Radiation induced bystander effects have changed our understanding of the biological effects of ionizing radiations. The original assumption was that biological effects require direct damage to DNA. The bystander effect eliminated that requirement and has become one main stream in radiation research ever since first reported over 20 years ago. Most bystander studies to date have been carried out by using conventional single cell in vitro systems , 2D cell array and 3D tissue samples, which are useful tools to characterize basic cellular and molecular responses. But to reveal the complexity of radiation responses and cellular communication, live animal models have many advantages. In recent years, models such as C. elegans and Zebrafish have been utilized in bystander effects research. In the Loma Linda/TAMU experiment, a L1 larva C. elegans model was devloped to study the radiation bystander effects by irradiating single intestine cell nuclei with a microbeam of protons. Due to the stochastic nature of particle interactions with matter and changing stopping power when protons slow down, precise dosimetry in the target nucleus is a difficult problem. This research was undertaken to provide a detailed description of the energy deposition in the targeted and surrounding non-targeted cell nuclei, and to evaluate the probabilities of the non-targeted cell nucleus being irradiated. A low probability is required to exclude the possibility of radiation biological an effect in non-targeted cells is caused by scattered particles. Mathematical models of the microbeam system and the worm body were constructed in this research. Performing Monte Carlo simulations with computer code, Geant 4, this research provided dosimetry data in cell nuclei in different positions and Geant 4, this research provided dosimetry data in cell nuclei in different positions and probabilities of scattering to non-targeted cell nuclei in various microbeam collima- tor configurations. The data provided will be useful for future collimated microbeam design.

The historical narrative and our understanding about the low dose effects of radiation on the immune system has changed drastically from the beginning of the 20th century to now. A paradigm shift from the DNA target hit model to the one that also considers non-targeted effects (NTE) has attracted a lot of interest recently. Investigations to delineate mechanisms of NTE in the biological tissue have been carried out by various research groups where radiation induced genomic instability (RIGI), bystander effect (RIBE) and abscopal effect (AE) are the effects with most evidence available. This thesis addresses the question of whether low dose ionizing radiation (LDIR) stimulates or suppresses the immune system and how NTEs contribute to this immune modulation by adopting a two-pronged approach where first a narrative review constituting the introduction and literature review was performed followed by a systematic review using PRISMA guidelines to synthesize existing LDIR literature. This was prompted by our recent discovery that UVA photons are emitted by the irradiated cells and that these photons can trigger bystander effects in unirradiated recipients of these photons. Given the well-known association between UV radiation and the immune response, where these biphotons may pose as bystander signals potentiating processes in deep tissues as a consequence of ionising radiation, it is timely to revisit the field with a fresh lens. After reviewing various pathways and immune components that contribute to the beneficial and adverse effects induced by LDIR, it was found that these modulations can occur by way of NTE. However, the exact mechanistic underpinnings are still unclear and the literature examining low to medium dose effects of ionising radiation on the immune system is complex and controversial. Early work was compromised by lack of good dosimetry while later work mainly focuses on the involvement of immune responses in radiotherapy which typically uses high dose radiation. There is a lack of research in the LDIR/NTE field focussing on immune responses although bone marrow stem cells and lineages were critical in the identification and characterisation of NTE. This may be in part, a result of the difficulty of isolating NTE in whole organisms which are essential for good immune response studies. Models involving inter organism transmission of NTE are a promising route to overcome these issues. It is concluded that the simple question of whether LDIR stimulates or suppress the immune system is not as simple as initially hypothesized. An attempt was made to analyze if LDIR shifts the balance to immune suppression or enhancement via systematic review but, due to too many differences in the experimental methods in the current radiation and immune studies, a cookie-cutter answer was not possible. However, this thesis did point out the areas of concern such as lack of standardised tools in the field of radiobiological experimental research and quality of methods used which requires urgent attention. / Thesis / Master of Science (MSc)