Radiation-Absorbed Dose from ²⁰¹Tl-Thallous Chloride

MATERIALS AND METHODS

²⁰¹Tl (physical half-life, 73.1 h) is cyclotron produced by the reaction ²⁰³Tl (p,3n) ²⁰¹Pb. ²⁰¹Pb decays with a 9.4 h physical half-life to ²⁰¹Tl by electron capture and β+ emission (29). ²⁰¹Tl is supplied as thallous chloride in isotonic solution. Possible contaminants (with the physical half-lives in parentheses) are ²⁰⁰Tl (26.1 h), ²⁰²Tl (12.23 d), and ²⁰³Pb (51.87 h). The physical half-life of ²⁰⁰Tl is considerably shorter than that of ²⁰¹Tl so that its contribution decreases with increased shelf life. On the other hand, the physical half-life of ²⁰²Tl is considerably longer than that of ²⁰¹Tl, so that its contribution to absorbed dose increases with increasing shelf life. Levels of the contaminants were taken from internal records of the Radiation Internal Dose Information Center in Oak Ridge, TN, derived from industry-reported values. The biokinetic model for lead was taken from ICRP Publication 30 (30).

The biologic data used in this dose estimate report are derived from (a) total-body pharmacokinetics, as determined through conjugate view imaging out to 216 h after injection in 14 male and 1 female patient undergoing diagnostic exercise myocardial scintigraphy and ranging in age from 41 to 62 y (17), and (b) quantitative testicular scintigraphy in 28 patients (56 studies) injected after peak exercise (25). The testes evaluation was a component of a clinical trial that had the primary objective of comparing bolus injection of an experimental pharmaceutical clearance agent with that of a placebo on the identification of thallium redistribution in the myocardium. Patients participated in a randomized crossover protocol with the second injection occurring at 1–2 wk after the first. No statistical difference was observed in the testes residence times for the paired (crossover) patient data; therefore, all 56 studies were combined for the analysis in this report. For this dedicated testicular study on 28 subjects, a lead vinyl shield (1 mm lead equivalent) was placed over the pelvis and upper thighs. The testes were pulled through an opening and placed on the lead vinyl such that they were sequestered and shielded from the body background during imaging. Anterior image data were acquired at 5–7 time points (nominally, 1, 2, 4, 8, 24, 48, and 168 h after administration) with a ²⁰¹Tl standard (vial with saline configured to approximate the size of one testis) imaged simultaneously within the field of view at each session. A 20% energy window centered over the 68- to 80-keV x-ray emissions for ²⁰¹Tl was used. The biokinetic data were fit to 2 exponential terms of the form α_h1exp(−λ_h1t) − α_h2exp(−λ_h2t) (Table 1) to accommodate the uptake component using standard regression software (31). For organs other than the testes, the metabolic model was based on the data of Krahwinkel et al. (15 patients) (17) as revised by Castronovo (18) (to achieve better correlation with then current estimates of ²⁰²Tl dosimetry through model incorporation of intravenous administration of tracer). The resultant residence times were used with the MIRD methodology to provide the dose estimates (27,28,32,33). The effective dose was calculated according to ICRP Publication 80 (20).

RESULTS

Table 1 presents the biologic parameters derived in this study for the source organs considered. As indicated, both mono- and biexponential functions have been fitted to the data as appropriate for the purpose of dosimetry calculations. A comparison of uptake in the human testes as determined by various investigators is presented in Table 2. The distribution data provided in Table 1, coupled with appropriate dose conversion factors (32), were used according to the MIRD schema (27,28,32,33) in the calculation of absorbed dose estimates for the various organs, with inclusion of contributions from contaminants (Tables 3 and 4). The effective dose is 0.155 mSv/MBq (0.57 rem/mCi) for the contaminant levels in Table 3 and 0.162 mSv/MBq (0.60 rem/mCi) for the contaminant levels in Table 4. Radiation dose estimates to the testes of children were determined by applying the new adult activity–time integrals generated in this work to the mathematical phantoms representing children of various ages (34) and using the MIRDOSE software (32). The results are presented in Table 5.

DISCUSSION

As shown in Table 2, the 24-h percentage uptake of ²⁰¹Tl in the testes reported in the literature covers an extended range (0.15%–1.1%). The values determined in the current study (0.3%) fall toward the lower end of this range in basic agreement with estimates by Atkins et al. (14), Krahwinkel et al. (17), Rao et al. (23), and Nettleton et al. (24). This suggests that the values given by Gupta et al. (21) and Hosain and Hosain (22) that are used in the ICRP dosimetry (19,20) overestimate testicular uptake and consequently lead to an overestimation of dose. The radiation dose per unit administered activity to adult testes calculated in this study of 0.21 mGy/MBq is approximately a factor of 2 less than the value of 0.45 mGy/MBq currently quoted within ICRP Publication 80 (20). In addition, as shown in Table 5, when testicular radiation dose is extrapolated to children, the ICRP values are about 2.5 times higher than the estimates provided in this report. However, of importance is the fact that the testes dose per administered activity for children increases significantly as age decreases, with a value of 7.5 mGy/MBq for a newborn. This potential for increased radiation dose at younger ages should be taken into consideration before performing procedures on children.

It is recognized that the calculated testicular dose in the current study may represent an overestimate, since the image-based data acquisition cannot differentiate testicular uptake alone from uptake in the surrounding tissues (scrotum and epididymis). Data by Hosain and Hosain in animals (22) indicate that the uptake in the testes becomes greater than that in the surrounding tissues within hours, with the activity accumulating predominately in the testes. The data of Nettleton et al. (24) for the excised testes show a lower uptake (0.19% vs. 0.30%) that might be indicative of the lack of contribution from surrounding tissues in vivo (Table 2); however, as the testes mass involved was below the normal standard, the lower percentage uptake would be due in part to this factor. Thus, if there is any overestimate in the testicular dose in this report, it is considered to be <30%.

The dose estimates provided here and in most publications are based on standard physical considerations (emission energy, geometry) and biologic clearance without taking into account possible effects of nonuniform energy distribution within the testes by low-energy electrons or enhancement factors such as relative biological effectiveness (RBE). An RBE constituting a 2- to 4-fold enhancement associated with the effect of Auger electron emission on spermatogonia has been found in mice administered ²⁰²Tl chloride via intratesticular injection (26). As noted, neither small-scale dosimetry considerations nor RBE effects are considered in this study. However, RBE effects as they ultimately may influence the interpretation and application of physical dose estimates represent an important area worthy of continuing investigation.

As shown by comparison of Tables 3 and 4, with increasing shelf life there is a progressive increase in radiation dose from the ²⁰²Tl contaminant due to its longer half-life. This contaminant is shown to contribute up to 20% of the total radiation dose to some organs under the delayed administration scenario. However, these conditions result in only about a 10% contribution to the effective dose. Dose estimates at intermediate times between calibration and 5 d may be obtained by interpolation.

The radiation-absorbed doses for an extended list of organs have been recalculated from the published biologic data and are in reasonable agreement with those of most authors (Table 6). The differences relative to those provided by Krahwinkel et al. (17) may be attributed to a modeling error in their analysis for the dosimetry, although the biokinetic data presented are considered sound. The current estimates differ from those in ICRP Publications 53 and 80 (19,20) for bone and marrow due to the fact that activity was not assigned directly to marrow as done by the ICRP task group. In addition, it is noted that the dose estimates here are nearly identical to those in NUREG/CR-6345 (35) as they were also based on the Krahwinkel biokinetic data and the testicular uptake data reported here and were calculated using standard techniques equivalent to those described in this report.

CONCLUSION

The radiation dosimetry of ²⁰¹Tl-thallous chloride has been revised introducing new data specifically acquired to address the issue of testicular uptake of this agent and reevaluating the extant data on biodistribution in other organs. It is recommended that the dose value determined through this study be used when estimating the radiation dose to the adult testes from intravenous administration of ²⁰¹Tl-thallous chloride (0.21 mGy/MBq) as opposed to the higher values currently quoted (0.45 mGy/MBq; ICRP Publication 80 (20)). The potential for increased radiation dose per administered activity to the testes at younger ages should be evaluated before performing procedures on children. The presence of radiocontaminants in the product should be considered when estimating radiation dose and may add a significant contribution to dose dependent on the specific radionuclide and concentration at the time of administration.