Absorption, Transport, Storage, and Excretion: Calcium is absorbed by all parts of the small intestine, but the most rapid absorption after a meal occurs in the more acidic (pH <7) duodenum. Absorption is slower in the remainder of the small bowel because of the alkaline pH, but the amount of calcium absorbed is actually greater in the lower segments of the small intestine, including the ileum. Small amounts of calcium can also be absorbed in the colon. Only approximately 30% of ingested calcium is absorbed by adults, but a few individuals may absorb as little as 10% and some (rarely) as much as 60% of ingested calcium. Late in life, bone retention of calcium from food and supplements is limited unless sufficient vitamin D or a bone-conserving drug is available.

Calcium is absorbed by two mechanisms: active transport, which operates predominantly at low luminal concentrations of calcium ions, and passive transport or paracellular transfer, which operates at high luminal concentrations of calcium ions. The active transport mechanism, mainly in the duodenum and proximal jejunum, has limited capacity. It is controlled through the action of 1,25(OH)₂D₃. This vitamin-hormone increases calcium uptake at the brush border of the intestinal mucosal cell by also stimulating the production of calcium-binding proteins (calbindins) and other mechanisms. The role of calbindins in the intestinal absorbing cells is to store calcium ions temporarily after a meal and ferry them to the basolateral membrane for the final step of absorption. The calcium-binding proteins bind two or more calcium ions per protein molecule.

The second absorption mechanism, which is passive, nonsaturable (with no limit), and independent of vitamin D, occurs along the entire length of the small intestine. When large amounts of calcium are consumed in a single meal (e.g., from a dairy food or a supplement), much of the calcium is absorbed by this passive route. The active transport mechanism is more important when calcium intakes are well below recommended intakes and body requirements are not being met.

Numerous factors influence the bioavailability and absorption of calcium within the gut lumen. The greater the need and the smaller the dietary supply, the more efficient is absorption. Increased needs during growth, pregnancy, lactation, calcium-deficient states, or exercise resulting in high bone density enhance calcium absorption. Low vitamin D intake or inadequate exposure to sunlight reduces calcium absorption, especially among older adults. In addition, the efficiency of skin production of vitamin D by older adults is lower than that of younger people. Aging is also characterized by achlorhydria, which results in less gastric acidity and reduced calcium absorption.

Calcium is absorbed only if it is present in an ionic form. Thus calcium is best absorbed in an acidic medium; the hydrochloric acid secreted in the stomach, such as that secreted during a meal, increases calcium absorption by lowering the pH in the proximal duodenum. This also applies to calcium supplements; therefore taking a calcium supplement with a meal improves absorption, especially in older adults. Lactose enhances calcium absorption. Even in adults with lactose intolerance, lactose probably improves calcium absorption.

Calcium is not absorbed if it is precipitated by another dietary constituent such as oxalate or if it forms soaps with free fatty acids. Oxalic acid (oxalate) in rhubarb, spinach, chard, and beet greens forms insoluble calcium oxalate in the digestive tract (see Chapter 36). For example, only 5% of the calcium in spinach is absorbed. Phytic acid (phytate) combines with calcium to form calcium phytate, which is insoluble and cannot be absorbed. These unabsorbed forms of calcium are excreted in the feces as calcium oxalates and calcium soaps.

Dietary fiber may decrease calcium absorption, but this may only be a problem for those who consume more than 30 g/day. Lower intakes of fiber have little effect on calcium availability. Medications can affect bioavailability or increase calcium excretion, both of which may contribute to bone loss. With fat malabsorption, calcium absorption is decreased because of the formation of calcium–fatty acid soaps. Calcium absorption does not seem to be affected by the amount of phosphate in the diet unless the intake of phosphate is excessively high or by the calcium/phosphorus ratio.

Functions: Adequate dietary calcium is needed to permit optimal gains in bone mass and density in the prepubertal and adolescent years. These gains are especially critical for girls because the accumulated bone may provide additional protection against osteoporosis in the years after menopause. Peak calcium retention by girls has been shown to occur in the prepubertal and early pubertal periods and is influenced by race, with black girls having significantly higher retention rates (Wigertz et al., 2005).

Postmenopausal women need to obtain sufficient amounts of calcium to maintain bone health and suppress PTH, which increases later in life in most individuals, perhaps as a result of inadequate calcium in the diet. Additional amounts of calcium are recommended to meet the needs of pregnancy and lactation, infancy, childhood, and adolescence.

In addition to its function in building and maintaining bones and teeth, calcium also has numerous critical metabolic roles in cells in all other tissues. However, compared with the significant needs of the skeleton, only small amounts of calcium are required for all other cellular and extracellular functions.

The transport functions of cell membranes are influenced by calcium, which affects membrane stability in poorly understood ways. Calcium also influences the transmission of ions across membranes of cell organelles, the release of neurotransmitters at synaptic junctions, the function of hormones, and the release or activation of intracellular and extracellular enzymes.

Calcium is required for nerve transmission and regulation of heart muscle function. The proper balance of calcium, sodium, potassium, and magnesium ions maintains skeletal muscle tone and controls nerve irritability. A significant increase in the serum calcium level can cause cardiac or respiratory failure, whereas a decrease results in tetany of skeletal muscles. In addition, calcium ions play a critical role in smooth muscle contractility.

Ionized calcium initiates the formation of a blood clot by stimulating the release of thromboplastin from blood platelets. Calcium ions also serve as required cofactors for several enzymatic reactions, including the conversion of prothrombin to thrombin, which aids in the polymerization of fibrinogen to fibrin and the final step in blood clot formation.

High dietary calcium intakes are associated with decreased prevalence of overweight and obesity. The mechanism for this affect appears to be related to (1) depression of the PTH and 1,25 hydroxy vitamin D, which leads to inhibition of lipogenesis and increased lipolysis; and (2) increased excretion of fecal fat caused by soaps formation (Heaney and Rafferty, 2009) (Table 3-25).

Dietary Reference Intakes: The IOM, Food and Nutrition Board (2010) has recently set the RDA for calcium, based on estimates of requirements of both genders throughout the life cycle. The tolerable UL has also been established for this nutrient. During several periods of the female life cycle, calcium intake is critical: prepuberty and adolescence, postmenopause, and during pregnancy and lactation (Kovacs, 2005). In a study of adolescent girls, calcium intakes of 1300 mg or more each day were necessary for maximum calcium retention by the body’s skeleton. Abrams (2005) noted that calcium supplementation was helpful to children and adolescents and that catch-up mineralization was possible later in puberty if intakes were adequate.

Food Sources and Intakes: Cow’s milk and dairy products are the most concentrated sources of calcium. Dark green leafy vegetables such as kale, collards, turnip greens, mustard greens, and broccoli; almonds; blackstrap molasses; the small bones of sardines and canned salmon; and clams and oysters are good sources of calcium. Soybeans also contain ample amounts. Oxalic acid limits the availability of calcium in rhubarb, spinach, chard, and beet greens. Fortified foods (orange juice, soy, nut, grain or rice milks) contain as much calcium as cow’s milk. Many bottled waters and energy bars have calcium and sometimes vitamin D added. Tofu prepared by calcium precipitation is also a source of calcium. Table 3-26 shows the calcium content of selected foods.

Calcium supplements are now commonly used to increase intake. The most common form is calcium carbonate, which is relatively insoluble, particularly at a neutral pH. Although it has less calcium than calcium carbonate by weight, calcium citrate is much more soluble and would be suitable for patients with a lack of hydrochloric acid in the stomach (achlorhydria). In patients with achlorhydria, the efficiency of calcium absorption is greatly decreased because of the higher pH of the stomach contents; however, calcium absorption is increased by the consumption of a meal, which improves the solubility of calcium ions because of the increased gastric acidity. The selection of the most appropriate calcium supplement depends on several factors, including physical and chemical properties, interactions with other medications being taken concurrently, current medical conditions, and age. Beginning at the age of 11 years, median dietary calcium intakes in the United States are considerably less than the AIs (Figure 3-27). Therefore calcium intakes of Americans are insufficient for the critical ages of bone deposition in both genders, as well as being inadequate at other critical stages.

Deficiency: The development of peak bone mass requires adequate amounts of calcium and phosphorus, vitamin D, and other nutrients. Compared with adulthood, greater amounts of calcium and phosphate are required for skeletal development; therefore AIs of these minerals and others have a significant effect on peak bone mass development until the time of puberty and throughout adolescence. After adolescence, bone gains may still occur, but the amounts of calcium required decrease. Vitamin D status may or may not be a problem, depending on the intakes of calcium and phosphorus. When calcium intake is well below the recommended amount, PTH is released; a persistent elevation may contribute to low bone mass. Calcium and vitamin D intakes of many older women are inadequate.

Hogan (2005) suggested that epidemic obesity and subsequent dieting may have a detrimental effect on bone status, leading to osteoporosis. An inadequate intake of calcium, in addition to an inadequate intake of vitamin D, may contribute to osteomalacia, colon cancer, and hypertension. Dietary Approaches to Stop Hypertension studies show that adequate dietary intakes of calcium, magnesium, potassium, and other micronutrients from low-fat dairy foods, fruits, and vegetables can substantially reduce blood pressure in those with hypertension or prevent its development.

Toxicity: A very high intake of calcium (>2000 mg/day) may lead to hypercalcemia. This can be exacerbated by high intakes of vitamin D. Such toxicity may lead to excessive calcification in soft tissues, especially the kidneys, and may be life-threatening. In addition, long-term high intakes of calcium may lead to increased bone fractures in older adults, perhaps because of high bone remodeling rates that lead to exhaustion of osteoblast (Klompmaker, 2005).

High intakes of calcium may also interfere with the absorption of other divalent cations such as iron, zinc, and manganese. Therefore supplements of certain minerals should be taken at different times. Another effect of excessive calcium intake is constipation, common among older women who take calcium supplements.

Physical Immobility: Prolonged bed rest or periods of weightlessness during space travel promote significant calcium losses in response to a lack of tension or gravity on the bones. Older individuals who require a prolonged recovery with limited activity, such as those with hip fractures or other illnesses, also have increased calcium losses. Physical activity, especially weight-bearing exercise, promotes bone health.

Absorption, Transport, Storage, and Excretion: The relative amounts of inorganic and organic phosphates in the diet vary with the food or supplement consumed. Regardless of the form, most phosphates are absorbed in the inorganic state. Organically bound phosphate is hydrolyzed in the lumen of the intestine and released as inorganic phosphate, primarily through the action of pancreatic or intestinal phosphatases. Bioavailability depends on the form of the phosphate and the pH. The acidic milieu of the most proximal portion of the duodenum is important in maintaining phosphorus solubility and therefore bioavailability. In vegetarian diets the major portion of the phosphorus exists as phytate, which is poorly digested. Humans do not have the phytase enzyme; however, intestinal bacteria have the enzyme needed to hydrolyze phosphates. The yeast used in making bread contains a phytase, which releases phosphate.

In general, the efficiency of phosphate absorption is 60% to 70% in adults, twice as high as that of calcium. Phosphate absorption is also much more rapid than that of calcium. Peak absorption of phosphates occurs approximately 1 hour after ingestion of a meal; calcium enters the blood 3 to 4 hours after a meal.

The primary route of phosphorus excretion is renal, which also is the primary site of phosphate regulation. Major determinants of urinary phosphorus loss are an increased intake of phosphate, an increase in phosphate absorption, and the plasma phosphorus concentration. Other factors contributing to increased urinary phosphate loss are hyperparathyroidism, acute respiratory or metabolic acidosis, diuretic use, and the expansion of extracellular volume. If PTH levels are high, the urinary route excretes additional phosphate. Starvation or chronic undernutrition typically contributes to most of the alterations in metabolism that result in hypophosphatemia and renal losses of phosphate. According to Berndt and Kumar (2009), long-term regulation of phosphorus homeostasis may be controlled by hormones such as the vitamin D endocrine system and PTH as well as and the phosphatonins (FGF-23, sFRP-4, MEPE). Endogenous fecal phosphate excretion can also contribute to phosphorus homeostasis by eliminating excessive phosphate when PTH levels are elevated and phosphate load in the blood or tissues is excessively high. Reduced phosphate excretion is associated with dietary phosphorus restriction; increased plasma insulin, thyroid hormone, growth hormone, glucagon, or glucocorticoids; metabolic or respiratory alkalosis; and extracellular volume contraction.

Functions: As phosphates, phosphorus participates in numerous essential functions of the body. DNA and RNA are based on phosphate. The major cellular form of energy, ATP, contains high-energy phosphate bonds, as do creatinine phosphate and PEP. Cyclic adenosine monophosphate (cAMP) acts as a secondary signal within cells following peptide hormone activation of many membrane receptors. As part of phospholipids, phosphorus is present in every cell membrane in the body. Numerous phospholipid molecules also act as secondary messengers within the cytosol. Phosphorylation-dephosphorylation reactions control various steps in the activation or deactivation of cytosolic enzymes by kinases or phosphatases. Total intracellular concentrations of phosphate (but not ionic concentrations) are much higher than extracellular concentrations because phosphorylated compounds do not cross cell membranes easily and are trapped within the cell.

The phosphate buffer system is important in intracellular fluid and the kidney tubules, where phosphate functions in the excretion of hydrogen ion. Filtered phosphate reacts with secreted hydrogen ions, releasing sodium in the process. In turn, the sodium can be resorbed under the influence of aldosterone. Finally, phosphate ions combine with calcium ions to form hydroxyapatite, the major inorganic molecule in teeth and bones. Bone mineral, but not tooth mineral, provides phosphate ions via homeostatic regulation of serum calcium by PTH.

Dietary Reference Intakes: DRIs for phosphorus are somewhat lower than those for calcium for all age groups. Tolerable ULs are also established.

Food Sources and Intakes: In general, good sources of protein are also good sources of phosphorus. Meat, poultry, fish, and eggs are excellent sources. Milk and milk products are good sources, as are nuts and legumes, cereals, and grains. Phosphorus is bound to serine, threonine, and tyrosine in proteins. In the outer coating of cereal grains, particularly wheat, phosphorus exists in the form of phytic acid, which can form a complex with some minerals to create insoluble compounds. In conventional breads phytic acid is converted to the soluble form of orthophosphate during the leavening process. However, in the unleavened breads commonly eaten in the Middle East, the availability of practically all minerals is much lower. Table 3-27 and Appendix 36 list the phosphorus content of selected foods.

The average intakes of phosphorus by adults in the United States are approximately 1300 mg/day for men and 1000 mg/day for women. More than 60% of phosphorus comes from milk, meat, poultry, fish, and eggs. Cereals and legumes provide another 20%. Less than 10% is derived from fruits and their juices; tea, coffee, vegetable oils, and spices supply only small amounts of phosphorus. The amount provided by food additives to such products as meats, cheeses, dressings, beverages, and bakery products can be significant.

Deficiency: Phosphate deficiency is rare. It could develop in individuals who are taking phosphate binders for renal disease or in older adults because of poor intake in general. The widespread, ultimately fatal consequences of severe phosphorus depletion reflect its ubiquitous roles in body functions. Symptoms result from decreased synthesis of ATP and other organic phosphate molecules. Neural, muscular, skeletal, hematologic, renal, and other abnormalities occur.

Because phosphorus is so widely available from foods, including processed foods and soda types of soft drinks, a dietary inadequacy is unlikely. Clinical phosphate depletion and hypophosphatemia can result from long-term administration of glucose or TPN without sufficient phosphate, excessive use of phosphate-binding antacids, hyperparathyroidism, or treatment of diabetic acidosis. It may develop in those who have alcoholism, with or without decompensated liver disease. Premature infants who are fed unfortified human milk may also develop hypophosphatemia.

Toxicity: A persistently high concentration of PTH may result after chronic consumption of a low-calcium, high-phosphorus diet, called nutritional secondary hyperparathyroidism. PTH levels in blood that result from this diet typically remain within a high normal range (Figure 3-29). This persistently high PTH contributes to increased bone turnover, reduction of bone mass and density, and even fragility fractures because of excessive resorption and thinning of trabecular plates at bone sites throughout the skeleton. Individuals with a low calcium/phosphorous ratio benefit from increasing calcium intake from foods or supplements. Adequate calcium intake reduces the serum PTH concentration and may inhibit bone loss. The persistently high PTH level contributes to the limited bone mineralization during growth; this yields inadequate peak bone mass accumulation and the loss of bone mass.

Absorption, Transport, Storage, and Excretion: The efficiency of absorption of magnesium varies widely from 35% to 45%. Magnesium may be absorbed along the length of the small intestine, but most absorption occurs in the jejunum. Like other divalent cation minerals, the entry of magnesium from the gut lumen occurs by two mechanisms: a carrier-facilitated process and simple diffusion. A saturable facilitated mechanism operates at low intraluminal concentrations, whereas paracellular movement across the mucosa predominates throughout the length of the small bowel when intraluminal concentrations are high. The efficiency of absorption varies with the magnesium status of the individual, the amount of magnesium in the diet, and the composition of the diet as a whole. Vitamin D has little or no effect on magnesium absorption.

Serum magnesium concentration is remarkably constant. Maintenance of these constant values depends on absorption, excretion, and transmembranous cation flux rather than on hormonal regulation. Once in the cells, magnesium is bound mainly to protein and energy-rich phosphates. The magnesium balance is illustrated in Figure 3-30.

The kidneys control magnesium balance by conserving magnesium efficiently, particularly when intake is low. Supplementing a normal intake increases urinary excretion while serum levels remains stable. Low dietary intake of magnesium results in reduced urinary excretion of magnesium. To allow nursing mothers to meet the increased needs for magnesium, urinary excretion of the mineral tends to decrease during lactation. Renal resorption varies inversely with that of calcium.

Functions: The major function of magnesium is to stabilize the structure of ATP in ATP-dependent enzyme reactions. Magnesium is a cofactor for more than 300 enzymes involved in the metabolism of food, synthesis of fatty acids and proteins, phosphorylation of glucose in the glycolytic pathway, and promoting transketolase reactions. Magnesium is important in the formation of cAMP, the first cytosolic messenger to be identified as a mechanism for transmitting messages from outside the cells in response to hormones, local hormonelike factors, or other molecules.

Magnesium plays a role in neuromuscular transmission and activity, working in concert with and against the effects of calcium, depending on the system involved. In a normal muscle contraction, calcium is a stimulator, and magnesium is a relaxant. Magnesium acts as a physiologic calcium-channel blocker. High magnesium intakes are associated with greater bone density. The reactivity of vascular and other smooth muscle cells depends on the ratio of calcium to magnesium in the blood.

Magnesium also plays a role in learning and memory. A new product, magnesium-L-threonate, leads to the enhancement of learning, working memory, and short and long-term memory in all ages of rats (Slatsky et al., 2010). Although it is too early to extrapolate to humans, this is an exciting area of research. Magnesium depletion has been detected in persons with migraine headaches, severe asthma, dysmenorrhea, leg cramps, diabetes mellitus, chronic renal failure, nephrolithiasis, osteoporosis, aplastic osteopathy, and heart and vascular disease (Guerrera et al., 2009; Musso, 2009).

Large doses of magnesium can result in central nervous system depression, anesthesia, or even paralysis, especially in patients with renal insufficiency. Thus patients with renal problems should not be given magnesium supplements.

Dietary Reference Intakes: The RDA for magnesium was increased in 1997; different recommendations were made for boys and girls beginning at puberty. ULs were also established, as were AIs for infants.

Food Sources and Intakes: Magnesium is abundant in many foods. Good sources are seeds, nuts, legumes, and milled cereal grains, as well as dark green vegetables, because magnesium is an essential constituent of chlorophyll. Milk is a moderately good source of magnesium, especially because milk and other dairy products are so widely consumed. Tofu prepared by magnesium precipitation (check the label) is a good source.

Fish, meat, oranges, apples, and bananas, are poor sources of magnesium. Diets high in refined foods, meat, and dairy products are usually lower in magnesium than diets rich in vegetables and unrefined grains (Table 3-28). Magnesium is lost during the processing of foods such as sugar; after refining wheat cereals, it is not generally replaced as enrichment.

The most commonly consumed food sources include milk, bread, coffee, ready-to-eat cereals, beef, potatoes, and dried beans and lentils. Americans have had median intakes of magnesium well below the RDAs, with older adults having the lowest intakes (Figure 3-31). This trend is implicated in development of diseases such as osteoporosis and diabetes (He et al., 2006). High intakes of calcium, protein, vitamin D, and alcohol all increase the requirements for magnesium; physical or psychologic stress may also increase magnesium needs.

Deficiency: Although rare, severe magnesium deficiency symptoms include tremors, muscle spasms, personality changes, anorexia, nausea, and vomiting. Tetany, myoclonic jerks, athetoid movements, convulsions, and coma have also been reported. Hypocalcemia and hypokalemia typically occur first, combined with impairment of the individual’s responsiveness to PTH and sodium retention.

The effects of severe magnesium depletion on bone metabolism include decreased PTH secretion by the parathyroid glands, very low serum PTH, impaired responsiveness of bone and kidneys to PTH, decreased serum 1,25(OH)₂D₃, vitamin D resistance, altered hydroxyapatite crystal formation, impaired bone growth in young patients, or the development of osteoporosis in seniors. With continued depletion of magnesium, PTH concentrations drop even further. Intravenous administration of magnesium reverses the clinical signs and symptoms within a short time.

Moderate depletion of magnesium apparently is prevalent in older populations in Western nations (Leenhardt et al., 2005). Such deficiencies are typically precipitated by low dietary intakes, especially in individuals who avoid consuming dark green leafy vegetables, milk, and other good sources of magnesium. An increased loss of electrolytes, especially potassium, or a shift in electrolyte balance also triggers a moderate magnesium deficiency. Conditions and situations that may cause acute deficiencies include renal disease, diuretic therapy, malabsorption, hyperthyroidism, pancreatitis, protein insufficiency, diabetes, parathyroid gland disorders, postsurgical stress, and vitamin D–resistant rickets. Magnesium deficiency has also been linked to insulin resistance and metabolic syndrome because magnesium is required for carbohydrate metabolism (He et al., 2006).

Magnesium status is difficult to determine from serum measurements of magnesium because the total serum magnesium level remains constant within a wide range of intake levels. Leukocyte magnesium contents are much more sensitive to nutritional status, which makes them a superior marker. Urinary excretion of magnesium (and often of potassium) is less in those with a magnesium deficiency than in those with sufficient magnesium, suggesting that those with magnesium deficiencies have greater retention of magnesium and improved tissue magnesium status throughout the body.

Attention has focused on the interrelationships of magnesium and other electrolytes, particularly potassium, and related effects. For example, a low magnesium intake contributes to hypertension along with inadequate intakes of potassium and calcium. Oral magnesium supplementation may lower systolic and diastolic blood pressure significantly. Low magnesium intakes have also been associated with coronary heart disease, myocardial infarction, and osteoporosis.

Toxicity: Although excess magnesium can inhibit bone calcification, excesses from dietary sources and supplements are unlikely to result in toxicity. However, the ULs for magnesium from supplements or pharmacologic agents were established in 1998. The only cases of toxicity that have been reported involve smelter workers who inhale or otherwise ingest toxic levels of magnesium dust.

Functions: Many enzymes require small amounts of one or more trace metals for full activity. Metals function in enzyme systems by participating directly in the catalyzed reaction, by combining with substrates to form complexes on which enzymes act, by forming metalloenzymes that bind substrates, by combining with reaction end products, or by maintaining quaternary structures. Minute concentrations of trace minerals affect the whole body through interactions with the enzymes or hormones that regulate masses of substrate. This ability is amplified if, in turn, the substrate has some regulatory function. Trace minerals may also interact with DNA to control the transcription of proteins important for the metabolism of that particular trace mineral.

Food Sources: Compared with other sources, foods of animal origin are generally superior sources of trace elements because concentrations of the elements tend to be higher and the metals more available for absorption. Seafood in particular is usually rich in nearly all micronutrients except manganese, which is more readily available from plant sources. The trace element content of many plants depend on the minerals content of the soil; in addition, trace elements are not distributed evenly in wheat grains, and the germ and outer layers that contain major amounts of most minerals are removed to a large extent by the milling process. However, the small quantities of minerals that remain in white flour are more biologically available than those in whole-wheat flour, which are in complexes with or bound by molecules in the inner layer such as phytate and fiber. Unless the pH is lowered during product production, these minerals remain unavailable.

Absorption, Transport, Storage, and Excretion: Dietary iron exists as heme iron, found in hemoglobin, myoglobin, and some enzymes; and as nonheme iron, found predominantly in plant foods, but also in some animal foods as nonheme enzymes and ferritin. Heme iron is absorbed across the brush border of intestinal absorbing cells after it is digested from animal sources. After heme enters the cytosol, the ferrous iron is enzymatically removed from the ferroporphyrin complex. The free iron ions combine immediately with apoferritin to form ferritin in the same way that free nonheme iron combines with apoferritin.

Ferritin is an intracellular store, a “ferry” that carries bound iron from the brush border to the basolateral membrane of the absorbing cell. The final step of absorption by which iron ions are moved into the blood involves an active transport mechanism. At this point, it is the same for heme and nonheme iron (Figure 3-32). The absorption of heme iron is affected only minimally by the composition of meals and GI secretions. Heme iron represents only 5% to 10% of the dietary iron in a mixed diet, but absorption may be as high as 25%, compared with only 5% for nonheme iron. Because vegans consume only plant foods, sufficient amounts of nonheme iron must be ingested and absorbed to meet body requirements or supplements would be needed.

Three steps of absorption also precede the entry of nonheme iron into the circulation. Nonheme iron must be digested from plant sources and enter the duodenum and upper jejunum in a soluble, ionized form if it is to be transferred across the brush border. The acid of gastric secretions enhances the solubility and changes iron to the ionic state—either as ferric (+3 oxidation state) or ferrous (+2 oxidation state) iron—within the gut luminal contents. Iron in the reduced, ferrous state is preferred for the entry step of absorption. The brush border iron transporter, divalent metal transporter 1 (DMT1), transports ferrous iron. Ferric iron may be reduced by a brush border enzyme, ferric reductase, for absorption. As chyme moves down the duodenum, pancreatic and duodenal secretions increase the pH of the contents to 7, at which point most ferric iron is precipitated unless it has been chelated. However, ferrous iron is significantly more soluble at a pH of 7, so these ions remain available for absorption in the remainder of the small intestine.

The efficiency of nonheme iron absorption seems to be controlled by the intestinal mucosa, which allows certain amounts of iron to enter the blood from the cytosolic ferritin pool according to the body’s needs. A small peptide hormone known as hepcidin is the main iron regulatory hormone. Production in the liver is responsive to liver iron levels, inflammation, hypoxia, and anemia. Its major action is to act on the mucosa cell and inhibit iron absorption. Therefore chronic inflammation can lead to decreased iron absorption from production of hepcidin (Muñoz et al., 2009).

Other signals from the body to the absorbing cells may be transferrin saturation, or the percentage of iron bound to transferrin (Figure 3-33). Normally transferrin saturation is 30% to 35% in healthy, iron-consuming individuals. The percentage can vary greatly, depending on iron intake and bioavailability. A low percentage (e.g., 15%) of the total iron-binding capacity (TIBC) of transferrin would stimulate the absorbing cells to transport iron by the exit step at the basolateral membrane to the blood. Conversely, if the iron concentration in the body is excessive, absorbing cells would be downregulated, and less iron would be absorbed. The latter situation occurs during iron overloads to protect the body against toxicity.

The life span of an intestinal absorbing cell is approximately 3 to 6 days. During this time the cell emerges from the crypt after cell division, passes up the villus to the tip, and eventually sloughs off as a dead cell. During the early life of the individual cell, signals resulting from the saturation percentage of circulating transferrin are sent to the young cells to adjust their number of receptors for transferrin (e.g., to increase iron absorption in a state of iron deficiency). Other cells formed before or after may have different numbers of receptors, depending on the nutritional supply of iron.

In individuals who persistently consume inadequate levels of iron, especially women in their childbearing years, the number of receptors may consistently be upregulated to maximize iron absorption. The efficiency of iron absorption by adults with normal hemoglobin values averages 5% to 15% of the iron, heme and nonheme, from food and supplements. Although absorption may be as high as 50% in those with iron deficiency anemia, this level is not common. Most women with an iron deficiency, but not anemia, probably have absorption efficiencies of 20% to 30%. From 2% to 10% of nonheme iron in vegetables is absorbed, and from 10% to 30% of iron heme and nonheme from animal sources is typically absorbed.

Several factors affect the intestinal absorption of iron. The efficiency of iron absorption is determined to some extent by the foods from which it is derived or with which it is consumed. Ascorbic acid, the most potent enhancer of iron absorption, reduces ferric to ferrous iron and forms a chelate with iron that remains soluble at the alkaline pH of the lower small intestine. Other food molecules, such as sugars and sulfur-containing amino acids, may also enhance iron entry by forming chelates with ionic iron. In addition, animal proteins from beef, pork, veal, lamb, liver, fish, and chicken enhance absorption. The substance responsible for this improved absorption—the meat-fish-poultry (MFP) factor—remains unknown, but specific amino acids or dipeptide digestion products may enhance iron absorption.

Although the iron content of human milk is very low, it is highly bioavailable because of the presence of milk lactoferrin, which enhances iron absorption. Infants retain more iron from human milk than from cow’s milk or infant formulas because of the presence of lactoferrin in breast milk. Whey protein (lactalbumin), which constitutes a greater percentage of the total protein in human milk than in cow’s milk, may also improve iron absorption.

The degree of gastric acidity enhances solubility and therefore bioavailability of iron derived from foods. Therefore achlorhydria, hypochlorhydria, or administration of alkaline substances such as antacids can interfere with nonheme iron absorption by not permitting the solubilization of iron in gastric and duodenal fluids. Gastric secretions also seem to increase the absorption of heme iron.

Certain physiologic states such as pregnancy and growth that involve increased blood formation stimulate iron absorption. In addition, more iron is absorbed during iron deficiency states because of adaptive mechanisms that enhance nonheme iron absorption.

Foods with high phytate content have low iron bioavailability, but whether phytate is the cause is not clear. Oxalates can inhibit absorption. Tannins, which are polyphenols, in tea also reduce nonheme iron absorption. On the other hand, the presence of an adequate amount of calcium helps to remove phosphate, oxalate, and phytate that would otherwise combine with iron and inhibit its absorption.

The availability of iron from various compounds used for food enrichment or as supplements varies widely according to their chemical composition. Although iron in the ferrous form is most readily absorbed, not all ferrous compounds are equally available. Ferrous pyrophosphate is used frequently in products such as breakfast cereals because it does not add a gray color to the food; however, this compound and others such as ferrous citrate and ferrous tartrate are poorly absorbed. Iron is usually added to baby foods in an elemental form, the absorbability of which depends on the iron particle size. Increased intestinal motility decreases iron absorption by decreasing contact time and rapidly removing the chyme from the area of highest intestinal acidity. Poor fat digestion leading to steatorrhea also decreases iron absorption and the absorption of other cations.

Functions: The functions of iron relate to its ability to participate in oxidation and reduction reactions. Chemically, iron is a highly reactive element that can interact with oxygen to form intermediates with the potential of damaging cell membranes or degrading DNA. Iron must be tightly bound to proteins to prevent these potentially destructive oxidative effects.

Iron metabolism is complex because this element is involved in so many aspects of life, including red blood cell function, myoglobin activity, and the roles of numerous heme and nonheme enzymes. Because of its oxidation-reduction (redox) properties, iron has a role in the blood and respiratory transport of oxygen and carbon dioxide, and it is an active component of the cytochromes (enzymes) involved in the processes of cellular respiration and energy (ATP) generation. Iron is also involved in immune function and cognitive performance; this underscores the importance of preventing iron deficiency anemia throughout the world.

Hemoglobin, which is present in red blood cells, is synthesized in immature cells in bone marrow. Hemoglobin works in two ways: the iron-containing heme combines with oxygen in the lungs; and the heme releases the oxygen in tissues, where it picks up carbon dioxide and then releases it in the lungs after its return from the tissues. Myoglobin, also a heme-containing protein, serves as an oxygen reservoir within muscle. Table 3-30 lists the major iron molecules in the body and their functions.

Oxidative production of ATP within the mitochondria involves many heme and nonheme iron-containing enzymes. The cytochromes, present in nearly all cells, function in the mitochondrial respiratory chain in the transfer of electrons and the storage of energy through the alternate oxidation and reduction (redox) of iron (Fe²⁺ to and from Fe³⁺). Numerous water-insoluble drugs and endogenous organic molecules are transformed by the iron-containing cytochrome P-450 system in the liver into more water-soluble molecules that can be secreted in the bile and eliminated. Ribonucleotide reductase, the rate-limiting enzyme involved in DNA synthesis, is also an iron enzyme. Although these vital enzymes represent only a small portion of the total iron in the body, a severe decrease in their concentrations can have long-term consequences. Other enzymes, including several in the brain, also require iron.

An adequate iron intake is essential for the normal function of the immune system. Iron overloads and deficiencies result in changes in the immune response. Iron is required by bacteria; therefore an iron overload (especially intravenously) may result in an increased risk of infection. Iron deficiency affects humoral and cellular immunity. Concentrations of circulating T-lymphocytes decrease in individuals with an iron deficiency, and the mitogenic response is typically impaired. Natural killer (NK) cell activity also decreases. Production of interleukin-1 is reduced in iron-deficient animals, and depressed interleukin-2 production has been reported.

Two iron-binding proteins—transferrin (in blood) and lactoferrin (in breast milk)—seem to protect the body against infection by withholding iron from microorganisms that need it for proliferation. Iron is used by brain cells for normal function in people of all ages. Iron is involved in the function and synthesis of neurotransmitters and possibly myelin. The detrimental effects of early iron deficiency anemia in children can persist for many years. For example, declines have been found between the scholastic performance, sensorimotor competence, attention, learning, and memory of children with anemia. Iron supplementation in children with iron deficiency anemia has been found to improve learning, as indicated by achievement test scores (Beard, 2001). Changes in iron metabolism occur in Alzheimer disease and other disorders.

Dietary Reference Intakes: DRIs have been established for iron. The RDA for men and postmenopausal women is 8 mg/day. The RDA for women of childbearing age (to replace iron loss from menstruation and provide for iron stores sufficient to support a pregnancy) is 18 mg/day. For teenage boys (ages 14 to 18) the iron RDA is 11 mg/day. Full-term infants are born with a reserve supply of iron from placental transfer during gestation, but normal-term infants still require adequate iron from food sources and fortified milk products during the first year of life. Premature infants have limited iron stores because they lack most of the iron and other trace minerals that are normally transferred during the last trimester of pregnancy. The need for iron to support rapid growth in premature infants becomes apparent at approximately 2 to 3 months of age. The RDAs for ages 1 year and older are (variably) 7, 8, or 10 mg/day until adolescence begins at age 14. Figure 3-34 shows the physiologic requirements for iron in relation to age. Requirements are highest during infancy and adolescence. Iron needs among males decrease after the adolescent growth spurt, whereas the iron needs of their female counterparts continue to be high until the menopause. Iron allowances increase during pregnancy from 15 to 27 mg/day, but not during lactation, although many lactating women are told to continue taking their iron supplements.

Food Sources and Intakes: By far the best source of dietary iron is liver, followed by seafood, kidney, heart, lean meat, and poultry. Dried beans and vegetables are the best plant sources. Some other foods that provide iron are egg yolks, dried fruits, dark molasses, whole-grain and enriched breads, wine, and cereal. Old-fashioned iron skillets used for cooking add to the total iron intake. Table 3-31 presents the iron content of selected foods.

The availability of iron derived from food is important in the consideration of dietary sources. For example, only 50% or less of the iron in whole-grain cereals and in some green vegetables is available in a usable form. Corn is a notoriously poor source of iron; milk and milk products are practically devoid of iron. When dietary intake focuses primarily on these foods, anemia levels can be high. Vegetarian or vegan women can obtain enough iron from their plant-based diet, but they must consume sufficient amounts of moderately iron-rich foods, such as legumes and dried fruits. Soy products are typically good sources of both iron and zinc.

Iron fortification of cereals, flours, and bread has added significantly to the total iron intake of the U.S. population. Fortified cereals are a substantial source of iron for infants and children, as well as for adolescents and adults. Concern about potential iron overloading from fortified breakfast foods has been raised because analyzed values of iron content may be considerably greater than labeled values. The foods that supply the greatest amount of iron in the U.S. diet include ready-to-eat cereals fortified with iron; bread, cakes, cookies, doughnuts, and pasta (all fortified with iron); beef; dried beans and lentils; and poultry.

Whereas the median iron intakes of most women are lower than the RDA, the median intakes of men generally exceed the RDA. An adequate diet containing meats and other animal sources typically has high iron content, containing approximately 6 mg of iron per 1000 kcal. Therefore the average omnivorous woman of childbearing age consuming 2000 kcal takes in only 12 mg of iron, or approximately 67% of the RDA of 18 mg/day. This intake level meets the needs of almost no menstruating woman. However, iron intakes totaling much less than 12 mg/day place women at more serious risk for developing deficiency anemia. Women with high daily iron losses compensate with an increased rate of absorption. Even with this adaptation, insufficient stores of iron typically exist and the risk of anemia remains high.

Deficiency: Iron deficiency, the precursor of iron deficiency anemia, is the most common of all nutritional deficiency diseases. In the United States and worldwide, iron deficiency anemia is prevalent among children and women of childbearing age. The groups considered to be at greatest risk for iron deficiency anemia are infants younger than 2 years of age, adolescent girls, pregnant women, and older adults. Pregnant teenagers are frequently at high risk because of poor eating habits and continuing growth. Women in their childbearing years who are iron deficient benefit from either a diet rich in iron-containing foods or supplements.

The final stages of iron deficiency include hypochromic, microcytic anemia. Anemia may be corrected by providing high-dose supplements in the form of ferrous sulfate or ferrous gluconate until blood parameters return to normal. To prevent worsening of the iron deficiency, individuals should be counseled regarding a diet that is appropriately rich in iron.

Iron deficiency can be caused by injury, hemorrhage, or illness (e.g., blood loss from hookworms, GI diseases that interfere with iron absorption). Iron deficiency may also be aggravated by an unbalanced diet containing insufficient iron, protein, folate, and vitamin C. Anemia typically develops because of an inadequate amount of dietary iron or faulty iron absorption.

Female athletes, especially cross-country runners and others involved in endurance sports, often have an iron deficiency at some point in their training if they are not taking iron supplements or do not have diets high in iron. The source of the additional iron losses in those with athletic amenorrhea may be through the gut; losses may increase during the stressful conditions of training. It seems that without supplementation, the greater the intensity of training, the lower the iron levels become in women.

Toxicity: The major cause of iron overload is hereditary hemochromatosis, whereas transfusion iron overload is rare. The latter may be seen in individuals with sickle cell disease or thalassemia major who require transfusions for their anemia. Iron overload is linked to a distinct gene that favors excessive iron absorption if the iron is available in the diet. Both are linked to decreased hepcidin levels (Nemeth and Ganz, 2009). The characteristic chemical parameters of iron overload are listed in Box 3-7.

Frequent blood transfusions or long-term ingestion of large amounts of iron can lead to abnormal accumulation of iron in the liver. Saturation of tissue apoferritin with iron is followed by the appearance of hemosiderin, which is similar to ferritin but contains more iron and is very insoluble. Hemosiderosis is an iron storage condition that develops in individuals who consume abnormally large amounts of iron or in those with a genetic defect resulting in excessive iron absorption. If the hemosiderosis is associated with tissue damage, it is called hemochromatosis. See Chapter 33.

Iron supplements may not be beneficial for postmenopausal women and older men because of increased risks for heart disease and cancer; iron contributes to an environment that favors oxidation of LDL cholesterol, arterial vessel damage, and other adverse effects. In addition, excessive iron may help generate free radicals that attack cellular molecules, thereby increasing the number of potentially carcinogenic molecules within cells. These potential adverse iron-disease linkages need to be confirmed.

Absorption, Transport, Storage, and Excretion: Zinc absorption and excretion are controlled by poorly understood homeostatic mechanisms. The mechanism of absorption involves two pathways. A saturable carrier mechanism operates most efficiently at low zinc intakes when luminal zinc concentrations are low; a passive mechanism works when zinc intakes and luminal concentrations are high. Solubility of zinc in the gut lumen is critical. Zinc ions are generally bound to amino acids or short peptides in the lumen, released at the brush border for absorption via the carrier mechanism (hZIPI family). The entry step of absorption across the brush border is followed by the binding of zinc ions to metallothionein and other proteins within the cytosol of the absorbing cell. Metallothionein carries the zinc (via transcellular movement) to the basolateral border for the exit step from the absorbing cell to the blood. The exit step occurs by active transport because the blood concentration of zinc is significantly greater than the cytosolic ion concentration. The process of zinc absorption is illustrated in Figure 3-35.

Zinc absorption is affected not only by the level of zinc in the diet but also by the presence of interfering substances, especially phytates. After the consumption of zinc in a meal, the serum zinc level rises and then decreases in a dose-response pattern. A protein-rich diet promotes zinc absorption by forming zinc–amino acid chelates that present zinc in a more absorbable form. Zinc absorption is slightly higher during pregnancy and lactation. Absorbed zinc is taken up from the portal circulation initially by the liver, but most of the zinc is subsequently redistributed to other tissues. Impaired absorption is associated with a variety of intestinal diseases such as Crohn disease or pancreatic insufficiency.

Several dietary factors affect zinc absorption. Phytate decreases zinc absorption, but other complexing agents (e.g., tannins) do not. Copper and cadmium compete for the same carrier protein; thus they reduce zinc absorption. High calcium or iron intakes reduce zinc absorption and balance. Folic acid may also reduce zinc absorption when zinc intake is low. On the other hand, high doses of zinc can impair absorption of iron from ferrous sulfate, the form in vitamin and mineral supplements. Dietary fiber may also interfere with zinc absorption, but the significance is unclear. Zinc absorption may be enhanced by glucose or lactose and by soy protein consumed alone or mixed with beef. Red table wine also increases zinc absorption, probably because of its congeners. Like iron, zinc is better absorbed from human milk than from cow’s milk.

Functions: Zinc has structural, catalytic, and regulatory functions in the cell, primarily as an intracellular ion (Tuerk and Fazel, 2009). Zinc plays important structural roles as components of several proteins. It also functions in association with more than 300 different enzymes, in reactions involving either synthesis or degradation of carbohydrates, lipids, proteins, and nucleic acids. It also functions as an intracellular signal in brain cells where it is stored in specific synaptic vesicles and is fundamental to normal central nervous system function (Bitanihirwe and Cunningham, 2009). In addition, zinc is involved in the stabilization of protein and nucleic acid structure and the integrity of subcellular organelles, as well as in transport processes, immune function, and expression of genetic information.

Metallothionein is the most abundant, nonenzymatic zinc-containing protein. This low-molecular-weight protein is rich in cysteine and exceptionally high in metals, among which are zinc and lesser amounts of copper, iron, cadmium, and mercury. The biologic role of metallothionein is not clear, but it does have a function in zinc absorption. Metallothionein may function as an intracellular reservoir that can donate zinc ions to other proteins, or it may have a redox role that reduces oxidative stress, especially in cells with high stress. Thus metallothionein may have a role in the detoxification of metals as well as in their absorption.

Zinc is abundant in the nucleus, where it stabilizes RNA and DNA structure, and is required for the activity of RNA polymerases important in cell division. Zinc also functions in chromatin proteins involved in transcription and replication, and it protects against age-related macular degenerative disease. Although widely touted to cure or prevent common colds, zinc gluconate lozenges or nasal sprays are not very effective.

Dietary zinc causes an increase in bone mass. Zinc appears in the crystalline structure of bone, in bone enzymes, and at the zone of demarcation. It is needed for adequate osteoblastic activity, formation of bone enzymes such as alkaline phosphatase, and calcification (see Table 3-25). Beta-alanyl-histidine (carnosine) is a zinc compound that stimulates bone formation intensively and restores bone loss from aging, skeletal unloading, aluminum bone toxicity, calcium and vitamin D deficiency, adjuvant arthritis, estrogen deficiency, diabetes, and fracture healing (Yamaguchi, 2010). Such new zinc compounds may become adjuvant therapy for osteoporosis and other disorders.

Dietary Reference Intakes: The zinc DRI for adolescent and adult males is 11 mg/day. Because of the lower body weight of adolescent and adult women, their DRI is 8 to 9 mg/day. The DRI for preadolescents is estimated to be 8 mg/day. The DRIs for infants are 2 mg/day for the first 6 months and 3 mg/day for the second 6 months of life.

Food Sources and Intakes: For most Americans, most daily intake of zinc is provided by meat, fish, poultry, ready-to-eat breakfast cereals fortified with zinc, and milk and milk products. Oysters are especially high in zinc, and other shellfish, liver, whole-grain cereals, dry beans, and nuts are all good sources (Table 3-32). Soy products may also be fairly good sources of zinc. In general, zinc intake correlates well with protein intake.

The zinc content of typical diets of adults in Western countries ranges between 10 and 15 mg/day; women consume less than men because of lower energy intakes. The zinc density of the American adult’s diet is approximately 5.6 mg/l000 kcal.

Deficiency: The clinical signs of zinc deficiency were first described as short stature, hypogonadism, mild anemia, and low plasma zinc level. This deficiency was caused by a diet high in unrefined cereals and unleavened breads, which contain high levels of fiber and phytate, which chelate with zinc in the intestine and prevent absorption. Additional symptoms of zinc deficiency include hypogeusia (decreased taste acuity), delayed wound healing, alopecia, and diverse forms of skin lesions. Acquired zinc deficiency may occur as the result of malabsorption, starvation, or increased losses via urinary, pancreatic, or other exocrine secretions. Patients with alcoholism may have altered zinc metabolism. Pregnant women and older adults are also at increased risk for deficiency. Low-dose zinc supplementation may improve measures of poor zinc status.

Acrodermatitis enteropathica, an autosomal-recessive disease characterized by zinc malabsorption, results in eczematoid skin lesions (Figure 3-36), alopecia, diarrhea, bacterial and yeast infections, and even death if left untreated. Symptoms generally first develop during weaning from human milk to cow’s milk. Researchers are working to identify the genetic basis of inherited nutritional deficiencies such as acrodermatitis enteropathica; the hZIP4 gene is involved. Zinc, biotin, protein, or essential fatty acid deficiency should be considered when there are systemic signs of failure to thrive (Gehrig and Dinulos, 2010).

Zinc deficiency results in various immunologic defects. Severe deficiency is accompanied by thymic atrophy, lymphopenia, reduced lymphocyte proliferative response to mitogens, a selective decrease in T-helper cells, decreased NK cell activity, anergy, and deficient thymic hormone activity. Even mild zinc deficiency can reduce immune function, such as impaired interleukin-2 production. Supplementation with zinc may improve immune status, but more studies are needed. Moderate zinc deficiency is associated with anergy and diminished NK cell activity but not with thymic atrophy or lymphopenia. Box 3-8 summarizes the clinical manifestations of human zinc deficiency. Similarities between patients with sickle cell anemia and zinc deficiency suggest the possibility of a secondary zinc deficiency in those with the anemia.

Problems caused by low zinc intakes seem to be increasing, partly because of the low bioavailability of zinc. Athletes may also have an increased risk for developing zinc deficiency. Physical activity may increase mobilization of zinc from bone stores for cellular needs (e.g., for the synthesis of zinc-metalloenzymes). Finally, patients on long-term parenteral nutrition who do not receive zinc will show signs of deficiency; requirements have been estimated to be 3 mg/day in patients without GI losses and a mean of 12 mg/day in patients with diarrhea and fistula losses (Jeejeebhoy, 2009).

Toxicity: Oral ingestion of toxic amounts of zinc (100 to 300 mg/day) is rare, but the UL for zinc in adults is 40 mg/day. Excessive zinc supplementation has long been known to interfere with copper absorption. A major form of zinc toxicity develops in patients receiving hemodialysis for renal failure, with contamination of dialysis fluids from the adhesive plastic used on the dialysis coils or from galvanized pipes. The toxic syndrome in these patients is characterized by anemia, fever, and central nervous system disturbances. Zinc sulfate in amounts of 2 g/day or more may cause GI irritation and vomiting. Inhalation of zinc fumes during welding may be toxic, but exposure to fumes can be prevented with proper precautions.

Functions: Fluoride is considered important, if not essential, because of its benefits for tooth enamel. Its incorporation into enamel produces more stable apatite crystals (Robinson et al., 2004). Fluoride also acts as an antibacterial agent in the oral cavity, serving as an enzyme inhibitor. Fluoride has no known requirement in human metabolic pathways.

The prevalence of dental caries has decreased by 50% in recent decades because of fluoridation of drinking water and the use of topical fluorides. The prevalence of dental caries has also decreased in communities without fluoridated water. This decrease probably results from the use of fluoridated toothpaste, topical fluoride applications, and use of fluoridated water used in food processing, all of which provide fluoride for incorporation into teeth. Soft drinks typically are prepared with fluoridated waters at bottling plants in urban areas.

Fluoride substitutes for the hydroxyl group on the lattice structure of calcium phosphate salts (i.e., hydroxyapatites) of the bones and teeth to form fluoroapatite, which is harder and less readily resorbed than hydroxyapatite (Chachra et al., 2008). After fluoridation, bone tissue formed at high fluoride blood levels is not healthy; it is subject to fractures from too tight binding of the fluoroapatite crystals compared with the hydroxyapatite in unfluoridated bone.

Dietary Reference Intakes: The AIs for fluoride were established for the first time in 1997. AIs for adult men and women are 4 and 3 mg/day, respectively. Depending on age, the AIs range from 2 to 3 mg/day for children and adolescents and from 0.7 to 1 mg/day for young children between the ages of 1 and 8 years. For comparison, an 8-oz glass of fluoridated water (1 ppm or 1 mg/L) provides approximately 0.2 mg of fluoride. ULs have also been established for fluoride.

Food Sources and Intakes: The major dietary sources of fluoride are drinking water and processed foods that have been prepared or reconstituted with fluoridated water. Seafood also is high in fluoride, but the content in freshwater fish is lower than that of saltwater fish. Soups and stews made with fish and meat bones also provide substantial fluoride, as do beef liver and mechanically deboned meat and fowl. Although fluorides exist in fruits and vegetables, the amounts in most foods are not significant.

The amount in tea leaves can be substantial, depending on the brewing strength. One cup of tea may contain as much as 1 mg of fluoride. Fluoridated toothpastes are also a source of fluoride; calcium carbonate–based fluoride toothpastes are effective in reducing caries and provide oral calcium as well (Lynch and Cate, 2005). The standard recommendation is 1 ppm for fluoridated community water supplies. Children who drink fluoridated water typically consume more total fluoride than those who do not. Intakes higher than 2 mg raise concerns about mild fluorosis, which has been reported in a few U.S. communities.

Deficiency: Because no known metabolic function exists for fluoride, fluoride cannot have a true deficiency that results in disease. Fortuitous binding in hydroxyapatite crystals, especially from fluoridated water supplies, reduces dental caries, but it does not seem to have any effect on reducing osteoporotic fractures.

Toxicity: A mild fluorosis can develop from daily doses of 0.1 mg/kg (i.e., greater than approximately 2 to 3 ppm of fluoride in the drinking water). The resulting discoloration of the teeth, or mottling, has no adverse effect except cosmetically. However, higher intakes lead to tooth flaking and more serious dental effects. Some evidence suggests that fluoride intakes are increasing among toddlers and young children because of the proliferating sources of fluoride. When drinking water contained less fluoride, the average intake was lower. Even the highest values did not exceed the recommendation of 0.08 mg/kg daily. Intakes of fluoride by young children may vary greatly from the use of dentifrices, fluoridated water, bottled drinks, and other sources. Some children may ingest total amounts of fluoride that exceed the optimum intake level (0.05 to 0.07 mg/kg daily), possibly causing dental fluorosis.

Absorption, Transport, Storage, and Excretion: Copper absorption, transport, storage and excretion are highly controlled (Kaplan and Lutsenko, 2009; Lalioti et al., 2009). Copper absorption occurs in the small intestine. Entry at the mucosal surface is by facilitated diffusion, and exit across the basolateral membrane is primarily by active transport; facilitated transfer may also occur. Competition between copper ions and other divalent cations exists at each step. Within the intestinal absorbing cells, copper ions are bound to metallothionein with greater affinity than zinc or other ions; the amount of copper absorbed may be regulated by the amount of metallothionein in the mucosal cells. Net absorption of copper varies from 25% to 60%. Low absorption efficiencies help to regulate the retention of copper in the body; therefore the percentage of absorption decreases with increased intake. Fiber and phytate intakes may slightly inhibit copper absorption.

Copper does not exist as a free ion in the body. Approximately 90% of the copper in serum is incorporated into ceruloplasmin, a functional enzyme at the erythrocyte-forming cells of the bone marrow. The remaining 10% is bound loosely to albumin, transcuprein, and other proteins; free amino acids; and possibly histidine. Serum copper and immunoreactive ceruloplasmin levels tend to be higher in women than in men. Serum copper concentration is greatest in the neonate, decreasing gradually during the first year of life.

Copper is transported bound to albumin, which serves as a temporary storage site for copper. In the liver copper binds to metallothionein. It serves as a storage form of copper and is incorporated into ceruloplasmin and secreted into the plasma for the transport of copper to cells. Copper is also secreted from the liver as a component of bile, its major route of excretion. Once in the GI tract, copper becomes part of the pool that may be resorbed or excreted, depending on bodily needs. Biliary excretion increases in response to excessive intakes of copper but may not be able to keep up with intake, sometimes allowing it to reach toxic levels.

Small amounts of copper are found in urine, sweat, and menstrual blood. Copper can be conserved by the kidney if necessary when substantial amounts are filtered through the glomeruli and resorbed in the tubules.

The interaction of copper with other nutrients negates the fallacy that taking vitamin and mineral supplements in amounts in excess of the recommended levels of consumption is good. In amounts of 150 mg/day, zinc induces copper deficiency by overwhelming the capacity of metallothionein in intestinal absorbing cells. High ascorbic acid intake (1500 mg/day) also reduces blood concentrations of copper, which may decrease the role of ceruloplasmin in red cell formation.

Functions: Copper is a component of many enzymes, and symptoms of copper deficiency are attributable to enzyme failures. Copper in ceruloplasmin has a well-documented role in oxidizing iron before it is transported in the plasma. Lysyl oxidase, a copper-containing enzyme, is essential in the lysine-derived cross-linking of collagen and elastin, connective tissue proteins with great tensile strength. Through the involvement of copper-containing electron transport proteins, copper also has roles in mitochondrial energy production. As part of copper-containing enzymes such as SOD, copper protects against oxidants and free radicals and promotes the synthesis of melanin and catecholamines. Other functions of copper-containing enzymes have not yet been completely defined.

Dietary Reference Intakes: An RDA of 900 mcg/day (0.9 mg/day) for adults of both genders has been established for copper (IOM, Food and Nutrition Board, 2001). Adolescents need 890 mcg. Copper intakes should range between 200 and 220 mcg/day for infants and between 340 and 440 mcg for young children. Premature infants are born with low copper reserves and may require additional dietary copper during their first few months of life.

Food Sources and Intakes: Copper is distributed widely in foods, including animal products (except for milk), and most diets provide between 0.6 and 2 mg/day. Foods high in copper are shellfish (oysters), organ meats (liver, kidney), muscle meats, chocolate, nuts, cereal grains, dried legumes, and dried fruits (Table 3-33).

In general, fruits and vegetables contain little copper. Cow’s milk, a poor source of copper, contains 0.015 to 0.18 mg/L, whereas the copper in human milk is well absorbed and ranges from 0.15 to 1.05 mg/L. Infants fed cow’s milk may be at risk for copper deficiency because of its low copper content.

Copper intakes of individuals in several age categories in the United States have been consistently below recommended amounts, with adolescent girls consuming only approximately 50% of the recommended intakes. Typically the copper content of drinking water is not considered in diet surveys. The amount of copper in water from copper pipes is considered insignificant. Copper intakes may be low in U.S. diets because until recently, ready-to-eat cereals typically were not fortified with copper as they were for iron and zinc. Another reason for the potential existence of low copper intakes is the inaccuracy associated with short-term assessments of dietary copper.

Deficiency: Serum copper and ceruloplasmin levels are useful biomarkers to assess copper status in populations. More sensitive indicators of copper status such as copper-containing enzymes in blood cells are needed (Harvey et al., 2009). Copper deficiency is characterized by anemia, neutropenia, and skeletal abnormalities, especially demineralization. Other changes may also develop, including subperiosteal hemorrhages, hair and skin depigmentation, and defective elastin formation. The failure of erythropoiesis, as well as cerebral and cerebellar degeneration, may lead to death. Neutropenia and leukopenia are the best early indications of copper deficiency in children.

Classic cases of copper deficiency were reported among infants who were poorly nourished, had diarrhea, and were fed diluted cow’s milk. Other cases of deficiency have been reported. Premature infants are likely to have copper deficiency unless given a supplement because most of the copper is normally transferred across the placenta during the last few months of a full-term pregnancy. Because diets in developing countries continue to be low in copper, pregnancy outcomes need to be monitored (Pathak and Kapil, 2004).

Copper is stored in the liver; deficiency develops slowly as stores become depleted. Deficiencies have not been reported in otherwise healthy humans consuming a varied diet. Low serum copper, ceruloplasmin, and SOD levels provide supportive evidence of copper deficiency, but these markers are not sensitive to marginal copper status. Bone changes, osteoporosis, metaphyseal spur formation, and soft tissue calcification in infants receiving prolonged TPN may resolve with copper supplementation. The only signs of copper deficiency found in adults are neutropenia and microcytic anemia; deficiency is very rare because copper accumulates in the liver throughout life in most individuals.

Wilson disease is an autosomal-recessive disorder of copper metabolism and liver dysfunction (Schilsky, 2009). Menkes syndrome, also known as kinky-hair syndrome, is a sex-linked recessive defect caused by at least 160 identified gene mutations (Møller et al., 2009). The syndrome results in copper malabsorption, increased urinary copper loss, and abnormal intracellular copper transport, all of which cause an abnormal distribution of copper among organs and within cells. Affected infants have retarded growth, defective keratinization and pigmentation of the hair, hypothermia, degenerative changes in aortic elastin, abnormalities of the metaphyses of long bones, and progressive mental deterioration. These infants typically do not survive the first few months of life. Many of the features of this disorder result from interference with the cross-linking of collagen and elastin, steps that require one or more copper enzymes. Brain tissue is practically devoid of cytochrome C oxidase, and a marked accumulation of copper occurs in the intestinal mucosa, although serum copper and ceruloplasmin levels remain very low. Many connective tissue defects occur in patients with Menkes syndrome.

Decreased plasma copper levels develop in patients with malabsorption diseases such as celiac disease, tropical sprue, protein-losing enteropathies, and nephrotic syndrome. Like zinc, low copper intakes may also contribute to reduced immune responses in otherwise healthy individuals.

Toxicity: Copper toxicity from food consumption is considered impossible. Excessive supplementation or copper salts used in agriculture may lead to liver cirrhosis and abnormalities in red blood cell formation.

Ceruloplasmin concentrations increase during pregnancy and with the use of oral contraceptives. Serum copper concentrations in pregnant women are approximately twice those in women who are not pregnant. Serum and biliary copper concentrations can be elevated in acute or chronic infections, liver disease, and pellagra. The physiologic significance of these elevations is not known.

Any chronic liver disease that interferes with the excretion of bile may contribute to the retention of copper. Primary biliary cirrhosis, as well as mechanical obstruction of the bile ducts, contributes to a progressive rise in liver copper content.

Absorption, Transport, Storage, and Excretion: Iodine is absorbed easily as iodide. In the circulation iodine exists freely and protein bound, but the bound iodide predominates. Excretion is primarily via urine, but small amounts are found in the feces as a result of biliary secretion.

Functions: Dietary iodine is needed for the synthesis of thyroid hormones. Iodine is stored in the thyroid gland, where it is used in the synthesis of triiodothyronine (T₃) and thyroxine (T₄). Uptake of iodide ions by the thyroid cells may be inhibited by goitrogens (substances that exist naturally in foods). Thyroid hormone is degraded in target cells and the liver, and the iodine is highly conserved under normal conditions. Selenium is important in iodine metabolism because of its presence in one enzyme responsible for forming active T₃ from thyroglobulin stored in the thyroid gland.

Dietary Reference Intakes: An iodine intake of 150 mcg/day has been suggested as sufficient for all adults and adolescents. The RDA for pregnant and lactating women increases to 220 mcg and 290 mcg, respectively. The AI is 110 mcg for infants up to 6 months of age and 130 mcg for older infants. The RDA for children is between 90 and 120 mcg and increases with age or body size. Urinary iodine, serum thyroxine, or thyroid-stimulating hormone levels are useful biomarkers of iodine status (Ristic-Medic et al., 2009). See Chapter 32.

Food Sources and Intakes: Iodine exists in variable amounts in food and drinking water. Seafood, such as clams, lobsters, oysters, sardines, and other saltwater fish, is the richest source. Saltwater fish contain 300 to 3000 mcg/kg of flesh; freshwater fish contain 20 to 40 mcg/kg, but they are still good sources. The iodine content of cow’s milk and eggs is determined by the iodides available in the diet of the animal; the iodide content of vegetables varies according to the iodine content of the soil in which they grow. Iodine also enters the food chain through iodophors, which are used as disinfectants in dairy processing, coloring agents, and dough conditioners. These sources add significant amounts of iodine to the food supply. Table 3-34 lists the iodine content of various foods.

The best way to obtain an AI of iodine is to use iodized salt (approximately 60 mcg of iodine per gram of salt) in food preparation. Sea salt naturally contains variable amounts of iodine and only approximately one-tenth the level of iodized salt. More than 50% of the table salt sold in the United States is iodized; however, iodized salt is not used in processed foods. Mandatory iodinization has been adopted by many nations, including Canada, but is not legally required in the United States, where iodine deficiency is now very rare. The use of iodized salt should still be advocated in certain areas to prevent goiter.

The Total Diet Study of the FDA showed that median adult iodine intakes from 1982 to 1991 ranged from 130 to 140 mcg/day for women and 182 to 204 mcg/day for men. The median iodine intake for male and female teenagers was even higher. Intakes of iodine in the United States seem adequate for most people because of iodinization of salt and the use of iodofors. Vegans consume iodine in seaweed or kelp tablets; some individuals may have excessive iodine intakes.

Deficiency: An estimated two billion people worldwide remain at risk for iodine deficiency. Most are in developing countries, especially those who do not have seafood as part of their diets. These individuals may have a moderate iodine deficiency, even when obvious goiter, a severe condition, is not evident. In children, iodine deficiency is associated with poor cognition. Use of iodized salt or the oral administration of a single dose of iodized oil and weekly iodine supplements are effective. Use of iodized salt should be encouraged during pregnancy, especially through the end of the second trimester.

Very low iodine intakes are associated with the development of endemic or simple goiter, which is an enlargement of the thyroid gland (Figure 3-37). Deficiency may be nearly total, especially in mountainous areas and regions of high goitrogen intakes, or relative, subsequent to an increased need for thyroid hormones (e.g., by females during adolescence, pregnancy, and lactation).

Although many countries have worked to eliminate iodine deficiency, goiter may affect as many as 200 to 300 million people worldwide (Kusic and Jukic, 2005). In some countries goiter is so common that it is regarded as a normal physical feature. In the United States the prevalence rate of goiter for all ages is 1.9/1000 persons. The rate is higher in women than in men and in older individuals than in younger ones.

Goitrogens, which exist naturally in foods, can also cause goiter by blocking uptake of iodine from the blood by thyroid cells. Foods containing goitrogens include cabbage, turnips, rapeseeds (from rape plants), peanuts, cassava, sweet potatoes, kelp, and soybeans. Goitrogens are inactivated by heating or cooking.

Severe iodine deficiency during gestation and early postnatal growth results in cretinism in infants, characterized by mental deficiency, spastic diplegia or quadriplegia, deaf mutism, dysarthria, a characteristic shuffling gait, shortened stature, and hypothyroidism. Less severe variations of this syndrome also exist, manifesting as moderate retardation in intellectual or neuromotor maturation. In some areas, use of iodine supplementation has been found to improve cognitive function in school-aged children who are mildly deficient (Gordon et al., 2009). The WHO has increased the recommended iodine intake during pregnancy from 200 to 250 mcg/day; in regions where less than 90% of households are using iodized salt, iodine supplementation should be used in pregnancy and infancy (Zimmerman, 2009).

Toxicity: Even though iodine intakes have a wide margin of safety, tolerable ULs have been established (IOM, Food and Nutrition Board, 2001). Adults have a UL of 1100 mcg/day, and young children have a UL of 200 to 300 mcg/day. In some cases goiter develops slowly as a consequence of long-term iodine intakes that are much higher than physiologic requirements. The role of excessive iodine in thyroid disease or disorder is not clear. Today the level of iodine in foods is not considered a significant public health problem in the United States or Canada. The level of iodine in most American diets is appropriate for good health. For small groups of people with underlying thyroid pathologic conditions, excessive iodine in the diet may result in hypothyroidism, goiter formation, or hyperthyroidism (Mussig et al., 2006).

Absorption, Transport, Storage, and Excretion: Absorption of selenium, which occurs in the upper segment of the small intestine, is more efficient under conditions of deficiency. Increased intake frequently results in increased excretion of selenium in the urine. Selenium status is assessed by measuring selenium or GSH-Px in serum, platelets, and erythrocytes or in whole blood. Erythrocyte selenium measurement is an indicator of long-term intake. Selenium is transported bound to albumin initially and subsequently to α₂-globulin.

Functions: Selenium, as selenomethionine or selenocysteine, exists in several proteins that are widely distributed in the body. Cellular GSH-Px has been found in almost all cells and extracellularly in serum and milk. GSH-Px acts with other antioxidants to reduce cellular peroxides and free radicals in general into water and other harmless molecules. This family of enzymes may help provide a reserve of selenium in proteins that can be drawn on when needed. Many but not all of the pathologic changes caused by selenium deficiency reflect inadequate levels of GSH-Px enzymes.

Phospholipid hydroperoxide GSH-Px is found in lipid-soluble fractions of the cell and has roles in lipid and eicosanoid metabolism. Type 1 iodothyronine 5′-deiodinase, an enzyme capable of converting T₄ to T₃, is a selenoprotein. Moderate selenium intakes (40 mcg/day) seem adequate to maintain activities of these deiodinases. However, high intakes (350 mcg/day) are associated with depressed T₃ levels. GSH-Px enzymes have also been shown to be critical in several endocrine systems (Beckett and Arthur, 2005).

Selenoprotein P may act as a free radical scavenger or a transporter of selenium. Selenium is used in the synthesis of these molecules in the anionic form. In the molecules, selenium is covalently bound, as is sulfur, which it typically replaces in some of these molecules. The antioxidant effects of selenium and vitamin E may reinforce each other by the overlap of their protective actions against oxidative damage. These two antioxidant nutrients may participate in other cooperative activities that help maintain healthy cells. GSH-Px acts in the cytosol and the mitochondrial matrix, whereas vitamin E exerts its antioxidative actions within cell membranes.

The GSH-Px reaction step is illustrated in Figure 3-38. Other selenium-dependent enzymes exist in mammalian systems, but less is known about their requirements for selenium. The selenium-containing enzymes may have an antioxidative role in preventing cancer. Many other selenoproteins have been identified, but their functions have not yet been elucidated.

Dietary Reference Intakes: The RDAs for selenium are 55 mcg/day for women, men, and adolescents (ages 14 to 18), whereas the RDAs for children range from 20 to 30 mcg/day. The AIs for infants is 15 to 20 mcg/day. The RDA during pregnancy is 60 mcg, and the RDA during lactation is 70 mcg/day. Requirements for selenium may increase with a high consumption of unsaturated fatty acids because of the need for higher antioxidant activity. However, low-dose chronic exposure to selenium may be widespread in some populations; the upper safe limit may actually be set too high (Vinceti et al., 2009).

Food Sources and Intakes: No comprehensive table of the selenium content of foods has been published. The selenium concentration in foods depends on the selenium content of the soil and water where the food was grown. Improvements in analytic techniques have resulted in changes being made to many previously published data of the selenium content of foods during the last few decades (Table 3-35).

Major food sources of selenium are Brazil nuts, seafood, kidney, liver, meat, and poultry. Highest intake in the United States is from animal flesh foods. Grains vary in selenium content, depending on where they are grown. Fruits and vegetables are low in selenium content.

Selenium content and GSH-Px activity in human breast milk are influenced directly by maternal intake and by the form of selenium consumed. Plasma selenium concentrations of infants fed unsupplemented formula are lower than those of infants fed supplemented formula or human milk. Selenium fortification of infant formulas has been shown to improve the status of infants.

Deficiency: Despite a wide range of selenium intakes from food, selenium deficiency is rare in populations throughout the world. Selenium deficiency takes years to develop when food intake is adequate. Severe selenium deficiency in a population has only been reported in China. Keshan disease, a cardiomyopathy that mainly affects children and women, was first observed in the Keshan province of China. Since its discovery, supplementation programs in Keshan have totally eradicated the disease. However, in individuals with established disease, the response to supplementation is poor, probably because of other factors contributing to myopathy; a viral infection combined with selenium deficiency has been suggested (Beck et al., 1995).

The second selenium deficiency disease, discovered in Mongolia, is known as Kashan-Beck disease and is common in preadolescent and adolescent children. These two diseases occur in areas where the soil content of selenium is very low. This disease may also have a viral component combined with the selenium deficiency. Illness initially involves symmetric stiffness, swelling, and often pain in the interphalangeal joints of the fingers, followed by generalized osteoarthritis. Here iodine deficiency may be another risk factor.

Patients with some cancers have been shown to have low serum selenium levels, although the underlying mechanisms for this correlation have not been established. One possible explanation lies in the possible failure of GSH-Px to scavenge free radicals efficiently in dividing cells. In addition, patients with cirrhosis have low plasma selenium concentrations, which may predispose them to cancer (Latavayova et al., 2006).

Selenium deficiency has been reported in malnourished patients receiving long-term TPN. Supplementation results in improved serum selenium levels, platelet GSH-Px activity, and reduced clinical symptoms. Selenium deficiency should no longer be a problem in patients receiving long-term TPN or enteral nutrition because these solutions now include a trace element supplement.

Toxicity: Indicators of selenium toxicity have been reported in China and Australia. Signs of toxicity (selenosis) include skin and nail changes, tooth decay, and nonspecific GI and neurologic abnormalities. Research also suggests that excessive intakes may be mutagenic or genotoxic, a point that is important to note for pregnant women. In addition, the long-term effects of selenium supplementation on the thyroid hormones have not been clearly identified (Combs et al., 2009). In countries such as New Zealand, where both selenium and iodine levels tend to be low, supplementation with selenium alone will not improve thyroid function; iodine is also required (Thomson et al., 2009).

Absorption, Transport, Storage, and Excretion: Manganese is absorbed throughout the small intestine. Iron and cobalt compete for common binding sites for absorption. Men absorb less manganese than women, a difference noted by iron status and plasma ferritin levels. Heme iron has no influence on manganese status, but diets high in nonheme iron can be associated with lower serum manganese values, higher urinary manganese losses, and lower activity of manganese-containing enzymes.

Manganese is transported bound to a macroglobin, transferrin, and transmanganin. Excretion occurs mainly in the feces after secretion into the intestine via the bile. The cytoplasmic iron exporter ferroportin (Fpn) functions as a manganese exporter; manganese exposure promotes Fpn protein expression, which reduces manganese accumulation and its related cytotoxicity (Yin et al., 2010). Antioxidants may also play a role in the excretion of toxic levels of manganese.

Functions: Manganese is associated with the formation of connective and skeletal tissues, growth, and reproduction. The 10 to 20 mg of manganese contained in the adult human body tends to be concentrated predominantly in mitochondria. Manganese activates many enzymes, especially in conjunction with magnesium. Manganese is essential for proper metabolism of amino acids, proteins and lipids.

Manganese is a component of many enzymes, including glutamine synthetase, pyruvate carboxylase, and mitochondrial SOD (MnSOD). It catalyzes detoxification of free radicals and may protect against some types of cancer. MnSOD converts superoxide anion into hydrogen peroxide but this must be detoxified by GSH-Px. If that does not occur, hydrogen peroxide forms a hydroxyl radical with iron, which is detrimental for patients with cirrhosis who have an altered SOD gene (Nahon et al., 2009).

Dietary Reference Intakes: The AIs for manganese are 2.3 mg/day for men and 1.8 mg/day for women. For children 9 years of age and older the AIs are 1.9 to 2.2 mg/day for boys and 1.6 mg/day for girls. For children younger than 9 the AIs are 1.2 to 1.5 mg/day, depending on their age.

Food Sources and Intakes: The manganese content of foods varies greatly. The richest sources are whole grains, legumes, nuts, and tea. Fruits and vegetables are moderately good sources. Relatively high amounts exist in instant coffee and tea.

Animal tissues, seafood, and dairy products are poor sources. Human milk is relatively low in manganese. Intakes are often low for adolescent girls.

Deficiency: Manganese deficiency, although rare, affects reproductive capacity, pancreatic function, and aspects of carbohydrate metabolism. Symptoms of deficiency are weight loss, transient dermatitis, occasionally nausea and vomiting, a change in hair color, and slow hair growth. In addition, there is a correlation between low blood manganese and convulsions (Gonzalez-Reyes et al., 2007).

Animal studies have established that manganese is necessary for reproduction. Sterility develops in both sexes; striking skeletal abnormalities and ataxia characterize the offspring of mothers who are manganese deficient. Lower blood manganese levels may be associated with fetal intrauterine growth retardation and lower birth weight in humans (Wood, 2009).

Toxicity: Manganese toxicity has developed in miners as a result of absorption of manganese through the respiratory tract. The excess, which accumulates in the liver and central nervous system, produces Parkinson-like symptoms. Manganese intake in excess leads to neurotoxicity, impairing energy metabolism and causing cell death (Puli et al., 2006). This is especially true for dopaminergic neurons.

Toxicity has also been reported in patients receiving TPN with added manganese. Symptoms include headaches, dizziness, and abnormal magnetic resonance imaging results and hepatic dysfunction (Masumoto et al., 2001).

The ULs of manganese from diet have been difficult to establish. Red wine may be a source of relatively high levels of metal ions, leading to a very high target hazard quotient for those individuals consuming at least 250 mL per day for many years (Hague et al., 2008). The implications for manganese require further study.

Absorption, Transport, Storage, and Excretion: As with other minerals, organic and inorganic forms of chromium are absorbed differently. Organic chromium is readily absorbed but quickly passes out of the body. Less than 2% of the trivalent chromium consumed is absorbed. Chromium absorption is increased by oxalate and is higher in iron-deficient animals than in animals with adequate iron, suggesting that it shares some similarities with the iron absorption pathway. With dietary intakes of 40 mcg or more per day, chromium absorption reaches and remains at a plateau; at such high intakes, urinary excretion increases to maintain balance.

The type of dietary carbohydrate consumed modifies absorption from chromium chloride. Starch rather than sugar increases absorption. Absorption is also greater from chromium picolinate than from chromium chloride, where absorption is 2% or less.

Chromium and iron are carried by transferrin; however, albumin is also capable of assuming this role if iron transferrin saturation is high. In addition, α- and β-globulins and lipoproteins can also bind chromium.

Primarily the kidney excretes inorganic chromium, with small amounts being excreted through hair, sweat, and bile. Organic chromium is excreted through bile. Strenuous exercise, physical trauma, or an increased intake of simple sugar results in increased chromium excretion.

Functions: Chromium potentiates insulin action and influences carbohydrate, lipid, and protein metabolism. It may have a beneficial effect on serum triglyceride levels. Although the chemical nature of the relationship between chromium and insulin activity has not been clearly identified, a possible chromium-NA (chromium polynicotinate) complex has been identified. Chromium may regulate the synthesis of a molecule that potentiates insulin action; this glucose tolerance factor (GTF) is controversial. However, chromium supplementation alone or combined with vitamins C and E minimizes oxidative stress; it also improves glucose metabolism in type 2 diabetes mellitus patients (Lai, 2008). Another possible role for chromium, similar to that of zinc, is in the regulation of gene expression.

Dietary Reference Intakes: The AIs recommended for chromium range from 25 to 35 mcg/day for males 9 years of age and older and 21 to 25 mcg/day for females of the same age. Depending on the age of the child, 11 to 15 mcg/day has been established for children 1 to 8 years of age.

Food Sources and Intakes: Precise assessment of chromium in foods is difficult; biologically available chromium and inorganic chromium cannot be distinguished from each other. Analyses done before 1980 must be considered with caution because determinations were flawed by contamination and analytic problems.

Brewer’s yeast, oysters, liver, and potatoes have high chromium concentrations; seafood, whole grains, cheeses, chicken, meats, and bran have medium chromium concentrations. The refining of wheat removes chromium with the wheat germ and the bran; refining sugar fractionates the chromium into the molasses portion. Dairy products, fruits, and vegetables are low in chromium. Table 3-36 and Appendix 52 present the chromium content of selected foods.

Usual chromium intakes range between 25 and 35 mcg/day for women and men, respectively. Chromium intakes are not assessed in the USDA, National Health and Nutrition Examination Survey, or Total Diet Study surveys because of inadequate methodology. Human breast milk contains 3 to 8 nmol/L of chromium, which is lower than the recommended intake for infants.

Deficiency: Chromium deficiency results in insulin resistance and a few lipid abnormalities, which can be ameliorated by chromium supplementation. Insufficient chromium may be consumed by some Americans; true deficiency is more likely to occur in populations with very low intakes. Some epidemiologic studies suggest low tissue levels of chromium in patients with diabetes. However, they recommend long-term clinical trials to assess safety of chronic chromium supplementation before it is used in these patients. Claims that the ingestion of high doses of chromium consumed as chromium picolinate improves strength, body composition, endurance, or other characteristics of physical fitness are controversial, with some studies supporting these claims and others not.

Toxicity: Chromium toxicity from food has not been reported. Chromium picolinate taken as a supplement in high doses by athletes and power lifters has resulted in some adverse effects, primarily skin lesions. An increase risk of cancer has been identified in China in a population that was exposed to high chromium levels in drinking water (Smith and Steinmaus, 2009).

Absorption, Transport, Storage, and Excretion: Molybdenum, which is found in minute amounts in the body, is readily absorbed from the stomach and small intestine, with the rate of absorption being higher in the proximal small intestine than in the distal small intestine. As with other minerals, molybdenum is absorbed by two mechanisms: carrier-mediated and passive diffusion. Molybdenum is excreted primarily in the urine. Excretion rather than absorption is the homeostatic mechanism. Some molybdenum is also excreted in the bile.

Functions: Xanthine oxidase, aldehyde oxidase, and sulfite oxidase, all enzymes that catalyze oxidation-reduction reactions, require a prosthetic group containing molybdenum (Schwarz et al., 2009). Sulfite oxidase is important to the degradation of cysteine and methionine and catalyzes the formation of sulfate from sulfite. Whether molybdenum is involved in the response of some asthmatics to sulfites is not known. Genetic sulfite oxidase deficiency is a fatal disorder of cysteine metabolism. Clinical symptoms include severe brain damage with mental retardation, dislocation of the lens, and increased urinary output of sulfate.

Dietary Reference Intakes: The RDAs for molybdenum throughout the life cycle range from 43 to 45 mcg/day for adolescents and adults. Depending on the child’s age, RDAs range from 17 to 34 mcg/day for children.

Food Sources and Intakes: Molybdenum is distributed widely in commonly consumed foods such as legumes, whole-grain cereals, milk and milk products, and dark green leafy vegetables. Estimated intakes, as determined by the Total Diet Study of the FDA, ranged from 50 mcg/day in infants to 80 and 126 mcg/day for 14- to 16-year-old girls and boys, respectively. These intakes were found to decrease slowly over the lifetime.

Deficiency: Molybdenum deficiency has not been established in humans other than patients treated with TPN. Symptoms of molybdenum deficiency include mental changes and abnormalities of sulfur and purine metabolism.

Toxicity: An excessive molybdenum intake of 10 to 15 mg/day is associated with a goutlike syndrome (Nielsen, 2009). However, no good biomarkers are available to assess the presence of molybdenum excess accurately. Nonetheless, plasma molybdenum does seem to reflect molybdenum intake.

Functions: Boron is associated with cell membranes and in plants is involved with the functional efficiency of cell membranes. Response to boron deprivation is enhanced when other nutrients that alter membrane functions are also deficient. Boron apparently binds to the active site of some enzymes, reducing their ability to function. Boron is also thought to compete with some enzymes for the coenzyme NAD.

Boron influences the activity of many metabolic enzymes and the metabolism of such nutrients as calcium, magnesium, and vitamin D (Devirian and Volpe, 2003). Evidence from animal studies shows that boron deprivation affects two major organs: the brain and bone. Boron deficiency alters brain composition and function and reduces bone composition, structure, and strength. Because of the role of boron in bone, studies in humans have focused on its potential role in the development of osteoporosis. Boron may have actions similar to estrogens on bone (Nielsen, 2009). Boron is also required for normal reproduction and healthy immune response. Other roles of boron in humans have not been well studied.

Dietary Reference Intakes: No DRIs have been established for boron.

Food Sources and Intakes: Foods that are good sources of boron include plant foods, especially noncitrus fruits, vegetables, nuts, and legumes. Wine, cider, and beer are other good sources of boron.

Deficiency and Toxicity: Symptoms of severe boron deficiency have not been established (Nielsen, 2009). No toxicity level has been identified.

Absorption, Transport, Storage, and Excretion: Cobalt may share part of the same intestinal transport mechanism as iron. Absorption is higher in patients with deficient iron intake, portal cirrhosis with iron overload, and idiopathic hemochromatosis. The major route of cobalt excretion is the urine; small amounts are excreted via feces, sweat, and hair.

Functions: The well-known essential role of cobalt is as a component of vitamin B₁₂ (cobalamin). This vitamin is essential for the maturation of red blood cells and the normal function of all cells. Methionine aminopeptidase, an enzyme involved in the regulation of translation (i.e., of DNA to RNA), is the only enzyme in humans known to have an established requirement of this trace element.

Dietary Reference Intakes: The dietary requirement for cobalt is expressed in terms of vitamin B₁₂. Approximately 2 to 3 mcg of vitamin B₁₂ is needed daily.

Food Sources and Intakes: Cobalt exists in foods; however, only microorganisms are able to synthesize vitamin B₁₂. Ruminant animals obtain cobalamin as the result of a symbiotic relationship with the microorganisms of their GI tract. The microorganisms of monogastric species such as humans have an extremely limited capacity for synthesis; therefore humans must obtain vitamin B₁₂—and thus cobalt—from animal foods such as organ and muscle meats. In some circumstances ordinary bacterial contamination of foods of vegetable origin may supply the minute required amounts of this vitamin. Strict vegetarians who avoid all animal products may develop vitamin B₁₂ deficiency, either after 3 to 6 years or not at all.

Deficiency: A cobalt deficiency develops only in relation to a vitamin B₁₂ deficiency. Insufficient vitamin B₁₂ causes a macrocytic anemia. A genetic defect limiting vitamin B₁₂ absorption results in pernicious anemia, which is treated appropriately with massive doses of the vitamin.

Toxicity: A high intake of inorganic cobalt (existing freely from cobalamin) in animal diets produces polycythemia (an overproduction of red blood cells), hyperplasia of bone marrow, reticulocytosis, and increased blood volume.

The information on the microminerals known to be required by humans is summarized in Table 3-36.