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Micronutrients in Parenteral Nutrition: Boron, Silicon, and Fluoride

  • Forrest H. Nielsen
    Correspondence
    Reprint requests Address requests for reprints to: Forrest H. Nielsen, PhD, USDA, ARS, Grand Forks Human Nutrition Research Center, 2420 2nd Avenue N, Stop 9034, Grand Forks, North Dakota 58202-9034. fax: (701) 795-8240
    Affiliations
    United States Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, North Dakota
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      Boron may be beneficial for bone growth and maintenance, central nervous system function, and the inflammatory response, and silicon may be beneficial for bone maintenance and wound healing. Fluoride is not an essential element but amounts provided by contamination may be beneficial for bone strength. Fluoride toxicity may be a concern in parenteral nutrition. Further studies are warranted to determine whether there are optimal amounts of boron and silicon that should be delivered to typical and special population patients receiving parenteral nutrition. In addition, further studies are needed to determine whether providing the dietary guideline of adequate intake amounts of fluoride parenterally would prevent or treat parenteral nutrition osteopenia.

      Abbreviations used in this paper:

      AI (adequate intake), B (boron), F (fluoride), PN (parenteral nutrition), SAM (S-adenosylmethionine), SI (silicon)
      Boron (B) is essential for some organisms in all phylogenetic kingdoms. Among the higher animals that require B are zebra fish and frogs. Boron-deprived male frogs show atrophied testes, decreased sperm counts, and sperm dysmorphology; female frogs show atrophied ovaries and impaired oocyte maturation.
      • Fort D.J.
      • Stover E.L.
      • Strong P.L.
      • et al.
      Chronic feeding of a low boron diet adversely affects reproduction and development in Xenopus laevis.
      • Fort D.J.
      • Rogers R.L.
      • McLaughlin D.W.
      • et al.
      Impact of boron deficiency on Xenopus laevisA summary of biological effects and potential biochemical roles.
      During rapid cell division in embryogenesis, B-deprived zebra fish zygotes show blebbing of cell membranes, followed by cytoplasmic and yolk extrusion.
      • Rowe R.I.
      • Eckhert C.D.
      Boron is required for zebrafish embryogenesis.
      These changes prevent the completion of the life cycle (ie, deficiency causes impaired growth, development, or maturation such that procreation does not occur), which is a criterion for essentiality.
      Although there are data suggesting that B deprivation impairs early embryonic development in mice,
      • Lanoue L.
      • Strong P.L.
      • Keen C.L.
      Adverse effects of a low boron environment on the preimplantation development of mouse embryos in vitro.
      the critical experiment showing that B is essential for a mammal to complete the life cycle, or defining a biochemical role for B necessary for life, is lacking. However, B-deprived experimental animals and human beings, when compared with controls fed nutritional amounts of B, show detrimental effects in bone growth and bone maintenance, brain function, and inflammatory response regulation. Boron deprivation impaired alveolar bone formation in mice, and alveolar bone repair after tooth extraction in rats; alveolus osteoblast surface was decreased and quiescent bone-forming surface was increased.
      • Gorustovich A.A.
      • Steimetz T.
      • Nielsen F.H.
      • et al.
      Histomorphometric study of alveolar bone healing in rats fed a boron-deficient diet.
      • Gorustovich A.A.
      • Steimetz T.
      • Nielsen F.H.
      • et al.
      A histomorphometric study of alveolar bone modeling and remodeling in mice fed a boron-deficient mice.
      Boron deprivation decreased vertebral bone volume fraction and trabecular thickness, and increased trabecular separation and structural model index in rats.
      • Nielsen F.H.
      • Stoecker B.J.
      • Penland J.G.
      Boron as a dietary factor for bone microarchitecture and central nervous system function.
      Boron deprivation exacerbated arthritis induced by an antigen in rats.
      • Hunt C.D.
      • Idso J.P.
      Dietary boron as a physiological regulator of the normal inflammatory response: a review and current research progress.
      Boron deprivation impaired cognitive processes of attention and memory, and psychomotor skills in human beings.
      • Penland J.G.
      The importance of boron nutrition for brain and psychological function.
      In addition, low dietary boron has been associated with prostate,
      • Cui Y.
      • Winton M.I.
      • Zhang Z.F.
      • et al.
      Dietary boron intake and prostate cancer risk.
      cervical,
      • Korkmaz M.
      • Uzgören E.
      • Bakirdere S.
      • et al.
      Effects of dietary boron on cervical cytopathology and on micronucleus frequency in exfoliated buccal cells.
      breast,
      • Touillaud M.S.
      • Pillow P.C.
      • Jakovljevic J.
      • et al.
      Effect of dietary intake of phytoestrogens on estrogen receptor status in premenopausal women with breast cancer.
      and lung
      • Mahabir S.
      • Spitz M.R.
      • Barrera S.L.
      • et al.
      Dietary boron and hormone replacement therapy as risk factors for lung cancer in women.
      cancer in human beings.
      The diverse responses (many that may be secondary to a primary action) reported for low intakes of B have made it difficult to pinpoint a primary mechanism responsible for its bioactivity. However, the chemical characteristics of B may provide some clues as to a mechanism. At the pH of most biological fluids, about 96% of B exists as boric acid, B(OH)3, a Lewis acid that accepts a hydroxyl group during the production of a proton. This property allows boric acid to react with biomolecules with hydroxyl groups to form B esters. Boron ester formation is best when hydroxyl groups are adjacent and cis.
      The phosphoinositides, glycoproteins, and glycolipids of membranes contain cis-hydroxyl groups that may form diester borate polyl complexes, which could act as calcium chelators and/or redox metabolism modifiers
      • Goldbach H.E.
      • Huang L.
      • Wimmer M.A.
      Boron functions in plants and animals: recent advances in boron research and open questions.
      affecting membrane integrity and function. Thus, a low B status may impair important hormone receptors and signal transduction functions. Supporting this suggestion are findings showing that B deprivation impairs the actions of some hormones. Boron deprivation reportedly decreases insulin sensitivity
      • Bakken N.A.
      • Hunt C.D.
      Dietary boron decreases peak pancreatic in situ insulin release in chicks and plasma insulin concentrations in rats regardless of vitamin D or magnesium status.
      and increases the requirement for vitamin D to prevent gross bone abnormalities
      • Hunt C.D.
      • Nielsen F.H.
      Interaction between boron and cholecalciferol in the chick.
      and the need for exogenous thyroxine for tail resorption in frog development.
      • Fort D.J.
      • Rogers R.L.
      • McLaughlin D.W.
      • et al.
      Impact of boron deficiency on Xenopus laevisA summary of biological effects and potential biochemical roles.
      Boron as boric acid also readily forms complexes with several biologically important sugars, including ribose, a component of adenosine.
      • Ricardo A.
      • Carrigan M.A.
      • Olcott A.N.
      • et al.
      Borate minerals stabilize ribose.
      S-adenosylmethionine (SAM) and diadenosine phosphates have higher affinities for B than any other currently recognized B ligands present in animal tissues.
      • Ralston N.V.C.
      • Hunt C.D.
      Diadenosine phosphates and S-adenosylmethionine: novel boron binding biomolecules detected by capillary electrophoresis.
      Diadenosine phosphates are present in all cells and function as signal nucleotides associated with neuronal response. SAM is one of the most frequently used enzyme substrates.
      • Loenen W.A.M.
      S-adenosylmethionine: jack of all trades and master of everything?.
      About 95% of SAM is converted into S-adenosylhomocysteine, which is important for methylation of DNA, RNA, proteins, phospholipids, hormones, and neurotransmitters.
      • Loenen W.A.M.
      S-adenosylmethionine: jack of all trades and master of everything?.
      Hydrolyzation of S-adenosylhomocysteine yields homocysteine. High circulating homocysteine and depleted SAM have been implicated in many human diseases including atherosclerosis, osteoporosis, arthritis, cancer, diabetes, and impaired brain function. The finding that B deprivation increased plasma homocysteine and decreased liver SAM levels in rats suggests that B may be bioactive through affecting the formation or use of SAM.
      • Nielsen F.H.
      Boron deprivation decreases liver S-adenosylmethionine and spermidine and increases plasma homocysteine and cysteine in rats.

      Assessment of Deficiency and Toxicity

      Boron is similar to most essential trace elements in that there is no single good indicator of status. About 90% of ingested B is absorbed and then efficiently excreted via the urine.
      • Hunt C.D.
      • Herbel J.L.
      • Nielsen F.H.
      Metabolic responses of postmenopausal women to supplemental dietary boron and aluminum during usual and low magnesium intake: boron, calcium, and magnesium absorption and retention and blood mineral concentrations.
      Thus, urinary B assesses only the recent intake. However, urinary B combined with a B intake assessment may give an indication of whether an individual has a low B status. Human beings consuming less than 0.5 mg/day for 2–3 months respond to a nutritional B supplement (3 mg/day).
      • Penland J.G.
      The importance of boron nutrition for brain and psychological function.

      Nielsen FH. Evidence for the nutritional essentiality of boron. J Trace Elem Exp Med 1196;9:215–229.

      Thus, a person on parenteral nutrition (PN) providing less than 0.5 mg B/day and excreting less than 0.5 mg B/day may have a low B status.
      Plasma or serum B also may have some value as an indicator of B status. In one human study, a 9.0-fold increase in dietary B (mean from 0.36 to 3.23 mg/day) increased plasma B concentrations 1.5-fold (mean from 64 to 95 ng/mL).
      • Hunt C.D.
      • Herbel J.L.
      • Nielsen F.H.
      Metabolic responses of postmenopausal women to supplemental dietary boron and aluminum during usual and low magnesium intake: boron, calcium, and magnesium absorption and retention and blood mineral concentrations.
      In another study, supplementing 43 perimenopausal women with 2.5 mg B/day for 60 days increased the median plasma B concentration from 33 ng/mL (range, 20–67 ng/mL) to 52 ng/mL (range, 28–75 ng/mL).
      • Nielsen F.H.
      • Penland J.G.
      Boron supplementation of peri-menopausal women affects boron metabolism and indices associated with macromineral metabolism, hormonal status and immune function.
      These findings suggest that persons with serum or plasma B concentrations in the lower part of these ranges might be suspected of having a low B status. Plasma or serum B also may be used as an indicator of excessive B intake. Mean blood B concentrations were 68, 347, 585, 450, and 659 ng/mL in people from areas where drinking water provided 0.02, 0.08, 0.3, 0.4, and 0.5 mg B/kg body wt/day, respectively, in the drinking water.
      • Barr R.D.
      • Clarke W.B.
      • Clarke R.M.
      • et al.
      Regulation of lithium and boron levels in normal human blood: environmental and genetic considerations.
      Thus, blood B concentrations greater than 300 ng/mL would indicate a B intake in excess of that needed to prevent signs of B deprivation. Plasma or serum B concentrations greater than 1 μg/mL may indicate B toxicity.
      World Health Organization, International Programme on Chemical Safety
      Environmental health criteria for boron.
      Boron is not very toxic when administered orally. Its relatively low toxicity allowed boric acid and borates to be used as food preservatives and in oral medicinal products in the late 19th and early 20th centuries. Toxicity in animals generally occurs only after dietary B exceeds 100 mg/kg. The signs of chronic B toxicity, based mainly on animal findings, include poor appetite, weight loss, and decreased sexual activity, seminal volume, sperm count, and sperm motility.
      World Health Organization, International Programme on Chemical Safety
      Environmental health criteria for boron.

      Dose Range Recommendation for Typical PN-Fed Patients

      The Food and Nutrition Board of the National Academy of Sciences set no Recommended Dietary Allowance for B, but did set tolerable upper limits.
      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.
      These tolerable upper limits in mg/day are as follows: adults (≥19 y), 20; adolescents (14–18 y), 17; children (9–13 y), 11; children (4–8 y), 6; and children (1–3 y), 3. In human depletion-repletion experiments, subjects responded to a boron supplement after consuming a diet supplying less than 0.50 mg/day for 63 days.
      • Penland J.G.
      The importance of boron nutrition for brain and psychological function.
      • Loenen W.A.M.
      S-adenosylmethionine: jack of all trades and master of everything?.
      An analysis of both human and animal data has suggested that an acceptable safe range of population mean intakes for B for adults could be 1–13 mg/day.
      World Health Organization
      Trace elements in human nutrition and health.
      Thus, a recommendation that patients receive 1 mg B/day through typical PN could be beneficial for their bone and brain health. A limited number of reports have indicated that most PN solutions do not supply this amount of B, which comes only from contamination of ingredients. The calculated daily intake for B from PN based on analyses of individual components was 0.148 mg/day in one study.
      • Berner Y.N.
      • Shuler T.R.
      • Nielsen F.H.
      • et al.
      Selected ultratrace elements in total parenteral nutrition solutions.
      In another study, the calculated intake for B in PN based on analyses of individual components was 1.796 mg/day,
      • Pluhator-Murton M.M.
      • Fedorak R.N.
      • Audette R.J.
      • et al.
      Trace element contamination of total parenteral nutrition. 1. Contribution of component solutions.
      but actual analysis of the intravenous delivered solution was only between 0.20 and 0.25 mg/day.
      • Pluhator-Murton M.M.
      • Fedorak R.N.
      • Audette R.J.
      • et al.
      Trace element contamination of total parenteral nutrition. 2. Effect of storage duration and temperature.
      Urinary analysis of trauma patients receiving PN indicated that they received only about 0.2 mg B/day.
      • Klein C.J.
      • Nielsen F.H.
      • Moser-Veillon P.B.
      Trace element loss in urine and effluent following traumatic injury.
      These findings suggest that depending on contamination to provide health-giving amounts of B may not be appropriate.

      Silicon

       Metabolic Function

      Silicon (Si) is nutritionally essential for some lower forms of life (diatoms, radiolarians, and some sponges) and may be essential for some higher plants (eg, rice). For more than 35 years, the nutritional interest in Si for higher animals and human beings has focused on its beneficial effects on collagen and glycosaminoglycan formation or function, which could influence bone formation and maintenance, cardiovascular health, and wound healing. Although numerous apparent Si deficiency signs have been described, Si still is not generally accepted as an essential nutrient for higher animals and human beings. The critical experiment showing that Si is essential for a mammal to complete the life cycle, or defining a biochemical role for Si necessary for life, is lacking.
      In 1978, Schwarz
      • Schwarz K.
      Significance and function of silicon in warm-blooded animals Review and outlook.
      described the difficulty in defining a biochemical function for Si. He first suggested that Si as an ether- or ester-like derivative of silicic acid had a cross-linking role in connective tissue; the low Si content of connective tissue negated that suggestion. Schwarz
      • Schwarz K.
      Significance and function of silicon in warm-blooded animals Review and outlook.
      subsequently hypothesized, because of the stability of the O-Si-O bond, that Si is involved in binding structures such as cell surfaces or macromolecules to each other. If this hypothesis is confirmed, it would indicate that Si may be involved in the interaction between an extracellular matrix macromolecule and osteotrophic cells such that it affects cartilage composition and ultimately cartilage calcification. Another hypothesized role for Si in higher animals is that it interacts (as silicic acid) with an aluminum species (eg, Al[OH]2+) to form an aluminosilicate that prevents aluminum from competing for iron-binding sites (eg, prolyl hydroxylase), and thus prevents adverse effects of iron replacement by aluminum on collagen synthesis and structure.
      • Birchall J.D.
      • Espie A.W.
      Biological implications of the interaction (via silanol groups) of silicon with metal ions.
      In addition to alleviating aluminum toxicity, high intakes of Si apparently can be beneficial through facilitating the absorption or use of some minerals, including copper
      • Emerick R.
      • Kayongo-Male H.
      Silicon facilitation of copper utilization in the rat.
      and magnesium,
      • Kikunaga S.
      • Kitano T.
      • Kikukawa T.
      • et al.
      Effects of fluoride and silicon on distribution of minerals in the magnesium-deficient rat.
      which are essential for bone growth and maintenance, cardiovascular health, and wound healing.

       Assessment of Deficiency and Toxicity

      An indicator of Si status has not been established. A recent report indicated that an average of 41% of dietary Si is excreted in the urine, and that the Si content of foods consumed is correlated with urinary Si excretion.
      • Jugadaohsingh R.
      • Anderson S.H.C.
      • Tucker K.L.
      • et al.
      Dietary silicon intake and absorption.
      Carlisle
      • Carlisle E.M.
      Silicon.
      suggested that a daily minimum requirement for Si might be near 10–25 mg/day based on the amount excreted in urine in 24 hours. Silicon entering the bloodstream is transferred rapidly to tissues, which results in the Si concentration in blood remaining relatively constant over a range of dietary intakes. Reported mean or median fasting human serum levels range from 11 to 31 μg Si/dL.
      • Van Dyck K.
      • Robberecht H.
      • Van Cauwenbergh R.
      • et al.
      Indication of silicon essentiality in humans Serum concentrations in Belgian children and adults, including pregnant women.
      • Bissé E.
      • Epting T.
      • Beil A.
      • et al.
      Reference values for serum silicon in adults.
      Thus, serum Si concentrations in the lower part of this range and urinary excretion of less than 10 μg/day may be an indication of a low Si status.
      In experimental animals, urinary excretion of Si increases with an increasing intake of siliceous substances, but reaches a maximum that is not exceeded by increasing intake. This maximum apparently is set by the rate and extent of Si absorption and not by the excretory ability of the kidney because peritoneal injection of Si can increase urinary excretion above the upper limit achieved by dietary intake.
      • Sauer F.
      • Laughland D.H.
      • Davidson W.M.
      Silica metabolism in guinea pigs.
      The limitation in absorption and efficient urinary excretion results in Si having a very low order of toxicity through oral intake. Moreover, these homeostatic control mechanisms would make effects of oral Si toxicity poor indicators of the effects of intravenously injected soluble Si, which apparently has been virtually ignored. One report stated that daily intravenous injection of 5 or more mg of “silica sol” in rabbits induced liver fibrosis, enlargement of the spleen, and interstitial nephritis.
      • Friedberg K.D.
      • Schiller E.
      Silicon.
      Two dialysis patients with high Si concentrations (385 and 235 μg/dL) showed skin eruptions, folliculitis, and disturbed hair growth.
      • Saldanha L.F.
      • Gonick H.C.
      • Rodriguez H.J.
      • et al.
      Silicon-related syndrome in dialysis patients.
      However, there was no mention of these effects in hemodialysis patients with high Si concentrations in plasma (420 μg/dL) in another study.
      • Parry R.
      • Plowman D.
      • Delves H.T.
      • et al.
      Silicon and aluminum interactions in haemodialysis patients.

       Dose Range Recommendation for Typical PN-Fed Patients

      The Food and Nutrition Board judged that animal and human data were too limited for setting any Dietary Reference Intakes for Si.
      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.
      Based on the amount excreted in urine in 24 hours, a daily minimum requirement for Si might be near 10–25 mg/day.
      • Carlisle E.M.
      Silicon.
      Thus, an intake near these amounts through typical PN may be beneficial for bone health and wound healing. High dietary molybdenum and aging may increase the amount of Si needed for beneficial effects.
      • Carlisle E.M.
      Silicon.
      A very limited number of reports have indicated that most PN solutions do not supply this amount of Si, which comes only from contamination of ingredients. Bohrer et al
      • Bohrer D.
      • Bortoluzzi F.
      • Nascimento P.C.
      • et al.
      Silicate release from glass for pharmaceutical preparations.
      determined the Si content in numerous commercial formulations used for parenteral administration and found that most supplied less than 1 mg Si/L. Urinary analysis of trauma patients receiving PN indicated that they received only 1–3 mg Si/day.
      • Klein C.J.
      • Nielsen F.H.
      • Moser-Veillon P.B.
      Trace element loss in urine and effluent following traumatic injury.

      Fluoride

       Metabolic Function

      Fluoride (F) has a well-established beneficial action in human beings. Through a pharmacologic action, F imparts caries resistance to the enamel of teeth. In addition, high or pharmacologic amounts of F prevented anemia and infertility caused by iron deficiency in mice, improved growth of suboptimally growing rats, and alleviated nephrocalcinosis induced by phosphorus feeding and soft-tissue calcification caused by magnesium deprivation (see article by Nielsen et al
      • Nielsen F.H.
      Ultratrace elements in nutrition: current knowledge and speculation.
      for original citations for these effects). Fluoride cannot be considered an essential nutrient because the critical experiment showing F is essential to complete the life cycle, or defining a biochemical role for F necessary for life, is lacking. Moreover, unequivocal or specific signs of F deprivation have not been described for higher animals or human beings. Fluoride deprivation in goats has been reported to decrease life expectancy and induce pathologic histology in the kidney and endocrine organs.
      • Anke M.
      • Groppel B.
      • Masaoka T.
      Recent progress in exploring the essentiality of the non-metallic ultratrace elements fluorine and bromine to the nutrition of animals and man.
      However, these findings need confirmation before being accepted as signs of F deprivation in higher animals. The mechanisms through which F has beneficial effects are making hydroxyapatite of tooth enamel and dentin less soluble and thus more resistant to acid attack, and altering calcium, magnesium and/or phosphorus metabolism, and tissue deposition and/or use.
      • Whitford G.M.
      Fluoride.
      • Ophaug R.H.
      • Singer L.
      Effect of fluoride on the mobilization of skeletal magnesium and soft-tissue calcinosis during acute magnesium deficiency in the rat.
      • Borke J.L.
      • Whitford G.M.
      Chronic fluoride ingestion decreases 45Ca uptake by rat kidney membranes.
      Manifestations of toxic amounts of F also may involve the alteration of calcium and magnesium metabolism and tissue deposition.
      • Ophaug R.H.
      • Singer L.
      Effect of fluoride on the mobilization of skeletal magnesium and soft-tissue calcinosis during acute magnesium deficiency in the rat.
      • Borke J.L.
      • Whitford G.M.
      Chronic fluoride ingestion decreases 45Ca uptake by rat kidney membranes.

       Assessment of Deficiency and Toxicity

      Because F deficiency has not been defined, there is no basis for assessing a low F status. One sign of F toxicity is dental fluorosis, which is characterized by a more porous enamel.
      • Whitford G.M.
      Fluoride.
      In some studies, high amounts of F in drinking water have been associated with an increased risk for bone fractures. However, in other studies, high F in drinking water was found to decrease risk, or had no relationship, to bone fractures.
      • Whitford G.M.
      Fluoride.
      The reason for this inconsistency may be that there is biphasic response to high F intake. Animal studies suggest that F increases bone strength, reaching peak strength when it contains 1200 μg F/g, followed by a decline at higher concentrations, which eventually leads to impaired bone quality.
      • Allolio B.
      • Lehmann R.
      Drinking water fluoridation and bone.
      Bone ash concentrations of 3500–5500 μg F/g result in osteosclerosis, stiffness and pain in joints, and slight calcification of ligaments, and concentrations of 9000 μg F/g in ash result in crippling skeletal fluorosis with bone exostoses and marked calcification of ligaments that limits joint mobility.
      • Whitford G.M.
      Fluoride.
      Essentially 100% of F as fluoridated water ingested in the fasted state, and 50%–80% of F ingested with food is absorbed. Approximately 50% of F absorbed each day is deposited in calcified tissue (bone and developing teeth), and 50% is cleared by the kidney.
      Food and Nutrition Board, Institute of Medicine
      Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D and fluoride.
      Thus, urinary F excretion may be used to assess the exposure to F. A urinary F concentration of 15 mg/L would suggest a daily exposure to 20–30 mg of F. It may take 10 years or more of daily exposure to about 20 mg F to reach skeletal F concentrations associated with crippling fluorosis.
      • Whitford G.M.
      Fluoride.
      A high serum F level also may be an indicator of risk for F toxicity. The use of F as a therapy for osteoporosis indicated that the threshold at which F affects bone cells is 95 ng/mL and the toxic threshold (fluorosis of bone characterized by enlarged lacunae, abnormal bone formation, impaired mineralization, and reduced bone strength) was 190 ng/mL of serum.
      • Pak C.Y.
      • Sakhaee K.
      • Rubin C.D.
      • et al.
      Sustained-release sodium fluoride in the management of established postmenopausal osteoporosis.

       Dose Range Recommendation for Typical PN-Fed Patients

      The Food and Nutrition Board set Adequate Intake (AI) levels for F based on the amounts that protect against dental caries and generally do not result in any mottling of teeth.
      Food and Nutrition Board, Institute of Medicine
      Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D and fluoride.
      These AI in mg/day are as follows: infants (0–6 mo), 0.01; infants (7–12 mo), 0.5; children (1–3 y), 0.7; children (4–8 y), 1; children (9–13 y), 2; adolescents (14–18 y), 3; adult women (≥19 y), 3; and adult men (≥19 y), 4. The tolerable upper limits were set on the basis of the possibility of dental fluorosis in children and skeletal fluorosis in adults. The tolerable upper limits set in mg/day are as follows: infants (0–6 mo), 0.7; infants (7–12 mo), 0.9; children (1–3 y), 1.3; children (4–8 y), 2.2; and children and adults (>8 y), 10. A recommended intake of F for typical PN-fed patients could be amounts that are near the AI. When F intake is determined, the amount in drinking water must be considered. In one study, patients with chronic intestinal failure received home PN that provided a mean of 0.74 mg F/day, but intake from water and tea increased the F intake to a mean of 8.03 mg/day.
      • Boulétreau P.H.
      • Bost M.
      • Fontanges E.
      • et al.
      Fluoride exposure and bone status in patients with chronic intestinal failure who are receiving home parenteral nutrition.
      This study and another study that determined the amount of F delivered in one feeding (1 mg) in a home PN program of a hospital in England
      • Forbes G.M.
      • Forbes A.
      Micronutrient status in patients receiving home parenteral nutrition.
      indicated that PN solutions do provide significant amounts of F, but below the AI.
      • Forbes G.M.
      • Forbes A.
      Micronutrient status in patients receiving home parenteral nutrition.

      Summary Recommendations

      Because B may be beneficial for bone growth and maintenance, central nervous system function, and the inflammatory response, and Si may be beneficial for bone maintenance and wound healing, further studies are warranted to determine whether there are optimal amounts of B and Si that should be delivered to typical and special populations of patients receiving PN. In addition, further studies are needed to determine whether providing AI amounts of F parenterally would prevent or treat PN osteopenia.

      Question and Answer Session

      DR BERGER: Are you advocating adding boron and silicon to standard solutions?
      DR NIELSEN: That probably has to be approved by the FDA, but my personal opinion is yes. I recommend a milligram of boron per day and about 10 mg of silicon per day, which I think will have some health benefits.
      DR DELUCA: When we make purified diets we don't add boron. How much boron is inherent in something like highly purified casein? We've run experiments of 3 generations of rats without any detrimental effects from not adding boron to the diet. I'm wondering whether that's because there is boron contamination in our diets.
      DR NIELSEN: Do you use sucrose or do you use starch?
      DR DELUCA: We use glucose monohydrate.
      DR NIELSEN: If there is no starch, then boron is most likely a contaminant of your mineral mix, especially the calcium and magnesium sources. Some starch sources may be high in boron; ground corn must be acid-washed to make it low in boron. I have made diets that used sucrose and fructose with small amounts of ground corn and found that the diets are quite low in boron. Boron must be around 0.1 to 0.2 mg/kg to see deprivation effects. If the boron is 0.3, 0.4, or 0.5, you see only minor effects.
      DR SHIKE: As you may remember, a number of years ago we did a study together.
      DR NIELSEN: Yes.
      DR SHIKE: We provided you with home PN solutions, which were complete solutions, and also the separate components to determine their trace element composition. As I remember, the conclusion of that study was that there were a number of unexpected trace elements, including silicon, provided in amounts through contamination that were more or less comparable to what people absorbed from a normal diet. However, boron was only about 10% of what we calculated people absorbed. So my question is, do you feel at this point there are adequate data that you would propose adding 1 mg boron/day?
      DR NIELSEN: I believe the data warrant adding 1 mg of boron/day to PN solutions. I have performed 3 human studies in which I fed 0.25 mg of boron a day, provided by natural diets low in fruits and vegetables, and the pulses. We observed altered responses to estrogen therapy, changes in lipid metabolism, and some effects on bone status indicators. When we supplemented these people with 3 mg/day of boron, we reversed these changes. We used 3 mg/day because that is what I thought was normally provided by diet, but I now know it is only 1.5 mg. I believe 1 mg/day in PN solutions would prevent the changes that occurred when dietary boron was low in my studies.
      DR PIRONI: A study published in the American Journal of Clinical Nutrition demonstrated that patients on long-term home parenteral nutrition with a short bowel may absorb fluoride from their drinking water. Is it possible to supplement these patients with boron and silicon through their drinking water?
      DR NIELSEN: Yes, it is possible. I don't think there is any worry about fluoride deficiency. Of more concern is that PN patients are getting too much fluoride. Most parenteral nutrition solutions are going to supply about 1 mg of fluoride per day, which is probably adequate. The fluoride might be useful in reducing the osteopenia that is associated with long-term parenteral nutrition. In regard to silicon, there are indications that, in contrast to the study we did with Moshe, higher purification of PN solutions, and the wider use of plastic bags rather than glass, now results in silicon concentrations in parenteral nutrition solutions below 10 mg/day, and in fact, are closer to 1–3 mg/day; so adding more silicon would probably be of benefit.
      DR BUCHMAN: Forrest, do you have any idea as to whether the water source for IV solutions, even though it is distilled and deionized, could in some locations be fluoridated?
      DR NIELSEN: I am not sure. In some areas there is a trace of fluoride in water used for IVs. It should be noted that there are parts of the country, for example, California, where the water supply can have high boron content.
      DR BERGER: You have provided evidence that boron and silicon are essential trace elements, what about vanadium and tin? Are we reaching the point where we should consider adding them also? Is vanadium involved in myocardial metabolism?
      DR NIELSEN: I think the evidence for tin being essential is pretty slim. The initial work was done by Schwarz back in the 1970s. I and several others have tried to repeat his findings, but have been unsuccessful. At present, there is no strong evidence that supports a tin requirement. There might be some need for vanadium, but if there is an essential requirement it is very small, and those minute amounts probably would be supplied through contamination. At present, various vanadium compounds are being studied pharmacologically because vanadium has a positive effect in diabetes.

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