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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline 8 Folate SUMMARY Folate functions as a coenzyme in single-carbon transfers in the metabolism of nucleic and amino acids. The primary indicator used to estimate the Recommended Dietary Allowance (RDA) for folate is erythrocyte folate in conjunction with plasma homocysteine and folate concentrations. The RDA for both men and women is 400 µg/day of dietary folate equivalents (DFEs). DFEs adjust for the nearly 50 percent lower bioavailability of food folate compared with that of folic acid: 1 µg of dietary folate equivalent = 0.6 µg of folic acid from fortified food or as a supplement taken with meals = 1 µg of food folate = 0.5 µg of a supplement taken on an empty stomach. To reduce the risk of neural tube defects for women capable of becoming pregnant, the recommendation is to take 400 µg of folic acid daily from fortified foods, supplements, or both in addition to consuming food folate from a varied diet. The evidence available on the role of folate in reducing the risk of vascular disease, cancer, and psychiatric and mental disorders is not sufficiently conclusive to use risk reduction of these conditions as a basis for setting the Estimated Average Requirement (EAR) and the RDA. In the U.S. adult population from 1988 to 1994, which was before cereal grains were fortified with folate, the reported median intake of folate from food was approximately 250 µg/day, but this value underestimates current intake. The ninety-fifth percentile of intake from food and supplements was close to 900 µg/day overall
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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline and nearly 1,700 µg/day for pregnant women. After the fortification of cereal grains with folate—which became mandatory for enriched grains in the United States as of January 1, 1998, and is now authorized in Canada—average intake of folate is expected to increase by about 80 to 100 µg/day for women and by more for men. The Tolerable Upper Intake Level (UL) for adults is set at 1,000 µg/day of folate from fortified food or as a supplement, exclusive of food folate. BACKGROUND INFORMATION Folate is a generic term for this water-soluble B-complex vitamin, which functions in single-carbon transfer reactions and exists in many chemical forms (Wagner, 1996). Folic acid (pteroylmonoglutamic acid), which is the most oxidized and stable form of folate, occurs rarely in food but is the form used in vitamin supplements and in fortified food products. Folic acid consists of a p-aminobenzoic acid molecule linked at one end to a pteridine ring and at the other end to one glutamic acid molecule. Most naturally occurring folates, called food folate in this report, are pteroylpolyglutamates, which contain one to six additional glutamate molecules joined in a peptide linkage to the γ-carboxyl of glutamate. Function The folate coenzymes are involved in numerous reactions that involve (1) deoxyribonucleic acid (DNA) synthesis, which depends on a folate coenzyme for pyrimidine nucleotide biosynthesis (methylation of deoxyuridylic acid to thymidylic acid) and thus is required for normal cell division; (2) purine synthesis (formation of glycinamide ribonucleotide and 5-amino-4-imidazole carboxamide ribonucleotide); (3) generation of formate into the formate pool (and utilization of formate); and (4) amino acid interconversions, including the catabolism of histidine to glutamic acid, interconversion of serine and glycine, and conversion of homocysteine to methionine. Folate-mediated transfer of single-carbon units from serine provides a major source of substrate in single-carbon metabolism. The conversion of homocysteine to methionine serves as a major source of methionine for the synthesis of S-adenosyl-methionine, an important in vivo methylating agent (Wagner, 1996).
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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Physiology of Absorption, Metabolism, and Excretion Absorption, Transport, and Storage Food folates (polyglutamate derivatives) are hydrolyzed to monoglutamate forms in the gut before absorption across the intestinal mucosa. This cleavage is accomplished by a γ-glutamylhydrolase, more commonly called folate conjugase. The monoglutamate form of folate is actively transported across the proximal small intestine by a saturable pH-dependent process. When pharmacological doses of the monoglutamate form of folate are consumed, it is also absorbed by a nonsaturable mechanism involving passive diffusion. Monoglutamates, mainly 5-methyl-tetrahydrofolate, are present in the portal circulation. Much of this folate can be taken up by the liver, where it is metabolized to polyglutamate derivatives and retained or released into the blood or bile. Approximately two-thirds of the folate in plasma is protein bound. A variable proportion of plasma folate is bound to low-affinity protein binders, primarily albumin, which accounts for about 50 percent of bound folate. Low levels of high-affinity folate binders are also present in plasma. Cellular transport of folate is mediated by a number of different folate transport systems, which can be characterized as either membrane carriers or folate-binding protein-mediated systems. These transport systems are not saturated by folate under physiological conditions, and folate influx into tissues would be expected after any elevation in plasma folate after supplementation. Folate concentrations in liver of 4.5 to 10 µg/g were reported after liver biopsies (Whitehead, 1973). Because the adult male liver weighs approximately 1,400 g, the total quantity of folate in the liver would be approximately 6 to 14 mg. If the liver is assumed to contain 50 percent of the body stores of folate, the estimated total body folate store would be 12 to 28 mg. Using the same assumption, Hoppner and Lampi (1980) determined average liver folate concentrations to be approximately 8 µg/g (range 3.6 to 14.8 µg/g) after autopsy; the liver folate content would be approximately 11 mg and total body folate 22 mg. Metabolism and Excretion Before being stored in tissue or used as a coenzyme, folate monoglutamate is converted to the polyglutamate form by the enzyme folylpolyglutamate synthetase. When released from tissues into circulation, folate polyglutamates are reconverted to the mono-
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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline glutamate form by γ-glutamylhydrolase. Folates must be reduced enzymatically and resynthesized to the polyglutamate form to function in single-carbon transfer reactions. The metabolic interrelationship between folate and vitamin B12 may explain why a single deficiency of either vitamin leads to the same hematological changes. Both folate and vitamin B12 are required for the formation of 5,10-methylenetetrahydrofolate and involved in thymidylate synthesis by way of a vitamin B12-containing enzyme. The formation of 5,10-methylene tetrahydrofolate depends on the regeneration of the parent compound (tetrahydrofolate) in the homocysteine-to-methionine conversion. This reaction involves the removal of a methyl group from methyl folate and the delivery of this group to homocysteine for the synthesis of methionine. Folate is involved as a substrate (5-methyl-tetrahydrofolate) and vitamin B12 as a coenzyme. The 5,10-methylenetetrahydrofolate delivers its methyl group to deoxyuridylate to convert it to thymidylate for incorporation into DNA. In either a folate or vitamin B12 deficiency, the megaloblastic changes occurring in the bone marrow and other replicating cells result from lack of adequate 5,10-methylene-tetrahydrofolate. The major route of whole-body folate turnover appears to be via catabolism to cleavage products. The initial step in folate catabolism involves the cleavage of intracellular folylpolyglutmate at the C9-N10 bond, and the resulting p-aminobenzoylpolyglutamates are hydrolyzed to the monoglutamate, which is N-acetylated before excretion. Folate freely enters the glomerulus and is reabsorbed in the proximal renal tubule. The net effect is that most of the secreted folate is reabsorbed. The bulk of the excretion products in humans are folate cleavage products. Intact urinary folate represents only a very small percentage of dietary folate. Biliary excretion of folate has been estimated to be as high as 100 µg/day (Herbert and Das, 1993; Whitehead, 1986); however, much of this is reabsorbed by the small intestine (Weir et al., 1985). Fecal folate losses occur, but it is difficult to distinguish actual losses from losses of folate synthesized by the intestinal microflora (Krumdieck et al., 1978). Clinical Effects of Inadequate Intake 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 tissues with rapidly dividing cells.
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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Within weeks of the development of early morphological abnormalities in the marrow, subtle changes appear in the peripheral blood (Eichner et al., 1971) when hypersegmentation of the neutrophils becomes apparent. The peripheral blood picture is variable before the development of a clearly increased mean cell volume or anemia (Lindenbaum et al., 1988). In some deficient individuals, macrocytes and macroovalocytes are seen on blood smears, but in others the erythrocytes may show only minimal anisocytosis or no abnormalities. When folate supply to the bone marrow becomes rate limiting for erythropoiesis, macrocytic cells are produced. However, because of the 120-day lifespan of normal erythrocytes, macrocytosis is not evident in the early stages of folate-deficient megaloblastosis. As folate depletion progresses further, the mean cell volume increases above normal. Neutrophil hypersegmentation (defined as more than 5 percent five-lobed or any six-lobed cells per 100 granulocytes) is typically present in the peripheral blood at this stage of macrocytosis and the neutrophil lobe average is elevated. Macrocytic anemia then develops, as first evidenced by a depression of the erythrocyte count. Eventually, all three measures of anemia (hematocrit, hemoglobin concentration, and erythrocyte concentration) are depressed. At this point, macroovalocytes and macrocytes are usually detectable in the peripheral blood, and hypersegmentation is more impressive (Lindenbaum et al., 1988). Because the onset of anemia is usually gradual, compensating cardiopulmonary and biochemical mechanisms provide adaptive adjustments to the diminished oxygen-carrying capacity of the blood until anemia is moderate to severe. Symptoms of weakness, fatigue, difficulty concentrating, irritability, headache, palpitations, and shortness of breath therefore typically appear at an advanced stage of anemia. They may be seen at milder degrees of anemia in some patients, especially the elderly (Lindenbaum et al., 1988). Atrophic glossitis may also occur (Savage et al., 1994). SELECTION OF INDICATORS FOR ESTIMATING THE REQUIREMENT FOR FOLATE The primary indicator selected to determine folate adequacy is erythrocyte folate, which reflects tissue folate stores, as described in detail below. For some life stage or gender groups, this is used in conjunction with plasma homocysteine (which reflects the extent of the conversion of homocysteine to methionine) and plasma or serum folate. Other indicators are discussed briefly below; risk reduc-
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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline tion of chronic disease or developmental abnormalities is covered in detail in a later section. Erythrocyte Folate Because folate is taken up only by the developing erythrocyte in the bone marrow and not by the circulating mature erythrocyte during its 120-day lifespan, erythrocyte folate concentration is an indicator of long-term status. Erythrocyte folate concentration was shown to be related to tissue stores by its correlation, although weak, with liver folate concentration determined by biopsy in the same individual in a study of 45 subjects (Wu et al., 1975). Erythrocyte folate concentration does not reflect recent or transient changes in dietary folate intake. A value of 305 nmol/L (140 ng/mL) of folate was chosen as the cutoff point for adequate folate status on the basis of the following experiments: On a diet containing only 5 µg/day of folate, the appearance of hypersegmented neutrophils in the peripheral blood of one subject coincided with the approximate time when the erythrocyte folate concentration decreased to less than 305 nmol/L (140 ng/mL) (Herbert, 1962a). On a diet containing less than 20 µg/day of folate, the appearance of hypersegmented neutrophils in two subjects preceded the reduction in erythrocyte folate to concentrations below 305 nmol/L (140 ng/mL) by about 2 weeks (Eichner et al., 1971). In a group of 40 patients with megaloblastic anemia caused by folate deficiency, 100 percent had erythrocyte folate values less than 305 nmol/L (140 ng/mL); values were the lowest in the most anemic subjects and the highest mean lobe counts occurred in the subjects with the lowest erythrocyte folate concentrations (Hoffbrand et al., 1966). All 238 pregnant women with erythrocyte folate concentrations below 327 nmol/L (150 ng/mL) were found to have megaloblastic marrow (Varadi et al., 1966). Eight subjects with erythrocyte folate of less than 305 nmol/L (140 ng/mL) had eight- to ninefold greater incorporation of uracil into DNA than did 14 control subjects and had a threefold increase in frequency of cellular micronuclei (a measure of DNA and chromosome damage); folate supplementation reduced the abnormalities (Blount et al., 1997). Plasma Homocysteine In this report, plasma homocysteine concentration refers to total homocysteine concentration. Plasma homocysteine concentration increases when inadequate quantities of folate are available to do-
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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline nate the methyl group that is required to convert homocysteine to methionine. Controlled metabolic and epidemiological studies provide evidence that plasma homocysteine rises with reductions in blood folate indices. Different cutoff values have been used by various investigators to define elevated homocysteine concentrations. The cutoff value for plasma homocysteine cited most often is greater than 16 µmol/L, but 14 µmol/L (Selhub et al., 1993) and 12 µmol/L (Rasmussen et al., 1996) have also been used. Ubbink and coworkers (1995a) used a prediction model to define a reference range as 4.9 to 11.7 µmol/L. Other investigators have proposed age-and gender-specific reference intervals (Rasmussen et al., 1996). Many investigators have reported that plasma homocysteine is significantly elevated in individuals who have been diagnosed as folate deficient on the basis of established serum folate, plasma folate, or erythrocyte folate norms (Allen et al., 1993; Chadefaux et al., 1994; Curtis et al., 1994; Kang et al., 1987; Savage et al., 1994; Stabler et al., 1988; Ubbink et al., 1993). The evidence supporting the use of homocysteine as an ancillary indicator of folate status is summarized as follows: In 10 young men, folate depletion led to a rise in plasma homocysteine and a decrease in plasma folate (Jacob et al., 1994). In young women, a folate intake equivalent to 320 µg/day of dietary folate equivalents was associated with elevated plasma homocysteine (greater than 14 µmol/L); at this level of intake plasma homocysteine concentrations were inversely associated with erythrocyte and serum folate concentrations (O’Keefe et al., 1995). In a cross-sectional analysis involving elderly individuals, plasma homocysteine exhibited a strong inverse association with plasma folate after age, gender, and intakes of other vitamins were controlled for (Selhub et al., 1993); homocysteine values appeared to plateau at folate intakes greater than approximately 350 to 400 µg/ day. A meta-analysis by Boushey and colleagues (1995) supports the existence of a plateau when adequate folate is consumed. Thus, in studies of different types, a similar inverse relationship between folate intake and plasma homocysteine values is seen for pre- and postmenopausal women, adult men, and the elderly. Ward and colleagues (1997) supplemented each of 30 male subjects with 100, 200, or 400 µg of folate. The men were consuming a regular diet that averaged 281 µg/day of folate. Plasma homocysteine, serum folate, and erythrocyte folate were assessed before, during, and 10 weeks after intervention. Results, expressed as tertiles of
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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline baseline plasma homocysteine, showed significant homocysteine lowering in the top (mean 11 µmol/L) and middle (mean 9 µmol/ L) homocysteine tertiles but not in the bottom tertile (mean 7 µmol/L). All baseline homocysteine values were within the normal range; the highest was 12.3 µmol/L. Of the three folate doses, 200 µg appeared to be as effective as 400 µg whereas 100 µg was less effective at lowering homocysteine. These data suggest that there is a concentration of plasma homocysteine below which folate has no further lowering effect. Maternal hyperhomocysteinemia has been implicated as a risk factor for complications during pregnancy (Burke et al., 1992; Goddijn-Wessel et al., 1996; Rajkovic et al., 1997; Steegers-Theunissen et al., 1992, 1994; Wouters et al., 1993), but the relationship between folate intake and the complications has not been established. Although plasma homocysteine is a sensitive indicator of folate status, it is not a highly specific one: it can be influenced by vitamin B12 status (Stabler et al., 1996), vitamin B6 status (Ubbink et al., 1995a), age (Selhub et al., 1993), gender (Selhub et al., 1993), race (Ubbink et al., 1995b), some genetic abnormalities (e.g., methyltetrahydrofolate reductase deficiency) (Jacques et al., 1996; Malinow et al., 1997), and renal insufficiency (Hultberg et al., 1993). Thus, plasma homocysteine alone is not an acceptable indicator on which to base the folate requirement. Knowledge of the relationships of folate, homocysteine, and risk of vascular disease was judged too weak to use as the basis for deriving the Estimated Average Requirement (EAR) for folate. This topic is described in more detail in “Reducing Risk of Developmental Disorders and Chronic Degenerative Disease.” Serum Folate A serum folate concentration of less than 7 nmol/L (3 ng/mL) indicates negative folate balance at the time the blood sample was drawn (Herbert, 1987). In all the experimental studies of human volunteers subjected to folate deprivation, a decrease in the serum folate concentration, usually occurring within 1 to 3 weeks, was the first event (Eichner and Hillman, 1971; Eichner et al., 1971; Halsted et al., 1973; Herbert 1962a; Sauberlich et al., 1987). This initial period of folate deprivation is followed by weeks or months when the serum folate concentration is low but there is no other evidence of deficiency. The circulating folate concentration may also be depressed in situations in which there is no detectable alteration in
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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline total body folate, such as acute alcohol ingestion (Eichner and Hillman, 1973). In population surveys it is generally assumed that measuring serum folate alone does not differentiate between what may be a transitory reduction in folate intake or chronic folate deficiency accompanied by depleted folate stores and functional changes. Serum or plasma folate is, however, considered a sensitive indicator of dietary folate intake, as illustrated by the report of Jacques and colleagues (1993) in which plasma folate doubled across quartiles of folate intake assessed in a study of 140 people. In a controlled metabolic study, repeated measures over time in the same individual do reflect changes in status. Serum folate concentration may be a worthwhile diagnostic test if used and interpreted correctly in conjunction with other folate status indices (Lindenbaum et al., 1988). Urinary Folate Data from a metabolic study in which graded doses of folate were fed showed that urinary folate is not a sensitive indicator of folate status (Sauberlich et al., 1987). In that study, approximately 1 to 2 percent of dietary folate was excreted intact in the urine; excretion continued even in the face of advanced folate depletion. Other reports indicate that daily folate excretion on a normal diet ranges from 5 to 40 µg/day (Cooperman et al., 1970; Retief, 1969; Tamura and Stokstad, 1973). The major route of whole-body folate turnover is by catabolism and cleavage of the C9-N10 bond producing pteridines and p-amino-benzoylglutamate (pABG) (Krumdieck et al. 1978; Saleh et al., 1982). Before excretion from the body, most pABG is N-acetylated to acetamidobenzoylglutamate (apABG). It is not known whether folate coenzymes are catabolized and excreted or whether they are recycled after metabolic utilization. In a study designed to estimate the folate requirements of pregnant and nonpregnant women, McPartlin and coworkers (1993) quantified the urinary excretion of pABG and apABG as a measure of daily folate utilization. This approach does not take into account endogenous fecal folate loss, which may be substantial (Krumdieck et al., 1978); thus, quantitation of urinary catabolites alone may result in an underestimation of the requirement. Indicators of Hematological Status The appearance of hypersegmented neutrophils, macrocytosis,
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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline and other abnormal hematological findings occurs late in the development of deficiency (see “Clinical Effects of Inadequate Intake”). Thus, hematological findings were not used to derive the EAR. Risk of Neural Tube Defects and of Chronic Degenerative Diseases The role of folate in the prevention of neural tube defects (NTDs) was very carefully considered, but not in the context of setting an EAR. Although the evidence is strong that the risk of having a fetus with an NTD decreases with increasing intake of folate during the periconceptional period (about 1 month before to 1 month after conception), this type of risk reduction was judged inappropriate for use as an indicator for setting the EAR for folate for women of childbearing age. There are several reasons for this. The population at risk is all women capable of becoming pregnant, but only those women who become pregnant would benefit from an intervention aimed at reducing NTD risk. The risk of NTD in the U.S. population is about 1 per 1,000 pregnancies, but the critical period for prevention—the periconceptional period—is very short. The definition of EAR, which indicates that half of the individuals in the population have intakes sufficient to meet a particular criterion, does not accommodate NTD prevention as an appropriate criterion. Because of the importance of this topic, it is covered separately in the later section “Reducing Risk of Developmental Disorders and Chronic Degenerative Disease.” The possible use of criteria involving reduction of risk of vascular disease, certain types of cancer, and psychiatric and mental disorders was also carefully considered. The evidence was not judged sufficient to use prevention of any chronic disease or condition as a criterion for setting the EAR; this evidence is also presented in the section “Reducing Risk of Developmental Disorders and Chronic Degenerative Disease.” METHODOLOGICAL ISSUES Measurement of Blood Folate Values Substantial variation within and across methods was evident from the results of an international comparative study of the analysis of serum and whole-blood folate (Gunter et al., 1996). Results for whole-blood pools were more variable than for serum pools. The authors concluded that folate concentrations measured in one lab-
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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline oratory cannot be compared reliably with those measured in another laboratory without considering interlaboratory differences and that comparing data for different study populations measured by different methods is difficult. The Bio-Rad Quantaphase Radioassay was used for the first 4 years of the Third National Health and Nutrition Examination Survey (NHANES III) (1988–1991). In 1991 it was determined that the Bio-Rad radioassay gave results that were 30 percent too high when external, purified pteroylglutamic acid (PGA) standard solutions were measured. The Bio-Rad assay was then recalibrated by using calibrator solutions of PGA concentrations of 2.3, 5.7, 11, 22.6, and 45 nmol/L (1.0, 2.5, 5.0, 10.0, and 20.0 ng/mL). The net effect of this recalibration was the expected 30 percent reduction in the measured folate concentrations of a sample. An analysis by another expert panel (LSRO/FASEB, 1994) provides further information. The NHANES III laboratory conducted a 19-day comparison study of NHANES III serum and erythrocyte specimens using the original and recalibrated Bio-Rad kits and confirmed the 30 percent reduction. Through the use of a regression equation developed from the comparison study, the correction was applied to the NHANES III data generated with the original assay (LSRO/FASEB, 1994). The NHANES III data (Appendix K) have been corrected for this method problem associated with inappropriate calibration. Data from NHANES III are believed to “provide as accurate and precise an estimation of serum and RBC [red blood cell] folate levels in the United States population as is possible until a definitive method has been developed and [this should be considered] as a stand-alone data set, without applying cutoffs established using other laboratory methods” (E.W.Gunter, Division of Environmental Health Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, personal communication, 1997). Earlier, after NHANES II, similar issues were addressed by a Life Sciences Research Office expert panel (LSRO/FASEB, 1984). Such an effort is even more warranted related to NHANES III because this survey (unlike NHANES II) had been designed to provide an assessment of folate status of the entire U.S. population. Measurement and Reporting of Food Folate It is recognized that food folate composition data contained in currently used databases provide inaccurate estimations of folate intake of the U.S. population. Because of the limitations of tradi-
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