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Dans le cadre de la gestion des déchets nucléaires, les coques et embouts des gaines de combustibles sont coupées, compactées et empilés dans les colis CSD-C (Colis Standards de Déchets Compactés). Actuellement entreposés à la Hague, ces déchets seront stockés en milieu géologique profond dans des alvéoles en béton. Ces déchets MA-VL contiennent des RN d’intérêts dont le carbone-14 qui provient de l’activation neutronique de l’azote-14 et de l’oxygène-17 présents dans le Zircaloy. L’objectif de cette thèse, qui est menée en collaboration avec EDF et AREVA, est de répondre à la question du devenir et du comportement du carbone-14 dans ZrO₂ et Zr-métal. Cette thèse consistera à utiliser la simulation numérique, au moyen de la Théorie de la Fonctionnelle de la Densité (DFT), afin demodéliser le comportement du carbone-14 dans les CSD-C. Les simulations sont effectuées avec une approche multi-échelles : 1) Échelle atomique, optimisation de modèles atomiques permettant de représenter les différentes phases de ZrO₂ ; identification des différents sites d’insertion possibles pour l’atome de carbone en sites interstitiels et en substitutions à un atome d’oxygène ou de zirconium ; modélisation des différentes chemins d’énergie minimum associées à la migration d’un atome de carbone d’un site à un autre par mécanismes interstitiels et lacunaires. 2) Échelle macroscopique, détermination des coefficients de diffusion par la méthode Monte-Carlo dans ZrO₂ monoclinique pure et Zr pure. / As part of the nuclear waste management, hulls and ends of fuel claddings are cut, compacted and put in CSD-C containers (compacted standard waste containers). Currently stored at La Hague, the waste will be stored in deep geological environment. The MA-VL waste contains RN including carbon-14, which comes from the neutron activation of nitrogen-14 and oxygen-17 present in the oxide Zircaloy. The objective of this thesis, which is taken in collaboration with EDF and AREVA, is to answer the question of the carbon-14 behavior in ZrO₂ and Zr metal. This thesis is to perform numerical simulations, using the Theory of Density Functional (DFT) to model the behavior of carbon-14 in the CSD-C. The simulations are performed with multi-scale approach: 1) At atomic scale, optimization of atomic models to represent the different phases of ZrO₂; identification of the insertion sites for the carbon atom in interstitial sites and substitutions of an oxygen or zirconium atom; modeling different minimum energy path for the migration of a carbon atom from one site to another by interstitial and vacancye mechanisms. 2) At macroscopic scale, determination of diffusion coefficients in pure bulk monoclinic ZrO₂ and pure bulk Zr by the Monte Carlo method.

Le marquage radioisotopique est un domaine d’intérêt d’un point de vue de la recherche fondamentale en santé et, de par ses nombreuses applications, aussi bien en industrie pharmaceutique et agrochimique que dans le milieu académique. Dans ce contexte, le carbone-14 joue un rôle primordial dans le développement de nouvelles drogues et dans les études ADME et toxicologiques. Les voies de synthèse traditionnelles impliquant le ¹⁴C sont longues et multi-étapes ce qui entrave la viabilité de cette stratégie. L’objectif de cette thèse est de développer de nouvelles techniques de radiomarquage par échange isotopique. Dans un premier temps, nos efforts se sont portés sur le développement d’un échange d’isotopes du carbone (EIC) dynamique entre le ¹³CO₂ ou le ¹⁴CO₂, une source fondamentale et facile d’accès de carbone radioactifs et des acides carboxyliques (hétéro)aromatiques par le biais d’une catalyse au cuivre. Le concept de EIC a ensuite été appliqué à d’autres fonctions, présentes dans de nombreux agents pharmaceutiques, les acides phénylacétiques. Une nouvelle approche, sans métaux de transition, a pu être décrite, permettant d’effectuer le marquage avec le ¹³CO₂, le ¹⁴CO₂ et le ¹¹CO₂. Enfin, un autre EIC faisant intervenir le cyanure comme source primaire de carbone radioactif a été conçu. Le développement de l’EIC a permis d’étendre le concept de marquage en dernière étape de synthèse à des substrats contenant une fonction nitrile ou acide carboxylique, en réduisant les coûts et en limitant la génération de déchets radioactifs. Ce concept, encore en voie de développement, offre des alternatives aux méthodes existantes. / Radioisotope labeling is a relevant topic both from a fundament research perspective and for health applications in academy and pharmaceutical and agrochemical industries. In this context, carbon-14 plays a basic role in drug development and ADME and toxicological studies. Traditional synthesis with radiocarbon (¹⁴C), based on lengthy and multistep approaches, have hampered the sustainable of the strategy. The aim of this thesis is to develop novel labeling techniques by isotope exchange. At first, our efforts were focused on the developement of a copper catalyzed dynamic carbon isotope exchange (CIE) using ¹³CO₂ and ¹⁴CO₂, a fundamental and readily available source of radiocarbon on (hetero)aromatic carboxylic acids. The concept of CIE was further extent to another relevant drug scaffolds such as phenyl acetic acids. Hence, it was described a transition metal-free approach able to exchange ¹³CO₂, le ¹⁴CO₂ and ¹¹CO₂, to the best of our knowledge this would be the first example. At last, another CIE with a different primary radiocarbon source such as cyanyde was envisioned. CIE technology expands the concept of late-stage carbon radiolabeling, with substrates bearing carboxylic acid and nitrile moieties, reducing the synthetic costs and limiting the generation of radioactive waste. This new process is still at its infancy and more work need to be done.

Human milk contains ~ 25 µg/mL of soluble cluster of differentiation 14 (sCD14) protein, a pattern recognition receptor (PRR) that triggers the innate immune system to respond to bacterial lipopolysaccharide (LPS). To date, the role of CD14 in the digestive tract of breast fed infants has not been well characterized and is the subject of this thesis. To investigate the biodistribution of proteins such as CD14 in vivo, a novel method for 14C radiolabeling of proteins to high specific radioactivity was developed using in vacuo methylation. Bovine serum albumin (BSA) and casein were used as test proteins to determine the following: 1) The efficacy of the in vacuo radiolabeling procedure; 2) The extent of incorporation of the 14C-label into the organs of oro-gastric gavaged 10 day old Sprague Dawley rats. [14C]BSA, [14C]casein and [14C]CD14 were prepared with specific radioactivities of 10 400, 10 800 and 163 000 dpm/µg, respectively. After feeding 6.25 µg of 14C-labeled proteins, quantifiable levels of 14C were found in the stomach, jejunum, duodenum, ileum, large intestine, intestinal luminal flushes, blood, liver, spleen and kidneys of rats. The accumulation of radiolabel in the organs of [14C]CD14 fed rats was temporally and spatially distinct from [14C]BSA and [14C]casein. Most notably, the label persisted in the stomach 480 min post-gavage. To design a neonate animal model for biodistribution, the segmental and total gastrointestinal transit times (GItt) were measured in two litters of 10 and 15 day old Sprague Dawley rat pups using barium sulfate. Ten day old rat pups that remained with and without the dam had a total gastrointestinal transit time of 13.8 ± 0.9 hr and 9.3 ± 0.7 hr, respectively. This decrease (p<0.05) in total gastrointestinal transit time in the absence of the dam was age dependent, as it was not observed (p>0.05) in the 15 day old rat pup litter. The immunological impact of an exogenous sCD14 source was examined in human peripheral blood mononuclear cells (PBMC). Pre-treatment of CD14+ monocytes with sCD14 had a protective effect, one of reducing the production of proinflammatory cytokines (TNF-α, IL-6, IL-8, IL-1β) when challenged with LPS. 14C was absorbed by neonate rats upon ingestion of [14C]CD14 and exposure to relatively high concentrations of rCD14 led to a reduction in inflammation. This may be beneficial to initial gut colonization in breast-fed newborns. / Alexander Graham Bell NSERC CGS M scholarship. Japan Society for the Promotion of Sciences, Summer in Japan Fellowship. Funded by the Canadian Institutes of Health Research, Institute of Nutrition Metabolism and Diabetes Grant #82816 “Fate and function of breast milk and recombinant human CD14 at mammary and newborn gastrointestinal mucosal epithelia”.

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