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Letter to the Editor Response to letter to the editor from Granado and Olmedilla Dear Sir, This is in response to the insightful comments from Granado and Olmedilla pertaining to the recently pub- lished risk assessment on the carotenoids lutein and lyco- pene (Shao and Hathcock, 2006). We thank the authors for pointing out a minor oversight in the text related to the duration and dosing regimen in their 2003 study on lu- tein supplementation (Olmedilla et al., 2003). This correc- tion however, does not change the overall conclusions from our analysis. We also appreciate the added comments on the safety assessments performed in their studies. How- ever, the enormous heterogeneity in study design, popula- tion, dosage, duration and outcome measures used in the human clinical trials precluded us from doing any further systematic review and analysis than was presented in our paper. Further, the overwhelming majority of human clin- ical trials conducted with non-provitamin A carotenoids have focused on efficacy rather than safety. In most cases, safety has been evaluated, if at all, by monitoring subjects’ self-reporting of adverse effects. This practice may stem from the lack of an established hazard or critical effect in healthy adults (save for carotenodermia, which is more of a nuisance than a hazard). Serum carotenoid levels, to the extent that may be indicative of safety or toxicity, which is debatable, was essentially the only consistent objective ‘‘safety’’ measure on which we could rely. Addi- tionally, studies performed with the higher dose range (>30 mg/d for lutein) are uncontrolled and lack any clini- cally relevant and objective safety measures. As a result, the Observed Safe Level (OSL) values we propose may ap- pear to be lower than what may be obtained based on acute or sub-chronic animal toxicity experiments. Howev- er, despite our somewhat conservative approach and the inconsistencies and heterogeneity in the human data set, at present there remains no basis to establish a critical ef- fect in humans or animals and thus no basis for a no ob- served adverse effect level (NOAEL) or lowest observed adverse effect level (LOAEL) for either carotenoid. Addi- tionally, we prefer to rely on human data, even when the dataset is very modest, rather than animal data due to the large uncertainty related to extrapolation between species. Another important note is that the proposed OSL values are intended to be applied to generally healthy adults, which is why we attempt, where possible, to rely on data from healthy adults. Establishing recommendations for tol- erable upper intake levels (or OSL) for other populations, such as those with a specific disease, children or pregnant or lactating women would require a separate risk assess- ment using a separate data set. References Olmedilla, B., Granado, F., Blanco, I., et al., 2003. Lutein, but not alpha- tocopherol, supplementation improves visual function in patients with age-related cataracts: a 2-y double-blind, placebo-controlled pilot study. Nutrition 19 (1), 21–24. Shao, A., Hathcock, J.N., 2006. Risk assessment for the carotenoids lutein and lycopene. Regul. Toxicol. Pharmacol. 45 (3), 289–298. Andrew Shao * John N. Hathcock Council for Responsible Nutrition, Science and Regulatory, 1828 L Street, NW, Suite 900, Washington, DC 20036, USA E-mail address: [email protected] (A. Shao) Received 24 October 2006 Available online 20 December 2006 0273-2300/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.yrtph.2006.10.006 * Corresponding author. Fax: +1 202 204 7980. www.elsevier.com/locate/yrtph Regulatory Toxicology and Pharmacology 47 (2007) 329

Response to letter to the editor from Granado and Olmedilla

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Regulatory Toxicology and Pharmacology 47 (2007) 329

Letter to the Editor

Response to letter to the editor from Granado and Olmedilla

Dear Sir,

This is in response to the insightful comments fromGranado and Olmedilla pertaining to the recently pub-lished risk assessment on the carotenoids lutein and lyco-pene (Shao and Hathcock, 2006). We thank the authorsfor pointing out a minor oversight in the text related tothe duration and dosing regimen in their 2003 study on lu-tein supplementation (Olmedilla et al., 2003). This correc-tion however, does not change the overall conclusionsfrom our analysis. We also appreciate the added commentson the safety assessments performed in their studies. How-ever, the enormous heterogeneity in study design, popula-tion, dosage, duration and outcome measures used in thehuman clinical trials precluded us from doing any furthersystematic review and analysis than was presented in ourpaper. Further, the overwhelming majority of human clin-ical trials conducted with non-provitamin A carotenoidshave focused on efficacy rather than safety. In most cases,safety has been evaluated, if at all, by monitoring subjects’self-reporting of adverse effects. This practice may stemfrom the lack of an established hazard or critical effect inhealthy adults (save for carotenodermia, which is moreof a nuisance than a hazard). Serum carotenoid levels, tothe extent that may be indicative of safety or toxicity,which is debatable, was essentially the only consistentobjective ‘‘safety’’ measure on which we could rely. Addi-tionally, studies performed with the higher dose range(>30 mg/d for lutein) are uncontrolled and lack any clini-cally relevant and objective safety measures. As a result,the Observed Safe Level (OSL) values we propose may ap-pear to be lower than what may be obtained based onacute or sub-chronic animal toxicity experiments. Howev-er, despite our somewhat conservative approach and the

0273-2300/$ - see front matter � 2006 Elsevier Inc. All rights reserved.

doi:10.1016/j.yrtph.2006.10.006

inconsistencies and heterogeneity in the human data set,at present there remains no basis to establish a critical ef-fect in humans or animals and thus no basis for a no ob-served adverse effect level (NOAEL) or lowest observedadverse effect level (LOAEL) for either carotenoid. Addi-tionally, we prefer to rely on human data, even when thedataset is very modest, rather than animal data due tothe large uncertainty related to extrapolation betweenspecies.

Another important note is that the proposed OSL valuesare intended to be applied to generally healthy adults,which is why we attempt, where possible, to rely on datafrom healthy adults. Establishing recommendations for tol-erable upper intake levels (or OSL) for other populations,such as those with a specific disease, children or pregnantor lactating women would require a separate risk assess-ment using a separate data set.

References

Olmedilla, B., Granado, F., Blanco, I., et al., 2003. Lutein, but not alpha-tocopherol, supplementation improves visual function in patients withage-related cataracts: a 2-y double-blind, placebo-controlled pilotstudy. Nutrition 19 (1), 21–24.

Shao, A., Hathcock, J.N., 2006. Risk assessment for the carotenoids luteinand lycopene. Regul. Toxicol. Pharmacol. 45 (3), 289–298.

Andrew Shao *

John N. HathcockCouncil for Responsible Nutrition,

Science and Regulatory, 1828 L Street, NW, Suite 900,

Washington, DC 20036, USA

E-mail address: [email protected] (A. Shao)

Received 24 October 2006Available online 20 December 2006

* Corresponding author. Fax: +1 202 204 7980.