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TABLE 1 Dietary Reference Intakes for Vitamin A by Life Stage Group DRI values (mg RAEa/day) EARb RDAc AId ULe,f males females males females Life stage group 0 through 6 mo 400 600 7 through 12 mo 500 600 1 through 3 y 210 210 300 300 600 4 through 8 y 275 275 400 400 900 9 through 13 y 445 420 600 600 1,700 14 through 18 y 630 485 900 700 2,800 19 through 30 y 625 500 900 700 3,000 31 through 50 y 625 500 900 700 3,000 51 through 70 y 625 500 900 700 3,000 > 70 y 625 500 900 700 3,000 Pregnancy £ 18 y 530 750 2,800 19 through 50 y 550 770 3,000 Lactation £ 18 y 885 1,200 2,800 19 through 50 y 900 1,300 3,000 a RAE = Retinol activity equivalent. 1 mg RAE = 1 mg retinol, 12 mg b-carotene, and 24 mg a-carotene or b-cryptoxanthin. The RAE for dietary provitamin A carotenoids in foods is twofold greater than retinol equivalents (RE), whereas the RAE for preformed vitamin A in foods is the same as RE. b EAR = Estimated Average Requirement. c RDA = Recommended Dietary Allowance. d AI = Adequate Intake. e UL = Tolerable Upper Intake Level. f The UL for vitamin A applies only to preformed vitamin A (e.g., retinol, the form of vitamin A found in animal foods, most fortified foods, and supplements). It does not apply to vitamin A derived from carotenoids.

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PART III: VITAMIN A 171 VITAMIN A V itamin A is a fat-soluble nutrient that is important for vision, gene ex- pression, reproduction, embryonic development, growth, and immune function. Forms of vitamin A include retinol (preformed vitamin A), retinal, retinoic acid, and retinyl esters. The term vitamin A also includes pro- vitamin A carotenoids that are dietary precursors of retinol. The term retinoids refers to retinol and its metabolites, and any synthetic analogues that have a similar structure. The requirements for vitamin A are now denoted in retinol activity equiva- lents (RAEs), such that 1 mg RAE = 1mg all-trans-retinol, 12 mg b-carotene, and 24 mg a-carotene or b-cryptoxanthin. This recognizes that 50 percent less bio- conversion of carotenoids to vitamin A occurs than was previously thought when vitamin A was expressed in retinol equivalents (REs). The change means that twice the amount of provitamin A–rich carotenoids contained in leafy green vegetables and certain fruits is required to provide a given amount of vitamin A activity. The requirements for vitamin A are based on the assurance of adequate liver stores of vitamin A. The Tolerable Upper Intake Level (UL) is based on liver abnormalities as the critical endpoint. For women of childbearing age, the UL is based on teratogenicity as the critical adverse effect. DRI values are listed by life stage group in Table 1. Preformed vitamin A (retinol) is naturally found in animal-based foods, whereas dietary carotenoids (provitamin A carotenoids), which are converted to vitamin A in the body, are present in oils, fruits, and vegetables. Common dietary sources of preformed vitamin A in the United States and Canada include liver, dairy products, and fish. Foods fortified with vitamin A are margarine and low-fat and nonfat (skim and partly skimmed) milk. Provita- min A carotenoids are found in carrots, broccoli, squash, peas, spinach, and cantaloupe. The most specific clinical effect of vitamin A deficiency is xerophthalmia and its various stages, including night blindness, conjunctival xerosis, Bitot’s spots, corneal xerosis, corneal ulceration, and scarring. Preformed vitamin A toxicity (hypervitaminosis A) due to high vitamin A intakes may be acute or chronic.

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 172 VITAMIN A AND THE BODY Function Vitamin A is a fat-soluble vitamin that is important for normal vision, gene expression, reproduction, embryonic development, growth, and immune func- tion. Forms of vitamin A include retinol (preformed vitamin A), retinal, retinoic acid, and retinyl esters. Some examples of vitamin A functions include retinal, which is required by the eye to transduce light into the neural signals necessary for vision; retinoic acid, which is required to maintain normal differentiation of the cornea and conjunctival membranes, thus preventing xerophthalmia; and retinioic acid, which is required to regulate the expression of various genes that encode for structural proteins (e.g., skin keratins), enzymes (e.g., alcohol dehy- drogenase), extracellular matrix proteins (e.g., laminin), and retinol binding proteins and receptors. The term vitamin A also includes provitamin A carotenoids that are the dietary precursors of retinol. The term retinoids refers to retinol and its me- tabolites, and any synthetic analogues that have a similar structure to retinol. Of the more than 600 forms of carotenoids found in nature, several have provi- tamin A nutritional activity, but food composition data are available for only three (a-carotene, b-carotene, and b-cryptoxanthin). The proposed functions of provitamin A carotenoids are described in Part III, “Carotenoids.” Absorption, Metabolism, Storage, and Excretion Preformed vitamin A (retinol) is absorbed in the small intestine. The efficiency of absorption of preformed vitamin A is generally high, ranging from 70 to 90 percent. Absorption is carrier-mediated and saturable, but becomes nonsaturable at high pharmacological doses. As the amount of ingested preformed vitamin A increases, its absorbability remains high. Carotenoids are absorbed into the small intestine by passive diffusion. Efficiency of absorption has been estimated at 9–22 percent, although this decreases as the amount ingested increases. Some carotenoids (b-carotene, a- carotene, and b-cryptoxanthin) are converted to vitamin A in the body. Along with exogenous lipids, retinal esters (newly formed in the intestine) and nonhydrolyzed carotenoids are transported from the intestine to the liver in chylomicrons and chylomicron remnants. Retinoic acid, another form of vi- tamin A, is absorbed via the portal system bound to albumin. Liver, lung, adi- pose, and other tissues possess carotene enzyme activity, and so it is presumed that carotenes may be converted to vitamin A as they are delivered to tissues. When vitamin A intake is adequate, more than 90 percent of total body vitamin A is located in the liver, which releases the nutrient into the circulation

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PART III: VITAMIN A 173 in a process that depends on the availability of retinol binding protein (RBP). That which is not released remains stored in the liver. The majority of vitamin A metabolites are excreted in the urine; some vitamin A is also excreted in the bile. Amounts excreted via the bile increase as the liver vitamin A exceeds a critical concentration. This serves as a protective mechanism for reducing the risk of excess storage. DETERMINING DRIS Determining Requirements The requirements for vitamin A are based on the assurance of adequate liver stores of vitamin A. Although a large body of observational epidemiological evidence suggests that higher blood concentrations of b-carotenes and other carotenoids obtained from foods are associated with a lower risk of several chronic diseases, there is currently insufficient evidence to support a recommendation that requires a certain percentage of dietary vitamin A to come from provitamin A carotenoids in meeting the vitamin A requirement. However, existing recom- mendations for the increased consumption of carotenoid-rich fruits and veg- etables for their health-promoting benefits are strongly supported (see Part III, “Carotenoids”). For example, consuming the recommended 5 servings of fruits and vegetables per day could provide 5.2–6 mg/day of provitamin A carotenoids, which would constitute approximately 50–65 percent of the adult male RDA for vitamin A. Special Considerations Vegetarian diets: Preformed vitamin A (retinol) is found only in animal-based foods. People who do not consume such foods must meet their requirements with foods that contain sufficient provitamin A carotenoids, such as deeply colored fruits and vegetables, or with fortified foods, such as margarine, some plant-based beverages, and cereals. Parasites and infection: Malabsorption of vitamin A can occur with diarrhea and intestinal infections, such as those observed in developing countries. With infection and fever, the requirement for vitamin A may be greater than the requirements listed in this chapter, which are based on generally healthy individuals.

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 174 Retinol Activity Equivalents (RAEs) Based on data demonstrating that the efficiency of absorption of b-carotene is less than what has been traditionally thought, retinol activity equivalents (RAEs) were developed to address the new findings about reduced absorption of b-carotene. The requirements for vitamin A are now denoted in RAEs rather than retinol equivalents (REs). Using mg RAEs, the vitamin A activity of provita- min A carotenoids is half of the vitamin A activity that is assumed when using mg REs. This change in equivalency values is based on data demonstrating that the vitamin A activity of purified b-carotene in oil is half of the activity of vita- min A. It is also based on recent data demonstrating that the vitamin A activity of dietary b-carotene is one-sixth, rather than one-third, of the vitamin activity of purified b-carotene in oil. This change in bioconversion means that a larger amount of provitamin A carotenoids, and therefore 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 RAEs for dietary b-carotene, a-carotene, and b-cryptoxanthin are 12, 24, and 24 mg, re- spectively, compared to the corresponding REs of 6, 12, and 12 mg reported by the National Research Council in 1989 (see Figure 1). Nutrient databases will need to be revised to provide total vitamin A activ- ity in mg RAE. In the meantime, it is possible to estimate total vitamin A activity in mg RAE from existing tables that list mg RE. For foods, such as liver, that FIGURE 1 Absorption and bioconversion of ingested provitamin A carotenoids to retinol based on new equivalency factors (retinol equivalency ratio).

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PART III: VITAMIN A 175 contain only vitamin A activity from preformed vitamin A (retinol), no adjust- ment is necessary. Vitamin A values for foods that contain only plant sources (provitamin A carotenoids) of vitamin A can be adjusted by dividing the mg RE by two. For foods that contain both plant and animal sources of vitamin A (e.g., a casserole containing meat and vegetables), the adjustment process is more complex. (See Appendix F for more information on determining the vitamin A content of foods.) Supplemental b-carotene has a higher bioconversion to vitamin A than does dietary b-carotene. With low doses, the conversion is as high as 2:1; developers of composition information for dietary supplements should use this higher conversion factor. Little is known about the bioconversion of the forms of b- carotene that are added to foods, so fortification of forms of b-carotene should be assumed to have the same bioconversion as food forms, 12:1. Food and supplement labels usually state vitamin A levels in International Units (IUs). One IU of retinol is equivalent to 0.3 mg of retinol, or 0.3 mg RAE. One IU of b-carotene in supplements is equivalent to 0.5 IU of retinol, or 0.15 mg RAE (0.3 ¥ 0.5). One IU of dietary b-carotene is equivalent to 0.165 IU retinol, or 0.05 mg RAE (0.3 ¥ 0.165). One IU of other dietary provitamin A carotenoids is equivalent to 0.025 mg RAE. Equivalency examples: • Example 1. A diet contains 500 mg retinol, 1,800 mg b-carotene and 2,400 mg b-carotene: 500 + (1,800 ∏ 12) + (2,400 ∏ 24) = 750 mg RAE • Example 2. A diet contains 1,666 IU of retinol and 3,000 IU of b- carotene: (1,666 ¥ 0.3) + (3,000 ¥ 0.05) = 650 mg RAE • Example 3. A supplement contains 5,000 IU of vitamin A: 5,000 ¥ 0.3 = 1,500 mg RAE For more information on vitamin A conversions, please see Appendix F. Criteria for Determining Vitamin A Requirements, by Life Stage Group Life stage group Criterion 0 through 6 mo Average vitamin A intake from human milk 7 through 12 mo Extrapolation from 0 through 6 mo AI 1 through 18 y Extrapolation from adult EAR 19 through > 70 y Adequate liver vitamin A stores

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 176 Pregnancy £18 y Age-specific requirement + estimated daily accumulation by fetus 19 through 50 y Age-specific requirement + estimated daily accumulation by fetus Lactation £18 y Age-specific requirement + average amount of vitamin A secreted in human milk 19 through 50 y Age-specific requirement + average amount of vitamin A secreted in human milk The UL The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse effects for almost all people. Members of the general population should not routinely exceed the UL, which for vitamin A applies to the chronic intake of preformed vitamin A from foods, fortified foods, and some supplements. The UL for adults is based on liver abnormalities as the critical adverse effect; for women of childbearing age, the UL is based on teratogenicity as the critical adverse effect. High b-carotene in- takes have not been shown to cause hypervitaminosis A. Based on data from the Third National Health and Nutrition Examination Survey (NHANES III, 1994–1996), the highest median intake of preformed vitamin A for any gender and life stage group was 895 mg/day for lactating women. The highest reported intake at the 95th percentile was 1,503 mg/day for lactating women. For U.S. adults who took supplements containing vitamin A, intakes at the 95th percentile ranged from approximately 1,500 to 3,000 mg/ day. Fewer than 5 percent of pregnant women had dietary and supplemental intake levels that exceeded the UL. The risk of exceeding the UL for vitamin A appears to be small based on the intakes cited above. Special Considerations Individuals susceptible to adverse effects: People 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 in- take. These individuals may not be protected by the UL for vitamin A for the general population. The UL is not meant to apply to communities of malnour- ished individuals prophylactically receiving vitamin A, either periodically or through fortification, as a means to prevent vitamin A deficiency, or for indi- viduals being treated with vitamin A for diseases such as retinitis pigmentosa.

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PART III: VITAMIN A 177 DIETARY SOURCES Foods Preformed vitamin A (retinol) is found naturally in animal-based foods, whereas dietary carotenoids, which are converted to vitamin A in the body, are present in oils, fruits, and vegetables. Common dietary sources of preformed vitamin A in the United States and Canada include liver, dairy products, and fish. How- ever, according to data from the Continuing Survey of Food Intakes by Indi- viduals (CSFII, 1994–1996), in the United States the major contributors of vitamin A from foods were grains (fortified with vitamin A) and vegetables (which contain provitamin A carotenoids) at approximately 55 percent, followed by dairy and meat products at approximately 30 percent. Foods fortified with vitamin A are margarine and low-fat and non-fat (skim and partly skimmed) milk. Major contributors as provitamin A carotenoids to dietary intake include: b-carotene found in carrots, broccoli, squash, peas, spin- ach, and cantaloupe; carrots as a-carotene; and fruits as the sole contributors of b-cryptoxanthin. Dietary Supplements According to NHANES III data, the median intake of vitamin A from supple- ments was approximately 1,430 mg RAE/day for men and women. According to U.S. data from the 1986 National Health Interview Survey (NHIS), approxi- mately 26 percent of adults in the United States took supplements that con- tained vitamin A. Bioavailability Factors such as dietary fat intake, intestinal infections, the food matrix, and food processing can affect the absorption of vitamin A by the body. Dietary fat appears to enhance absorption, whereas absorption is diminished in individuals with diarrhea, intestinal infections, and infestations. The matrix of foods affects the ability of carotenoids to be released from food. For example, serum b-carotene concentration was significantly lower when individuals consumed b-carotene from carrots than from b-carotene supplements. Food processing affects the absorp- tion of carotenoids. For example, absorption is greater from cooked compared to raw carrots and spinach. Dietary Interactions There is evidence that vitamin A may interact with certain nutrients and dietary substances (see Table 2).

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 178 TABLE 2 Potential Interactions with Other Dietary Substances Substance Potential Interaction Notes SUBSTANCES THAT AFFECT VITAMIN A Dietary fat Dietary fat may enhance the Research results in this area are mixed. absorption of vitamin A and provitamin A carotenoids. Iron Iron deficiency may negatively It was reported that iron deficiency alters the affect vitamin A status. distribution of vitamin A concentration between the plasma and liver. Zinc Zinc deficiency may negatively Zinc deficiency influences the mobilization of affect vitamin A status. vitamin A from the liver and its transport into the circulation. However, human studies have not established a consistent relationship between zinc and vitamin A status. It has been suggested that zinc intake may positively affect vitamin A status only in individuals with moderate to severe protein- energy malnutrition. Alcohol Alcohol consumption may Because both retinol and ethanol are alcohols, negatively affect vitamin A there is potential for overlap in the metabolic status. pathways of these two compounds. Ethanol consumption results in a depletion of liver vitamin A stores in humans. Although the effect on vitamin A is due, in part, to liver damage associated with chronic alcohol intake and to malnutrition, the reduction in liver stores of vitamin A is also a direct effect of alcohol consumption. VITAMIN A AFFECTING OTHER SUBSTANCES Iron Vitamin A deficiency may Studies suggest that vitamin A deficiency impairs negatively affect iron status. iron mobilization from stores and that, therefore, vitamin A supplementation improves hemoglobin concentrations.

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PART III: VITAMIN A 179 INADEQUATE INTAKE AND DEFICIENCY The most specific clinical effect of inadequate vitamin A intake is xerophthalmia, which is estimated to affect 3 million to 10 million children (mostly in develop- ing countries) annually. Of those affected, 250,000 to 300,000 go blind every year. Xerophthalmia is an irreversible drying of the conjunctiva and cornea. Various stages of the disease include night blindness (impaired dark adaptation due to the slowed regeneration of rhodopsin), conjunctival xerosis, Bitot’s spots, corneal xerosis, corneal ulceration, and scarring, all related to vitamin A defi- ciency. Night blindness is the first ocular symptom to be observed with vitamin A deficiency; however, it does respond rapidly to treatment with vitamin A. Other adverse effects associated with vitamin A deficiency include decreased immune function and an increased risk of infectious morbidity and mortality, such as respiratory infection and diarrhea. Although vitamin A supplementa- tion has been shown to reduce the severity of diarrhea, it has had little effect on the risk or severity of respiratory infections, except when associated with measles. The World Health Organization (WHO) recommends treating children who suffer from xerophthalmia, measles, prolonged diarrhea, wasting malnutrition, and other acute infections with vitamin A. Furthermore, the American Acad- emy of Pediatrics recommends vitamin A supplementation for children in the United States who are hospitalized with measles. EXCESS INTAKE Preformed vitamin A toxicity (hypervitaminosis A) due to high vitamin A in- takes may be acute or chronic. (High b-carotene intake has not been shown to produce vitamin A toxicity.) Acute toxicity usually produces transient effects resulting from single or short-term large doses of retinol ≥ 150,000 mg in adults and proportionately less in children and is characterized by the following: • Nausea • Vomiting • Headache • Increased cerebrospinal fluid pressure • Vertigo • Blurred vision • Muscular incoordination • Bulging fontanel (in infants) Chronic toxicity is usually associated with the ingestion of large doses of retinol ≥ 30,000 mg/day for months or years. Chronic toxicity generally pro- duces less specific and more varied symptoms, such as birth defects, liver ab-

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 180 normalities, reduced bone mineral density, and disorders of the central nervous system. More research is needed to clarify whether chronic vitamin A intake may lead to loss in bone mineral density and a consequent increased risk of hip fracture in certain population groups, particularly among premenopausal and postmenopausal women. Human and animal data show a strong causal association between excess vitamin A intake and liver abnormalities because the liver is the main storage site and target organ for vitamin A toxicity. These abnormalities range from reversibly elevated liver enzymes to widespread fibrosis, cirrhosis, and some- times death. Special Considerations Teratogenicity: Concern for the possible teratogenicity of high vitamin A in- take in humans is based on the unequivocal demonstration of human teratoge- nicity following high-dose supplementation of vitamin A. The critical period for susceptibility appears to be during the first trimester of pregnancy. The pri- mary birth defects associated with excess vitamin A intake are those derived from cranial neural crest cells, such as craniofacial malformations and abnor- malities of the central nervous system (except neural tube defects), thymus, and heart. Most of the human data on teratogenicity of vitamin A involve doses ≥ 7,800 mg/day. Adverse effects in infants and children: There are several case reports of toxic effects of vitamin A in infants, toddlers, and children who have ingested excess vitamin A for a period of months to years. Of particular concern are intracranial (bulging fontanel) and skeletal abnormalities that can result in infants who are given vitamin A doses of 5,500–6,750 mg/day. Other effects of toxicity in infants and children include bone tenderness and pain, increased intracranial pres- sure, desquamation, brittle nails, mouth fissures, alopecia, fever, headache, leth- argy, irritability, weight loss, vomiting, and hepatomegaly.

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PART III: VITAMIN A 181 KEY POINTS FOR VITAMIN A Vitamin A is a fat-soluble vitamin that is important for normal 3 vision, gene expression, reproduction, embryonic development, growth, and immune function. The requirements for vitamin A are now denoted in retinol 3 activity equivalents (RAEs), such that 1 RAE = 1 mg all-trans- retinol, 12 mg b-carotene, and 24 mg a-carotene or b- cryptoxanthin. The requirements for vitamin A are based on the assurance of 3 adequate liver stores of vitamin A. The UL is based on liver abnormalities as the critical endpoint; for women of childbearing age, the UL is based on teratogenicity as the critical adverse effect. People with high alcohol intake, preexisting liver disease, 3 hyperlipidemia, or severe protein malnutrition may not be protected by the UL set for the general population. Food and supplement labels usually state vitamin A levels in 3 International Units, or IUs. One IU of retinol is equivalent to 0.3 mg of retinol, or 0.3 mg RAE. There is currently insufficient evidence to support a 3 recommendation that requires a certain percentage of dietary vitamin A to come from provitamin A carotenoids in meeting the vitamin A requirement. However, existing recommendations for the increased consumption of carotenoid-rich fruits and vegetables for their health-promoting benefits are strongly supported. Preformed Vitamin A (retinol) is found naturally only in animal- 3 based foods. Good sources of provitamin A carotenoids are fruits and 3 vegetables, including carrots, broccoli, squash, peas, spinach, and cantaloupe. The most specific clinical effect of inadequate vitamin A intake 3 and deficiency is xerophthalmia, an irreversible drying of the conjunctiva and cornea. Vitamin A toxicity (hypervitaminosis A) may be acute or chronic. 3 (High b-carotene intake has not been shown to produce vitamin A toxicity.) The adverse effects of excess vitamin A are from excessive intake of preformed vitamin A, or retinol.