Paper

SCIENTIFIC AND LOGISTICAL CONSIDERATIONS WHEN SCREENING FOR

RADIATION RISKS BY USING BIODOSIMETRY BASED ON BIOLOGICAL
EFFECTS OF RADIATION RATHER THAN DOSE: THE NEED FOR PRIOR
MEASUREMENTS OF HOMOGENEITY AND DISTRIBUTION OF DOSE

Harold M. Swartz,1,2 Ann Barry Flood,1 Vijay K. Singh,3,4 and Steven G. Swarts5
Downloaded from http://journals.lww.com/health-physics by BhDMf5ePHKbH4TTImqenVDXKvZuamIgsJa6Csq5NoASuDZuXZJmFAIs/wUAhyI6ggRhdQA1/brU= on 07/04/2020

conclude that combining the capability of methods such as in vivo

Abstract—An effective medical response to a large-scale radiation
event requires prompt and effective initial triage so that appropri-
ate care can be provided to individuals with significant risk for se-
vere acute radiation injury. Arguably, it would be advantageous to
use injury rather than radiation dose for the initial assessment;
i.e., use bioassays of biological damage. Such assays would be
based on changes in intrinsic biological response elements; e.g.,
up- or down-regulation of genes, proteins, metabolites, blood cell
counts, chromosomal aberrations, micronuclei, micro-RNA, cyto-
kines, or transcriptomes. Using a framework to evaluate the feasi-
bility of biodosimetry for triaging up to a million people in less
than a week following a major radiation event, Part 1 analyzes
the logistical feasibility and clinical needs for ensuring that bio-
markers of organ-specific injury could be effectively used in this
context. We conclude that the decision to use biomarkers of
organ-specific injury would greatly benefit by first having inde-
pendent knowledge of whether the person’s exposure was hetero-
geneous and, if so, what was the dose distribution (to determine
which organs were exposed to high doses). In Part 2, we describe
how these two essential needs for prior information (heterogeneity
and dose distribution) could be obtained by using in vivo nail do-
simetry. This novel physical biodosimetry method can also meet
the needs for initial triage, providing non-invasive, point-of-care
measurements made by non-experts with immediate dose esti-
mates for four separate anatomical sites. Additionally, it uniquely
provides immediate information as to whether the exposure was
homogeneous and, if not, it can estimate the dose distribution. We
1
Department of Radiology, Geisel School of Medicine at Dartmouth
College, Hanover, NH; 2Department of Medicine/Radiation Oncology,
Geisel School of Medicine at Dartmouth College, Hanover, NH; 3Department
of Pharmacology & Molecular Therapeutics, F. Edward Hébert School of
Medicine, Uniformed Services University of the Health Sciences, Bethesda,
MD; 4Armed Forces Radiobiology Research Institute, Uniformed Ser-
vices University of the Health Sciences, Bethesda, MD; 5Department of
Radiation Oncology, University of Florida, Gainesville, FL.
HMS and ABF are co-owners of Clin-EPR, LLC, which manufac-
tures and sells clinical EPR instruments for investigational use only; there
are are no other conflicts of interest.
For correspondence contact: H. M. Swartz, Department of Radiology,
Geisel School of Medicine at Dartmouth College, Hanover, NH, or email
at harold.m.swartz@dartmouth.edu.
(Manuscript accepted 11 November 2019)
0017-9078/20/0
Copyright © 2020 Health Physics Society
DOI: 10.1097/HP.0000000000001244
72
EPR nail dosimetry with bioassays to predict organ-specific dam-
age would allow effective use of medical resources to save lives.
Health Phys. 119(1):72–82; 2020
Key words: bioassay; dosimetry, personnel; emergencies, radiological;
emergency planning
INTRODUCTION
AFTER A radiation/nuclear event in which there is a potential
for significant risk to large numbers of people being ex-
posed, the first need is to rapidly determine who is at a signif-
icant risk of having severe acute effects from the radiation
exposure. This step (to triage people whether to enter the
medical care system or not) is particularly important when
the number of potentially exposed individuals exceeds the
capacity of the medical response efforts to follow all ex-
posed individuals closely. The traditional approach has been
to carry out the initial decisions based on estimates of dose
received by the individual using biodosimetry, if available,
to decide who should move to the next stage of triage. Usu-
ally this is based on estimates of the radiation dose to which
the individual is exposed and the associated biological in-
jury (Sullivan et al. 2013; Coleman and Koerner 2016).
However, some experienced scientists and clinicians in
the field of radiation biology are in favor of using indicators
of biological effects rather than radiation dose per se. Their
rationale is based on evidence suggesting that people re-
ceiving the same dose of radiation can manifest different re-
sponse to the radiation injury, sustaining acute injury at
different doses. Therefore, it is argued that the initial deci-
sions for triage should be based on a patient’s biological re-
sponse and not on the radiation dose received (Dainiak 2018;
Singh et al. 2018).
While this has been accomplished by using the conven-
tional approach for small-scale incidents in which all exposed
individuals at risk can be placed into an advanced medical care
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 Screening for radiation risks by using biodosimetry c H. M. SWARTZ ET AL.
system and their biological responses closely monitored, this
would not be feasible for a large-scale scenario involving
considerable numbers of exposed victims. New biodosimetry
methods, as well as ways to improve traditional biodosimetry
methods (e.g., via high throughput automation and comput-
erized analyses) have been proposed to handle an emergency
radiation scenario involving thousands of victims (Brenner
et al. 2015; Flood et al. 2016; Paul and Amundson 2008;
Rothkamm et al. 2013a and 2013b; Swartz et al. 2012;
Wang et al. 2019; Xu et al. 2013; Rogan et al. 2016).
Therefore, considerable recent effort has been directed
into developing screening approaches that are relevant to
large-scale scenarios and can provide information that is
more specific/accurate in predicting the possibility of devel-
oping serious injury to radiosensitive organs; e.g., hematopoi-
etic system (lymphocyte, neutrophil, and platelet depletion in
blood), gastrointestinal system (low citrulline levels in small
intestine), lung, and kidney. Such assays would be based on
changes in intrinsic biological response elements; e.g., up-
or down-regulation of genes, proteins, metabolites, blood cell
counts, chromosomal aberrations, micronuclei, micro-RNA,
cytokines, or transcriptomes. This focus on organ injury
has not only been advocated especially in the context of
screening for acute risk but also for assessing risk for sub-
acute and chronic effects to specific organs with the ex-
pectation that there would be the possibility of initiating
radiation mitigating strategies to decrease the probability
of long-term effects (NIH 2019).
The homogeneity of the exposure is another important
factor that goes beyond dose in predicting the response, be-
cause the predominant mode of life-threatening acute ef-
fects due to moderate radiation dose is usually injury to
the hematopoietic system. Therefore, the sparing of even a
modest amount of bone marrow is known to greatly improve
the probability of survival after receiving an otherwise poten-
tially lethal dose of radiation (Prasanna et al. 2010a). Conse-
quently, if it can be determined that the exposure is very
heterogeneous, then it might be especially useful to have in-
dicators of organ-specific damage; i.e., such information is
useful because the individual is less likely to have succumbed
to acute suppression of the hematopoietic system.
We discuss three aspects crucial to the success of organ-
specific biodosimetry:
1. What characteristics are important for a bioassay method
to have in order for it to be an effective tool to screen for
biological damage in specific organs?
2. How should such a method be integrated into an effec-
tive early triage system?
3. What additional information could make the use of organ-
specific bioassays of organ damage more effective for the
initial medical response in the context of a large-scale
radiation scenario?
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73
PART 1: REQUIREMENTS FOR THE EFFECTIVE
USE OF BIOMARKERS OF ORGAN-SPECIFIC
BIOLOGICAL DAMAGE FOR INITIAL TRIAGE
The mechanism of most or all of the biomarker induc-
tion assays whose purpose is to predict organ-specific injury
is based on dynamic changes in the levels of naturally occur-
ring biological response elements, such as genes and/or prod-
ucts produced through metabolism after radiation damage
occurs. Fig. 1 illustrates the general dynamic flow of these
changes over time following radiation exposure (shown
for upregulated responses in this case). (Fig. 1a illustrates
biologically-based biodosimeters; Fig. 1b illustrates physically-
based biodosimeters.) The dynamics in Fig. 1a apply to
all biologically-based biomarkers, including those intended
to estimate dose/system-based injury as well as those
intended to predict organ-specific injury.
Because these dynamics are common to all biologically-
based biomarkers, we can build upon our previous frame-
work (Flood et al. 2011, 2014, 2016), which evaluated the
practical feasibility of methods of biodosimetry used for es-
timating radiation dose or the likelihood of having life-
threatening systemic injuries. This framework can also
analyze the logistical needs and feasibility of using organ-
specific biomarkers in the context of planning the initial
medical response to large radiation scenarios.
As noted in our previous analyses, in order to use a
biodosimeter or biomarker effectively in a large radiation
scenario, it must be suitable for use under the circumstances
that are likely to be present, and the assays must be completed
within the specified window of time. For our purposes, we use
the standard planning scenarios in the US, which stipulate that
each method intended for triage during a large-scale radiation
scenario must be capable of acquiring the data for at least
1 million people within ~6 d and make such data available
to triage decision-makers (Sullivan et al. 2013; Coleman
and Koerner 2016).
In order to evaluate the feasibility and practicality of
achieving this goal for a large scale radiation scenario, it is
important to consider the full timeframe needed; i.e., starting
with collecting a sample from a potential victim in a disaster
setting, to delivering the results to the decision-makers re-
sponsible for deciding on the next steps for the individual,
with an emphasis on whether the individual should be
brought into the health care system for further evaluation or
not. The length of the various time intervals can vary widely
depending on the method of biodosimetry being used and on
the specifics of the emergency (e.g., type of radiation, num-
bers of people potentially exposed, timeliness of the response
team). These varying times and logistical challenges in turn
impact the number of potential victims who can be screened
in a timely manner to save lives—our ultimate goal.
In our previous publications, we identified a number of
principal time intervals (briefly listed below) and provided
74 Health Physics July 2020, Volume 119, Number 1

Fig. 1. Screening for radiation risks using biodosimetry. Typical time course following exposure to ionizing radiation of: (a) biologically-based and
(b) physically-based biodosimetry markers: Schema shows upregulated response for both types. AXES: x = level of biomarker at baseline and in
response to exposure; y = time following initial perturbation. TIME POINTS: 1 = initial state prior to injury (baseline level); 2 = time when response
becomes detectable; 3 = time when change becomes relatively stable; 4 = time when response starts to decline; 5 = time when changes become
stabilized ~ at baseline value. Notes: (a) this illustration shows an initial increase in the biomarkers; analogous dynamics in the opposite direction
would occur with a radiation-induced decrease; (b) not portrayed here is individual variation in the baseline level and degree of response to the same
biomarker at the same exposure (adapted from Swarts et al. 2018).

estimates for most of the major biodosimetry methods being
considered (Flood et al. 2011, 2014, 2016). Using the best
available estimates of these time intervals for each method,
we then predicted how many people could be evaluated in
the 6 d following a large-scale event. Note that this list of
principal time intervals applies to all types of biodosimetry/
biomarker methods, including the organ-specific biomarkers
proposed. Below (in italics) we also describe attributes that
are especially important for biologically-based biomarkers
such as organ-specific assays.
Principal time intervals for evaluation biomarkers
1. The initial time from the event before a valid sample can
be collected. This is indicated in Fig. 1a by both the La-
tent Period (i.e., before changes are detectable) plus the
Evolving Changes period (i.e., when the level of the bio-
marker is changing rapidly). Sampling during these times
would underestimate the magnitude of the response and
may result in a false negative reading. Both the baseline
level and the magnitude of the evolving period may vary
among individuals, due to intrinsic variability, the im-
pact of prior events, or concomitant physical injury or
stress. In the case of organ-specific markers, individual
variation in the biomarker may also be impacted by ra-
diation damage to other organs.
2. The time interval during which a valid sample can be ob-
tained. For virtually all biologically based biomarkers,
the time during which the biomarker is stable and most
accurately reflective of the magnitude of the response to
the exposure/injury will end, and the level will start to
return toward the baseline. Unfortunately, for many
biologically-based biodosimeters, the end of the stable
period for sampling occurs before or during the time
when acute medical treatment is being decided. (In
contrast, for some, such as the dicentric chromosome
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analysis [DCA] assay, and for most physically based
biodosimeters, the diagnostic period can extend for
months or years, making the sample valid to obtain
for long term surveillance of health effects; Simon et al.
2019.) The interval during which an accurate quantita-
tive response can be obtained is indicated as the Diag-
nostic Period in Fig. 1. As noted above, the length of
time during which the sample is valid to collect may vary
among individuals due to intrinsic physiological vari-
ability, the impact of prior events, or concomitant phys-
ical injury or stress.
3. The time required to locate the victims where the sam-
pling and/or measurements will be made and to deliver
the equipment, provide facilities and personnel needed.
If assays are to be completed in the field, this time pe-
riod includes the time required to place the equipment
needed to carry out the assay and trained personnel at
the site.
4. The time and resources needed to collect a valid sample
from each victim. This time includes preparing it for
transportation, storage, or processing; obtaining identi-
fying information sufficient to link results uniquely to
an individual; and recording key demographics or med-
ical information needed to interpret results for a given
victim. As needed, it will also include any time needed
to determine that the sample is valid, as described above
in 2. It is likely that most organ-specific biomarkers will
be based on fairly readily obtained body fluids so that the
logistics will be similar for most types of biologically-
based assays. Obtaining a sufficient, accurate, and
uniquely identified sample from a large number of indi-
viduals will be challenging for any type of biodosimetry.
5. The preparation time needed for each sample to be ready
for conducting the actual assays. Some assays do not
require additional preparation before a measurement

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 Screening for radiation risks by using biodosimetry c H. M. SWARTZ ET AL.
can be run; others require hours or days before mea-
surements can be made.
6. The time it takes to transport the sample to the appropri-
ate facilities needed to perform the assay. If such trans-
port is needed, this could be challenging both because
of the intrinsic logistics of dealing with a large number
of samples to transport out of an area and the severely
compromised infrastructure in the affected area.
7. The number of samples that can be processed in a given
time. These challenges include both the availability of
sufficient amounts of the equipment needed for carrying
out the assays and the appropriate manpower; e.g., having
sufficient personnel is a known bottleneck for the DCA
(Maznyk et al. 2012; Wilkins et al. 2011).
8. The time it takes to measure the prepared sample to ob-
tain the desired result in an appropriate format suitable
for use for the persons making the decision on the next
steps for the victim. Depending on the specific assay,
this can vary from almost no time to a considerable ad-
ditional time.
9. The time to deliver the information to the appropriate
medical response decision maker. This includes any
time needed to locate the victim in order to carry out
any actions. This may be challenging for all assays that
need to be done remotely, because usual forms for com-
munication systems such as cell phones and internet are
likely to be compromised, and the victims may not be lo-
catable at their usual contact sites at home or work.
The above time windows focus on the entire time pe-
riod needed for analysis from the onset of the event until
the results are made available to the decision maker and vic-
tim. However, there is another factor that is critical to the
success of a given biomarker: Namely, the results must be
made available during the “window of opportunity” in which
medical interventions can be effectively administered to the
victim. The duration of this time window depends on the
particular radiation mitigator or therapeutic that is being
considered. The time of administration for the mitigators
for the optimal effect might be shorter than the 6 d allocated
in the planning scenario to process samples for up to one
million people. For example, in the case of Neupogen and
Neulasta (Amgen 2019a and b), it is only 24 h, and for
Leukine, it is 48 h post-radiation exposure (Sanofi-Aventis
U.S. LLC 2019). Currently, only these three countermea-
sures are FDA-approved as radio-mitigators for the indica-
tion of hematopoietic acute radiation syndrome (H-ARS)
(Farese and MacVittie 2015; Singh and Seed 2018).
There are several additional basic science/clinical is-
sues that need to be taken into consideration before organ
specific biomarkers can be optimally used. Arguably, sev-
eral of the biodosimetry methods/assays that have been de-
veloped for initial triage in large scale scenarios are in fact
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75
“organ-specific” markers that assess damage to the hemato-
poietic system; e.g., DCA. However, the organ-specific bio-
markers of interest in this article are those being developed
with the specific intent to predict the magnitude of a given
organ’s damage with the intent to inform treatment directed
toward specific organ injury:
1. Organ-specific biomarkers intended to predict organ
damage will be most useful when the dose is heteroge-
neous and when the victim is likely to survive any acute
assault on the hematopoietic system. That is because the
first line of treatment for homogeneous and life-threatening
doses will focus on the hematopoietic system; thereafter,
organ-specific damage assessments may be useful for the
next stage of triage and treatment planning. However,
when the dose is heterogeneous and thought to be life-
threatening to specific radiation-sensitive organs, targeted
treatment or mitigators can help save lives in the short- and
long-term and would greatly benefit from identifying the
magnitude of the damage to the specific organ so that re-
sources can be optimally deployed to those who can
benefit most. Additionally, in order to identify which or-
gans to assess, it also is crucial to know the distribution
of the dose.
2. It will be important to know whether and how the bio-
marker of radiation injury itself is affected by the individ-
ual’s overall health and lifestyle habits (e.g., smoking);
concomitant perturbations from the event experienced
by the individual, including physical trauma and stress;
and whether the technical validity of the assay is im-
pacted by damage to other organ systems, such as sup-
pression of the immune response.
In summary, after a radiation scenario that puts large
numbers of individuals at risk for clinically significant acute
or long-term health consequences, in order to derive full ben-
efit from the use of organ-specific biomarkers as well as
to provide essential information so that informed decision-
making can be implemented, several essential types of
information are needed. The information is needed to deter-
mine who is at risk, what is the type and severity of the risk,
and to guide appropriate medical intervention with treatment
and/or the use of mitigators. In particular, prior to deciding
which organ-specific biomarker of damage should be used,
the following information is important to know:
• Whether the individual has a credible risk of a having
had a clinically significant exposure to radiation;
• Whether the exposure was homogeneous (total-body) or
heterogeneous (partial body);
• If the exposure is homogeneous, whether the individual
is expected to survive the initial injury to the hematopoi-
etic system; and
76 Health Physics
• If the exposure was heterogeneous, the distribution of
dose throughout the body. Knowing the distribution of
dose would be a key to deciding which organs to assess
for damage, (i.e., which are unlikely to have received a
high dose vs those at risk) in order to target injured or-
gans for effective and efficient treatment. The dose distri-
bution could also influence the decision to prioritize the
patient for treatment. Additionally, knowledge of the
dose to the organ would provide a very useful check on
potential false positive or false negative results from the
organ-based biomarkers.
PART 2: POTENTIAL ROLE OF IN VIVO NAIL
DOSIMETRY TO ENHANCE THE USEFULNESS
OF ORGAN-SPECIFIC BIOMARKERS IN
PLANNING MEDICAL RESPONSE FOR A
LARGE-SCALE SCENARIO
In Part 1 of this paper, we concluded there are two im-
portant factors for the effective use of biomarkers of organ-
specific injury; i.e., determine first whether the exposure is
homogeneous (total-body exposure) and, if it is not, to deter-
mine the distribution of the dose. If the radiation exposure is
mostly homogeneous with no areas of bone marrow receiv-
ing substantially lower doses, then biodosimetry based on
physical dose should be adequate for effective screening for
risk of ARS. That is because, for mostly homogeneous expo-
sure, the physical dose can be assumed to be the same for all
organ systems and, for exposures in the treatable range, the
predominant short-term risk for morbidity and mortality will
be acute suppression of the bone marrow. In addition, the
information on dose obtained using in vivo nail Electron
Paramagnetic Resonance (EPR), combined with the infor-
mation from the organ-specific biomarkers, will provide
potentially important data about the heterogeneity of bio-
logical responses to irradiation.
On the other hand, if the exposure is significantly het-
erogeneous, then it would be desirable to have detailed infor-
mation on the distribution of the dose to various organs. That
would enable the most effective use of the biomarkers of or-
gan specific damage, because they could be used in those
subjects with the highest possibility of significant damage
to particular organs. This could contribute significantly to
understanding and treating acute and long-term effects.
In Part 2, we consider how a newly emerging physical
biodosimetry method based on the use of EPR to measure
in vivo the level of radiation-induced free radicals in the nails
of hands and feet can provide the types of information needed
to meet these objectives.
EPR is a magnetic resonance technique which, for this
application, uses a moderate magnetic field (340 mT) and
an electromagnetic frequency that is similar to the fre-
quency used in microwave ovens. EPR selectively responds
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July 2020, Volume 119, Number 1
to unpaired electrons such as those occurring in free radicals.
EPR nail dosimetry is based on the measurement of the rela-
tively stable (lasting at least several weeks) radiation-induced
free radicals generated in the keratin of the human nail, both
fingernails and toenails. These radicals are produced by the
direct interactions of the reactive intermediates generated by the
ionizing radiation with keratin, and the intensity of the EPR sig-
nals of these radicals is directly proportional to the dose received.
Characteristics of in vivo EPR nail dosimetry that make
them effective and complementary to the use of
biomarkers of organ damage
Data on the feasibility of in vivo EPR nail dosimetry
have been previously reported (Swarts et al. 2018). Swartz
et al. (2014b) also reported on the dose resolution (about
10 Gy) that had been achieved with the preliminary work
and discussed areas of planned improvements that are ex-
pected to achieve a resolution of at least 1 Gy.6 In the follow-
ing discussion we assume the successful implementation of
the improvements and therefore assume a resolution of
~1 Gy. In vivo EPR nail dosimetry has several characteristics
that are favorable for their original intended use (initial triage
in large-scale radiation events) and which in aggregate in-
dicate that this technique can provide information not
available from any other biodosimetry technique that is
necessary in order for biomarkers of organ-specific damage
to be effectively deployed. These characteristics are described
below and, in italics, their relationship to the characteristics of
biologically based bioassays.
1. In vivo EPR nail dosimetry is based on a physical pro-
cess (generation of stable free radicals, proportional to
dose in the dose ranges of interest) that is not confounded
by the types of trauma and stress that are likely to occur
in a disaster (Coleman and Koerner 2016). This is in
contrast to the biological assays that can be impacted
by concomitant stress or injury. Therefore, EPR mea-
surements can be used to evaluate whether biomarkers
of organ-specific damage could be misleadingly high
if these conditions were present.
2. The measurable effect of radiation on nails occurs in-
stantaneously upon radiation exposure, is independent
of the dose rate of exposure, and reflects the cumula-
tive dose at the site of the nails. Although there is a
need to confirm the observation, preliminary data indi-
cate that in vivo, the radiation-induced signal remains
stable from the time of exposure to several weeks or
6
Some of these characteristics apply equally to EPR dosimetry based on
nail clippings. However, this paper is restricted to in vivo nail dosimetry
for two principal reasons. Measuring nail beds in vivo obviates the prob-
lems that occur because clipping of nails produces a confounding signal.
To deal with these problems, clipped nails need to be sent to specialized
laboratories for analysis and require complex handling of the clippings.
In contrast, in vivo nail EPR can be accomplished at the point-of-care
without special handling to eliminate the effects of clipping.
 Screening for radiation risks by using biodosimetry c H. M. SWARTZ ET AL.
months afterward. (If this is not the situation, then
some modifications to the protocol will be needed,
but these should not impact the usefulness of the meth-
odology.) This is in contrast to biologically based bio-
markers which typically have a time-dependent pattern
of changes (as illustrated in Fig. 1a). (See Fig. 1b for
the contrasting dynamics for in vivo nails which are es-
sentially unchanging during the pertinent periods for
triage.) Consequently, as discussed in Part 1 of this pa-
per, almost all of the “Principal Time Intervals for
Evaluation Biomarkers” delineated in Part 1 (i.e., those
numbered 1,2,4–6, and 8,9) are minimal or non-existent
for measurements of in vivo nails.
3. The measurements can be made immediately after the
event and at any time throughout the relevant time periods
(Fig. 1b). In contrast, biologically based biomarkers often
have a limited time during which a valid sample can
be collected (the diagnostic period in Fig. 1a).
4. Measurements can be repeated as desired because they
are non-invasive and non-destructive of the “sample”
and, as noted above, the response remains stable dur-
ing the relevant time period when measurements
would be appropriate. This provides opportunities for
confirmation and validation of initial results, including
modifying the measurement techniques to enhance ac-
curacy. Such a capability might also be available for
some biologically-based bioassays.
5. EPR measurements can be carried out in the desig-
nated temporary facilities that are set up near the event
site as part of the response to the scenario. The instru-
ment is easily deployable and can be operated with
minimal needs for supplies and by operators with lim-
ited training; i.e., training can be completed via a few-
minute video embedded into the software. In contrast,
at least some of the biomarkers are likely to require
that analyses be carried out using specialized equip-
ment and experts located remotely.
6. The results are immediately available. Data processing
of the measurements by the software will produce re-
sults instantaneously following completion of data ac-
quisition that are appropriate for use by the medical
decision makers. This capability is likely to vary with
the type of biologically based biomarker assays.
7. Measurements are completely noninvasive; there is no
sample to be collected, as the measurement is done in
vivo. Most biomarker assays will require collection
of a sample (often a small amount of blood, but some-
times a small amount of tissue, feces, or urine), which
is then brought to the analytic instrument in the field or
at a distant site.
8. Measurements of nails from multiple limbs can be
used to compute dose distribution immediately, pro-
viding unambiguous evidence on probability of the
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77
exposure being homogeneous. It should also be feasi-
ble to compute the distribution of dose throughout
the body if the exposure was heterogeneous. The sim-
ulation models will be focused particularly on provid-
ing the dose to any and all radiation-sensitive organs.
The software can produce this information at the same
time as providing individual dose estimates for each
limb. This type of information is unlikely to be avail-
able from biomarker assays. Although some have been
argued to distinguish partial body vs. whole body ex-
posures, the biomarkers cannot be used to establish
dose distribution (Vaurijoux et al. 2012).
9. The EPR dosimetric measurements can be made with
throughput times of less than 5 min of measurement
time per subject from “sampling” the nails on each limb
to providing all of the results. In contrast, throughput
for biologically-based biomarkers varies from several
minutes to several days, not including any limitations
on when samples can be taken after exposure and
any transportation times to send samples to distant
laboratories and the time to send results back to the
medical response team.
10. Because the method is based on physical changes that
are unlikely to be perturbed by disease or stress (Swartz
2016), patients undergoing therapeutic whole-body ir-
radiation (or partial body irradiation that includes expo-
sure of the nails) are suitable test subjects, providing a
means to test the effectiveness of measurements made
directly in human subjects who were exposed to radia-
tion in vivo. Biologically-based biomarkers typically
are potentially confounded by the underlying diseases
and their medical treatments, such as chemotherapy.
Therefore, they need to be developed by a preclinical
model irradiating and measuring in vivo in animals.
Method for making measurements of radiation dose
with EPR in vivo nail dosimetry
In vivo nail biodosimetry is applicable to the entire
population as long as the individual can cooperate. (Sepa-
rate versions would need to be developed for unconscious
subjects and infants/very young children, because the existing
versions assume that the subject can actively cooperate with
being measured, especially in regard to restricting motion of
the limbs.) Details of the prototype for the resonator and
methods for measuring nails in vivo are reported elsewhere
(Swarts et al. 2018; Sidabras et al. 2014). Briefly, each digit
that is to be measured is first placed into a digit/resonator
holder (see Fig. 2). This support system facilitates accurate
and rapid placement of the nail plate under a novel Surface
Resonator Array (SRA) (Sidabras et al. 2014) that is held in
place inside one of four magnets, each of which is placed
for ideal use for a specific limb (Fig. 3). The magnetic field
of the permanent magnet provides a uniform magnetic field
78 Health Physics
Fig. 2. Support for finger and SRA resonator (shown on one digit only): support is placed on digits outside of spectrometer and is used for proper
placement of the digit into the resonator held inside the magnet.
in the region of the nail. Up to five digits per limb can be
measured simultaneously within each magnet.
The region of the nail that is measured is deliberately
located away from the margins of the nails; therefore, there
will be no need to be concerned with dirt under the nails or
the impact of recent clipping, etc. (He et al. 2014; Wilcox
et al. 2010; Wang et al. 2015). Variation in curvature and
size of the nailbed (Murdan 2011) has been investigated
and appears not to be a problem in preliminary studies.7
There is a remaining need to determine if the in vivo mea-
surements of nails are perturbed by the presence of nail pol-
ish or other cosmetic treatments (Trompier et al. 2015). If
perturbations are determined to impact in vivo measure-
ments, there will be a need for a step to remove the polish/
cosmetic treatment prior to the measurements.
It is feasible to make simultaneous measurements on
each digit. In addition, measurements can be carried out si-
multaneously on all four limbs (Fig. 3). The total measure-
ment time can be less than 5 min because all measurements
of the digits can be done simultaneously. All aspects of the
technique can readily be automated so that the measurements
can be carried out by operators with no previous experience
in the technique. The results, expressed as dose in each
measured digit and aggregated by limb, will be immediately
available at the conclusion of the measurements.
The data output will also include an automated calcula-
tion of the probability that the exposure was inhomogeneous
7
Whether certain kinds of nail diseases and/or their treatment affect mea-
surements has not yet been determined.
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July 2020, Volume 119, Number 1
and the extent (dose distribution) of the heterogeneity. Al-
though estimates of dose distribution are not yet fully devel-
oped, it should be quite feasible, based on techniques already
in use in radiation therapy, to go from doses at each of the
four limbs to a map of the dose distribution throughout the
whole body, including estimates of doses to each radiation-
sensitive organ system (Petroccia et al. 2017; Herve et al.
2007; Borrego et al. 2017; Sands et al. 2017; Wayson
and Bolch 2018; Khailov et al. 2015). This calculation should
be able to be made automatically by the software, with
the results available immediately after the measurements
are completed.
Use of in vivo EPR nail dosimetry to determine
homogeneity of the exposure
While the need to have information about the homoge-
neity of the exposure to radiation has long been recognized
as essential in order to determine the risk for ARS (Coleman
and Koerner 2016), there is currently no other method avail-
able for determining the homogeneity of an exposure to radia-
tion in the context of a large-scale radiation incident. In small
incidents, such as accidents involving ionizing radiation, deter-
mining homogeneity of exposure usually requires physical do-
simetry, but in large-scale scenarios, there seems to be no
practical method to do this; e.g., by having pre-placed phys-
ical dosimeters throughout the general population and then
using computational reconstruction of the exposure based
on where each person was located at the time of the event.
Biologically-based biodosimetry does not currently
have the capability to provide rapid indications of the
 Screening for radiation risks by using biodosimetry c H. M. SWARTZ ET AL.
Fig. 3. Person being measured by in vivo nail EPR spectroscopy on all four limbs simultaneously.
homogeneity of the exposure, and none can estimate dose
distribution. While in principle the DCA assay can provide
some indication of the presence of heterogeneous exposure,
this technique requires considerable time because of the
need to transport the samples to laboratories outside of the
affected area and the intrinsic times for sampling and com-
pleting the assay (Prasanna et al. 2010b). As already noted,
there also are significant logistical problems with available
capacity to complete large numbers of assays within the re-
quired timeframe of a large-scale radiation scenario.
On the other hand, EPR in vivo nail dosimetry has the
capability of making the determination of heterogeneity of
exposure in a few minutes, directly on the individual in
the field, eliminating the need to send samples to a distant
site. It can provide rapid and robust indications of homoge-
neity by measurements at four widely separated anatomical
sites, the two hands and the two feet.
If simplification is needed, the simplest situation would
be to use estimates based on measuring only a single digit
on two limbs, which would provide a limited but useful indica-
tor of homogeneity of exposure. A more robust indication
could be obtained by measuring a digit on at least three limbs.
Because each digit is measured individually with its own res-
onator, the precision of the measurements on each limb can be
enhanced by measuring additional digits on the same limb.
Use of EPR nail dosimetry to determine the full
distribution of the radiation dose
In order to determine the physical distribution of expo-
sure dose, geometrically defined information seems likely
to be essential. This is unlikely to be achieved by assays that
use changes in body fluids. While information on distribution
might be obtained by biopsy at multiple sites in principle, that
is very unlikely to be practical for a large-scale scenario.
One of the very attractive features of in vivo EPR nail
dosimetry is that it can obtain information on dose at four
distinctly different sites. As noted above, with these data
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79
we should be able to provide a robust indication of whether
the exposure was homogeneous unless there were markedly
heterogeneous exposures to the head or to a very small vol-
ume elsewhere in the body. Based on existing use of point
measurements to determine dose distribution and with the
information on dose from four sites, it should be feasible
to map the variation of the exposure over the entire body.
The algorithm to carry out this calculation could include in-
put on the quality of the radiation, the dose rate associated
with the incident, and whether there were particles from fall-
out on any of the digits. (The method will not consider inter-
nal radiation, but that is not likely to be a major factor for
acute effects; Swartz et al. 2014a.)
While there is considerable experience in radiation ther-
apy for making such calculations based on measurements at
well characterized locations, in order to calculate dose distri-
butions based on a few experimental dose measurements
(Petroccia et al. 2017; Herve et al. 2007; Borrego et al.
2017; Sands et al. 2017; Wayson and Bolch 2018; Khailov
et al. 2015), the situation gets more complex when there is
some uncertainty in the position of the limbs, as would be
likely for the hands. If the exposure was over a very short pe-
riod of time (e.g., primarily from prompt radiation), it may be
possible to have the subject describe the likely position of the
hands. If the exposure occurs over a longer period of time,
such as from fallout, then it will be reasonable to assume
an averaged position.
The algorithm for calculating the whole body distribu-
tion of dose can include a consideration of the additional un-
certainties, such as those due to the lack of precision of
knowledge of the position of the limbs. While we will need
to develop the specific algorithm based on the use of dose at
the nails, we will be able to use well investigated techniques
to do this as applied previously for diagnostic radiology, radi-
ation therapy, and accident dosimetry (Petroccia et al. 2017;
Herve et al. 2007; Borrego et al. 2017; Sands et al. 2017;
Wayson and Bolch 2018; Khailov et al. 2015).
80 Health Physics
SUMMARY
In order to respond effectively to a large-scale radiation
scenario in which there are many more individuals potentially
at risk than can be brought immediately into the medical care
system for direct medical observation for development of clin-
ical manifestations, it is essential that effective triage be carried
out as promptly as possible. There also is a need for the early
identification of individuals who have received clinically sig-
nificant exposures that could be ameliorated by available
mitigators or early treatment.
Recently, there has been increased interest in using in-
jury rather than dose to carry out the initial triage. The focus
on estimating injury is based on the assumption that individ-
uals with the same exposure can vary significantly in their
organ-specific responses to radiation injury. More impor-
tantly, the assumption is that treatments will be more effec-
tive if based on information that estimates an individual’s
organ-specific damage. The suggested approach is the use
of biomarkers that could provide organ-specific predictions
of the radiation injury. While the biological base for such
assumptions has not been fully demonstrated, work on the
development of such bioassays is under development.
In Part 1, using prior analyses of the suitability of
biodosimeters for the response to a large-scale radiation
scenario, we examined the logistical and practical features
of bioassays of organ-specific damage and whether there
are important pieces of information that would make such
biomarkers suitable for use in the early triage decisions.
We concluded that there are two especially important pieces
of information that are needed prior to being able to effec-
tively use such biomarkers: 1) whether the exposure was ho-
mogeneous and 2) if there was significant heterogeneity,
determination of the distribution of the dose.
The rationale for our conclusions rests on well understood
clinical grounds: if radiation exposure is mostly homogeneous,
with no area containing significant amounts of bone mar-
row receiving substantially lower doses, then biodosimetry
based on physical dose should be adequate for effective tri-
age for risk of ARS. On the other hand, if the exposure is sig-
nificantly heterogeneous, then it would be desirable to have
detailed information on the distribution of the dose. That
would enable the most effective use of the biomarkers
of organ specific injury because they could be used in
those subjects with the highest possibility of significant
damage to particular organs to predict the need for acute
and long term medical intervention, using criteria that
presumably will be developed by the government in the
plans for response.
In Part 2, we describe how a newly emerging physical
biodosimetry method (i.e., the in vivo use of EPR to mea-
sure the amount of radiation-induced radicals in the nails
on all limbs) appears to be to provide the types of information
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July 2020, Volume 119, Number 1
needed to optimize the use of biomarkers of organ-specific
injury. Because in vivo nail dosimetry obtains data from
four separate, dispersed anatomical locations, it can be used
to assess homogeneity, and if there is significant heterogeneity,
the measurements from the four limbs can be used to estimate
the distribution of the dose to radiation-sensitive organs.
Also importantly, because in vivo nail dosimetry can
rapidly provide quantitative data about the level of exposure
and can be used at point-of-care settings, these measure-
ments should clearly distinguish between the worried well
and subjects who have received doses of radiation that could
lead to significant morbidity and mortality. It also could
help to identify subjects whose dose is likely to be greater
than would be compatible with short term survival so that
they could be handled appropriately.
It is important to note that this combined approach is
complementary, not competitive to the information obtained
by bioassays based on organ-specific damage. The combi-
nation of physical biodosimetry, biological biodosimetry,
and clinical observation will optimally serve the goal of
providing the most effective response to a large-scale
radiation scenario.
Acknowledgments—The opinions or assertions contained herein are the private
views of the authors and are not necessarily those of the Uniformed Services
University of the Health Sciences or the Department of Defense, USA. Mention
of trade names, commercial products, or organizations does not imply endorse-
ment by the United States Government.
This study was funded in part by grant U19AI091173 from Centers for
Medical Countermeasures Against Radiation (CMCR) in the National Institute
of Allergy and Infectious Diseases (NIAID).
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