Small-Scale Dosimetry for the Testis: Applications in Nuclear Medicine Diagnostics and Therapy

Sammanfattning: Popular Abstract in English 111-Indium is a radioactive isotope that can be chemically linked to different molecules. When this compound is given to patients is distributed heterogeneously within the structures that build up the testicle. Different parts of the so-called germ cells are sensitive to radiation in different ways. Therefore, if a radioisotope that send out electrons with low energies and with short ranges are close to these sensitive parts then this part of the testis can receive high deposit energy and consequently a high risk for an effect as compared to if the energy are uniformly distributed over the whole testis volume. This local energy deposition may then result in temporary or permanent sterility of the patient. A general calculation procedure, called the MIRD-formalism, is often used to calculate the energy deposition to an organ (the absorbed dose). If the procedure is based on an assumption of an isotope that is distributed homogenous in the testis then this assumption may lead to either under-estimation or the opposite when considering local regions within the testis. To account for this problem in the calculation a more detailed model of the tissue structures and geometry is needed. In this work, we have developed such a small-scale model of the human testis. With this model there is possibility to calculate dose factors (so-called “S” values) for several source-to-target combinations and for radioisotopes that are commonly used in both diagnostic and therapeutic applications. This new testis model was used together with data obtained from a patient study where 111-Indium have been attached to an antibody called Zevalin® that is used to treat patients for cancer. The uptake of the isotope in the testes was estimated from images for different time points by the use of a special device called a scintillation camera. In the study, we also collected blood samples at various time points. By using a mathematical method that estimates the transport through different compartments we could separate the total amount of radioactivity in the testis into a vascular part and an extravascular part. By using a relevant distribution of the radioisotope within the testis and combine this with our calculated S values obtained from the new geometrical model, we could calculated the absorbed doses to different regions in the testis and also estimate the uncertainties associated with this calculation. With a special method called autoradiography the activity distribution in a mouse testis for both 111-InCl3 and 111-In attached to an antibody, called Rituximab, was revealed. This was made to verify our assumptions on how the activity was distributed in a human testis. In a study in rodents, we also developed a method that was able to detect double-strand breaks in the DNA of the germ cells from ionizing radiation from 111-InCl3. This was performed by use of a biomarker, called γH2AX, and with visualization equipment, called immunofluorescence laser confocal microscopy. Our results show that the absorbed dose to the sensitive parts of the testis that is called spermatogonia depends of the localization of the radioisotope. The absorbed dose as calculated by this new geometrical model might exceed the absorbed dose that is obtained by averaging over the whole testis by a factor of 1.6-2.3. This variation comes from natural geometric variations in the diameter of the, so-called, interstitial tubules in the male testis. For radioisotopes that send out electrons of low energy, such as is the case for 111-In, the localization of the radioisotope is, thus, essential because the absorbed dose to different targets in the testis may express large difference. This may affect the estimation of possible biological effects and other side effects related to ionizing radiation especially in cases for therapy using radioisotopes that emits radiation with a high intensity. Our results also indicate that the use of the γ-H2AX biomarker can be useful to detect DNA damages in the testicular germ cells as a result of ionizing radiation.