Purpose To measure the levels of gadolinium present in the rat brain 1 and 20 weeks after dosing with contrast agent and to determine if there are any histopathologic sequelae. Materials and Methods The study was approved by the GE Global Research Center Institutional Animal Care and Use Committee. Absolute gadolinium levels were quantified in the blood and brains of rats 1 week after dosing and 20 weeks after dosing with up to 20 repeat doses of gadodiamide (cumulative dose, 12 mmol per kilogram of body weight) by using inductively coupled plasma-mass spectrometry. Treatment groups (n = 6 rats per group) included low-dosage and high-dosage gadodiamide and osmolality-matched saline controls. Brain sections were submitted (blinded) for standard toxicology assessment per Registry of Industrial Toxicology Animal data guidelines. Analysis of variance and Mann-Whitney U tests with post hoc correction were used to assess differences in absolute gadolinium levels and percentage of injected dose, respectively. Results Dose-dependent low levels of gadolinium were detected in the brain, a mean ± standard deviation of 2.49 nmol per gram of brain tissue ± 0.30 or 0.00019% of the injected dose 1 week after dosing. This diminished by approximately 50% (to 1.38 nmol per gram of brain tissue ± 0.10 or 0.00011% of the injected dose) 20 weeks after dosing. As a percentage of injected dose, the levels of gadolinium measured were comparable between different doses, indicating that mechanisms of uptake and elimination were not saturated at the tested doses. There were no histopathologic findings associated with the levels of gadolinium measured. Conclusion Low levels of gadolinium are present in the brain after repeat dosing with gadodiamide, which is partially cleared over 20 weeks with no detectable neurotoxicity.

Gadolinium based contrast agents (GBCA) are used to image patients using magnetic resonance (MR) imaging. In recent years, there has been controversy around gadolinium retention after GBCA administration. We sought to evaluate the potential toxicity of gadolinium in the rat brain up to 1-year after repeated gadodiamide dosing and tissue retention kinetics after a single administration. Histopathological and ultrastructural transmission electron microscopy (TEM) analysis revealed no findings in rats administered a cumulative dose of 12 mmol/kg. TEM-energy dispersive X-ray spectroscopy (TEM-EDS) localization of gadolinium in the deep cerebellar nuclei showed ~ 100 nm electron-dense foci in the basal lamina of the vasculature. Laser ablation-ICP-MS (LA-ICP-MS) showed diffuse gadolinium throughout the brain but concentrated in perivascular foci of the DCN and globus pallidus with no observable tissue injury or ultrastructural changes. A single dose of gadodiamide (0.6 mmol/kg) resulted in rapid cerebrospinal fluid (CSF) and blood clearance. Twenty-weeks post administration gadolinium concentrations in brain regions was reduced by 16–72-fold and in the kidney (210-fold), testes (194-fold) skin (44-fold), liver (42-fold), femur (6-fold) and lung (64-fold). Our findings suggest that gadolinium does not lead to histopathological or ultrastructural changes in the brain and demonstrate in detail the kinetics of a human equivalent dose over time in a pre-clinical model.

Accurate and precise means for quantifying Ta in tissues, bodily fluids, and bone is critical in understanding anticipated safety-profiles for tantalum oxide (TaO) nanoparticle-based X-ray/CT diagnostic imaging agents and has prompted the development of three digestion methods which are the focus of this work. Spike recovery studies were employed to evaluate bias, precision, and sample matrix effects in the quantification of Ta in (1) liver, blood and femur by microwave-assisted digestion, (2) urine by open-beaker digestion, and (3) carcass, liver and feces by dry-ash digestion. All analyses were performed with inductively coupled plasma optical emission spectrometry (ICP-OES). Spike recoveries were 98.5-102.3% for all biological matrices except femur (91.6%); however, a modified version of the original microwave digestion procedure improved the recovery of Ta in femur to 103.8%. Precision of spike recovery reported as one standard deviation ranged from 0.1 to 3.8% for within-run and from 0.5 to 3.3% for overall recovery depending on the tissue type and digestion method. Limit of detection (LOD) was 0.006 to 6 mg Ta per g and limit of quantification (LOQ) was 0.02 to 20 mg Ta per g depending on the method. The presented methods were applied to the determination of Ta in liver, kidney, spleen and carcass from an in vivo TaO nanoparticle retention study, and the results for percent injected dose (% ID) of Ta retained are given. † Electronic supplementary information (ESI) available: Sample digestion reagents, instrument calibration standards, tantalum oxide nanoparticle contrast agent digestion procedures and results, within-run recovery and precision for each biological material per digestion method, and in vivo retention case study results. See

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