Canthaxanthin Deposition in the Retina: A Biostatistical Evaluation of 411 Patients

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Abstract
Canthaxanthin (4,4′-diketo-β-carotene) is a naturally occurring carotenoid that has been used in both medical applications and for cosmetic skin coloration. In some individuals who have histories of long-term, high-dosage canthaxanthin intake, there has been reported an associated asymptomatic appearance of reversible golden crystals in the retina. Because of the potential for continued medical use of this agent, it is important to ascertain whether a dose-response relationship can be described for canthaxanthin-related crystal formation. In addition, the delineation of a dose-response relationship is important in assessing the safety of the much lower dose food coloring applications of canthaxanthin, and would provide a statistical basis for the establishment of a “no-effect level.” The possibility of a dose-response relationship between crystal formation in the retina and high-dosage canthaxanthin use was investigated biostatistically by analyzing the dosage information from 691 cases, as described by 25 different research groups in both published and unpublished reports. Of these 691 cases, 131 showed retinal crystals, however, only 411 cases yielded information that could be used for a detailed biostatistical evaluation. Of these 411, 95 demonstrated crystals in the retina. In this population of 411 cases that could be statistically evaluated, daily dosages varied from 15 to 240 mg, yearly dosages ranged from 420 to 50,400 mg, and total dosages were from 630 to 201,600 mg within a duration of treatment that varied from 1 to 14 years. In reviewing the data of this study, a number of significant statistical relationships emerge. The increasing percentage of cases with crystals as a function of both total and daily (<30 mg = 0%, 30 mg = 9.6%, 45 mg = 20.3%, 60 mg = 23.4%, 75–105 mg = 43.1%) dosage indicates clearly that a highly significant (p<0.0001) dose-response relationship exists. The daily, yearly, and total dosage parameters, along with duration of dosage and age, were also found to be significantly higher (p< 0.0001) for those cases with crystals compared with those with no crystals. These dose-response relationships demonstrate statistically for the first time that the phenomenon of crystallization in the retina after intake of canthaxanthin is associated only with high-dose and long-term treatment. Furthermore, the minimum dosage at which crystals were seen in any reported case was at least 30 mg per day, with no crystals appearing in patients ingesting levels below this dosage.

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