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Safety Assessment of Nutritional Supplements for Prevention and Treatment of Ophthalmic Disease
Author Response: Safety Assessment of Nutritional Supplements for Prevention and Treatment of Ophtha
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Bruce I. Gaynes
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dchin{at}arvo.org Bruce I. Gaynes
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I have read with interest the recent article by Rosenthal et al.1 describing a "dose-ranging" study of lutein in older adults. The conclusion is made by the authors that "the highest dose of lutein (10 mg) was safe as a supplement." Based on content and internal study validity, I believe this statement is misleading and is a result of oversimplification of essential concepts in clinical drug testing as related to study power and detectable event rate. Predictive dose escalation studies for experimental drugs are designed in large part to ascertain safety and toxicity of prospective drug products for human use. Natural products intended for use as therapeutic entities in doses not typically encountered in foodstuffs are often marketed to the public, who have free access to self-medicate with virtually an unlimited range of dosages. Lutein is a natural product, perceived by many individuals to be inert in terms of remarkable toxicity.2 Although safety assessments of natural products such as lutein as performed by Rosenthal are an important element of product evaluation, it is important to note the power of such is limited to the detection of adverse events that occur with relative frequency. For illustration, it has been previously demonstrated that utilizing a cohort of five subjects, a safety trial would have 90% power to detect a drug-related change in hepatic enzyme activity of 2X the upper limit of normal when such event occurs with a frequency of at least 40% (or higher) in any given population.3,4 Due to the markedly low incidence, if any, of hepatic toxicity with lutein administration, one may predict a priori with reasonable accuracy that detection of liver toxicity with a sample size of five among any of the dose ranges utilized by Rosenthal et al. would be extremely unlikely. Clearly the empiric choice of sample size must be tempered within the context of specific population characteristics, such as those at risk for liver toxicity, as well as the rate at which the event is expected to occur within a given population. Lack of this consideration may easily lead to misleading conclusions regarding safety through use of flawed and/or presumptuous methodology often implemented at considerable expense both in terms of economics and time. Characteristics of toxicity of any drug or chemical product, either synthetic or naturally occurring, in the context of a safety evaluation requires a thorough understanding of relevant toxicologic parameters such as target organ(s) and the biologic ramifications of such exposure in order to ascertain histopathologic findings to base subsequent clinical examinations. It is important to note that animal studies involving intravenous administration of lutein have identified three target organs that appear to concentrate lutein to an appreciable extent, most notably the liver, spleen, and lung.5 Following a single intravenous dose, 25% of lutein was found to accumulate within the liver, with amounts of approximately 5% (or less) found in the spleen and lung.5 With chronic high dose administration, the amount of lutein in these target organs would not be inconsequential. A particularly curious and unexpected finding was the accumulation of lutein in erythrocytes rather than plasma, as noted by the relatively high accumulation of the compound in the spleen.5 Rosenthal et al. may have better addressed the topic of the safety of lutein in older adults by first examining and exploiting results of histopathologic examination of liver, lung, and hemaopoetic organs following experimental high dose chronic administration of lutein in aged and/or diseased animal models as means to predict toxicity in the human. Although studies have demonstrated safety of lutein in healthy animals, the case for toxicity in specific population groups is less well defined.6 It should be noted that a close chemical correlate of lutein, beta carotene, is metabolized to vitamin A, which is a demonstrable cause of liver toxicity.7 Interestingly, vitamin A-induced hepatic toxicity can manifest in a variety of symptoms and signs that range from subtle portal hypertension and/or fatigue with or without elevation in hepatic enzymes to frank hepatic cirrhosis. Although Rosenthal et al. note no demonstrable hepatic toxicity in their small study sample, the safety of lutein among populations with various forms of renal, liver, and/or splenic disease, including individuals with diabetes mellitus or cirrhosis, should be carefully examined prior to unqualified statements regarding safety assessments of dietary supplements easily and fully accessible by the general public. Bruce I. Gaynes References 1. Rosenthal JM, Kim J, de Monasterio F, et al. Dose-ranging study of lutein supplementation in persons aged 60
years or older. Invest Ophthalmol Vis Sci. 2006;47:5227-5233. |
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Emily Chew
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echew{at}nei.nih.gov Emily Chew
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Author Response: Safety Assessment of Nutritional Supplements for Prevention and Treatment of Ophthalmic Disease We would like to respond to Dr. Gaynes' letter regarding our report on a dose ranging study of oral supplementation of lutein.1 He has raised the following issues: 1. The conclusion that an oral dose of lutein 10 mg daily is safe may be an oversimplification and a misleading statement because the power to detect adverse events may be seriously limited in a sample size of five. We evaluated 45 participants, with 15 participants taking each dose tested, with 5 having no age-related macular degeneration (AMD), 5 with large drusen and 5 with advanced AMD. We were able to pool across the AMD status to have a total of 15 participants for each dose. The power to detect a large treatment effect is seen in the following table:
Table 1. Potential true differences in post-treatment serum lutein levels and the associated power to detect them in pairwise comparisons between dose groups within disease (AMD) groups (n=5) and across disease groups (n=15). We would agree with Dr. Gaynes that we have low power to detect adverse side effects. Our study is one of a number of studies that have evaluated lutein as an oral supplement, with daily doses as high as 10 to 40 mg.2,3,4,5 It is indeed possible to achieve dietary intake of lutein through a number of food sources.6 In a population living on the Fiji Islands, the normal daily dietary intake of lutein is 25 mg/day.7 This is considerably higher than the dose tested in our report and other studies of oral supplementation. No toxicity has been noted in this population, and, in fact, this study was conducted because of their low rates of incident lung cancer. The totality of evidence would suggest that the dose of lutein of 10 mg/day is safe. We may have oversimplified our conclusions and should have expanded our discussion regarding previous studies and dietary intakes. We welcome this opportunity to give further evidence of the lack of toxicity detected in these studies. The oral route of supplementation may result in different metabolic patterns than the intravenous route of administration. Khachik8 conducted oral supplementation of lutein and zeaxanthin in 18 female moneys and significant increase in concentrations of lutein and zeaxanthin in plasma, tissues (liver, lung, colon, kidney, breast, ovaries, spleen, and cervix) and other ocular tissue without detectable toxicity. Biomarkers of kidney toxicity were also evaluated and found not to have increased significantly. The doses of lutein and zeaxanthin given in this study were equivalent to about 600 mg daily for a 60 kg man. Although lutein is a member of the carotenoid family, it does not share the metabolic pathways of other carotenoids because it is not a substrate for the 15,15'-monooxygenase enzyme that cleaves b-carotene into vitamin A. Lutein, therefore, does not possess provitamin A activity.9 Although our ability to detect adverse events of low frequency is limited by our small sample size, we maintain that oral supplementation with lutein appears to be associated with low adverse effects, both from the results of this study and a number of studies previously reported. These adverse effects will be evaluated in the large controlled clinical trial of lutein/zeaxanthin and/or omega-3 long chain polyunsaturated fatty acids in the ongoing Age-Related Eye Disease Study 2 (AREDS2).10 We look forward to evaluating these data in the future. Emily Y. Chew1 1National Eye Institute/NIH, Division of Epidemiology and Clinical Research, Bethesda, Maryland References 1. Rosenthal JM, Kim J, de Monasterio F, et al. Dose-ranging study of lutein supplementation in persons aged 60 years of older. Invest Ophthalmol Vis Sci. 2006;47:5227-5233. |
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