**3. Radionuclide vascular disruption therapy using microspheres**

Conventional radiotherapy often involves the deposition of the radionuclide within a tumor mass. It is also feasible to attack the tumor by disrupting its blood supply. Vascular disruption agents have been developed and utilized in chemotherapy and radiotherapy.

#### **3.1. Tumor vasculature**

proton dose requires a continuous proton energy distribution. The 27 proton generating devices are distributed in a 10 × 10 × 10 cm volume of water. Each device is assumed to radiate isotropically. The results of irradiating this water volume with 27 internal devices generating an output of 10, 20, 30, 40, 50, 60, 70, and 80 MeV protons are illustrated in **Figure 1**.

Since the total absorbed dose of **Figure 1** is the superposition of a number of manifolds (i.e., the various isodose surfaces), the structure of the surface is governed by the proton output spectrum, fluence, attenuating medium characteristics, ion stopping power, and reaction cross section as noted in Eqs. (1) and (2). **Figure 1** represents the three-dimensional absorbed dose profile. In **Figure 1**, the dose at each point is proportional to the plotted circle radius.

**Figure 1.** Normalized absorbed dose distribution from 27 internal radiation-generating devices producing a spectrum of eight proton groups (i.e., 10, 20, 30, 40, 50, 60, 70, and 80 MeV protons). The absorbed dose is proportional to the plotted

**Figure 1** illustrates the symmetry of the absorbed dose distribution associated with the 27 internal radiators. Although the distribution is not uniform, the IRGDs effectively irradiate the target volume. The average dose to the target 10 × 10 × 10 cm volume depends on the IRGD proton spectrum. For example, proton energy groups of 10 MeV; 10 and 20 MeV; 10, 20, 30, and 40 MeV; and 10, 20, 30, 40, 50, 60, 70, and 80 MeV produce to an average dose over the target volume of 5.89 × 10−6, 5.75 × 10−4, 3.00 × 10−2, and 9.79 × 10−2 relative to the peak dose, respectively. Increasing the number of proton energy groups between 10 and 80 MeV range will continue to increase the average absorbed dose to the tumor site. The discussion of the characteristics of the detailed three-dimensional absorbed dose profile illustrates the complexity of therapy

planning when implementing a new technology.

circle radius.

216 Radiotherapy

The fluence at each proton energy is selected to be the same.

The vascular structure of normal tissue provides an efficient method to deliver nutrients. Growing tumors have a poorly developed vasculature that does not adequately nourish the cells [17]. The tumor's weak vascular structure can be degraded using a chemical or radioactive agent.

Vessels that are dilated and have elongated shapes, blind ends, bulges, leaky sprouts, and abrupt diameter changes are defects that occur in a tumor's vascular structure. These vessel defects create sluggish and irregular blood flow that poorly nourish cancer cells and result in hypoxic tumors. Hypoxic conditions limit the effectiveness of both chemotherapy and radiotherapy and provide a measure of radioresistance to tumor cells when compared to normal, oxygenated cells. Since a tumor's growth is dependent on sufficient nourishment, eliminating its blood supply provides an additional opportunity to facilitate its destruction [17].

#### **3.2. Current radiological efforts**

Radiological efforts at tumor vascular disruption have focused on 90Y. 90Y was a logical choice for anti-angiogenic therapy since the dose to destroy a tumor is ≥70 Gy. However, the 2.27 MeV 90Y beta particles have a range in tissue of about 1.1 cm, which deposits dose to healthy tissue well beyond the target vasculature. Bremsstrahlung from the 90Y beta particles provides additional dose to healthy tissue. The properties of 90Y microspheres used in therapy applications are summarized by Kennedy et al. [22].

Medical reviews suggest that the 90Y approach is a safe and effective therapy method for selected patients. However, a number of negative features are associated with 90Y microsphere therapy [22]. First, 90Y bremsstrahlung affects healthy tissue well beyond the vasculature. Second, resin microspheres may have trace 90Y on their surface, which is excreted through urine. As the 90Y is excreted, additional absorbed dose is delivered to healthy tissues. Third, the total dose delivered to the lung should not exceed 30 Gy to prevent radiation pneumonitis. Fourth, patients can exhibit abdominal pain, fatigue, and nausea within three days posttreatment. Fifth, dose delivered to healthy tissue causes acute damage that includes pancreatitis, gastrointestinal ulceration, and radiation pneumonitis. Radiation-induced liver disease is a possible late effect of 90Y microsphere therapy.

#### **3.3. Theoretical methodology**

A tumor's blood supply is reduced by a vascular disruption agent that causes the vessel wall to become restricted or breached to increase leakage. IRGDs and microspheres using alphaemitting radionuclides (MAs) preferentially deliver absorbed dose to the blood vessel wall to facilitate its disruption. The wall thicknesses for a variety of human blood vessel types [30] are summarized in **Table 1**.


**Table 1.** Characteristics of various blood vessel typesa .

Tumor vessel wall sizes, including arterioles, are usually <100 μm [17]. Although arterioles are used as the base case in this chapter, the vessel sizes summarized in **Table 1** suggest that a variety of blood vessel types could service a developing tumor [30].

#### **3.4. Microsphere radionuclide selection and characteristics**

An alternative to the use of 90Y is provided by radionuclides that emit low-energy photons, low-energy beta particles, or alpha particles. These radionuclides would replace 90Y as the radioactive material loading the microspheres.

Desirable characteristics for the radionuclide and candidate microsphere to facilitate tumor blood vessel disruption include the (1) nuclide has a short effective half-life, (2) range of the emitted radiation is <100 μm or the maximum vessel wall thickness, (3) arteriole wall dose is at least 100 Gy, (4) healthy tissue dose is minimized, (5) microsphere preferentially attaches to the wall of the tumor's arteriole, (6) candidate radionuclide is compatible with the microsphere, and (7) the microsphere can be removed from the body at a desired time.

Although these characteristics provide a basis for the calculations presented in this chapter, they have not been optimized to produce a viable alternative to the 90Y microsphere approach. As noted in Refs. [4–6], both alpha-emitting and low-energy beta-gamma loaded microspheres can be utilized to disrupt a tumor's vasculature. However, the daughter radiation presents a problem, and this radiation can often irradiate healthy tissue that was an original concern associated with the 90Y approach.

Production challenges and associated availability are impediments for the use of alpha-emitting radionuclides. Therefore, the availability of the selected radionuclide is an important consideration. 222Rn is readily available and would be a candidate for microsphere use. The 222Rn daughters yield additional dose to the tumor vasculature, which could enhance the approach if healthy dose is avoided.

### *3.4.1. Selection of radionuclide*

emitting radionuclides (MAs) preferentially deliver absorbed dose to the blood vessel wall to facilitate its disruption. The wall thicknesses for a variety of human blood vessel types [30]

**Blood vessel type Wall thickness Lumen diameter**

Aorta 2 mm 25 mm Artery 1 mm 4 mm Arteriole 20 μm 30 μm Capillary 1 μm 8 μm Venule 2 μm 20 μm Vein 0.5 mm 5 mm Vena Cava 1.5 mm 30 mm

Tumor vessel wall sizes, including arterioles, are usually <100 μm [17]. Although arterioles are used as the base case in this chapter, the vessel sizes summarized in **Table 1** suggest that

.

An alternative to the use of 90Y is provided by radionuclides that emit low-energy photons, low-energy beta particles, or alpha particles. These radionuclides would replace 90Y as the

Desirable characteristics for the radionuclide and candidate microsphere to facilitate tumor blood vessel disruption include the (1) nuclide has a short effective half-life, (2) range of the emitted radiation is <100 μm or the maximum vessel wall thickness, (3) arteriole wall dose is at least 100 Gy, (4) healthy tissue dose is minimized, (5) microsphere preferentially attaches to the wall of the tumor's arteriole, (6) candidate radionuclide is compatible with the micro-

Although these characteristics provide a basis for the calculations presented in this chapter, they have not been optimized to produce a viable alternative to the 90Y microsphere approach. As noted in Refs. [4–6], both alpha-emitting and low-energy beta-gamma loaded microspheres can be utilized to disrupt a tumor's vasculature. However, the daughter radiation presents a problem, and this radiation can often irradiate healthy tissue that was an original concern

Production challenges and associated availability are impediments for the use of alpha-emitting radionuclides. Therefore, the availability of the selected radionuclide is an important

sphere, and (7) the microsphere can be removed from the body at a desired time.

a variety of blood vessel types could service a developing tumor [30].

**3.4. Microsphere radionuclide selection and characteristics**

radioactive material loading the microspheres.

**Table 1.** Characteristics of various blood vessel typesa

associated with the 90Y approach.

are summarized in **Table 1**.

a

218 Radiotherapy

Barrett et al. [30].

In Refs. [4–6], a list of candidate alpha- and beta-gamma-emitting radionuclides was created. Unfortunately, most candidate radionuclides, including 149Tb, 211At, 212Bi, 213Bi, 223Ra, 225Ac, and 227Th, have daughter gamma, beta, or bremsstrahlung radiation that irradiates healthy tissue well beyond the target volume, which does not meet the goal of minimizing the dose delivered beyond the arteriole wall. As part of that goal, 222Rn was noted as an interesting possibility since it occurs naturally as part of the 238U decay chain. Eq. (3) lists the 222Rn decay daughters with the associated decay scheme:

$$\begin{aligned} \text{daughters with the associated decay scheme:}\\ ^{22}\text{R }\mathbf{n}\xrightarrow{a} ^{218}\mathbf{P}\mathbf{o}\xrightarrow{a} ^{214}\mathbf{P}\mathbf{b}\xrightarrow{\beta^{\*}} ^{214}\mathbf{B}\mathbf{i}\xrightarrow{\beta^{\*}} ^{214}\mathbf{P}\mathbf{o}\xrightarrow{a} ^{210}\mathbf{P}\mathbf{b}\xrightarrow{\beta^{\*}}\\ ^{210}\mathbf{B}\mathbf{i}\xrightarrow{\beta^{\*}} ^{210}\mathbf{P}\mathbf{o}\xrightarrow{a} ^{206}\mathbf{P}\mathbf{b} \end{aligned} \tag{3}$$

Although 222Rn has a number of desirable characteristics, its daughters emit beta and gamma radiation that deliver absorbed dose well beyond the thickness of the arteriole wall. Therefore, 222Rn is not a primary candidate to achieve selective dose delivery to the vascular wall. However, a review of the 222Rn daughters suggests that 210Po has the desired characteristics for vascular disruption without significantly irradiating healthy tissue. In particular, the 210Po 5.3 MeV alpha particle irradiates the arteriole wall and limits the absorbed dose beyond the target tissue. In addition, the weak 803 keV 210Po photon radiation with a yield <1.0 × 10−3% delivers minimal dose beyond the target tissue.

#### *3.4.2. Basic microsphere design*

The base case microsphere is loaded with 0.3 Bq of 210Po uniformly distributed in a 1-μm-diameter 12C sphere having a density of 2.0 g/cm3 . Subsequent discussion provides the basis for the 0.3 Bq activity.

Subsequent discussion is based on a single microsphere. However, treatment procedures will utilize many spheres with the actual number determined by the cancer type and its progression. Although microsphere delivery methods other than the usual catheter approach [2–6] may be feasible, initial efforts will likely focus on the traditional delivery method [17–23].

#### *3.4.3. Absorbed dose computational model*

A 210Po activity of 0.3 Bq delivers an absorbed dose of about 100 Gy to the arteriole wall. Defining a more exact activity value is not necessary because the design has yet to be refined. The activity value also depends on the insertion and removal methods, fabrication details, and relative biological effectiveness values for the 210Po alpha and gamma radiation.

#### *3.4.3.1. Absorbed dose from alpha particles*

The absorbed dose (*D*) delivered by ions of a specific energy as a function of penetration distance *x* into tissue is [1, 12]:

$$\mathbf{D}(\mathbf{x}) = \frac{1}{\rho} \left( - \frac{d\mathbf{E}}{d\mathbf{x}} \right) \Phi(\mathbf{x}) \tag{4}$$

where ρ is the density of tissue attenuating the ion, −dE/dx is the stopping power, and Φ(x) is the alpha particle fluence at the location of interest. The particle fluence varies with tissue penetration depth according to the relationship:

$$\mathfrak{O}(\mathbf{x}) = \mathfrak{O}(\mathbf{0}) \,\mathrm{e}^{-\mathbb{E}\times} \tag{5}$$

where Φ(0) is the entrance fluence and Σ is the macroscopic reaction cross section. Alpha particle stopping powers are derived from Bethe's formulation [31] and follow an approach similar to the SPAR code [32]. The energy-dependent cross sections are obtained from Shen et al's parameterization [29] or models [1–6].

#### *3.4.3.2. Photon absorbed dose*

The photon absorbed dose is derived from the standard point source relationships [4–6]:

$$\mathbf{D} = \frac{\mathbf{S}}{4\pi\mathbf{r}^2} \frac{\mu\_m}{\rho} \to \mathbf{B}(\mu\mathbf{x}) \,\mathrm{e}^{-\mu\mathbf{x}} \tag{6}$$

where S is the total number of photons irradiating the arteriole wall, r is the distance from the microsphere, μen/ρ is the mass-energy absorption coefficient, E is the photon energy, B is a buildup factor, and μ is the attenuation coefficient. The gamma absorbed dose contribution is obtained from the ISO-PC computer code [33]. Requisite photon data for 210Po are based on Rittman [33].

#### *3.4.4. Relative biological effectiveness*

In therapy applications, the absorbed dose is multiplied by the relative biological effectiveness (RBE) to reflect the cell killing efficiency of a radiation type. The RBE of radiation type x is defined as the ratio of the dose of a reference energy photon to produce an effect and the dose of radiation type x to produce the same biological effect. Although the RBE is a simple concept, its therapy application is complex [34], because the RBE depends on a number of factors. These include the radiation type and its energy, the delivered absorbed dose, the delivery method (e.g., dose fractionization sequence), and the irradiated cell and tissue types. No RBE is applied to the absorbed doses calculated in this chapter because the design of the 210Po microsphere is being developed. However, the alpha particle RBE is greater than unity. Therefore, the calculated absorbed doses for tumor disruption represent a lower bound for the dose delivered by the 210Po microsphere.

#### *3.4.5. Microsphere results and discussion*

*3.4.3.1. Absorbed dose from alpha particles*

D(x) = \_\_1

penetration depth according to the relationship:

al's parameterization [29] or models [1–6].

D = \_\_\_\_ <sup>S</sup>

*3.4.4. Relative biological effectiveness*

the dose delivered by the 210Po microsphere.

*3.4.3.2. Photon absorbed dose*

Rittman [33].

tance *x* into tissue is [1, 12]:

220 Radiotherapy

The absorbed dose (*D*) delivered by ions of a specific energy as a function of penetration dis-

<sup>ρ</sup> (<sup>−</sup> \_ dE

where ρ is the density of tissue attenuating the ion, −dE/dx is the stopping power, and Φ(x) is the alpha particle fluence at the location of interest. The particle fluence varies with tissue

Φ(x) = Φ(0) e−Σ <sup>x</sup> (5)

where Φ(0) is the entrance fluence and Σ is the macroscopic reaction cross section. Alpha particle stopping powers are derived from Bethe's formulation [31] and follow an approach similar to the SPAR code [32]. The energy-dependent cross sections are obtained from Shen et

The photon absorbed dose is derived from the standard point source relationships [4–6]:

where S is the total number of photons irradiating the arteriole wall, r is the distance from the microsphere, μen/ρ is the mass-energy absorption coefficient, E is the photon energy, B is a buildup factor, and μ is the attenuation coefficient. The gamma absorbed dose contribution is obtained from the ISO-PC computer code [33]. Requisite photon data for 210Po are based on

In therapy applications, the absorbed dose is multiplied by the relative biological effectiveness (RBE) to reflect the cell killing efficiency of a radiation type. The RBE of radiation type x is defined as the ratio of the dose of a reference energy photon to produce an effect and the dose of radiation type x to produce the same biological effect. Although the RBE is a simple concept, its therapy application is complex [34], because the RBE depends on a number of factors. These include the radiation type and its energy, the delivered absorbed dose, the delivery method (e.g., dose fractionization sequence), and the irradiated cell and tissue types. No RBE is applied to the absorbed doses calculated in this chapter because the design of the 210Po microsphere is being developed. However, the alpha particle RBE is greater than unity. Therefore, the calculated absorbed doses for tumor disruption represent a lower bound for

4πr<sup>2</sup> μ\_\_\_en dx) <sup>Φ</sup> (x) (4)

<sup>ρ</sup> E B(μx) e<sup>−</sup>μx (6)

In subsequent discussion, the 210Po microsphere resides at the inner wall of an arteriole. **Figures 2** and **3** illustrate absorbed dose profiles for water thicknesses ≤100 μm. Following previous work, the vessel wall is assumed to be water that is a good approximation for tissue [1–6, 12].

**Figure 2.** Absorbed dose profile for 210Po alpha particles in a water medium. The absorbed dose is delivered by 0.3 Bq of 210Po uniformly deposited within a 1-μm-diameter microsphere following the total decay of the radioactive material.

**Figure 3.** Absorbed dose profile for 210Po photons in a water medium. The absorbed dose is delivered by 0.3 Bq of 210Po uniformly deposited within a 1-μm-diameter microsphere following the total decay of the radioactive material.

**Figures 2** and **3** provide the results of alpha and gamma contributions to the absorbed dose from a 210Po microsphere, respectively. Since the gamma absorbed dose is significantly less than the alpha absorbed dose, **Figure 2** represents the total absorbed dose delivered by the 210Po MA.

Since the peak dose is delivered at 35.9 μm, the 100 μm dose localization value is achieved. At the Bragg peak, the alpha to gamma dose ratio is 1.7 × 1010. Beyond the Bragg peak, 210Po photons deliver less than 0.1 μGy. Although 210Po MAs achieve the desired dose localization, its longer half life (138 d) relative to 32P (14.28 days) and 90Y (2.669 days) [35] must be addressed.

The time (t)-dependent dose rate to the arteriole wall is given by the relationship:

$$
\dot{\mathbf{D}}(\mathbf{t}) = \dot{\mathbf{D}}(0) \,\mathrm{e}^{-\mathrm{\&t}} \tag{7}
$$

where λ is the physical decay constant of the radionuclide. Integrating Eq. 7 yields the total dose at time T:

$$\mathbf{D(T)} = \frac{\mathbf{D(0)}}{\lambda} \left( 1 - \mathbf{e^{-\lambda T}} \right) = \mathbf{D(os)} \left( 1 - \mathbf{e^{-\lambda T}} \right) \tag{8}$$

Since the activity is proportional to the delivered dose, early removal of the microsphere at time T requires an increase in the initial activity loading by a factor (F), which is the ratio of D(∞)/D(T) [5]:

$$\mathbf{F} = \frac{1}{(\mathbf{1} - \mathbf{e}^{\times \mathbf{D}})} \tag{9}$$

This activity increase delivers the required dose to disrupt the microsphere as noted in **Figures 2** and **3**. For example, an activity of about 2 Bq (0.3 Bq × 7.19) is the requisite 210Po activity loading to produce the doses summarized in **Figures 2** and **3** if the microspheres are removed at 30 days (F(30 days) = 7.19).

#### *3.4.6. Microsphere delivery methods*

In initial studies, a catheter will introduce the MA into the tumor vasculature. Following the methodology developed in 90Y microsphere liver cancer therapy, the catheter enters through the femoral artery into the liver and deposits the microspheres into the tumor's blood vessels. Image-guided radiation therapy [26, 36] facilitates guiding the catheter to specifically target the tumor vasculature.

The catheter delivery method could be utilized in the treatment of a number of tumors. Specific catheter paths for the various tumor types will be refined and developed in a manner that was similar to the evolution of the 90Y microsphere treatment of liver cancers [17–23]. For example, renal artery access would facilitate 210Po MA deposition into the vasculature of kidney tumors.

Developing a method for preferentially depositing the MA into the desired blood vessel requires additional research and development. The microsphere research and design effort should investigate a number of chemical and physical approaches. These approaches include the use of electric charge, heat, pH, and electromagnetic fields to achieve the desired attachment of the MA to the tumor's vascular wall. The specific design options that require experimental effort include the MAs (1) electric charge and its spatial distribution, (2) dielectric and diamagnetic characteristics, (3) physical size and shape, and (4) material composition. Activating agents could be used to optimize the MA design. Electromagnetic fields heat, lasers, and a spectrum of electromagnetic radiation are possible activating agents.

#### *3.4.7. Microsphere removal methods*

**Figures 2** and **3** provide the results of alpha and gamma contributions to the absorbed dose from a 210Po microsphere, respectively. Since the gamma absorbed dose is significantly less than the alpha absorbed dose, **Figure 2** represents the total absorbed dose delivered by the 210Po MA. Since the peak dose is delivered at 35.9 μm, the 100 μm dose localization value is achieved. At the Bragg peak, the alpha to gamma dose ratio is 1.7 × 1010. Beyond the Bragg peak, 210Po photons deliver less than 0.1 μGy. Although 210Po MAs achieve the desired dose localization, its longer half life (138 d) relative to 32P (14.28 days) and 90Y (2.669 days) [35] must be addressed.

where λ is the physical decay constant of the radionuclide. Integrating Eq. 7 yields the total

Since the activity is proportional to the delivered dose, early removal of the microsphere at time T requires an increase in the initial activity loading by a factor (F), which is the ratio of

(1 − e −λT)

This activity increase delivers the required dose to disrupt the microsphere as noted in **Figures 2** and **3**. For example, an activity of about 2 Bq (0.3 Bq × 7.19) is the requisite 210Po activity loading to produce the doses summarized in **Figures 2** and **3** if the microspheres are

In initial studies, a catheter will introduce the MA into the tumor vasculature. Following the methodology developed in 90Y microsphere liver cancer therapy, the catheter enters through the femoral artery into the liver and deposits the microspheres into the tumor's blood vessels. Image-guided radiation therapy [26, 36] facilitates guiding the catheter to specifically target

The catheter delivery method could be utilized in the treatment of a number of tumors. Specific catheter paths for the various tumor types will be refined and developed in a manner that was similar to the evolution of the 90Y microsphere treatment of liver cancers [17–23]. For example, renal artery access would facilitate 210Po MA deposition into the vasculature of

Developing a method for preferentially depositing the MA into the desired blood vessel requires additional research and development. The microsphere research and design effort

˙ (t ) = D ˙ (0 ) e −λt (7)

<sup>λ</sup> (1 − e −λT) = D (∞) (1 − e −λT) (8)

(9)

The time (t)-dependent dose rate to the arteriole wall is given by the relationship:

˙ (0 ) \_\_\_\_

D

D (T ) = <sup>D</sup>

removed at 30 days (F(30 days) = 7.19).

*3.4.6. Microsphere delivery methods*

the tumor vasculature.

kidney tumors.

F = \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ <sup>1</sup>

dose at time T:

222 Radiotherapy

D(∞)/D(T) [5]:

Eqs. (7)–(9) suggest that extraction of MAs at a specified time requires the development of removal mechanisms. Removal could be accomplished by reversing the delivery methods discussed previously. For example, deposition and removal could be achieved by incorporating a magnetic material in the MA. The magnetic particles facilitate placement in the desired location using an active, localized magnetic field. Eliminating the magnetic field would facilitate microsphere removal. The protocol for microsphere implantation and removal requires additional research and development.

#### *3.4.8. Effective half-life*

As noted previously, the 210Po physical half-life (Tp) must be addressed before the MA therapy application becomes a reality. The physical half-lives of 210Po and 90Y are 138 and 2.7 days, respectively. A 90Y delivery approach will not be successful for 210Po if the MA design does not shorten the biological half-life of the device.

In the case of the shorter half-life 90Y, some microspheres are transported via blood into the lung and irradiate healthy tissue. Since the physical half-life of 90Y is short, this deposition yields a relatively insignificant dose. Assuming the same transfer characteristics, 210Po produces a larger lung dose and could create a significant biological detriment. This concern is eliminated if the 210Po MA design produces a shorter biological half-life in the lung.

In view of these considerations, constructing 210Po MAs with a short effective half-life is a design requirement. For example, the 210Po MAs could be constructed using a material having ICRP 30 [37] Class D lung retention characteristics. Following the ICRP 30 methodology, Class D materials have a biological half-life <10 days. Part of 210Po MA development is the use of a material with a short biological half-life. The 210Po MA effective half-life in the lung is [38]:

$$\mathbf{T}\_{\circ} = \frac{\mathbf{T}\_{p} \cdot \mathbf{T}\_{b}}{\mathbf{T}\_{p} + \mathbf{T}\_{b}} \tag{10}$$

Following Eq. (10), the effective half-life (T<sup>e</sup> ) of a radionuclide depends on its biological and physical half-lives. Therefore, a long physical half-life is not a limiting factor if the biological half-life (Tb ) is short. For example, the 210Po effective half-life for a material with 2- and 10-day biological half-lives is 1.97 and 9.32 days, respectively. A MA design requirement for a Class D biological half-life eliminates the longer 210Po physical half-life concern.

#### *3.4.9. 210Po toxicity and patient safety*

210Po has a specific activity of 1.7 × 1014 Bq/g, and its inhalation (ingestion) effective dose coefficient (EDC) is 3.0 × 10−6 Sv/Bq (2.4 × 10−7 Sv/Bq) [39]. The intake pathway caused by MA leaching has not been evaluated. In view of the inhalation and ingestion EDCs, the leaching EDC is probably in the range of the established conventional intake pathway values. For an initial scooping assessment, the leaching EDC is approximately 10−6 Sv/Bq. Considering the proposed 0.3 Bq 210Po MA, complete 210Po leaching from a single microsphere produces to an effective dose of about 0.3 μSv.

The effective dose from complete MA leakage is mitigated if the microspheres have good retention characteristics. With good 210Po retention characteristics, the radiological hazard to the patient is not significant. For example, if 10<sup>6</sup> 0.3 Bq MAs were administered with a 210Po retention of 90%, the patient's 50-year effective dose commitment is only 30 mSv.
