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A small-scale anatomical dosimetry model of the liver

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 Institute of Physics and Engineering in Medicine Physics in Medicine and Biology

Phys. Med. Biol. 59 (2014) 3353–3371 doi:10.1088/0031-9155/59/13/3353

A small-scale anatomical dosimetry model

of the liver
Anna Stenvall, Erik Larsson, Sven-Erik Strand
and Bo-Anders Jönsson
Department of Medical Radiation Physics, Clinical Sciences, Lund University, Lund,
Sweden

E-mail: anna.stenvall@med.lu.se

Received 13 November 2013, revised 17 February 2014

Accepted for publication 2 May 2014
Published 30 May 2014

Abstract
Radionuclide therapy is a growing and promising approach for treating
and prolonging the lives of patients with cancer. For therapies where high
activities are administered, the liver can become a dose-limiting organ;
often with a complex, non-uniform activity distribution and resulting non-
uniform absorbed-dose distribution. This paper therefore presents a small-
scale dosimetry model for various source–target combinations within the
human liver microarchitecture. Using Monte Carlo simulations, Medical
Internal Radiation Dose formalism-compatible specific absorbed fractions were
calculated for monoenergetic electrons; photons; alpha particles; and 125I, 90Y,
211
At, 99mTc, 111In, 177Lu, 131I and 18F. S values and the ratio of local absorbed
dose to the whole-organ average absorbed dose was calculated, enabling a
transformation of dosimetry calculations from macro- to microstructure level.
For heterogeneous activity distributions, for example uptake in Kupffer cells of
radionuclides emitting low-energy electrons (125I) or high-LET alpha particles
(211At) the target absorbed dose for the part of the space of Disse, closest to
the source, was more than eight- and five-fold the average absorbed dose to the
liver, respectively. With the increasing interest in radionuclide therapy of the
liver, the presented model is an applicable tool for small-scale liver dosimetry
in order to study detailed dose–effect relationships in the liver.

Keywords: liver, Monte Carlo, small-scale, dosimetry, S values

(Some figures may appear in colour only in the online journal)

1. Introduction

In recent years, increasing interest has been directed towards the potential radiation effects
on normal liver tissues after administration of very high activities to patients undergoing

0031-9155/14/133353+19$33.00 © 2014 Institute of Physics and Engineering in Medicine Printed in the UK & the USA 3353
Phys. Med. Biol. 59 (2014) 3353 A Stenvall et al

radionuclide therapy (Welsh et al 2006, Murthy et al 2005, Kennedy et al 2004, Guha

and Kavanagh 2011, Sjögreen-Gleisner et al 2011). Although in most radiation exposure
situations the liver is normally considered a rather radiation-resistant organ, fractionated
external radiotherapy has shown that radiation-induced liver disease (RILD) can occur a few
weeks to three months after a threshold absorbed dose of approximately 30–35 Gy to the
whole-liver and has a 5% incidence (Emami et al 1991, ICRP 2012, Pan et al 2010, Marks
et al 2010). Above this threshold absorbed dose, the severity of functional damage may
increase with increasing absorbed dose. Nevertheless, the tolerance dose is usually increased
during partial-organ (external) irradiation, since the functional subunits (FSU) of the liver are
arranged in parallel and thus the remaining tissue can compensate for damaged FSU (ICRP
2012). Whether and to what degree this is also true for radioactive agents that typically localize
heterogeneously in the tissue remains to be studied.
Microstructure scale dosimetry (small-scale dosimetry) of the normal liver tissue
architecture, where the absorbed dose in the different microstructures of the tissue is calculated,
is a needed complement to the macroscopic dosimetry. The conventional a priori dosimetry
calculation performed on a macroscopic level, using predefined voxel-based whole-body
phantoms (among others the Cristy–Eckerman phantoms (Cristy and Eckerman 1987), where
the different organs are delineated and can be defined as source and/or target regions (e.g.
OLINDA/EXM (Stabin et al 2005)), gives the average absorbed dose to the whole-organ
region defined as target, based to the assumption of homogeneous distribution of radioactivity
within the source organ. The formulation of the absorbed dose is established by the Medical
Internal Radiation Dose (MIRD) Committee, where the absorbed dose (DrT ) is the mean energy
imparted in a target region (rT ) divided by the mass of the target region (mrT ) (Bolch et al
2009). The mean energy imparted in turn is the cumulated activity (ÃrS ) in the source region
(rS ) multiplied by the mean energy emitted per nuclear transformation () multiplied by the
fraction of the radiation energy emitted from a source region that is absorbed in the target
region (φ(rT ← rS )). The product of the latter two quantities,  and φ(rT ← rS ), divided
by the mass of the target region (mrT ), is denoted as the S value in the MIRD formalism,
and is radionuclide- and anatomy-specific, whereas the cumulated activity, (ÃrS ), required
for the calculation of absorbed dose, is depending on the physical and biological half-life
of the radionuclides in the source region. Combining these quantities yields equation (1)
for (DrT ):
 Ãr φ(r ←r ) 
DrT = S T S
= ÃrS S(rT ← rS ). (1)
r
mrT r
T T

One limitation of the a priori macroscopic application of the MIRD formalism arises when
the activity distribution does not fulfil the assumption of being homogeneously distributed
within the target region and the radionuclides are emitting particles (α-particles, β-particles
and low-energy electrons) having ranges in tissue close or equal to the dimensions of the
tissue microstructures. In such situations, small-scale dosimetry is required for biologically
meaningful dosimetric calculations. However, since activity distributions at this scale are not
deducible with current clinical imaging modalities, they must be determined pre-clinically and
applied to suitable micro-structure phantoms (ICRU 2002).

1.1. Anatomy and radiation pathology of the liver

The liver is the largest gland in the body and is functionally very complex. It is involved
in the production and secretion of bile and has numerous metabolic functions that are
essential for normal homeostasis. Extensive surveys of the liver anatomical structure and

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Figure 1. Outline of the hepatic microstructure at the organ level (left) and the detailed
structure of the liver microvasculature (right) via division into the hepatic functional
subunits and the hepatic lobules. The small space between the hepatocyte- and the
sinusoidal-surface comprises the space of Disse. Reprinted with permission (Mescher
2010).

function have been described elsewhere (Dancygier 2010, Mescher 2010, Burt et al 2012).
Histologically, the liver comprises thousands of nearly identical lobules that are divided by
sheets of connective tissue. The lobule is the functional and structural subunit of the liver
and is a good representative of the whole-organ for radiobiology and small-scale dosimetry
studies. The lobule is a hexagonal structure, 2 mm in height and 1–1.3 mm in diameter with the
central vein at its origin. It is delimited at the six vertices by portal tracts, including branches
of the hepatic portal artery, the portal vein, small bile ducts, nerve fibers, and lymphatic
vessels (figure 1). The lobule consists mainly of hepatocytes that are arranged radially in
plates from the central vein to the portal tracts. Between the hepatocyte plates are sinusoids,
also arranged radially, that connect the vessels in the portal tract to the central vein, thus
allowing nutrient and oxygen-rich blood to enter the lobule from the portal vessels and empty
into the central vein. The hepatocyte sinusoidal membrane faces the small perisinusoidal space
of Disse, which is located between the hepatocytes and the endothelium of the sinusoid and
gives rise to a two-way exchange between the blood and hepatocytes. The sinusoid lumen
houses the mononuclear phagocytic system, which comprises generally stationary Kupffer
cells as well as some migrating macrophages. These cells play an essential role in host
defense mechanisms and the removal of foreign small particles and substances that enter the
liver.
Radiation pathology of the liver is not fully understood, but the target of fatal damage is
likely to be the endothelial cells in areas around the central veins and the adjacent sinusoids
(Kennedy et al 2004, Jirtle et al 1990). Clinically, this is expressed as sinusoidal obstruction
syndrome (earlier known as veno-occlusive disease) and is characteristic of RILD due to
external irradiation (Dancygier 2010, DeLeve and Garcia-Tsao 2011, Mauss et al 2012).
Therefore, the hepatocytes are not thought to be the main target but become secondarily
affected because of the loss of vascular access, leading to necrosis and fibrosis. However, little
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is known about the absorbed dose tolerated and radiobiological characteristics of different liver
cell types and remains to be studied in detail. In a recent work by Park et al (2012) the radio-
sensitivity of different human endothelial cells were studied by clonogenic survival in vitro,
after irradiation with 137Cs γ -rays (0–8 Gy). Although the hepatic sinusoidal endothelial cells
were found to be the most radio-resistant among the endothelial cell lines studied, the absorbed
dose to give a 10% survival was estimated to be only 4 Gy, compared to the whole-liver dose
thought to give RILD (i.e. 30–35 Gy).

1.2. Inhomogeneous radiopharmaceutical distribution

In radionuclide therapy, the increased use of selective internal radiation treatments (SIRT) via
the intrahepatic arterial administration of 90Y-microspheres to treat hepatocellular carcinoma
(Ahmadzadehfar et al 2010, Murthy et al 2005) has resulted in a need for refined dosimetry
models that better account for the detailed localization of the radioactive sources and the
subsequent energy distribution patterns (Chiesa et al 2011, Claudio Traino et al 2012).
Recently, Gulec et al (2010) presented a Monte Carlo dosimetry model based on the hepatic
lobule microstructure in order to more realistically evaluate hepatic radiation effects due to a
non-uniform distribution of 90Y microspheres. This model provided a detailed calculation of
the absorbed dose distribution in the hepatic subunits after a total activity administration of
3 GBq, calculated for four different scenarios representing two different total volumes of tumor
involvement (150 and 300 cm3) and two types of microspheres (resin spheres at 50 Bq/sphere
and glass spheres at 2500 Bq/sphere). The results indicated that the absorbed dose to the
central vein was close to or similar to the average absorbed dose to the liver (for resin spheres
and a tumor volume of 150 cm3 the absorbed dose was 64 and 59 Gy to the liver and central
vein, respectively), whereas the absorbed dose to the hepatic artery was significantly higher.
Hence, the model made it possible to better understand the relationship between SIRT-induced
liver failure and the absorbed dose.
Nanoparticles and nanocolloids are well-known to accumulate in the liver after an I.V.
administration (Wilhelm et al 1999, Moghimi et al 2001). In a recent study by Madru et al
Wistar rats were injected with 99mTc labeled superparamagnetic iron oxide nanoparticles
(SPIONs) for multimodality imaging. The uptake of nanoparticles in the liver 4 h after injection
yielded 1.4 ± 0.7 percent of the injected activity (IA) per gram, that is approximately 15%
of IA accumulated in the liver (Madru et al 2012). After intravenous injection the SPIONs are
removed from the circulation by the mononuclear phagocytic system, including the Kupffer
cells in the liver (Ferrucci and Stark 1990). It has been shown that SPIONs with an average
diameter of 18 nm have after an intraperitonial injection an uptake pattern in the hepatic
sinusoids corresponding to the distribution of Kupffer cells (Tsuchiya et al 2011).
Quantitative autoradiography has shown heterogeneous activity distribution in the liver
tissue after injection of different 111In-labeled radiopharmaceuticals and 99mTc-nanocolloids
(Gardin et al 1992, Hindie et al 1988, ICRU 2002, Jönsson et al 1992). The nanocolloids are
phagocytized by Kupffer cells, which thus represent radioactive ‘hotspots’ in the liver tissue.
Makrigiorgos et al (1990) showed that the intracellular activity concentration was 200- to
1000-fold higher in these Kupffer cells, compared to the extracellular activity concentration,
and that conventional dosimetry calculations underestimated the absorbed dose to the human
liver Kupffer cells by 8- to 30-fold. Gardin et al estimated the absorbed dose to the Kupffer
cells after administering 99mTc-sulfur colloids in rats. The absorbed dose to these Kupffer
cells was estimated to be 0.5 to 0.9 Gy MBq−1 of administered activity, which is roughly
15 000-fold greater than the estimated mean absorbed dose to the liver. Significant liver uptake
of other radiopharmaceuticals, including radiolabeled antibodies and peptides, has also been

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observed in patients undergoing nuclear medicine examinations and therapies, and these may
have various uptake patterns (Arico et al 2009, Firer and Gellerman 2012, Fisher et al 2009,
Sjögreen-Gleisner et al 2011). Radionuclides that emit alpha particles for targeted therapy, for
example 211At and 212Bi, are of growing interest and are increasing the need for improvements
in dosimetry (Guérard et al 2013, Kassis 2005).
In addition, actinides like plutonium and thorium that emit alpha particles are known to
induce severe radiation effects in the liver. Thorium-232 dioxide (232ThO2) which forms part of
Thorotrast, a well-known diagnostic contrast medium associated with microvascular injuries
as well as with angiosarcoma and other primary hepatic neoplasms. It was a used extensively
for arteriography from the late 1920s to 1955 in Europe, the USA, and Japan. Thousands
of patients were exposed to lifelong chronic alpha particle exposure during the decay of
232
Th and its decay products, because of the long-term storage of thorium dioxide particles in
the mononuclear phagocytic system (i.e. in Kupffer cells) after intravascular administration
(UNSCEAR 2006).
Plutonium dioxide is also known to have very long retention in the liver. In an experiment
by Brooks et al the liver was used as a model to study the biological effects occurring after
a non-uniform absorbed dose distribution on a cellular level from 239Pu (Brooks et al 1974).
Chinese hamsters were administered with 239Pu-citrate and 239PuO2 particles with different
sizes (170–840 nm) but with the same activity, resulting in chronic low-dose radiation exposure
and the same average absorbed dose to the liver. In contrast to uniformly distributed 239Pu-
citrate, the 239PuO2 particles accumulated in the Kupffer cells resulted in an absorbed dose
rate and dose being highest to liver cells located in the vicinity of the Kupffer cells. However,
the induction of chromosome aberrations after exposure to each of the 239PuO2 particle sizes
compared 239Pu citrate was not significantly different as a function of local absorbed dose
distribution. These observations were interpreted that all liver cells were at the same risk
of induced chromosome damage despite partial irradiation of the liver. In another study the
cumulative incidence of liver cancer as a function of time and absorbed dose, after injection of
239
PuO2 particles was investigated (Brooks et al 1983). It was concluded that 239PuO2 particle
size did not influence the tumor onset or incidence, and that the tumor induction was related
to the total liver absorbed dose, rather than the dose to individual cells or the number of cells
traversed by α-particles. Further investigations described elsewhere, have raised the possibility
of existence of bystander effects in the liver (Barcellos-Hoff and Brooks 2001, Morgan 2003),
which makes the development of new dosimetry models for the liver microstructure interesting.
The examples above are all observations in which the common average absorbed dose
calculations according to the conventional use of the MIRD formalism may not correspond to
the biological liver response. Thus, for future basic radiobiological investigations of radiation
responses, it is desirable to have a generally applicable small-scale dosimetry model of the
liver with the optional selection of source–target regions on a microstructure scale. The
aim of this project was to develop a Monte Carlo small-scale dosimetry model based on
the microarchitecture of the liver lobule in order to determine the S values for common
radionuclides used for therapy as well as diagnostics for different source–target combinations
within the liver tissue microstructure.

2. Materials and methods

2.1. The anatomical model

The small-scale anatomical model was based on a simplification of the FSU of the liver, the
hexagonal hepatic lobule. The approach was to create an idealized hepatic lobule specified by

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simple geometrical shapes, defined by first and second degree analytical surface equations.
The source- and/or target-regions are thus defined as the intersection, union or complement
of the regions bounded by the surfaces. Each defined region will be associated with a specific
number, making them identifiable as source- and/or target-regions.
The hepatic lobule was modeled as a hexagonal prism, having a height of 2.0 mm and the
hexagonal surface, at a radius of 500 μm and an inscribed radius of 433 μm, in the x–y plane.
The different structures of the liver microarchitecture, hepatocytes, sinusoids, bile canaliculi,
space of Disse, Kupffer cells, central vein, portal vein, portal artery and the bile duct, were
defined within this hexagonal prism. The central vein, defined as a cylinder along z-axis with
a diameter of 70 μm, marks the center of the hexagonal prisms, whereas the portal vein,
portal artery and bile duct are positioned at the each edge of the hexagonal prism, defined as
cylinders with diameters of 30 μm, 10 μm and 20 μm, respectively, see figure 2(b). Next, the
constituents of the hepatic lobule; hepatocytes, sinusoids, bile canaliculi, space of Disse and
Kupffer cells, are defined within another hexagonal prism, defined along the y-axis, running
from central vein to portal tract, that is oriented orthogonal to the former, hexagonal hepatic
lobular prism, as seen in figures 2(b) and (c). To be comprised within the former, the length
of the orthogonally oriented hexagonal prism cannot exceed 450 μm, since it is limited by
the radius of the hepatic lobule and the radius of the central vein and the portal vein. It is
defined with a radius of 35 μm. The bile canaliculi, marking the outer surface of this hexagonal
prism, was defined as the spacing between this and one inner hexagonal prism, having the
radius of 33 μm. As illustrated in figure 2(c), it gives the bile canaliculi associated with each
hexagonal prism a thickness of 1 μm, however the effective thickness of the bile canaliculi
becomes 2 μm, due to repetition the hexagonal prisms. The bulk of the inner hexagonal prism
comprises the hepatocytes, which divided into smaller hexagonal prisms with the height of
25 μm along the axis running from central vein to portal tract. The sinusoid marks the center
of this hexagonal prism, defined as a cylinder along the axis from central vein to portal tract,
with a diameter of 7 μm and the circular surface in the x–z plane. As a concentric cylinder
around the sinusoid, the space of Disse was defined with a width of 1 μm. To create individual
target cells, the space of Disse was, as the hepatocytes, divided into 25 μm thick slices along
the axis from portal tract to central vein. Inside the sinusoid, the Kupffer cells are defined as
ellipsoids with a 16 μm major axis and two 7 μm minor axes. The Kupffer cells are positioned
at five distances, (i.e. five possible source and/or target regions) 63, 163, 263, 363, and 463 μm
from the center of the lobule, along the axis from the central vein to the portal tract. This gives
a fraction of 0.14% of the total liver mass occupied by Kupffer cells, according to reported
fractions of Kupffer cells active in phagocytic processes (Gardin et al 1992, Makrigiorgos
et al 1990).
The hexagonal prism, containing the sinusoids, hepatocytes, space of Disse, Kupffer
cells and the bile canaliculi, was repeated in a lattice of hexagonal prisms along the positive
and negative x- and z-axes, seen in figure 2(c), however delimited by the surfaces defining
the hexagonal hepatic lobular prism, and additional three surfaces running from portal tract to
portal tract along the diameter of the hexagonal prism, dividing it into six wedges, delineated in
figure 2(b). The repetition creates a three-dimensional wedge of hexagonal prisms, all oriented
along the y-axis. The wedge-like structure was then repeated six times, and consecutively
rotated 60◦ around the z-axis, to fill the hexagonal hepatic lobule with microstructures. Next,
the now microstructure-filled hexagonal hepatic lobular prisms was repeated in another lattice
of hexagonal prisms, having dimensions and direction equal to the first defined hexagonal
hepatic lobular prisms, creating the contents of the whole-liver model, as seen in figure 2(a).
The model was defined inside a sphere with the radius 7.3 cm to mimic the average liver mass
(ICRP 2009).

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(a)

(b)

(c)

Figure 2. The small-scale dosimetry model of the liver. (a) The orientation and the
organization of the hexagonal hepatic lobular prisms, in a lattice of hexagonal prisms.
(b) The hexagonal hepatic lobular prism, showing the orientation and position of the
vessels and the defined microstructures. (c) Orthogonally oriented hexagonal prisms
(i.e. along the y-axis).

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2.2. The Monte Carlo simulation parameters

The radiation transport was performed using the general purpose Monte Carlo codes MCNP5
1.6 (X-5 Monte Carlo Team (I), X-5 Monte Carlo Team (II)) for photons, electrons, and
positrons and MCNPX 2.7 (Pelowitz, 2011) for alpha particles. Since the more detailed
energy straggling mode for electrons, which samples the energy loss separated from adjacent
steps (selected with the option DBCN 17j 2), is not included in MCNPX, that code was only
used to simulate alpha particles as primary particles, since alpha particles are not supported
by MCNP5. The deposited energy was tallied over all defined structures in the model with
the MCNP energy deposition tally, ∗ F8, scoring MeV per history and structure. Tracks of
different particles emitted from the same radionuclide were simulated separately and the
resulting energies deposited scaled by their respective yields were then summed. The number
of electron substeps per energy step was set to the maximum number, 99, which implies
using the shortest step length possible in the electron transport, therefore a more accurate
trajectory and energy loss in small regions. Approximately 106 particles were simulated to
keep the relative errors of the calculated quantities below 1% and to pass the ten statistical
tests provided by the MCNP package, which all are referring to the precision of the calculation
itself. The source was defined as one or several of the defined structures within the central
hexagonal hepatic lobular prism in the model, whereas all the hexagonal hepatic lobular
prisms throughout the model was target regions, thus the tallied energy (MeV) per structure
represents the total absorbed energy per defined structure. This was manageable because of
the dose reciprocity theorem, stating that the specific absorbed fraction, for any pair of regions
is independent of which is the source—and which is the target region, provided that the
escape of charged particles from the model is negligible. The volume of each defined structure
was determined by stochastic volume calculation, converted to mass by multiplication by the
density assigned to each structure.
The absorbed energy from monoenergetic particles was tallied for electron energies of
5–2000 keV, photon energies of 5–200 keV, and alpha particle energies of 3–10 MeV. Moreover,
calculations were performed for some radionuclides of interest to liver dosimetry, including 18F,
Y, Tc, 111In, 125I, 131I, 177Lu, and 211At (and its daughter 211Po, T1/2 = 0.52 s). The energies
90 99m

and yields of the radionuclides used in the simulation were obtained using the Radiation Decay
3 software package (Charles Hacker, Griffith University, Gold Cost, Australia), which is based
on data from the Radiation Shielding Information Center at Oak Ridge National Laboratories
(TN, USA). The beta particle energy spectra were obtained from the National Nuclear Data
Center at Brookhaven National Laboratory (Upton, NY, USA).

3. Results

3.1. Kupffer cells as the source

3.1.1. Self-absorbed dose to the Kupffer cells. This small-scale anatomical model provides
the possibility of calculating self-absorbed doses to the Kupffer cells, which here are expressed
as the ratio of the locally absorbed dose to the average absorbed dose to the liver, see
equation (2)
 
Dregion
. (2)
Dmean liver
For 125I the greatest discrepancy from the average absorbed dose is seen, by a factor of 135. The
discrepancy for 99mTc and 111In decrease to factors of 45 and 26, respectively, subsequently
followed by the other nuclides of interest, see figure 3.

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Figure 3. The ratio of the self-absorbed dose in the Kupffer cells to the average absorbed
dose to the liver.

3.1.2. Specific absorbed fractions. The specific absorbed fractions of monoenergetic

electrons in the hepatocytes and space of Disse along the radius from the central vein to the
portal tract, along with radioactivity located in all of the Kupffer cells in the central hexagonal
hepatic lobular prisms in the model, are shown in figures 4(a) and (b). The graph values are
the average values received for each specific defined structure in the liver volume and were
plotted at the center position of each defined structure along the central vein-to-portal tract
axis. For the lowest electron energy, 5 keV, the specific absorbed fraction in the hepatocytes
close to a radioactive Kupffer cell is close to zero because of near-total absorption by the
source cell itself. In the Kupffer cells, the absorbed fraction for 5 keV electrons is 92%. For
30 keV electrons, the average specific absorbed fraction in the hepatocytes close to the Kupffer
cell is 1.8 × 10−3 kg−1. Higher energies result in a more evenly absorbed energy distribution
and a lower specific absorbed fraction near the Kupffer cells. The space of Disse receives the
highest average specific absorbed fraction of 3.4 × 10−2 kg−1 for 10 keV electrons, followed
by specific absorbed fractions of 2.3 × 10−2 kg−1 and 8.2 × 10−3 kg−1 for 30 keV and
5 keV, respectively. For energies between 30 and 100 keV, the specific absorbed fraction will
decrease, and for energies above 100 keV, it is below 2.2 × 10−3 kg−1.
The average specific absorbed fraction in the hepatocytes close to the source,
from 5 keV monoenergetic photons emitted by the radioactive Kupffer cells is
7.3 × 10−4 kg−1 (figure 4(d)). For higher-energy photons, the specific absorbed fractions
will be more uniformly distributed, resulting in an almost even profile along the central vein-
to-portal tract axis. The average specific absorbed fraction in the space of Disse near the
radioactive Kupffer cells will be 2.6 × 10−3 kg−1 for 5 keV photons, whereas for higher
energies, the specific absorbed fraction along the central vein-to-portal tract axis will be more
evenly distributed.
For 3 or 10 MeV alpha particles emitted from the all of the Kupffer cells in the central
hexagonal hepatic lobular prism in the model, the average specific absorbed fractions in the
proximal hepatocytes will be 1.7 × 10−3 kg−1 and 7.8 × 10−4 kg−1, respectively, shown in
figure 4(f). For the same alpha energies, the average specific absorbed fractions to the space of
Disse will be increased by a factor of 3- to 9.5-fold or 1.6 × 10−2 kg−1 and 2.6 × 10−3 kg−1,
respectively.

3.1.3. Dose ratios. Figure 5 shows the target structure absorbed dose-ratio volume
histograms for the absorbed doses to the space of Disse (a) and hepatocytes (b) relative

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(a) (b)

(c) (d)

(e) (f)

Figure 4. Specific absorbed fractions (kg−1) in two different target structures, the space
of Disse (left panels) and the hepatocytes (right panels) with activity accumulated in
Kupffer cells. The two target structures are divided into 25 μm thick sub-regions along
the axis from central vein to portal tract. Sub-figures (a) and (b) show the specific
absorbed fractions in the space of Disse and hepatocytes, respectively, for electrons
emitted from the sources (Kupffer cells). Similarly, sub-figures (c) and (d) show the
specific absorbed fractions for monoenergetic photons, and sub-figure (e) and (f), the
specific absorbed fractions for monoenergetic alpha particles. Kupffer cells are placed
at 63, 163, 263, 363, and 463 μm from the center of the lobule, along the axis from
the central vein to the portal tract, and all Kupffer cells in the central hexagonal hepatic
lobule are considered as source regions.

to the average absorbed dose to the liver (according to 2) when activity is accumulated in
all of the Kupffer cells. For the space of Disse as a target region, the discrepancy from the
average absorbed dose are most noticeable for 125I and 211At, which emit low-energy electrons
and short-range alpha particles and from which 25% of the target region receives more than
eight- and five-fold the average absorbed dose, respectively. While 18F and 90Y, which emit
high-energy positrons and electrons, have absorbed dose ratios that are close to one, the

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(a) (b)

(c) (d)

Figure 5. Dose–ratio volume histogram of the target structures space of Disse ((a) and
(c)) and hepatocytes ((b) and (d)) with activity localized in all of the Kupffer cells in
the central hexagonal hepatic lobular prims. The dose-ratio volume histograms show
the percentage volumes of the two different hepatic microstructures having a given dose
ratio or lower, where the dose ratio is indicated as the average absorbed dose of the
target region to the average absorbed dose to the liver.

radionuclides 111In, 131I, 177Lu, and 99mTc, which emit intermediate energy particles, have
absorbed dose ratios of 1.5- to 4-fold greater than the average absorbed doses for 25% of the
target region. The absorbed dose ratio to the hepatocyte-occupied liver structure is generally
lower. For instance, 20% of the target region will receive an absorbed dose higher than the
average absorbed dose for 125I, whereas 75% of the hepatocytes will receive an absorbed dose
ratio of 0.7 or less.

3.2. Portal artery as the source

3.2.1. Dose ratio. In figure 6, the ratio of the absorbed dose to the central vein to the average
absorbed dose to the liver is presented (according to 2), for activity localization within the portal
artery. The localization within the portal artery may represent SIRT microsphere treatment.
For comparison, the dose ratios received for activity localized within the Kupffer cells are also
included in the figure. In this case, the absorbed dose to the central vein will be approximately
0.95-fold of the average absorbed dose to the liver for 90Y, but will be zero for 211At, since the
range of alpha particles is too short to reach the central vein. When the Kupffer cells form the
source region, the ratio of the absorbed dose to the central vein to the average absorbed dose to
the liver is higher for all studied radionuclides, since some Kupffer cells are positioned closer

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Phys. Med. Biol. 59 (2014) 3353 A Stenvall et al

Figure 6. The ratio of the absorbed dose to the central vein to the average absorbed
dose to the whole-liver with activity accumulated in the Kupffer cells (black bars) or
the portal artery (gray bars). The absorbed dose ratio from 211At, when originating from
the portal artery, is less than 2.0 × 10−3.

Table 1. Dimensions and fractions of the lobule microarchitecture structure used in the
small-scale liver model.
Diameter Length or Density Volume of model
Structure (μm) width (μm) (g cm−3) Reference lobule (%)

Lobulea 1000 2000 1.003d (Kuntz and Kuntz 2006, –

Mescher 2010)
Central vein 70 – 1.060 (Burt et al 2012) 0.55
Portal vein 30 – 1.060 (Burt et al 2012) 0.23
Portal artery 10 – 1.060 (Burt et al 2012) 0.10
Portal bile duct 20 – 1.030 (Dancygier 2010) 0.03
Sinusoid space 7 – 1.060 (Braet and Wisse 2002) 6.57
Space of Disse – 1 1.000 (Burt et al 2012) 0.82
Bile canaliculi – 2 1.030 (Burt et al 2012) 1.11
Hepatocyteb 66 25 1.000 (Burt et al 2012, 90.4
Mescher, 2010)
Kupffer cellc 7 16 1.000 (Burt et al 2012, 0.14
(minor axes) (major axis) Makrigiorgos et al 1990) 0.14
a The lobule is approximately 0.7 mm × 2 mm (Mescher 2010), 1.0–1.3 mm × 1.5–2.0 mm (Kuntz and Kuntz
2006).
b Defined as a 25 μm thick slice of a hexagonal prism with a radius of 33 μm.
c The shape varies but can be defined as an ellipsoid in which two of the axes cannot exceed the dimension of the

sinusoid, although the major axes can extend along the sinusoids. In the model, lengths of the major and minor axes
were set to 16 μm and 7 μm, respectively.
d Weighted according to the volume and density of defined structures.

to the central vein. For 90Y, the absorbed dose ratio to the central vein is 0.99, whereas 211At
has the lowest ratio, 0.71.

3.3. S values

With the model developed and presented in this paper, it is possible to generate S values,
that is absorbed dose per cumulated activity (mGy MBq−1 s−1) for various source–target liver
microstructure regions. Simulated S values for the radionuclides selected in this project, with

3364
Phys. Med. Biol. 59 (2014) 3353 A Stenvall et al

various source regions such as Kupffer cells, portal artery, portal vein, central vein and the
sinusoids are presented in tables 2 and 3, for target regions such as the central and periportal
Kupffer cell, central and periportal hepatocytes and space of Disse, the central vein, the vessels
in the portal tract and the sinusoids. In order to illustrate an actual clinical situation, however
excluding self-absorption in the Kupffer cells or the portal artery, the highest value of S,
1.08 × 10−3 mGy MBq−1 s−1, was obtained for the portal vein for 211At, when Kupffer
cells were the source. If the portal artery is the source, the portal vein will again receive the
highest absorbed dose, with a value of S equal to 5.68 × 10−2 mGy MBq−1 s−1. Among
the radionuclides, with Kupffer cells set as the source, the lowest value of S is obtained for
the central vein with 125I (4.41 × 10−10 mGy MBq−1 s−1), whereas S (central vein ← portal
artery) is 5.80 × 10−8 mGy MBq−1 s−1.

4. Discussion

The non-uniform tissue distribution of radiopharmaceuticals or radionuclides is an important

factor to consider when predicting biological effects after radionuclide therapy. In contrast
to uniform external irradiation, the heterogeneous microdistribution of radioactivity within
tissues and cells result in a non-uniform absorbed dose distribution with numerous highly
radioactive foci that as sources. The local effects are most likely dependent on the radionuclide
distribution within the tissue and the resulting differences between the local and the average
liver absorbed doses. Thus, small-scale dosimetric models, which consider non-uniform
activity distribution, have been developed during the last decade (Hobbs et al 2012, Howell et al
2006, ICRU 2002, Jönsson et al 2002, Larsson et al 2012). Such models allow the calculation
of S values for microstructural source and target regions and thus of small-scale absorbed
doses, which may better explain observed radiobiological effects of internal radionuclides
than average organ absorbed doses as by the conventional (i.e. organ-level) implementation
of the MIRD schema (Bolch et al 2009). For the S values to be real useful, the cumulated
activity in the defined source regions should be known. The activity distribution and biokinetics
must be obtained on the degree of spatial resolution matching the details of the model. Due
to limited spatial resolution of clinical imaging systems, the non-uniformity of the activity
distribution for small-scale dosimetry has to be determined from in vitro autoradiography
of human or animal biopsies and tissue sections. Under special circumstances animal 3D
micro-imaging may be useful for the quantification. Using compartment modeling, it may
be possible to determine the time-dependent ratio between activity in blood and the tissue
of interest. Different approaches and techniques for measurements of the small-scale activity
distributions as well as the dosimetry are developing and have been discussed in the ICRU
Report 67 (ICRU 2002).
The Monte Carlo model developed in this study permits selection of different source and
target regions in the lobular microanatomy. As illustrated in the current analysis, portal vein,
central vein and the sinusoid, Kupffer cells and portal artery were selected as source regions
since they represent realistic irradiation situations, the latter two the significant uptake of
radioactive colloids or nanoparticles in the mononuclear phagocytic system and localization
of microspheres in the portal tract, respectively. Several hepatic components can be chosen as
target tissues, but the space of Disse is of special interest since it may represent the endothelial
cells that surround the sinusoids, the presumptive target for fatal radiation damage to the liver
(Dancygier 2010, DeLeve and Garcia-Tsao 2011, Mauss et al 2012, UNSCEAR 2006).
All Monte Carlo internal dosimetry models idealize real anatomical geometry to some
extent, since some simplifications must be incorporated. The current liver model is no
exception. For instance, the stacking pattern of the different microstructure units, that forms
3365
 Table 2. S factors (mGy MBq−1s−1) for 211At (a), 18F (b), 125I (c) and 131I (d).

Phys. Med. Biol. 59 (2014) 3353

(a) S values (mGy MBq−1s−1) for 211Atd (b) S values (mGy MBq−1s−1) for 18F
Source Kupffer Portal Portal Central Kupffer Portal Portal Central
Target cellsa artery vein vein Sinusoid cellsa artery vein vein Sinusoid

Kupffer cell (centrala) 1.60E-02 2.23E-07 2.58E-07 1.09E-02 1.10E-03 1.23E-04 2.84E-05 4.00E-05 9.98E-05 1.97E-05
Kupffer cell (periportala) 1.67E-02 8.16E-03 8.04E-03 3.82E-09 1.05E-03 1.05E-04 6.18E-05 5.82E-05 5.94E-05 5.48E-05
Hepatocyte (proximalb/centralc) 9.96E-04 2.21E-07 2.26E-07 1.32E-03 6.55E-04 4.29E-05 3.59E-05 3.35E-05 6.16E-05 4.36E-05
Hepatocytes (distalb/periportalc) 4.19E-04 2.20E-03 2.09E-03 1.07E-09 6.54E-04 4.17E-05 5.51E-05 5.37E-05 3.53E-05 4.23E-05
Space of Disse (proximalb/centralc) 4.75E-03 2.23E-07 2.60E-07 1.17E-03 1.72E-03 5.25E-05 3.36E-05 3.70E-05 5.35E-05 5.45E-05
Space of Disse (distalb/periportalc) 4.84E-04 2.01E-03 2.09E-03 1.51E-09 1.77E-03 4.21E-05 5.42E-05 5.04E-05 3.12E-05 4.52E-05
Portal artery 1.11E-03 2.34E-01 5.69E-02 <1.0E-10 4.12E-04 3.90E-05 1.07E-03 2.83E-04 4.88E-05 3.52E-05
Portal vein 1.08E-03 5.68E-02 1.94E-01 <1.0E-10 4.39E-04 4.69E-05 2.63E-04 8.65E-04 4.51E-05 2.48E-05
Central vein 4.86E-04 3.78E-08 2.04E-08 5.19E-02 3.69E-04 4.30E-05 2.90E-05 3.55E-05 2.43E-04 5.10E-05
Sinusoid 1.16E-03 4.10E-04 4.36E-04 3.40E-04 2.74E-03 4.49E-05 3.77E-05 4.18E-05 4.16E-05 4.79E-05
(c) S values (mGy MBq−1s−1) for 125I (d) S values (mGy MBq−1s−1) for 131I
Source Kupffer Portal Portal Central Kupffer Portal Portal Central
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Target cellsa artery vein vein Sinusoid cellsa artery vein vein Sinusoid
Kupffer cell (centrala) 7.37E-04 4.48E-07 <1.0E-10 6.10E-08 9.30E-06 1.57E-04 1.23E-05 1.07E-05 8.90E-05 2.24E-05
Kupffer cell(periportala) 7.25E-04 1.01E-06 7.80E-07 8.35E-09 8.04E-06 1.62E-04 5.99E-05 6.43E-05 9.94E-06 2.48E-05
Hepatocyte (proximalb/centralc) 3.09E-06 5.70E-07 6.11E-07 5.26E-09 1.29E-06 2.23E-05 1.17E-05 1.16E-05 3.74E-05 1.98E-05
Hepatocytes (distalb/periportalc) 6.75E-07 2.11E-06 1.62E-06 2.35E-09 1.38E-06 1.85E-05 3.36E-05 3.30E-05 1.04E-05 2.00E-05
Space of Disse (proximalb/centralc) 4.95E-05 5.25E-07 5.67E-07 1.67E-08 1.60E-05 5.25E-05 1.18E-05 1.12E-05 3.75E-05 2.78E-05
Space of Disse (distalb/periportalc) 7.04E-07 1.12E-06 2.06E-06 1.34E-09 1.67E-05 1.84E-05 3.23E-05 3.33E-05 1.06E-05 2.87E-05
Portal artery 1.47E-06 4.85E-03 1.00E-04 <1.0E-10 6.36E-07 2.29E-05 1.80E-03 3.51E-04 9.76E-06 1.94E-05
Portal vein 7.99E-07 1.02E-04 3.37E-03 <1.0E-10 7.74E-07 2.23E-05 3.49E-04 1.45E-03 9.92E-06 1.93E-05
Central vein 4.41E-10 5.80E-09 1.43E-08 2.81E-04 1.72E-07 1.71E-05 1.08E-05 1.09E-05 3.34E-04 1.80E-05
Sinusoid 9.26E-06 7.23E-07 1.00E-06 1.75E-07 8.56E-05 2.41E-05 1.85E-05 1.86E-05 1.74E-05 3.80E-05
a For Kupffer cells as source region, all Kupffer cells within the central hexagonal hepatic lobular prism are defined as the source region. For Kupffer cells as target region, the central-
and the periportal Kupffer cell are positioned 63 μm and 463 μm from the center of the central vein, respectively.

A Stenvall et al
b For Kupffer cells as the source region and hepatocytes or space of Disse as target regions, the proximal target region is the weighted S value for the hepatocyte/space of Disse regions

closest to the source and distal target region is the weighted S value of the hepatocyte/space of Disse regions 50 μm away from the source.
c For portal artery, portal vein and central vein as source, the periportal target region is the weighted S value for the five hepatocyte/space of Disse structures closest to the portal tract

and the central target region is the weighted S value for the five hepatocyte/space of Disse structures closest to the central vein.
d The daughter nuclide 211Po is included due to its short half-life (0.52 s).
 Table 3. S factors (mGy MBq−1s−1) for 111In (a), 177Lu (b), 99mTc (c) and 90Y (d).

Phys. Med. Biol. 59 (2014) 3353

(a) S values (mGy MBq−1s−1) for 111In (b) S values (mGy MBq−1s−1) for 177Lu
Source Kupffer Portal Portal Central Kupffer Portal Portal Central
Target cellsa artery vein vein Sinusoid cellsa artery vein vein Sinusoid

Kupffer cell (centrala) 3.15E-04 9.20E-07 2.24E-06 1.82E-05 7.21E-06 2.18E-04 5.27E-06 4.81E-06 1.00E-04 2.29E-05
Kupffer cell (periportala) 3.08E-04 1.18E-05 1.14E-05 3.56E-07 7.15E-06 2.25E-04 6.57E-05 6.47E-05 5.09E-06 1.98E-05
Hepatocyte (proximalb/centralc) 4.89E-06 1.84E-06 1.88E-06 8.90E-06 1.98E-05 1.75E-05 5.47E-06 5.46E-06 3.48E-05 1.44E-05
Hepatocytes (distalb/periportalc) 4.01E-06 7.67E-06 7.55E-06 5.23E-07 2.00E-05 1.27E-05 3.09E-05 3.02E-05 5.15E-06 1.46E-05
Space of Disse (proximalb/centralc) 3.10E-05 1.73E-06 1.95E-06 8.94E-06 2.78E-05 5.73E-05 5.42E-06 5.63E-06 3.40E-05 2.65E-05
Space of Disse (distalb/periportalc) 3.95E-06 7.11E-06 7.27E-06 5.53E-07 2.87E-05 1.28E-05 2.92E-05 3.06E-05 5.15E-06 2.66E-05
Portal artery 5.64E-06 2.07E-03 6.29E-05 3.61E-07 3.72E-06 1.63E-05 2.44E-03 4.33E-04 4.95E-06 1.22E-05
Portal vein 4.81E-06 6.38E-05 1.43E-03 3.45E-07 4.98E-06 1.65E-05 4.31E-04 1.93E-03 4.38E-06 1.28E-05
Central vein 2.50E-06 4.63E-07 4.22E-07 1.40E-04 2.84E-06 1.18E-05 4.83E-06 4.94E-06 4.16E-04 1.27E-05
Sinusoid 7.93E-06 3.92E-06 4.06E-06 2.59E-06 3.99E-05 2.02E-05 1.28E-05 1.32E-05 1.23E-05 4.09E-05
(c) S values (mGy MBq−1s−1) for 99mTc (d) S values (mGy MBq−1s−1) for 90Y
3367

Source Kupffer Portal Portal Central Kupffer Portal Portal Central

Target cellsa artery vein vein Sinusoid cellsa artery vein vein Sinusoid
a
Kupffer cell (central ) 1.77E-04 8.37E-08 5.50E-08 1.73E-05 2.46E-06 1.12E-04 9.07E-05 9.76E-05 1.40E-04 1.00E-04
Kupffer cell (periportala) 1.73E-04 1.06E-05 1.03E-05 1.32E-09 2.37E-06 1.34E-04 1.16E-04 1.33E-04 9.42E-05 1.06E-04
Hepatocyte (proximalb/centralc) 1.86E-06 2.93E-07 2.84E-07 5.98E-06 1.61E-06 9.46E-05 8.85E-05 8.86E-05 1.05E-04 9.30E-05
Hepatocytes (distalb/periportalc) 1.54E-06 4.78E-06 4.79E-06 1.32E-09 1.63E-06 9.34E-05 1.01E-04 1.01E-04 8.84E-05 9.38E-05
Space of Disse (proximalb/centralc) 6.72E-06 3.15E-07 2.99E-07 5.93E-06 3.21E-06 1.07E-04 8.46E-05 8.80E-05 1.00E-04 9.80E-05
Space of Disse (distalb/periportalc) 1.53E-06 4.64E-06 4.78E-06 7.99E-10 3.27E-06 9.44E-05 1.00E-04 1.03E-04 8.92E-05 1.02E-04
Portal artery 1.63E-06 1.01E-03 4.21E-05 3.40E-10 1.23E-06 9.26E-05 7.40E-04 2.23E-04 9.12E-05 9.71E-05
Portal vein 2.08E-06 4.19E-05 6.88E-04 1.19E-09 1.59E-06 9.18E-05 2.34E-04 6.33E-04 9.00E-05 8.33E-05
Central vein 1.02E-06 2.24E-08 3.05E-08 7.72E-05 1.12E-06 9.30E-05 8.90E-05 9.07E-05 2.30E-04 9.27E-05
Sinusoid 2.51E-06 1.46E-06 1.52E-06 1.10E-06 2.09E-05 9.31E-05 9.27E-05 9.42E-05 9.27E-05 9.86E-05
a For Kupffer cells as source region, all Kupffer cells within the central hexagonal hepatic lobular prism are defined as the source region. For Kupffer cells as target region, the central-
and the periportal Kupffer cell are positioned 63 μm and 463 μm from the center of the central vein, respectively.

A Stenvall et al
b For Kupffer cells as the source region and hepatocytes or space of Disse as target regions, the proximal target region is the weighted S value for the hepatocyte/space of Disse regions

closest to the source and distal target region is the weighted S value of the hepatocyte/space of Disse regions 50 μm away from the source.
c For portal artery, portal vein and central vein as source, the periportal target region is the weighted S value for the five hepatocyte/space of Disse structures closest to the portal tract

and the central target region is the weighted S value for the five hepatocyte/space of Disse structures closest to the central vein.
Phys. Med. Biol. 59 (2014) 3353 A Stenvall et al

the height of the hepatic lobule, implies that the Kupffer cells are fixed at specific positions
along the axis from central vein to portal tract. Additionally, some discrepancies that is found
in human liver microstructures, such as the microvilli that are present on the surfaces of
hepatocytes, and some gradient changes in the diameters of the microstructures, broadened
or narrowed along the central vein-to-portal tract axis, are not reproduced in the current liver
model. The percentage volume distribution of microstructures in the model of the hepatic
lobule, presented in table 1, differs slightly from the literature (Dancygier 2010). This is
because the extracellular space, stellate Ito cells, and Kupffer cells which are not active in the
phagocytic process were not included in the model. Instead, the hepatocyte fraction, which
has the same density (1.00 g cm−1) as the excluded structures, accounts for 91% of the lobule.
An indication of the implication of a change in the dimensions of defined structures,
can be considered in the calculation of specific absorbed fraction by, for example, increasing
the thickness of the space of Disse from 1 to 2 μm. For all Kupffer cells in the central
hexagonal hepatic lobular prism as source region, for the radionuclides 90Y, 131I and 211At,
having different mean ranges in tissue of 5 mm, 0.8 mm and 0.05 mm, respectively, the specific
absorbed fraction decreased to 96%, 89% and 88% of the specific absorbed fraction received
for the 1 μm thick space of Disse. It is however shown in the present work, that the minimum
specific absorbed fraction, visually seen as the valleys between the Kupffer cells acting as
source for monoenergetic particles (figures 4(a)–(f)), is equal to 90% or less of the average
maximum specific absorbed fraction for electrons with energies of 150 keV or less for the
hepatocytes as target. For the space of Disse as target structure, the minimum specific absorbed
fraction reaches 90% or less of the average maximum for electrons with energies of 500 keV
or less. Similarly, for low-energy photons (5 keV), the minimum specific absorbed fractions
is 90% or less of the average maximum specific absorbed fraction for the hepatocytes, which
was reached for energies of 15 keV or less when the space of Disse was the target structure.
For monoenergetic alpha particles of 3 to 10 MeV, the minimum specific absorbed fraction is
less than 90% of the average maximum specific absorbed fraction for both target structures.
The profile of the five peaks of the specific absorbed fractions for the two microstructure target
regions will differ in shape due to the intrinsic differences in the distances between the source
and the target regions in the model. This applies generally along the central vein-to-portal tract
axis, but particularly at the boundaries, that is at the center and periphery of the lobule.
The largest ratios of the local to the average liver absorbed doses for the hepatocytes and
the space of Disse was found for 125I and 211At. The former results in an 8- to 11-fold increase
in the local over the average liver absorbed dose for the space of Disse closest to the radioactive
Kupffer cells, which is attributable to the presence of many low-energy electrons and photons
after the electron capture decay of 125I. The smallest difference in the absorbed dose ratio was
found for the pure high-energy beta emitter 90Y. For instance, for SIRT with 90Y, wherein the
radioactive microspheres accumulate in the portal artery, the absorbed dose to the central vein
is approximately 95% of the average absorbed dose to the liver. By increasing the radius of
the hepatic lobule in our small-scale anatomical model from 500 to 700 μm, as used by Gulec
et al (2010) in their Monte Carlo lobular model, the absorbed dose to the central vein was
decreased to 93% of the average absorbed dose to the liver. The absorbed dose to the central
vein for the four simulation scenarios presented by Gulec et al ranged from 92% to 89% of
the absorbed dose to the liver, depending on tumor involvement and the type of microspheres
simulated. Thus, as concluded in Gulec et al and in the current analysis, the absorbed dose
to the central vein is similar to the average absorbed dose to the liver for high-energy beta
emitters such as 90Y.
The uptake of colloids in Kupffer cells and the resulting self-absorbed-doses were
previously estimated to be significant for 99mTc-labeled colloids (Gardin et al 1992,

3368
Phys. Med. Biol. 59 (2014) 3353 A Stenvall et al

Makrigiorgos et al 1990). In the present study, we suggest that the average absorbed dose
to the liver underestimates the absorbed dose to the Kupffer cells by a factor of 45 when
radioactive Kupffer cells occupy 0.14% of the liver mass. The self-dose ratio will increase
to approximately 6300 if the liver volume fraction occupied by radioactive Kupffer cells
decreases to 10−5, as previously reported (Gardin et al 1992). The difference in Kupffer
cell size between the two papers and hence absorbed fraction can account for the remaining
difference in absorbed dose ratio.
Finally, the results presented above indicate the importance of internal dosimetry
improvements at a microstructural level. Our simulation shows that absorbed doses within the
hepatic tissues may vary considerably between different target cells because of heterogeneously
distributed radioactive sources in the tissues and the ranges of the emitted particles.

5. Conclusions

The present work presents a small-scale dosimetry model of the human liver tissue and its
application to derive Monte Carlo-based reference data, according to the MIRD schema. With
an increasing interest in microsphere-based radionuclide therapies and the use of radionuclide-
labeled nanoparticles for multimodality imaging and therapies, small-scale hepatic dosimetry
is a suitable tool to achieve a better understanding of the relationships between absorbed doses
and local radiobiological effects. Additionally, this model is useful for retrospective absorbed
dose estimations in different radiation protection situations.

Acknowledgments

We thank Dr Pehr Rissler, Department of Pathology, Skåne University Hospital, Lund, for
sharing his expert knowledge of liver function and microstructure. This research was supported
by grants from the Swedish Cancer Society (CAN 2012/536), the Berta Kamprad Foundation
(BKS 16/2012), and the Gunnar Nilsson foundation (2012/366).

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