Human Lymphocytes Exposed to Co Irradiations and I Decays

Human Lymphocytes Exposed to Co Irradiations and I DecaysChapter 1 Introduction1.1. Microdosimetry hassle statementNuclear medicine and molecular imaging uptake unsealed radionuclides for diagnostic or therapeutic purposes. In targeted radiotherapy, the aim is to address tumor cells victimisation suitable radiopharmaceuticals and achieve a high battery-acid deposition inside the target structures. Macrodosimetry generally entails estimating the dose effect in organs (or dimensions of at to the lowest degree some millimeters) and is outlined in detail by the Medical Internal Dose (MIRD) Committee, the U.S. Society of Nuclear Medicine and the International Commission of Radiological protection (ICRP) 1. Microdosimetry therefore entails estimating the dose enwrapped in microscopic objects such as cells. Dose deposition in cells can originate from extracellular media, intracellular wasting disease in a single cell and from surrounding cells.As an alternative to characteristic pho ton emissions,radionuclides roting by electron capture or internal conversionmay undergo a dish known as the Auger effect. In the Auger effect, an electron from an outer shell fills the lower electron vacancy, but the energy released in the process is transferred to another orbital electron. This electron is then emitted from the atom instead of a characteristic X-ray 2. The emitted electron is called an Auger electron,with ranges in tissue typically at the micro- or nanometer level 3.Their unique property of depositing significant amounts of energy in minute volumes around the decay site opens up the possibility of victimisation them as microscopic probes to study fundamental questions regarding the interaction of radiation with cells.123I is used mainly in nuclear medicine because of its ideal -ray energy (159 keV) and relatively rook half-life (13.2 h). The decay of 123I is, however, also associated with the production of Auger electrons. These low energy particles (4.Knowled ge of the absorbed dose is required for evaluation of the observed biologic effectuate and to predict or compare the effectiveness of different radiation modalities. However, rent dose measurements in cells are impossible due to the small cellular dimensions 5. agree to the stochastic character of all of the decay processes, a large number of pathways exist by means of which a radioactive particle can decay and the excited atom can de-excite, i.e. each initial inner shell vacancy may cause a different number of Auger electrons to be emitted resulting in a more or less broad distribution of differently charged ions. Because these electron transitions and particle interactions are random processes, the Monte Carlo proficiency is an appropriate tool for the color of Auger emissions and electron spectra, as well as a feasible method to obtain correct absorbed dose determine under consideration of all irradiation aspects like geometry and activity distributions 5,6, 7. Bingham et al . found that the dose delivered to the cell nucleus is underestimated by a factor of 7.4 for 123I in cells with nuclear radius of 4 m and cell radius of 12 m when compared to conventional electron dosimetry, indicating the need of developing dosimetric calculations for electrons emission at a cellular level 8.Geant4 is an open source Monte Carlo (MC) toolkit, based on object orientated programming rules using the C++ language, which provides functions for simulating the passage of particles through bailiwick 9. The code is freely downloadable from the Geant4 web site. Detailed descriptions of the toolkit design and the physical fundamentals may be found in the Geant4 Users Guide for action Developers and the Physics Reference Manual 10, 11. Besides the fact that it is entirely open-source and freely available to all users, the main advantage of this toolkit is its receptiveness to modification and extensions. earlier Geant4 comes from high-energy physics but it also provides low- energy physics processes necessary for medical applications. Users may construct stand-alone applications or applications built upon another object-oriented framework. In either case the toolkit offers support from the initial problem definition to the production of results and graphics for publication. At the heart of Geant4 is an abundant set of physics models to handle the interactions of particles with matter crosswise a very wide energy range. Data and expertise have been drawn from many sources around the world,and in this respect Geant4 acts as a secretaire which incorporates a large part of all that is known about particle interactions12. All aspects of the simulation process have been included in the toolkit the geometry of the system, the substantives involved,the fundamental particles of interest, the contemporaries of primary feather events, the tracking of particles through materials and electromagnetic fields, the physics processes governing particle interactions, the response of sensitive sensor components, the generation of event data,the storage of events and tracks, the visualization of the detector and particle trajectories, and the capture and analysis of simulation data at different levels of detail and refinement.1.2. Objectives AimsThe level of biological effects of certain radiations is not always instantaneously proportional to the dose they impart. Since the delivered dose on a cellular level is not directly measurable using current instrumentation, scientists and physicians have developed correlations amongst the biological response and the exposed dose through experiment and theory of atomic physics. An alternative method of predicting the delivered dose in a cell is by using Monte Carlo simulations. These simulations however, have to describe the biological composition and geometries of the material as accurately as possible, as well as the interactions of different particles with the material and can therefore result in c omplex codes and extremely long computation times.In our study, the aim was to determine (through experiments and using Monte Carlo simulations) the relative biological effectiveness1 (RBE) of isolated and stimulated valet lymphocytes exposed to 60Co irradiations and 123I decays.The first phase of experiments was the exposure of 3 different types of cellsto a 60Co-teletherapy unit. The proposed cell lines were human lymphocytes, rat brain endothelial cells(bEND5, a cell with high radiosensitivity) andChinese hamster ovarian cells (CHO-K1, a cell with low radiosensitivity). The cells were exposed to graded doses of 60Co -radiation, after which they were cultured and the micronuclei formations in binucleated cells were used to tumble the effects of -radiation on the cell types.The second phase of experiments was the exposure of a known number of isolated and stimulatedhuman lymphocytes to certain activities of 123I for a discrete amount of time. The deoxythymidine analogue 5-123I-io do-2-deoxyuridine (123IUdR) was prepared and used to incorporate123I into theDNA of human lymphocytes. This was done such that the radionuclide could be transported across the cell and nuclear membrane to permit the deposition of Auger and Coster-Kronigelectrons in close proximity to cellular DNA. After exposure, the samples werecultured to express residual radiation damage. The cellular damage was quantified by numerating the micronuclei (MNi) frequency in binucleated (BN) cells.The experiments were done at iThemba LABS under the supervision and guidance of Prof. Slabbert and Philip Beukes.The experimental work followed the same approach as that of Slabbert, et al13. In the study they focused on the targeting and accumulation of 123I in human lymphocytes and CHO-K1 (a Chinese hamster ovary cell line). They found that the combined effect of intracellular and extracellular disintegrations of 123I is about 3.7 times more potent to lymphocytes compared to when the disintegration of the radionuclide is restricted to only the extracellular medium, among other results. It was concluded that this enhancement is due to the short range Auger electrons emitted by the isotope.Next, we wished to recreate the above experiments through Monte Carlo simulations and thereby determine as accurately as possible the absorbed energy and dose due to the irradiations,specifically the energy and dose deposited by Auger electrons produced during the decay of 123I. We will make use of a Monte Carlo based simulation code Geant4. The code must be mastered and used to simulate the scenarios mentioned above.We attempted to simulate the above 60Co exposures. This simulation was an investigation into the irradiation of a macroscopic volume by a radioactive source. The geometry was set up to replicate the experimental setup with regards to the source repair and type, collimation, build-up and backscatter, the Petri dish and cellular media. The individual cells were not used as detectors, onl y the effective volume in the Petri dish. The energy and the dose deposited by the 60Co source (-rays, primary and secondary electrons) was then quantified by the Monte Carlo simulation.Our main endeavor was to simulate the energy deposition from the decay of 123I within a cell using Geant4. Basically, a geometry representing a biologicalcell (with the same density, etc. as the proposed lymphocytes) was created as a detector to measure the dose, energy and particles traversing it due to a radionuclide prone to emit Auger electrons, i.e. 123I. A similar simulation was performed by Bousis, et al (2012), using their in-house Monte Carlo code 14. More advanced simulations are the calculation of DNA strand breaks due to direct and indirect effects of Auger electrons as was demonstrated by Raisali, et al (2013), which werehowever not attempted in this investigation 15, 16, 17.Furthermore, an empirical formula relating the activity(and consequently the absorbed dose) to the biological resp onse was determined. The curveswere compared to other dose-response curves from literature, thereby indicating if the simulations are a viable option for predicting accurate dose depositions. We could then calculate the RBE values from our dose-response curves and compare them to values available in literature.Finally, we aimed to determine the accuracy and feasibility of Geant4 as a simulation toolkit for medical and radiobiological purposes. To this end we considered the practicality, effort and time spent using Geant4, as well as by the comparison of RBE values and dose-response curves.Geant4 is an advanced, extensive and comprehensive simulation toolkit. Its advantage over similar packages with regards to availability, artistic and geometric freedom, physics models and materials libraries and openness to modification are undeniable. It is a very powerful simulation toolkit and can be used in a large number of areas of expertise as is shown by the examples supplied alongside the toolkit.1RBE values indicate the effectiveness of two radiation qualities to produce a certain biological response.