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TABLE 1 Dietary Reference Intakes for Vitamin E (a -Tocopherol a) by Life Stage Group DRI values (mga/day) EARb RDAc AId ULe,f Life stage groupg NDh 0 through 6 mo 4 7 through 12 mo 5 ND 1 through 3 y 5 6 200 4 through 8 y 6 7 300 9 through 13 y 9 11 600 14 through 18 y 12 15 800 19 through 30 y 12 15 1,000 31 through 50 y 12 15 1,000 51 through 70 y 12 15 1,000 > 70 y 12 15 1,000 Pregnancy £ 18 y 12 15 800 19 through 50 y 12 15 1,000 Lactation £ 18 y 16 19 800 19 through 50 y 16 19 1,000 a For the EAR, RDA, and AI: a-Tocopherol includes RRR-a-tocopherol, the only form of a-tocopherol that occurs naturally in foods, and the 2R-stereoisomeric forms of a-tocopherol (RRR-, RSR-, RRS-, and RSS-a-tocopherol) that occur in fortified foods and supplements. This does not include the 2S-stereoisomeric forms of a- tocopherol (SRR-, SSR-, SRS-, and SSS-a-tocopherol), also found in fortified foods and supplements. The 2S-stereoisomers are not stored in the body. b EAR = Estimated Average Requirement. c RDA = Recommended Dietary Allowance. d AI = Adequate Intake. e UL = Tolerable Upper Intake Level. Unless otherwise specified, the UL represents total intake from food, water, and supplements. f As a-tocopherol; applies to any form of supplemental a-tocopherol since all are absorbed and can potentially contribute to vitamin E toxicity. The UL applies to synthetic forms obtained from supplements, fortified foods, or a combination of the two. Little information exists on the adverse effects that might result from ingestion of other forms. g All groups except Pregnancy and Lactation represent males and females. h ND = Not determinable. This value is not determinable due to the lack of data of adverse effects in this age group and concern regarding the lack of ability to handle excess amounts. Source of intake should only be from food to prevent high levels of intake.

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PART III: VITAMIN E 235 VITAMIN E V itamin E is a fat-soluble nutrient that functions as a chain-breaking antioxidant in the body by preventing the spread of free-radical reac- tions. Of the eight naturally occurring forms of vitamin E only the a-tocopherol form of the vitamin is maintained in the plasma. The requirements for vitamin E are based on the prevention of hydrogen peroxide–induced hemolysis. The Estimated Average Requirement (EAR), Rec- ommended Dietary Allowance (RDA), and Adequate Intake (AI) values for vita- min E only apply to intake of the 2R-stereoisomeric forms of a-tocopherol from food, fortified foods, and supplements. Other naturally occurring forms of vita- min E do not meet the vitamin E requirement because they are not converted to a-tocopherol in humans and are poorly recognized by the a-tocopherol trans- fer protein in the liver. The Tolerable Upper Intake Level (UL) is based on the adverse effect of increased tendency to hemorrhage. The UL for vitamin E applies to any forms of supplemental a-tocopherol because all are absorbed; these forms of syn- thetic vitamin E are almost exclusively used in supplements, food fortification, and pharmacological agents. Little information exists on the adverse effects that might result from the ingestion of other forms of vitamin E. DRI values are listed by life stage group in Table 1. Food sources of vitamin E include vegetable oils and spreads, unprocessed cereal grains, nuts, fruits, vegetables, and meats (especially the fatty portion). Overt deficiency of vitamin E in the United States and Canada is rare and is generally only seen in people who are unable to absorb the vitamin or who have inherited conditions that prevent the maintenance of normal blood concentra- tions. There is no evidence of adverse effects from the consumption of vitamin E naturally occurring from foods. The possible chronic effects of lifetime expo- sures to high supplemental levels of a-tocopherol remain uncertain. VITAMIN E AND THE BODY Function Unlike most nutrients, vitamin E does not appear to play a specific role in certain metabolic pathways. Its major function seems to be as a nonspecific chain-breaking antioxidant that prevents the spread of free-radical reactions. It scavenges peroxyl radicals and protects polyunsaturated fatty acids within mem- brane phospholipids and in plasma lipoproteins.

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 236 On the molecular level, vitamin E (a-tocopherol form) inhibits protein ki- nase C activity (involved in cell proliferation and differentiation) in smooth muscle cells, platelets, and monocytes. It may also improve vasodilation and inhibit platelet aggregation by enhancing the release of prostacyclin. Absorption, Metabolism, Storage, and Excretion Vitamin E is absorbed in the intestine, although the precise rate of absorption is not known. All of the forms of vitamin E appear to have similar low absorption efficiency. Absorbed vitamin E in the form of chylomicron remnants is taken up by the liver, and then only one form of vitamin E, a-tocopherol, is preferentially secreted in very low density lipoproteins. Thus, it is the liver, not the intestine, that discriminates between tocopherols. Tissues take up vitamin E from the plasma. Vitamin E rapidly transfers between various lipoproteins and also be- tween lipoproteins and membranes, which may enrich membranes with vita- min E. Vitamin E is excreted in both the urine and feces, with fecal elimination being the major mode of excretion. DETERMINING DRIS There are eight naturally occurring forms, or isomers, of vitamin E: four toco- pherols (a-, b-, g-, and d-tocopherols) and four tocotrienols (a-, b-, g-, and d-tocotrienols). These various forms of vitamin E are not interconvertible in humans, and thus do not behave the same metabolically. Of the eight, only a- tocopherol is maintained in the plasma. The isomer a-tocopherol has eight possible stereoisomers: four in the 2R- stereoisomeric form (RRR-, RSR-, RRS-, and RSS-a-tocopherol) and four in the 2S-stereoisomeric form (SRR-, SSR-, SRS-, and SSS-a-tocopherol). Of these, only one—the RRR form—naturally occurs in foods. All eight stereoisomers are rep- resented by synthetic forms (together called all-rac-a-tocopherol) and are present in fortified foods and in vitamin supplements. Of the eight stereoisomers of a-tocopherol, the only forms that are main- tained in the plasma are naturally occurring RRR-a-tocopherol and the 2R-ste- reoisomeric forms present in synthetic forms. Since the 2S-stereoisomers are not maintained in the plasma or tissues, they are not included in the definition of active components for vitamin E activity in humans. For the purpose of establishing the requirements, vitamin E activity is de- fined here as being limited to the 2R-stereoisomeric forms of a-tocopherol. How- ever, all eight stereoisomeric forms of supplemental a-tocopherol are used as the basis for establishing the UL for vitamin E. This is because all eight forms are absorbed. These recommended intakes and ULs vary from past definitions and recommendations for vitamin E.

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PART III: VITAMIN E 237 Determining Requirements The adult requirements for vitamin E are based largely on induced vitamin E deficiency in humans and the intake that correlated with in vitro hydrogen peroxide–induced red blood cell hemolysis and plasma a-tocopherol concen- trations. Although some studies have reported a possible protective effect of vitamin E on conditions such as cardiovascular and neurological diseases, can- cer, cataracts, and diseases of the immune system, the data are inadequate to support population-wide dietary recommendations that are specifically based on preventing these diseases. The EAR, RDA, and AI values for vitamin E apply only to intake of the 2R- stereoisomeric forms of a-tocopherol from food, fortified foods, and supple- ments. The other naturally occurring isomers of vitamin E (b-, g-, and d-toco- pherols and a-, b-, g-, and d-tocotrienols) do not contribute to meeting the vitamin E requirement because they are not converted to a-tocopherol in hu- mans; these forms of synthetic vitamin E are almost exclusively used in supple- ments, food fortification, and pharmacological agents. Little information exists on the adverse effects that might result from ingestion of excess amounts of other isomeric forms (such as g- and b-tocopherol). Currently, most nutrient databases, as well as nutrition labels, do not dis- tinguish among all the different forms of vitamin E found in food. These data- bases often present the data as a-tocopherol equivalents (a-TE), and thus in- clude the contributions of all eight naturally occurring forms of vitamin E, after adjustment for bioavailability using previously determined equivalencies. It is recommended that the use of a-TE be abandoned due to the lack of evidence of bioavailability via transport in the plasma or tissues. Because these other forms of vitamin E occur in foods, the intake of a-TE is greater than the intake of a- tocopherol alone. The values above were converted from a-TE to a-tocopherol using a factor of 0.8 as described later in this chapter (see “Dietary Sources”). Criteria for Determining Vitamin E Requirements, by Life Stage Group Life stage group Criterion 0 through 6 mo Human milk content 7 through 12 mo Extropolation from 0 to 5.9 mo 1 through 18 y Extrapolation from adult 19 through 30 y Prevention of hydrogen peroxide–induced hemolysis 31 through > 70 y Extrapolation of hydrogen peroxide–induced hemolysis from 19 through 30 y

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 238 Pregnancy £ 18 y through 50 y Age-specific requirement + plasma concentration Lactation £ 18 y through 50 y Age-specific requirement + vitamin E secreted in 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 consume more than the UL. The UL for vitamin E is based on the adverse effect of increased ten- dency to hemorrhage. The UL applies to all supplemental a-tocopherol forms of vitamin E (RRR-a-tocopherol and all-rac-a-tocopherol), since all are absorbed and can thus potentially contribute to vitamin E toxicity. Sources of vitamin E available as supplements are usually labeled as inter- national units (IUs) of natural vitamin E and its esters or as synthetic vitamin E and its esters. Table 2 shows the IUs of various sources of supplemental vitamin E that are equivalent to the UL for adults of 1,000 mg/day of any form of supple- mental a-tocopherol. Based on the Third National Health and Nutrition Examination Survey (NHANES III, 1988–1994) data, the highest mean reported intake of vitamin E from food and supplements for all life stage and gender groups was approxi- mately 45 mg/day of a-tocopherol equivalents (reported by women aged 51 to 70 years). This group also had the highest reported intake at the 99th percen- tile, at 508 mg/day of a-tocopherol equivalents, which is well below the UL of 1,000 mg/day for any form of a-tocopherol. Vitamin E supplement use is high in the U.S. population. In the 1986 National Health Interview Survey (NHIS), supplements containing vitamin E were used by 23 percent of men, 29 percent of women, and 37 percent of young children in the United States. The risk of adverse effects resulting from excess intake of a-tocopherol from food and supple- ments appears to be very low based on this information. Special Considerations Vitamin K deficiency or anticoagulant therapy: The UL for vitamin E pertains to individuals in the general population with adequate vitamin K intake. Indi- viduals who are deficient in vitamin K or who are on anticoagulant therapy are at increased risk of coagulation defects and should be monitored when taking vitamin E supplements.

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PART III: VITAMIN E 239 TABLE 2 Amounts in International Units (IU) of Any Forms of a -Tocopherola Contained in Vitamin Eb Supplements Equivalent to the UL for Adultsc UL for Adults Total a-Tocopherol Sources of Vitamin E IU from Source Available as Supplements (mg/day) Providing Adult UL Synthetic Vitamin E and Esters dl-a-Tocopheryl acetate 1,000 1,100 dl-a-Tocopheryl succinate 1,000 1,100 dl-a-Tocopherol 1.000 1,100 Natural Vitamin E and Esters d-a-Tocopheryl acetate 1,000 1,500 d-a-Tocopheryl succinate 1,000 1,500 d-a-Tocopherol 1,000 1,500 a All forms of supplemental a-tocopherol include all eight stereoisomers of a-tocopherol. The UL is based on animal studies feeding either all racemic- or RRR-a-tocopherol, both of which resulted in equivalent adverse effects. b Vitamin E supplements have been historically, although incorrectly, labeled d- or dl-a-tocopherol. Sources of vitamin E include the a ll racemic- ( dl - a-tocopherol [ RRR-, RRS-, RSR-, RSS-, SSS-, SRS-, SSR-, and SRR-] or synthetic) form and its esters. All of these forms of vitamin E may be present in supplements. c The conversion factors used in this table are based on 2S-forms contributing to the adverse effects DIETARY SOURCES Foods The main dietary sources of vitamin E are vegetable oils, such as wheat-germ oil, sunflower oil, cottonseed oil, safflower oil, canola oil, olive oil, palm oil, and rice-bran oil. Fats and oils in the form of spreads often contribute to vita- min E intake. Other sources of vitamin E include unprocessed cereal grains, nuts, fruits, vegetables, and meats (especially the fatty portion). As previously stated, only the natural form of a-tocopherol (RRR-a-tocopherol) found in these unfortified foods counts toward meeting the RDA. Other non-a-tocopherol forms of vitamin E present in food do not. It is important to note that because vitamin E is generally found in fat- containing foods and is more easily absorbed from fat-containing meals, in- takes of vitamin E by people who consume low-fat diets may be less than opti- mal unless food choices are carefully made to enhance vitamin E intake.

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 240 Estimating a-tocopherol content of foods and diets: As discussed, many data- bases of nutrient content and many food-intake surveys list vitamin E in the form of a-tocopherol equivalents (a-TE) rather than a-tocopherol. To estimate a-tocopherol content, multiply the number of a-tocopherol equivalents by a factor of 0.8: mg of a-tocopherol in a meal = mg of a-TEs in a meal ¥ 0.8 Dietary Supplements Vitamin E supplement use appears to be high in the U.S. population. Data from the Boston Nutritional Status Survey (1981–1984) on adults aged 60 years and older found that 38 percent of men took dietary supplements and, of them, 68 percent took a vitamin E supplement. Of the women surveyed, 49 percent used supplements, and 73 percent of them took a vitamin E supplement. In the 1986 NHIS, 26 percent of all adults reported using supplements that contained vitamin E. Converting IUs to mg of a-tocopherol: To determine the milligrams of a-toco- pherol in a dietary supplement labeled in international units (IUs), one of two conversion factors may be used: • If the form of the supplemental vitamin E is naturally occurring or RRR- a-tocopherol (which has been historically and incorrectly labeled as d- a-tocopherol), the correct factor is 0.67 mg/IU. Thus, 30 IUs of RRR-a- tocopherol (labeled as d-a-tocopherol) in a multivitamin supplement would equate to 20 mg of a-tocopherol (30 ¥ 0.67). The same factor is used for 30 IUs of either RRR-a-tocopherol acetate or RRR-a-tocopherol succinate because the amount in grams of these forms in a capsule has been adjusted based on their molecular weight. Mg of a-tocopherol in food, fortified food, or multivitamin = IU of the RRR-a-tocopherol compound ¥ 0.67 • If the form of the supplement is all-rac-a-tocopherol (historically and incorrectly labeled as dl-a-tocopherol), the appropriate factor is 0.45 mg/IU. (This reflects the inactivity of the 2S-stereoisomers.) Thus, 30 IU of all-rac-a-tocopherol (labeled as dl-a-tocopherol) in a multivita- min supplement would equate to 13.5 mg of a-tocopherol (30 ¥ 0.45). The same factor is used for the all-rac-a-tocopherol acetate and succi- nate forms. Mg of a-tocopherol in food, fortified food, or multivitamin = IU of the all-rac-a-tocopherol compound ¥ 0.45

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PART III: VITAMIN E 241 See Appendix F on conversion factors on converting IUs of vitamin E to a-tocopherol. Bioavailability Because vitamin E is a fat-soluble nutrient, its absorption is enhanced when it is consumed in a meal that contains fat; however, the optimal amount of fat to enhance absorption has not been reported. This is probably more of a consider- ation for people who take vitamin E in supplement form, rather than for those who consume it from foods, since most dietary vitamin E is found in foods that contain fat. Dietary Interactions There is evidence that vitamin E may interact with certain dietary substances (see Table 3). TABLE 3 Potential Interactions with Other Dietary Substances Substance Potential Interaction Notes SUBSTANCES THAT AFFECT VITAMIN E Polyunsaturated Vitamin E requirements may High PUFA intakes should be accompanied fatty acids (PUFAs) increase when intakes of by increased vitamin E intakes. PUFAs are increased. INADEQUATE INTAKE AND DEFICIENCY Vitamin E deficiency is very rare; overt symptoms of deficiency in healthy indi- viduals consuming diets low in vitamin E have never been described. Vitamin E deficiency occurs only as a result of genetic abnormalities of vitamin E metabo- lism, fat malabsorption syndromes, or protein-energy malnutrition. The signs and symptoms of deficiency include the following: • Peripheral neuropathy (primary symptom) • Spinocerebellar ataxia • Skeletal myopathy • Pigmented retinopathy • Increased erythrocyte fragility • Increased ethane and pentane production

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 242 EXCESS INTAKE There is no evidence of adverse effects from the excess consumption of vita- min E naturally occurring in foods. With regard to supplemental vitamin E intake in the form of synthetic α-tocopherol (as a supplement, food fortificant, or pharmacological agent), most studies in humans showing the safety of vita- min E were conducted in small groups of individuals who received supple- mental amounts of 3,200 mg/day or less (usually less than 2,000 mg/day) of α-tocopherol for periods of a few weeks to a few months Thus, the possible chronic effects of longer exposure to high supplemental levels of α-tocopherol remain uncertain and some caution must be exercised in judgments regarding the safety of supplemental doses of α-tocopherol over multiyear periods. The potential adverse effects of excess vitamin E intake include hemorrhagic toxic- ity and diminished blood coagulation in individuals who are deficient in vita- min K or on anticoagulant therapy. Special Considerations Premature infants: Hemolytic anemia due to vitamin E deficiency is of frequent concern in premature infants. However, its management via vitamin E supple- mentation must be carefully controlled because small premature infants are particularly vulnerable to the toxic effects of α-tocopherol.

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PART III: VITAMIN E 243 KEY POINTS FOR VITAMIN E Vitamin E (a-tocopherol) is a fat-soluble nutrient that functions 3 as a chain-breaking antioxidant in the body by preventing the spread of free-radical reactions. The adult requirements for vitamin E are based on prevention 3 of hydrogen peroxide–induced hemolysis. The UL is based on the adverse effect of increased tendency to hemorrhage. The EAR, RDA, and AI values for vitamin E apply only to intake 3 of the 2R-stereoisomeric forms of a-tocopherol from food, fortified foods, and supplements. The UL applies to any form of supplemental a-tocopherol because all are absorbed; these forms of synthetic vitamin E are almost exclusively used in supplements, food fortification, and pharmacological agents. Food sources of vitamin E include vegetable oils and spreads, 3 unprocessed cereal grains, nuts, fruits, vegetables, and meats (especially the fatty portion). Vitamin E deficiency is very rare in the United States and 3 Canada, generally occurring only as the result of genetic abnormalities of vitamin E metabolism, fat malabsorption syndromes, or protein-energy malnutrition. The primary effect of vitamin E deficiency is peripheral neuropathy. There is no evidence of adverse effects from the consumption 3 of vitamin E naturally occurring in foods. The primary known adverse effect resulting from excessive 3 supplemental vitamin E intake is hemorrhagic toxicity.