title: Occurrence of birefringent retinal inclusions in cynomolgus monkeys after high doses of canthaxanthin.
abstract: OBJECTIVE
  To reproduce and investigate in a primate animal model the phenomenon of the red carotenoid canthaxanthin (beta, beta-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 (Macaca fascicularis) per gender and dose were administered 5.4, 16.2, or 48.6 mg canthaxanthin/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 light-reflecting 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 the 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 canthaxanthin-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.
authors.affiliation: Department of Exploratory Research, F. Hoffmann-La Roche AG, Basel, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Goralczyk
authors.forename: S
authors.initials: S
authors.lastname: Buser
authors.forename: J
authors.initials: J
authors.lastname: Bausch
authors.forename: W
authors.initials: W
authors.lastname: Bee
authors.forename: U
authors.initials: U
authors.lastname: Zühlke
authors.forename: F M
authors.initials: FM
authors.lastname: Barker
mesh_terms: D000818:Animals; D016644:Canthaxanthin / Q000008:administration & dosage / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D003460:Crystallization; D004195:Disease Models, Animal; D004596:Electroretinography; D005260:Female; D005505:Food Coloring Agents / Q000008:administration & dosage / Q000633:toxicity*; D008252:Macaca fascicularis; D008297:Male; D009887:Ophthalmoscopy; D012160:Retina / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D012164:Retinal Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology
chemical_list: D005505:Food Coloring Agents; D016644:Canthaxanthin