Evaluation of gadolinium-based contrast agents in juvenile CD-1 mice including behavioral evaluations
Elise M Lewis1, Paul Jones2, Guenther Clemens3
1Charles River Laboratories, Inc., Safety Assessment, Horsham, Pennsylvania, USA.
Insights
Gadolinium-based contrast agents (GBCAs) showed no long-term developmental or neurodevelopmental effects in juvenile mice. The highest tested dose was found to be a no-observable-adverse-effect level for all GBCAs.
Area of Science:
- Pharmacology
- Developmental Toxicology
- Neuroscience
Background:
- Gadolinium-based contrast agents (GBCAs) are widely used in medical imaging.
- Potential effects of GBCAs on developing organisms require thorough investigation.
Purpose of the Study:
- To evaluate the potential developmental and neurodevelopmental effects of seven GBCAs in juvenile mice.
- To assess gadolinium (Gd) accumulation in various tissues following GBCA administration.
Main Methods:
- Seven GBCAs (four linear, three macrocyclic) were administered intravenously to juvenile CD-1 mice daily from postnatal day 9 to 21.
- Doses were administered up to twice the human equivalent clinical dose.
- Gadolinium levels were measured in plasma and tissues (liver, spleen, brain, skin, bone, kidneys).
- Toxicity, growth, survival, sexual maturation, behavior, and neurodevelopment were assessed.
Main Results:
- Gadolinium was detected in brain tissues, with levels decreasing over time.
- No long-term adverse effects on growth and development were observed across all tested GBCAs.
- Brain histology and neurobehavioral tests (functional observational battery, motor activity, Morris water maze) showed no impact on neurodevelopment.
- The highest dose administered for each GBCA represented the no-observable-adverse-effect level.
Conclusions:
- Developmental exposure to the evaluated GBCAs did not result in long-term adverse effects in juvenile mice.
- Neurodevelopmental assessments confirmed no detrimental impact from GBCA exposure.
- The study establishes a no-observable-adverse-effect level for these GBCAs in juvenile mice.
Introduction:
Seven gadolinium-based contrast agents (GBCAs), four linear and three macrocyclic, were evaluated for potential effects on development, including behavior of juvenile CD-1 mice.
Methods:
The GBCAs were administered via intravenous injection once daily on postnatal day (PND) 9, 12, 15, 18, and 21 (PND 1 was the day of delivery) at doses up to twice the human equivalent clinical dose (i.e., 0.63 mmol Gd/kg for gadoxetate disodium and 2.5 mmol Gd/kg for the other GBCAs). Mice were bled for evaluation of exposure (plasma) to gadolinium (Gd) on PND 9, 12, and 70. At scheduled euthanasia, the liver, spleen, brain, skin (dorsal surface), bone (left femur), and kidneys were excised from up to six mice/sex/group on PND 10, 22, or 70 for the determination of Gd levels and histopathological analysis. All mice were monitored for toxicity, growth and survival, sexual maturation, and behavior.
Conclusion:
Gd was quantifiable in the brain tissues with levels declining over time. There was no long-term effect on the growth and development for mice exposed to any of the GBCAs. There was no impact on neurodevelopment as assessed by brain histology and validated neurobehavioral tests, including a functional observational battery, motor activity, and learning and memory as evaluated in the Morris water maze. For all GBCAs, the highest dose tested represented the no-observable-adverse-effect level in juvenile mice.
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