Gadolinium (Gd) is commonly used in contrast agents (GBCAs) to improve magnetic resonance imaging. GBCAs improve tumor imaging and were thought to be stable and clear from the body through excretion after administration. However, they have been found to dissociate and remain in organs such as the liver and kidneys. In these studies, a non-invasive Cd-109 based K x-ray fluorescence (K-XRF) “Clover-Leaf” detection system to study liver and kidney Gd levels was investigated to improve the minimum detection limit (MDL). Two Cd-109 sources, one with a relatively low activity of 0.78 GBq and a second high activity source of 5 GBq irradiated a human torso water phantom containing liver and kidney phantoms with Gd concentrations ranging from 0-100 ppm. The MDL was calculated from two different time measurements 5 hours (weak source) and 30 minutes (strong source). In addition, liver and kidney phantom measurements with overlaying tissue thicknesses from 6-26 mm were investigated. At present, the K-XRF detection system is able to detect the Gd in each phantom with both sources. The MDL for the liver and kidney with the weaker source is 2.95 ppm and 3.60 ppm, respectively. The MDL for the stronger source is 3.61 ppm and 3.87 ppm, respectively. The overlaying tissue thickness MDLs decreased exponentially since the thickness increased which increases the scattering and attenuation. Simulations with MCNP successfully modelled the experiments. MCNP simulations of the kidney with varying Gd concentrations in the cortex and medulla suggest that the XRF measurement is not sensitive to the Gd distribution in the phantom. To conclude, this detection system can measure Gd in liver and kidney phantoms and has low MDLs. Future work should focus on varying the detection capabilities, measuring the effects to the organs at risk, possible clinical trials, and improving the MCNP model and peak extraction. / Thesis / Master of Science (MSc)

L’utilisation de plus en plus fréquente des agents de contraste à base de Gd (AC-Gd) au cours des examens d’Imagerie par Résonnance Magnétique (IRM), engendre le rejet de ces produits pharmaceutiques dans les eaux usées retraitées en STation d’EPuration (STEP). En l’absence de retraitement spécifique de ces AC-Gd en STEP, ils sont rejetés dans le milieu aquatique, où de nombreuses études ont relevé leur présence aussi bien dans les eaux de surface que dans les eaux souterraines et jusqu’à l’eau du robinet. Le manque de connaissances concernant les effets des AC-Gd suite à leur rejet a mis en évidence la nécessité d’étudier leurs impacts environnementaux sur les organismes vivants dans les milieux aquatiques. Dans ce contexte, nous avons choisi de déterminer les concentrations en Gd d’origine anthropique à proximité de rejets de STEP et de zones de captage en eau potable situés en région Lorraine. Nos mesures ont permis de montrer la présence Gd d’origine anthropique sur l’ensemble des échantillons prélevés, avec des concentrations mesurées comprises de quelques ng(Gd)/L à quelques dizaines de µg(Gd)/L. Ces concentrations de Gd anthropique seraient dues à la présence d’AC-Gd. Nous nous sommes plus particulièrement intéressés aux effets de l’AC-Gd le plus stable et l’un des plus fréquemment commercialisé : le Gd-DOTA (Dotarem®). Pour cela, nous avons choisis plusieurs espèces représentatives des taxons rencontrés dans les cours d’eau Lorrains. Des essais ont été menés en conditions contrôlées de laboratoire afin de mesurer l’accumulation du Gd-DOTA dans les tissus et les effets de l’AC-Gd ont été appréhendés au travers de mesures de croissance, de reproduction et de mortalité au niveau individuel chez les microalgues vertes unicellulaires (Chlorella vulgaris et Pseudokirchneriella subcapitata), chez un microcrustacé (Daphnia magna) et chez un vertébré aquatique (Danio rerio) exposés à des concentrations en Gd-DOTA réalistes d’un point de vue environnemental. L’accumulation du Gd-DOTA a aussi été mesurée chez les bivalves (Corbicula fluminea et Dresseina rostriformis bugensis) et comparée à des mesures d’accumulation du Gd in situ. Les réponses physiologiques des bivalves ont été évaluées à l’aide d’une batterie de 11 biomarqueurs dans leurs branchies et leur glande digestive. Les effets de l’AC-Gd ont également été étudiés in vitro sur des fibroblastes de D. rerio (cellules ZF4 - ATCC-2050). Nos travaux ont montré que les AC-Gd et le Gd-DOTA en particulier étaient responsables d’effets écotoxiques indirects à différents niveaux d’organisation biologiques. Seuls les bivalves accumulent le Gd-DOTA mais tous les individus semblent mettre en place des mécanismes de dépuration pour parer à la toxicité de l’AC-Gd. Les résultats obtenus au cours de cette recherche ont confirmé la nécessité d’un suivi des concentrations en AC-Gd dans le milieu aquatique et la nécessité d’approfondir les études de l’écotoxicité de ces produits pharmaceutiques. Ceci pourra aboutir à une évaluation pertinente de leur risque environnemental et de proposer des solutions pour la gestion environnementale de ces composés / The increasing use of Gadolinium-based Contrast Agents (Gd-CA) for Magnetic Resonance Imaging (MRI) results in their rejection in Waste Water Treatment Plants (WWTPs). Due to the lack of specific recycling process in European WWTPs, these pharmaceutical produces enter the aquatic environment from river to tap water. The effects of Gd-CA in aquatic media have been not studied yet. The lack of knowledge about these effects highlighted the need to study their environmental impacts on aquatic organisms. In this context, we decided to measure anthropogenic concentrations of Gd in the aquatic environment in the Lorraine region (France) closed to WWTPs outputs and catchment areas used for drinking water. Our measurements underlined the presence of anthropogenic Gd on all the collected samples at concentrations ranging from few ng/L to several dozen of µg/L. In this research we focused on the effects of the most frequently used Gd-CA, the gadoteric acid (Gd-DOTA - Dotarem®) which is also the most stable one. Several representative species of aquatic environment were selected for ecotoxicological assays: i.e. unicellular green microalgae (Chlorella vulgaris and Pseudokirchneriella subcapitata), microcrustacean (Daphnia magna) and aquatic vertebrate (Danio rerio). Assays were conducted in laboratory under controlled conditions as well as in situ. Gd-DOTA accumulation was measured in the tissues of the different organisms. Environmental realistic concentrations of Gd-CA were used to assess their effects at the individual level by means of growth, reproduction and mortality measurements. The Gd-DOTA accumulation was also measured in bivalves’ tissues (Corbicula fluminea and Dresseina rostriformis bugensis) and compared to Gd ones in situ in these organisms. Physiological responses were assessed based on a battery of 11 complementary biomarkers measured in the digestive gland and in the gills of both bivalve species. At cellular level, the effects of Gd-DOTA were studied in vitro on D. rerio fibroblasts (ZF4 – ATCC-2050). Indirect ecotoxicological effects of Gd-CA and of Gd-DOTA especially have been highlighted at all biological levels. Accumulation of Gd-DOTA was observed in bivalves only, but defense systems were mobilized in all organisms to limit toxicity. Our results demonstrated that following both research on ecotoxicological effects of the Gd-CA and evolution of their concentrations in aquatic ecosystem are necessary to assess more precisely their environmental risk and to propose solutions for their environmental management

Gadolinium-based contrast agents (GBCAs) are in widespread use to enhance magnetic resonance angiography images for evaluating vascular pathology. However, there are safety concerns and limitations regarding the use of GBCAs. It has been shown that the magnetic resonance imaging (MRI) signal intensity (T1-weighted images) in some of the brain's tissues is higher for patients who had multiple exposures to GBCAs compared to patients who had never had exposure to GBCAs. This implies that GBCAs are not sufficiently removed from body such that GBCAs may potentially have long-term effects on the human body. These potential safety concerns have led to an increased interest in alternative contrast agents. Methemoglobin (metHb) and oxygen-free hemoglobin (HHb) are two forms of hemoglobin with paramagnetic properties. It has been shown that the T1-weighted signal intensity of blood is changed during MRI scans for metHb and HHb, leading to enhanced contrast of MRI images. The ability of metHb and HHb to change the signal intensity has led to the idea that they can be used as effective contrast agents. MetHb can be made by exposing oxyhemoglobin (oxyHb) to nitric oxide (NO) and HHb can be made by removing the oxygen from hemoglobin using nitrogen (N2). In this study, a new gas delivery system was developed to make metHb and HHb. The new gas delivery system was developed to have greater experimental control compared to the PermSelect hollow-fiber module that was used in preliminary studies to make metHb. The same system can be used to make HHb. Initial experiments showed significant amounts of undesired nitrite (NO2-) formation during metHb formation due to the presence of contaminants in the NO gas source. To minimize this problem, flow of NO from the gas source was bubbled in a sodium hydroxide solution in order to reduce the NO2- concentration. Following metHb formation, continuous delivery of NO also led to the formation of ferrous nitrosyl hemoglobin (HbIINO). MRI studies showed that HbIINO can also increase the signal intensity of an MRI image. It is unknown as to whether metHb, HHb, or HbIINO would be a stronger and more appropriate contrast agent and to what extent the T1-weighted signal is affected by the concentration. This study evaluated T1-weighted images of blood samples over a range of metHb and HHb concentrations, as well as HbIINO concentrations. Comparison of T1 values showed that metHb is the strongest contrast agent and that HHb is a relatively weak contrast agent. This study showed for the first time that HbIINO can provide a contrast effect, although not as strong as metHb but stronger than HHb. With metHb providing a viable contrast between 10-20%, metHb has the potential to be a safe and effective contrast agent since it can be naturally converted back to hemoglobin.