Dose dependency of canthaxanthin crystals in monkey retina and spatial distribution of its metabolites

PURPOSE. TO establish the threshold level of canthaxanthin crystals in the retina of cynomolgus monkeys. To correlate the spatial distribution of all- trans canthaxanthin and its metabolites with the grade of crystals. METHODS. Monkeys were orally administered 0, 0.2, 0.6, 1.8, 5.4, 16.2, and 48.6 mg/kg body wt canthaxanthin daily for 2.5 to 3 years. A second group o f monkeys were administered 200 and 500 mg/kg body wt/d for 5 years. Ophtha lmoscopy, electroretinography (ERG), retina and carotenoid analysis were pe rformed as previously reported. RESULTS. Crystals in the retina periphery were observed by ophthalmoscopy p reterminally only in the extreme high doses of 200 to 500 mg/kg body wt/d. There were no adverse effects on visual functions as measured by ERG. Cryst als in the peripheral retina, and/or in the macula, were detected microscop ically in all canthaxanthin treated groups except at the lowest dose of 0.2 mg/kg body wt/d. The grade of crystals increased up to a dose of 16.2 mg/k g body wt/d. Dose-dependent increases in canthaxanthin content also were no ted in the retina, the liver, and in plasma. All-trans canthaxanthin was th e major compound in the peripheral and paracentral retina of very highly do sed animals, where its concentration correlated largely with the grade of i nclusions. In the macula, 4'-OH-echinenone was the dominant canthaxanthin m etabolite. CONCLUSIONS. The grade of crystals in monkey retinas was dose dependent wit h a threshold level at 0.6 mg canthaxanthin/kg body wt/d. It correlated in the retinal periphery with the concentrations of all-trans-canthaxanthin an d in the macula with its metabolites.