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4 Vitamin A SUMMARY Vitamin A is important for normal vision, gene expression, repro- duction, embryonic development, growth, and immune function. There are a variety of foods rich in vitamin A and provitamin A carotenoids that are available to North Americans. Thus, current dietary patterns appear to provide sufficient vitamin A to prevent deficiency symptoms such as night blindness. The Estimated Aver- age Requirement (EAR) is based on the assurance of adequate stores of vitamin A. The Recommended Dietary Allowance (RDA) for men and women is 900 and 700 Âµg retinol activity equivalents (RAE)/day, respectively. The Tolerable Upper Intake Level (UL) for adults is set at 3,000 Âµg/day of preformed vitamin A. There are a number of sources of dietary vitamin A. Preformed vitamin A is abundant in some animal-derived foods, whereas pro- vitamin A carotenoids are abundant in darkly colored fruits and vegetables, as well as oily fruits and red palm oil. For dietary provitamin A carotenoidsâÎ²-carotene, Î±-carotene, and Î²-cryptoxanthinâRAEs have been set at 12, 24, and 24 Âµg, respectively. Using Âµg RAE, the vitamin A activity of provitamin A carotenoids is half the vitamin A activity assumed when using Âµg retinol equivalents (Âµg RE) (NRC, 1980, 1989). This change in equivalency values is based on data demonstrating that the vitamin A activity of purified Î²-carotene in oil is half the activity of vitamin A, and based on recent data demonstrating that the vitamin A activity of dietary Î²-carotene is one-sixth, rather than one-third, the vitamin 82
VITAMIN A 83 activity of purified Î²-carotene in oil. This change in bioconversion means that a larger amount of provitamin A carotenoids, and there- fore darkly colored, carotene-rich fruits and vegetables, is needed to meet the vitamin A requirement. It also means that in the past, vitamin A intake has been overestimated. The median intake of vitamin A ranges from 744 to 811 Âµg RAE/ day for men and 530 to 716 Âµg RAE/day for women. Using Âµg RAE, approximately 26 and 34 percent of vitamin A activity consumed by men and women, respectively, is provided from provitamin A carotenoids. Ripe, colored fruits and cooked, yellow tubers are more efficiently converted to vitamin A than equal amounts of dark green, leafy vegetables. Although a large body of observational epidemiological evidence suggests that higher blood concentrations of Î²-carotenes and other carotenoids obtained from foods are associated with a lower risk of several chronic diseases, there is currently not sufficient evidence to support a recommendation that requires a certain percentage of dietary vitamin A to come from provitamin A carotenoids in meet- ing the vitamin A requirement. However, the existing recommenda- tions for increased consumption of carotenoid-rich fruits and vege- tables for their health-promoting benefits are strongly supported (see Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids [IOM, 2000]). BACKGROUND INFORMATION Vitamin A is a fat-soluble vitamin that is essential for humans and other vertebrates. Vitamin A comprises a family of molecules con- taining a 20 carbon structure with a methyl substituted cyclohexenyl ring (beta-ionone ring) (Figure 4-1) and a tetraene side chain with a hydroxyl group (retinol), aldehyde group (retinal), carboxylic acid group (retinoic acid), or ester group (retinyl ester) at carbon- 15. The term vitamin A includes provitamin A carotenoids that are dietary precursors of retinol. The term retinoids refers to retinol, its metabolites, and synthetic analogues that have a similar structure. Carotenoids are polyisoprenoids, of which more than 600 forms exist. Of the many carotenoids in nature, several have provitamin A nutritional activity, but food composition data are available for only three (Î±-carotene, Î²-carotene, and Î²-cryptoxanthin) (Figure 4-1). The all-trans isomer is the most common and stable form of each carotenoid; however, many cis isomers also exist. Carotenoids usually contain 40 carbon atoms, have an extensive system of conjugated double bonds, and contain one or two cyclic structures at the end
84 DIETARY REFERENCE INTAKES CH2OH all trans -Retinol all trans -Î² -Carotene all trans- Î±-Carotene HO all trans -Î² -Cryptoxanthin FIGURE 4-1 Structure of retinol and provitamin A carotenoids. of their conjugated chain. An exception is lycopene, which has no ring structure and does not have vitamin A activity. Preformed vita- min A is found only in animal-derived food products, whereas dietary carotenoids are present primarily in oils, fruits, and vegetables. Function The 11-cis-retinaldehyde (retinal) form of vitamin A is required by the eye for the transduction of light into neural signals necessary for vision (Saari, 1994). The retinoic acid form is required to main-
VITAMIN A 85 tain normal differentiation of the cornea and conjunctival mem- branes, thus preventing xerophthalmia (Sommer and West, 1996), as well as for the photoreceptor rod and cone cells of the retina. Rods contain the visual pigment rhodopsin (opsin protein bound to 11-cis-retinal). The absorption of light catalyzes the photoisomer- ization of rhodopsinâs 11-cis-retinal to all-trans-retinal in thousands of rods, which triggers the signaling to neuronal cells associated with the brainâs visual cortex. After photoisomerization, all-trans- retinal is released, and for vision to continue, 11-cis-retinal must be regenerated. Regeneration of 11-cis-retinal requires the reduction of all-trans retinal to retinol, transport of retinol from the photo- receptor cells (rods) to the retinal pigment epithelium, and esterifi- cation of all-trans-retinol, thereby providing a local storage pool of retinyl esters. When needed, retinyl esters are hydrolyzed and isomerized to form 11-cis-retinol, which is oxidized to 11-cis-retinal and transported back to the photoreceptor cells for recombination with opsin to begin another photo cycle. Vitamin A is required for the integrity of epithelial cells through- out the body (Gudas et al., 1994). Retinoic acid, through the activa- tion of retinoic acid (RAR) and retinoid X (RXR) receptors in the nucleus, regulates the expression of various genes that encode for structural proteins (e.g., skin keratins), enzymes (e.g., alcohol dehydrogenase), extracellular matrix proteins (e.g., laminin), and retinol binding proteins and receptors. Retinoic acid plays an important role in embryonic development. Retinoic acid, as well as RAR, RXR, cellular retinol-binding protein (CRBP), and cellular retinoic acid-binding proteins (CRABP-I and CRABP-II), is present in temporally specific patterns in the embry- onic regions known to be involved in the development of structures posterior to the hindbrain (e.g., the vertebrae and spinal cord) (Morriss-Kay and Sokolova, 1996). Retinoic acid is also involved in the development of the limbs, heart, eyes, and ears (Dickman and Smith, 1996; Hofmann and Eichele, 1994; McCaffery and Drager, 1995). Retinoids are necessary for the maintenance of immune function, which depends on cell differentiation and proliferation in response to immune stimuli. Retinoic acid is important in maintaining an adequate level of circulating natural killer cells that have antiviral and anti-tumor activity (Zhao and Ross, 1995). Retinoic acid has been shown to increase phagocytic activity in murine macrophages (Katz et al., 1987) and to increase the production of interleukin 1 and other cytokines, which serve as important mediators of inflam- mation and stimulators of T and B lymphocyte production (Trechsel
86 DIETARY REFERENCE INTAKES et al., 1985). Furthermore, the growth, differentiation, and activa- tion of B lymphocytes requires retinol (Blomhoff et al., 1992). Proposed functions of provitamin A carotenoids are described in Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Caro- tenoids (IOM, 2000). Physiology of Absorption, Metabolism, and Excretion Absorption and Bioconversion Absorption of Vitamin A. Intestinal absorption of preformed vita- min A occurs following the processing of retinyl esters in the lumen of the small intestine. Within the water-miscible micelles formed from bile salts, solubilized retinyl esters as well as triglycerides are hydrolyzed to retinol and products of lipolysis by various hydrolases (Harrison, 1993). A small percentage of dietary retinoids is convert- ed to retinoic acid in the intestinal cell. In addition, the intestine actively synthesizes retinoyl Î²-glucuronide that is hydrolyzed to ret- inoic acid by Î²-glucuronidases (Barua and Olson, 1989). The effi- ciency of absorption of preformed vitamin A is generally high, in the range of 70 to 90 percent (Sivakumar and Reddy, 1972). A specific retinol transport protein within the brush border of the enterocyte facilitates retinol uptake by the mucosal cells (Dew and Ong, 1994). At physiological concentrations, retinol absorption is carrier mediated and saturable, whereas at high pharmacological doses, the absorption of retinol is nonsaturable (Hollander and Muralidhara, 1977). As the amount of ingested preformed vitamin A increases, its absorbability remains high (Olson, 1972). Vitamin A absorption and intestinal retinol esterification are not markedly dif- ferent in the elderly compared to young adults, although hepatic uptake of newly absorbed vitamin A in the form of retinyl ester is slower in the elderly (Borel et al., 1998). Absorption and Bioconversion of Provitamin A Carotenoids. Carotenoids are also solubilized into micelles in the intestinal lumen from which they are absorbed into duodenal mucosal cells by a passive diffusion mechanism. Percent absorption of a single dose of 45 Âµg to 39 mg Î²-carotene, measured by means of isotopic methods, has been re- ported to range from 9 to 22 percent (Blomstrand and Werner, 1967; Goodman et al., 1966; Novotny et al., 1995). However, the absorption efficiency decreases as the amount of dietary carotenoids increases (Brubacher and Weiser, 1985; Tang et al., 2000). The relative carotene concentration in micelles can vary in response to
VITAMIN A 87 the physical state of the carotenoid (e.g., whether it is dissolved in oil or associated with plant matrix materials). A number of factors affect the bioavailability and bioconversion of carotenoids (Casten- miller and West, 1998). Carotene bioavailability can differ with dif- ferent processing methods of the same foods and among different foods containing similar levels of carotenoids (Boileau et al., 1999; Hume and Krebs, 1949; Rock et al., 1998; Torronen et al., 1996; Van den Berg and van Vliet, 1998) (also see Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids [IOM, 2000]). Absorbed Î²-carotene is principally converted to vitamin A by the enzyme Î²-carotene-15, 15â²-dioxygenase within intestinal absorptive cells. The central cleavage of Î²-carotene by this enzyme will, in theory, result in two molecules of retinal. Î²-Carotene can also be cleaved eccentrically to yield Î²-apocarotenals that can be further degraded to retinal or retinoic acid (Krinsky et al., 1993). The pre- dominant form of vitamin A in human lymph, whether originating from ingested vitamin A or provitamin A carotenoids, is retinyl ester (retinol esterified with long-chain fatty acids, typically palmitate and stearate) (Blomstrand and Werner, 1967; Goodman et al., 1966). Along with exogenous lipids, the newly synthesized retinyl esters and nonhydrolyzed carotenoids are transported from the intestine to the liver in chylomicrons and chylomicron remnants. Derived from dietary retinoids, retinoic acid is absorbed via the portal sys- tem bound to albumin (Blaner and Olson, 1994; Olson, 1991). Vitamin A Activity of Provitamin A Carotenoids: Rationale for Develop- ing Retinol Activity Equivalents. The carotene:retinol equivalency ratio (Âµg:Âµg) of a low dose (less than 2 mg) of purified Î²-carotene in oil is approximately 2:1 (i.e., 2 Âµg of Î²-carotene in oil yields 1 Âµg of retinol) (Table 4-1). This ratio was derived from the relative amount of Î²-carotene required to correct abnormal dark adaptation in vita- min A-deficient individuals (Hume and Krebs, 1949; Sauberlich et al., 1974). The data by Sauberlich et al. (1974) were given greater consideration because (1) the actual amount (Âµg) of vitamin A and Î²-carotene consumed was cited, (2) varied amounts of vitamin A or Î²-carotene were consumed by each individual, and (3) a greater sample size was employed (six versus two subjects). In addition to these studies, an earlier study by Wagner (1940) estimated a carotene:retinol equivalency ratio of 4:1; however, the method em- ployed for measuring dark adaptation was not standardized and used an imprecise outcome measure. Studies have been performed to compare the efficiency of absorp- tion of Î²-carotene after feeding physiological amounts of Î²-carotene
88 DIETARY REFERENCE INTAKES TABLE 4-1 Relative Absorption of Vitamin A and Supplemental Î²-Carotene Reference Study Groupa Study Design Diet/Dos Hume and Krebs, 1 adult per Depletion/repletion study; depletion Low (< 21 1949 treatment group, phase ranged from 18 to 22 mo and single d England the repletion phase ranged from or Î²-ca 3 wk to 6 mo after de Sauberlich et al., 2 or 4 men per Depletion/repletion study; depletion Low vitam 1974 treatment group, phase ranged from 361 to 771 d and doses o United States the repletion phase ranged from 2 to (37.5â2 455 d (150â2 the dep a Treatment group received supplemental vitamin A or Î²-carotene. b Based on the assumption that 1 IU is equivalent to 0.3 Âµg of vitamin A (WHO, 1950). c One IU is equivalent to 0.6 Âµg of Î²-carotene (Hume and Krebs, 1949). in oil, in individual foods, and as part of a mixed vegetable and fruit diet. Many of the earlier studies analyzed the fecal content of Î²- carotene after the consumption of a supplement, fruit, or vegeta- ble. Data from these studies were not considered because the por- tion of unabsorbed Î²-carotene that is degraded by the intestinal microflora is not known. The efficiency of absorption of Î²-carotene in food is lower than the absorption of Î²-carotene in oil by a repre- sentative factor of a. Assuming that after absorption of Î²-carotene, whether from oil or food, the metabolism of the molecule is similar and that the retinol equivalency ratio of Î²-carotene in oil is 2:1, the vitamin A activity of Î²-carotene from food can be derived by multi- plying a by 2:1. Until recently it was thought that 3 Âµg of dietary Î²-carotene was equivalent to 1 Âµg of purified Î²-carotene in oil (NRC, 1989) due to a relative absorption efficiency of about 33 percent of Î²-carotene from food sources. Only one study has compared the relative ab- sorption of Î²-carotene in oil versus its absorption in a principally mixed vegetable diet in healthy and nutritionally adequate individ- uals (Van het Hof et al., 1999). This study concluded that the rela- tive absorption of Î²-carotene from the mixed vegetable diet com- pared to Î²-carotene in oil is only 14 percent, as assessed by the increase in plasma Î²-carotene concentration after dietary interven-
VITAMIN A 89 Diet/Dose Results pletion Low (< 21 Âµ g/d) vitamin A diet plus a Abnormal dark adaptation was mo and single dose of supplemental vitamin A reversed with 1,300 IU (390 Âµg) b from or Î²-carotene were provided to subjects of vitamin A and 2,500 IU after depletion period (1,500 Âµg) c of Î²-carotene; thus the retinol equivalency ratio is assumed to be 3.8:1 pletion Low vitamin A diet (< 23 Âµg) plus varying 600 Âµg/d retinol corrected dark 71 d and doses of supplemental vitamin A adaptation; 1,200 Âµg/d Î²-carotene from 2 to (37.5â25,000 Âµ g/d) or Î²-carotene corrected dark adaptation; (150â2,400 Âµ g/d) were provided after therefore the retinol equivalency the depletion period ratio was concluded to be 2:1 HO, 1950). tion. Based on this finding, approximately 7 Âµg of dietary Î²-carotene is equivalent to 1 Âµg of Î²-carotene in oil. This absorption efficiency value of 14 percent is supported by the relative ranges in Î²-carotene absorption reported by others using similar methods for mixed green leafy vegetables (4 percent) (de Pee et al., 1995), carrots (18 to 26 percent) (Micozzi et al., 1992; Torronen et al., 1996), broccoli (11 to 12 percent) (Micozzi et al., 1992), and spinach (5 percent) (Castenmiller et al., 1999) (Table 4-2). Only one study has been published to assess the relative bio- conversion of Î²-carotene from fruits versus vegetables by measuring the rise in serum retinol concentration after the provision of a diet high in vegetables, fruits, or retinol (de Pee et al., 1998). This study used methods similar to those employed by other researchers (Castenmiller et al. , de Pee et al. , Micozzi et al. , Torronen et al. , and Van het Hof et al. ), and indicated that the vitamin A activity was approximately half the activity for dark, green leafy vegetables compared to equal amounts of Î²-carotene from orange fruits and some yellow tubers, such as pumpkin squash (de Pee et al., 1998) (Table 4-2). Because of the low content of fruits contained in the principally mixed vegetable diet of Van het Hof et al. (1999) and the low proportion of dietary Î²-carotene that is consumed from fruits compared to vegetables in
90 DIETARY REFERENCE INTAKES TABLE 4-2 Relative Absorption of Supplemental and Dietary Î²-Carotene Reference Subjects Study Design Diet/Dos Micozzi et al., 30 men, 20â45 y, Diet/supplementation intervention, Suppleme 1992 United States 6 wk Carrots, 3 Broccoli, de Pee et al., 173 children, Diet intervention, 9 wk Vegetable 1995 7â11 y, Indonesia Fruit diet Torronen et al., 42 women, Diet/supplementation intervention, Low caro 1996 20â53 y, Finland 6 wk + Raw car + Supplem de Pee et al., 188 anemic school Diet intervention, 9 wk Fruit/squ 1998 children, 7â11 y, Dark gree Indonesia + carro Low vitam diet, 44 Castenmiller et al., 72 men and Diet/supplementation intervention, Control d 1999 women, 18â58 y, 3 wk Suppleme Netherlands Spinach d Van het Hof et al., 55 men and Diet/supplementation intervention, Suppleme 1999 women, 18â45 y, 1 mo High vege Netherlands 5.1 mg/ the United States (16 percent from the 14 major dietary contribu- tors of Î²-carotene which provide a total of 70 percent of dietary Î²- carotene) (Chug-Ahuja et al., 1993), it is estimated that 6 Âµg, rather than 7 Âµg, of Î²-carotene from a mixed diet is nutritionally equivalent to 1 Âµg of Î²-carotene in oil. Therefore, the retinol activity equivalency (Âµg RAE) ratio for Î²-carotene from food is estimated to be 12:1 (6 Ã 2:1) (Figure 4-2). Unfortunately, studies using a positive con- trol group (preformed vitamin A) at a level equivalent to Î²-carotene from a mixed vegetable and fruit diet using levels similar to the RAE have not been conducted in healthy and nutritionally adequate individuals. An RAE of 12 Âµg for dietary Î²-carotene is supported by Parker et al. (1999) who reported that 8 percent of ingested Î²- carotene from carrots was absorbed and converted to retinyl esters
VITAMIN A 91 etary Diet/Dose of Î²-Carotene Results ention, Supplement, 30 mg/d Increase of plasma Î²-carotene from carrots Carrots, 30 mg/d compared to supplemental Î²-carotene in Broccoli, 6 mg/d gelatin beadlets was 18% Increase of plasma Î²-carotene from broccoli compared to supplemental Î²-carotene in gelatin beadlets was 12% Vegetable diet, 3.5 mg/d Increase of serum Î²-carotene from fruit diet was Fruit diet, 2.3 mg/d 5â6 times higher than from vegetable diet ention, Low carotenoid diet Increase of serum Î²-carotene from raw carrots + Raw carrots, 12 mg/d was 26% compared to that from supplemental + Supplement, 12 mg/d Î²-carotene in a gelatin beadlet Fruit/squash diet, 509 Âµg/d Increase of serum Î²-carotene from fruit/squash Dark green leafy vegetables diet was 3.5-fold greater than that for the + carrots, 684 Âµ g/d dark green leafy vegetables + carrots diet Low vitamin A/Î²-carotene diet, 44 Âµg/d ention, Control diet, 0.5 mg/d Increase of serum Î²-carotene from spinach was Supplement diet, 9.8 mg/d 5% compared to that from supplemental Spinach diet, 10.4 mg/d Î²-carotene in oil ention, Supplement, 7.2 mg/day Increase of plasma Î²-carotene from high High vegetable diet, vegetable diet compared to supplemental 5.1 mg/d Î²-carotene in oil was 14% contained in chylomicrons, resulting in a carotene:retinol equiva- lency ratio of 13:1. One RAE for dietary provitamin A carotenoids other than Î²-caro- tene is set at 24 Âµg on the basis of the observation that the vitamin A activity of Î²-cryptoxanthin and Î±-carotene is approximately half of that for Î²-carotene (Bauernfeind, 1972; Deuel et al., 1949). There- fore, the amount of vitamin A activity of provitamin A carotenoids in Âµg RAE is half the amount obtained if using Âµg RE (Table 4-3). Example: A diet contains 500 Âµg retinol, 1,800 Âµg Î²-carotene and 2,400 Âµg Î±-carotene. 500 + (1,800 Ã· 12) + (2,400 Ã· 24) = 750 Âµg RAE.
92 DIETARY REFERENCE INTAKES Consumed Absorbed Bioconverted Dietary or Supplemental Retinol Retinol (1 Âµg) Vitamin A (1 Âµg) Supplemental Î²-carotene Retinol (1 Âµg) Î²-carotene (2 Âµg) Dietary Î²-carotene (12 Âµg) Î²-carotene Retinol (1 Âµg) Dietary Î±-carotene or Î±-carotene or Retinol (1 Âµg) Î²-cryptoxanthin (24 Âµg) Î²-cryptoxanthin FIGURE 4-2 Absorption and bioconversion of ingested provitamin A carotenoids to retinol based on new equivalency factors (retinol activity equivalency ratio). TABLE 4-3 Comparison of the 1989 National Research Council and 2001 Institute of Medicine Interconversion of Vitamin A and Carotenoid Units NRC, 1989 IOM, 2001 1 retinol equivalent (Âµg RE) 1 retinol activity equivalent (Âµg RAE) = 1 Âµg of all-trans-retinol = 1 Âµg of all-trans-retinol = 2 Âµg of supplemental all-trans-Î²- = 2 Âµg of supplemental all-trans-Î²- carotene carotene = 6 Âµg of dietary all-trans-Î²-carotene = 12 Âµg of dietary all-trans-Î²-carotene = 12 Âµg of other dietary = 24 Âµg of other dietary provitamin provitamin A carotenoids A carotenoids NOTE: 1 Âµg retinol = 3.33 IU vitamin A activity from retinol (WHO, 1966); 10 IU Î²-carotene = 3.33 IU retinol (WHO, 1966); 10 IU is based on 3.33 IU vitamin A activity Ã 3 (the relative vitamin activity of Î²-carotene in supplements versus in diets). Thus, when converting from IU Î²-carotene from fruits or vegetables to Âµg RAE, IU is divided by 20 (2 Ã 10).
VITAMIN A 93 Example: A diet contains 1,666 IU of retinol and 3,000 IU of Î²- carotene. (1,666 Ã· 3.33) + (3,000 Ã· 20) = 650 Âµg RAE. Example: A supplement contains 5,000 IU of vitamin A (20 per- cent as Î²-carotene). 5,000 Ã· 3.33 = 1,500 Âµg RAE. The use of Âµg RAE rather than Âµg RE or international units (IU) is preferred when calculating and reporting the amount of the total vitamin A in mixed foods or assessing the amount of dietary and supplemental vitamin A consumed. Given the need to be able to calculate the intake of carotenoids, food composition data tables should report food content in amounts of each carotenoid when- ever possible. Metabolism, Transport, and Excretion Retinyl esters and carotenoids are transported to the liver in chylo- micron remnants. Apoprotein E is required for the uptake of chylo- micron remnants by the liver. Some retinyl esters can also be taken up directly by peripheral tissues (Goodman et al., 1965). Several specific hepatic membrane receptors (low density lipoprotein [LDL] receptor, LDL receptor-related protein, lipolysis-stimulated receptor) have been proposed to also be involved with the uptake of chylomicron remnants (Cooper, 1997). The hydrolysis of retinyl ester to retinol is catalyzed by retinyl ester hydrolase following endo- cytosis. To meet tissue needs for retinoids, retinol binds to retinol- binding protein (RBP) for release into the circulation. In the blood, holo-RBP associates with transthyretin (a transport protein) to form a trimolecular complex with retinol in a 1:1:1 molar ratio. Retinol is transported in this trimolecular complex to various tissues, includ- ing the eye. The mechanism through which retinol is taken up from the circulation by peripheral cells has not been conclusively estab- lished. Retinol that is not immediately released into circulation by the liver is reesterified and stored in the lipid-containing stellate (Ito) cells of the liver until needed to maintain normal blood retin- ol concentrations. Carotenoids are incorporated into very low density lipoproteins (VLDL) and exported from the liver into the blood. VLDL are con- verted to LDL by lipoprotein lipase on the surface of blood vessels.
94 DIETARY REFERENCE INTAKES Plasma membrane-associated receptors of peripheral tissue cells bind apolipoprotein B100 on the surface of LDL, initiating recep- tor-mediated uptake of LDL and their lipid contents. The liver, lung, adipose, and other tissues possess carotene 15, 15â²-dioxygenase activity (Goodman and Blaner, 1984; Olson and Hayaishi, 1965), and thus it is presumed that carotenes may be converted to vitamin A as they are delivered to tissues. The major end products of the enzymeâs activity are retinol and retinoic acid (Napoli and Race, 1988). It is unclear, however, whether carotenoids stored in tissues other than the intestinal mucosa cells are cleaved to yield retinol. Thatcher et al. (1998) demonstrated that Î²-carotene stored in liver is not utilized for vitamin A needs in gerbils. Typically, the majority of vitamin A metabolites are excreted in the urine. Sauberlich et al. (1974) reported that the percentage of a radioactive dose of vitamin A recovered in breath, feces, and urine ranged from 18 to 30 percent, 18 to 37 percent, and 38 to 60 percent, respectively, after 400 days on a vitamin A-deficient diet. Almost all of the excreted metabolites are biologically inactive. Retinol is metabolized in the liver to numerous products, some of which are conjugated with glucuronic acid or taurine for excretion in bile (Sporn et al., 1984). The portion of excreted vitamin A metabolites in bile increases as the liver vitamin A exceeds a critical concentration. This increased excretion has been suggested to serve as a protective mechanism for reducing the risk of excess storage of vitamin A (Hicks et al., 1984). Body Stores The hepatic vitamin A concentration can vary markedly depend- ing on dietary intake. When vitamin A intake is adequate, over 90 percent of total body vitamin A is located in the liver (Raica et al., 1972) as retinyl ester (Schindler et al., 1988), where it is concentrat- ed in the lipid droplets of perisinusoidal stellate cells (Hendriks et al., 1985). The average concentration of vitamin A in postmortem livers of American and Canadian adults is reported to range from 10 to as high as 1,400 Âµg/g liver (Furr et al., 1989; Hoppner et al., 1969; Mitchell et al., 1973; Raica et al., 1972; Schindler et al., 1988; Underwood et al., 1970). In developing countries where vitamin A deficiency is prevalent, the vitamin A concentration in liver biopsy samples is much lower (17 to 141 Âµg/g) (Abedin et al., 1976; Flores and de Araujo, 1984; Haskell et al., 1997; Olson, 1979; Suthutvora- voot and Olson, 1974). A concentration of at least 20 Âµg retinol/g of liver in adults is suggested to be the minimal acceptable reserve
VITAMIN A 95 (Loerch et al., 1979; Olson, 1982). The mean liver stores of vitamin A in children (1 to 10 years of age) have been reported to range from 171 to 723 Âµg/g (Flores and de Araujo, 1984; Mitchell et al., 1973; Money, 1978; Raica et al., 1972; Underwood et al., 1970), whereas the mean liver vitamin A stores in apparently healthy in- fants is lower, ranging from 0 to 320 Âµg/g of liver (Flores and de Araujo, 1984; Huque, 1982; Olson et al., 1979; Raica et al., 1972; Schindler et al., 1988). With use of radio-isotopic methods, the efficiency of storage (reten- tion) of vitamin A in liver has been estimated to be approximately 50 percent (Bausch and Rietz, 1977; Kusin et al., 1974; Sauberlich et al., 1974). More recently, stable-isotopic methods have shown an efficiency of storage of 42 percent for individuals with concentra- tions greater than or equal to 20 Âµg retinol/g of liver (Haskell et al., 1997). The efficiency of storage was lower in those with lower vita- min A status. The percentage of total body vitamin A stores lost per day was approximately 0.5 percent in adults consuming a vitamin A- free diet (Sauberlich et al., 1974). Clinical Effects of Inadequate Intake The most specific clinical effect of inadequate vitamin A intake is xerophthalmia. It is estimated that 3 to 10 million children, mostly in developing countries, become xerophthalmic, and 250,000 to 500,000 go blind annually (Sommer and West, 1996; WHO, 1995). The World Health Organization (WHO, 1982) classified various stages of xerophthalmia to include night blindness (impaired dark adaptation due to slowed regeneration of rhodopsin), conjunctival xerosis, Bitotâs spots, corneal xerosis, corneal ulceration, and scar- ring, all related to vitamin A deficiency. Night blindness is the first ocular symptom to be observed with vitamin A deficiency (Dowling and Gibbons, 1961), and it responds rapidly to treatment with vita- min A (Sommer, 1982). High-dose (60 mg) vitamin A supplementa- tion reduced the incidence of night blindness by 63 percent in Nepalese children (Katz et al., 1995). Similarly, night blindness was reduced by 50 percent in women after weekly supplementation with either 7,500 Âµg RE of vitamin A or Î²-carotene (Christian et al., 1998b). An association of vitamin A deficiency and impaired embryonic development is well documented in animals (Morriss-Kay and Sokolova, 1996; Wilson et al., 1953). In laboratory animals, fetal resorption is common in severe vitamin A deficiency, while fetuses that survive have characteristic malformations of the eye, lungs, uro- genital tract, and cardiovascular system. Similar abnormalities are
96 DIETARY REFERENCE INTAKES observed in rat embryos lacking nuclear retinoid receptors (Wendling et al., 1999). Morphological abnormalities associated with vitamin A deficiency are not commonly found in humans; however, functional defects of the lungs have been observed (Chytil, 1996). Because of the role of vitamin A in maintaining the structural integrity of epithelial cells, follicular hyperkeratosis has been observed with inadequate vitamin A intake (Chase et al., 1971; Sauberlich et al., 1974). Men who were made vitamin A deficient under controlled conditions were then supplemented with either retinol or Î²-carotene, which caused the hyperkeratosis to gradually clear (Sauberlich et al., 1974). Vitamin A deficiency has been associated with a reduction in lym- phocyte numbers, natural killer cells, and antigen-specific immuno- globulin responses (Cantorna et al., 1995; Nauss and Newberne, 1985). A decrease in leukocytes and lymphoid organ weights, im- paired T cell function, and decreased resistance to immunogenic tumors have been observed with inadequate vitamin A intake (Dawson and Ross, 1999; Wiedermann et al., 1993). A generalized dysfunction of humoral and cell-mediated immunity is common in experimental animals and is likely to exist in humans. In addition to xerophthalmia, vitamin A deficiency has been asso- ciated with increased risk of infectious morbidity and mortality in experimental animals and humans, especially in developing coun- tries. A higher risk of respiratory infection and diarrhea has been reported among children with mild to moderate vitamin A deficiency (Sommer et al., 1984). Mortality rates were about four times greater among children with mild xerophthalmia than those without it (Sommer et al., 1983). The risk of severe morbidity and mortality decreases with vitamin A repletion. In children hospitalized with measles, case fatality (Barclay et al., 1987; Hussey and Klein, 1990) and the severity of complications on admission were reduced when they received high doses (60 to 120 mg) of vitamin A (Coutsoudis et al., 1991; Hussey and Klein, 1990). In some studies, vitamin A sup- plementation (30 to 60 mg) has been shown to reduce the severity of diarrhea (Barreto et al., 1994; Donnen et al., 1998) and Plasmodium falciparum malaria (Shankar et al., 1999) in young children, but vitamin A supplementation has had little effect on the risk or sever- ity of respiratory infections, except when associated with measles (Humphrey et al., 1996). In developing countries, vitamin A supplementation has been shown to reduce the risk of mortality among young children (Ghana VAST Study Team, 1993; Muhilal et al., 1988; Rahmathullah et al., 1990; Sommer et al., 1986; West et al., 1991), infants (Humphrey et
VITAMIN A 97 al., 1996), and pregnant and postpartum women (West et al., 1999). Meta-analyses of the results from these and other community-based trials are consistent with a 23 to 30 percent reduction in mortality of young children beyond 6 months of age after vitamin A supplemen- tation (Beaton et al., 1993; Fawzi et al., 1993, Glasziou and Mackerras, 1993). WHO recommends broad-based prophylaxis in vitamin A-deficient populations. It also recommends treating chil- dren who suffer from xerophthalmia, measles, prolonged diarrhea, wasting malnutrition, and other acute infections with vitamin A (WHO, 1997). Furthermore, the American Academy of Pediatrics (AAP, 1993) recommends vitamin A supplementation for children in the United States who are hospitalized with measles. SELECTION OF INDICATORS FOR ESTIMATING THE REQUIREMENT FOR VITAMIN A Dark Adaptation The ability of the retina to adapt to dim light depends upon an adequate supply of vitamin A, because 11-cis retinal is an integral part of the rhodopsin molecule of the rods. Without adequate levels of vitamin A in the retina, the function of the rods in dim light situations becomes compromised, resulting in abnormal dark adap- tation (night blindness). Before clinically apparent night blindness occurs, abnormal rod function may be detected by dark adaptation testing. In addition to vitamin A deficiency, zinc deficiency and severe protein deficiency also may affect dark adaptation responses (Bankson et al., 1989; Morrison et al., 1978). Dark Adaptation Test To perform a dark adaptation test, the eye is first dilated and the subject fixates on a point located approximately 15 degrees above the center of the test light. The test stimulus consists of light flashes of approximately 1-second duration separated by 1-second intervals of darkness. A tracking method is used with the luminance of the test light being increased or decreased depending upon the re- sponse of the subject. The ascending threshold is the intensity at which the subject first sees the test light as its luminance is increased. The descending threshold is the intensity at which the subject ceases to see the test light as its luminance is lowered. Each threshold intensity is plotted versus time and the values are read from the graph at the end of a test session. Testing is continued
98 DIETARY REFERENCE INTAKES until the final threshold is stabilized. The final dark-adapted thresh- old is defined as the average of three ascending and three descend- ing thresholds and is obtained after 35 to 40 minutes in darkness. When the logarithm of the light perception is plotted as a func- tion of time in darkness, the change in threshold follows a charac- teristic course. There is an initial rapid fall in threshold attributed to cones, followed by a plateau. A steeper descent, referred to as the rod-cone break, usually occurs at 3 to 9 minutes followed by a slow- er descent attributed to adaptation of the rods. The final threshold attained at about 35 to 40 minutes is the most constant indicator of dark adaptation. Among stable subjects, test results are reproduc- ible over a 1- to 6-month interval with final threshold differences ranging from 0 to 0.1 log candela/meter2. In one series, the dark adapted final threshold among 50 normal subjects (aged 20 to 60 years) was â5.0 Â± 0.3 candela/ meter2 (Carney and Russell, 1980). Similar information on retinal function may be obtained by an electroretinogram or an electrooculorgram. However, these tests are more invasive than dark adaptation and there are not as many data relating these functional tests to dietary vitamin A levels. There is literature relating dark adaptation test results to dietary levels of vitamin A under controlled experimental conditions (Table 4-4). Under controlled feeding conditions, dark adaptation, objec- tively measured by dark adaptometry, is one of the most sensitive indicators of a change in vitamin A deficiency status (Figure 4-3). Epidemiological evidence suggests that host resistance to infection is impaired at lesser stages of vitamin A deficiency, prior to clinical onset of night blindness (Arroyave et al., 1979; Arthur et al., 1992; Barreto et al., 1994; Bloem et al., 1990; Ghana VAST Study Team, 1993; Loyd-Puryear et al., 1991; Salazar-Lindo et al., 1993). More- over, laboratory animals fed a vitamin A-deficient diet maintain ocular levels of vitamin A despite a significant reduction in hepatic vitamin A levels (Bankson et al., 1989; Wallingford and Underwood, 1987). Nevertheless, this approach can be used to estimate the aver- age requirement for vitamin A but without assurance of adequate tissue levels to meet nonvisual needs for vitamin A. Pupillary Response Test Another test of ability to dark adapt, one that avoids reliance on psychophysical responses, is the pupillary response test that mea- sures the threshold of light at which a pupillary reflex (contraction) first occurs under dark-adapted conditions (Stewart and Young, 1989). The retina of one eye is briefly exposed to incremental pulses
VITAMIN A 99 of light while a trained observer monitors the consensual response of the other pupil under dark conditions. A high scotopic (vision in dim light) threshold indicates low retinal sensitivity, a pathophysio- logical response to vitamin A deficiency. An early report of pupil- lary nonresponse to candlelight among night blind Confederate soldiers in the Civil War (Hicks, 1867) led to the development and validation of instrumentation for this test as a reliable, functional measure of vitamin A deficiency in Indonesian (Congdon et al., 1995) and Indian (Sanchez et al., 1997) children. However, data do not currently exist relating pupillary threshold sensitivity as deter- mined by this test to usual vitamin A intakes, and so measures of pupillary response cannot be used at the present to establish dietary vitamin A requirements. Plasma Retinol Concentration The concentration of plasma retinol is under tight homeostatic control in individuals and therefore is insensitive to liver vitamin A stores. The relationship is not linear and over a wide range of ade- quate hepatic vitamin A reserves there is little change in plasma retinol or retinol binding protein (RBP) concentrations (Under- wood, 1984). When liver vitamin A reserves fall below a critical con- centration, thought to be approximately 20 Âµg/g of liver (Olson, 1987), plasma retinol concentration declines. When dietary vitamin A is provided to vitamin A-deficient children, plasma retinol con- centration increases rapidly, even before liver stores are restored (Devadas et al., 1978; Jayarajan et al., 1980). Thus, a low concentra- tion of plasma retinol may indicate inadequacy of vitamin A status, although median or mean concentrations for plasma retinol may not be well correlated with valid indicators of vitamin A status. In malnourished populations, often 25 percent or more individu- als exhibit a plasma retinol concentration below 0.70 Âµmol/L (20 Âµg/dL), a level considered to reflect vitamin A inadequacy in a population (Flores, 1993; Underwood, 1994). However, a low plas- ma retinol concentration also may result from an inadequate sup- ply of dietary protein, energy, or zinc, all of which are required for a normal rate of synthesis of RBP (Smith et al., 1974). Plasma retin- ol concentration may also be low during infection as a result of transient decreases in the concentrations of the negative acute phase proteins, RBP, and transthyretin, even when liver retinol is adequate (Christian et al., 1998a; Filteau et al., 1995; Golner et al., 1987; Rosales et al., 1996). The presence of one or more of these factors could lead to an overestimation of the prevalence of vitamin
100 DIETARY REFERENCE INTAKES TABLE 4-4 Correction of Abnormal Dark Adaptation with Vitamin A Vitamin A Dark Intake Serum Adapta- Reference Subject (Âµg/d) Duration Retinol tiona ERGb Blanchard DA, man, 90â165 A and 20 y +450 3 d C Harper, +600 2 d SI 1940 JK, man, 90â165 A 23 y +300 4 d C +1,081 2 d C TH, man, 90â165 A 20 y +150 3 d PC +721 4 d N Batchelder GG, young 60 A and adult 600 A Ebbs, woman 1,201 N 1943 KY, young 60 A adult 600 A man 1,201 N MW, young 60 A adult 600 440 and 620 A woman IU/dL 1,200 6 d TC 1,200 17 d A 3,000 C Hume and Golding, 21 14 mo 22 IU/dL 2.81, A Krebs, man, 390 1 mo 50 IU/dL 2.38, A 1949 32 y, 2 mo 88 IU/dL 2.26, M vitamin A 6 mo 88 IU/dL 1.81, N depleted continued
VITAMIN A 101 TABLE 4-4 Continued Vitamin A Dark Intake Serum Adapta- Reference Subject (Âµg/d) Duration Retinol tiona ERGb Sauberlich Subject #1, < 24 771 d et al., man, 37.5 14 d 8 Âµg/dL A A 1974 37 y, 75 14 d 7 Âµg/dL A A vitamin A 150 15 d 4 Âµg/dL C A depleted 300 14 d 12 Âµg/dL C PC 600 11 d 19 Âµg/dL C Subject #5, < 24 359 d man, 150 82 d 4 Âµg/dL C A 43 y, 300 372 d 27 Âµg/dL C PC vitamin A 600 14 d 42 Âµg/dL C depleted 1,200 14 d 42 Âµg/dL C C 2,400 14 d 47 Âµg/dL C C Subject #7, < 24 505 d man, 150 82 d 9 Âµg/dL C A 41 y, 300 42 d 16 Âµg/dL C A vitamin A 600 16 d 20 Âµg/dL C depleted 1,200 9 d 24 Âµg/dL C Subject # 8, < 24 595 d man, 75 10 d 8 Âµg/dL A A 32 y, 150 17 d 9 Âµg/dL C A vitamin A 300 3 d C depleted KC, 60 40 d A medical 570 10 d C student, vitamin A depleted MS, 60 52 d A medical 255 10 d C student, vitamin A depleted NOTE: Subjects from the four studies were included based on two rules: (1) only sub- jects with intake gaps less than 600 Âµg/day were used and (2) the lowest corrected/ normal intake value was chosen as that level at which dark adaptation was corrected or normal and for which no abnormal ERG was recorded. a Dark adaptation normal = 1.37 to 2.3 log Âµm lamberts. A = abnormal, C = corrected, SI = slight improvement, PC = partially corrected, N = normal, TC = temporarily corrected, M = marginal. b ERG = electroretinogram.
102 DIETARY REFERENCE INTAKES Final dark adapted thrershold (log candela/m2) â3.3 â3.7 â4.1 â4.5 â4.9 â5.3 â5.7 10 20 30 40 50 60 70 80 90 Serum vitamin A (micrograms %) FIGURE 4-3 Serum vitamin A concentrations and dark adaptation final thresh- olds. Upper limit of normal final threshold = â4.6 log candela/m2. Adapted from Carney and Russell (1980). A deficiency when serum retinol concentration is used as an indica- tor. According to an analysis of the Third National Health and Nutrition Examination Survey, individuals in the highest quartile for vitamin A intake had only slightly higher serum retinol concen- trations than those in the lowest quartile for vitamin A intake (Ap- pendix Tables H-1 and H-2). In the United States (Looker et al., 1988; Pilch, 1987) (Appendix Table G-4), serum retinol concentration is rarely low (< 0.7 Âµmol/ L) in more than 5 percent of preschool children, although 20 to 60 percent may exhibit concentrations between 0.70 and 1.05 Âµmol/L, a range that may be marginal for some individuals (Underwood, 1994). Excluding pregnant women, less than 5 percent of adults had a serum retinol concentration less than 1.05 Âµmol/L (Appen- dix Table G-4). The median concentration of serum retinol in adults was 1.7 to 2.2 Âµmol/L (48 to 63 Âµg/dL). At the usual U.S. range of plasma retinol concentration, the con- centration is neither related to observed levels of usual vitamin A intake, from either dietary preformed vitamin A or provitamin A carotenoid sources (Hallfrisch et al., 1994), nor responsive to sup- plement use (Krasinski et al., 1989; Nierenberg et al., 1997; Stauber et al., 1991). Because of the relatively insensitive relationship be-
VITAMIN A 103 tween plasma retinol concentration and liver vitamin A in the ade- quate range, and because of the potential for confounding factors to affect the level and interpretation of the concentration, it was not chosen as a primary status indicator for a population for esti- mating an average requirement for vitamin A. Total Liver Reserves by Isotope Dilution Body stores of vitamin A can be estimated directly by liver biopsy, but this is not an appropriate indicator of status, except at autopsy, for a population. Vitamin A stores can also be estimated by an indi- rect approach using an isotope dilution technique. This technique involves administering an oral dose of stable-isotopically labeled vi- tamin A and, after a period of equilibration, drawing blood for measurement of the isotopic ratio in plasma. The Bausch and Rietz (1977) equation used to calculate liver reserves is: TLR = F Ã dose Ã [(H:D) â 1] where TLR is the pretreatment total liver reserve of vitamin A in millimoles of retinol, F is a factor that expresses the efficacy of storage of an early administered dose, dose is the oral dose of labeled retinol in millimoles, H:D is the ratio of hydrogen to deuterated retinol in the plasma after an equilibration period, and â1 corrects TLR for the contribution of the administered dose to the total body pool. Furr et al. (1989) have suggested modification of this formula to: TLR = F Ã dose Ã (S Ã a Ã [H:D) â1]) where S is the ratio of the specific activities of retinol in serum to that in liver and a is the fraction of the absorbed dose of deuterated retinol remaining in the liver at the time of blood sampling. Liver reserves of vitamin A can be correlated with known dietary intake levels of vitamin A. An Estimated Average Requirement (EAR) could be derived by knowing the population median intake of vitamin A at which half the population has hepatic stores above a certain desired level (e.g., 20 Âµg/g) and half has stores below it. Although theoreti- cally such an approach could be used to establish an EAR, no studies have been conducted in which detailed and long-term dietary data have been obtained in the tested subjects. Relative Dose Response and Modified Relative Dose Response In healthy individuals, approximately 90 percent of vitamin A in the body is stored in the liver and this percentage decreases to 50 percent or less in severely deficient individuals (Olson, 1987). He- patic vitamin A stores can thus be interpreted to reflect nutrient adequacy to meet total body needs, barring factors that impede
104 DIETARY REFERENCE INTAKES their release into circulation (e.g., liver disease and severe protein malnutrition). The relative dose response (RDR) is a method that permits indirect assessment of the relative adequacy of hepatic vita- min A stores. The RDR test was first demonstrated in rats where the release of RBP from liver was shown to depend on the availability of retinol (Loerch et al., 1979). In experimental vitamin A deficiency in rats, RBP accumulated in liver but was rapidly released after vita- min A (retinol) was administered (Carney et al., 1976; Keilson et al., 1979). This observation led Loerch et al. (1979) to propose that a positive plasma retinol response to a small test dose of vitamin A could be used as an indicator of inadequate liver vitamin A reserves. The test was subsequently validated against measured liver retinol stores in humans (Amedee-Manesme et al., 1984, 1987; Mobarhan et al., 1981). For the test, a blood sample is drawn before retinol administration (zero time), and then a small dose of vitamin A is administered; a second blood sample is taken after an interval, gen- erally 5 hours. The concentration of retinol in each sample is deter- mined and the difference (response) in plasma retinol concentra- tion (5 hours minus zero hours) is calculated and expressed as a percentage of the 5-hour concentration. Although various cutoff levels have been used, a plasma retinol response greater than or equal to 20 percent is generally consid- ered to indicate that liver vitamin A is inadequate (Tanumihardjo, 1993). The synthesis of RBP depends on the adequacy of other nutrients, and other deficiencies, such as zinc deficiency and pro- tein energy malnutrition, can confound the results of the RDR test, particularly when a repeat test is conducted within a week or less after the first or baseline test. With proper controls the RDR test is considered a valid test to determine inadequate vitamin A status. However, just as plasma retinol concentration is insensitive across a wide range of âadequateâ liver vitamin A reserves, the RDR test does not distinguish among different levels of adequate vitamin A reserves (Solomons et al., 1990). The modified relative dose response (MRDR) test is a variation of the RDR test (Tanumihardjo and Olson, 1991). The MRDR requires a single blood sample and uses as the test dose vitamin A2 (dehydro- retinol), which combines with RBP in the same manner as retinol but is not found endogenously in human plasma (with the possible exception of populations consuming high levels of fresh water fish). The test is subject to the same limitations as the RDR test. Neither the RDR nor the MRDR was chosen for estimating an EAR because little data exist relating usual dietary intakes of individuals or popu- lations to RDR or MRDR test value distributions.
VITAMIN A 105 Conjunctival Impression Cytology Before the clinical onset of xerophthalmia, mild vitamin A defi- ciency leads to early keratinizing metaplasia and losses of mucin- secreting goblet cells on the bulbar surface of the conjunctiva of the eye. These functional changes on the ocular surface can be detected by microscopic examination of PAS-hematoxylin stained epithelial cells obtained by briefly applying a cellulose acetate filter paper strip (Hatchell and Sommer, 1984; Natadisastra et al., 1987; Wittpenn et al., 1986) or disc (Keenum et al., 1990) against the temporal conjunctivum. An alternative approach involves transfer- ring cell specimens from the filter paper to a glass slide before staining and examination (Carlier et al., 1991). Specimens are clas- sified as normal or into degrees of abnormality, depending on the density and distribution of stained normal epithelial cells, goblet cells, and mucin âspotsâ (contents of goblet cells). Vitamin A status is defined by target tissue cellularity, integrity, and function, which, unlike biochemical measures, if compromised may take several weeks to normalize following vitamin A repletion (Keenum, 1993). In spite of that, there is an association between the prevalence of conjunctival impression cytology (CIC) abnormality and serum retinol and RDR test results (Sommer and West, 1996). Although CIC is used for assessment, there are few data that relate CIC status to dietary vitamin A intake in the United States, other well-nourished populations, or malnourished populations. As a result, CIC was not selected as the functional indicator for the EAR for vitamin A. Immune Function There is sound evidence for a role of vitamin A in the mainte- nance of both humoral antibody responses and cell-mediated im- munity. In experimental animals, both nonspecific immunity (Butera and Krakowka, 1986; Cohen and Elin, 1974) and antigen- specific responses, including delayed-type hypersensitivity (Smith et al., 1987), blastogenesis (Butera and Krakowka, 1986; Friedman and Sklan, 1989), and antibody production (Carman et al., 1989, 1992; Pasatiempo et al., 1990; Ross, 1996; Stephensen et al., 1993), have been shown to be altered by a deficiency of vitamin A or enhanced by vitamin A supplementation. The number and cytotoxic activity of natural killer cells (Dawson et al., 1999; Zhao et al., 1994) is reduced in vitamin A deficiency, although responsiveness to activa- tion is maintained. Several human studies have linked impairment in immunity to
106 DIETARY REFERENCE INTAKES low plasma or serum vitamin A concentrations (Coutsoudis et al., 1992; Semba et al., 1992, 1996). However, there are no human studies using controlled diets that have evaluated immune function tests as a means to assess the adequacy of different levels of dietary vitamin A. In addition to a lack of relevant dietary studies, there are some inherent limitations to using immune functions as indicators to establish dietary recommendations. Most changes in immune functions that have been associated with a nutrient deficiency are not specific to the nutrient under study (e.g., low T cell-mediated immunity may be caused by a lack of vitamin A, but also by a defi- ciency of protein or energy, zinc, or other specific nutrient defi- ciencies or imbalances). Thus, human dietary studies would have to be highly controlled with respect to the contents of potentially con- founding nutrients. Another limitation of many immune function tests is related to difficulties encountered in standardizing tests of immunity (e.g., proliferative responses to antigen or mitogen chal- lenge which are often used within studies to assess T and B cell responses). These tests are affected by many factors, such as the type and quality of mitogen used, cell culture conditions, and how subjectsâ cells have been collected, that cannot be readily controlled among laboratories or over time. Thus, for these reasons, immune function tests could not be used as an indicator for establishing the EAR for vitamin A. FACTORS AFFECTING THE VITAMIN A REQUIREMENT Intestinal Absorption Dietary Fat Dietary vitamin A is digested in mixed micelles and absorbed with fat. In some studies, increasing the level of fat in a low fat diet has been shown to improve retinol and carotene absorption (Reddy and Srikantia, 1966) and vitamin A nutriture (Jalal et al., 1998; Roels et al., 1963). Other studies, however, have not demonstrated a ben- eficial effect of fat on vitamin A absorption (Borel et al., 1997; Figueira et al., 1969). For optimal carotenoid absorption, a number of research groups have demonstrated that dietary fat must be consumed along with carotenoids. Roels and coworkers (1958) reported that the addition of 18 g/day of olive oil improved carotene absorption from 5 to 25 percent. Jayarajan and coworkers (1980) reported that the addition 5 g of fat to the diet significantly improved serum vitamin A concen-
VITAMIN A 107 trations among children after the consumption of a low fat vegetable diet. The addition of 10 g of fat did not improve serum vitamin A concentrations any more than did 5 g of fat. Infections Malabsorption of vitamin A can occur with diarrhea and intestinal infections and infestations. Sivakumar and Reddy (1972) demon- strated depressed absorption of labeled vitamin A in children with gastroenteritis and respiratory infections. Malabsorption of vitamin A is also associated with intestinal parasitism (Mahalanabis et al., 1979; Sivakumar and Reddy, 1975). The malabsorption of vitamin A that is observed in children with Ascaris lumbricoides infection was associated with an altered mucosal morphology that was reversed with deworming (Jalal et al., 1998; Maxwell et al., 1968). Food Matrix The matrix of foods affects the ability of carotenoids to be released from food and therefore affects intestinal absorption. The rise in serum Î²-carotene concentration was significantly less when individ- uals consumed Î²-carotene from carrots than when they received a similar amount of Î²-carotene supplement (Micozzi et al., 1992; Tang et al., 2000; Torronen et al., 1996). This observation was similar for broccoli (Micozzi et al., 1992) and mixed green leafy vegetables (de Pee et al., 1995; Tang et al., 2000) as compared with a Î²-carotene supplement. The food matrix effect on Î²-carotene bioavailability has been reviewed (Boileau et al., 1999). Food Processing The processing of foods greatly affects the absorption of caro- tenoids (Van het Hof et al., 1998). The absorption of carotene was 24 percent from sliced carrots, whereas the absorption of carotene from homogenized carrots was 56 percent (Hume and Krebs, 1949). Rock et al. (1998) reported that the rise in serum Î²-carotene con- centration was significantly greater in subjects consuming cooked carrots and spinach as compared with those consuming an equal amount of raw carrots and spinach. Similarly, the rise in serum Î²- carotene concentration was greater after the consumption of carrot juice than after the same amount of raw carrots (Torronen et al., 1996).
108 DIETARY REFERENCE INTAKES Nutrient-Nutrient Interactions Iron A direct correlation between hemoglobin and serum retinol con- centrations has been observed (Suharno et al., 1993; Wolde-Gebriel et al., 1993). Anemic rats have been shown to have reduced plasma retinol concentrations when fed a vitamin A-rich diet (Amine et al., 1970), although normal hepatic stores of vitamin A were observed (Staab et al., 1984). Rosales and coworkers (1999) reported that iron deficiency in young rats alters the distribution of vitamin A concentration between plasma and liver. In a cross-sectional study of children in Thailand, serum retinol concentration was positively associated with serum iron and ferritin concentrations (Bloem et al., 1989). Intervention studies among Indonesian girls demonstrated that combining vitamin A with iron supplementation was more effec- tive in increasing hemoglobin concentrations than was giving iron alone (Suharno et al., 1993). As discussed in further detail in Chap- ter 9, various studies suggest that vitamin A deficiency impairs iron mobilization from stores and therefore vitamin A supplementation improves hemoglobin concentrations (Lynch, 1997). Zinc Zinc is required for protein synthesis, including the hepatic synthesis and secretion of retinol binding protein (RBP) and transthyretin; therefore, zinc deficiency influences the mobilization of vitamin A from the liver and its transport into the circulation (Smith et al., 1974; Terhune and Sandstead, 1972). In animal models, circulating and hepatic concentrations of retinol decline and rise with experi- mental zinc deficiency and repletion, respectively (Baly et al., 1984; Duncan and Hurley, 1978). In humans, cross-sectional studies and supplementation trials have failed to establish a consistent relation- ship between zinc and vitamin A status (Christian and West, 1998). Because zinc is important in the biosynthesis of RBP, it has been suggested that zinc intake may positively affect vitamin A status only when individuals are moderately to severely protein-energy deficient (Shingwekar et al., 1979). Although the alcohol dehydrogenase enzymes involved in the for- mation of retinal from retinol in the eye are not zinc dependent (Duester, 1996; Persson et al., 1995), zinc-deficient rats had a signif- icant reduction in the synthesis of rhodopsin (Dorea and Olson,
VITAMIN A 109 1986), which was postulated to be due to impaired protein (opsin and alcohol dehydrogenase) synthesis. Morrison and coworkers (1978) reported that dark adaptation improved after the provision of 220 mg/day of zinc to zinc-deficient patients. Carotenoids Competitive interactions among different carotenoids have been observed. When subjects were given purified Î²-carotene and lutein in a combined dose, Î²-carotene significantly reduced lutein absorp- tion, and therefore serum lutein concentration, compared to when lutein was given alone (Kostic et al., 1995). However, lutein given in combination with Î²-carotene significantly increased Î²-carotene serum concentrations compared to when Î²-carotene was given alone. Johnson et al. (1997) reported that lycopene does not affect the absorption of Î²-carotene, and Î²-carotene improved the absorption of lycopene. Alcohol Because both retinol and ethanol are alcohols, there is potential for overlap in the metabolic pathways of these two compounds. Competition with each other for similar enzymatic pathways has been reported (Leo and Lieber, 1999), while other retinol and al- cohol dehydrogenases show greater substrate specificity (Napoli et al., 1995). Ethanol consumption results in a depletion of hepatic vitamin A concentrations in animals (Sato and Lieber, 1981) and in humans (Leo and Lieber, 1985). Although the effect on vitamin A is due, in part, to hepatic damage (Leo and Lieber, 1982) and mal- nutrition, the reduction in hepatic stores is also a direct effect of alcohol consumption. Patients with low vitamin A stores, in the study by Leo and Lieber (1982), were otherwise well nourished. Further- more, the reduction in hepatic vitamin A stores was reduced before the onset of fibrosis or cirrhosis of the liver (Sato and Lieber, 1981). Results suggest that vitamin A is mobilized from the liver to other organs (Mobarhan et al., 1991) with ethanol consumption. Chronic ethanol intake resulted in increased destruction of retinoic acid through the induction of P450 enzymes, resulting in reduced hepatic retinoic acid concentrations (Wang, 1999).
110 DIETARY REFERENCE INTAKES FINDINGS BY LIFE STAGE AND GENDER GROUP Infants Ages 0 through 12 Months Method Used to Set the Adequate Intake No functional criteria of vitamin A status have been demonstrated that reflect response to dietary intake in infants. Thus, recommended intakes of vitamin A are based on an Adequate Intake (AI) that reflects a calculated mean vitamin A intake of infants principally fed human milk. Ages 0 through 6 Months. Using the method described in Chapter 2, the AI of vitamin A for infants ages 0 though 6 months is based on the average amount of vitamin A in human milk that is con- sumed. After rounding, an AI of 400 Âµg retinol activity equivalents (RAE)/day is set based on the average volume of milk intake of 0.78 L/day (see Chapter 2) and an average concentration of vitamin A in human milk of 1.70 Âµmol/L (485 Âµg/L) during the first 6 months of lactation (Canfield et al., 1997, 1998) (see Table 4-5). Because the bioconversion of carotenoids in milk and in infants is not known, the contribution of carotenoids in human milk to meeting the vitamin A requirement of infants was not considered. TABLE 4-5 Vitamin A in Human Milk Reference Study Group Average Maternal Intake Stage of L Butte and Calloway, 1981 23 Navajo women Not reported 1 mo Chappell et al., 1985 12 women Not reported 3â4 d 37 d Canfield et al., 1997 6 women, 23â36 y 2,334 Âµg/d < 6 mo Canfield et al., 1998 5 women, 23â36 y 2,544 Âµg/d > 1 mo a Vitamin A intake based on reported data or concentration (Âµg/L) Ã 0.78 L/day.
VITAMIN A 111 Ages 7 through 12 Months. Using the method described in Chapter 2 to extrapolate from the AI for infants ages 0 through 6 months fed human milk, the intake from human milk for the older infants is 483 Âµg RAE/day of vitamin A. The vitamin A intake for older infants can also be determined by estimating the intake from human milk (concentration Ã 0.6 L/ day) and complementary foods (Chapter 2). Vitamin A intake data (n = 45) from complementary foods was estimated to be 244 Âµg/day based on data from the Third National Health and Nutrition Exam- ination Survey. The average intake from human milk is approxi- mately 291 Âµg/day (485 Âµg/L Ã 0.6 L/day). Thus, the total vitamin A intake is estimated to be 535 Âµg RAE/day (244 Âµg/day + 291 Âµg/day). On the basis of these two approaches and rounding, the AI was set at 500 Âµg RAE/day. The AI for infants is greater than the Recom- mended Dietary Allowance (RDA) for young children because the RDA is based on extrapolation of adult data (see âChildren and Adolescents Ages 1 through 18 Yearsâ). Vitamin A AI Summary, Ages 0 through 12 Months AI for Infants 0â6 months 400 Âµg RAE/day of vitamin A 7â12 months 500 Âµg RAE/day of vitamin A Milk Concentration Estimated Vitamin A nal Intake Stage of Lactation (Âµg/L) Intake of Infants (Âµg/d)a 1 mo 329 256 3â4 d 2,000 1,560 37 d â600 468 < 6 mo 314 245 485 380 > 1 mo 640 500 /day.
112 DIETARY REFERENCE INTAKES Special Considerations Concentrations of 520 to 590 Âµg/L of vitamin A in milk from Holstein cows have been reported (Tomlinson et al., 1976), which is significantly less than the levels observed in human milk (Table 4-5). The majority of vitamin A and carotenes are located in the fat globule and fat globule membrane in cow milk (Patton et al., 1980; Zahar et al., 1995). The concentrations of retinol and Î²-carotene in cow milk averaged 18 to 27 Âµg/g of milk fat in one study (Jensen and Nielsen, 1996). Retinol in cow milk is bound to Î²-lactoglobulin, which has a structure very similar to retinol binding protein (Papiz et al., 1986). There is minimal isomerization of trans-retinol to cis- retinol in unheated cow milk (Panfili et al., 1998), the latter being less well absorbed. Cow milk submitted to pasteurization resulted in 3 to 6 percent isomerization to cis-retinol. Greater isomerization was observed with severe heat treatments (16 percent in ultra high temperature milk and 34 percent in sterilized milk). Children and Adolescents Ages 1 through 18 Years Method Used to Estimate the Average Requirement No data are available to estimate an average requirement for chil- dren and adolescents. A computational method is used that includes an allowance for adequate liver vitamin A stores to set the Esti- mated Average Requirement (EAR) (see âAdults Ages 19 Years and Olderâ). The EAR for children and adolescents is extrapolated from adults by using metabolic body weight and the method described in Chapter 2. If total body weight is used, the RDA for children 1 through 3 years would be 200 Âµg RAE/day. If metabolic weight (kg0.75) is used, the RDA would be 300 Âµg RAE/day. Studies con- ducted in developing countries indicate that xerophthalmia and serum retinol concentrations of less than 20 Âµg/dL exist among preschool children with daily intakes of up to 200 Âµg of vitamin A, whereas 300 Âµg/day of vitamin A is associated with serum retinol concentrations greater than 30 Âµg/dL (Reddy, 1985). Although sim- ilar data are lacking in developed countries, to ensure that the RDA will meet the requirement of almost all North American preschool children, metabolic weight was used to extrapolate from adults.
VITAMIN A 113 Vitamin A EAR and RDA Summary, Ages 1 through 18 Years EAR for Children 1â3 years 210 Âµg RAE/day of vitamin A 4â8 years 275 Âµg RAE/day of vitamin A EAR for Boys 9â13 years 445 Âµg RAE/day of vitamin A 14â18 years 630 Âµg RAE/day of vitamin A EAR for Girls 9â13 years 420 Âµg RAE/day of vitamin A 14â18 years 485 Âµg RAE/day of vitamin A The RDA for vitamin A is set by using a coefficient of variation (CV) of 20 percent based on the calculated half-life values for liver vitamin A (see âAdults Ages 19 Years and Olderâ). The RDA is de- fined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of individuals in the group (therefore, for vitamin A the RDA is 140 percent of the EAR). The calculated values for the RDAs have been rounded to the nearest 100 Âµg. RDA for Children 1â3 years 300 Âµg RAE/day of vitamin A 4â8 years 400 Âµg RAE/day of vitamin A RDA for Boys 9â13 years 600 Âµg RAE/day of vitamin A 14â18 years 900 Âµg RAE/day of vitamin A RDA for Girls 9â13 years 600 Âµg RAE/day of vitamin A 14â18 years 700 Âµg RAE/day of vitamin A Adults Ages 19 Years and Older Evidence Considered in Estimating the Average Requirement The calculation described below can be used for estimating the vitamin A requirement and is calculated on the basis of the amount of dietary vitamin A required to maintain a given body-pool size in well-nourished subjects. Olson (1987) determined the average re- quirement of vitamin A by this approach using the calculation:
114 DIETARY REFERENCE INTAKES AÃBÃCÃDÃEÃF A = Percent of body vitamin A stores lost per day when ingesting a vitamin A-free diet B = Minimum acceptable liver vitamin A reserve C = The liver weight:body weight ratio D = Reference weight for a specific age group and gender E = Ratio of total body:liver vitamin A reserves F = Efficiency of storage of ingested vitamin A. By using this approach, a daily vitamin A intake can be deter- mined that will assure vitamin A reserves to cover increased needs during periods of stress and low vitamin A intake. That value can be used for estimating the average requirement for vitamin A. The portion of body vitamin A stores lost per day has been esti- mated to be 0.5 percent based on the rate of excretion of radio- activity from radiolabeled vitamin A and by the calculation of the half-life of vitamin A. The minimal acceptable liver reserve is esti- mated to be 20 Âµg/g and is based on the concentration at which (1) no clinical signs of a deficiency are observed, (2) adequate plasma retinol concentrations are maintained (Loerch et al., 1979), (3) induced biliary excretion of vitamin A is observed (Hicks et al., 1984), and (4) there is a protection against a vitamin A deficiency for approximately 4 months while the person consumes a vitamin A-deficient diet. The liver weight:body weight ratio is 1:33 (0.03) and is an average of ratios for infants and adults. The reference weights for adult women and men are 61 and 76 kg, respectively (see Chapter 1). The ratio of total body:liver vitamin A reserves is 10:9 (1.1) and is based on individuals with adequate vitamin A status. Finally, the efficiency of storage can be determined by iso- tope dilution methods following the administration of either radio- active or stable-isotopically labeled vitamin A to subjects adequate in vitamin A (Bausch and Reitz, 1977; Haskell et al., 1997). Recent studies by Haskell and coworkers (1997) suggest that the efficiency of storage is approximately 40 percent, rather than the 50 percent that was previously reported (Olson, 1987). Based on these current estimations, the EAR of preformed vitamin A required to assure an adequate body reserve in an adult man is 0.005 Ã 20 Âµg/g Ã 0.03 Ã 76 kg Ã 1.1 Ã 2.5, or 627 Âµg RAE/day. With a reference weight of 61 kg for women, the EAR would be 503 Âµg RAE/day. Based on the study of Sauberlich and coworkers (1974), Olson (1987) estimated that the liver vitamin A concentration was less than 10 Âµg/g at the time the first clinical signs of vitamin A defi-
VITAMIN A 115 ciency appeared. From this assumption, it was estimated that the half-life of vitamin A is approximately 128 days, and the CV is 21 percent. Because the portion of this variability that is due to experi- mental error is not known, a CV of 20 percent is used for setting the RDA. Vitamin A EAR and RDA Summary, Ages 19 Years and Older EAR for Men 19â30 years 625 Âµg RAE/day of vitamin A 31â50 years 625 Âµg RAE/day of vitamin A 51â70 years 625 Âµg RAE/day of vitamin A > 70 years 625 Âµg RAE/day of vitamin A EAR for Women 19â30 years 500 Âµg RAE/day of vitamin A 31â50 years 500 Âµg RAE/day of vitamin A 51â70 years 500 Âµg RAE/day of vitamin A > 70 years 500 Âµg RAE/day of vitamin A The RDA for vitamin A is set by using a CV of 20 percent (see Chapter 1) using the EAR for adequate body stores of vitamin A. The RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of the individuals in the group (there- fore, for vitamin A the RDA is 140 percent of the EAR). The calcu- lated values for the RDAs have been rounded to the nearest 100 Âµg. RDA for Men 19â30 years 900 Âµg RAE/day of vitamin A 31â50 years 900 Âµg RAE/day of vitamin A 51â70 years 900 Âµg RAE/day of vitamin A > 70 years 900 Âµg RAE/day of vitamin A RDA for Women 19â30 years 700 Âµg RAE/day of vitamin A 31â50 years 700 Âµg RAE/day of vitamin A 51â70 years 700 Âµg RAE/day of vitamin A > 70 years 700 Âµg RAE/day of vitamin A
116 DIETARY REFERENCE INTAKES Pregnancy Evidence Considered in Estimating the Average Requirement Direct studies of the requirement for vitamin A during pregnancy are lacking. The model used to establish the EAR is based on the accumulation of vitamin A in the liver of the fetus during gestation and an assumption that liver contains approximately half of the bodyâs vitamin A when liver stores are low, as in the case of new- borns. Liver vitamin A concentrations for full-term stillborn infants (Dorea et al., 1984; Hoppner et al., 1968; Montreewasuwat and Olson, 1979; Olson, 1979) have ranged from less than 10 to greater than 100 Âµg/g liver, with values tending to be skewed towards the lower range (Olson, 1979). A vitamin A concentration of 1,800 Âµg per liver for 37 to 40 week gestation age (Montreewasuwat and Olson, 1979) was used to calculate a concentration of 3,600 Âµg per fetus. Assuming the efficiency of maternal vitamin A absorption to average 70 percent and vitamin A to be accumulated mostly in the last 90 days of pregnancy, the motherâs requirement would be in- creased by approximately 50 Âµg/day during the last trimester. Be- cause vitamin A in the motherâs diet may be stored and mobilized later as needed and some vitamin A may be retained in the placenta, the EAR is estimated to be ~50 Âµg/day in addition to the EAR for nonpregnant adolescent girls and women for the entire pregnancy period. Vitamin A EAR and RDA Summary, Pregnancy EAR for Pregnancy 14â18 years 530 Âµg RAE/day of vitamin A 19â30 years 550 Âµg RAE/day of vitamin A 31â50 years 550 Âµg RAE/day of vitamin A The RDA for vitamin A is set by using a CV of 20 percent based on the calculated half-life values for liver vitamin A (see âAdults Ages 19 Years and Olderâ). The RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of individuals in the group (therefore, for vitamin A the RDA is 140 percent of the EAR). The calculated values for the RDAs have been rounded up to the nearest 10 Âµg.
VITAMIN A 117 RDA for Pregnancy 14â18 years 750 Âµg RAE/day of vitamin A 19â30 years 770 Âµg RAE/day of vitamin A 31â50 years 770 Âµg RAE/day of vitamin A Lactation Evidence Considered in Estimating the Average Requirement As indicated earlier in the section on infants, human milk-fed infants consume on average 400 Âµg/day of vitamin A in the first 6 months of life. The carotenoid content of human milk has been summarized in Dietary Reference Intakes for Vitamin C, Vitamin E, Sele- nium, and Carotenoids (IOM, 2000). Because the bioconversion of carotenoids in milk and in infants is not known, the contribution of carotenoids in human milk to meeting the vitamin A requirement of infants was not considered. To set an EAR during pregnancy, 400 Âµg RAE/day is added to the EAR for nonpregnant adolescent girls and women to assure adequate body stores of vitamin A. Vitamin A EAR and RDA Summary, Lactation EAR for Lactation 14â18 years 885 Âµg RAE/day of vitamin A 19â30 years 900 Âµg RAE/day of vitamin A 31â50 years 900 Âµg RAE/day of vitamin A The RDA for vitamin A is set by using a CV of 20 percent based on the calculated half-life values for liver vitamin A (see âAdults Ages 19 Years and Olderâ). The RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of individuals in the group (therefore, for vitamin A the RDA is 140 percent of the EAR). The calculated values for the RDAs have been rounded to the nearest 100 Âµg. RDA for Lactation 14â18 years 1,200 Âµg RAE/day of vitamin A 19â30 years 1,300 Âµg RAE/day of vitamin A 31â50 years 1,300 Âµg RAE/day of vitamin A
118 DIETARY REFERENCE INTAKES Requirement for Provitamin A Carotenoids Although a large body of observational epidemiological evidence suggests that higher blood concentrations of Î²-carotene and other carotenoids obtained from foods are associated with a lower risk of several chronic diseases (see Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids [IOM, 2000]), no evidence pointed to the need for a certain percentage of dietary vitamin A to come from provitamin A carotenoids to meet the vitamin A require- ment. In view of the health benefits associated with consumption of fruits and vegetables, existing recommendations for increased con- sumption of carotenoid-rich fruits and vegetables are strongly sup- ported (see IOM, 2000). Consumption of five servings of fruits and vegetables per day could provide 5.2 to 6 mg/day of provitamin A carotenoids (Lachance, 1997), which would contribute approxi- mately 50 to 65 percent of the menâs RDA for vitamin A. Special Considerations Alcohol Consumption Excessive alcohol consumption results in a depletion of liver vita- min A stores (Leo and Lieber, 1985). Depletion is partly due to the reduced consumption of foods. Furthermore, mobilization of vita- min A out of the liver may be increased with excessive alcohol con- sumption (Lieber and Leo, 1986). Because alcohol intake has been shown to enhance the toxicity of vitamin A (Leo and Lieber, 1999) (see âTolerable Upper Intake Levelsâ), individuals who consume alcohol may be distinctly susceptible to the adverse effects of vita- min A and any increased intake to meet oneâs needs should be in the context of maintaining health. Developing Countries and Vegetarian Diets A number of factors can influence the requirement for vitamin A, including iron status, the presence and severity of infection and parasites, the level of dietary fat, protein energy malnutrition, and the available sources for preformed vitamin A and provitamin A carotenoids. Parasites and Infection. Malabsorption of vitamin A can occur with diarrhea and intestinal infestations (Jalal et al., 1998; Sivakumar and Reddy, 1972). Furthermore, the urinary excretion of vitamin A
VITAMIN A 119 is increased with infection, and especially with fever (Alvarez et al., 1995; Stephensen et al., 1994). For these reasons, with parasitic in- festation and during infection, the requirement for vitamin A may be greater than the requirements set in this report, which are based on generally healthy individuals. Protein Energy Malnutrition. Protein synthesis generally, and specif- ically retinol binding protein synthesis, is reduced with severe pro- tein energy malnutrition (PEM) (marasmus and kwashiorkor), and therefore release of retinol from the liver (assuming stores are present) is also reduced (Large et al., 1980). With successful dietary treatment of PEM, growth and tissue weight gain will be stimulated, and the relative requirement of vitamin A will increase during the recovery period. Vegetarianism. Preformed vitamin A is found only in animal-derived food products. A clinical sign of vitamin A deficiency, night blind- ness, is prevalent in developing countries where animal and vitamin A-fortified products are not commonly available. Although caro- tenoids such as Î²-carotene are abundant in green leafy vegetables and certain fruits, because it takes 12 Âµg of dietary Î²-carotene to provide 1 retinol activity equivalent (RAE) (as compared to previous recommendations where 1 Âµg of retinol was thought to be provided by 6 Âµg of Î²-carotene [NRC, 1989 and Table 4-3]), a greater amount of fruits and vegetables than previously recommended are required to meet the daily vitamin A requirement for vegetarians and those whose primary source of vitamin A is green leafy vegetables. Analyzing intakes of vitamin A and Î²-carotene and using an RAE of 12 Âµg for dietary Î²-carotene indicate that the RDA for vitamin A can be met by those consuming a strict vegetarian diet containing the deeply colored fruits and vegetables (1,262 Âµg RAE) that are major sources of Î²-carotene in the United States (Chug-Ahuja et al., 1993) (Table 4-6). The United States has several vitamin A-fortified foods, including milk, cereals, and infant formula. Furthermore, certain food products, such as sugar, are being fortified with vita- min A in some developing countries. If menus are restricted in the amounts of provitamin A carotenoids consumed and such fortified products are not part of routine diets, then vitamin A supplements may be required. Populations Where Consumption of Vitamin A-Rich Foods is Limited. Three major intervention trials have been conducted in developing countries to evaluate the efficacy of provitamin A carotenoids in
120 DIETARY REFERENCE INTAKES TABLE 4-6 Vitamin A Intake from a Vegan Diet High in Carotene-Rich Fruits and Vegetables Î²-Carotene Retinol Vitamin A Equivalents Intake Intake Meal Foods Eaten Intakea (Âµg) (Âµg) (Âµg RAE b) Breakfast Bagel (1 medium) 0 0 0 Peanut butter (2 T) 1 0 0 Canned pineapple, juice pack (1/2 cup) 40 0 3 Orange juice (3/4 cup) 103 0 9 Total for meal 143 0 12 Snack Banana (1 medium) 28 0 2 Total for snack 28 0 2 Lunch Vegetable soup, prepared from ready-to-serve can (1 cup) 1,195 0 166 Hummus (2 T) 2 0 0 White pita (1 large) 0 0 0 Soy milk (1 cup) 0 0 0 Apple, with skin (1 medium) 70 0 6 Total for meal 2,067 0 172 Dinner Lettuce salad: romaine lettuce (1 cup) with tomato (2 wedges) and oil and vinegar dressing (2 T) 850 0 71 Baked sweet potato (1 medium) 10,195 0 850 Bean burrito (1 medium) with avocado (3 slices) and salsa (2 T) 165 0 13 Soy milk (1 cup) 0 0 0 Total for meal 11,210 0 934 Snack Vegetable juice (3/4 cup) 1,697 0 141 Nuts, seeds and dried fruit mixture (1/4 cup) 2 0 0 Total for snack 1,699 0 141 Daily Totals 15,148 0 1,262 NOTE: Source of food composition data: NDS-R Food and Nutrient Data Base, Version 30, 1999, Nutrition Coordinating Center, University of Minnesota. Nutrient totals may not equal the sum of the parts. a Î²-Carotene equivalents (Âµg) = Âµg Î²-carotene + 1/2(Âµg Î±-carotene + Âµg Î²-cryptoxanthin). b RAE = retinol activity equivalents; 1 RAE = 1 Âµg retinol + 1/12(Âµg Î²-carotene equivalents).
VITAMIN A 121 maintaining or improving vitamin A status in lactating women (de Pee et al., 1995), preschool children (Jalal et al., 1998), and young children (Takyi, 1999). Vitamin A status, as determined by serum retinol concentration, was not improved in Indonesian lactating women after the consumption of dark green leafy vegetables (de Pee et al., 1995). These women had hemoglobin concentrations less than 13 mg/dL. There is evidence that iron deficiency impairs the metabolism of vitamin A in laboratory animals (Jang et al., 2000; Rosales et al., 1999). In some, but not all, studies (Suharno et al., 1993), iron supplementation improved vitamin A status in humans (Munoz et al., 2000). Therefore the presence of iron deficiency, which is prevalent in developing countries, may impair the efficacy of dark green leafy vegetables. Jalal and coworkers (1998) reported that the addition of Î²-carotene-rich foods to the diets of preschool children improved vitamin A status, however, vitamin A status improved almost as well when fat was added to the diet and an anthelmintic drug to destroy parasitic worms was provided. This finding demonstrates the importance of dietary fat, which is often low in the diets of developing countries and the importance of in- testinal parasites on vitamin A status. Takyi (1999) reported that the vitamin A status of young children improved similarly when fed either a pureed Î²-carotene-rich diet or provided a similar amount of Î²-carotene as a supplement. Here, in contrast to the findings of Jalal et al. (1998), dietary fat and anthelmentic drugs did not ap- pear to have a beneficial effect on vitamin A status, possibly because the carotenoid was already provided in a highly absorbable, pureed form. The EARs that have been set for the North American population are achievable through diet because of the abundance of vitamin A- rich foods. Populations of less developed countries may have diffi- culty in meeting the EAR that ensures adequate vitamin A stores. Therefore, an EAR that does not assure adequate vitamin A stores has been determined on the basis of the level of vitamin A for cor- rection of abnormal dark adaptation in adults. This approach does not assure adequate stores of vitamin A because animal studies indi- cate that vitamin A depletion of the eye occurs after the depletion of hepatic vitamin A reserves (Bankson et al., 1989; Lewis et al., 1942). Furthermore, epidemiological studies in children suggest impaired host resistance to infection, presumably reflecting com- promised immunity and represented by increased risk of morbidity and mortality at lesser stages of depletion (Arroyave et al., 1979; Arthur et al., 1992; Barreto et al., 1994; Bloem et al., 1990; Ghana
122 DIETARY REFERENCE INTAKES VAST Study Team, 1993; Loyd-Puryear et al., 1991; Rahmathullah et al., 1990; Salazar-Lindo et al., 1993; West et al., 1991). An EAR of 300 Âµg RAE/day can be calculated based on the dark adaptation data obtained from 13 individuals from four studies on adults (Table 4-4). The duration of depletion and repletion varied among these four studies and the majority of the studies were con- ducted on men. Interpolation of the level of vitamin A at which dark adaptation of each individual was corrected in these four studies results in a median intake of 300 Âµg RAE/day, which can be used to set an EAR based on dark adaptation for adults. Using this method, there was insufficient evidence to support setting a different EAR for men and for women, as there were too few women studied. EARs using dark adaptation as the indicator for children (1â3 years, 112 Âµg RAE/day; 4â8 years, 150 Âµg RAE/day; 9â13 years, 230 Âµg RAE/day) and adolescents (14â18 years, 300 Âµg RAE/day) are based on extrapolation from the adult EAR as described in Chapter 2. INTAKE OF VITAMIN A Food Sources Common dietary sources of preformed vitamin A in the United States and Canada include liver, dairy products, and fish. Chug- Ahuja et al. (1993) reported that carrots were the major contributor of Î²-carotene (25 percent). Other major contributors to Î²-carotene intakes included cantaloupe, broccoli, squash, peas, and spinach. Carrots were also the major contributor (51 percent) of Î±-carotene. Fruits were the sole contributors of Î²-cryptoxanthin. According to data collected from the 1994â1996 Continuing Survey of Food In- takes by Individuals (CFSII), the major contributors of vitamin A from foods were grains and vegetables (approximately 55 percent), followed by dairy and meat products (approximately 30 percent). Dietary Intake The Third National Health and Nutrition Examination Survey (NHANES III) (Appendix Table C-8) estimated that the median dietary intake of vitamin A is 744 to 811 Âµg/day for men and 530 to 716 Âµg/day for women using the new provitamin A carotenoid con- version factors for calculating retinol activity equivalents (RAE) (see Table 4-3). When one examines Appendix Table C-8 to determine the proportion of individuals with intakes that were less than the EAR (500 Âµg RAE/day for women and 625 Âµg RAE/day for men), it
VITAMIN A 123 is apparent that for most age groups between 25 and 50 percent of adults fell in this category. The EAR for vitamin A is based on a criterion of adequate liver stores; thus, these data suggest that con- siderable proportions of adults have liver vitamin A stores that are less than desirable. It should be recognized that this does not repre- sent a clinical deficiency state, such as abnormal dark adaptation. Because the level of vitamin A intake varies greatly (Beaton et al., 1983), it is very important that the daily intake distribution be ad- justed for day-to-day variability in intakes when assessing intake dis- tributions of groups to determine the proportion with intakes below the EAR. This adjustment can be carried out using the methods of Nusser et al. (1986) and the National Research Council (NRC, 1986). When reporting as RAE, the vitamin A activity of provitamin A carotenoids is half the activity given as retinol equivalents (RE) (Table 4-3). Therefore, vitamin A intakes calculated using RAE are less than intakes determined using RE (compare Appendix Tables C-7 and C-8) resulting in a higher percentage of certain groups who consume levels of vitamin A less than the EAR. Thus, a greater amount of provitamin A carotenoids, and therefore darkly colored, carotene-rich fruits and vegetables, is needed to meet the vitamin A requirement. Data from NHANES III indicate that for men 31 to 50 years of age, the median intakes of the provitamin A carotenoids Î±-carotene, Î²-carotene, and Î²-cryptoxanthin, were 51 (2 Âµg RAE), 1,942 (162 Âµg RAE), and 39 (1.6 Âµg RAE) Âµg/day, respectively (Appendix Tables C-1, C-2 and C-3). Using RAE, dietary Î²-carotene contributes ap- proximately 21 percent of the total vitamin A intake. All provitamin A carotenoids contributed 26 and 34 percent of vitamin A con- sumed by men and women, respectively. The median intake of other carotenoids, lutein and zeaxanthin, ranged from 1,353 Âµg/day to 1,966 Âµg/day for men and women (Appendix Table C-4). For men and women, the median intake of lycopene ranged from 842 to 5,079 Âµg/day (Appendix Table C-5). The menus in Table 4-7 show that the total dayâs vitamin A intake (1,168 Âµg RAE/day) exceeds the Recommended Dietary Allowance (RDA) when consuming an omnivorous diet and choosing five fruits and vegetables that are major contributors of Î²-carotene in the United States. The RDA can also be achieved for individuals con- suming vegetarian diets high in carotene-rich fruits and vegetables (Table 4-6).
124 DIETARY REFERENCE INTAKES TABLE 4-7 Vitamin A Intake from an Omnivorous Diet High in Carotene-Rich Fruits and Vegetables Î²-Carotene Retinol Vitamin A Equivalents Intake Intake Meal Foods Eaten Intakea (Âµg) (Âµg) (Âµg RAE b) Breakfast Ready-to-eat oat cereal (1 cup) 1 150 150 Skim milk (1/2 cup) 0 75 75 Toasted wheat bread (2 medium slices) with margarine (2 pats) 53 95 99 Orange juice (3/4 cup) 103 0 9 Total for meal 157 319 332 Lunch Roast beef sandwich (1 medium) 49 0 4 Vegetable soup, prepared from ready-to-serve can (1 cup) 1,195 0 166 Nectarine (1 medium) 177 0 15 Cola (12 fl oz) 0 0 0 Total for meal 2,221 0 185 Dinner Lettuce salad: iceberg lettuce (1 cup) with tomato (2 wedges) and creamy dressing (2 T) 247 6 27 Chicken pot pie (8 oz) 2,333 3 197 Cooked broccoli (1/2 cup) 943 0 79 White dinner roll (1 medium) with margarine (1 pat) 23 47 49 Skim milk (1 cup) 0 149 149 Total for meal 3,547 205 501 Snack Skim milk (1 cup) 0 149 149 Oatmeal cookie (1 medium) 0 0 0 Total for snack 0 149 149 Daily Totals 5,925 647 1,168 NOTE: Source of food composition data: NDS-R Food and Nutrient Data Base, Version 30, 1999, Nutrition Coordinating Center, University of Minnesota. Nutrient totals may not equal the sum of the parts. a Î²-Carotene equivalents (Âµg) = Âµg Î²-carotene + 1/2(Âµg Î±-carotene + Âµg Î²-cryptoxanthin). b RAE = retinol activity equivalents; 1 RAE = Âµg retinol + 1/12(Âµg Î²-carotene equivalents).
VITAMIN A 125 Intake from Supplements Information from NHANES III on Americansâ use of supplements containing vitamin A is given in Appendix Table C-9. The median intake of vitamin A from supplements was approximately 1,430 Âµg RAE/day for men and women. In 1986, approximately 26 percent of adults in the United States took supplements that contained vita- min A (Moss et al., 1989; see Table 2-2). TOLERABLE UPPER INTAKE LEVELS The Tolerable Upper Intake Level (UL) is the highest level of daily vitamin A intake that is likely to pose no risk of adverse health effects in almost all individuals. Although members of the general population should be advised not to routinely exceed the UL, intake above the UL may be appropriate for investigation within well- controlled clinical trials. Clinical trials of doses above the UL should not be discouraged as long as subjects participating in these trials have signed informed consent documents regarding possible toxic- ity and as long as these trials employ appropriate safety monitoring of trial subjects. In addition, the UL is not meant to apply to indi- viduals who are receiving vitamin A under medical supervision. The UL for provitamin A carotenoids has been addressed in the report Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Caro- tenoids (IOM, 2000). Hazard Identification There are substantial data on the adverse effects of high vitamin A intakes. Acute toxicity is characterized by nausea, vomiting, head- ache, increased cerebrospinal fluid pressure, vertigo, blurred vision, muscular incoordination (Olson, 1983), and bulging fontanel in infants (Persson et al., 1965). These are usually transient effects involving single or short-term large doses of greater than or equal to 150,000 Âµg in adults and proportionately less in children (Bendich and Langseth, 1989). The clinical picture for chronic hyper- vitaminosis A is varied and nonspecific and may include central nervous system effects, liver abnormalities, bone and skin changes, and other adverse effects. Chronic toxicity is usually associated with ingestion of large doses greater than or equal to 30,000 Âµg/day for months or years. Both acute and chronic vitamin A toxicity are asso- ciated with increased plasma retinyl ester concentrations (Krasinski et al., 1989; Ross, 1999).
126 DIETARY REFERENCE INTAKES For the purpose of deriving a UL, three primary adverse effects of chronic vitamin A intake are discussed below: (1) reduced bone mineral density, (2) teratogenicity, and (3) liver abnormalities. High Î²-carotene intake has not been shown to cause hypervitaminosis A. Therefore, this review is limited to the adverse effects of preformed vitamin A or retinol. The terms vitamin A and retinol will be used interchangeably in the following sections. Because provitamin A car- otenoids were not included in vitamin A supplements until the late 1980s, it is assumed that studies and case reports published before 1990 used preformed vitamin A in supplements. The UL derived here applies to chronic intake of preformed vitamin A from food, fortified food, and/or supplements. Adverse Effects in Adults Bone Mineral Density. Chronic, excessive vitamin A intake has been shown to lead to bone mineral loss in animals (Rohde et al., 1999), making such a consequence in humans biologically plausible. Most human case reports are not well described and epidemiological studies are inadequate in design. However, four studies provide interpretable evidence relating changes in bone mineral density (BMD) and risk of hip fracture with variation in dietary intake of preformed vitamin A (Freudenheim et al., 1986; Houtkooper et al., 1995; Melhus et al., 1998). The studies are distinguished by their well-described study designs and populations, adequate dietary in- take estimates, and accurate methods for measuring BMD at multi- ple sites. One two-part study (Melhus et al., 1998) suggests that a chronic intake of 1.5 mg/day of preformed vitamin A is associated with osteoporosis and increased risk of hip fracture. The first part, a cross-sectional multivariate regression analysis in 175 Swedish women 28 to 74 years of age, showed a consistent loss in BMD at four sites and in total BMD with increased preformed vitamin A intake. Numerous nutritional and non-nutritional exposures were concurrently assessed, allowing substantial control of potential con- founders. With the use of stratified estimates of retinol intake in a univariate regression analysis, BMD was shown to increase with each 0.5 mg/day increment in intake above a reference intake of less than 0.5 mg/day, until intakes exceeded 1.5 mg/day. Above this level, mean BMD decreased markedly at each site. In a multivariate model, adjusting for effects of 14 other covariates, similar results were found. It is not clear whether the findings are equally applica- ble to pre- and postmenopausal women.
VITAMIN A 127 The second part was a nested case-control study on the risk factors for hip fracture. Cases were mostly postmenopausal women with first hip fracture within 2 to 64 months after entry into the large cohort study, or 5 to 67 months after the mid-point of the recalled dietary assessment. Four matched control subjects were selected for each case. A total of 247 cases and 873 control subjects completed the study. Univariate and multivariate conditional logistic regres- sion analysis showed a dose-dependent increase in the risk of hip fracture with each 0.5 mg/day increment in reported retinol intake above 0.5 mg/day (baseline). The odds ratio was 2.05 (95 percent confidence interval, 1.05â3.98) at intakes above 1.5 mg/day. In contrast to the results of Melhus and coworkers (1998), which suggest that risk of bone mineral loss and hip fracture occurs at estimated intakes above 1.5 mg/day, two U.S. studies provide no evidence of increased bone mineral loss in women with intakes of preformed vitamin A up to 1.5 to 2.0 mg/day (Freudenheim et al., 1986; Houtkooper et al., 1995). Freudenheim and coworkers (1986) evaluated the correlation between mean 3-year vitamin A intakes ranging from approximately 2 to 3 mg/day and rates of change in BMD in 84 women, 35 to 65 years of age (17 pre- and 67 post- menopausal). No consistent relationship was reported between vita- min A intake and the rate of bone mineral content loss in pre- and postmenopausal women. The single subject who showed rapid bone mineral loss with very high vitamin A intake also appeared to have consumed large amounts of other micronutrients as well, obscuring the significance of this relationship. Further, this study suffers from a small sample size in each of the four key groups (i.e., pre- and postmenopausal women by calcium supplement status), making cor- relations of potential nutritional or pathological importance inde- terminate. Houtkooper and coworkers (1995), in a longitudinal study of 66 women 28 to 39 years of age, showed that vitamin A intake was significantly associated with the increased annual rate of change in total body BMD. The mean rate of change in total body BMD over the 18-month study was negative, although several sites (lumbar spine, trochanter, and Wardâs triangle) showed small positive slopes. The estimated mean intake of preformed vitamin A from the diet was 1,220 Â± 472 (standard deviation [SD]) Âµg/day. The estimated vitamin A intake from provitamin A carotenoids was 595 Â± 352 (SD) Âµg/day. In multivariable regression models that included covari- ables for body composition and treatment (exercise versus seden- tary) status, the slopes for vitamin A and carotene (two separate models) were both positive [b = 0.007 and 0.008 mg/(cm2-year)]
128 DIETARY REFERENCE INTAKES with r2 values of ~0.30 for each model. While the positive associa- tion between vitamin A and carotene intake and change in BMD may not be causal, the data provide evidence that vitamin A does not adversely affect premenopausal bone health within this range of intake. The findings from these studies are provocative but conflicting, and therefore, they are not useful for setting a UL for vitamin A. More research is needed to clarify whether chronic vitamin A intake, at levels that characterize upper-usual intake ranges for many Amer- ican and European populations, may lead to loss in BMD and con- sequent increased risk of hip fracture in certain population groups, particularly among pre- and postmenopausal women. Teratogenicity. Concern for the possible teratogenicity of high vita- min A intake in humans is based on the unequivocal demonstration of human teratogenicity of 13-cis-retinoic acid (Lammer et al., 1985) after supplementation with high doses of vitamin A (Eckhoff and Nau, 1990; Eckhoff et al., 1991). Numerous studies in experimental animals clearly establish the teratogenic potential of excessive in- takes of vitamin A (Cohlan, 1953, 1954; Geelen, 1979; Hutchings and Gaston, 1974; Hutchings et al., 1973; Kalter and Warkany, 1961; Pinnock and Alderman, 1992). Epidemiological data show the possibility of teratogenic effects with high intakes of preformed vitamin A (Table 4-8). The critical period for susceptibility appears to be the first trimester of preg- nancy and the primary birth defects associated with excess vitamin A intake are those derived from cranial neural crest (CNC) cells such as craniofacial malformations and abnormalities of the central nervous system (except neural tube defects), thymus, and heart. Examination of the data suggests a likely dose-dependent association between vitamin A intake at excessive levels and the risk of birth defects. One case-control report showed a statistically nonsignificant associ- ation between a reported maternal intake of greater than 12,000 Âµg/day and malformations, but not below that level (Martinez-Frias and Salvador, 1990). Two other large case-control studies showed no relationship between risk of malformation and likely supplemen- tal daily doses of 2,400 to 3,000 Âµg by mothers (Khoury et al., 1996; Shaw et al., 1996). An observational study by Rothman and co- workers (1995) involving 22,748 pregnant women found that those who ingested greater than 4,500 Âµg/day of preformed vitamin A from food and supplements were at greater risk of delivering infants with malformations of CNC cell origin (e.g., cleft lip or palate) than were women consuming less than 1,500 Âµg/day. But questions have
VITAMIN A 129 been raised about the accuracy of intake estimates and birth defects diagnosed. It has been argued further that the limited number of excess cases used to identify a toxicity threshold of 4,500 Âµg/day of preformed vitamin A (or 3,000 Âµg from supplements) permits the studyâs findings to be consistent with a larger threshold than other studies would suggest (Brent et al., 1996; Mastroiacovo et al., 1999; Watkins et al., 1996; Werler et al., 1996). Thus, while few dispute a causal association between excessive periconceptual vitamin A in- take and risk of malformation, the threshold at which risk increases remains a matter of debate. However, in the context of the totality of data on vitamin A and birth defects, the data of Rothman and coworkers (1995) provide supportive evidence of a causal associa- tion. Case reports of malformations exist to support an increased risk of birth defects above a maternal intake of 7,800 Âµg/day of vitamin A (Bauernfeind, 1980; Bernhardt and Dorsey, 1974). Human case reports support a temporal association between maternal ex- posure to elevated vitamin A intakes and birth defects (Bernhardt and Dorsey, 1974; Von Lennep et al., 1985). Liver Abnormalities. There is a strong causal association shown by human and animal data between excess vitamin A intake and liver abnormalities because the liver is the main storage site and target organ for vitamin A toxicity. The wide spectrum of vitamin A-induced liver abnormalities ranges from reversibly elevated liver enzymes to wide- spread fibrosis, cirrhosis, and sometimes death. Table 4-9 shows consis- tency and specificity of the following effects in liver pathology: sponta- neous green fluorescence of sinusoidal cells, perisinusoidal fibrosis, hyperplasia, and hypertrophy of Ito cells. Human data are potentially confounded by other factors related to liver damage such as alcohol intake, hepatitis A, B, and C, hepatotoxic medications, or preexisting liver disease. A thorough evaluation of the liver data is provided in the later section, âDose-Response Assessmentâ. Adverse Interactions. Alcohol intake has been shown to enhance the toxicity of vitamin A (Leo and Lieber, 1999). In particular, the hepa- totoxicity of vitamin A may be potentiated by alcohol use. There- fore, alcohol drinkers may be distinctly susceptible to the adverse effects of vitamin A. Adverse Effects in Infants and Children There are numerous case reports of infants (Table 4-10), tod- dlers, and children who have demonstrated toxic effects due to ex-
130 DIETARY REFERENCE INTAKES TABLE 4-8 The Relationship Between Reproductive Risk and Excess Preformed Vitamin A in Humans Time of Study Design Subjects Daily Dose (Âµ g/day) Exposure Martinez-Frias Case control 11,293 cases of NA and Salvador, study birth defects 1990 11,193 controls < 12,000 â¥ 12,000 (supplemental forms) Dudas and Letter 1,203 exposed 1,800 -1 to 3 mo Czeizel, 1992 1,510 nonexposed gestatio Rothman et Cohort study 22,748 pregnant First al., 1995 women trimest â¤ 1,500 control > 3,000 supplement > 4,500 supplement + food Khoury et al., Case control 1,623 casesb < 2,400c -1 to 3 mo 1996 study 3,029 controlsb gestatio Shaw et al., Case control 925 cases of birth â¥ 3,000 (presumed) -1 to 3 mo 1996 study defects gestatio 871 controls Mills et al., Case control 89 cases -15 d to 1997 study 573 controls < 1,500 (supplement + 1 mo fortification) gestatio > 2,400 (supplement + fortification) > 3,000 (supplement + fortification) Czeizel and Case control 20,830 cases Estimated range: 1 to 9 mo Rockenbauer, pair 35,727 controls 150â30,000 gestatio 1998 analysis Most < 3,000
VITAMIN A 131 k and Time of ay) Exposure Results Conclusions NA Risk ratio for birth defects This suggests women of 0.5 (p = 0.15) reproductive age may be at 2.7 (p = 0.06) increased risk of teratogenicity mental at vitamin A exposures â¥ 12,000 Âµ g/day -1 to 3 mo Cranial neural crest The comparison of the rate and gestation defects not observed in pattern of congenital exposed group abnormalities in exposed and nonexposed groups did not indicate any teratogenic effect of vitamin A First Risk ratio for neural Vitamin A intakes > 3,000 Âµ g/d, trimester crest defects significant increased risk of cranial 1.0 neural crest defects nt 4.8 nt + food 3.5a -1 to 3 mo Risk ratio for cranial No increased risks of defects from gestation neural crest defects cranial neural crest among 1.36 vitamin A supplement vitamin A and multivitamin users 0.69 vitamin A + multivitamin supplement d) -1 to 3 mo Risk ratio 0.55 No increased risk of orofacial clefts gestation at vitamin A intakes â¥ 3,000 Âµ g/d compared to controls -15 d to Risk ratio No association between ent + 1 mo 1.0 periconceptional vitamin A at gestation doses > 2,400 or > 10,000 Âµg/d ent + 0.76 and malformations in general and cranial neural crest defects ent + 1.09 1 to 9 mo Fewer cases were treated Vitamin A doses < 3,000 Âµg/d during gestation with vitamin A (1,642 or the first trimester of pregnancy is 7.9%) than controls not teratogenic (3,399 or 9.5%) (p < 0.001) continued
132 DIETARY REFERENCE INTAKES TABLE 4-8 Continued Time of Study Design Subjects Daily Dose (Âµ g/day) Exposure Mastroiacovo Cohort study 311 infants Median: 15,000 0 to 9 wk et al., 1999 evaluated Range: 3,000â100,000 gestatio a 3.5 = the ratio of the prevalence among babies born to women who consumed more than 4,500 Âµg/d of preformed vitamin A/d from food and supplements to the preva- lence among the babies whose mothers consumed 1,500 Âµg or less/d. For vitamin A from supplements alone, the ratio of the prevalence among the babies born to women who consumed more than 3,000 Âµg/day to that among the babies whose mothers con- sumed 1,500 Âµg/d or less was 4.8. cess vitamin A intakes for months to years. Of particular concern are intracranial (bulging fontanel) and skeletal abnormalities that can result in infants given vitamin A doses of 5,500 to 6,750 Âµg/day (Persson et al., 1965). The clinical presentation of vitamin A toxicity in infants and young children varies widely. The more commonly recognized signs and symptoms include skeletal abnormalities, bone tenderness and pain, increased intracranial pressure, desquamation, brittle nails, mouth fissures, alopecia, fever, headache, lethargy, irri- tability, weight loss, vomiting, and hepatomegaly (Bush and Dahms, 1984). Furthermore, tolerance to excess vitamin A intake also ap- pears to vary (Carpenter et al., 1987). Carpenter and coworkers (1987) described two boys who developed hypervitaminosis A by age 2 years for one and by age 6 years for the other. Both were given chicken liver that supplied about 690 Âµg/day of vitamin A and various supplements that supplied another 135 to 750 Âµg/day. An older sister who had been treated similarly remained completely healthy. Summary Based on considerations of causality, quality, and completeness of the database, teratogenicity was selected as the critical adverse effect on which to base a UL for women of childbearing age. For all other adults, liver abnormalities were the critical adverse effect. Abnormal
VITAMIN A 133 Time of ay) Exposure Results Conclusions 0 to 9 wk Risk ratio of prevalence of Daily intake of preformed vitamin A 000 gestation major malformations in supplement â¥ 3,000 Âµ g/d does not treated group vs. controls seem to increase risk of serious was 0.5 anomalies of structures with a cranial neural crest cell contribution b Cases refer to mothers of infants with cranial neural crest-derived defects ascertained within the first year of life. Controls represent mothers of infants without birth defects, frequency-matched to cases by period of birth, race, and hospital of birth. c There was no information to quantify the actual vitamin A content of the supplements or multivitamins. During the period of the study, most were expected to contain under 2,400 Âµg and contained preformed vitamin A. liver pathology, characteristic of vitamin A intoxication (or grossly elevated hepatic vitamin A levels), was selected rather than elevated liver enzymes because of the uncertainties regarding other possible causes such as concurrent use of hepatotoxic drugs, alcohol intake, and hepatitis B and C. Bone changes were not used because of the conflicting findings and the lack of other data confirming the find- ings of Melhus et al. (1998). Dose-Response Assessment Women of Reproductive Age Data Selection. Epidemiological studies evaluating the teratogenicity of vitamin A intake shortly before or during pregnancy (Table 4-8) were used to derive a UL for women of reproductive age. Because adequate human data were available, animal data were not used to derive a UL. Identification of a No-Observed-Adverse-Effect Level (NOAEL). A NOAEL of approximately 4,500 Âµg/day of preformed vitamin A from food and supplements was based on a critical evaluation of the data in Table 4-8. There are numerous reports showing no adverse effects at doses below 3,000 Âµg/day of vitamin A from supplements (Czeizel and Rockenbauer, 1998; Dudas and Czeizel, 1992; Khoury et al.,
134 DIETARY REFERENCE INTAKES TABLE 4-9 Evidence of Liver Abnormalities After Excess Preformed Vitamin A Intakes (< 30,000 Âµg/day), Based on Increasing Dose Duration Case Reports Subject Dose ( Âµg/d) (y) Outcomea Hepatitis Oren and Ilan, Woman, 1,515 10 Severe fibrosis to portal No histor 1992 56 y areas; ALP (870 U/L) blood t immun Weber et al., Man, 6,000 6 Increase of vitamin A in Hepatitis 1982 62 y (supplement) liver (5,700 Âµg/g); 10,000 (foodb) decrease in serum 1 vitamin A & RBP; liver 4,500 (foodc) biopsy: lipid vacuoles 7,500 within hepatocyte (supplement) cytoplasm; sinusoidal fibrosis; lipid-filled Ito cells Hatoff et al., Vege- 7,600d 10 Acute hypervitaminosis A Hepatitis 1982 tarian (supplement) precipitated by viral man, 7,600 (foode) hepatitis B infection; 42 y liver biopsy showed many lipid-filled Ito cells; enlarged Kupffer cells; perisinusoidal fibrosis; increase in liver and serum vitamin A; headache, skin desquamation, hypercalcemia, and confusion Kowalski Woman, 7,600 6 Severe hepatotoxicity Hepatitis et al., 1994 45 y Eaton, 1978 Woman, 8,300â10,600 30 Cirrhosis; portal Unknown 51 y (diet + hypertension; marked supplements) fibrosis Woman, 14,000 from 10 AST (73 U/L), Two bloo 63 y supplements ALT (96 U/L), 30 y pr (information ALP (258 U/L); Hepatitis on diet not vacuolated, lipid-filled HbsAg provided) Ito cells anti-HBc
VITAMIN A 135 s on Increased Alcohol Other Hepatitis Use Factors o portal No history of hepatitis or No None 70 U/L) blood transfusions; negative immunological profiles min A in Hepatitis B No It is possible g/g); that effects erum were due to RBP; liver protein vacuoles deficiency cyte nusoidal filled minosis A Hepatitis B Limited by viral (3 beers/ fection; wk) howed led Ito d Kupffer soidal ase in m adache, ation, a, and xicity Hepatitis A, B, and C No Patientâs health status; meds l Unknown No marked Two blood transfusions Extremely ), 30 y previously rare L); Hepatitis A pid-filled HbsAg anti-HBc continued
136 DIETARY REFERENCE INTAKES TABLE 4-9 Continued Duration Case Reports Subject Dose ( Âµg/d) (y) Outcomea Hepatitis Minuk et al., Man, 14,000 from 10 AST (124 U/L), Hepatitis 1988 62 y supplement ALT (256 U/L), 5 y earl (diet ALP (76 U/L), contained albumin (46 g/L), no raw meat increase in total or seafood) bilirubin; tests for IgM antibody to hepatitis A virus, HbsAg and anti-HBc were negative Zafrani et al., Man, 15,000 from 12 Increase in liver vitamin Negative 1984 36 y supplement A concentration; antigen spontaneous green hepatit fluorescence of core an sinusoidal cells; perisinusoidal fibrosis and hyperplasia; hypertrophy of Ito cells; portal and periportal fibrosis; lesions of hepatic sinusoids randomly distributed areas of sinusoidal dilation; RBCs present in Disseâs spaces; sinusoidal barrier abnormalities mimicking peliosis hepatitis Zafrani et al., Woman, 26,000 8 Hepatic lesions; Negative 1984 25 y spontaneous green antigen fluorescence of hepatit sinusoidal cells; core an perisinusoidal fibrosis, hyperplasia, and hypertrophy of Ito cells; randomly distributed areas of sinusoidal dilation; RBCs present in Disseâs spaces; sinusoidal barrier abnormalities mimicking peliosis hepatitis
VITAMIN A 137 Increased Alcohol Other Hepatitis Use Factors , Hepatitis A virus infection Not excessive No meds L), 5 y earlier ), g/L), tal s for IgM epatitis A and e r vitamin Negative hepatitis B surface No No meds on; antigen; positive serum green hepatitis B surface and of core antibodies ls; l fibrosis sia; of Ito nd rosis; patic domly eas of ation; in Disseâs idal malities liosis Negative hepatitis B surface No None green antigen; negative serum of hepatitis B surface and ls; core antibodies l fibrosis, nd f Ito cells; ributed oidal s present ces; rrier mimicking itis continued
138 DIETARY REFERENCE INTAKES TABLE 4-9 Continued Duration Case Reports Subject Dose ( Âµg/d) (y) Outcomea Hepatitis Geubel et al., 41 cases, Mean, 29,000 Mean, Cirrhosis (n = 9); mild, No hepat 1991 9â76 y 4.6 chronic hepatitis (n = 10); noncirrhotic portal hypertension (n = 5); fat storing cell hyperplasia and hypertrophy (n = 9); death (n = 6) Farrell et al., Woman, 30,000 4 Serum ALP (108 U/L); Not repor 1977 57 y (supplement) serum AST (72 U/L); 1,600 (food) increased size and number of fat storing cells a ALP = alkaline phosphatase (normal range = 0â36 U/L), AST = aspartate aminotrans- ferase (normal range = 45â110 U/L), ALT = alanine aminotransferase (normal range = 0â41 U/L). b Ingestion of sweet potatoes, carrots, peaches, tomatoes, and desiccated beef liver ac- counted for this high vitamin A intake. c Diet included sweet potatoes, carrots, peaches, tomatoes, and desiccated beef liver. 1996; Rothman et al., 1995) or 4,500 Âµg/day of preformed vitamin A from food and supplements (Rothman et al., 1995). Rothman and coworkers (1995) showed a significantly increased risk of birth defects at the cranial neural crest sites among women who con- sumed greater than 4,500 Âµg of preformed vitamin A/day from food and supplements during the first trimester compared to those who took 1,500 Âµg/day or less. Most of the human data on teratogenicity of vitamin A involve doses equal to or greater than 7,800 Âµg/day. There are limited epidemiological data to clearly define a dose- response relationship in the dose range of 3,000 to 7,800 Âµg/day. Nevertheless, 4,500 Âµg/day represents a conservative value for a NOAEL in light of the evidence of no adverse effects at or below that level.
VITAMIN A 139 Increased Alcohol Other Hepatitis Use Factors ); mild, No hepatitis B virus No Meds titis cirrhotic ension oring cell nd n = 9); 8 U/L); Not reported Unknown 2 U/L); and t storing d Subject took an additional vitamin A capsule (7,500 Âµg/d) âwhen under stressâ or not feeling well. e Diet included carrot and raisin salad daily, large amounts of leafy, green vegetables. Subject also took 1,000 IU vitamin D/d and unknown quantities of vitamin E, B-com- plex, and bone meal. Uncertainty Assessment. An uncertainty factor (UF) of 1.5 was selected on the basis of inter-individual variability in susceptibility. Because there are substantial data (Table 4-8) showing no adverse effects at doses up to 3,000 Âµg/day of vitamin A supplements, a higher UF was not justified. Derivation of a UL. The NOAEL of 4,500 Âµg/day was divided by the UF of 1.5 to obtain a UL value of 3,000 Âµg/day for women of repro- ductive age. UL = NOAEL = 4,500 Âµg/day = 3,000 Âµg/day UF 1.5
140 DIETARY REFERENCE INTAKES TABLE 4-10 Cases of Subchronic and Chronic, Low-Dose Vitamin A Toxicity in Infants, Based on Increasing Dose Age, Dose Dose Duration Report Gender (Âµg/kg/day) (Âµg/day) Form (mo) Persson et al., 4.5 mo, F 840 5,500a Dropsb 3 1965 4.5 mo, M 1,100 6,750 Drops 2 4 mo, M 1,200 6,750 Drops 1 5.5 mo, M 820 6,750 Drops 2.5 Mahoney et al., 7 mo, F 1,700 c 12,100 Chicken liver 4 1980 (total) (11,000 Âµ g)d; milk (600 Âµ g); supplement (600 Âµg) Arena et al., 6.5 mo, F 1,650â4,400e 9,100â24,200 Drops in oil 4 1951 solution Persson et al., 2.5 mo, F 4,250f 18,200 Drops 1.5 1965 Woodard et al., 2 mo, M 5,250 g 21,200 Aqueous drops 2 1961 Bush and 11 d, M 14,000 27,300 Drops-Aqualsol A 0.4 Dahms, 1984 Naz and 9 mo, F 28,570h 60,000 Drops in oil 5.5 Edwards, 1952 a 50 capsules (38,000 Âµg vitamin A) were consumed over a period of several weeks. The daily dose was not specified. b AD-viminÂ®. Astra, aqueous suspension. Ten drops correspond to 2,300 Âµg of vitamin A and 1,500 IU of vitamin D. c Calculation of 1,700 Âµg/kg/d is based on a reference body weight of 7 kg (for infants 2â6 mo). Because these infants weighed slightly more than 7 kg at 7 mo, using the reference weight of 9 kg would have been inappropriate. Therefore, 12,000 Âµg/day (total preformed vitamin A intake) Ã· 7 kg = 1,700 Âµg/kg/d. d The source of 11,000 Âµg/d of vitamin A was homogenized chicken livers. The actual total vitamin A intake was higher as the children were also consuming a vitamin supple-
VITAMIN A 141 e Duration (mo) Adverse Effect 3 Bulging fontanels 2 Bulging fontanels, anorexia, hyperirritability, edema of occipital area, bone changes, skin lesions, desquamation 1 Bulging fontanels, hyperirritability, anorexia, occipital edema, increased head circumference 2.5 Anorexia, hyperirritability, edema of the occipital area, pronounced craniotabes, increased intracranial pressure, skin lesions, skin desquamation, x-ray findings: epiphyseal line changes n liver 4 Bulging anterior fontanels, irritability, vomiting 00 Âµ g)d; (600 Âµ g); ement Âµg) n oil 4 Anorexia, hyperirritability, pronounced craniotabes, x-ray findings: n cortical hyperostosis 1.5 Anorexia, hyperirritability, edema of the occipital area, pronounced craniotabes, increased intracranial pressure, skin lesions, skin desquamation, x-ray findings: epiphyseal line changes us drops 2 Anorexia, hyperirritability, edema of the occipital area, pronounced craniotabes, increased intracranial pressure, skin lesions, skin desquamation, falling out of hair, x-ray findings: cortical hyperostosis Aqualsol A 0.4 Hypercalcemia, metastatic calcification of the lungs, kidneys, stomach, soft tissue, and skin; peeling skin; erythematous rash; hyperphosphatemia, bleeding disorder; pulmonary insufficiency; and death after 2-week hospital stay n oil 5.5 Anorexia, hyperirritability, edema of the occipital area, increased intracranial pressure, skin lesions, skin desquamation, x-ray findings: cortical hyperostosis ment containing 600 Âµg vitamin A, along with a mixed diet high in fruits and veg- etables. When the use of the chicken livers was discontinued, the children recovered with no lingering effects. e Dose in Âµg/kg/d was calculated assuming the average body weight equaled the arith- metic mean of 3.5 (weight at birth) and 7.5 kg (weight on admission to hospital) = 5.5 kg. f Dose in Âµg/kg/d was calculated using the arithmetic mean of the body weight at birth (2,850 g) and the body weight on admission to the hospital (5,590 g) or about 4.2 kg. g Dose in Âµg/kg/d was calculated assuming a body weight of 4 kg (body weight at birth). h Dose in Âµg/kg/d was calculated using the standard reference weight of 7 kg for infants 0 to 6 mo.
142 DIETARY REFERENCE INTAKES The UL for adolescent girls was adjusted on the basis of relative body weight as described in Chapter 3 with the use of reference weights from Chapter 1 (Table 1-1). Vitamin A UL Summary, Adolescent Girls and Women Ages 14 through 50 Years, Pregnancy, Lactation UL for Women 14â18 years 2,800 Âµg/day of preformed vitamin A 19â50 years 3,000 Âµg/day of preformed vitamin A UL for Pregnancy 14â18 years 2,800 Âµg/day of preformed vitamin A 19â50 years 3,000 Âµg/day of preformed vitamin A UL for Lactation 14â18 years 2,800 Âµg/day of preformed vitamin A 19â50 years 3,000 Âµg/day of preformed vitamin A All Other Adults Ages 19 Years and Older, Excluding Women of Childbearing Age Data Selection. Data on liver abnormalities in humans were used to derive a UL. Because clear toxicity has been demonstrated in nu- merous studies at doses above 15,000 Âµg/day, only data involving doses less than 30,000 Âµg/day of vitamin A were included in Table 4-9. Data were thoroughly evaluated for other potential causes of liver abnormalities. The following criteria for selecting the data sets were used: (1) data must show grossly elevated liver vitamin A levels or hypertrophy of Ito cells, (2) no alcoholism, (3) no concomitant liver hepatitis, and (4) no hepatotoxic drug use. While hepatitis A and B status are known in most cases, testing for hepatitis C did not begin until the early 1990s and is unknown in most cases. There- fore, hepatitis C was not used as a criterion for exclusion. Two case studies reported hypertrophy of Ito cells in a 63-year-old woman after vitamin A intake of 14,000 Âµg/day for 10 years (Minuk et al., 1988) and in a 36-year-old man who took about 15,000 Âµg/ day for 12 years (Zafrani et al., 1984). Neither of these reports ap- pear to be confounded by hepatitis A or B viral infections or con- comitant exposure to other hepatotoxic agents including alcohol. Reports of vitamin A-induced hepatotoxicity at doses less than 14,000 Âµg/day were found (Eaton, 1978; Hatoff et al., 1982; Kowalski et al., 1994; Oren and Ilan, 1992). However, as Table 4-9 shows,
VITAMIN A 143 these studies fail to provide information on other predisposing or confounding factors such as alcohol intake, drugs and medications used, and history of viral hepatitis infection. Uncertainty Assessment. A UF of 5.0 was selected to account for the severe, irreversible nature of the adverse effect, extrapolation from a lowest-observed-adverse-effect level (LOAEL) to a NOAEL, and interindividual variation in sensitivity. Derivation of a UL. Hepatotoxicity was reported at vitamin A sup- plement doses of 14,000 Âµg/day. A LOAEL of 14,000 Âµg/day was divided by a UF of 5 to obtain a UL after rounding of 3,000 Âµg/day for adults other than women of reproductive age. This UL is the same as that set for women of reproductive age, given that the UL is defined as the highest level of daily nutrient intake likely to pose no risk of adverse health effects to almost all of the general population. UL = LOAEL = 14,000 Âµg/day â 3,000 Âµg/day UF 5 Vitamin A UL Summary, Ages 19 Years and Older, Excluding Women of Childbearing Age UL for Men â¥ 19 years 3,000 Âµg/day of preformed vitamin A UL for Women â¥ 51 years 3,000 Âµg/day of preformed vitamin A Infants, Children, and Adolescent Boys Data Selection. Case reports of hypervitaminosis A in infants were used to identify a LOAEL and derive a UL. Data were not available to identify a NOAEL. Identification of a LOAEL. A LOAEL of 6,460 Âµg/day of vitamin A (which was rounded to 6,000 Âµg/day) was identified by averaging the lowest doses of four case reports (Persson et al., 1965). Four cases of hypervitaminosis A occurred after doses of 5,500 to 6,750 Âµg/day of vitamin A for 1 to 3 months (Table 4-10). The age of onset of symptoms ranged from 2.5 to 5.5 months and included anorexia, hyperirritability, occipital edema, pronounced craniotabes, bulging fontanels, increased intracranial pressure, and skin lesions
144 DIETARY REFERENCE INTAKES and desquamation. The lowest dose associated with a bulging fon- tanel involved a 4-month-old girl given a daily dose of 24 drops of AD-vimin (about 5,500 Âµg of vitamin A) for 3 months. Her fontanels bulged 0.5 centimeters above the plane of the skull. The other three cases involved a dose of 6,750 Âµg/day of vitamin A for 1 to 2.5 months. Increased intracranial pressure and bulging fontanels were observed in these cases as well. Other effects observed at the higher dose included anorexia, hyperirritability, occipital edema, pro- nounced craniotabes, skin lesions, skin desquamation, epiphyseal line changes, and cortical hyperostosis on x-rays. Uncertainty Assessment. A UF of 10 was selected to account for the uncertainty of extrapolating a LOAEL to a NOAEL for a nonsevere and reversible effect (i.e., bulging fontanel) and the interindividual variability in sensitivity. Derivation of a UL. The LOAEL of 6,000 Âµg/day was divided by a UF of 10 to calculate a UL of 600 Âµg/day of preformed vitamin A for infants. Children and Adolescent Boys. There are limited case report data of hypervitaminosis A (e.g., bulging anterior fontanels, increased in- tracranial pressure, hair loss, increased suture markings on the skull, and periosteal new bone formation) in children and adolescents after doses ranging from 7,000 Âµg/day in young children to 15,000 Âµg/day in older children and adolescents (Farris and Erdman, 1982; Siegel and Spackman, 1972; Smith and Goodman, 1976). Given the dearth of information and the need for conservativism, the UL val- ues for children and adolescents are extrapolated from those estab- lished for adults. Thus, the adult UL of 3,000 Âµg/day of preformed vitamin A was adjusted for children and adolescents on the basis of relative body weight as described in Chapter 2 with use of reference weights from Chapter 1 (Table 1-1). Values have been rounded. Vitamin A UL Summary, Infants, Children, and Adolescent Boys UL for Infants 0â12 months 600 Âµg/day of preformed vitamin A UL for Children 1â3 years 600 Âµg/day of preformed vitamin A 4â8 years 900 Âµg/day of preformed vitamin A 9â13 years 1,700 Âµg/day of preformed vitamin A
VITAMIN A 145 UL for Boys 14â18 years 2,800 Âµg/day of preformed vitamin A Special Considerations A review of the literature revealed that individuals with high alcohol intake, pre-existing liver disease, hyperlipidemia, or severe protein malnutrition may be distinctly susceptible to the adverse effects of excess preformed vitamin A intake (Ellis et al., 1986; Hathcock et al., 1990; Leo and Lieber, 1999). These individuals may not be pro- tected by the UL for vitamin A for the general population. Intake Assessment Based on data from the Third National Health and Nutrition Survey (NHANES III), the highest median intake of preformed vitamin A for any gender and life stage group was 895 Âµg/day (Ap- pendix Table C-6). This intake was being consumed by lactating women. The highest reported intake at the ninety-fifth percentile was 1,503 Âµg/day in lactating women. For adult Americans who take supplements containing vitamin A, intakes at the ninety-fifth per- centile ranged from approximately 1,500 to 3,000 Âµg/day (Appen- dix Table C-9). Less than 5 percent of pregnant women had dietary and supplemental intake levels exceeding the UL. Risk Characterization The risk of exceeding the UL for vitamin A appears to be small based on the intakes cited above. There is not a large difference between the UL for infants (600 Âµg/day) and the Adequate Intake for older infants (500 Âµg/day). There is a body of evidence support- ing the reversibility of bulging fontanels following the elimination of intermittent supplementation (de Francisco et al., 1993) or chronic ingestion (Naz and Edwards, 1952; Persson et al., 1965; Woodard et al., 1961) of high doses of vitamin A. The UL is based on healthy populations in developed countries. Supplemental doses exceeding the UL for vitamin A (60 to 120 mg) are currently used in fortification and supplementation programs for the prevention and treatment of vitamin A deficiency, especially in developing countries. The UL is not meant to apply to communities of malnourished individuals receiving vitamin A prophylactically, either periodically or through fortification, as a means to prevent
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