Occurrence of birefringent retinal inclusions in cynomolgus monkeys after high doses of canthaxanthin

urpose. To reproduce and investigate in a primate animal model the phenomenon of the red carotenoid canthaxanthin (/?,/5-carotene-4'4'-dione) to induce crystal-like retinal deposits as they have been observed in the ocular fundus of humans after high canthaxanthin intake (i.e., more than 30 mg/day). Methods. Groups of four cynomolgus monkeys (Macaco, fascicularis) per gender and dose were administered 5.4, 16.2, or 48.6 mg candiaxanthin/kg body weight daily by oral gavage for 2.5 years. Eight control animals received placebo. In vivo ophthalmoscopy was performed at intervals of 3 months along with electroretinography after 12 and 24 months and retinal biomicroscopy just before the monkeys were killed. Retinal wholemounts or frozen sections were investigated postmortem by polarization, bright field, and differential interference contrast microscopy. Retinal and preterminal plasma canthaxanthin concentrations were determined by high-performance liquid chromatography (HPLC). Results. By ophthalmoscopy and retinal biomicroscopy in vivo, no crystals or other lightreflecting particles were observed in the central paramacular retina. However, postmortem polarization microscopy of all 24 canthaxanthin-treated animals showed a circular zone in the peripheral retina containing birefringent, polymorphous red, orange, or white inclusions. The density of these inclusions was diminished within 1 to 8 mm posterior to the ora serrata. These inclusions were located mainly in the inner retinal layers, that is, the nerve fiber layer and ganglion cell layer, inner plexiform layer, and inner nuclear layer. Twelve of the 24 canthaxanthin-treated animals showed yellow, golden birefringent inclusions in die macula. Retinas of placebo-treated monkeys were free of birefringent, crystal-like inclusions. The HPLC confirmed the presence of all-trans canthaxanthin, and 4-OH-echinenone and isozeaxanthin as well, in the retinas of all can thaxan dim-treated animals. Neither electroretinography nor histopathology indicated any adverse effects of the canthaxanthin-induced retinal inclusions seen in this study. Conclusions. A high intake of canthaxanthin for 2.5 years led to the deposition of crystal-like birefringent inclusions in the inner layers of the peripheral retina and, to some extent, the central retina of cynomolgus monkeys. The presence of these deposits did not interfere with morphology nor with retinal function. Invest Ophthalmol Vis Sci. 1997;38:741-752. A he carotenoid canthaxanthin (/?,/3-carotene-4'4'-dione) is synthesized in nature by the mushroom Cantharellus cinnabarinus. It also occurs in a variety of other plants and animals (e.g., in algae, Crustacea, birds, o