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TABLE 1 Dietary Reference Intakes for Folate by Life Stage Group DRI values (mg /daya) EARb RDAc AId ULe,f males females males females Life stage group NDg 0 through 6 mo 65 7 through 12 mo 80 ND 1 through 3 y 120 120 150 150 300 4 through 8 y 160 160 200 200 400 9 through 13 y 250 250 300 300 600 400h 14 through 18 y 330 330 400 800 400h 19 through 30 y 320 320 400 1,000 400h 31 through 50 y 320 320 400 1,000 51 through 70 y 320 320 400 400 1,000 > 70 y 320 320 400 400 1,000 Pregnancy £ 18 y 600i 520 800 600i 19 through 50 y 520 1,000 Lactation £ 18 y 450 500 800 19 through 50 y 450 500 1,000 a As dietary folate equivalents (DFEs). 1 DFE = 1 mg food folate = 0.6 mg of folic acid from fortified food or as a supplement consumed with food = 0.5 mg of folic acid from a supplement taken on an empty stomach. 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 The UL for folate applies to synthetic forms obtained from supplements, fortified foods, or a combination of the two. g 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. h To reduce risk of neural tube defects, women capable of becoming pregnant should take 400 mg of folic acid daily from fortified foods, supplements, or both, in addition to consuming food folate from a varied diet. i It is assumed that women will continue consuming 400 mg from supplements or fortified food until their pregnancy is confirmed and they enter prenatal care, which ordinarily occurs after the end of the periconceptional period—the critical time for formation of the neural tube.

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PART III: FOLATE 245 FOLATE F olate is a B vitamin that functions as a coenzyme in the metabolism of nucleic and amino acids. Folate is a generic term that includes both the naturally occurring form of the vitamin (food folate or pteroyl- polyglutamates) and the monoglutamate form (folic acid or pteroylmonoglutamic acid), which is used in fortified foods and dietary supplements. The requirements for folate are based on the amount of dietary folate equiva- lents (DFEs, with values adjusted for differences in the absorption of food folate and folic acid) needed to maintain erythrocyte folate. DFEs adjust for the nearly 50 percent lower bioavailability of food folate compared to that of folic acid. The Tolerable Upper Intake Level (UL) is based on the precipitation or exacer- bation of neuropathy in vitamin B12–deficient individuals as the critical end- point and represents total intake from fortified food or dietary supplements. The UL does not include naturally occurring food folate. Although epidemio- logical evidence suggests that folate may protect against vascular disease, can- cer, and mental disorders, the evidence was not sufficient to use risk reduction of these conditions as a basis for setting folate requirements. DRI values are listed by life stage group in Table 1. Rich food sources of folate include fortified grain products, dark green vegetables, and beans and legumes. Chronic inadequate folate intake results in macrocytic anemia. The adverse effect of consuming excess supplemental folate is the onset or progression of neurological complications in people with vita- min B12 deficiency. Excess folate can obscure or mask and thus potentially delay the diagnosis of vitamin B12 deficiency, which can result in an increased risk of progressive, unrecognized neurological damage. To reduce the risk of neural tube defects, women able to become pregnant should take 400 mg of folic acid daily from fortified foods, supplements, or both, in addition to consuming food folate from a varied diet. It is important to note that this recommendation specifically calls for folic acid, which is more bioavailable than food folate. Since foods fortified to a level of 400 mg are not available in Canada, the recommendation is to consume a multivitamin con- taining 400 mg of folic acid every day in addition to the amount of folate in a healthful diet.

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 246 FOLATE AND THE BODY Function Folate is a water-soluble B-complex vitamin that functions as a coenzyme in the metabolism of nucleic and amino acids. The term folate refers to two forms: naturally occurring folates in food, referred to here as food folates (pteroylpolyglutamates), and folic acid (pteroylmonoglutamic acid), which is rarely naturally found in foods but is the form used in dietary supplements and fortified foods. Folic acid is the most stable form of folate. Absorption, Metabolism, Storage, and Excretion Folate is absorbed from the gut across the intestinal mucosa via a saturable, pH- dependent active transport process. When pharmacological doses of folic acid are consumed, it is also absorbed by nonsaturable passive diffusion. Folate is taken up from the portal circulation by the liver, where it is metabolized and retained or released into the blood or bile. Approximately two-thirds of folate in plasma is bound to protein. Some folate is excreted in the urine, bile, and feces. DETERMINING DRIS Determining Requirements The requirements for folate are based on the amount of dietary folate equiva- lents (DFEs) needed to maintain erythrocyte folate; ancillary data on plasma homocysteine and plasma folate concentrations were also considered. DFEs adjust for the nearly 50 percent lower bioavailability of food folate compared with that of folic acid (see “Bioavailability”), such that: 1 DFE = 1 mg food folate = 0.6 mg of folic acid from fortified food or as a supplement consumed with food = 0.5 mg of folic acid from a supplement taken on an empty stomach Currently, nutrition labels do not distinguish between sources of folate (food folate and folic acid) or express the folate content in DFEs. Although epidemio- logical evidence suggests that folate may protect against vascular disease, can- cer, and mental disorders, the evidence was not sufficient to use risk reduction of these conditions as a basis for setting folate requirements.

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PART III: FOLATE 247 Special Considerations Individuals with increased needs: Intakes of folate higher than the RDA may be needed by women who are carrying more than one fetus, mothers nursing more than one infant, individuals with chronic heavy intake of alcohol, and individu- als on chronic anticonvulsant or methotrexate therapy. To reduce the risk of neural tube defects, women able to become pregnant should take 400 mg of folic acid daily from fortified foods, supplements, or both, in addition to consuming food folate from a varied diet. It is important to note that this recommendation specifically calls for folic acid, which is more bioavailable than food folate. Since foods fortified to a level of 400 mg are not available in Canada, the recommendation is to consume a multivitamin con- taining 400 mg of folic acid every day in addition to the amount of folate in a healthful diet. Intake of Folate Currently nutrient databases and nutrition labels do not express the folate con- tent of food in DFEs, which take into account the different bioavailabilities of folate sources. (See Box 1 for information on how DFEs and types of folate are BOX 1 The Relationship Between DFEs and Types of Folate DFEs and types of folate are related as follows: 1 mg of DFEs = 1.0 mg of food folate = 0.6 mg of folate added to foods (as a fortificant or folate supplement with food) = 0.5 mg of folate taken as a supplement (on an empty stomach) 1 mg food folate = 1.0 mg of DFEs 1 mg of folate added as a fortificant or = 1.7 mg of DFEs as a supplement consumed with meals 1 mg of folate supplement taken on an empty stomach = 2.0 mg of DFEs When intakes of folate in an individual’s diet are assessed, it is possible to approximate the DFE intake by estimating the amount present that has been added in fortification and the amount present that naturally occurs as food folate by using the relationship of 1 mg of folate added as a fortificant = 1.7 mg of DFEs (the reciprocal of 1 mg of DFEs = 0.6 mg folate added to food).

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 248 related.) Thus, nutrient intake data substantially underestimates the actual cur- rent intake. This is due to problems associated with analyzing the folate content of food, underreported intake, and the change in U.S. fortification laws insti- tuted in 1998 (see “Dietary Sources” for information on fortification). Criteria for Determining Folate Requirements, by Life Stage Group Life stage group Criterion 0 through 6 mo Human milk content 7 through 12 mo Extrapolation from younger infants and from adults 1 through 18 y Extrapolation from adults 19 through > 70 y Maintenance of normal erythrocyte folate, plasma homocysteine, plasma or serum folate Pregnancy £ 18 y through 50 y Maintenance of normal erythrocyte and serum folate levels Lactation £ 18 y through 50 y Folate intake necessary to replace folate secreted in human milk + folate needed to maintain folate status 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 folate is from fortified foods or dietary supplements, or both. The UL does not include naturally occurring food folate and is based on the precipitation or exacerbation of neuropathy in vitamin B12–deficient indi- viduals as the critical endpoint. It has been recognized that excessive intake of folate supplements may obscure or mask and potentially delay the diagnosis of vitamin B12 deficiency. The intake of folate in the United States is currently higher than indicated by the National Health and Nutrition Examination Survey (NHANES III, 1988– 1994) because enriched cereal grains in the U.S. food supply, to which no folate was added previously, are now fortified with folate at 140 mg/100 g of cereal grain. The Food and Drug Administration (FDA) estimated that those who fol- low the guidance of the U.S. Food Guide Pyramid (1992) and consume cereal grains at the upper end of the recommended range might obtain an additional 440 mg/day of folate under the U.S. fortification regulations. Using this estimate and with the assumption of regular use of an over-the-counter supplement (400

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PART III: FOLATE 249 mg per dose), it is unlikely that the intake of folate would regularly exceed 1,000 mg/day for members of any life stage or gender group. Special Considerations Individuals at increased risk: People who are at risk of vitamin B12 deficiency include those who follow a vegan diet, older adults with atrophic gastritis, and those with pernicious anemia and bacterial overgrowth of the gut. These indi- viduals may place themselves at an increased risk of neurological disorders if they consume excess folate because folate may mask vitamin B12 deficiency. Females of childbearing age: In general, the prevalence of vitamin B12 defi- ciency in women of the childbearing years is very low and the consumption of supplemental folate at or above the UL in this subgroup is unlikely to produce adverse effects. DIETARY SOURCES Foods Rich food sources of folate include fortified grain products, dark green veg- etables, and beans and legumes. According to data from the Continuing Survey of Food Intakes by Individuals (CSFII, 1994–1996), the greatest contribution to folate intake in U.S. adults came from fortified ready-to-eat cereals and a category called “other vegetables.” This category includes vegetables such as green beans, green peas, lettuces, cabbages, and vegetable soups. Many of the vegetables in the “other vegetables” category have lower folate content than dark green vegetables, but are so commonly eaten that their contribution to total folate intake is relatively high compared to other sources such as citrus juices and legumes. During the period when data were collected for CSFII (1994–1996), the only grain products fortified with folate were mainly hot and cold breakfast cereals. However, as of January 1, 1998, in the United States, all enriched cereal grains, such as bread, pasta, flour, breakfast cereal, and rice, are required to be fortified with folic acid at 1.4 mg/kg of grain. In Canada, the fortification of all white flour and cornmeal with folate is at a level of 1.5 mg/kg and fortification of alimentary paste is at a level of at least 2.0 mg/kg. Because enriched grains are widely consumed in Canada and the United States, these foods are now an important contributor to folate intake. It is estimated that folate fortification will increase the folate intake of most U.S. women by 80 mg/day (136 mg DFE/day) or more. This amount could be provided by 1 cup of pasta plus 1 slice of bread. Depending on the cereal grains

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 250 chosen and the amount consumed, 5 servings daily might add 220 mg/day or more of folate from fortified foods (nearly 400 mg DFE/day) to the diet. Dietary Supplements Folic acid supplements in doses of 400 mg are widely available over the counter. Supplements containing 1,000 mg or more are available by prescription in the United States and Canada. In a nationwide telephone survey conducted by the Centers for Disease Control and Prevention (CDC) during January and February 1997, 43 percent of women of childbearing age reported taking some form of vitamin supple- ment containing folic acid; 32 percent reported taking a folic acid supplement daily and 12 percent reported taking a supplement less frequently. Bioavailability The bioavailability of folate varies, depending on the form of the vitamin in- gested and whether it is consumed with or without food. Folic acid supple- ments taken on an empty stomach are nearly 100 percent bioavailable. No pub- lished information was found regarding the effect of food on the bioavailability of folate supplements. Folate in the form of folic acid added to foods is about 85 percent bioavailable. Naturally occurring food folates are about 50 percent bioavailable. Dietary Interactions There is evidence that folate may interact with certain nutrients, dietary sub- stances, and drugs (see Table 2). INADEQUATE INTAKE AND DEFICIENCY Inadequate folate intake first leads to a decrease in serum folate concentration, then to a decrease in erythrocyte folate concentration, a rise in homocysteine concentration, and megaloblastic changes in the bone marrow and other tis- sues with rapidly dividing cells. These changes ultimately lead to macrocytic anemia, at first evidenced by a low erythrocyte count and eventually by a low hematocrit and hemoglobin, as well. The effects of moderate to severe macro- cytic anemia may include the following: • Weakness • Fatigue • Difficulty in concentrating • Irritability

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PART III: FOLATE 251 TABLE 2 Potential Interactions with Other Dietary Substances Substance Potential Interaction Notes SUBSTANCES THAT AFFECT FOLATE Alcohol Inadequate folate intake Ethanol intake may aggravate folate deficiency in people with chronic by impairing intestinal folate absorption and alcoholism leads to hepatobiliary metabolism and by increasing folate deficiency. renal folate excretion. Cigarettes Chronic smoking may Low intake, rather than an increased requirement, lead to folate deficiency. in smokers may account for the poorer folate status of smokers. Nonsteroidal Very large therapeutic Routine use of low doses of these drugs has not anti- doses (e.g., 3,900 mg/day) been reported to impair folate status. inflammatory of NSAIDS may exert drugs antifolate activity. (NSAIDS): aspirin, ibuprofen, and acetaminophen Anticonvulsant Chronic use of anti- Few studies have controlled for folate intake drugs convulsant drugs, such between groups of anticonvulsant users. as diphenylhydantoin and Therefore, definitive conclusions could not be phenobarbital, may impair drawn regarding the potential adverse effects folate status. of these drugs on folate status. Methotrexate Chronic methotrexate It has been recommended that patients undergoing therapy may impair folate chronic methotrexate therapy for rheumatoid status. arthritis increase their folate consumption or consider folate supplements (1 mg/day). Other drugs Pyrimethamine (for malaria), with antifolate trimethoprim (for bacterial activity infections), triamterene (for hypertension), trimetrexate (for Pneumocystis carinii infection), and sulfasalazine (for chronic ulcerative colitis) have been shown to exert antifolate activity.

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 252 • Headache • Palpitations • Shortness of breath • Atrophic glossitis Special Considerations Coexisting deficiencies: Coexisting iron or vitamin B12 deficiencies may interfere with the diagnosis of folate deficiency. In contrast to folate deficiency, iron defi- ciency leads to a decrease in mean cell volume. When there is a deficiency of both iron and folate, the interpretation of hematological changes may be un- clear. A vitamin B12 deficiency results in the same hematological changes that occur with folate deficiency because the vitamin B12 deficiency results in a sec- ondary folate deficiency. EXCESS INTAKE No adverse effects have been associated with the excess consumption of the amounts of folate normally found in fortified foods. The adverse effect that may result from excess intake of supplemental folate is the onset or progression of neurological complications in people with vitamin B12 deficiency. Excess folate may obscure or mask and thus potentially delay the diagnosis of vitamin B12 deficiency, which can result in an increased risk of progressive, unrecognized neurological damage. KEY POINTS FOR FOLATE Folate is a B vitamin that functions as a coenzyme in the 3 metabolism of nucleic and amino acids. Folate is a generic term that includes both the naturally 3 occurring form of the vitamin (food folate) and the monoglutamate form (folic acid), which is used in fortified foods and dietary supplements. The requirements for folate are based on the amount of DFEs 3 needed to maintain erythrocyte folate; plasma homocysteine and plasma folate concentrations were also considered. The UL is based on precipitation or exacerbation of neuropathy in vitamin B12–deficient individuals as the critical endpoint. Although epidemiological evidence suggests that folate may 3 protect against vascular disease, cancer, and mental disorders, the evidence was not sufficient to use risk reduction of these conditions as a basis for setting folate requirements.

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PART III: FOLATE 253 DFEs adjust for the nearly 50 percent lower bioavailability of 3 food folate compared with that of folic acid, such that 1 DFE = 1 mg food folate = 0.6 mg of folic acid from fortified food or as a supplement consumed with food = 0.5 mg of folic acid from a supplement taken on an empty stomach. The UL for adults is from fortified foods or supplements. The 3 UL does not include naturally occurring food folate. To reduce the risk of neural tube defects, women able to 3 become pregnant should take 400 mg of folic acid daily from fortified foods, supplements, or both, in addition to consuming food folate from a varied diet. It is important to note that this recommendation specifically calls for folic acid, which is more bioavailable than food folate. Rich food sources of folate include fortified grain products, 3 dark green vegetables, and beans and legumes. Chronic inadequate folate intake results in macrocytic anemia. 3 Coexisting iron or vitamin B12 deficiency may interfere with the 3 diagnosis of folate deficiency. No adverse effects have been associated with the excess 3 consumption of the amounts of folate normally found in fortified foods. The adverse effect that may result from excess intake of 3 supplemental folate is the onset or progression of neurological complications in people with vitamin B12 deficiency. Excess folate can obscure or mask and thus potentially delay the diagnosis of vitamin B12 deficiency, which can result in an increased risk of progressive, unrecognized neurological damage.