Radiation dose to trabecular bone marrow stem cells from 3H, 14C and selected α-emitters

incorporated in a bone remodeling compartment

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Phys. Med. Biol. 54 (2009) 963–979 doi:10.1088/0031-9155/54/4/010

Radiation dose to trabecular bone marrow stem cellsfrom 3H, 14C and selected α-emitters incorporated in abone remodeling compartment

Huiling Nie1,2 and Richard B Richardson3

1 Department of Environmental Health, Harvard School of Public Health, Harvard University,Boston, MA 02115, USA2 Channing Laboratory, Brigham and Women’s Hospital, Harvard Medical School3 Radiation Biology and Health Physics Branch, Atomic Energy of Canada Limited,Chalk River Laboratories, Chalk River, ON K0 J 1J0, Canada

E-mail: nieh@hsph.harvard.edu and richardr@aecl.ca

Received 8 August 2008, in final form 17 December 2008Published 16 January 2009Online at stacks.iop.org/PMB/54/963

Abstract

A Monte Carlo simulation of repeated cubic units representing trabecular bonecavities in adult bone was employed to determine absorbed dose fractionsevaluated for 3H, 14C and a set of α-emitters incorporated within a boneremodeling compartment (BRC). The BRC consists of a well-oxygenatedvascular microenvironment located within a canopy of bone-lining cells. TheInternational Commission on Radiological Protection (ICRP) considers that animportant target for radiation-induced bone cancer is the endosteum marrowlayer adjacent to bone surface where quiescent bone stem cells reside. It isproposed that the active stem cells and progenitor cells located above the BRCcanopy, the ‘BRC stem cell niche’, is a more important radiation-induced cancertarget volume. Simulation results from a static model, where no remodelingoccurs, indicate that the mean dose from bone and bone surface to the 50 μmquiescent bone stem cell niche, the current ICRP target, was substantiallylower (two to three times lower) than that to the narrower and hypoxic 10 μmendosteum for 3H, 14C and α-particles with energy range 0.5–10 MeV. Theresults from a dynamic model indicate that the temporal α-radiation doseto active stem/progenitor cells located in the BRC stem cell niche from thematerial incorporated in and buried by forming bone was 9- to 111-fold greaterthan the dose to the quiescent bone stem cell niche. This work indicates that theremodeling portion of the bone surface, rather than the quiescent (endosteal)surface, has the greatest risk of radiation-induced bone cancer, particularlyfrom short-range radiation, due to the elevated dose and the radiosensitizingoxygen effect.

0031-9155/09/040963+17$30.00 © 2009 Institute of Physics and Engineering in Medicine Printed in the UK 963

964 H Nie and R B Richardson

1. Introduction

In the calculation of committed effective dose, radiation absorbed fraction (AF) values arerequired for bone surface and bone marrow (ICRP 2007). The International Commissionon Radiological Protection in Publication 30 (ICRP 30 1979) recommend the calculationof the dose to the endosteum, a 10 μm thick marrow layer lining the walls of all cavitiesin bone, in the assessment of the radiation-induced bone tumor risk. However, as Gossner(2003) pointed out, bone-lining cells found within the endosteum are unlikely potential targetcells for osteosarcomas, and a 50 μm thick bone-replacement fibrotic layer is a better sitefor radiation-induced sarcomas. Currently, the ICRP are considering revising the marrowlayer target adjacent to bone surface from 10 μm to 50 μm. This target, referred to by theICRP by the misnomer ‘bone surfaces’ (ICRP 2007) and here as the 50 μm marrow target or‘quiescent bone stem cell niche’, extends beyond the stem cells residing within the endosteumto incorporate the osteoblastic niche. The whole red marrow is historically and currently theICRP’s target tissue for calculating dose and risk of radiation-induced leukemias. The averagedose to red bone marrow (including and overlapping the 50 μm marrow layer) continues to becalculated as the ICRP target for leukemia.

A Monte Carlo simulation model of multiple trabecular bone cavities was initiallydeveloped by Richardson et al (2007). The simulation incorporated a bone remodeling unit orbasic multicellular unit (BMU) that removes and replaces existing bone with new bone, calleda hemiosteon for trabecular bone. Bone lining cells line quiescent bone but were absent overthe BMU excavation in bone.

In this paper, a bone remodeling compartment (BRC) is now included in the Monte Carlosimulation of the BMU. A BRC is a vascular microenvironment located within a canopy ofbone lining cells (Hauge et al 2001). The model considers a ‘BRC stem cell niche’ as beinglocated just outside the BRC canopy. The endosteum or wider quiescent bone stem cell nicheis simulated as marrow where hematopoietic stem cells (HSCs) and perhaps mesenchymalstem cells (MSCs) are preferentially located and involved in hematopoietic renewal of bloodcells, whereas the BRC stem cell niche is proffered as a region where HSCs and MSCs andtheir osteoprogenitors migrate to, and where these cells are involved in bone remodeling thatcommences with an enhanced sinus system. In this location, active stem cells self-renew andalso form osteoprogenitors that are the precursors of osteoclasts (derived from HSCs) andosteoblasts (from MSCs).

Quiescent stem cells in bone marrow, especially HSCs, reside in hypoxic niches locatedin the endosteum. The hypoxia protects them from reactive oxygen species, ROS (Arai et al2005). The preferred environmental niches of differentiated and undifferentiated cells inrelative proximity in bone marrow have radically different oxygen tension and consumptionlevels. Stem cells remain quiescent in a hypoxic environment, and stem/progenitor cellsproliferate under higher oxygen pressures. The vascular niche can provide differentiatedprogenitors with the nutrients and vascular access needed in the massive daily replenishmentof the blood system (Kopp et al 2005).

Use of a Monte Carlo simulation is necessary to evaluate radionuclide AFs in targettissues for radiation-induced bone cancer and leukemia. These AFs allow the assessment ofcommitted equivalent dose, in conjunction with biokinetic activity–time curves. We presentour study of radiation AFs and dose ratios to critical regions in the trabecular cavity for twoβ-emitting radionuclides, 3H and 14C, that have maximum ranges of 6 μm and 290 μm,respectively, and selected α-emitters that have maximum ranges in water of up to 80 μm intable 1. These short ranges are on the same order as components of the trabecular marrowcavity and therefore subject radiation-sensitive targets to inhomogeneous doses.

Radiation dose to trabecular bone marrow stem cells 965

Table 1. Energies and maximum range in water of the α particles and the corresponding α-emittersa.

Radionuclide N/Eb 144Nd 146 Sm 148Gd 232Th 226Ra 239Pu 224Ra 220Rn 212Po N/E

Energy (MeV) 0.5 1.8 2.5 3.2 4.0 4.8 5.2 5.7 6.3 8.8 10.0Maximum range (μm) 3 9 13 18 26 33 38 44 51 80 109

a Shleien (1992).b None exists: no specific radionuclide assigned.

2. Materials and methods

2.1. MC simulations and sources

The Monte Carlo MCNP/MCNPX transport code (version 4, Los Alamos NationalLaboratory) was used to simulate nine α-particles and two β-particles originating fromuniformly distributed point sources. Beta-particle energy distributions for 3H and 14C wereobtained from Cross et al (1983). The average energy of 3H and 14C β-particles is 5 keVand 47 keV, respectively. Nine α-emitters and their corresponding energies are listed intable 1. A minimum of 106 histories were followed for each source to achieve a variation inthe calculation dose of less than ±2%, except for the smallest target volumes. The MonteCarlo code accounts for variation in linear energy transfer (LET) along the α- and β-particletrack lengths.

2.2. Static simulation

Repeated cubic units arranged in a 3 × 3 × 3 orthogonal lattice were constructed to representtrabecular cavities within bone. The similarities and differences of the cubic units with reportedmeasurements made in vivo and in vitro in trabeculae were described in detail by Richardsonet al (2007). The cubit unit (1.25 mm sides) consisted of bone rods/plates (dimensions1250 × 600 × 800 μm), bone marrow and other model compartments including bone surface,bone lining cells, connective tissue, HSCs, quiescent bone stem cell niche, BRC stem cellniche, BRC and BMU shown in figures 1(a) and (b). The plates and rods at neighboring cubesconnect to each other, with all the cubes having the same structure. The 10 μm endosteum orthe 50 μm quiescent bone stem cell niche is the bone marrow layer that covers bone plate androd surfaces and edges, and only contains hemotopoietic marrow. The quiescent bone surfacesource was 1 μm thick as this better corresponds with measurements than an infinitely thinsource (Schlenker and Oltman 1986). Bone marrow, excluding the peripheral target layers,was constructed as fat cells (diameter 62 μm) positioned in an orthogonal lattice (67 μm sides)surrounded by hematopoietic marrow, with 59% cellularity for adults (Rozman et al 1989).When bone marrow is referred to as a source, then activity is presumed to be in both fat cellsand hemotopoietic marrow. A BMU or hemiosteon is a scalloped concavity that lies parallelto the plane of the trabecular plates, which was simulated without a bone-lining cell canopy byRichardson et al (2007), and here with a canopy. In the static model, the BMU was partiallyfilled with new bone and was simulated at the temporal midpoint of bone formation. Table 2lists the composition of different skeletal tissues.

2.3. Dynamic simulation

Salmon et al (1999) considered five stages in the bone remodeling process of the cancellousBMU as first depicted by Eriksen (1986). The first three stages occur over about 50 days,

966 H Nie and R B Richardson

(a) (b)

Figure 1. (a) Schematic diagram of the cross-section of one trabecular bone cavity and (b) detailedstructure of BMU and BRC (not to scale).

Table 2. Composition for skeletal tissues based on the data of Woodard and White (1986) andRichardson et al (2007).

Elemental composition (% by mass)Density

H C N O Na Mg P S Cl K Ca (kg m−3)

Fat 12 77 11 920Non-fat marrow etca 10.2 14.3 3.4 70.8 0.2 0.3 0.3 0.2 0.3 1060Cartilage 9.6 9.9 2.2 74.4 0.5 2.2 0.9 0.3 1100Osteoid seam, 40% mineralization 7.2 12.4 3.1 62.7 0.3 0.1 5.0 0.7 0.2 8.5 1410New bone, 90% mineralization 4.1 15.4 4.1 48.0 0.1 0.2 8.6 0.4 19.0 1800Adult bone (35 years old) 3.5 15.9 4.3 44.7 0.1 0.2 9.5 0.3 21.5 1900Blood 10.2 11.0 3.3 74.5 0.1 0.1 0.2 0.3 0.2 (Fe 0.1) 1060

a Hemopoietic marrow, endosteum, quiescent bone and BRC stem cell niches, bone lining cells and osteoblasts.

where resorption by osteoclasts, then by mononuclear cells, is followed with the appearanceof preosteoblasts in the excavated cavity. Only the two-stage bone-forming process followingthis was simulated, called phases I and II. Phase I is the formation of osteoid, which takesabout 15 days; phase II is the osteoid transforming and bone mineralization process, whichtakes about 135 days. During the bone-forming process, preosteoblasts migrate to the BMUand maturate to osteoblasts. Osteoblasts are bone-forming cells that synthesize and secreteunmineralized bone matrix, the osteoid. The osteoid seam is about 15–20 μm when firstformed but becomes progressively mineralized and thinner until it eventually disappears

Radiation dose to trabecular bone marrow stem cells 967

Figure 2. Dynamic simulation: bone cavity filling and bone apposition rate over time, formingphases of remodeling cycle from void (0 day) to fully filled BMU (150 day, 56 μm deep).

(Parfitt 1983). Extracellular mineralization occurs at the junction of the osteoid and newlyformed bone and results in lamellae about 8–10 μm thick (Jee 2001). A twofold reductionin volume (and increased density) from an initial thickness of 16 μm to an 8 μm seam ofnew bone is assumed. The initial rapid rate of mineralization (80%) is considered to occurin the osteoid seam, and the slower terminal phase of mineralization (20%) occurs in newbone progressively filling in the BMU cavity. The BMU has a depth of 56 μm; hence, sevensubphases, equivalent to the formation of lamellae of 8 μm thickness, were constructed forthe bone mineralization process. The thickness of the osteoblast for each lamellae depositedin the BMU cavity is set such that the mineral apposition rate of the osteoid seam is decliningexponentially over time (Martin et al 1998). The bone apposition rate and bone filling overtime are plotted in figure 2. The formation of the last lamellae in the remodeling process,which commences at ∼100 d, eliminates the BRC sinus and the two layers of lining cellsbecome a single layer (Hauge et al 2001).

2.4. Absorbed fraction (AF) and absorbed dose ratio

The average absorbed fraction AF (T ← S, t) in target T per particle emission in source S attime t is calculated as the average energy absorbed by the target region per radiation emissionfrom source S, divided by the average energy of the radiation

AF(T ← S; t) = E(T ← S; t)

Eave. (1)

At any point in time, there is a relatively small fraction of trabeculae surface that is in theprocess of excavating or refilling a BMU cavity (1.2 and 6.0%, respectively, for adults, ICRP70 (1995)), with the great majority of the surface in a quiescent or resting stage. Nevertheless,at any moment there are many trabeculae, even in a small bone volume, that are at all majorstages of the boneremodeling cycle. Therefore the cycle-averaged AFs are an appropriatemeasure for dosimetry.

The formation phases I and II of the bone remodeling process were divided up into sevensubphases. The following formula is used to calculate the dose ratios from activity in forming

968 H Nie and R B Richardson

bone (osteoid and new bone) irradiating the BRC stem cell niche and 10 μm endosteum or50 μm quiescent bone stem cell niche:

Dose ratio =∑7

n=1Sn×AFn,a× tn

T

ma

∑7n=1

Sn×AFn,b× tnT

mb

, (2)

where n is the number of the subphases, Sn is the weighted source activity fractions of eachsubphases from osteoid or new bone, AFn,a is the AF for the corresponding subphases, tn isthe time period for the corresponding substage, T is the total time for all the seven subphases,ma is the mass for the BRC stem cell niche and mb is the mass for the 10 μm endosteum or the50 μm quiescent bone stem cell niche. The weighting is by the fraction of the total formingtime, i.e. tn/T, that any of the seven subphases occupies in the nonlinear filling of the BMUcavity.

3. Results

3.1. Static model AFs and dose ratios: comparing sources irradiating the 10 μm endosteumand 50 μm quiescent bone stem cell niche

For a particular source, the dose ratio of two targets is calculated as

Dose ratio = AF50 μm/m50 μm

AF10 μm/m10 μm, (3)

where AF50 μm and AF10 μm are AFs of source irradiating the 50 μm quiescent bone stem cellniche and 10 μm endosteum, and m50 μm and m10 μm are the masses of these two compartments.

The mean dose from bone surface or bone volume to the 50 μm quiescent bone stem cellniche decreased by a factor of 2–5 compared with dose delivered to a 10 μm endosteum for3H, 14C and selected α-emitters as seen in figures 3(a) and (b). The largest decrease in dose(fivefold) with the ICRP’s change in the thickness of the bone cancer target is seen with 3H andthe lowest energy α-emitters. However, the dose from activity in bone marrow to the 50 μmquiescent bone stem cell niche increased by only 1.03–1.36, with the largest increase for highenergy α-emitters >4 MeV (figure 3(c)). Hence, changing of the bone cancer target from10 μm endosteum to 50 μm quiescent bone stem cell niche resulted in a substantially decreaseddose for bone-volume-seeking (calcium or Ca-like elements barium, strontium, radium andthe lesser analogues of Ca, i.e. lead and uranium) and bone-surface-seeking (plutonium orPu-like elements Th, neptunium, americium and curium) α- or β-emitters, and a moderatelyincreased dose for α- or β-emitters that have a relatively high uptake in marrow (e.g. Po).

There is very little difference in the 3H and 14C dose to the 10 and 50 μm thick targetlayers from radioactivity distributed in all skeletal tissues according to their hydrogen andcarbon concentration, which will be the case after a chronic exposure or long after an acuteexposure. The simulated dose ratio of targets 50 μm quiescent bone stem cell niche to 10 μmendosteum from 3H and 14C sources in tissue compartments determined by H and C contentis around 1.02 for 3H and 0.76 for 14C.

3.2. Static model AFs: for sources in quiescent bone surface, quiescent bone volume,forming bone and marrow irradiating stem cell niches and hematopoietic marrow

The AFs from activity in quiescent bone surface, quiescent bone volume and forming bone(osteoid or new bone) to 10 μm endosteum, 50 μm quiescent bone stem cell niche, BRC stemcell niche and hematopoietic marrow were estimated for 3H, 14C and selected α-emitters.

Radiation dose to trabecular bone marrow stem cells 969

(a)

(b)

(c)

Figure 3. Static simulation AF and dose ratios from different sources: (a) bone volume, (b) bonesurface, (c) hematopoietic bone marrow, to 10 μm endosteum and 50 μm quiescent bone stem cellniche for 3H, 14C and α-emitter curves for energies ranging from 0.5 to 10 MeV.

The AFs are listed in table 3. In addition, AFs for sources in bone marrow, fat cellsand hematopoietic marrow irradiating the same targets as previously given are estimated intable 4. The AFs for α-emitters with energies ranging from 0.5 MeV to 10 MeV were simulatedand the values were fitted to a polynomial function:

AF = a × E3α + b × E2

α + c × Eα + d. (4)

970 H Nie and R B Richardson

Table 3. Static simulation AFs from radiation sources in quiescent bone volume, quiescent bonesurface and forming bone to critical target regions for β-emitters, 3H and 14C, and two α-emitters,232Th and 212Po (4.0 and 8.8 MeV respectively). Coefficients are given for best fits of the formAF = a × E3

α + b × E2α + c × Eα + d. Also given are the masses for the Monte Carlo compartments

within one trabecular cubic unit.

Target

10 μm 50 μm quiescent BRC bone Hematopoieticendosteum bone stem cell stem cell marrow

Radionuclide (55.20 μg) niche (0.28 mg) niche (10.20 μg) (1.14 mg)a

Quiescent bonevolume (0.46 mg)

3H 0.001 0.001 0.000 0.00114C 0.040 0.105 0.001 0.119232Th 0.034 0.040 0.000 0.040212Po 0.053 0.148 0.000 0.155α-emitters −0.000 18 −3.0 × 10−5 −7.3 × 10−5

best fit, 0.0037 −0.000 19 0.0025a, b, c and d −0.0024 0.0109 0.0012(R2 > 0.99) 0.0021 −0.0063 ∼0 −0.000 33

Quiescent bonesurface (7.89 μg)

3H 0.158 0.158 0.000 0.15814C 0.204 0.426 0.001 0.470232Th 0.325 0.448 0.000 0.448212Po 0.141 0.409 0.001 0.465α-emitters 0.0024 0.0008 0.0011best fit, −0.0416 −0.0207 −0.0228a, b, c and d 0.1775 0.1490 0.1532(R2 > 0.93) 0.1462 0.1431 0.000–0.001 0.1417

Osteoid (formingbone surface) (5.41 g)

3H 0.001 0.001 0.000 0.00114C 0.015 0.035 0.072 0.057232Th 0.012 0.014 0.009 0.014212Po 0.018 0.047 0.117 0.059α-emitters −0.000 12 −0.0010 0.000 11best fit, 0.0019 0.0154 −0.000 69a, b, c and d −0.0030 −0.0445 0.0054(R2 > 0.95) N/A 0.0018 0.023 38 −0.0039

New bone(27.60 μg)

3H 0.001 0.001 0.000 0.00114C 0.012 0.030 0.026 0.040232Th 0.007 0.008 0.000 0.008212Po 0.014 0.034 0.056 0.035α-emitters 1.3 × 10−6 1.5 × 10−5 5.8 × 10−5

best fit, 0.000 37 0.0011 −0.000 31a, b, c and d 0.000 47 −0.0063 0.0027(R2 > 0.97) N/A 0.000 46 0.0056 −0.0011

a Hematopoietic marrow includes 50 μm quiescent bone stem cell niche.N/A: not available.

Radiation dose to trabecular bone marrow stem cells 971

Table 4. Static simulation AFs from radiation sources in marrow to critical target regions forβ-emitters, 3H and 14C, and two α-emitters, 232Th and 212Po (4.0 and 8.8 MeV, respectively).Coefficients are given for best fits of the form AF = a × E3

α + b × E2α + c × Eα + d. Also given

are the masses for the Monte Carlo compartments within one trabecular cubic unit.

Target

50 μm quiescent BRC bone10 μm bone stem stem cell Hematopoietic

Radionuclide endosteum cell niche niche marrow

Bone marrow(1.67 mg)

3H 0.030 0.161 0.000 0.65314C 0.022 0.135 0.001 0.639232Th 0.023 0.150 0.000 0.643212Po 0.019 0.125 0.001 0.616α-emitters −1.4 × 10−6 4.0 × 10−5 1.1 × 10−5

best fit, 0.000 18 −0.000 81 −0.000 55a, b, c and d −0.0030 3.9 × 10−5 −6.0 × 10−5

(R2 > 0.99) 0.0322 0.1605 0.000–0.001 0.6517

Fat cells(0.53 mg)

3H 0.001 0.002 0.000 0.03114C 0.015 0.033 0.001 0.492232Th 0.011 0.013 0.000 0.336212Po 0.016 0.041 0.001 0.567α-emitters −2.8 × 10−5 4.1 × 10−5 −0.000 91best fit, 0.000 18 −0.000 23 0.0075a, b, c and d 0.0027 0.0032 0.0733(R2 > 0.98) −0.0015 0.000 34 0.000–0.001 −0.0211

Hematopoieticmarrow (1.14 mg)

3H 0.052 0.245 0.000 0.98414C 0.026 0.190 0.001 0.717232Th 0.032 0.224 0.000 0.821212Po 0.021 0.172 0.001 0.671α-emitters 1.6 × 10−5 3.8 × 10−5 0.000 42best fit, 0.000 20 −0.0011 −0.0039a, b, c and d −0.0070 −0.0017 −0.0383(R2 > 0.99) 0.0565 0.2462 0.000–0.002 1.0102

The coefficients a, b, c and d are listed in tables 3 and 4. Figure 4 shows three fittedpolynomial curves for AFs from activities in quiescent bone volume to 10 μm endosteum,50 μm quiescent bone stem cell niche and hematopoietic marrow, respectively. The AFs fortwo of the α-emitters of the elements thorium and polonium, 232Th and 212Po, are also listedin tables 3 and 4.

Richardson et al (2007) compared the AFs recommended by ICRP 30 (1979) for betaemitters in the skeleton with those of the trabecular cubic unit simulation. The ICRP (1979)recommends AFs of 0.025 and 0.05 for the dosimetry of all alpha-emitting radionuclides inthe quiescent bone volume irradiating 10 μm endosteum and red marrow, respectively. TheICRP recommends AFs of 0.25 and 0.5 for alpha-emitting radionuclides in the quiescent

972 H Nie and R B Richardson

(a)

(b)

(c)

Figure 4. Static simulation AFs from activities in quiescent bone volume to (a) 10 μm endosteum,(b) 50 μm quiescent bone stem cell niche, (c) hematopoietic marrow for α-emitters, fitted to thirddegree polynomial curves.

bone surface irradiating 10 μm endosteum and red marrow, respectively. The AFs given intable 3 are of the same order as the ICRP recommendations, even allowing that ICRP assumesan infinitely thin bone surface as opposed to the finite size (1 μm thick) selected for thesimulation described here.

The AFs for the static model are calculated at the temporal midpoint of the boneremodeling process, when the cavity was about two-thirds full. The AFs from activity sourcesin forming bone irradiating the BRC stem cell niche, where active stem cells and progenitorcells of osteoblasts and osteoclasts are located, are significantly greater than those in forming

Radiation dose to trabecular bone marrow stem cells 973

(a) (b)

(c) (d)

Figure 5. Dynamic stimulation AFs for the BRC stem cell niche irradiated by 3H, 14C and α-emitters (232Th 4.0 MeV and 212Po 8.8 MeV) incorporated with unchanging activity concentrationinto forming bone (phase II, 15–150 d) during remodeling process.

bone irradiating targets in 10 μm endosteum or 50 μm quiescent stem cell niche for higherenergy α- or β-emitters (14C with average energy 47 keV and 212Po with energy 8.8 MeV).The AFs for activity in forming bone targeting the BRC stem cell niche are slightly lowerthan those to the 10 μm endosteum or the 50 μm quiescent stem cell niche for lower energyα- or β-emitters (3H with average energy 5 keV and 232Th with energy 4.0 MeV). Nevertheless,the absorbed dose to active stem cells in BRC stem cell niche will still be greater than to thequiescent stem cells (in quiescent stem cell niche) taking into account the masses of thesecompartments (tables 3 and 4).

Fat cells were modeled as a source of α- and β-emitters in table 4. The major componentof fat cells is carbon; therefore, higher concentrations of organically bound 3H and 14C can beexpected to be eventually located in fat cells compared to other tissues having lower carbonconcentrations (Richardson and Dunford 2003). However, only 3% and 49% of the β-radiationdose originating from 3H and 14C, respectively, in fat cells is absorbed within the hematopoiticmarrow.

3.3. Dynamic model AFs and dose ratios: for sources in forming bone irradiating quiescentbone stem cell niche and BRC stem cell niche

The temporal change of AFs from radioactive sources incorporated from blood into formingbone (osteoid and new bone) that irradiate BRC stem cell niche for 3H, 14C and twobone-seeking α-emitters (232Th and 212Po with energy 4.0 and 8.8 MeV) is illustrated infigures 5(a)–(d). The AFs from activity in osteoid and new bone irradiating the BRC stemcell niche increase as the hemiosteon is filled from 15 to 150 d and the activity is depositednearer and nearer to the BRC canopy. The exception is tritium, whose very short mean range

974 H Nie and R B Richardson

Table 5. Dynamic simulation dose ratios from forming bone to BRC stem cell niche and 10 μmendosteum or 50 μm quiescent bone stem cell niche.

Source Ratio of 3H 14C 232Th 212Po

Osteoid BRC niche/10 μma 2 30 24 36Osteoid BRC niche/50 μmb 2 75 111 75New bone BRC niche/10 μma 0 20 9 26New bone BRC niche/50 μm 0 42 39 54

a The ratio of dose from osteoid to BRC stem cell niche and 10 μm endosteum.b The ratio of dose from osteoid to BRC stem cell niche and 50 μm quiescent bone stem cell niche.

of 1 μm means that the dose to BRC stem cell niche is negligible at all times of infill of thecavity.

A biokinetic radionuclide model usually is needed to calculate the committed equivalentdose from forming bone sources targeting stem cell niches in order to estimate the changein deposited activity with time after intake. Nevertheless, by making a few reasonableassumptions, the dose ratio from activity in forming bone irradiating both the quiescentstem cell niche and BRC stem cell niche can be estimated. These assumptions include: (a)BRC stem cell niche has the same volume during the bone remodeling process; (b) radiationsource concentration, in units of Bq kg−1, in osteoid and new bone is a constant value withtime. Dose ratios comparing different targets can be calculated with formula (2). Table 5 liststhe dose ratios from activity in forming bone (osteoid and new bone) irradiating active stemcells or quiescent stem cells. Overall, we observe much a higher dose to active stem cellscompared with quiescent stem cells for 14C, 232Th and 212Po, with dose ratios ranging from 9to 111.

4. Discussion

The simulation results confirm that changing the bone cancer target tissue from the 10 μmendosteum to the 50 μm quiescent bone stem cell niche will decrease the dose 2- to 5-foldfrom bone to the target tissue for bone-seeking α- and β-emitters. There is also a moderateincrease in dose ranging from 1.03- to 1.36-fold from activity in bone marrow to the targettissue for α- and β-emitters that are only deposited in bone marrow. ICRP’s increase intarget thickness from 10 to 50 μm means changes to the dosimetry of epidemiologic studiesinvolving exposure to bone-seeking alpha emitters, whereas the evidence for alpha-particle-induced bone cancers remains, of course, the same (BEIR IV, 1988). This dosimetric changeresults in substantially increased relative biology effectiveness (RBE) for bone-seeking radiumα-emitters (e.g. 224,226,228Ra) and a moderately decreased RBE for α-emitters residing in bonemarrow. This change in α-emitter RBE for bone cancer induction means the risk determinedfrom the calculated target dose more in line with incidence and mortality rates derived fromepidemiological studies (Harrison and Muirhead 2003).

It is conceivable that radiation has an influence on osteoblast-expressed regulatorycomponents (Taichman 2005), e.g. cell surface cytokines and growth factors. The ICRP’senlargement of the bone cancer target beyond the preferred location of HSCs and perhapsMSCs, i.e. the endosteum, will embrace the supporting osteoblasts within the 50 μm quiescentbone stem cell niche.

Salmon et al (1999) assumed a five-stage serial process for the whole bone remodelingcycle whose participating cells and associated durations are adopted here for bone formation.This study emphasizes the need to assess AFs and dose to active stem and progenitor cells

Radiation dose to trabecular bone marrow stem cells 975

located in the BRC stem cell niche. The doses from forming bone to the BRC stem cell nicheare much greater than those to the quiescent stem cell layer by a factor of 9–111, indicating amuch higher dose arising from relatively high energy bone seeking α-emitters and β-emittersto the albeit small niche of active stem cells than to the larger volume occupied by quiescentstem cells. Biokinetic modeling of radionuclides of both bone-surface-seeking and bone-volume-seeking elements are initially taken up by bone surfaces, e.g. as described by Priest(1990) and Leggett (1992). The AFs from sources in forming bone to the BRC stem cell nichetarget are greater than those to the quiescent bone surface by one or two orders of magnitudefor the radionuclides studied. This finding indicates that a greater portion of irradiative energy(1–13%) will be deposited in the active stem and progenitor cells associated with formingbone, while only a very small portion of the energy (<0.1%) will be deposited in the endostealstem cells located adjacent to the quiescent bone surface. However, this does not mean thatthe dose contribution from activity located at the quiescent bone surface and forming boneto the BRC’s active stem/progenitor cells will differ by the same magnitude. A biokineticmodel of radionuclide uptake and transfer in the human body has to be employed to calculaterelative temporal affinity to quiescent and forming bone surfaces. Nevertheless, short-rangeradionuclides incorporated within forming bone will contribute more to the dose to the BRC’sactive stem/progenitor cells than will activity resident at the quiescent bone surface.

There is increased vascular delivery of oxygen and other nutrients in the proximity of theBMU compared with the quiescent bone surface. Hauge et al (2001) report that the BMUcommences with increased blood flow and perhaps additional paratrabecular sinusoidal loops.This induces an elevated oxygen concentration at the BMU location, which is another factorthat could contribute to a higher bone tumor risk at the bone-remodeling site. The oxygenenhancement ratio (OER) is defined as the ratio of radiation-induced measurements of celldeath or other health effects when O2 is present to that when it is not (Thoday and Read1947). Radiosensitivity varies most rapidly with oxygen tensions below ∼15 torr or mmHg(2% O2). Radiosensitivity decreases with increasing LET, e.g. Barendsen et al (1966) measureda maximum OER of 2.7 for 250 kVp (kilovolt peak) x-rays and an OER of 1.0 for 2.5 MeVα-particles. The partial pressure of oxygen in bone marrow aspirates was 55 mmHg, measuredby Harrison et al (2002). No measurements of oxygen pressure have been performed in theendosteum although modeling by Chow et al (2001) points to almost anoxic O2 levels. Theendosteum allows stem cells to exist in a quiescent state protected from damaging reactiveoxygen species. For an oxygen concentration of 7% in the vascular niche, the OER of low LETβ-emitters is 2.5 employing a maximum OER of 2.7 and other representative oxygen effectparameters used by Richardson (at press). The OER is 2.0 for an endosteal O2 concentrationof 1%, but falls to 1.25 at 0.1% O2. An equal radiation dose to stem/progenitor cells in thevascular niche accompanying the BRC will have up to about twice the biological effect of thesame dose to quiescent stem cells within the endosteum. Based on the above discussion, bothradiation doses and OER are elevated to the vascular niche in the vicinity of α- and β-emitterstaken up by the BRC. Therefore, the remodeling site is a particularly vulnerable locationfor the induction of bone cancer and no substantive evidence to support this for leukemia,especially by short-range radiation incorporated in forming bone (BEIR IV, 1988).

In developed countries, osteosarcoma is the commonest cancer in children and the secondmost common cancer in aged adults (Gurney et al 1999). Osteosarcoma is a cancer causedby the abnormal proliferation of osteoblasts. A risk factor for this bone neoplasm is the rapidbone growth that occurs in adolescence. This work shows that higher doses from short-rangeradiations are delivered to MSCs and their osteoblastic progenitors during the remodelingprocess. This process matches the epidemiological evidence that populations going throughmore active bone remodeling, such as children and adolescents, have a higher risk radiation-

976 H Nie and R B Richardson

induced bone cancers than adults, e.g. patients treated with high doses of 224Ra (Nekolla et al2005). Age-related bone microdosimetry will be investigated to better evaluate this risk in afuture study.

Gossner (2003) made the case that pre-existing lesions (e.g. Paget’s disease), and radiation-induced bone lesions (e.g. radiation osteitis or inflammation of the bone) and related fibrosis,may be an important prerequisite for the malignant transformation to bone sarcomas offibroblastic and fibrohistiocytic origin. This is consistent with our conclusion that activebone remodeling sites are at higher risk for the induction of bone tumor than quiescent bonesurfaces as Paget’s disease and inflammation are hypermetabolic conditions and, therefore,one can expect pre-existing lesions and fibrosis to be associated with active bone remodeling.

Schlenker et al (1989) compared histological type, by age and by anatomical locationof bone sarcomas occurring among radium-exposed females with those that were naturallyoccurring within non-exposed individuals. Osteogenic sarcomas, osteosarcomas andfibrosarcomas were observed in both groups. There was no significant difference in anatomicaldistribution between naturally occurring and radium-induced tumors. The radiation dosedistribution did not influence the tumor’s location. There was greater abundance of tumorsin the appendicular skeleton compared to the axial skeleton, even though the latter has thegreater bone surface area. Schlenker et al’s study does appear to support the premise thatbone remodeling sites are important locations of radium-induced and naturally occurring bonetumors as these occur in greater preponderance in the proximal and distal ends of the majorlimb bones which have large surface areas, a relatively high portion of which are remodeling.

There are improvements that could be made to both the static and dynamic simulations.At present the fat cells are modeled as not entering the endosteum or quiescent stem cell niche.In a future simulation, the fat cells would approach the quiescent bone surface within a fewmicrons as observed by Allen et al (1995). The initial resorbing stages of the remodeling cyclehave not been modeled in the dynamic simulation, and this may also be investigated in furtherwork. Osteoclasts that commence the excavation of the BMU have been shown to resorbplutonium from bone surface and transfer the alpha-activity to macrophages with a half-life of70 h (Priest and Giannola 1980). However, osteoclasts, which are HSC progenitors, are a rarephenotype for bone cancer: giant cell bone tumors, often benign, can be partially composedof osteocyte-like cells but are not a significant form of radiation-induced bone cancer (Unni1996).

In this paper, the target tissue for calculating dose and risk of radiation-induced leukemiasis the whole red marrow. However, Watchman et al (2007) demonstrated a spatial gradient forthe hematopoietic stem and progenitor cells near the bone surfaces, with the maximal arealconcentration of the stem cells near the bone surfaces. Kvinnsland et al (2001) furtherinvestigated the effect of dose distribution to target cell survival from radionuclides onquiescent (endosteal) bone surfaces. Their analysis assumed that the target cells had anexponential spatial concentration gradient away from bone surfaces. The dose distributioncalculated by Kvinnsland et al (2001), as opposed to the mean dose, provides a better estimateof the radiation risk for leukemia. On the basis of the oxygen effect mentioned earlier, itis proposed that the risk analysis could be further enhanced by allowing for the reducedsensitivity of HSCs located proximate to quiescent bone surfaces compared to the rest of thered marrow.

For radionuclides that uptake in bone, the activity is deposited initially and predominatelyon quiescent bone surfaces and then either is lost by back exchange to tissue fluids or slowlyredistributes by the remodeling process throughout the bone volume via the forming bonesurface. This latter scenario especially applies to long-lived radionuclides e.g. 232Th, 239Puthat remain on surfaces until they are remodeled and to calcium-analogue elements e.g. 226Ra

Radiation dose to trabecular bone marrow stem cells 977

and 235U that are preferentially deposited at sites of bone apposition. Animal studies haveshown that radiation-induced osteosarcomas are less prevalent from 226Ra and 241Am intakesthat deposit alpha energy at sites of lower bone turnover (cortical bone or quiescent trabecularsurface) than the much more toxic 224Ra and 239Pu that preferentially deposit and irradiatesites of high bone turnover, in particular forming trabecular surfaces (Priest et al 1995).This experimental evidence supports our premise that meaningful dose and risk assessmentsnecessitate the modeling of the distribution of radionuclide activity associated with quiescentand forming bone surfaces to provide AFs and the temporal variation in biokinetic activity.

The findings in this study can be applied to cancer risk estimates for patients treatedwith short range α- and β-particles that accumulate in marrow or bone, as well as the riskassessment of environmental exposure of such radionuclides to the general population. TheMonte Carlo simulations can also be extended in the future to estimate the age-dependent riskresulting from intakes of these radionuclides. One limitation of models by Kvinnsland et al(2001) and Richardson et al (2007) with repeated cubic units representing trabecular bonecavities is that the model and its chord length distributions (Beddoe et al 1976) are not infacsimile, which will affect the value of the AFs generated. Nevertheless, the model shownin figure 1 provides a reasonable match to the adult’s fraction of spongiosa volume occupiedby trabecular bone and quiescent/forming bone surfaces to bone volume ratios. However,with the help of a modern imaging facility such as micro-CT or MRI, an even more realisticskeletal model could be constructed (Guldberg et al 2004).

The main aim of this paper was to supply cogent arguments based on contemporarybiological research that the site of bone remodeling and its associated stem/progenitor cellpopulation is the most important skeletal target for evaluating the risk of radiation-inducedbone cancer. The authors concur with the ICRP that targets in trabecular bone, having ∼6-fold higher bone turnover, constitute a more important location of potential risk than thosein cortical bone. However, the authors request that the stem/progenitor cells associated withbone remodeling be considered by the ICRP as the most critical target for radiation inductionof bone cancer, in preference to the marrow layer adjacent to the quiescent bone surface.

Acknowledgments

Many thanks to Dr Jacques Dubeau of DETEC (Gatineau, Quebec) for his help with theMonte Carlo simulations. Drs Sara Carlisle and Nick Priest of AECL of Canada are thankedfor their internal reviews: the paper especially benefited from the latter’s expertise in skeletaldosimetry. The authors also thank the ICRP DOCAL/INDOS Task Groups (author RBR isa corresponding member) chaired by Drs Wesley Bolch and John Harrison for encouragingthe reassessment of radiation targets in bone marrow, with recommendations to be givenin a forthcoming publication. The authors acknowledge support from NIEHS grants R01-ES013744 (PI: Dr Robert Wright, Harvard School of Public Health) and editorial assistancefrom Ms Jaylyn Olivo of Brigham and Women’s Hospital Boston, MA.

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