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ARTICLE IN PRESS
JTEMB-25559; No. of Pages 3
Journal of Trace Elements in Medicine and Biology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Journal of Trace Elements in Medicine and Biology journal homepage: www.elsevier.de/jtemb
X. ISTERH CONFERENCE Review
Should bioactive trace elements not recognized as essential, but with beneficial health effects, have intake recommendations Forrest H. Nielsen U.S. Department of Agriculture, Agricultural Research Service,1 Grand Forks Human Nutrition Research Center, Grand Forks, ND, USA
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Keywords: Boron Chromium Nickel Silicon Dietary recommendations
a b s t r a c t Today, most nutritionists do not consider a trace element essential unless it has a defined biochemical function in higher animals or humans. As a result, even though it has been found that trace elements such as boron and silicon have beneficial bioactivity in higher animals and humans, they generally receive limited attention or mention when dietary guidelines or intake recommendations are formulated. Recently, the possibility of providing dietary intake recommendations such as an adequate intake (AI) for some bioactive food components (e.g., flavonoids) has been discussed. Boron, chromium, nickel, and silicon are bioactive food components that provide beneficial health effects by plausible mechanisms of action in nutritional and supra nutritional amounts, and thus should be included in the discussions. Although the science base may not be considered adequate for establishing AIs, a significant number of findings suggest that statements about these trace elements should be included when dietary intake guidance is formulated. An appropriate recommendation may be that diets should include foods that would provide trace elements not currently recognized as essential in amounts shown to reduce the risk of chronic disease and/or promote health and well-being. Published by Elsevier GmbH.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dietary intake guidance standards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Basis for dietary intake guidance for beneficial trace elements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction Nutrients are chemical substances found in foods that are necessary for life. For animals and humans, nutrients that the body cannot synthesize are called essential nutrients. Initially, essential nutrients were identified when low intakes resulted in the failure to grow or reproduce, or caused a pathological change such as anemia, a disease such as scurvy, or death. Currently, trace
E-mail address: [email protected] The U.S. Department of Agriculture, Agricultural Research Service, Northern Plains Area, is an equal opportunity/affirmative action employer and all agency services are available without discrimination. 1
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elements accepted as essential are copper, iron, iodine, manganese, molybdenum, selenium, and zinc. During the 1960s and 1970s, the concept of essentiality was modified for mineral elements that were bioactive but could not be fed at dietary intakes low enough to cause death or impair growth and development such that procreation was prevented. Several definitions of essentiality were proposed that often included several criteria. One criterion that appeared in all definitions was that a dietary deficiency had to consistently and adversely change a biological function from optimal, and this change was preventable or reversible by physiological or nutritional amounts of the mineral element. In the 1980s and 1990s, establishing essentiality on the basis of this criterion began to receive resistance when many trace elements were suggested to be essential based on some small
http://dx.doi.org/10.1016/j.jtemb.2014.06.019 0946-672X/Published by Elsevier GmbH.
Please cite this article in press as: Nielsen FH. Should bioactive trace elements not recognized as essential, but with beneficial health effects, have intake recommendations. J Trace Elem Med Biol (2014), http://dx.doi.org/10.1016/j.jtemb.2014.06.019
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change in a physiological or biochemical variable in an experimental animal model supposedly fed a diet deficient in a specific element. Questions arose about whether some of the changes were really the result of low intakes causing a sub-optimal function, or whether the trace element supplementation of the “deficient diets” was having a pharmacological effect such as alleviating a pathological condition caused by a poor diet or environmental conditions, substituting for another essential nutrient provided in a deficient amount, or an effect on intestinal organisms in a manner that was beneficial to the host. As a result, if the lack of a trace element cannot be shown to cause death or interrupt the life cycle, it generally is not considered essential unless it has a defined biochemical function in higher animals and humans. Trace elements that were once suggested to be essential, but cannot meet the current definition of essentiality include boron, chromium, nickel, and silicon. However, in humans and higher animals, supplements in nutritional and supra nutritional amounts of these elements have beneficial effects (vide infra) [1], and thus are designated as beneficial bioactive trace elements. In addition to dietary studies, support for the suggestion that these elements might be beneficial for humans includes their being found essential for some lower forms of life or a component of a known biologically important biomolecule in some life form [1]. Dietary intake guidance standards An estimated average requirement (EAR) is the average nutrient intake level estimated to meet the requirement of half the healthy individuals in a particular life stage and gender group [2]. A recommended dietary allowance (RDA) is the average daily dietary nutrient intake level sufficient to meet the nutrient requirement of nearly all (97%–98%) healthy individuals in a particular life stage and gender group [2]. When an EAR and a RDA cannot be established for an essential nutrient, an adequate intake (AI) is set. An AI is defined as a recommended average daily intake value based on observed or experimentally determined approximations or estimates of nutrient intake by a group, or groups, of healthy people that are assumed to be adequate [2]. It is generally accepted that a poor diet increases the risk for chronic diseases that can disable and/or lead to premature death. In 1994, the U.S. Food and Nutrition Board of the Institute of Medicine [3] suggested that the reduction in the risk of chronic disease is a concept that should be included in the formulation of future dietary reference intakes (DRIs) where sufficient data for efficacy and safety exists. This concept apparently was used for setting the DRIs for the essential nutrient potassium. RDAs were not established for potassium because of insufficient dose–response data to estimate an EAR [4]. The median potassium intake in the U.S. is about 2.9–3.2 g (74–82 mmol)/d for men and 2.1–2.3 g (54–59 mmol)/d for women. Instead of using these intakes of mostly healthy people, the Food and Nutrition Board set an AI of 4.7 g (120 mmol)/d for all adults because available evidence indicated that this intake would beneficially affect blood pressure, reduce the risk for kidney stones, and possibly reduce bone loss [4]. Interestingly, based on NHANES III data, the potassium intakes of only 10% of men and less than 1% of women in the U.S. are ≥the AI [4]. Reduction in the risk for disease or promotion of health also apparently was the basis for setting an AI for fiber. Although fiber is not an essential nutrient, an AI for healthy individuals older than 12 mo was estimated to be 14 g/1000 kcal/d [5], which would amount to about 38 g/d for men and 25 g/d for women. Note that these levels far exceed the average intake of dietary fiber estimated to be 15 g/d for American adults. Promotion of health also has been used to set DRIs for some non-essential minerals. For example, findings have not been obtained that satisfy the definition of essentiality for fluoride and chromium. AIs have been set for fluoride because it has been shown
to prevent the pathological demineralization of calcified tissues [6] and for chromium because it apparently promotes insulin action [2]. Thus, there is precedence for providing dietary intake guidance for nonessential minerals and food components based on the promotion of health or the reduction of disease. This precedence suggests that it would not be inappropriate to provide dietary intake guidance for some the beneficial bioactive trace elements. Basis for dietary intake guidance for beneficial trace elements Recently, consideration about whether the scientific data were adequate to make dietary recommendations for flavonoids (Flavonoids: Case Study, presented by J. Dwyer, Experimental Biology 2013, Boston, MA). Dwyer indicated that flavonoid benefits may justify consumption recommendations such as an AI when their safety and efficacy in intended uses are supported by a strong science base. Dwyer also stated that the benefits needed to be based on actual health outcomes, not just on surrogate biomarkers, because biomarkers of risk do not always reflect disease endpoints. These statements could be applied to the beneficial bioactive trace elements, especially boron, chromium and silicon. Thus, consideration for providing dietary intake guidance that would promote health and prevent chronic disease for these elements may be appropriate. Because the beneficial trace elements do not have a clearly defined specific mechanism of actions or biochemical functions, and generally do not have a good functional indicator to assess when intakes are too low, EARs cannot be established that could be used to establish RDAs. Thus, the question is whether there is enough evidence for some of the beneficially bioactive trace elements to receive consideration for AIs. According to Dwyer, setting an AI requires four criteria. These are: plausible mechanism of action; established beneficial effect; functional indicator or marker of status; and dose–response of some beneficial indicator. How well boron, chromium, nickel, and silicon meet these criteria will be briefly described here and will be presented in more detail in the following presentations at this ISTERH symposium. Including chromium in the group of elements to be assessed might be considered inappropriate because an AI has been set for this element. However, the AI was set when meeting the rather rigid criteria indicated above was not required. Now that an AI has been set for chromium, it apparently is going to take a high level of evidence to change its status, which is ironic, because a high level of evidence was not required to establish the AI. If chromium was to be considered for an AI today, it most likely would receive the same treatment as other beneficial bioactive trace elements. Boron, chromium, nickel and silicon have plausible, albeit not definitively defined, mechanisms for their beneficial actions based on in vitro and animal findings. Boron as boric acid readily forms complexes with cis-hydroxyl groups such as those in ribose [7]. Formation of these complexes can influence the action of biomolecules containing ribose such as adenosine diphosphates that function as signal molecules, and S-adenosylmethionine that is one of the most frequently used enzyme substrates in the body. The wide range of beneficial responses to nutritional intakes of boron [7] could be secondary manifestations of its influence on these biomolecules that have a multiplicity of actions. A plausible role for chromium is binding a ligand in the proper orientation to facilitate enzymatic action. This may be the function of the chromium-containing oligopeptide that is hypothesized as having potentiating effects on insulin action through amplifying insulin-dependent protein tyrosine kinase activity of the insulin receptor [8]. Nickel is an essential component of at least eight different enzymes in lower life involving the use or production of gases [1]. Thus, the mechanism of action of nickel might be an effect on the production or use of gaseous molecules that have signaling roles such as oxygen, nitric
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oxide, and carbon monoxide. Silicon easily forms stable complexes with polyols that have at least four hydroxyl groups [9], which might be the reason it affects the formation of glycosaminoglycans, mucopolysaccharides, and collagen involved in connective tissue stabilization and/or formation. The reported specific beneficial actions of boron, chromium, nickel and silicon are numerous. Boron has been shown to be beneficial for bone growth and maintenance, central nervous system function, the inflammatory or immune response, and perhaps, some cancer prevention [7]. Chromium has been found beneficial to subjects with varying degrees of glucose intolerance, ranging from hypoglycemia to insulin-dependent diabetes [10]. Nickel has been found to improve bone strength, alleviate renal damage and high blood pressure induced by a high salt diet, and alleviate iron and vitamin B12 deficiencies [11]. Silicon has been positively associated with bone mineral density in humans, and with bone, hexosamine and collagen formation in animals [12]. The AI criterion for which boron, chromium, nickel and silicon have limited findings is having a defined functional indicator or marker of status. However, this may not be a critical impediment to establishing dietary intake recommendations for these elements because such a shortcoming did not prevent setting AIs for manganese and molybdenum [2]. The best marker for status for these elements in humans may be a plasma or serum concentration below that usually found. For example, a plasma or serum concentration below 3.1 mol (34 g)/L for boron and 3.9 mol (110 g)/L for silicon might be an indication of a sub-optimal status for these elements [11]. There is some evidence for dose responses to boron, chromium, nickel and silicon for their beneficial effects. Humans responded to boron supplementation when their intakes were less than 0.5 mg/d [13]. A relatively high (>200 g/d) chromium intake apparently is needed to have a beneficial effect on glucose metabolism [14]. Only experimental animal data exists to suggest an intake below which nickel supplementation might give a beneficial effect; these data indicate an intake below 50 g/d [15]. In a cross-sectional, population-based study, bone mineral density was higher in men and pre-menopausal women when the dietary intake of silicon was >40 mg/d than when it was 1000 g/d for several months [2]. Animal studies have not found similar effects. Nonetheless, individuals with preexisting renal and liver disease may have an increased risk for adverse effects with high chromium supplementation [2]. Animal studies indicate that high amounts of inorganic
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trivalent chromium are needed to produce adverse effects [18]. Toxic amounts of trivalent chromium are usually stated in mg, not g, per kg feed for experimental animals. The preceding shows that boron, chromium, nickel, and silicon have low orders of toxicity and safe intakes are much higher than reported typical dietary intakes that range from 0.35 to 3.0 mg/d for boron [2]; from 13 to 54 g/d for chromium [2]; from 70 to 260 g/d for nickel [11]; and 15 to 50 mg/d for silicon [12]. Conclusion Increasing evidence indicates that the trace elements boron, chromium, nickel and silicon in safe amounts are efficacious in reducing the risk of chronic diseases such as osteoporosis and diabetes, and are beneficial to central nervous system function and bone development. There are plausible mechanisms of actions for these beneficial effects that are found when dietary intakes are above identified low levels. Consideration should be given for providing dietary guidance for these trace elements. If the science base is not considered adequate to set an AI, an appropriate action would be to recommend the consumption of foods that assures intakes of boron, chromium, nickel and silicon in amounts that promote health and well-being. Conflict of interest The author has no conflicts of interest to declare. References [1] Nielsen FH. Molybdenum and beneficial bioactive trace elements. In: Stipanuk MH, Caudill MA, editors. Biochemical, physiological molecular aspects of human nutrition. St. Louis: Elsevier; 2013. p. 899–912. [2] Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Academies Press; 2001. [3] Food and Nutrition Board, Institute of Medicine. How should the recommended dietary allowances be revised? Washington, DC: National Academy Press; 1994. [4] Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for water, potassium, sodium, chloride, and sulfate. Washington, DC: National Academies Press; 2005. [5] Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein, and amino acids (macronutrients). Washington, DC: National Academies Press; 2002. [6] Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington, DC: National Academy Press; 1997. [7] Nielsen FH, Meacham SL. Growing evidence for human health benefits of boron. J Evid-Based Complement Med 2011;16:169–80. [8] Vincent JB, Bennett R. Potential and purported roles for chromium in insulin signaling: the search for the holy grail. In: Vincent JB, editor. The nutritional biochemistry of chromium (III). Amsterdam: Elsevier; 2007. p. 1–40. [9] Kinrade S, Del Nin JW, Schach AS, Sloan TA, Wilson KL, Knight CT. Stable fiveand six-coordinated silicate anions in aqueous solution. Science 1999;285: 1542–5. [10] Anderson RA. Chromium, glucose intolerance and diabetes. J Am Coll Nutr 1998;17:548–55. [11] Nielsen FH. Boron, manganese, molybdenum, and other trace elements. In: Bowman BA, Russell RM, editors. Present knowledge in nutrition, vol. 1, 9th ed. Washington, DC: ILSI Press; 2006. p. 506–26. [12] Jugdaohsingh R. Silicon and bone health. J Nutr Health Aging 2007;11:99–110. [13] Nielsen FH. Is boron nutritionally relevant? Nutr Rev 2008;66:183–91. [14] Cefalu WT. Clinical effect of chromium supplements on human health. In: Vincent JB, editor. The nutritional biochemistry of chromium (III). Amsterdam: Elsevier; 2007. p. 163–81. [15] Nielsen FH. Ultratrace elements in nutrition: current knowledge and speculation. J Trace Elem Exp Med 1998;11:251–74. [16] Jugdaohsingh R, Tucker KL, Qiao N, Cupples LA, Kiel DP, Powell JJ. Dietary silicon intake is positively associated with bone mineral density in men and premenopausal women of the Framingham Offspring Cohort. J Bone Miner Res 2004;19:297–307. [17] Anderson RA, Bryden NA, Polansky MM. Dietary chromium intake: freely chosen diets, institutional diets, and individual foods. Biol Trace Elem Res 1992;32:117–21. [18] National Research Council. Mineral tolerance of animals. 2nd revised ed. Washington, DC: National Academies Press; 2005.
Please cite this article in press as: Nielsen FH. Should bioactive trace elements not recognized as essential, but with beneficial health effects, have intake recommendations. J Trace Elem Med Biol (2014), http://dx.doi.org/10.1016/j.jtemb.2014.06.019
ARTICLE IN PRESS
JTEMB-25559; No. of Pages 3
Journal of Trace Elements in Medicine and Biology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Journal of Trace Elements in Medicine and Biology journal homepage: www.elsevier.de/jtemb
X. ISTERH CONFERENCE Review
Should bioactive trace elements not recognized as essential, but with beneficial health effects, have intake recommendations Forrest H. Nielsen U.S. Department of Agriculture, Agricultural Research Service,1 Grand Forks Human Nutrition Research Center, Grand Forks, ND, USA
a r t i c l e
i n f o
Keywords: Boron Chromium Nickel Silicon Dietary recommendations
a b s t r a c t Today, most nutritionists do not consider a trace element essential unless it has a defined biochemical function in higher animals or humans. As a result, even though it has been found that trace elements such as boron and silicon have beneficial bioactivity in higher animals and humans, they generally receive limited attention or mention when dietary guidelines or intake recommendations are formulated. Recently, the possibility of providing dietary intake recommendations such as an adequate intake (AI) for some bioactive food components (e.g., flavonoids) has been discussed. Boron, chromium, nickel, and silicon are bioactive food components that provide beneficial health effects by plausible mechanisms of action in nutritional and supra nutritional amounts, and thus should be included in the discussions. Although the science base may not be considered adequate for establishing AIs, a significant number of findings suggest that statements about these trace elements should be included when dietary intake guidance is formulated. An appropriate recommendation may be that diets should include foods that would provide trace elements not currently recognized as essential in amounts shown to reduce the risk of chronic disease and/or promote health and well-being. Published by Elsevier GmbH.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dietary intake guidance standards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Basis for dietary intake guidance for beneficial trace elements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction Nutrients are chemical substances found in foods that are necessary for life. For animals and humans, nutrients that the body cannot synthesize are called essential nutrients. Initially, essential nutrients were identified when low intakes resulted in the failure to grow or reproduce, or caused a pathological change such as anemia, a disease such as scurvy, or death. Currently, trace
E-mail address: [email protected] The U.S. Department of Agriculture, Agricultural Research Service, Northern Plains Area, is an equal opportunity/affirmative action employer and all agency services are available without discrimination. 1
00 00 00 00 00 00
elements accepted as essential are copper, iron, iodine, manganese, molybdenum, selenium, and zinc. During the 1960s and 1970s, the concept of essentiality was modified for mineral elements that were bioactive but could not be fed at dietary intakes low enough to cause death or impair growth and development such that procreation was prevented. Several definitions of essentiality were proposed that often included several criteria. One criterion that appeared in all definitions was that a dietary deficiency had to consistently and adversely change a biological function from optimal, and this change was preventable or reversible by physiological or nutritional amounts of the mineral element. In the 1980s and 1990s, establishing essentiality on the basis of this criterion began to receive resistance when many trace elements were suggested to be essential based on some small
http://dx.doi.org/10.1016/j.jtemb.2014.06.019 0946-672X/Published by Elsevier GmbH.
Please cite this article in press as: Nielsen FH. Should bioactive trace elements not recognized as essential, but with beneficial health effects, have intake recommendations. J Trace Elem Med Biol (2014), http://dx.doi.org/10.1016/j.jtemb.2014.06.019
G Model JTEMB-25559; No. of Pages 3
ARTICLE IN PRESS F.H. Nielsen / Journal of Trace Elements in Medicine and Biology xxx (2014) xxx–xxx
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change in a physiological or biochemical variable in an experimental animal model supposedly fed a diet deficient in a specific element. Questions arose about whether some of the changes were really the result of low intakes causing a sub-optimal function, or whether the trace element supplementation of the “deficient diets” was having a pharmacological effect such as alleviating a pathological condition caused by a poor diet or environmental conditions, substituting for another essential nutrient provided in a deficient amount, or an effect on intestinal organisms in a manner that was beneficial to the host. As a result, if the lack of a trace element cannot be shown to cause death or interrupt the life cycle, it generally is not considered essential unless it has a defined biochemical function in higher animals and humans. Trace elements that were once suggested to be essential, but cannot meet the current definition of essentiality include boron, chromium, nickel, and silicon. However, in humans and higher animals, supplements in nutritional and supra nutritional amounts of these elements have beneficial effects (vide infra) [1], and thus are designated as beneficial bioactive trace elements. In addition to dietary studies, support for the suggestion that these elements might be beneficial for humans includes their being found essential for some lower forms of life or a component of a known biologically important biomolecule in some life form [1]. Dietary intake guidance standards An estimated average requirement (EAR) is the average nutrient intake level estimated to meet the requirement of half the healthy individuals in a particular life stage and gender group [2]. A recommended dietary allowance (RDA) is the average daily dietary nutrient intake level sufficient to meet the nutrient requirement of nearly all (97%–98%) healthy individuals in a particular life stage and gender group [2]. When an EAR and a RDA cannot be established for an essential nutrient, an adequate intake (AI) is set. An AI is defined as a recommended average daily intake value based on observed or experimentally determined approximations or estimates of nutrient intake by a group, or groups, of healthy people that are assumed to be adequate [2]. It is generally accepted that a poor diet increases the risk for chronic diseases that can disable and/or lead to premature death. In 1994, the U.S. Food and Nutrition Board of the Institute of Medicine [3] suggested that the reduction in the risk of chronic disease is a concept that should be included in the formulation of future dietary reference intakes (DRIs) where sufficient data for efficacy and safety exists. This concept apparently was used for setting the DRIs for the essential nutrient potassium. RDAs were not established for potassium because of insufficient dose–response data to estimate an EAR [4]. The median potassium intake in the U.S. is about 2.9–3.2 g (74–82 mmol)/d for men and 2.1–2.3 g (54–59 mmol)/d for women. Instead of using these intakes of mostly healthy people, the Food and Nutrition Board set an AI of 4.7 g (120 mmol)/d for all adults because available evidence indicated that this intake would beneficially affect blood pressure, reduce the risk for kidney stones, and possibly reduce bone loss [4]. Interestingly, based on NHANES III data, the potassium intakes of only 10% of men and less than 1% of women in the U.S. are ≥the AI [4]. Reduction in the risk for disease or promotion of health also apparently was the basis for setting an AI for fiber. Although fiber is not an essential nutrient, an AI for healthy individuals older than 12 mo was estimated to be 14 g/1000 kcal/d [5], which would amount to about 38 g/d for men and 25 g/d for women. Note that these levels far exceed the average intake of dietary fiber estimated to be 15 g/d for American adults. Promotion of health also has been used to set DRIs for some non-essential minerals. For example, findings have not been obtained that satisfy the definition of essentiality for fluoride and chromium. AIs have been set for fluoride because it has been shown
to prevent the pathological demineralization of calcified tissues [6] and for chromium because it apparently promotes insulin action [2]. Thus, there is precedence for providing dietary intake guidance for nonessential minerals and food components based on the promotion of health or the reduction of disease. This precedence suggests that it would not be inappropriate to provide dietary intake guidance for some the beneficial bioactive trace elements. Basis for dietary intake guidance for beneficial trace elements Recently, consideration about whether the scientific data were adequate to make dietary recommendations for flavonoids (Flavonoids: Case Study, presented by J. Dwyer, Experimental Biology 2013, Boston, MA). Dwyer indicated that flavonoid benefits may justify consumption recommendations such as an AI when their safety and efficacy in intended uses are supported by a strong science base. Dwyer also stated that the benefits needed to be based on actual health outcomes, not just on surrogate biomarkers, because biomarkers of risk do not always reflect disease endpoints. These statements could be applied to the beneficial bioactive trace elements, especially boron, chromium and silicon. Thus, consideration for providing dietary intake guidance that would promote health and prevent chronic disease for these elements may be appropriate. Because the beneficial trace elements do not have a clearly defined specific mechanism of actions or biochemical functions, and generally do not have a good functional indicator to assess when intakes are too low, EARs cannot be established that could be used to establish RDAs. Thus, the question is whether there is enough evidence for some of the beneficially bioactive trace elements to receive consideration for AIs. According to Dwyer, setting an AI requires four criteria. These are: plausible mechanism of action; established beneficial effect; functional indicator or marker of status; and dose–response of some beneficial indicator. How well boron, chromium, nickel, and silicon meet these criteria will be briefly described here and will be presented in more detail in the following presentations at this ISTERH symposium. Including chromium in the group of elements to be assessed might be considered inappropriate because an AI has been set for this element. However, the AI was set when meeting the rather rigid criteria indicated above was not required. Now that an AI has been set for chromium, it apparently is going to take a high level of evidence to change its status, which is ironic, because a high level of evidence was not required to establish the AI. If chromium was to be considered for an AI today, it most likely would receive the same treatment as other beneficial bioactive trace elements. Boron, chromium, nickel and silicon have plausible, albeit not definitively defined, mechanisms for their beneficial actions based on in vitro and animal findings. Boron as boric acid readily forms complexes with cis-hydroxyl groups such as those in ribose [7]. Formation of these complexes can influence the action of biomolecules containing ribose such as adenosine diphosphates that function as signal molecules, and S-adenosylmethionine that is one of the most frequently used enzyme substrates in the body. The wide range of beneficial responses to nutritional intakes of boron [7] could be secondary manifestations of its influence on these biomolecules that have a multiplicity of actions. A plausible role for chromium is binding a ligand in the proper orientation to facilitate enzymatic action. This may be the function of the chromium-containing oligopeptide that is hypothesized as having potentiating effects on insulin action through amplifying insulin-dependent protein tyrosine kinase activity of the insulin receptor [8]. Nickel is an essential component of at least eight different enzymes in lower life involving the use or production of gases [1]. Thus, the mechanism of action of nickel might be an effect on the production or use of gaseous molecules that have signaling roles such as oxygen, nitric
Please cite this article in press as: Nielsen FH. Should bioactive trace elements not recognized as essential, but with beneficial health effects, have intake recommendations. J Trace Elem Med Biol (2014), http://dx.doi.org/10.1016/j.jtemb.2014.06.019
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oxide, and carbon monoxide. Silicon easily forms stable complexes with polyols that have at least four hydroxyl groups [9], which might be the reason it affects the formation of glycosaminoglycans, mucopolysaccharides, and collagen involved in connective tissue stabilization and/or formation. The reported specific beneficial actions of boron, chromium, nickel and silicon are numerous. Boron has been shown to be beneficial for bone growth and maintenance, central nervous system function, the inflammatory or immune response, and perhaps, some cancer prevention [7]. Chromium has been found beneficial to subjects with varying degrees of glucose intolerance, ranging from hypoglycemia to insulin-dependent diabetes [10]. Nickel has been found to improve bone strength, alleviate renal damage and high blood pressure induced by a high salt diet, and alleviate iron and vitamin B12 deficiencies [11]. Silicon has been positively associated with bone mineral density in humans, and with bone, hexosamine and collagen formation in animals [12]. The AI criterion for which boron, chromium, nickel and silicon have limited findings is having a defined functional indicator or marker of status. However, this may not be a critical impediment to establishing dietary intake recommendations for these elements because such a shortcoming did not prevent setting AIs for manganese and molybdenum [2]. The best marker for status for these elements in humans may be a plasma or serum concentration below that usually found. For example, a plasma or serum concentration below 3.1 mol (34 g)/L for boron and 3.9 mol (110 g)/L for silicon might be an indication of a sub-optimal status for these elements [11]. There is some evidence for dose responses to boron, chromium, nickel and silicon for their beneficial effects. Humans responded to boron supplementation when their intakes were less than 0.5 mg/d [13]. A relatively high (>200 g/d) chromium intake apparently is needed to have a beneficial effect on glucose metabolism [14]. Only experimental animal data exists to suggest an intake below which nickel supplementation might give a beneficial effect; these data indicate an intake below 50 g/d [15]. In a cross-sectional, population-based study, bone mineral density was higher in men and pre-menopausal women when the dietary intake of silicon was >40 mg/d than when it was 1000 g/d for several months [2]. Animal studies have not found similar effects. Nonetheless, individuals with preexisting renal and liver disease may have an increased risk for adverse effects with high chromium supplementation [2]. Animal studies indicate that high amounts of inorganic
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trivalent chromium are needed to produce adverse effects [18]. Toxic amounts of trivalent chromium are usually stated in mg, not g, per kg feed for experimental animals. The preceding shows that boron, chromium, nickel, and silicon have low orders of toxicity and safe intakes are much higher than reported typical dietary intakes that range from 0.35 to 3.0 mg/d for boron [2]; from 13 to 54 g/d for chromium [2]; from 70 to 260 g/d for nickel [11]; and 15 to 50 mg/d for silicon [12]. Conclusion Increasing evidence indicates that the trace elements boron, chromium, nickel and silicon in safe amounts are efficacious in reducing the risk of chronic diseases such as osteoporosis and diabetes, and are beneficial to central nervous system function and bone development. There are plausible mechanisms of actions for these beneficial effects that are found when dietary intakes are above identified low levels. Consideration should be given for providing dietary guidance for these trace elements. If the science base is not considered adequate to set an AI, an appropriate action would be to recommend the consumption of foods that assures intakes of boron, chromium, nickel and silicon in amounts that promote health and well-being. Conflict of interest The author has no conflicts of interest to declare. References [1] Nielsen FH. Molybdenum and beneficial bioactive trace elements. In: Stipanuk MH, Caudill MA, editors. Biochemical, physiological molecular aspects of human nutrition. St. Louis: Elsevier; 2013. p. 899–912. [2] Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Academies Press; 2001. [3] Food and Nutrition Board, Institute of Medicine. How should the recommended dietary allowances be revised? Washington, DC: National Academy Press; 1994. [4] Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for water, potassium, sodium, chloride, and sulfate. Washington, DC: National Academies Press; 2005. [5] Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein, and amino acids (macronutrients). Washington, DC: National Academies Press; 2002. [6] Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington, DC: National Academy Press; 1997. [7] Nielsen FH, Meacham SL. Growing evidence for human health benefits of boron. J Evid-Based Complement Med 2011;16:169–80. [8] Vincent JB, Bennett R. Potential and purported roles for chromium in insulin signaling: the search for the holy grail. In: Vincent JB, editor. The nutritional biochemistry of chromium (III). Amsterdam: Elsevier; 2007. p. 1–40. [9] Kinrade S, Del Nin JW, Schach AS, Sloan TA, Wilson KL, Knight CT. Stable fiveand six-coordinated silicate anions in aqueous solution. Science 1999;285: 1542–5. [10] Anderson RA. Chromium, glucose intolerance and diabetes. J Am Coll Nutr 1998;17:548–55. [11] Nielsen FH. Boron, manganese, molybdenum, and other trace elements. In: Bowman BA, Russell RM, editors. Present knowledge in nutrition, vol. 1, 9th ed. Washington, DC: ILSI Press; 2006. p. 506–26. [12] Jugdaohsingh R. Silicon and bone health. J Nutr Health Aging 2007;11:99–110. [13] Nielsen FH. Is boron nutritionally relevant? Nutr Rev 2008;66:183–91. [14] Cefalu WT. Clinical effect of chromium supplements on human health. In: Vincent JB, editor. The nutritional biochemistry of chromium (III). Amsterdam: Elsevier; 2007. p. 163–81. [15] Nielsen FH. Ultratrace elements in nutrition: current knowledge and speculation. J Trace Elem Exp Med 1998;11:251–74. [16] Jugdaohsingh R, Tucker KL, Qiao N, Cupples LA, Kiel DP, Powell JJ. Dietary silicon intake is positively associated with bone mineral density in men and premenopausal women of the Framingham Offspring Cohort. J Bone Miner Res 2004;19:297–307. [17] Anderson RA, Bryden NA, Polansky MM. Dietary chromium intake: freely chosen diets, institutional diets, and individual foods. Biol Trace Elem Res 1992;32:117–21. [18] National Research Council. Mineral tolerance of animals. 2nd revised ed. Washington, DC: National Academies Press; 2005.
Please cite this article in press as: Nielsen FH. Should bioactive trace elements not recognized as essential, but with beneficial health effects, have intake recommendations. J Trace Elem Med Biol (2014), http://dx.doi.org/10.1016/j.jtemb.2014.06.019
