuming with
limited sample throughput. Efforts are under way to auto-
mate the biodosimetric cytogenetic analysis and to increase
throughput by increasing efficiency at various steps in sam-
ple processing, preparation, analysis and reporting (25–27).
Existing technologies can be tapped to achieve this goal.
Some currently available, off-the-shelf technologies that
can be applied include robotic devices for handling blood
and isolating blood cells, microprocessor-controlled auto-
mated pipetting devices for transferring reagents, modules
for 20 to 50 slides for simultaneous staining, and using
automated instruments to ensure good laboratory practice.
Biodosimetry assay automation efforts should be consistent
with the relevant International Standard Organization (ISO)
standards used by certified reference laboratories.
Similarly, rapid throughput for analysis of radionuclides
in biological specimens is needed. In the event of a radio-
logical incident, it will be critical to determine not only the
radiation dose received but also the type and amount of
internal radionuclide contamination to provide appropriate
medical countermeasures. The current laboratory generally
has the capability of processing tens of samples per day
and requires several days to more than a week to provide
results. Improved, automated systems ensuring high
throughput and good laboratory practices must be devel-
BIOMARKERS AND DEVICES FOR BIODOSIMETRY
To develop bioassays that can identify radiation-exposed
individuals and that can provide individual radiation dose
assessments to enable triage and optimal medical manage-
In the event of a mass radiological casualty incident, new
technologies will be required for rapid and early identifi-
cation of those who are exposed and for accurate assess-
ment of exposure levels. Biodosimetric tools must be avail-
able in the field as well as in hospitals.
Hematological, cytological and molecular biomarkers are
radiation-responsive candidates for bioassays (1, 11, 28).
However, work remains for complete validation of candi-
date radiation biomarkers over the full range of possible
scenarios. Existing biodosimetry has limited usefulness at
doses less than 1 Gy. Development of hand-held devices
for measurement of lymphocyte counts, cytological mark-
ers, and molecular biomarkers is needed to allow deploy-
ment to the field. The throughput of both hand-held and
hospital-based systems needs to be enhanced to handle
mass casualties. There are opportunities to integrate the as-
sessment of radiation exposure with the determination of
exposure to other threat agents (i.e. biological and chemi-
cal). In the long term, biomarkers may be able to predict
individual risk with high sensitivity, high specificity and
long-term stability, and at low cost. Such biomarkers may
also serve as tools for epidemiological studies of exposed
TRAINING IN RADIATION SCIENCES
To train new scientists capable of addressing the critical
research requirements described in this document.
The national capacity to foster new developments in ra-
diation science and to translate that science to medical
countermeasures for response to radiological/nuclear ter-
rorism is limited by a shortfall in the number of appropri-
ately trained personnel (2, 29). Radiation scientists will be
needed to develop the medical countermeasures, to treat
radiation casualties, and to provide expert advice in radio-
logical and nuclear emergencies. The cadre of experts needs
to include those trained in applied sciences such as health
physics, nuclear engineering, radiation medicine, radiation
safety, and dosimetry as well as the more basic sciences
relevant to radiobiology.
The education and training of the next generation of ra-
diation scientists must begin now to ensure that the nec-
essary cadre of experts is available to meet the current and
future needs of society. Opportunities need to be created
for the development of new or expanded training programs.
Because of the multidisciplinary nature of radiation biolo-
gy, broad-based training programs such as inter-institutional
consortia should be encouraged.
In the event of a radiological or nuclear terrorist attack,
radiation sciences professionals will be called upon to talk
to the public about health risks and available countermea-
sures. For these communications to be effective, it will be
essential to provide scientists with the skills needed to con-
vey complicated ideas clearly and effectively to non-spe-
1. To understand the mechanisms of the interactions of ex-
posures to radiation in combination with chemical
agents, pathogens and traumatic injury (burn and blast).
2. To develop medical interventions for radiation injury in
combination with other chemical, biological or physical
Experimental data that define the interactions of threat
agents and the implications of combined exposures for
treatment and prophylaxis are needed. Existing data suggest
that the interaction of radiation with other injuries could
produce severe medical complications (30, 31).
Since exposure to radiation impairs immune responses,
a radiation casualty would become more susceptible to in-
fection. Similarly, since both ionizing radiation and certain
chemical warfare agents, such as sulfur mustard, cause
bone marrow suppression and DNA damage, synergistic
effects would be expected. Interaction of radiation injuries
with physical injuries such as burns and wounds also com-
plicates therapy. Radiation impairs the healing process and
predisposes to infectious complications. Other less well-un-
derstood interactions between radiation and other exposures
could complicate the pathology and medical treatment.
Because of these risks, understanding the mechanisms of
interactions and developing countermeasures for combined
exposures are important for full preparedness in the event
of a radiological or nuclear attack.
INFORMATION REPOSITORY OF INVESTIGATIONAL
To establish an information repository (both public and
commercial confidential) of pharmaceuticals and bioassays
under development as radiological/nuclear threat counter-
The federal government is taking steps to facilitate the
development of medical countermeasures to diagnose, pre-
vent, mitigate or treat diseases caused by ionizing radiation
related to a terrorist attack. To ensure coordinated and time-
ly actions by the federal government to foster development
of medical countermeasures for civilian biodefense, it is
important that the relevant federal agencies have access to
commercial confidential information and that such infor-
mation be maintained by a single entity to avoid duplicative
Because of intellectual property issues, many product de-
velopers in the private sector are reluctant to make their
efforts publicly available. This obstacle can be overcome
by ensuring confidentiality by the federal agency that
serves as the repository of information. Information would
be released only to other appropriate federal agencies that
have an official need to use the information and will certify
that they will not release such information publicly.
Before a federal agency could formally accept this re-
sponsibility, the logistics of the proposal, the cost of the
proposal, and the availability of adequate funding for this
function should be established. Since many of the logistics
are already in place at the Food and Drug Administration
(FDA) to protect commercial confidential information, it is
a logical candidate. Other agencies with the potential to
serve this function include the Department of Homeland
Security, Department of Health and Human Services (Na-
tional Institutes for Health), and the White House’s Office
of Science and Technology Policy. There may be a similar
need for repositories of medical countermeasures for bio-
logical and chemical threat agents.
MEDICAL FOLLOW-UP OF EXPOSED POPULATIONS
To follow the health outcomes of an appropriate fraction
of an exposed population to evaluate the effectiveness of
therapeutic measures and the correlation of health effects
with dosimetry. These data will suggest modifications in
medical approaches to improve emergency preparedness.
After a terrorist radiological event, there will be a pop-
ulation that has been exposed to a range of doses, evaluated
biodosimetrically, and treated with the most up-to-date ther-
apeutic agents. This population would provide an excellent
resource for outcome studies. Biomarkers for dosimetry can
be assessed over time to improve delayed dose reconstruc-
tion capabilities and to evaluate the correlations of health
effects with dosimetry. By following the health of this pop-
ulation, information regarding the efficacy of particular in-
terventions could be obtained. Results would be directly
applicable to preparedness for subsequent events.
There are additional needs to assess the impact of inter-
ventions (prophylaxis, treatment or diagnostics) on popu-
lations and to assess the safety and efficacy of these mea-
sures. If an investigational product is administered, FDA’s
investigational new drug (IND) regulations require that pa-
tients be evaluated for safety and efficacy. Similarly, if a
patient is given a product that was approved under FDA’s
‘‘animal rule’’, confirmatory human studies are also needed.
In addition to these regulatory considerations, there is also
the federal government’s public health mission to develop
generalizable medical knowledge from these cohorts and to
develop public health policy for future events.
In addition, valuable data might be obtained from ret-
rospective studies of the impact of the interventions used
to treat victims of previous radiation accidents and radio-
therapy complications. For example, more than 300 persons
have suffered from the acute radiation syndrome, and thou-
sands have had local radiation injuries and burns (32, 33).
Although there have been some studies of the effects of the
various medical interventions used for these patients or of
the long-term changes in biomarkers in these people, more
systemic studies could well provide valuable insights. In
addition, one could critically examine the radiation oncol-
ogy data on treatments given to minimize complications to
determine which are effective and which would apply to
the scenarios of importance here.
To develop and assess novel approaches using progenitor
cells to treat the severe loss of bone marrow cells and other
organ stem cells occurring after exposure to radiation.
A life-threatening consequence of radiation exposure is
the severe decrease in neutrophils, white blood cells pro-
duced in the bone marrow to fight infection. When these
cells fall below a certain level, survival is unlikely (1). If
the cells can be replaced, survival should be enhanced.
Some of the pharmacological agents discussed elsewhere
in this document stimulate the progenitors of these cells to
make new cells. Another approach is to transplant bone
marrow from a healthy donor. This requires careful match-
ing of several tissue features to prevent rejection of the
transplanted cells. In 1986, bone marrow transplants and
fetal liver transplants were attempted in patients exposed to
high doses of radiation after the accident at Chernobyl, but
they were without benefit (34). However, relevant technol-
ogies have advanced significantly since then, and progeni-
tor cell transplants continue to be developed for use in pa-
tients with advanced malignancies. These same technolo-
gies may benefit patients who develop acute radiation syn-
drome with bone marrow ablation (4, 11).
Alternative progenitor cell technologies (e.g. cell banks,
ex vivo amplification, etc.) are also in development. These
approaches avoid the need to match cell types either by
using the patient’s own cells and amplifying them outside
the body or by using cells from an early stage of devel-
opment. These technologies may avoid the need for the
invasive interventions required with bone marrow trans-
plants. Much research remains to be done to develop and
assess these approaches to the treatment of radiation injury.
In addition, basic research programs are needed to de-
velop progenitor cells for other radiosensitive organs, in-
cluding liver, lung, kidney, gastrointestinal tract and central
To develop improved decorporation therapies and better
delivery systems for chelators.
No significant original research to improve radioisotope
chelation therapy or to identify new agents for radioisotope
decorporation therapy has occurred in the U.S. in over 30
years. The DTPAs and Prussian Blue have a role in the
decorporation of radioisotopes. Insoluble Prussian Blue
(PB), ferric hexacyanoferrate, enhances excretion of iso-
topes of cesium and thallium from the body by means of
ion exchange. PB is most likely to be used orally for treat-
ment of victims of a137Cs ?-radiation dispersal device. PB
is FDA-approved as 500-mg capsules and is marketed as
Radiogardase?. Ca-DTPA and Zn-DTPA have recently
been approved by the FDA for treating internal contami-
nation with plutonium, americium and curium. These che-
lating agents generally are administered intravenously, al-
though they can also be administered by inhalation in a
nebulizer. An oral delivery system for DTPA would offer
significant logistic advantages. Pediatric formulations of PB
are also needed.
RISK COMMUNICATION AND PSYCHOLOGICAL
1. To understand the characteristics of at-risk populations
for effective communication and intervention.
2. To develop approaches to mitigate the psychological im-
pact of a terrorist event.
Terrorism is specifically designed to have psychological
impact. Psychological effects may well be the major con-
sequence of a terrorist radiological event even if other med-
ical effects are limited (4, 35, 36). Those most vulnerable
are pregnant women, mothers of young children, children,
first responders and those with prior mental illness. The
anxiety and stress that result from terrorism can cause med-
ical facilities to be overwhelmed with concerned individ-
uals. People worried about minor symptoms are likely to
flood hospitals and other health care facilities. Because of
the physiological consequences of stress, an increase in the
incidence of disease within the population can be expected.
The psychological effects as a result of disasters, accidents
and terrorist events often extend for many years after ex-
posure. Good risk communication can go far in mitigating
the fear and panic in the population. Developing effective
strategies to prepare for and to respond to an event is likely
to limit the psychological consequences. Research is need-
ed to provide a greater understanding of the at-risk popu-
lations in the contexts of the individual, family, social net-
works, and community and to develop approaches to mit-
igate the psychological impact of terrorist events.
DEVELOPMENT OF ANIMAL MODELS
To develop and validate animal models for the assess-
ment of radiation injury and the evaluation of potential
Improved animal models are required for testing of ther-
apeutics for treatment and prophylaxis of radiation injury
(12). Safety and efficacy of new therapeutic agents must be
demonstrated in animals before clinical trials can be initi-
ated. Since FDA’s ‘‘animal rule’’ is likely to be applied to
treatments of radiation injury for determination of FDA ap-
proval, having improved animal models available is very
important. Non-human primates are increasingly difficult to
obtain for these assessments and in fact may not always be
the best model of the human condition. In addition, animal
experimentation is necessary to accurately predict the med-
ical consequences of radiation exposure in humans and to
develop new, mechanistically targeted interventions. De-
velopment of new models can provide appropriate tools to
carefully assess mechanisms of radiation damage, biomark-
ers for biodosimetry, etc. Primates, dogs, ferrets, mice and
non-mammalian species are each optimal for particular end
points, but each also has limitations. Such new systems as
‘‘humanized’’ mice and genetically engineered animals
might provide improved models of a human condition or
expedite research efforts by providing well-defined model
systems (3, 12). Use of a wide range of model systems may
well be necessary to thoroughly address relevant questions.
MECHANISMS OF RADIATION-INDUCED
1. To understand the mechanisms of radiation-induced cel-
lular and tissue injury that lead to cancer.
2. To develop pharmaceuticals that prevent cancers in-
duced by radiation.
Research on radiation-induced cancer involves micro-
dosimetry, molecular genetics and other basic science ef-
forts, epidemiological studies of exposed populations, and
translational research to develop and implement prevention
and intervention strategies.
Prevention of carcinogenesis requires an understanding
of the basic mechanisms of DNA damage and repair at the
molecular and cellular level. However, carcinogenesis also
involves interactions among the cells in an organ or even
the organism; for example, cell-to-cell communication and
whole-body homeostatic mechanisms (e.g. immune re-
sponses) can have an impact on the ultimate development
of a cancer. By understanding these mechanisms, therapeu-
tic and protective drugs might be developed that target ap-
propriate biochemical or physiological mechanisms.
Currently a few drugs are under investigation for their
ability to prevent late effects of radiation, including carci-
nogenesis. Amifostine and nitroxides, for example, can pre-
vent mutagenesis in cell systems and are anticarcinogenic
in rodents (37, 38). The applicability of these findings to
humans is still unknown.
To conduct epidemiological studies to acquire scientific
evidence regarding the long-term health effects of ionizing
radiation, especially cancer.
Radiation epidemiology is the statistical analysis of ra-
diation effects in exposed populations, to derive correla-
tions between the observed end point and exposure, and to
generate hypotheses about possible causation. In the past,
radiation epidemiology has concentrated on the observation
of health effects, mainly related to cancer. Populations that
have been studied extensively include atomic bomb survi-
vors, nuclear workers, uranium miners, patients who have
received medical exposure, those exposed to fallout, and
those living in areas of high background radiation (33, 39).
Ongoing epidemiological studies of various populations,
especially those exposed to low-dose external and internal
radionuclides, will provide information on long-term health
effects in various exposure scenarios (33, 39).
Research is needed to improve epidemiological and bio-
statistical methods and models. These efforts will address
the limitations in epidemiology that result from low inci-
dence rates and long latent periods. In addition, in the lon-
ger term, biological markers of both dose and radiation-
induced health effects should be developed. Recent bio-
medical research suggests that new end points that serve as
predictors for both cancer and non-cancer outcomes might
offer high sensitivity and specificity in a shorter time. One
current study (40) is showing a distinctive molecular
change in lung tissue only in workers exposed to plutoni-
um; another (41) shows distinctive chromosome changes in
the lymphocytes of workers exposed to neutrons, which
could assist dose reconstruction. These biomarkers cannot
stand alone; they need to be developed and validated. Their
use after a radiological event can be useful in tracking ther-
apeutic outcomes and predicting health consequences of ra-
diation exposures as described above.
TERATOGENESIS AND HEREDITARY EFFECTS
To assess the mechanisms of teratogenic and hereditary
effects of exposure to radiation and to develop counter-
measures for the effects.
Teratogenesis in this context refers to malformations after
in utero exposure to radiation. There has been extensive
research on animal models and studies of the children of
women who were pregnant at the time of the atomic bomb-
ings or during radiation therapy (42). There appears to be
a threshold dose for teratogenic effects at a fetal dose of
0.1–0.2 Gy. Above this threshold, the most sensitive tissue
is the central nervous system, which shows pronounced ef-
fects, especially at 8–16 weeks estimated gestational age.
Development of protective agents for the in utero exposures
would require an understanding of the mechanisms of in-
jury and targeted therapeutics to prevent or treat the effects.
With maternal exposures to radionuclides, particularly io-
dine and strontium, radioactive materials can transfer to the
fetus; intake of these radionuclides can be minimized
through standard protective actions.
Hereditary effects that are passed on to subsequent gen-
erations have been studied extensively in animal models as
well as in atomic bomb survivors, radiation therapy pa-
tients, and nuclear workers. Current scientific literature sug-
gests that the risk of hereditary effects is very low, signif-
icantly less than the risk of radiation-induced cancer.
1. C. N. Coleman, W. F. Blakely, J. R. Fike, T. J. MacVittie, N. F.
Metting, J. B. Mitchell, J. E. Moulder, R. J. Preston, T. M. Seed and
R. S. Wong, Molecular and Cellular Biology of Moderate-Dose (1–
10 Gy) Radiation and Potential Mechanisms of Radiation Protection:
Report of a workshop at Bethesda, Maryland, December 17–18,
2001. Radiat. Res. 159, 812–834 (2003).
2. C. N. Coleman, H. B. Stone, G. A. Alexander, M. H. Barcellos-Hoff,
J. S. Bedford, R. G. Bristow, J. R. Dynlacht, Z. Fuks, L. S. Gorelic
and E. M. Zeman, Education and Training for Radiation Scientists:
Radiation Research Program and American Society of Therapeutic
Radiology and Oncology Workshop, Bethesda, Maryland, May 12–
14, 2003. Radiat Res. 160, 729–737 (2003).
3. H. B. Stone, W. H. McBride and C. N. Coleman, Modifying Normal
Tissue Damage Postirradiation. Report of a workshop sponsored by
the Radiation Research Program, National Cancer Institute, Bethesda,
Maryland, September 6–8, 2000. Radiat Res. 157, 204–223 (2002).
4. J. K. Waselenko, T. J. MacVittie, W. F. Blakely, N. Pesik, A. L. Wiley,
W. E. Dickerson, H. Tsu, D. L. Confer, C. N. Coleman and T. Seed,
Medical management of the acute radiation syndrome: Recommen-
dations of the Strategic National Stockpile Radiation Working Group.
Ann. Intern. Med. 140, 1037–1051 (2004).
5. C. R. Culy and C. M. Spencer, Amifostine: An update on its clinical
status as a cytoprotectant in patients with cancer receiving chemo-
therapy or radiotherapy and its potential therapeutic application in
myelodysplastic syndrome. Drugs 61, 641–684 (2001).
6. M. H. Whitnall, T. B. Elliott, R. A. Harding, C. E. Inal, M. R. Lan-
dauer, C. L. Wilhelmsen, L. McKinney, V. L. Miner, W. E. Jackson
3rd and T. M. Seed, Androstenediol stimulates myelopoiesis and en-
hances resistance to infection in gamma-irradiated mice. Int. J. Im-
munopharmacol. 22, 1–14 (2000).
7. M. H. Whitnall, C. L. Wilhelmsen, L. McKinney, V. Miner, T. M.
Seed and W. E. Jackson 3rd, Radioprotective efficacy and acute tox-
icity of 5-androstenediol after subcutaneous or oral administration in
mice. Immunopharmacol. Immunotoxicol. 24, 595–626 (2002).
8. K. S. Kumar, V. Srinivasan, R. Toles, L. Jobe and T. M. Seed, Nu-
tritional approaches to radioprotection: Vitamin E. Mil. Med. 167
(Suppl. 2), 57–59 (2002).
9. M. R. Landauer, V. Srinivasan and T. M. Seed, Genistein treatment
protects mice from ionizing radiation injury. J. Appl. Toxicol. 23,
10. J. F. Weiss and M. R. Landauer, Protection against ionizing radiation
by antioxidant nutrients and phytochemicals. Toxicology 189, 1–20
11. J. E. Moulder, Post-irradiation approaches to treatment of radiation
injuries in the context of radiological terrorism and radiation acci-
dents: A review. Int. J. Radiat. Biol. 80, 1–8 (2004).
12. H. B. Stone, J. E. Moulder, C. N. Coleman, K. K. Ang, M. S. Ansch-
er, M. H. Barcellos-Hoff, W. S. Dynan, J. R. Fike, D. J. Grdina and
D. Zaharevitz, Models for Evaluating Agents Intended for the Pro-
phylaxis, Mitigation and Treatment of Radiation Injuries. Report of
an NCI workshop, December 3–4, 2003. Radiat. Res. 162, 711–728
13. I. Brook, R. I. Walker and T. J. MacVittie, Effect of antimicrobial
therapy on bowel flora and bacterial infection in irradiated mice. Int.
J. Radiat. Biol. 53, 709–716 (1988).
14. I. Brook, T. B. Elliott, G. D. Ledney, M. O. Shoemaker and G. B.
Knudson, Management of postirradiation infection: Lessons learned
from animal models. Mil. Med. 169, 194–197 (2004).
15. T. J. MacVittie and A. M. Farese, Cytokine-based treatment for acute
radiation-induced myelosuppression: Preclinical and clinical perspec-
tive. In The Medical Basis for Radiation-Accident Preparedness: The
Clinical Care of Victims (R. C. Ricks, M. E. Berger and F. M.
O’Hara, Eds.), pp. 53–72. Parthenon, Boca Raton, FL, 2002.
16. C. E. Dunbar, M. Takatoku and R. E. Donahue, The impact of ex
vivo cytokine stimulation on engraftment of primitive hematopoietic
cells in a non-human primate model. Ann. NY Acad. Sci. 938, 236–
17. F. Herodin, P. Bourin, J. F. Mayol, J. J. Lataillade and M. Drouet,
Short-term injection of antiapoptotic cytokine combinations soon af-
ter lethal gamma-irradiation promotes survival. Blood 101, 2609–
18. M. A. Mouthon, A. Van der Meeren, M. H. Gaugler, T. P. Visser, C.
Squiban, P. Gourmelon and G. Wagemaker, Thrombopoietin pro-
motes hematopoietic recovery and survival after high-dose whole
body irradiation. Int. J. Radiat. Oncol. Biol. Phys. 43, 867–875
19. K. M. Zsebo, K. A. Smith, C. A. Hartley, M. Greenblatt, K. Cooke,
W. Rich and I. K. McNiece, Radioprotection of mice by recombinant
rat stem cell factor. Proc. Natl. Acad. Sci. USA 89, 9464–9468
20. C. L. Farrell, J. V. Bready, K. L. Rex, J. N. Chen, C. R. DiPalma,
K. L. Whitcomb, S. Yin, D. C. Hill, B. Wiemann and D. L. Lacey,
Keratinocyte growth factor protects mice from chemotherapy and ra-
diation-induced gastrointestinal injury and mortality. Cancer Res. 58,
21. E. S. Yi, S. T. Williams, H. Lee, D. M. Malicki, E. M. Chin, S. Yin,
J. Tarpley and T. R. Ulich, Keratinocyte growth factor ameliorates
radiation- and bleomycin-induced lung injury and mortality. Am. J.
Pathol. 149, 1963–1970 (1996).
22. W. H. McBride, C-S. Chiang, J. L. Olson, C-C. Wang, J-H. Hong, F.
Pajonk, G. J. Dougherty, K. S. Iwamoto, M. Pervan and Y-P. Liao,
A sense of danger from radiation. Radiat. Res. 162, 1–19 (2004).
23. J. E. Moulder, B. L. Fish and E. P. Cohen, ACE inhibitors and AII
receptor antagonists in the treatment and prevention of bone marrow
transplant nephropathy. Curr. Pharm. Des. 9, 737–749 (2003).
24. S. Delanian, R. Porcher, S. Balla-Mekias and J. L. Lefaix, Random-
ized, placebo-controlled trial of combined pentoxifylline and tocoph-
erol for regression of superficial radiation-induced fibrosis. J. Clin.
Oncol. 21, 2545–2550 (2003).
25. W. F. Blakely, A. L. Brooks, R. S. Lofts, G. P. van der Schans and
P. Voisin, Overview of low-level radiation exposure assessment: Bio-
dosimetry. Mil. Med. 167 (Suppl. 2), 20–24 (2002).
26. R. Kanda, Improvement of accuracy of chromosome aberration anal-
ysis for biological radiation dosimetry. J. Radiat. Res. (Tokyo) 41,
27. J. D. Tucker, FISH cytogenetics and the future of radiation biodosi-
metry. Radiat. Prot. Dosim. 97, 55–60 (2001).
28. P. Dent, A. Yacoub, J. Contessa, R. Caron, G. Amorino, K. Valerie,
M. P. Hagan, S. Grant and R. Schmidt-Ullrich, Stress and radiation-
induced activation of multiple intracellular signaling pathways, Ra-
diat. Res. 159, 283–300 (2003).
29. S. Rockwell, Training in the radiation sciences: A national and in-
ternational need. Radiat. Res. 159, 703–704, (2003). [editorial]
30. P. Kumar and G. C. Jagetia, A review of triage and management of
burn victims following a nuclear disaster. Burns 20, 397–402 (1994).
31. T. C. Pellmar, Effects of radiation in combination with biological or
chemical warfare agents. In Public Protection from Nuclear, Chem-
ical, and Biological Terrorism (A. Brodsky, R. H. Johnson, Jr. and
R. E. Goans, Eds.), pp. 503–511. Medical Physics Publishing, Mad-
ison, WI, 2004.
32. R. C. Ricks, M. E. Berger, E. C. Holloway and R. E. Goans, REAC/
TS radiation accident registry: Update of accidents in the United
States, 2000. Available online at http://www.irpa.net/irpa10/cdrom/
33. National Research Council, Committee on the Biological Effects of
Ionizing Radiation, Health Effects of Exposure to Low Levels of Ion-
izing Radiation (BEIR V). National Academy Press, Washington, DC,
34. A. Baranov, R. P. Gale, A. Guskova, E. Piatkin, G. Selidovkin, L.
Muravyova, R. E. Champlin, N. Danilova, L. Yevseeva and L. Pe-
trosyan, Bone marrow transplantation after the Chernobyl nuclear
accident. N. Engl. J. Med. 321, 205–212 (1989).
35. C. A. Salter, Psychological effects of nuclear and radiological war-
fare. Mil. Med. 166 (Suppl.), 17–18 (2001).
36. NCRP, Management of Terrorist Events Involving Radioactive Ma-
terials, pp. 54–73. Report No. 138, National Council on Radiation
Protection and Measurements, Bethesda, MD, 2001.
37. D. J. Grdina, Y. Kataoka and J. S. Murley, Amifostine: Mechanisms
of action underlying cytoprotection and chemoprevention. Drug Me-
tabol. Drug Interact. 16, 237–279 (2000).
38. J. B. Mitchell and M. C. Krishna, Nitroxides as radiation protectors.
Mil. Med. 167 (Suppl. 2), 49–50 (2002).
39. D. L. Preston, Y. Shimizu, D. A. Pierce, A. Suyama and K. Mabuchi,
Studies of mortality of atomic bomb survivors. Report 13: Solid can-
cer and noncancer disease mortality: 1950–1997 Radiat. Res. 160,
40. S. A. Belinsky, D. M. Klinge, K. C. Liechty, T. H. March, T. Kang,
F. D. Gilliland, N. Sotnic, G. Adamova, G. Rusinova and V. Telnov,
Plutonium targets the p16 gene for inactivation by promoter hyper-
methylation in human lung adenocarcinoma. Carcinogenesis 25,
41. R. Kanda, M. Minamihisamatsu and I. Hayata, Dynamic analysis of
chromosome aberrations in three victims of the Tokai-mura criticality
accident. Int. J. Radiat. Biol. 78, 857–862 (2002).
42. C. Streffer, R. Shore, G. Konermann, A. Meadows, P. Uma Devi,
J. P. Withers, L. E. Holm, J. Stather and K. H. R. Mabuchi, Biological
effects after prenatal irradiation (embryo and fetus). A report of the
International Commission on Radiological Protection. Ann. ICRP 33,