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Basic in vitro cell experiments were conducted on the P388 mouse leukaemia cell line to determine whether a supra-additive cell killing effect from combining hyperthermia with ionising radiation exists in the case of leukaemia. Methods were established to measure the cell kill, using a Coulter counter, from hyperthermia alone, radiation alone and several combined regimes. The cell kill from hyperthermia, in the range of 38-50 degrees for 30 minutes, 1 hour, 2 hours and 3 hours, and radiation, for 1, 3, 5, 9, 11 and 15 Gy was investigated. The approach used had various limitations, such as the underestimation of cell kill. Consistent trends, however, were found for the hyperthermia and radiation data, in accordance with the literature, which killed cells in a predictable manner. Subsequently, after other preliminary combined experiments were completed, the cell kill from both 5 and 11 Gy combined with hyperthermia at 43, 45 and 47 degrees for 2 hours were investigated. 5 Gy in combination with all levels of hyperthermia resulted in a direct additive cell killing effect. This, however, was not observed for 11 Gy in which a diminished effect was found. The overall level of cell kill from 5 Gy combined with hyperthermia was found to be equal, in the case of 43 degrees, or higher, as for 45 and 47 degrees, to that of those combined with 11 Gy. A supra-additive effect was not observed.

Telomeres are physical ends of chromosomes consisting of (TTAGGG)n DNA sequence and a specialized set of proteins that protect chromosomal ends from degradation and from eliciting DNA damage response. These specialized set of proteins, known as shelterin, directly bind to telomeric DNA. In addition, some DNA double-strand break (DSB) repair proteins such as, DNA-PKcs and KU70/80, play active roles in telomere maintenance. Mouse knock-out experiments have revealed that deletion of either DNA-PKcs or Ku70/80 resulted in elevated levels of telomeric fusion, indicative of dysfunctional telomeres. Artemis protein is involved in DNA DSB repair through non-homologous end joining (NHEJ) and it is phosphorylated by DNAPKcs. Human cells defective in Artemis have been identified and shown to be radiosensitive and patients with an Artemis defective gene suffer from radiosensitive severe-combined immune deficiency syndrome (RS-SCID). Mouse cells defective in Artemis have elevated levels of telomeric fusion. We have demonstrated in this thesis that Artemis defective human cell lines show a mild telomeric dysfunction phenotype detectable at the cytological level. The nature of telomere dysfunction phenotype appears to be similar to that observed in DNAPKcs defective cells as exemplified by the presence of IR induced chromatid telomeric fusions. We have also shown that (a) DNA damage occurring within the telomeric DNA is difficult to repair or irreparable in older cells and that (b) Artemis defective older cells show higher proportion of DNA damage at telomeres than their normal counterparts. Finally, we have demonstrated that inhibition of DNA-PKcs causes (a) an increase in telomeric fusions in Artemis defective cell lines relative to both normal cell lines after inhibition and Artemis cell lines before inhibition and (b)elevated levels of DNA damage at telomeres following exposure of cells to radiation relative to both irradiated normal cells exposed to a DNA-PKcs inhibitor and irradiated Artemis defective cells but not exposed to the DNA-PKcs inhibitor. These results suggest that the effects of Artemis and DNA-PKcs on telomeres are cumulative. We have also performed (a) experiments to examine telomere function in Artemis defective cell lines after knocking down DNA-PKcs levels by RNAi and b) preliminary experiments to knock-down Artemis in DNA-PKcs defective cells. Taken together, our results suggest that the Artemis defect causes mild telomere dysfunction phenotype in human cells.

By dosimetric, radiometric research and by modelling the formation of exposure dose in the air layer close to the ground surface, by a set of experiments in the urbanised and non-urbanised environment it was identified that man while building houses, digging quarries, building roads etc., changes the intensity of natural ionising radiation at the same time changing the distribution of natural radionuclides. While identifying that: ·the ionising radiation changes due to anthropogenic activities, caused by natural radionuclides, were evaluated. ·the methodology of dosimetric research using global positioning system (GPS) was improved. ·a computer model was created with the help of which it is possible to evaluate the change of ionising radiation, moving away from or approaching different buildings.

Basic in vitro cell experiments were conducted on the P388 mouse leukaemia cell line to determine whether a supra-additive cell killing effect from combining hyperthermia with ionising radiation exists in the case of leukaemia. Methods were established to measure the cell kill, using a Coulter counter, from hyperthermia alone, radiation alone and several combined regimes. The cell kill from hyperthermia, in the range of 38-50 degrees for 30 minutes, 1 hour, 2 hours and 3 hours, and radiation, for 1, 3, 5, 9, 11 and 15 Gy was investigated. The approach used had various limitations, such as the underestimation of cell kill. Consistent trends, however, were found for the hyperthermia and radiation data, in accordance with the literature, which killed cells in a predictable manner. Subsequently, after other preliminary combined experiments were completed, the cell kill from both 5 and 11 Gy combined with hyperthermia at 43, 45 and 47 degrees for 2 hours were investigated. 5 Gy in combination with all levels of hyperthermia resulted in a direct additive cell killing effect. This, however, was not observed for 11 Gy in which a diminished effect was found. The overall level of cell kill from 5 Gy combined with hyperthermia was found to be equal, in the case of 43 degrees, or higher, as for 45 and 47 degrees, to that of those combined with 11 Gy. A supra-additive effect was not observed.

The problem I am dealing with in the diploma thesis : Processing of education schedule the areas: {\clqq}Dosimetry of ionising radiation``, {\clqq}Clinical dosimetry``, is connected with a creating of practical internet applications of formal training of university´s students. To design certain applications which would tend to be more effective in teaching and would lead to easier understading of given curriculum is the main aim of this work. It also concerns a didactic approach to teaching the subjects, such as: {\clqq}Dosimetry of ionising radiation``, {\clqq}Clinical dosimetry``, which is included in curriculum of Bachelor and Master degree studies in the Department of Radiology and Toxicology at University of South Bohemia České Budějovice. The important component of the thesis is a teaching program which is accesible also on the web side : http://www.lestinas.webzdarma.cz

Résumé : L’objectif de la thèse est de considérer différentes sources de biais dans l’analyse du risque de cancer associé à l’exposition externe aux rayonnements ionisants dans la cohorte CEA-AREVA-EDF de travailleurs du nucléaire. Cette cohorte inclut 59004 salariés de ces entreprises surveillés pour une exposition externe aux rayonnements ionisants. La dose externe cumulée des travailleurs a été reconstituée sur la base des résultats de leurs dosimètres individuels. Le premier axe a étudié la possible exposition des travailleurs à l’incorporation de radionucléides. En l’absence de données individuelles, un indicateur basé sur les unités de travail a été défini pour attribuer un niveau de risque de contamination interne à chaque travailleur et a été intégré aux analyses du risque de mortalité par cancer lié aux expositions externes.Le second axe a porté sur les expositions non professionnelles des travailleurs aux rayonnements ionisants, notamment l’exposition environnementale d’origine naturelle et l’exposition médicale due aux examens radiologiques réalisés dans le cadre de la médecine du travail. Des scénarios de doses dues à ces expositions ont été établis, et l’impact de la prise en compte de ces expositions sur le risque de mortalité par cancer a été étudié. Le troisième axe a porté sur les seuils d’enregistrement des dosimètres. Sous ces seuils, les doses sont mal quantifiées. Par le passé, les doses sous le seuil étaient enregistrées comme nulles, entraînant une sous-estimation de la dose reçue. Un historique complet des pratiques dosimétriques dans la cohorte a été réalisé et a permis la création de scenarios d’imputation des doses sous seuil. / The aim of the thesis is to study three potential sources of bias in the analyses on the cancer risk associated with chronic external exposure to low doses of ionizing radiation in the CEA-AREVA-EDF cohort. This cohort includes 59 004 nuclear workers from those companies who were badge-monitored for external exposure to radiation. The first part of this thesis is devoted to potential internal exposure to radionuclides among the workers. Given the lack of available individual data on internal contaminations, a flag attributing for each worker and for each year a potential contamination risk based on workstations was defined and added to the analyses on cancer mortality risk associated with external radiation exposure. The second part of this work focuses on non-occupational exposures to radiation.Nuclear workers are exposed to radiation from environmental and medical sources, in particular from radiological examinations carried out in an occupational health framework. Scenarios characterising non-occupational exposures to radiation were constructed and their impact on the cancer mortality risk associated with occupational exposure was examined. The third part of this thesis addresses dosimeters recording thresholds. Below those thresholds, dose quantification is deemed too imprecise. Historically, below the threshold doses were recorded as null, resulting in systemic dose underestimation. A comprehensive review of the dosimetry practices in the cohort was accomplished and led to the conception of scenarios aiming to impute below the threshold.

Current protection of the marine environment from radiation is based largely on measuring, estimating and modelling accumulation and impact(s) of radionuclides in a few marine species. Using a relevant marine organism, this thesis focusses on investigating some poorly described phenomena that could cause deviations from predicted measurements. Paper I investigated the biological transformation of tritium (radioactive hydrogen) into an organic compound. The resulting organically bound tritium (OBT) showed increased accumulation in mussels, unique incorporation into a key biological molecule (DNA), extended persistence in tissues, and greater toxicity than the inorganic form. Paper II demonstrated significant disparity in OBT accumulation between functionally similar microalgae species and that OBT in algae is readily transferred to a consumer. Highly radioactive particles are a complex issue in radioecology due to their concentrated dose geometry, potentially inducing very different impacts in organisms, compared to external irradiation. Paper III developed a method to introduce radioactive particles that would facilitate their recovery, improve dose-calculation, and aid the measurement of toxicological endpoints. It also showed that such particles can be incorporated into mussel tissues, causing significant effects. In Paper IV, hypoxia – another major ecological hazard in the marine environment – was expected to reduce radiosensitivity. The minimal observable effect from radiation prevented identification of such an interaction, and indicates drawbacks in the (otherwise sensitive) endpoints used. It appears that stressors like hypoxia may be more of a health hazard to marine organisms than environmental levels of ionising radiation. By understanding such causes of variation in accumulation and impact, it is possible to improve risk assessment, providing more justification for regulations chosen and minimising conservatism in setting environmental standards. / <p>At the time of doctoral defense, the following papers were not published and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript.</p>

By dosimetric, radiometric research and by modelling the formation of exposure dose in the air layer close to the ground surface, by a set of experiments in the urbanised and non-urbanised environment it was identified that man while building houses, digging quarries, building roads etc., changes the intensity of natural ionising radiation at the same time changing the distribution of natural radionuclides. While identifying that: ·the ionising radiation changes due to anthropogenic activities, caused by natural radionuclides, were evaluated. ·the methodology of dosimetric research using global positioning system (GPS) was improved. ·a computer model was created with the help of which it is possible to evaluate the change of ionising radiation, moving away from or approaching different buildings.

The effects of Sr90 beta radiation and Co60 gamma radiation on the operation of EEV buried channel charge coupled devices (CCDs) have been studied. This work was instigated by the need to qualify CCDs for the SLD vertex detector. However, the work is also relevant to other small signal, low noise applications. The results of the batch qualification are presented and the data base of ionising radiation effects on EEV CCDs has been extended to include the effects of irradiation whilst clocking at 180K. Particular attention has been aimed at investigating the charge transfer degradation due to low levels of bulk defects. The measured energy level, capture cross section and introduction rate of the main radiation induced defect agrees well with published results for the Si-E centre. Annealing studies are also presented. A model for the charge transfer degradation is proposed. This includes the effects of temperature, readout rate, signal density and irradiation type and energy. Observations are also presented on the effect of irradiation on the noise characteristics of the single stage output circuit. For low noise applications the output is run in buried channel mode. In this mode the increase in noise is dominated by the change in the operating point of the output MOSFET.