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Dietary Supplements: A Framework for Evaluating Safety Appendix G Chromium Picolinate: Prototype Monograph Summary1 V. SUMMARY AND CONCLUSIONS Chromium picolinate is chromium(III) trispicolinate, the chromium salt of three picolinic acid molecules. The chemical formula of chromium picolinate is C18H12CrN3O6, and the formula weight is 418. Chromium is present in the diet and in human tissues. The normal range of plasma chromium values is 0.1 to 2.1 μg/mL (Cerulli et al., 1998). The content of chromium in human liver has been reported at 5.4 to 470 η/g wet weight liver (~0.1–9 μM) (Versieck, 1985). The tolerable upper intake level for chromium is 25 μg/day (IOM, 2001). The estimated chromium content of 1 This is a summary of a prototype monograph, prepared for the purpose of illustrating how a safety review of a dietary supplement ingredient might be prepared following the format described in this report. While it was prepared as a prototype using the processes described in the report, it was not conducted under the auspices of the Food and Drug Administration utilizing all the resources available to the agency. Thus some pertinent information not available to the Committee could be of importance in evaluating safety to determine if use of this dietary supplement ingredient would present an unreasonable risk of illness or injury. Also, the development and review of this prototype was conducted by individuals whose backgrounds are in general aspects of evaluating science and whose expertise is not necessarily focused specifically on this dietary ingredient, although significant additional assistance was provided by consultants with relevant expertise. Therefore, this prototype monograph, while extensive, does not represent an authoritative statement regarding the safety of this dietary supplement ingredient. The full prototype monograph and its data tables on chromium picolinate may be accessed at http://www.iom.edu/fnb.
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Dietary Supplements: A Framework for Evaluating Safety the usual diet consumed in the United States is 15 μg/1,000 kcal (Anderson and Kozlovsky, 1985). Picolinic acid, as an endogenous metabolite of tryptophan metabolism, is present in human tissues only in trace amounts (Rebello et al., 1982). Some picolinic acid is expected to be present in the diet in small amounts; however, this subject has not been studied extensively. Chromium picolinate is widely included in dietary supplements, especially in multivitamin, multimineral products. These supplements are usually available in capsule or tablet form. Typical amounts of chromium picolinate used in multivitamin, multimineral dietary supplements range from 50 to 400 μg/day. Specialty dietary supplements may contain much more chromium picolinate and may include other forms of both chromium and picolinate. Chromium picolinate is also readily available in single-ingredient preparations or in combination with a few ingredients. A. Summary This monograph summary considers the safety of chromium picolinate as well as Cr(III) and picolinic acid to the degree to which they are expected to impact the safety of chromium picolinate. The human data regarding chromium picolinate safety was derived from 17 randomized, double-blind, placebo-controlled human clinical trials of oral chromium picolinate; 2 similar trials (confounded by the choice of subjects with gestational diabetes or publication in German); 3 cross-over-design trials; 1 uncontrolled study in subjects with diabetes; 1 phase II study; 2 pilot studies; 1 questionnaire; 11 clinical case reports; 1 case series report; and 21 spontaneous adverse event reports to Special Nutrition/ Adverse Event Monitoring System where chromium picolinate was the lone supplement reported. Data were also examined from adverse event reports in which two or more supplements containing chromium picolinate were ingested; all of these reports involved serious adverse events. Animal and in vitro general toxicity data, as well as data addressing the questions raised by human data, were collected using literature searches. The quality and quantity of the data from in vitro, animal, and human experiments and studies is good and also reasonable. The benchmark for this conclusion is the quality and quantity of data for nutritional supplements in general. Data from questionable sources outside the widely accepted medical literature were included in footnotes to the data tables in the full monograph to indicate awareness of this data; however, little value was placed on this type of data. No consistent, frequent adverse events were evident from the human data, although most of the human studies were not informative with regard
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Dietary Supplements: A Framework for Evaluating Safety to adverse effects of chromium picolinate that might manifest after long-term consumption. Similarly, no clear or distinct patterns were observed from the diverse congeries of literature. Possible concerns arise from in vitro data that suggest Cr(III) increases oxidative stress and carcinogenesis (including carcinogenesis that may not be mediated by oxidative stress). However, data about such intracellular effects of Cr(III) (e.g., DNA fragmentation) are difficult to integrate into the evaluation of the safety of chromium picolinate as a dietary supplement; it is not clear whether intracellular Cr(III) concentrations sufficient to cause nuclear mutations and/or oxidative stress would result from chromium picolinate ingestion at doses found in the dietary supplements. Controversy concerning the relevance of in vitro studies to human health commonly evolves from a general skepticism about the physiologic relevance of high intracellular concentrations attained during in vitro studies. In the case of chromium picolinate, the controversy comes from a different source; a particular question arises about picolinate as a carrier of chromium into the cell and the subsequent release of Cr(III). At this time, there is insufficient experimental data to evaluate the long-term safety of chromium picolinate regarding carcinogenesis. The human studies evaluated would not have detected carcinogenesis; only two of the studies might have detected oxidative stress if it did occur. These two studies examined measures indicative of oxidative stress and did not detect them; an 8-week study using 400 μg/day of Cr(III) failed to demonstrate oxidative damage to DNA (Kato et al., 1998), and a 12-week study using 924 μg/day Cr(III) failed to demonstrate a shift from proteinbound iron to the free (reactive) metal ion (Campbell et al., 1997). Additionally, animal studies provide some mitigation of the concern raised by in vitro studies; a 24-week study in female Sprague-Dawley rats with chromium picolinate (up to 100 μg Cr(III)/g diet) and lifespan studies in several strains of rats with chromium chloride (at 5–25 ppm Cr(III) in the drinking water) or chromium oxide (up to 5 percent w/w in bread dough) failed to demonstrate toxicity or carcinogenicity. B. Conclusions and Recommendations About the Safety of the Ingredient Based on the Strength of the Scientific Evidence Considering the totality of the data reviewed, there is no consistent evidence of reasonable expectation of harm from chromium picolinate. There is also not sufficient evidence to raise concern regarding the safety or toxicity of chromium picolinate when used in the intended manner for a length of time consistent with the published clinical data, that is, up to 1.6 mg of chromium picolinate/day (200 μg of Cr(III)/day) for 3 to 6 months. This conclusion is consistent with the findings of the Agency for Toxic
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Dietary Supplements: A Framework for Evaluating Safety Substances and Disease Registry in a recent toxicological profile for chromium (ATSDR, 2000). C. Unresolved Issues and Uncertainties in the Available Data There are some unresolved issues given the currently available data regarding the safety of chromium picolinate. However, at this time, the totality of the data does not indicate an urgent need for additional research studies or data gathering. An issue of concern is the lack of information on the long-term effects of chronic chromium picolinate at the recommended doses. Long-term effects might be addressed by determining if ingestion of chromium picolinate in the amount and duration typical of dietary supplements results in sufficient intracellular Cr(III) concentration to cause nuclear damage and/or oxidative stress. The individual usage patterns of chromium picolinate are needed in a published format that is readily accepted by the scientific community. To know how many people take how much chromium and for how long is an important consideration in evaluating long-term safety. Since there are studies in which adverse effects are not mentioned or in which the rate of subject withdrawal data is missing, it is advised that the authors of those studies be contacted and specifics be obtained. D. Data Gaps and Future Research Recommended There are no recommendations for future research at this time. REFERENCES Anderson RA, Kozlovsky AS. 1985. Chromium intake, absorption and excretion of subjects consuming self-selected diets. Am J Clin Nutr 41:1177–1183. ATSDR (Agency for Toxic Substances and Disease Registry). 2000. Toxicologial Profile for Chromium. Atlanta: ATSDR. Campbell WW, Beard JL, Joseph LJ, Davey SL, Evans WJ. 1997. Chromium picolinate supplementation and resistive training by older men: Effects on iron-status and hematologic indexes. Am J Clin Nutr 66:944–949. Cerulli J, Grabe DW, Gauthier I, Malone M, McGoldrick MD. 1998. Chromium picolinate toxicity. Ann Pharmacother 32:428–431. IOM (Institute of Medicine). 2001. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press. Kato I, Vogelman JH, Dilman V, Karkoszka J, Frenkel K, Durr NP, Orentreich N, Toniolo P. 1998. Effect of supplementation with chromium picolinate on antibody titers to 5-hydroxymethyl uracil. Eur J Epidemiol 14:621–626. Rebello T, Lonnerdal B, Hurley LS. 1982. Picolinic acid in milk, pancreatic juice, and intestine: Inadequate for role in zinc absorption. Am J Clin Nutr 35:1–5. Versieck J. 1985. Trace elements in human body fluids and tissues. Crit Rev Clin Lab Sci 22:97–184.
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