7

Vitamin D

BACKGROUND INFORMATION

Overview

Vitamin D (calciferol), which comprises a group of fat soluble seco-sterols that are found in very few foods naturally, is photosynthesized in the skin of vertebrates by the action of solar ultraviolet B radiation (Holick, 1994). Vitamin D comes in many forms, but the two major physiologically relevant ones are vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol) (Fieser and Fieser, 1959). Vitamin D2 originates from the yeast and plant sterol, ergosterol; vitamin D3 originates from 7-dehydrocholesterol, a precursor of cholesterol, when synthesized in the skin (Figure 7-1). Major metabolic steps involved with the metabolism D2 are similar to those of the metabolism of D3. Vitamin D without a subscript represents either D2 or D3 or both and is biologically inert, requiring two obligate hydroxylations to form its biologically active hormone, 1,25-dihydroxyvitamin D (1,25(OH)2D) (DeLuca, 1988; Reichel et al., 1989).

Vitamin D's major biologic function in humans is to maintain serum calcium and phosphorus concentrations within the normal range by enhancing the efficiency of the small intestine to absorb these minerals from the diet (DeLuca, 1988; Reichel et al., 1989) (Figure 7-2). 1,25(OH)2D enhances the efficiency of intestinal calcium absorption along the entire small intestine, but primarily in the duodenum and jejunum. 1,25(OH)2D3 also enhances dietary phosphorus absorption along the entire small intestine (Chen et



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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride 7 Vitamin D BACKGROUND INFORMATION Overview Vitamin D (calciferol), which comprises a group of fat soluble seco-sterols that are found in very few foods naturally, is photosynthesized in the skin of vertebrates by the action of solar ultraviolet B radiation (Holick, 1994). Vitamin D comes in many forms, but the two major physiologically relevant ones are vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol) (Fieser and Fieser, 1959). Vitamin D2 originates from the yeast and plant sterol, ergosterol; vitamin D3 originates from 7-dehydrocholesterol, a precursor of cholesterol, when synthesized in the skin (Figure 7-1). Major metabolic steps involved with the metabolism D2 are similar to those of the metabolism of D3. Vitamin D without a subscript represents either D2 or D3 or both and is biologically inert, requiring two obligate hydroxylations to form its biologically active hormone, 1,25-dihydroxyvitamin D (1,25(OH)2D) (DeLuca, 1988; Reichel et al., 1989). Vitamin D's major biologic function in humans is to maintain serum calcium and phosphorus concentrations within the normal range by enhancing the efficiency of the small intestine to absorb these minerals from the diet (DeLuca, 1988; Reichel et al., 1989) (Figure 7-2). 1,25(OH)2D enhances the efficiency of intestinal calcium absorption along the entire small intestine, but primarily in the duodenum and jejunum. 1,25(OH)2D3 also enhances dietary phosphorus absorption along the entire small intestine (Chen et

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride FIGURE 7-1 The photochemical, thermal, and metabolic pathways for vitamin D3. Specific enzymes abbreviated as follows: ∆7ase,7-dehydrocholesterol reductase; 25OHase, vitamin D-25-hydroxylase; 1α-OHase, 25-OH-D-1α-hydroxylase; 24R-OHase, 25(OH)D-24R-hydroxylase. Inset: the structure of vitamin D2. Reproduced with permission, Holick (1996).

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride FIGURE 7-2 Photosynthesis of vitamin D3 and the metabolism of vitamin D3 to 25(OH)D3 and 1,25 (OH)2D3. Once formed, 1,25(OH)2D3 carries out the biologic functions of vitamin D3 on the intestine and bone. Parathyroid hormone (PTH) promotes the synthesis of 1,25(OH)2D3, which, in turn, stimulates intestinal calcium transport and bone calcium mobilization, and regulates the synthesis of PTH by negative feedback. Reproduced with permission, Holick (1996).

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride al., 1974), but its major influence is in the jejunum and ileum. When dietary calcium intake is inadequate to satisfy the body's calcium requirement, 1,25(OH)2D, along with parathyroid hormone (PTH), mobilizes monocytic stem cells in the bone marrow to become mature osteoclasts (Holick, 1995; Merke et al., 1986). The osteoclasts, in turn, are stimulated by a variety of cytokines and other factors to increase the mobilization of calcium stores from the bone (Figure 7-2). Thus, vitamin D maintains the blood calcium and phosphorus at supersaturating concentrations that are deposited in the bone as calcium hydroxyapatite. A multitude of other tissues and cells in the body can recognize 1,25(OH)2D (Stumpf et al., 1979). Although the exact physiologic function of 1,25(OH)2D in the brain, heart, pancreas, mononuclear cells, activated lymphocytes, and skin remains unknown, its major biologic function has been identified as a potent antiproliferative and prodifferentiation hormone (Abe et al., 1981; Colston et al., 1981; Eisman et al., 1981; Smith et al., 1987). There is little evidence that vitamin D deficiency leads to major disorders in these organ and cellular systems. Physiology of Absorption, Metabolism, and Excretion Because dietary vitamin D is fat soluble once it is ingested, it is incorporated into the chylomicron fraction and absorbed through the lymphatic system (Holick, 1995). It is estimated that approximately 80 percent of the ingested vitamin D enters the body via this mechanism. Vitamin D is principally absorbed in the small intestine. Vitamin D is principally excreted in the bile. Although some of it is reabsorbed in the small intestine (Nagubandi et al., 1980), the enterohepatic circulation of vitamin D is not considered to be an important mechanism for its conservation (Fraser, 1983). However, since vitamin D is metabolized to more water-soluble compounds, a variety of vitamin D metabolites, most notably calcitroic acid, are excreted by the kidney into the urine (Esvelt and DeLuca, 1981). Once vitamin D enters the circulation from the skin or from the lymph via the thoracic duct, it accumulates in the liver within a few hours. In the liver, vitamin D undergoes hydroxylation at the 25-carbon position in the mitochondria, and soon thereafter, it appears in the circulation as 25-hydroxyvitamin D (25(OH)D) (DeLuca, 1984) ( Figure 7-1 and Figure 7-2). The circulating concentration of 25(OH)D is a good reflection of cumulative effects of exposure to sunlight and dietary intake of vitamin D (Haddad and Hahn, 1973; Holick, 1995; Lund and Sorensen, 1979). In the liver, vitamin D-25-

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride hydroxylase is regulated by vitamin D and its metabolites, and therefore, the increase in circulating concentration of 25(OH)D after exposure to sunlight or ingestion of vitamin D is relatively modest compared with cumulative production or intake of vitamin D (Holick and Clark, 1978). The appearance in the blood of the parent compound, vitamin D, is short-lived as it is either stored in the fat or metabolized in the liver (Mawer et al., 1972). The half-life of 25(OH)D in the human circulation is approximately 10 days to 3 weeks (Mawer et al., 1971; Vicchio et al., 1993). Administration of 25(OH)D results in approximately two to five times more activity than giving vitamin D itself in curing rickets and in inducing intestinal calcium absorption and mobilization of calcium from bones in rats. However, at physiologic concentrations, it is biologically inert in affecting these functions (DeLuca, 1984). In order to have biologic activity at physiologic concentrations, 25(OH)D must be hydroxylated in the kidney on the 1-carbon position to form 1,25(OH)2D (Holick et al., 1971; Lawson et al., 1971) (Figure 7-1 and Figure 7-2). It is 1,25(OH)2D that is thought to be the biologically active form of vitamin D and that is responsible for most, if not all, of its biologic functions (DeLuca, 1988; Fraser, 1980; Reichel et al., 1989). The production of 1,25(OH)2D in the kidney is tightly regulated, principally through the action of PTH in response to serum calcium and phosphorus levels (DeLuca, 1984; Portale, 1984; Reichel et al., 1989) (Figure 7-2). The half-life of 1,25(OH)2D in the circulation of humans is approximately 4 to 6 hours (Kumar, 1986). Because of the tight regulation of the production of 1,25(OH) 2D and its relatively short serum half-life, it has not proven to be a valuable marker for vitamin D deficiency, adequacy, or excess. 25(OH)D and 1,25(OH)2D may undergo a hydroxylation on the 24-carbon to form their 24-hydroxy counterparts, 24,25-dihydroxyvitamin D (24,25(OH)2D) (Figure 7-1) and 1,24,25-trihydroxyvitamin D (DeLuca, 1984; Holick, 1995). It is believed that the 24-carbon hydroxylation is the initial step in the metabolic degradation of 25(OH)D and 1,25(OH)2D (DeLuca, 1988). The final degradative product of 1,25 (OH)2D3 is calcitroic acid, which is excreted by the kidney into the urine (Esvelt and DeLuca, 1981) (Figure 7-1). Although the kidney supplies the body with 1,25(OH)2D to regulate calcium and bone metabolism, it is recognized that activated macrophages, some lymphoma cells, and cultured skin and bone cells also make 1,25(OH)2D (Adams et al., 1990; Holick, 1995; Pillai et al., 1987). Although the physiologic importance of locally produced 1,25 (OH)2D is not well understood, the excessive unregulat-

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride ed production of 1,25(OH)2D by activated macrophages and lymphoma cells is responsible for the hypercalciuria associated with chronic granulomatous disorders and the hypercalcemia seen with lymphoma (Adams, 1989; Davies et al., 1994). Factors Affecting the Vitamin D Requirement Special Populations Elderly. Aging significantly decreases the capacity of human skin to produce vitamin D3 (MacLaughlin and Holick, 1985). In adults over age 65 years, there is a fourfold decrease in the capacity to produce vitamin D3 when compared with younger adults aged 20 to 30 years (Holick et al., 1989; Need et al., 1993). Although one study suggested that there may be a defect in intestinal calcium absorption of tracer quantities of vitamin D3 in the elderly (Barragry et al., 1978), two other studies demonstrated that aging does not significantly affect absorption of pharmacologic doses of vitamin D (Clemens et al., 1986; Holick, 1986). It is not known whether the absorption of physiologic amounts of vitamin D is altered in the elderly. Malabsorption Disorders. Patients suffering from various intestinal malabsorption syndromes such as severe liver failure, Crohn's disease, Whipple's disease, and sprue often suffer from vitamin D deficiency because of their inability to absorb dietary vitamin D (Lo et al., 1985). Thus, patients who are unable to secrete adequate amounts of bile or who have a disease of the small intestine are more prone to develop vitamin D deficiency owing to their inability to absorb this fat-soluble vitamin. Sources of Vitamin D Vitamin D intake from food and nutrient supplements is expressed in either international units (IU) or micrograms (µg). One IU of vitamin D is defined as the activity of 0.025 µg of cholecalciferol in bioassays with rats and chicks. Thus, the biological activity of 1 µg of vitamin D is 40 IU. The activity of 25(OH)D is 5 times more potent than cholecalciferol; thus, 1 IU = 0.005 µg 25(OH)D. Sunlight Throughout the world, the major source of vitamin D for humans is the exposure of the skin to sunlight (Holick, 1994). During sun

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride exposure, the ultraviolet B photons with energies between 290 and 315 nm are absorbed by the cutaneous 7-dehydrocholesterol to form the split (seco) sterol previtamin D3 (Holick et al., 1980; MacLaughlin et al., 1982). This photosynthesis of vitamin D occurs in most plants and animals (Holick et al., 1989). However, a variety of factors limit the cutaneous production of vitamin D3. Excessive exposure to sunlight causes a photodegradation of previtamin D3 and vitamin D3 to ensure that vitamin D3 intoxication cannot occur (Holick, 1994; Holick et al., 1981; Webb et al., 1989) (Figure 7-2). An increase in skin melanin pigmentation or the topical application of a sunscreen will absorb solar ultraviolet B photons and thereby significantly reduce the production of vitamin D3 in the skin (Clemens et al., 1982; Matsuoka et al., 1987). Latitude, time of day, and season of the year have a dramatic influence on the cutaneous production of vitamin D3. Above and below latitudes of approximately 40° N and 40° S, respectively, vitamin D3 synthesis in the skin is absent during most of the three to four winter months (Ladizesky et al., 1995; Webb et al., 1988). The far northern and southern latitudes extend this period for up to 6 months (Holick, 1994; Oliveri et al., 1993). Dietary Intake Accurate estimates of vitamin D intakes in the United States are not available, in part because the vitamin D composition of fortified foods is highly variable (Chen et al., 1993; Holick et al., 1992) and because the U.S. intake surveys do not include estimates of vitamin D intake. Using food consumption data from the second National Health and Nutrition Examination Survey (NHANES II), median vitamin D intakes from food by young women were estimated to be 2.9 µg (114 IU)/day, with a range of 0 to 49 µg (0 to 1,960 IU)/day (Murphy and Calloway, 1986). A similar median vitamin D intake, 2.3 µg (90 IU)/day, was estimated for a sample of older women (Krall et al., 1989). Food Sources In nature, very few foods contain vitamin D. Those that do include some fish liver oils, the flesh of fatty fish, the liver and fat from aquatic mammals such as seals and polar bears, and eggs from hens that have been fed vitamin D (Holick, 1994; Jeans, 1950). Almost all of the human intake of vitamin D from foods comes from fortified milk products and other fortified foods such as breakfast cereals. The vitamin D content of unfortified foods is generally low, with the exception of fish, many of which contain 5 to 15 µg (200 to

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride 600 IU)/100 g; Atlantic herring contain up to as much as 40 µg (1,600 IU)/100 g (USDA, 1991). After vitamin D was recognized as being critically important for the prevention of rickets, the United States, Canada, and many other countries instituted a policy of fortifying some foods with vitamin D (Steenbock and Black, 1924). Milk was chosen as the principal dietary component to be fortified with either vitamin D2 or vitamin D3. In other countries, some cereals, margarine, and breads also have small quantities of added vitamin D (Lips et al., 1996). In the United States and Canada, all milk, irrespective of its fat content, is fortified with 10 µg (400 IU)/quart and 9.6 µg (385 IU)/liter, respectively, of vitamin D. However, during the past decade, three surveys in which the vitamin D content in milk was analyzed revealed that up to 70 percent of milk sampled throughout the United States and Canada did not contain vitamin D in the range of 8 to 12 µg (320 to 480 IU)/quart (the 20 percent variation allowed by current labeling standards). Furthermore, 62 percent of 42 various milk samples contained less than 8 µg (320 IU)/quart of vitamin D, and 14 percent of skim milk samples had no detectable vitamin D (Chen et al., 1993; Holick et al., 1992; Tanner et al., 1988). All proprietary infant formulas must also contain vitamin D in the amount of 10 µg (400 IU)/liter. However, these products have also been found to have wide variability in their vitamin D content (Holick et al., 1992). Intake from Dietary Supplements In the one available study of dietary supplement intake in the United States, use of vitamin D supplements in the previous 2 weeks in 1986 was reported for over one-third of the children 2 to 6 years of age, over one-fourth of the women, and almost 20 percent of the men (Moss et al., 1989). For supplement users, the median dose was the same for men, women, and children: 10 µg (400 IU)/day. However, the ninety-fifth percentile was the same as the median for the children (still 10 µg [400 IU]/day), indicating little variation in the upper range for young children, while the ninety-fifth percentile for adults was considerably higher: 20 µg (800 IU)/day for men and 17.2 µg (686 IU)/day for women. Effects of Vitamin D Deficiency Vitamin D deficiency is characterized by inadequate mineralization or demineralization of the skeleton. In children, vitamin

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride D deficiency results in inadequate mineralization of the skeleton causing rickets, which is characterized by widening at the end of the long bones, rachitic rosary, deformations in the skeleton including frontal bossing, and outward or inward deformities of the lower limbs causing bowed legs and knocked knees, respectively (Goldring et al., 1995). In adults, vitamin D deficiency leads to a mineralization defect in the skeleton causing osteomalacia. In addition, the secondary hyperparathyroidism associated with vitamin D deficiency enhances mobilization of calcium from the skeleton, resulting in porotic bone (Favus and Christakos, 1996). Any alteration in the cutaneous production of vitamin D3, the absorption of vitamin D in the intestine, or the metabolism of vitamin D to its active form, 1,25(OH)2D, can lead to a vitamin D-deficient state (Demay, 1995; Holick, 1995). In addition, an alteration in the recognition of 1,25(OH) 2D by its receptor can also cause vitamin D deficiency, metabolic bone disease, and accompanying biochemical abnormalities (Demay, 1995). Vitamin D deficiency causes a decrease in ionized calcium in blood, which in turn leads to an increase in the production and secretion of PTH (Fraser, 1980; Holick, 1995). PTH stimulates the mobilization of calcium from the skeleton, conserves renal loss of calcium, and causes increased renal excretion of phosphorus leading to a normal fasting serum calcium with a low or low-normal serum phosphorus (Holick, 1995). Thus, vitamin D deficiency is characterized biochemically by either a normal or low-normal serum calcium with a low-normal or low-fasting serum phosphorus and an elevated serum PTH. Serum alkaline phosphatase is usually elevated in vitamin D deficiency states (Goldring et al., 1995). The elevated PTH leads to an increase in the destruction of the skeletal tissue in order to release calcium into the blood. The bone collagen by-products, including hydroxyproline, pyridinoline, deoxypyridinoline, and N-telopeptide, are excreted into the urine and are usually elevated (Kamel et al., 1994). It is well recognized that vitamin D deficiency causes abnormalities in calcium and bone metabolism. The possibility that vitamin D deficiency is associated with an increased risk of colon, breast, and prostate cancer was suggested in epidemiologic surveys of people living at higher latitudes (Garland et al., 1985, 1990; Schwartz and Hulka, 1990). At this time, it is premature to categorically suggest that vitamin D deficiency increases cancer risk. Prospective studies need to be carried out to test the hypothesis.

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride ESTIMATING REQUIREMENTS FOR VITAMIN D Selection of Indicators for Estimating the Vitamin D Requirement Serum 25(OH)D The serum 25(OH)D concentration is the best indicator for determining adequacy of vitamin D intake of an individual since it represents a summation of the total cutaneous production of vitamin D and the oral ingestion of either vitamin D2 or vitamin D3 (Haddad and Hahn, 1973; Holick, 1995). Thus, serum 25(OH)D will be used as the primary indicator of vitamin D adequacy. The normal range of serum 25(OH)D concentration is the mean serum 25(OH)D ± 2 standard deviations (SD) from a group of healthy individuals. The lower limit of the normal range can be as low as 20 nmol/liter (8 ng/ml) and as high as 37.5 nmol/liter (15 ng/ml) depending on the geographic location where the blood samples were obtained. For example, the lower and upper limits of the normal range of 25(OH)D in California will be higher than those limits in Boston (Clemens and Adams, 1996). Two pathologic indicators, radiologic evidence of rickets (Demay, 1995) and biochemical abnormalities associated with metabolic bone disease, including elevations in alkaline phosphatase and PTH concentrations in the circulation (Demay, 1995), have been correlated with serum 25(OH)D. A 25(OH)D concentration below 27.5 nmol/liter (11 ng/ml) is considered to be consistent with vitamin D deficiency in infants, neonates, and young children (Specker et al., 1992) and is therefore used as the key indicator for determining the vitamin D reference value. Little information is available about the level of 25(OH)D that is essential for maintaining normal calcium metabolism and peak bone mass in older children and in young and middle-aged adults. For the elderly, there is mounting scientific evidence to support their increased requirement for dietary vitamin D in order to maintain normal calcium metabolism and maximize bone health (Dawson-Hughes et al., 1991; Krall et al., 1989; Lips et al., 1988). Therefore, the serum 25(OH)D concentration was utilized to evaluate vitamin D deficiency in this age group, but it was not the only indicator used to determine the vitamin D reference value for the elderly. Serum PTH concentrations are inversely related to 25(OH)D serum levels (Krall et al., 1989; Kruse et al., 1984; Lips et al., 1988; Webb et al., 1990; Zeghoud et al., 1997). Therefore, the serum PTH

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride concentration, in conjunction with 25(OH)D, has proven to be a valuable indicator of vitamin D status. The few studies conducted in African Americans and Mexican Americans suggest that these population groups have lower circulating concentrations of 25(OH)D and higher serum concentrations of PTH and 1,25(OH)2D when compared with Caucasians (Bell et al., 1985; Reasner et al., 1990). It is likely that increased melanin pigmentation (which decreases the cutaneous production of vitamin D) and the lack of dietary vitamin D (due to a high incidence of lactose intolerance) are the contributing causes for this. Serum Vitamin D The serum concentration of vitamin D is not indicative of vitamin D status. As stated previously, its half-life is relatively short, and the blood concentrations can range from 0 to greater than 250 nmol/liter (0 to 100 ng/ml) depending on an individual's recent ingestion of vitamin D and exposure to sunlight. Serum 1,25(OH)2D Similarly, the serum 1,25(OH)2D level is not a good indicator of vitamin D. This hormone's serum concentrations are tightly regulated by a variety of factors, including circulating levels of serum calcium, phosphorus, parathyroid hormone, and other hormones (Fraser, 1980; Holick, 1995). Evaluation of Skeletal Health The ultimate effect of vitamin D on human health is maintenance of a healthy skeleton. Thus, in reviewing the literature for determining vitamin D status, one of the indicators that has proven to be valuable is an evaluation of skeletal health. In neonates and children, bone development and the prevention of rickets, either in combination with serum 25(OH)D and PTH concentrations, or by itself, are good indicators of vitamin D status (Gultekin et al., 1987; Koo et al., 1995; Kruse et al., 1984; Markested et al., 1986; Meulmeester et al., 1990). For adults, bone mineral content (BMC), bone mineral density (BMD), and fracture risk, in combination with serum 25(OH)D and PTH concentrations, have proven to be the most valuable indicators of vitamin D status (Brazier et al., 1995; Dawson-

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride Lactation Indicator Used to Set the AI Serum 25(OH)D. During lactation, small and probably insignificant quantities of maternal circulating vitamin D and its metabolites are secreted into human milk (Nakao, 1988; Specker et al., 1985a). Although there is no reason to expect the mother's vitamin D requirement to be increased during lactation, some investigators have determined whether the infant can be supplemented via the mother's milk. Ala-Houhala (1985) and Ala-Houhala et al. (1986) evaluated the vitamin D status of mothers and their infants supplemented with vitamin D. Healthy mothers delivering in January received either 50 µg (2,000 IU)/day, 25 µg (1,000 IU)/day, or no vitamin D. Their infants were exclusively breast-fed and received 10 µg (400 IU)/day of vitamin D if their mothers received none. After 8 weeks of lactation, 25(OH)D concentrations of infants who were breast-fed from women receiving 50 µg (2,000 IU)/day of vitamin D were similar to those of infants supplemented with 10 µg (400 IU)/day. The serum 25(OH)D levels in the infants from mothers receiving 25 µg (1,000 IU)/day were significantly lower. None of the infants showed any clinical or biochemical signs of rickets, and all infants showed equal growth. Although it was concluded that postpartum maternal supplementation with 50 µg (2,000 IU)/day of vitamin D, but not 25 µg (1,000 IU)/day, seemed to normalize serum 25(OH)D concentration in infants fed human breast milk in the winter, the maternal 25(OH)D level increased in the two groups of mothers receiving 50 or 25 µg (2,000 or 1,000 IU)/day of vitamin D compared with mothers who received no vitamin D supplementation. AI Summary: Lactation There is no scientific literature that has determined a minimum vitamin D intake to sustain serum 25(OH)D concentration in the normal range during lactation, and there is no evidence that lactation increases a mother's AI for vitamin D. Therefore, it is reasonable to extrapolate from observations in nonlactating women that when sunlight exposure is inadequate, an AI of 5.0 µg (200 IU)/day is needed. However, an intake of 10 µg (400 IU)/day, which is supplied by postnatal vitamin supplements, would not be excessive. AI for Lactation 14 through 18 years 5.0 µg (200 IU)/day   19 through 30 years 5.0 µg (200 IU)/day   31 through 50 years 5.0 µg (200 IU)/day

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride TOLERABLE UPPER INTAKE LEVELS Hazard Identification Hypervitaminosis D is characterized by a considerable increase in plasma 25(OH)D concentration to a level of approximately 400 to 1,250 nmol/liter (160 to 500 ng/ml) (Jacobus et al., 1992; Stamp et al., 1977). Because changes in circulating levels of 1,25(OH)2D are generally small and unreliable, the elevated levels of 25(OH)D are considered the indicator of toxicity. However, increases in circulating levels of 1,25(OH)2D in the range of 206.5 to 252.6 pmol/liter (85.9 to 105.1 pg/ml) have been reported (DeLuca, 1984; Holick, 1995; Reichel et al., 1989), which might contribute to the expression of toxic symptoms. As indicated earlier, serum 25(OH)D is a useful indicator of vitamin D status, both under normal conditions and in the context of hypervitaminosis D (Hollis, 1996; Jacobus et al., 1992). The data in Table 7-1 suggest a direct relationship between vitamin D intake and 25(OH)D levels. Serum levels of 25(OH)D have diagnostic value, particularly in distinguishing the hypercalcemia due to hypervitaminosis D from that due to other causes, such as hyperparathyroidism, thyrotoxicosis, humoral hypercalcemia of malignancy, and lymphoma (Lafferty, 1991; Martin and Grill, 1995). The adverse effects of hypervitaminosis D are probably largely mediated via hypercalcemia, but limited evidence suggests that direct effects of high concentrations of vitamin D may be expressed in various organ systems, including kidney, bone, central nervous system, and cardiovascular system (Holmes and Kummerow, 1983). Human case reports of pharmacologic doses of vitamin D over many years describe severe effects at intake levels of 250 to 1,250 µg/day (10,000 to 50,000 IU/day) (Allen and Shah, 1992). The available evidence concerning the adverse effects of hypervitaminosis D mediated by hypercalcemia and direct target tissue toxicity are briefly discussed below. Hypercalcemia of Hypervitaminosis D Hypercalcemia results primarily from the vitamin D-dependent increase in intestinal absorption of calcium (Barger-Lux et al., 1996) and the enhanced resorption of bone. Resorption of bone (hyperosteolysis) has been shown to be a major contributor to the hypercalcemia associated with hypervitaminosis D in studies that demonstrated rapid decreases in blood calcium levels following the

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride TABLE 7-1 Vitamin D Intake and Blood and Urinary Parameters in Adults Taking Vitamin D Supplements Vitamin D Intake (IU/day) Duration Serum Calcium (mmol/L) Serum 25(OH)D (nmol/L) Serum Creatinine (µmol/liter) Urinary Calcium (mmol/liter GFR) Study 800 4–6 months NCaa 60-105 (5 studies; n = 188) — — Byrne et al., 1995 1,800 3 months NCa 65, 80 (2 studies; n = 55) — — Byrne et al., 1995 1,800 3 months NCa 57–86 82.4–83.8 — Honkanen et al., 1990 2,000 6 months NCa — — — Johnson et al., 1980 10,000 4 weeks — 105b — — Stamp et al., 1977 10,000 10 weeks — 110b — — Davies et al., 1982 20,000 4 weeks — 150b — — Stamp et al., 1977 50,000 6 weeks 3.75 320 388 — Schwartzman and Franck, 1987 50,000 15 years 3.12 560 — — Davies and Adams, 1978 100,000 10 years 3.20 865 215 0.508 Selby et al., 1995 200,000 2 years 3.78 1202 207 — Selby et al., 1995 300,000 6 years 3.30 1692 184 0.432 Rizzoli et al., 1994 300,000 3 weeks 2.82 800 339 0.065 Rizzoli et al., 1994 Vitamin D poisoning   4.0 (n = 11) 1162 (n = 11) — — Pettifor et al., 1995 Overfortification of milk   3.28 (n = 35) 560 (n = 35) — — Blank et al., 1995 Reference levels   2.15–2.65 20–100 (10) 25–200 (9) 18–150 < 0.045 Blank et al., 1995 Haddad, 1980 a NCa = normo-calcemic. b Indicates extrapolation from graphic data.

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride administration of a bone resorption inhibitor, bisphosphonate (Rizzoli et al., 1994; Selby et al., 1995). As Table 7-1 illustrates, hypercalcemias can result either from clinically prescribed intakes of vitamin D or from the inadvertent consumption of high amounts of the vitamin. The plasma (or serum) calcium levels reported range from 2.82 to 4.00 mmol/liter (normal levels are 2.15 to 2.62 mmol/liter) in those individuals with intakes of 1,250 µg (50,000 IU)/day or higher. There is no apparent trend relating “vitamin D intake-days” with plasma calcium levels. The hypercalcemia associated with hypervitaminosis D gives rise to multiple debilitating effects (Chesney, 1990; Holmes and Kummerow, 1983; Parfitt et al., 1982). Specifically, hypercalcemia can result in a loss of the urinary concentrating mechanism of the kidney tubule (Galla et al., 1986), resulting in polyuria and polydipsia. A decrease in glomeruler filtration rate also occurs. Hypercalciuria results from the hypercalcemia and the disruption of normal reabsorption processes of the renal tubules. In addition, the prolonged ingestion of excessive amounts of vitamin D and the accompanying hypercalcemia can cause metastatic calcification of soft tissues, including the kidney, blood vessels, heart, and lungs (Allen and Shah, 1992; Moncrief and Chance, 1969; Taylor et al., 1972). The central nervous system may also be involved: a severe depressive illness has been noted in hypervitaminosis D (Keddie, 1987). Anorexia, nausea, and vomiting have also been observed in hypercalcemic individuals treated with 1,250 to 5,000 µg (50,000 to 200,000 IU)/day of vitamin D (Freyberg, 1942). Schwartzman and Franck (1987) reviewed cases in which vitamin D was used to treat osteoporosis in middle-aged and elderly women. These women had health problems in addition to osteoporosis. Intake of vitamin D between 1,250 µg (50,000 IU)/week and 1,250 µg (50,000 IU)/day for 6 weeks to 5 years was found to be associated with reduced renal function and hypercalcemia. Renal Disease Some evidence supports calcification of renal and cardiac tissue following excess vitamin D intake that is not associated with hypercalcemia. In a study of 27 patients with hypoparathyroidism, Parfitt (1977) found that a mean intake of 2,100 µg (84,000 IU)/day of vitamin D for 5 years was associated with reduced renal function, nephrolithiasis, and nephrocalcinosis. Parfitt hypothesized that these results were a direct effect of vitamin D, since it was not associated with hypercalcemia in these patients. However, these results

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride were judged inappropriate for use in deriving a tolerable upper intake level (UL) since the study subjects had hypoparathyroidism, which possibly increased their susceptibility to vitamin D toxicity. Irnell (1969) also reported a case of nephrocalcinosis and renal insufficiency in a thyroidectomized patient taking 1,125 µg (45,000 IU)/day of vitamin D for 6 years. Cardiovascular Effects Animal data in monkeys (Peng and Taylor, 1980; Peng et al., 1978), rabbits (Lehner et al., 1967), and pigs (Kummerow et al., 1976) suggest that calcification may also occur in nonrenal tissue. Human studies of cardiovascular effects are largely negative or equivocal. Although Linden (1974) observed that myocardial infarct patients in Tromso, Norway, were more likely to consume vitamin D in excess of 30 µg (1,200 IU)/day than were matched controls, two subsequent studies (Schmidt-Gayk et al., 1977; Vik et al., 1979) failed to confirm these results. Although the data for nephrocalcinosis and arteriosclerosis are insufficient for determination of a UL, they point to the necessity for conservatism. There is a large uncertainty about progressive health effects, particularly on cardiovascular tissue and the kidney, with regular ingestion of even moderately high amounts of vitamin D over several decades. Dose-Response Assessment Adults: Ages > 18 Years Data Selection. The most appropriate data available for the derivation of a UL for adults are provided by several studies evaluating the effect of vitamin D intake on serum calcium in humans (Honkanen et al., 1990; Johnson et al., 1980; Narang et al., 1984). The available animal data were not used to derive a UL for adults because the data were judged to have greater associated uncertainty than the human data. Identification of a NOAEL (or LOAEL) and a Critical Endpoint. Narang et al. (1984) studied serum calcium levels in humans, with and without tuberculosis, where diet was supplemented with daily vitamin D doses of 10, 20, 30, 60, and 95 µg (400, 800, 1,200, 2,400, and 3,800 IU) for 3 months. Thirty healthy males and females rang-

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride ing in age from 21 to 60 years and without tuberculosis were in one study group. Statistically significant increases in serum calcium were observed in these subjects at vitamin D doses of 60 and 95 µg (2,400 and 3,800 IU)/day. However, increases in serum calcium level in some subjects, while statistically significant, were not necessarily adverse, or indicative of hypercalcemia (for example, serum calcium levels above 2.75 mmol/liter). For example, the mean serum calcium level in normal controls following administration of 60 µg (2,400 IU)/day of vitamin D increased from 2.43 mmol/liter to 2.62 mmol/liter (p < 0.01). The mean serum calcium level in normal controls treated with 95 µg (3,800 IU)/day of vitamin D increased from 2.46 mmol/liter to 2.83 mmol/liter. At 30 µg (1,200 IU)/day, in normal controls, the increase was from 2.35 mmol/liter to 2.66 mmol/liter, but this was not a significant increase. The study thus demonstrates an effect of relatively low doses of supplementary vitamin D on serum calcium levels, although the degree of hypercalcemia was modest. It should also be noted that the effect developed over a relatively short time (3 months or less), so it is not known whether the effect would have progressed and worsened, or whether it would have disappeared, over a longer time period. Hypercalcemia, defined as a serum calcium level above 2.75 mmol/liter (11 mg/dl), was observed at the highest dose of 95 µg (3,800 IU)/day, which is, therefore, the lowest-observed-adverse-effect level (LOAEL). Although a significant rise in serum calcium levels occurred at 60 µg (2,400 IU)/day, they were still within a normal range. Therefore, 60 µg (2400 IU)/day is designated as a no-observed-adverse-effect level (NOAEL). Uncertainty and Uncertainty Factors. In using a NOAEL of 60 µg (2,400 IU)/day based only on the results of Narang et al. (1984) to derive a UL for adults, it appears to be uncertain whether any increase in serum calcium, even though still within normal limits, might be adverse for sensitive individuals and whether the short duration of this study and small sample size affected the results. The selected uncertainty factor (UF) of 1.2 was judged to be sufficiently conservative to account for the uncertainties in this data set. A larger UF was judged unnecessary due to the availability of human data and a reasonably well-defined NOAEL in a healthy population. Derivation of a UL. Based on a NOAEL of 60 µg (2,400 IU)/day divided by a composite UF of 1.2, the estimated UL for adults is 50 µg (2,000 IU)/day. Supportive evidence for a UL of 50 µg (2,000 IU)/day is provided by Johnson et al. (1980) and Honkanen et al.

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride (1990). Johnson et al. (1980) conducted a double-blind clinical trial of men (all over 65 years) and women (all over 60 years) treated with 50 µg (2,000 IU)/day of vitamin D for approximately 6 months. Assuming a normally distributed population, these data as presented would appear to suggest that the risk of hypercalcemia in a population exposed to intakes of 50 µg (2,000 IU)/day ranges from 5/1,000 to less than 1/10,000. In addition, Honkanen et al. (1990) reported that 45 µg (1,800 IU)/day of supplementary vitamin D administered to Finnish women aged 65 to 72 years for 3 months produced no ill effects. UL for Adults > 18 years 50 µg (2,000 IU)/day Infants: Ages 0 through 12 Months Data Selection. Data from several studies in infants (Fomon et al., 1966; Jeans and Stearns, 1938; Stearns, 1968) were judged appropriate for use in deriving a UL for infants up to 1 year of age since the data document the duration and magnitude of intake, and as an aggregate, they define a dose-response relationship. Available data from animal studies were judged inappropriate due to their greater uncertainty. Identification of a NOAEL (or LOAEL) and Critical Endpoint. Jeans and Stearns (1938) found retarded linear growth in 35 infants up to 1 year of age who received 45 to 112.5 µg (1,800 to 4,500 IU)/day of vitamin D as supplements (without regard to sunlight exposure, which was potentially considerable during the summer months) when compared with infants receiving supplemental doses of 8.5 µg (340 IU)/day or less for a minimum of 6 months. At 45 weeks of age, infants were found to have a linear growth rate 7 cm lower than the controls. Fomon et al. (1966), in a similar study, explored the effects on linear growth in infants (n = 13) ingesting 34.5 to 54.3 µg (1,380 to 2,170 IU)/day of dietary vitamin D (mean = 44.4 µg or 1,775 IU/day) from fortified evaporated milk formulas as the only source of vitamin D compared with infants who were receiving 8.8 to 13.8 µg (350 to 550 IU)/day (n = 11) from another batch of formula. No effect was found in infants who were enrolled in the study during the first 9 days after birth up to 6 months of age. Given the small sample size used in this study, it was deemed appropriate to deviate from the model for the development of ULs (see Chapter 3 which

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride defines a NOAEL as the highest intake at which no adverse effects have been observed) and identify the NOAEL for infants in this study based on the mean intake (for example, 44.4 µg or 1,775 IU/day) rather than the high end of the range. The NOAEL was rounded up to 45 µ g (1,800 IU)/day. Stearns (1968) subsequently commented that Fomon et al. (1966) did not study the infants long enough since the greatest differences in the Jeans and Stearns (1938) study appeared after 6 months. However, taken together, these papers support a NOAEL of 45 µg (1,800 IU)/day. In two different surveys at two different time periods, the British Paediatric Association (BPA) (BPA, 1956, 1964) reported a marked decline in hypercalcemia in infants, from 7.2 cases per month in a 1953–1955 survey, to 3.0 cases per month in a 1960–1961 survey. This change occurred at the same time as new guidelines were introduced for fortification of food products with vitamin D. Data from BPA (1956) and Bransby et al. (1964) also show the estimated total vitamin D intake in infants at the seventy fifth percentile of 100 µg (4,000 IU)/day declining to a range of 18.1 to 33.6 µg (724 to 1,343 IU)/day between the two surveys. Graham (1959) studied 38 infants aged 3 weeks to 11 months with hypercalcemia in Glasgow from 1951 to 1957. The data as reported offer no definitive proof of a relationship between vitamin D intake and hypercalcemia. However, Graham does report that the highest serum calcium value obtained, 4.65 mmol/liter (18.6 mg/dl), occurred in an infant with an estimated daily intake of 33 µg (1,320 IU)/day of vitamin D and that the infant made a complete recovery when vitamin D was omitted from the diet. Taken together, these data indicate that excessive vitamin D intake is probably a risk factor for hypercalcemia in a few sensitive infants. However, these data are inadequate for quantitative risk assessment because the daily dosage is so uncertain. This is because of the inaccuracies of survey data, but also and more importantly, because sunlight exposure was not reported, and the level of fortification of food was probably not accurately determined, and was most likely underestimated. Uncertainty and Uncertainty Factors. Given the insensitivity of the endpoint, the fact that sample sizes were small, and that little data exist about sensitivity at the tails of the distributions, an adjustment in the NOAEL or use of a UF of 1.8 is warranted. Derivation of the UL. Based on a NOAEL of 45 µg (1,800 IU)/day for infants and a UF of 1.8, the UL for infants up to 1 year of age is set at 25 µg (1,000 IU)/day.

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride UL for Infants 0 through 12 months 25 µg (1,000 IU)/day Children: Ages 1 through 18 Years No specific data are available for age groups other than adults and infants. Increased rates of bone formation in toddlers (1 year of age and older), children, and adolescents suggest that the adult UL is appropriate for these age groups. In addition, serum calcium levels must support the increased deposition occurring, and no data indicate impairment or insufficiency in renal handling mechanisms by 1 year of age. Therefore, the UL of 50 µg (2,000 IU)/day for adults is also specified for toddlers, children, and adolescents. UL for Children 1 through 18 years 50 µg (2,000 IU)/day Pregnancy and Lactation The available data were judged inadequate to derive a UL for pregnant and lactating women that is different from other adults. Given the minor impact on either circulating vitamin D levels or serum calcium levels in utero or in infants seen with vitamin D supplements of 25 and 50 µg (1,000 and 2,000 IU)/day as previously discussed (Ala-Houhala et al., 1984, 1986), a concern about increased sensitivity during this physiologic period is not warranted. UL for Pregnancy 14 through 50 years 50 µg (2,000 IU)/day UL for Lactation 14 through 50 years 50 µg (2,000 IU)/day Special Considerations The UL for vitamin D, as with the ULs for other nutrients, only applies to healthy individuals. Granulomatous diseases (for example, sarcoidosis, tuberculosis, histoplasmosis) are characterized by hypercalcemia and/or hypercalciuria in individuals on normal or less-than-normal vitamin D intakes or with exposure to sunlight. This association is apparently due to the extrarenal conversion of 25(OH)D to 1,25(OH) 2D by activated macrophages (Adams, 1989; Sharma, 1996). Increased intestinal absorption of calcium and a proposed increase in bone resorption contributes to the hypercalcemia and hypercalciuria, and the use of glucocorticoids is a well-established treatment in these disorders (Grill and Martin, 1993).

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride Exposure Assessment The vitamin D content of unsupplemented diets is, for the most part, low and averages about 2.5 µg (100 IU)/day for women (Krall et al., 1989; Murphy and Calloway, 1986). Diets high in fish, an exceptionally rich natural source of vitamin D (USDA, 1991) are considerably higher in vitamin D. Because milk is fortified to contain 10 µg (400 IU)/quart (9.6 µg [385 IU]/liter) of vitamin D, persons with high milk intakes also may have relatively high vitamin D intakes. A 1986 survey estimated that the ninety-fifth percentile of supplement intake by users of vitamin D supplements was 20 µg (800 IU)/day for men and 17.2 µg (686 IU)/day for women (Moss et al., 1989). The endogenous formation of vitamin D3 from sunlight irradiation of skin has never been implicated in vitamin intoxication. This is due to the destruction of the previtamin and vitamin D3 remaining in skin with continued exposure to ultraviolet irradiation (Holick, 1996). Risk Characterization For most people, vitamin D intake from food and supplements is unlikely to exceed the UL. However, persons who are at the upper end of the ranges for both sources of intake, particularly persons who use many supplements and those with high intakes of fish or fortified milk, may be at risk for vitamin D toxicity. RESEARCH RECOMMENDATIONS Research is needed to evaluate different intakes of vitamin D throughout the lifespan by geographical and racial variables that reflect the mix of the Canadian and American population and the influence of sunscreens. Regarding puberty and adolescence, research is needed to evaluate the effect of various intakes of vitamin D on circulating concentrations of 25 (OH)D and 1,25(OH)2D during winter at a time when no vitamin D comes from sunlight exposure. During this time, the body adapts by increasing the renal metabolism of 25(OH)D to 1,25(OH)2D and the efficiency of intestinal calcium absorption, thereby satisfying the increased calcium requirement by the rapidly growing skeleton. It is very difficult to determine the reference values for vitamin D in healthy young adults aged 18 through 30 and 31 through 50

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride years in the absence of sunlight exposure because of their typically high involvement in outdoor activity and the unexplored contribution of sunlight to vitamin D stores. More studies are needed that evaluate various doses of vitamin D in young and middle-aged adults in the absence of sunlight exposure. A major difficulty in determining how much vitamin D is adequate for the body's requirement is that a normal range for serum 25(OH)D is 25 to 137.5 nmol/liter (10 to 55 ng/ml) for all gender and life stage groups. However, there is evidence, especially in the elderly, that in order for the PTH to be at the optimum level, a 25(OH)D of 50 nmol/liter (20 ng/ml) or greater may be required. Therefore, more studies are needed to evaluate other parameters of calcium metabolism as they relate to vitamin D status including circulating concentrations of PTH. The development of methodologies to assess changes in body stores of vitamin D is needed to accurately assess requirements in the absence of exposure to sunlight. Such work would markedly assist in the estimation of reference values for all life stage groups.