Received: 24 July 2021 Revised: 10 November 2021 Accepted: 21 December 2021

DOI: 10.1002/mp.15487

RESEARCH ARTICLE

Dose calculations for preclinical radiobiology experiments

conducted with single-field cabinet irradiators

Courage Mahuvava1 Nolan Matthew Esplen1 Yannick Poirier2

Stephen F. Kry3 Magdalena Bazalova-Carter1

1
Department of Physics and Astronomy,
University of Victoria, Victoria, British
Columbia, Canada
2
Department of Radiation Oncology,
University of Maryland School of Medicine,
Baltimore MD, USA
3
Department of Radiation Physics, University
of Texas MD Anderson, Cancer Centre,
Houston, Texas, USA
Correspondence
Courage Mahuvava, Department of Physics
and Astronomy, University of Victoria, Victoria,
BC V8P 5C2, Canada.
Email: mahuvavac@uvic.ca
Funding information
Compute Canada; Natural Sciences and
Engineering Research Council of Canada
(NSERC); Canada Research Chair Program
Abstract
Purpose: To provide percentage depth dose (PDD) data along the central axis
for dosimetry calculations in small-animal radiation biology experiments per-
formed in cabinet irradiators. The PDDs are provided as a function of source-
to-surface distance (SSD), field size, and animal size.
Methods: The X-ray tube designs for four biological cabinet irradiators, the
RS2000, RT250, MultiRad350, and XRAD320, were simulated using the BEAM-
nrc Monte Carlo code to generate 160, 200, 250, and 320 kVp photon beams,
respectively. The 320 kVp beam was simulated with two filtrations: a soft F1 alu-
minium filter and a hard F2 thoraeus filter made of aluminium, tin, and copper.
Beams were collimated into circular fields with diameters of 0.5–10 cm at SSDs
of 10–60 cm. Monte Carlo dose calculations in 1–5-cm diameter homogeneous
(soft tissue) small-animal phantoms as well as in heterogeneous phantoms with
3-mm diameter cylindrical lung and bone inserts (rib and cortical bone) were
performed using DOSXYZnrc. The calculated depth doses in three test-cases
were estimated by applying SSD, field size, and animal size correction factors
to a reference case (40-cm SSD, 1-cm field, and 5-cm animal size), and these
results were compared with the specifically simulated (i.e., expected) doses to
assess the accuracy of this method. Dosimetry for two test-case scenarios of
160 and 250 kVp beams (representative of end-user beam qualities) was also
performed, whereby the simulated PDDs at two different depths were compared
with the results based on the interpolation from reference data.
Results: The depth doses for three test-cases calculated at 200, 320 kVp F1,
and 320 kVp F2 with half value layers (HVLs) ranging from ∼0.6 to 3.6 mm
Cu, agreed well with the expected doses, yielding dose differences of 1.2%,
0.1%, and 1.0%, respectively. The two end-user test-cases for 160 and 250 kVp
beams with respective HVLs of ∼0.8 and 1.8 mm Cu yielded dose differences
of 1.4% and 3.2% between the simulated and the interpolated PDDs. The dose
increase at the bone-tissue proximal interface ranged from 1.2 to 2.5 times the
dose in soft tissue for rib and 1.3 to 3.7 times for cortical bone. The dose drop-off
at 1-cm depth beyond the bone ranged from 1.3% to 6.0% for rib and 3.2% to
11.7% for cortical bone. No drastic dose perturbations occurred in the presence
of lung, with lung-tissue interface dose of >99% of soft tissue dose and <3%
dose increase at 1-cm depth beyond lung.
Conclusions: The developed dose estimation method can be used to translate
the measured dose at a point to dose at any depth in small-animal phantoms,
making it feasible for preclinical calculation of dose distributions in animals irra-
diated with cabinet-style irradiators. The dosimetric impact of bone must be
accurately quantified as dramatic dose perturbations at and beyond the bone
interfaces can occur due to the relative importance of the photoelectric effect

Med Phys. 2022;1–13. wileyonlinelibrary.com/journal/mp © 2022 American Association of Physicists in Medicine 1

2 DOSIMETRY FOR RADIOBIOLOGY STUDIES
at kilovoltage energies. These results will help improve dosimetric accuracy in
preclinical experiments.
KEYWORDS
depth-dose, Monte Carlo, radiobiology dosimetry, small-animal radiotherapy, TG-319
1 INTRODUCTION
Translational radiotherapy research requires preclinical
in vivo models to facilitate the shift from in vitro experi-
ments toward clinical application as an important inter-
mediary step prior to clinical trials.1 Evaluating novel or
revised radiotherapy treatments directly in human sub-
jects is unfeasible due to the high costs associated with
clinical trial length and logistics, and ethical considera-
tions from unknown or unanticipated adverse effects.2
As a result, there has been increased focus in develop-
ing radiation research platforms to study radiation biol-
ogy in small animals.3–5 However, as in human clini-
cal treatments, the success and reproducibility of these
experiments still relies on the ability of investigators to
deliver an accurate amount of radiation dose, which has
proven challenging in preclinical research.6,7
Many preclinical radiation research experiments are
performed with small animals using kilovoltage (kV) X-
rays, which is expected to increase in importance due
to security concerns surrounding radioactive gamma
sources.8–10 However, there is currently a lack of tools
with which to perform accurate preclinical dosimetry
from kV X-rays. Reference dosimetry protocols pro-
vide methodologies to calculate and measure dose to
a point,11 but not dose distributions in the rest of the
animal. While more advanced conformal kV X-ray irradi-
ators are equipped with image-guidance and treatment
planning systems,these represent a minority of all radio-
biological research. Indeed, a reanalysis of data from a
previous systematic review10 shows that of 82 studies
performed on small animals using kV X-rays between
2010 and 2017, only six used conformal small animal
irradiators, while Monte Carlo simulations were only
used in one of the 82 studies. Instead, the vast major-
ity of small animal research performed with kV X-rays
is performed using cabinet irradiators, simple devices
which consist only of a fixed X-ray source without image
guidance or treatment planning capabilities.
Accurate dosimetry for these irradiators is very chal-
lenging. The low energy beams result in a large amount
of scatter that depends strongly on experimental con-
ditions. This can result in a high degree of uncertainty,
even for simple fields. Complications are even greater
in the presence of high atomic number heterogeneities
such as bone.8 Unlike megavoltage (MV) X-ray sources
used in human clinical treatments, to the best of the
authors’ knowledge, no commercial treatment planning
system is currently available to calculate dose distri-
butions delivered by cabinet irradiators without image-
guidance. Monte Carlo simulations can be used but are
complex and time-intensive, particularly when attempt-
ing to describe complex irradiation geometries without a
computed tomography (CT) dataset.
In kV X-ray clinical treatments performed on humans,
physicists have typically relied on published percent-
age depth dose (PDD) curves such as those from the
British Journal of Radiology Supplement 25 (BJR-25).12
However, these are difficult to apply to small animals, as
they are provided for a limited number of beam quali-
ties, assume a semi-infinite backscattering environment
not present in biological research, and are only provided
for large field sizes. Even when a given irradiator closely
matches the BJR-25 dataset, the accuracy of the PDD
can be poor.13 In this context, individual users, who may
or may not possess radiation physics knowledge, are left
to perform dosimetry on an ad hoc basis, their approach
varying from institution to institution, which is frequently
not reported in many radiobiological publications.10,14,15
In this study, we provide PDD data for five of the
most common beam qualities10 used in cabinet kV X-
ray irradiators, for a variety of irradiation geometries of
varying animal size, source-to-surface-distance (SSD),
and field size. These provide a framework to allow for
interpolation of doses across a wide range of beams
and can therefore facilitate more accurate dose calcula-
tions than are often currently employed. This method-
ology and published PDD values are supplied to the
community in the context of the new methodology pro-
posed by the American Association of Physicists in
Medicine (AAPM) Task Group (TG)-319‘s new guide-
lines for accurate dosimetry in radiation biology experi-
ments performed with cabinet irradiators.16
2 MATERIALS AND METHODS
2.1 Dosimetric methodology proposed
by TG-319
The TG-319 report will provide medical physicists with
general information on how to measure the dose to
a point within an animal phantom (could be on the
surface of a phantom, as illustrated in the schematic
in Figure 1a, but the dose at depth might also be of
interest to either estimate the dose in the target or to
healthy tissues (Figure 1b). To provide this information
for TG-319 and the broader community in general, a
DOSIMETRY FOR RADIOBIOLOGY STUDIES
F I G U R E 1 (a) Measured dose to a point (red circle) in the small animal. (b) The focus of this study, which is to determine the percentage
depth-dose (PDD) correction to convert this dose to the location where dose is of interest (green circle) in a small animal phantom mimicking
the experimental animal using Monte Carlo simulations. This is useful for dose calculation at a prescribed position in the organ of interest (target
or organ at risk)
large set of Monte Carlo dose calculations was carried
out in this work for small-animal radiotherapy beams.
These will provide central-axis PDD data containing
information on a number of aspects that affect accurate
dosimetry; namely the beam quality, SSD, field size,
animal size as well as the presence of lung and bone
heterogeneities in the animal m odel. This information
will facilitate the translation of the experimentally mea-
sured dose at a given point to the dose at the desired
depth in the organ of interest, and therefore support
improved dose calculations for preclinical studies.
2.2 BEAMnrc simulations
The Monte Carlo technique used throughout this work
involved a two-step process: Firstly, Monte Carlo source
models based on four small-animal irradiators, namely
the PXi XRAD320 (PXi, North Branford, CT), the Fax-
itron MultiRad350 (Faxitron Bioptics, Tucson, AZ), the
Phillips RT250 (Philips Medical System, Cleveland, OH),
as well as the Rad Source RS2000 (Rad Source, Buford,
GA) units were used to simulate the production of 320,
250, 200, and 160 kV X-ray beams in BEAMnrc.17 The
XRAD320 has two different beam filters (F1 and F2),
which were simulated separately. Table 1 gives the spec-
ifications of each filter. The irradiator models were com-
missioned or validated with experimental data from pre-
vious studies.18–20
In the second simulation stage, DOSXYZnrc21 was
used to calculate 3D absorbed dose distributions
in cylindrical small-animal phantoms using BEAMnrc
phase-space files scored just below the beam collima-
tion system as the “source.” The global electron and
photon energy cut-off values, ECUT and PCUT, were
respectively set to 0.521 and 0.01 MeV in all BEAMnrc
and DOSXYZnrc simulations. All simulations were run
3
remotely on the Compute Canada Cedar cluster22 using
Intel processors running at 2.1–2.4 GHz. BEAMnrc sim-
ulation times ranged from ∼60 to 100 h and DOSXYZnrc
simulation times ranged from ∼5 to 40 h.
2.2.1 Source description
Table 1 summarizes the specifications of the irradiator
models/beams, which were used in this work. For all of
the X-ray units simulated, the SSD is varied using an
adjustable steel shelf, while circular beam shaping is
assumed to be achieved with a 2-mm thick lead shield
placed just above the animal. Also given are the speci-
fications for two cabinet irradiators (based on the Fax-
itron MultiRad350 and the Rad Source RS2000) used
for end-user test-case dose calculations.
2.2.2 Simulation geometry
BEAMnrc simulations were split into two stages, which
together comprised the full geometry of the X-ray
source and the physical collimator setup, based on
manufacturer specifications. Figure 2 shows the simu-
lation geometry used to model the biological irradiators,
including the source and phase space file (PSF) scor-
ing planes Figure 2a, as well as the orientation of the
homogenous cylindrical phantom relative to the beam
Figure 2b. Dose calculations were also performed in
2-cm diameter cylindrical phantoms with 3-mm diame-
ter lung, rib, or cortical bone inserts located at 2.5-mm
depth, as shown in Figure 2c.
In the first simulation stage, a mono-energetic elec-
tron beam was simulated in a vacuum, impinging
upon a tungsten anode to generate Bremsstrahlung X-
rays, which were subsequently transported through the
4 DOSIMETRY FOR RADIOBIOLOGY STUDIES

TA B L E 1 Manufacturer specifications for the small-animal cabinet irradiators used in this study. These parameters were used for beam
production simulations in BEAMnrc. The half -value layers (HVL) of the five beams calculated in MATLAB based on the beam energy spectra in
Figure 3, are also shown

Focal spot HVL

Energy Anode diameter values
Irradiator model (kVp) Filter specificationsǂ angle (◦ ) (mm) (mm Cu)

PXi XRAD320 320 F1: 2 mm Al 30 4.0 0.59

PXi XRAD320 320 F2: 0.75 mm Sn, 0.25 30 4.0 3.57
Cu, 1.5 mm Al
Phillips RT250 200 2 mm Al, 0.5 mm Cu 26 3.0 1.00
Faxitron MultiRad350 250 2 mm Al, 0.5 mm Cu 26 3.0 1.80
Rad Source RS2000 160 0.3 mm Cu 26 3.0 0.78
ǂ
Al = aluminium, Cu = copper, Sn = Tin.
Abbreviation: HVL, half value layer.

F I G U R E 2 Geometry of the X-ray unit and relative orientation of cylindrical small-animal phantoms for simulating beam production and
collimation in BEAMnrc (a) as well as dose calculations in DOSXYZnrc (b). Heterogeneous phantoms (2-cm diameter) with two different bone
materials as well as lung are shown in (c). Irradiator geometry and material compositions were provided by the manufacturers, while bone
compositions were obtained from the International Commission on Radiation Units and Measurements (ICRU)-44 tissue data.23 The
composition of lung (LUNG521ICRU) is available in the ICRU PEGS4 (preprocessor for Electron Gamma Shower v4.0) data in EGSnrc

inherent beryllium filtration and stored in the phase
space file PSF1 scored at 5 cm from the focal spot.
The energy spectra for each beam in PSF1 are shown
in Figure 3. A total of 2 × 109 primary particles were
simulated in the PSF1 X-ray phase space simulations.
Directional bremsstrahlung splitting (without cross sec-
tion enhancement)21 with a splitting factor of 2000 and
a splitting radius of 3.0 cm, defined at 5.0 cm from the
source, was employed to increase simulation efficiency.
In the second BEAMnrc simulation stage, particle
transport through air and the variable aperture 2-mm
thick lead collimators was simulated. The output of this
simulation was a set of phase-space files scored at
PSF2 (Figure 2a, collected 0.1 cm below the variable
collimator) for each beam size and SSD; these files were
later used as sources for the final DOSXYZnrc dose cal-
culations.
The total number of particles scored in PSF2 ranged
from 7.5 × 106 , for the smallest (0.5 cm diameter) field
size in the heavily filtered 320 kVp F2 beam, up to 109
for the largest (10-cm diameter) field in the 320 kVp
F1 beams. The 521ICRU PEGS4 material cross section
data were used. All other user-adjustable transport con-
trol parameters such as the maximum fractional energy
loss per step, Russian roulette, skin depth etc., were set
to their default values or switched off.
DOSIMETRY FOR RADIOBIOLOGY STUDIES
F I G U R E 3 Normalized energy spectra for the PXi 320 kVp F1,
PXi 320 kVp F2, RT250 200 kVp, MultiRad350 250 kVp as well as the
RS2000 160 kVp open beams at the PSF1 scoring plane (see
Figure 2), located just below the filter. The half value layer (HVL)
values for the five beams were calculated from these energy spectra
in MATLAB and are summarized in Table 1. The energy spectra data
were generated by BEAMDP24
2.3 DOSXYZnrc simulations
The total dose deposited in each voxel of the cylin-
drical phantoms was calculated using DOSXYZnrc.
The cylindrical phantom files, representative of small-
animal subjects, were generated in MATLAB ver-
sion R2015a (Mathworks, Nattick, MA). Voxel sizes
were 0.5 × 0.5 × 2 mm3 , with the 2-mm dimension set
along the rotational axis of the cylinder. The statistical
uncertainty in the 20 highest-dose voxels was kept
below 1% in all cases. Photon splitting with a factor of
20 was used to increase the efficiency of dose calcula-
tions in all DOSXYZnrc simulations. A total of 106 −109
particle histories were simulated for dose deposition
calculations depending on the number of BEAMnrc
phase space particles. Interactions important for low
energy photons, such as Rayleigh scattering and bound
Compton scattering, were included in all BEAMnrc and
DOSXYZnrc simulations. Depth dose curves were then
calculated by scoring the total dose deposited in the
central section of the phantom along the beam axis in
0.5 × 0.5 × 2 mm3 voxels. The plots were normalized
to the maximum dose for their respective data sets.
2.3.1 Reference cases
For estimation of dose in test cases, a number of
reference cases with the simulation parameter combi-
nations shown in Table 2 were used. These reference
case simulations were performed for the 320 kVp F1,
200 kVp, and 320 kVp F2 beams with HVLs of 0.59,
1.00, and 3.57 mm Cu, respectively. Let these be called
5
the reference beam qualities. Reference cases were
defined (1) as a function of animal size with a default
SSD and field size, (2) as a function of field size with a
default SSD and animal size, and (3) as a function of
SSD with a default field size and animal size. That is,
by keeping two parameters to their default values and
varying the third parameter. The default SSD, field size,
and animal size values were 40 cm, 1 cm, and 5 cm,
respectively. The reference cases provide the basis for
test-case dose calculations based on derived correction
factors (CFs) for these three quantities.
2.3.2 Dose estimation and test-case
validation
This section outlines the process by which the PDDs cal-
culated in this study can be used for an arbitrary irradi-
ation geometry.
Let SSD, FS, and AS be the reference/default sim-
ulation parameters and SSD′ , FS′ and AS′ be the test-
case parameters for source-to-surface distance (SSD),
field size, and animal size, respectively. For a given
beam energy, the calculated dose at depth d for a
test case, Dcalc (d, SSD′ , FS′ , AS′ ), was estimated by
applying CFs for SSD, field size, and animal size to the
dose in the reference case, Dref (d, SSD, FS, AS). Equa-
tion (1) summarizes the formalism for dose calculation
at depth d in an arbitrary test case.
( )
Dcalc d, SSD′ , FS′ , AS′ = Dref (d, SSD, FS, AS)
( ( ))
Dtest d, SSD′ , FS, AS
×
Dref (d, SSD, FS, AS)
( ( ))
Dtest d, SSD, FS′ , AS
×
Dref (d, SSD, FS, AS)
( ( ))
Dtest d, SSD, FS, AS′
×
Dref (d, SSD, FS, AS)
(1)
The CF for a given dosimetric parameter (e.g., SSD
CF, first bracketed term in Equation (1)) is simply the
ratio of the dose at the desired depth with the test-case
SSD (SSD′ ) (and all other parameters equal to refer-
ence parameters) to the dose at the same depth with all
parameters set to their default values.
The accuracy of this formalism was evaluated by
comparing the Dcalc value at depth d for several non-
reference fields with the dose at d directly simulated
with Monte Carlo Dsim (d, SSD′ , FS′ , AS′ ). The non-
reference test cases are summarized in Table 3. Dose
calculations were also performed in heterogeneous
phantoms with lung, rib, or cortical bone inserts located
at 2.5-mm depth, as shown in Figure 2c. The PDDs for
these phantoms were normalized to the maximum dose
in a homogenous, soft tissue phantom.
6 DOSIMETRY FOR RADIOBIOLOGY STUDIES

TA B L E 2 Summary of reference-case parameter combinations used in this study

Parameter Default Variable

combination Fixed parameter value parameter Values investigated

1 SSD (cm) 40 Animal size (cm) 1, 2, 3, 4, 5

Field size (cm) 1
2 SSD (cm) 40 Field size (cm) 0.5, 1, 2, 3, 5, 7, 10
Animal size (cm) 5
3 Field size (cm) 1 SSD (cm) 10, 20, 30, 40, 50, 60
Animal size (cm) 5
Abbreviation: SSD, source-to-surface distance.

TA B L E 3 Summary of test-case parameters for the reference and nonreference cabinet irradiators that were used in this study. The
nonreference cases represent end-user irradiators

Beam quality Reference Nonreference

Parameter Test-case 1 Test-case 2 Test-case 3 End-user test-cases
Model XRAD320 XRAD320 RT250 MultiRad350 RS2000

Energy (kVp) 320 F1 320 F2 200 250 160

Depth (cm) 4 2 1 2 3
Animal size (cm) 5 4 3 5 5
SSD (cm) 60 30 10 20 40
Field size (cm) 3 10 0.5 1 5
Abbreviation: SSD, source-to-surface distance.

TA B L E 4 Composition of lung, rib, and cortical bone used to generate PEGS4 cross-sectional data for Monte Carlo simulations in animal
models

Bone type Cortical bone Rib (2, 6) LUNG521ICRU

Mass density, (g/cm3 ) 1.92 1.41 0.26

Effective atomic number, Zeff 13.96
Composition by weight (%) H (3.4), C (15.5), N (4.2), O
(43.5), Ca (22.5), P
(10.3), S (0.3), Mg (0.2),
Na (0.1)
12.14
H (6.4), C (26.3), N (3.9), O
(43.6), Ca (13.1), P (6.0),
S (0.3), Mg (0.1), Na
(0.1), K (0.1), Cl (0.1)
7.88
H (10.3), C (10.5), N (3.1),
O (74.9), Na (0.2), P
(0.2), S (0.3), CL (0.3), K
(0.2)

The specific cross‑sectional data for the two bone 𝛿Dref , and DSSD be the dose for the test case SSD (first
materials were calculated in MATLAB based on ICRU- numerator in Equation (1)) with associated uncertainty
44 data23 while that of lung (LUNG521ICRU) is avail- 𝛿DSSD , etc.
able in the default 521ICRU PEGS4 data in EGSnrc.The √
√ (
material compositions of lung, rib, and cortical bone are √ 𝛿D )2 ( 𝛿D )2 (
𝛿DFS
)2 (
𝛿DAS
)2
√ ref SSD
𝛿Dcalc = |Dcalc | 2 + + +
summarized in Table 4. Dref DSSD DFS DAS
Dose to the medium (bone) was calculated (as
(2)
opposed to dose to water with bone density) as
per international recommendations for clinical trial
consistency.25,26 The propagated uncertainty for the calculated dose
(Dcalc ) is the quadratic sum in Equation (2). The
combined uncertainty of the dose difference (𝛿Ddiff )
between the calculated and simulated dose is found by
2.3.3 Uncertainty propagation adding their respective uncertainties (𝛿Dcalc and 𝛿Dsim )
in quadrature as shown in Equation (3).
Let the symbol 𝛿 represent the uncertainty for each of
√
the dose quantities in Equation (1). For simplicity, also let 2 2
Dref be the reference dose with associated uncertainty 𝛿Ddiff = (𝛿Dcalc ) + (𝛿Dsim ) (3)
DOSIMETRY FOR RADIOBIOLOGY STUDIES
F I G U R E 4 Reference-case percentage depth-doses (PDDs) as a function of animal size for the (a) PXi 320 kVp F1, (b) PXi 320 kVp F2,
and (c) RT250 200 kVp beams calculated for 40-cm source-to-surface distance (SSD) and 1-cm field size
Equations (2) and (3) assume that the original uncer-
tainties associated with the simulated doses in Equation
(1) are uncorrelated and random, which is a reasonable
assumption in this Monte Carlo study.
2.4 Dosimetry formalism for end-users
(HVL interpolation)
Radiation units come with manufacturer-provided HVLs,
and these values should also be measured by the user,
as will be prescribed in the TG-319 report. So far, the
methodology for dose calculation and test case valida-
tion has been provided for the reference beam quali-
ties investigated, that is, the 320 kVp F1, 200 kVp, and
320 kVp F2 beams with HVLs of 0.59,1.00,and 3.57 mm
Cu, respectively.
To perform dosimetry for nonreference irradia-
tors/beam qualities, let the right-hand side of Equation
(1), excluding the reference dose term, be the full CF to
rescale the dose from the measured to the prescribed
position for any given cabinet irradiator. The doses at
3-cm and 2-cm depth for the 160 and 250 kVp beams
with HVLs 0.78 and 1.80 mm Cu, respectively, were sim-
ulated in a 5-cm diameter phantom and compared with
the results based on the interpolation from reference
data and the calculation formalism of Section 2.3.2. This
was accomplished by calculating the full CFs for each of
the reference beam qualities investigated as a function
of their corresponding HVLs and then interpolating
the CFs for the end-user HVLs under investigation
to rescale the reference dose to the treatment field
dose.
3 RESULTS
The following figures (Figures 4–6) illustrate the effect
of varying animal size, field size, or SSD on the PDD
for cylindrical small-animal phantoms under reference
conditions.
7
3.1 Small-animal phantom PDDs for
reference cases
Some general trends are evident from the plots, such
as the relatively high surface dose (>50% of the maxi-
mum dose) as compared to MV beams (≤15% PDD)27
generally used in radiotherapy treatments. The simu-
lated surface dose is, however, lower as compared to
typical values for kV beams (usually ∼90%–100%),27
and this may be due to partial volume averaging of the
calculation voxel size used (0.5 × 0.5 × 2 mm3 ). The
dose fall-off per centimetre can also be observed in
Figure 4, with very small differences in doses at depth
for different animal sizes, except near the beam exit
regions of the phantom due to missing backscatter. The
PDD decreases with increasing depth due to the inverse
square law and beam attenuation. In Figure 5, the dose
increases in going from a 0.5-cm to 10-cm diameter field
size due to increased scatter contribution from the col-
limator and the phantom. The effect is relatively pro-
nounced - dose differences up to 15% are apparent as a
function of field size. The decrease in dose with increas-
ing SSD in Figure 6 is because of the inverse square
law, which dictates a reduction in beam intensity with
increasing distance from the source. This effect is more
pronounced for smaller SSDs.
Tables S1 and S2 (provided in the supplementary
data) give PDD values at depths of 0.5–5.0 cm (in steps
of 0.5 cm) in a small-animal phantom as a function
of beam size and SSD, respectively, for beam qualities
ranging from 0.6 to 3.6 mm Cu.
3.2 Dose estimation and validation for
test cases
Figure 7 shows test-case PDDs for the reference beams
(the PXi and RT250 beams) and nonreference end-user
beams (the MultiRad350 and RS2000 beams) simu-
lated for different dosimetric parameters (in Table 3)
in small-animal phantoms of different sizes. Dose
8 DOSIMETRY FOR RADIOBIOLOGY STUDIES

F I G U R E 5 Reference-case percentage depth-doses (PDDs) as a function of field size for the (a) PXi 320 kVp F1, (b) PXi 320 kVp F2, and
(c) RT250 200 kVp beams for 40-cm source-to-surface distance (SSD) and 5-cm animal size

F I G U R E 6 Reference-case percentage depth-doses (PDDs) as a function of source-to-surface distance (SSD) for the (a) PXi 320 kVp F1,
(b) PXi 320 kVp F2, and (c) RT250 200 kVp beams calculated for 1-cm field size and 5-cm animal size

calculations (estimated using Equation 1) for the refer-

F I G U R E 7 Test-case small-animal phantom percentage
depth-doses (PDDs) for the 320 kVp F1 beam simulated in a 5-cm
diameter animal phantom with 60-cm source-to-surface distance
(SSD) and 3-cm field size (blue curve), 320 kVp F2 beam simulated
in a 4-cm diameter phantom with 30-cm SSD and 10-cm field size
(brown curve), and 200 kVp beam simulated in a 3-cm diameter
phantom with 10-cm SSD, and 0.5-cm field size (orange curve). Two
end-user test-cases are also shown, the MultiRad350 250 kVp beam
(green curve) simulated in a 5-cm diameter phantom with 20-cm
SSD and 1-cm field size, and the RS2000 160kVp beam (red curve)
simulated in a similar phantom with 40-cm SSD and 5-cm field size
ence beam test-cases, and comparisons with their cor-
responding simulated (i.e., expected) doses, are shown
in Table 5a-c. The dose calculation results for end-
user beam test-cases are presented in Section 3.4. In
Table 5a-c, the calculated dose, Dcalc , and its uncertainty
were calculated from Equations (1) and (2), respectively,
while the dose-difference uncertainty was calculated
using Equation (3). The CF uncertainties were also
calculated using Equation (2), excluding the reference
dose term. The uncertainty for Dsim was read from the
DOSXYZnrc .3ddose file21 using a MATLAB function.
For these reference beam test-cases, the discrepan-
cies between the dose calculated using CFs derived
from this work (Dcalc ) and the simulated doses (Dsim )
were −0.1%, 1.0%, and 1.2% for the 320 kVp F1,
320 kVp F2, and RT 250 kVp beams, respectively.
3.3 Dose calculation in the presence of
lung and bone
Depth doses and perturbations in the presence of differ-
ent bone types – either cortical or rib, as well as lung -
are shown in Figure 8a-c for reference beam qualities
DOSIMETRY FOR RADIOBIOLOGY STUDIES 9

TA B L E 5 Test-case dose calculation and comparison with the simulated dose for the (a) 320 kVp F1 beam; (b) 320 kVp F2 beam, and (c)
200 kVp beam. Uncertainties (δ) for the doses and for correction factors (CFs) are shown. Dcalc is the calculated dose, Dsim is the simulated
dose, and Ddiff is the dose difference (Dcalc − Dsim ). The CF is the corresponding ratio of the test and reference doses in Equation (1)

(a) PXi XRAD 320 kVp F1 (b) PXi XRAD 320 kVp F2 (c) RT250 200 kVp
Value PDD ± Value PDD ± PDD ±
(cm) δPDD (%) CF ± 𝜹CF (cm) δPDD (%) CF ± 𝜹CF Value (cm) δPDD (%) CF ± 𝜹CF

Depth 4 – – 2 – – 1 – –
Animal size 5 ǂ 38.9 ± 0.6 1.00 ± 0.02 4 ǂ 73.6 ± 0.6 1.00 ± 0.01 3 ǂ 84.7 ± 0.8 1.00 ± 0.01
SSD 60 41.3 ± 0.9 1.06 ± 0.03 30 70.5 ± 0.5 0.96 ± 0.01 10 74.1 ± 0.2 0.87 ± 0.01
Field size 3 44.4 ± 0.3 1.14 ± 0.02 10 82.8 ± 0.4 1.13 ± 0.01 0.5 82.2 ± 0.8 0.97 ± 0.01
Dcalc (%) 47.0 ± 1.7 79.8 ± 1.3 71.5 ± 1.4
Dsim (%) 47.1 ± 0.5 78.8 ± 0.3 70.3 ± 0.2
Ddiff ( %) –0.1 ± 1.8 1.0 ± 1.3 1.2 ± 1.4
ǂ
indicates the reference case for each beam.

TA B L E 6 Maximum dose (Dmax ) as well as dose at 1-cm depth (D1cm ) for reference beams with the associated dose difference, Ddiff (in
brackets) relative to dose in a homogenous (soft tissue) phantom

Beam Soft tissue Cortical bone Rib (2, 6) Lung

(kVp) Dmax (%) D1cm (%) Dmax (%) D1cm & Ddiff (%) Dmax (%) D1cm & Ddiff (%) Dmax (%) D1cm & Ddiff (%)

320 F1 100.0 80.9 367.3 69.2 (–11.7) 253.4 74.9 (–6.0) 98.6 83.5 +2.6
320 F2 100.0 87.0 133.0 83.8 (–3.2) 118.0 85.7 (–1.3) 99.7 89.2 +2.2
200 100.0 84.4 291.4 78.1 (–6.3) 208.2 81.5 (–2.9) 98.9 86.5 +2.1
*Ddiff = dose @ 1 cm depth with lung/bone −− dose @ 1 cm depth in soft tissue.

investigated. Expected dose enhancement at the bone- 4 DISCUSSION

tissue interface and the proximal dose fall-off relative to
the no-bone case are immediately evident. The 320 kVp
F1 beam (with the lowest HVL) is the most sensitive to
heterogeneities, especially in the presence of cortical
bone.
Since lung tissue has similar atomic number to soft
tissue, lung tissues do not exhibit such a drastic change
in dose. Table 6 shows the maximum dose as well as
dose at 1-cm depth (downstream of the lung/bone) for
the three beams with the associated dose differences
relative to dose in homogenous soft tissue, that is, in the
absence of bone/lung.
3.4 End-user dose calculations for 160
and 250 kVp beams
Table 7 shows the CFs for each HVL, which enable dose
calculation for the 160 and 250 kVp test-case scenarios
with respective HVLs of 0.78 and 1.80 mm Cu. The
simulated doses, Dsim (as shown in Figure 7), calculated
doses (Dcalc ), and dose differences (Ddiff = Dsim –Dcalc )
are shown. The calculated doses are in reasonable
agreement with the simulated doses, with respective
dose differences of 1.4% and 3.2% for the RS2000 and
the MultiRad350.
This study provides physicists and radiobiologists with
Monte Carlo PDD data in simplified small-animal phan-
toms under different irradiation scenarios with varying
SSD, field sizes, and animal sizes for some of the most
common beam qualities used in radiobiology research.
These PDDs are provided in the context of the new
dosimetric guidelines proposed by the upcoming AAPM
Task Group 319 report16 to perform and report more
accurate dosimetry in kV X-ray cabinet irradiators.
There are currently few alternatives for cabinet
irradiator end-users to perform dosimetric calculations
themselves. Unlike for MV X-rays with which most physi-
cists are familiar, few published datasets are available
for these beam qualities. The most widespread, BJR 25,
is only provided for a single SSD, a limited number of
beam qualities, and no field sizes between 0 × 0 cm2
and 4 × 4 cm2 – the majority of partial body irradiations
in small animals.12 Furthermore, they are acquired
in a conventional wide water tank, which represents a
semi-infinite scatter environment. However, small animal
experiments are virtually never performed with infinite
backscatter, which has been shown to introduce up to
5%–25% of dosimetric error for field sizes 1–5 cm in
diameter.28,29 For this reason, even if investigators were
able to measure PDD in their own systems (a nontrivial
10
TA B L E 7 Dose calculation for the MultiRad350 beam (at 2-cm depth) and the RS2000 beam (at 3-cm depth) with simulation parameters
summarized in Table 3
Correction
Irradiator HVL factor
model (mm Cu) (2-cm depth)
XRAD320 F1 0.59 1.18
RT250 1.00 1.13
XRAD320 F2 3.57 1.10
Multirad350 1.80 1.08
RS2000 0.78 – 1.13
Abbreviations: HVL, half value layer; PDD, percentage depth-dose; SSD, source-to-surface distance.
challenge due to size constraints), these will not be
representative of their experimental conditions. Some
investigators were able to characterize their biological
irradiators using Monte Carlo techniques and calculate
animal-specific dose distributions.30,31 However, these
techniques are difficult to implement by the average
end-user, who often has limited access to resources.14,15
With these PDDs, an investigator can now relate dose
from a point – which they measure experimentally – to
dose at another depth for small animal experiments per-
formed on kV X-ray cabinet irradiators. On their own,
the PDDs do not provide depth-dose information for a
real animal model but provide the basis for depth dose
estimation based on derived corrections to measured
doses, as long as heterogeneities are avoided. Dose cal-
culations in three different test cases, using PDD CFs
derived from the data, and comparisons with their cor-
responding simulated doses were performed to evalu-
ate feasibility for preclinical implementation of the calcu-
lation methodology. The dosimetric impact of lung and
bone was also evaluated. These data will facilitate the
calculation of dose at the required depth in small-animal
models, thereby increasing the accuracy of small animal
dosimetry.
The depth doses for the three test-cases at 320 F1,
320 F2, and 200 kVp agreed well with expected doses,
yielding dose difference magnitudes of 0.1%, 1.0%,
and 1.2%, respectively. Taking into account the prop-
agated uncertainties, the maximum dose differences
increase to 2.3%, 2.6%, and 1.7%, respectively, which
is small compared to the uncertainty generally tolerated
in radiotherapy.32 The dose estimation technique used
in this work assumes that the CFs for SSD, field size,
and animal size are uncorrelated; therefore, the over-
all PDD CF can be obtained by simply multiplying CFs
for these three terms. However, this still propagates the
uncertainty in the calculated dose.It is interesting to note
that the uncertainties in the dose differences (Ddiff ) of
Table 5a-c can be of the same order of magnitude or
larger than the dose difference itself,especially when the
doses in comparison are very close to each other. Never-
theless, the small percentage dose differences demon-
DOSIMETRY FOR RADIOBIOLOGY STUDIES
Correction
factor Dcalc
(3-cm depth) Dsim (%) (%) Ddiff (%)
1.24 – – –
1.06 – – –
0.94 – – –
– 63.5 66.7 - 3.2
64.0 65.4 -1.4
strate that the results support the use of compiled PDD
data sets, such as those provided in this work, to trans-
late from a reference field depth-dose to that expected
in the treatment field.
Dose at the bone-tissue proximal interface ranged
from 1.2 to 2.5 times higher than the dose in soft tissue
for rib and 1.3 to 3.7 times higher for cortical bone.These
results are in agreement with a similar published study,33
which reported a dramatic bone dose-enhancement in a
mouse model—up to three times higher when simulating
irradiation with 225 kV X-rays. In the present study, dose
reductions at 1-cm depth beyond the bone interface, rel-
ative to the case without bone, ranged from 1.3% to
6.0% for rib and 3.2% to 11.7% for cortical bone. These
dose perturbations occur due to electron backscatter on
the bone surface and absorption inside the bone, owing
to the importance of photoelectric interactions in high
atomic number materials for kV beams. On the other
hand, lung did not exhibit such drastic dose perturba-
tions, with lung-tissue interface dose >99% of the dose
in a homogeneous phantom and <3% dose increase at
1-cm depth beyond the lung. This is due to the lung’s
similar effective atomic number with soft tissue.However,
the lower density lung (𝜌 = 0.26 g/cc) receives a slightly
higher dose, due to the increased scattering of electrons
from the higher density soft tissue (𝜌 = 1.0 g/cc).
The proportion of photons interacting via the photo-
electric effect depends on the energy spectrum (and
consequently the HVL) of the X-ray beam, with more
interactions occurring in beams, which contain a larger
number of low-energy photons.34 The calculated HVLs
of the 320 kVp F1, 200 kVp, and 320 kVp F2 beams
based on the X-ray spectra in Figure 3 were found to be
0.6, 1.0, and 3.6-mm Cu, respectively. The 200 kVp beam
HVL agreed with measured data.20 It must be noted that
since we did not have access to the geometry of the mir-
ror and ionization chamber, these components were not
included in the Monte Carlo model of the PXi XRAD unit,
which might account for the softer beam compared to
what was measured experimentally (with HVL values of
0.8–1.12 mm Cu for F1 and 3.7–4.0 mm Cu for F2).30
In Figure 8, the dose perturbation in the presence of
DOSIMETRY FOR RADIOBIOLOGY STUDIES
F I G U R E 8 Effect of cortical bone, rib, and lung on small-animal percentage depth-doses (PDDs) for the (a) PXi 320 kVp F1, (b) PXi 320 kVp
F2, and (c) RT250 200 kVp beams calculated for a 40-cm source-to-surface distance (SSD) and 1-cm field size in a 2-cm diameter cylindrical
phantom. The graphs were plotted on the same y-axis range to easily compare changes in dose perturbations with changing beam quality
bone for the 320 kVp F1 beam is highest, owed to hav-
ing the lowest HVL of the three beams, followed by the
200 kVp and then the 320 kVp F2 beam. The 320 kVp
F2 beam exhibits a smaller dose perturbation, due to
the increased X-ray filtration in the beam, which attenu-
ates most of the lower-energy photons. The high sensi-
tivities of kV beams to tissue heterogeneities demon-
strate the importance of including these structures in
the dose estimation framework. In small animals, this
sensitivity can be reflected in treatment planning uncer-
tainties within the organs of interest (targets or organs
at risk).
These estimated doses were only validated in the
absence of bone. In cases where dose calculations
are desired near heterogeneities (especially bone inter-
faces), additional attention (e.g., Monte Carlo) is needed
for accurate dose determination. CFs are unlikely to
be a feasible approach – first, due to difficulties in
quantifying the effective thickness of bone (particularly
the dense cortical bone) in a given animal in the path
of the beam without CT image guidance. Second, due
to the very high dependence of the attenuation of kV
beams on the soft X-ray component of the spectrum,
which leads even modest changes in beam quality to
have a disproportionate impact on the attenuation in
cortical bone.35,36 Thankfully, in irradiations performed
using cabinet irradiators, targets tend to be relatively
large (≥1 cm), and bones seldom obscure the entire
treatment area outside the cranium. In the absence of
3D dose computation techniques, investigators typically
calculate dose to water or lung, ignoring the confounding
effects of bone. A recently published paper by Dewert
and Kunugi37 addresses the difficulty of performing
reference dosimetry on orthovoltage machines.
The presented work gives data for three beams
with HVL values between 0.6 and 3.6 mm Cu. For
a system with different a beam energy or HVL, it is
likely possible to interpolate the data presented in
Figures 4–6 to beams with other HVL values. To test the
11
HVL interpolation methodology for cabinet irradiators
with different HVLs, two test-case scenarios, one for
a 160 kVp beam and another for a 250 kVp beam
with respective HVLs of 0.78 and 1.80 mm Cu, were
simulated and the PDDs at two different depths com-
pared with the interpolated, formalism-derived results
based on the reference data. The results demonstrate a
reasonable agreement, at least for our test-case cabinet
irradiators, with respective dose differences of 1.4%
and 3.2% between the simulated and the interpolated
doses.
An expanded body of work could include the cre-
ation of a web-based program to calculate dose at
any depth in the animal for an arbitrary beam. Further-
more, the current work concerns itself only with the
distribution of physical absorbed dose – the effects
of beam quality, attenuation, and heterogeneities on
radiobiological effectiveness (RBE) are not investigated.
Previous research in microdosimetry has shown there
is a high dependence on the absorbed dose delivered
in bone marrow immediately adjoining cortical bone.
It is speculated that this may be driving much of the
RBE differences in bone marrow effects with beam
quality.38
5 CONCLUSIONS
The developed dose estimation method can be used
to translate measured doses in the reference point to
any depth along the central beam axis in a small-animal
experiments performed on kV X-ray cabinet irradiators.
The dosimetric impact of bone must be accurately quan-
tified and included in the dose calculation framework as
dramatic dose perturbations at and beyond the bone
interfaces can occur due to the relative importance of
the photoelectric effect at kV beam energies. These
results will help improve dosimetric accuracy in preclin-
ical experiments.
12
AC K N OW L E D G M E N T S
This research was enabled in part by computing
resources and support provided by Compute Canada.
The author thank the Natural Sciences and Engineering
Research Council of Canada (NSERC) and the Canada
Research Chair program for their support.
CONFLICTS OF INTEREST
The authors declare that they have no conflict of interest.
DATA AVA I L A B I L I T Y S TAT E M E N T
Data are available on request from the authors.
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S U P P O R T I N G I N F O R M AT I O N
Additional supporting information may be found in the
online version of the article at the publisher’s website.
13
How to cite this article: Mahuvava C, Esplen
NM, Poirier Y, Kry SF, Bazalova-Carter M. Dose
calculations for preclinical radiobiology
experiments conducted with single-field cabinet
irradiators. Med Phys. 2022;1-13.
https://doi.org/10.1002/mp.15487