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5
Riboflavin

SUMMARY

Riboflavin functions as a coenzyme in numerous redox reactions. A combination of criteria is used to estimate the Recommended Dietary Allowance (RDA) for riboflavin, including the erythrocyte glutathione reductase activity coefficient and urinary riboflavin excretion. The RDA for riboflavin for adults is 1.3 mg/day for men and 1.1 mg/day for women. Recently, the median intake of riboflavin from food in the United States and two Canadian populations was estimated to be approximately 2 mg/day for men and 1.5 mg/day for women. The ninety-fifth percentile of U.S. intake from both food and supplements ranged from 4 to 10 mg/day. The evidence on adverse effects is not sufficient to set a Tolerable Upper Intake Level (UL) for riboflavin.

BACKGROUND INFORMATION

Subsequent to the discovery of thiamin was the discovery of a more heat-stable factor that was named vitamin B2, or riboflavin. Riboflavin is a water-soluble, yellow, fluorescent compound. The primary form of the vitamin is as an integral component of the coenzymes flavin mononucleotide (FMN) and flavin-adenine dinucleotide (FAD) (McCormick, 1994; McCormick and Greene, 1994; Merrill et al., 1981). It is in these bound coenzyme forms that riboflavin functions as a catalyst for redox reactions in numerous



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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline 5 Riboflavin SUMMARY Riboflavin functions as a coenzyme in numerous redox reactions. A combination of criteria is used to estimate the Recommended Dietary Allowance (RDA) for riboflavin, including the erythrocyte glutathione reductase activity coefficient and urinary riboflavin excretion. The RDA for riboflavin for adults is 1.3 mg/day for men and 1.1 mg/day for women. Recently, the median intake of riboflavin from food in the United States and two Canadian populations was estimated to be approximately 2 mg/day for men and 1.5 mg/day for women. The ninety-fifth percentile of U.S. intake from both food and supplements ranged from 4 to 10 mg/day. The evidence on adverse effects is not sufficient to set a Tolerable Upper Intake Level (UL) for riboflavin. BACKGROUND INFORMATION Subsequent to the discovery of thiamin was the discovery of a more heat-stable factor that was named vitamin B2, or riboflavin. Riboflavin is a water-soluble, yellow, fluorescent compound. The primary form of the vitamin is as an integral component of the coenzymes flavin mononucleotide (FMN) and flavin-adenine dinucleotide (FAD) (McCormick, 1994; McCormick and Greene, 1994; Merrill et al., 1981). It is in these bound coenzyme forms that riboflavin functions as a catalyst for redox reactions in numerous

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline metabolic pathways and in energy production (McCormick and Greene, 1994). Function The redox reactions in which flavocoenzymes participate include flavoprotein-catalyzed dehydrogenations that are both pyridine nucleotide (niacin) dependent and independent, reactions with sulfur-containing compounds, hydroxylations, oxidative decarboxylations (involving thiamin as its pyrophosphate), dioxygenations, and reduction of oxygen to hydrogen peroxide (McCormick and Greene, 1994). There are obligatory roles of flavocoenzymes in the formation of some vitamins and their coenzymes. For example, the biosynthesis of two niacin-containing coenzymes from tryptophan occurs via FAD-dependent kynurenine hydroxylase, an FMN-dependent oxidase catalyzes the conversion of the 5'-phosphates of vitamin B6 to coenzymic pyridoxal 5'-phosphate, and an FAD-dependent dehydrogenase reduces 5,10-methylene-tetrahydrofolate to the 5'-methyl product that interfaces with the B12-dependent formation of methionine from homocysteine and thus with sulfur amino acid metabolism. Physiology of Absorption, Metabolism, and Excretion Absorption Most dietary riboflavin is consumed as a complex of food protein with FMN and FAD (Merrill et al., 1981; Nichoalds, 1981). In the stomach, gastric acidification releases most of the coenzyme forms of riboflavin (FAD and FMN) from the protein. The noncovalently bound coenzymes are then hydrolyzed to riboflavin by nonspecific pyrophosphatases and phosphatases in the upper gut (McCormick, 1994; Merrill et al., 1981). Primary absorption of riboflavin occurs in the proximal small intestine via a rapid, saturable transport system (McCormick, 1994; Merrill et al., 1981). The rate of absorption is proportional to intake, and it increases when riboflavin is ingested along with other foods (Jusko and Levy, 1967, 1975) and in the presence of bile salts (Jusko and Levy, 1975; Mayersohn et al., 1969). A small amount of riboflavin circulates via the enterohepatic system (McCormick, 1994). At low intake levels most absorption of riboflavin is via an active or facilitated transport system. Although older studies in animals (Daniel et al., 1983; Meinen et al., 1977; Rivier, 1973) suggested

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline that this transport may depend on sodium ions, more recent work in humans (Said and Ma, 1994) indicates that uptake is independent of sodium ions. A small amount of riboflavin is absorbed in the large intestine (Sorrell et al., 1971). In plasma some riboflavin is complexed with albumin; however, a large portion of riboflavin associates with other proteins, mainly immunoglobulins, for transport (Innis et al., 1985). Pregnancy increases the level of carrier proteins available for riboflavin (Natraj et al., 1988). This results in a higher rate of riboflavin uptake at the maternal surface of the placenta (Dancis et al., 1988). At physiological concentrations the uptake of riboflavin into the cells of organs such as the liver is facilitated and may require specific carriers. At higher levels of intake, riboflavin can be absorbed by diffusion (Bowman et al., 1989; McCormick, 1989). Metabolism The metabolism of riboflavin is a tightly controlled process that depends on the riboflavin status of the individual (Lee and McCormick, 1983). Riboflavin is converted to coenzymes within the cellular cytoplasm of most tissues but mainly in the small intestine, liver, heart, and kidney (Brown, 1990; Darby, 1981). The metabolism of riboflavin begins with the adenosine triphosphate (ATP)-dependent phosphorylation of the vitamin to FMN. Flavokinase, the catalyst for this conversion, is under hormonal control. FMN can then be complexed with specific apoenzymes to form a variety of flavoproteins; however, most is converted to FAD by FAD synthetase. As a result, FAD is the predominant flavocoenzyme in body tissues (McCormick and Greene, 1994). Production of FAD is controlled by product inhibition such that an excess of FAD inhibits its further production (Yamada et al., 1990). Excretion When riboflavin is absorbed in excess, very little is stored in the body tissues. The excess is excreted, primarily in the urine. A wide variety of flavin-related products have been identified in the urine of humans. In healthy adults consuming well-balanced diets, riboflavin accounts for 60 to 70 percent of the excreted urinary flavins (McCormick, 1989). Urinary excretion of riboflavin varies with intake, metabolic events, and age (McCormick, 1994). In newborns, urinary excretion is slow (Jusko and Levy, 1975; Jusko et al., 1970);

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline however, the cumulative amount excreted is similar to the amount excreted by older infants. Clinical Effects of Inadequate Intake Clinical Signs of Deficiency The signs of riboflavin deficiency (ariboflavinosis) in humans are sore throat; hyperemia and edema of the pharyngeal and oral mucous membranes; cheilosis; angular stomatitis; glossitis (magenta tongue); seborrheic dermatitis; and normochromic, normocytic anemia associated with pure erythrocyte cytoplasia of the bone marrow (Wilson, 1983). Riboflavin deficiency is most often accompanied by other nutrient deficiencies. Severe riboflavin deficiency may impair the metabolism of vitamin B6 by limiting the amount of FMN required by pyridoxine (pyridoxamine) 5-phosphate oxidase and the conversion of tryptophan to functional forms of niacin (McCormick, 1989). Prevalence of Deficiency Riboflavin deficiency has been documented in industrialized and developing nations and across various demographic groups (Komindr and Nichoalds, 1980; Nichoalds, 1981). Diseases such as cancer (Rivlin, 1975), cardiac disease (Steier et al., 1976), and diabetes mellitus (Cole et al., 1976; Prager et al., 1958) are known to precipitate or exacerbate riboflavin deficiency. SELECTION OF INDICATORS FOR ESTIMATING THE REQUIREMENT FOR RIBOFLAVIN Several indicators have been used to estimate the adequacy of riboflavin status in humans (McCormick, 1994; McCormick and Greene, 1994). Principal among them are erythrocyte glutathione reductase; erythrocyte flavin concentration; and urinary excretion of the vitamin in fasting, random, or 24-hour specimens or by load tests. Erythrocyte Glutathione Reductase Currently, one of the most commonly used methods for assessing riboflavin status involves the determination of erythrocyte glutathione reductase (EGR) activity, as described by Sauberlich and coworkers

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline (1972). The EGR value is an enzymatic and hence functional indicator that is conventionally determined with and without the addition of flavin-adenine dinucleotide (FAD) —the coenzyme required for the activity of EGR. Results are expressed as an activity coefficient (EGRAC), which is the ratio of activities in the presence of added FAD and without its addition. An EGRAC ratio of 1.0 indicates no stimulation by FAD and the presence of holoenzyme only, which means that more than adequate amounts of FAD (and riboflavin) were present in the original erythrocytes. Suggested guidelines for interpreting such coefficients are as follows: less than 1.2, acceptable; 1.2 to 1.4, low; and greater than 1.4, deficient (McCormick and Greene, 1994). However, many different cutoff values have been used by investigators. An upper limit of normality has been set at 1.34 based on the mean plus 2 standard deviations of the EGRAC value of several hundred apparently healthy elderly individuals aged 60 years and older (Sadowski, 1992). Because FAD is a labile compound, the EGRAC must be obtained by using fresh erythrocytes that are washed, lysed, and measured promptly for enzymatic activity (McCormick and Greene, 1994). Because the glutathione reductase in the erythrocytes of individuals with glucose 6-phosphate dehydrogenase deficiency has an increased avidity for FAD (Nichoalds, 1981), this test is not valid in individuals with that condition. The dehydrogenase deficiency has been estimated to occur in 10 percent of black Americans (Frischer et al., 1973). Erythrocyte Flavin Erythrocyte flavin has been used as an indicator of the cellular concentration of the vitamin in its coenzyme forms because these coenzymes comprise over 90 percent of flavin (Burch et al., 1948). Because of the instability of the predominant FAD, which is rapidly hydrolyzed enzymatically when cells rupture, erythrocyte flavins are deliberately hydrolyzed and measured either microbiologically or fluorometrically as riboflavin. Values greater than 400 nmol/L (15 µg/100 mL) of cells are considered adequate (based on other observations and measurements) and values below 270 nmol/L (10 µg/100 mL) reflect deficiency (e.g., see the study by Ramsay et al. [1983] on the correlation between cord blood and maternal erythrocyte riboflavin deficiencies). Because the margin of difference between adequacy and inadequacy is rather small, there is some concern about the sensitivity and interpretation of results. After mild hydrolysis to convert FAD to the more stable flavin mono-

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline nucleotide (FMN), high-performance liquid chromatography (HPLC) separation leads to a more exact determination of FMN plus traces of riboflavin. This is a useful indicator that reflects the functional, cellularly trapped forms of riboflavin. Urinary Flavin Urinary riboflavin has often been used in metabolic studies to estimate the riboflavin requirement. It can be measured by fluorometric HPLC methods (Chastain and McCormick, 1987; Rough-head and McCormick, 1991) as well as by microbiological procedures. Without Chromatographic separation by HPLC or other means, the fluorometric assessment of the vitamin may lead to incorrectly high values, as was the case in early studies. In some cases, flavin catabolites found in food (such as the 10-formylmethyl- and 2'-hydroxyethyl-flavins found in milk) are a significant fraction of flavin catabolites that comprise as much as one-third of the total assay of urinary flavin. Such dietary flavin catabolites can also interfere with the response of bacteria or even rats used for assay of riboflavin. Additionally, in some cases flavin catabolites such as these can depress the cellular uptake of riboflavin (Aw et al., 1983) or its conversion to coenzymes (McCormick, 1962). As HPLC techniques evolved to allow easier separation of riboflavin from other fluorescent flavin catabolites (such as 7- and 8-hydroxymethylriboflavins [McCormick, 1994]), specific quantitations of the vitamin (which contributes more than two-thirds of the total flavin) were found generally useful to relate the recent dietary intake to urinary output. Under conditions of sufficiency (that is, an average riboflavin intake of approximately 1.5 mg/day), the amount of riboflavin excreted per day exceeded 319 nmol (120 µg) riboflavin (Roughead and McCormick, 1991). The amount of riboflavin excreted per gram of creatinine was greater for children than adults. For adults, a low urinary concentration of riboflavin is considered to be 50 to 72 nmol/g (19 to 27 µg/g) creatinine and a deficient concentration to be below 50 nmol/g (19 µg/g) creatinine. Sauberlich and colleagues (1974), reviewing the literature based on fluorometric methods without HPLC, suggested that riboflavin values less than 72 nmol/g (27 µg/g) creatinine be considered deficient, 72 to 210 nmol/g (27 to 79 µg/g) creatinine be considered low, and greater than 213 nmol/g (80 µg/g) creatinine be considered acceptable. Compared with the fluorometric method alone, the HPLC method with fluorometry tends to give lower values because riboflavin is separated from other flavins (Smith, 1980).

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Load tests may be used to gauge the degree to which the body is saturated with riboflavin; the result generally agrees with tests using other indicators. Subcutaneous administration of 1 mg of riboflavin followed by assessment of urinary flavin output for a 4-hour period was found by Horwitt et al. (1950) to correspond well to riboflavin excretion over 24 hours. A break point for increased urinary excretion of riboflavin occurred with or without the load when adult men received more than 1.1 mg/day of dietary riboflavin (see Figure 5-1). Above this level, there is a sharp linear increase in the slope of urinary excretion for riboflavin intakes up to 2.5 mg/day (Sauberlich FIGURE 5-1 Relationship of riboflavin intake to urinary excretion of riboflavin as observed in the studies of Horwitt (1972) and Horwitt et al. (1950). Reprinted with permission, from Sauberlich et al. (1974). Copyright 1994 by CRC Press.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline et al., 1974). Adapting the work of Lossy et al. (1951), Sauberlich and colleagues (1974) suggested a reference value of 1.4 mg or more for the normal 4-hour urinary excretion of riboflavin after a 5-mg load. The change in slope of urinary excretion of riboflavin after a load test is an especially useful status assessment. Caution in interpretation is needed because the size of the test dose, method of administration, and method of calculating amount recovered have varied among studies. Moreover, the break point may reflect not only tissue saturation but also renal threshold and solubility (compartment) effects (Sauberlich et al., 1974). Urinary riboflavin has been shown to increase under conditions causing negative nitrogen balance and with the administration of antibiotics and certain psychotropic drugs (e.g., phenothiazine) (McCormick, 1994). Indicators of Carbohydrate Metabolism In an early study (Horwitt et al., 1949), indices of carbohydrate metabolism (lactic and pyruvic acid concentrations) were measured in riboflavin-depleted subjects after a short period of exercise. Because no changes were observed, these do not appear to be promising indicators of riboflavin status. Possible Reduction of Chronic Disease Risk Riboflavin status (low as assessed by EGRAC) has been related to certain site-specific cancers (e.g., esophageal) in areas of China (Merrill et al., 1991). However, randomized nutrition intervention trials in Linxian, China, indicated that a riboflavin and niacin combination, given for about 5 years, did not reduce total or cancer mortality (Blot et al., 1995). Although lens opacities in humans have been associated with high glutathione reductase activity (with FAD) (Leske et al., 1995), evidence is insufficient for considering the use of risk of cataract as the basis for setting the Estimated Average Requirement (EAR). Concurrent Analyses Overall, greatest credence is given to status assessments that use more than one indicator, because the response variables indicate somewhat different aspects of riboflavin status. Many investigators have obtained data concurrently on several indicators of riboflavin status. Sauberlich and colleagues (1972) noted that, for the most

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline part, “subjects with elevated EGR activity coefficients…had urinary excretion levels considered low or deficient.” Boisvert and colleagues (1993) indicated that the EGRAC method is preferred for the assessment of riboflavin status whereas the urinary excretion method is better for determining riboflavin requirements. Both EGRAC and urinary riboflavin respond more rapidly to dietary riboflavin intake than does erythrocyte riboflavin (Bamji, 1969), but Bates (1987) showed a good relationship between EGRAC and erythrocyte riboflavin expressed as micrograms of riboflavin per gram of hemoglobin. FACTORS AFFECTING THE RIBOFLAVIN REQUIREMENT Bioavailability Overall, a reasonable estimation of bioavailability is approximately 95 percent of food flavin, up to a maximum of about 27 mg absorbed per single meal or dose (Zempleni et al., 1996). There is considerable diversity of flavins in foods, but over 90 percent of riboflavin is estimated to be in readily digested flavocoenzymes (mainly flavin-adenine dinucleotide [FAD] and to a lesser degree flavin mononucleotide [FMN]), with lesser amounts of the free vitamin and traces of glycosides and esters that are also hydrolyzed during absorption from the gut (McCormick, 1994; Merrill et al., 1981). Perhaps no more than 7 percent of food flavin is found as covalently attached 8α-FAD. In these substituted flavins, the methylene carbon at position 8 of the isoalloxazine ring is bound to heterocyclic atoms (N, S, and O) of proteins that function catalytically (e.g., mitochondrial succinate dehydrogenase and monoamine oxidase). Although some portion of the 8α-(amino acid) riboflavins are released by proteolysis of such flavoproteins, they do not have vitaminic activity (Chia et al., 1978). Nutrient-Nutrient Interactions Composition of the Diet The proportions of fat and carbohydrate in the diet appear to influence the riboflavin requirements of the elderly (Boisvert et al., 1993); when fat was decreased from 31.4 to 20.0 percent of calories and carbohydrate was increased from 57.5 to 68.2 percent of calories, the riboflavin requirement was lower. Thus, a lower ratio of fat

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline to carbohydrate decreased the requirement. This relationship has not been examined in other age groups. Other B Vitamins Riboflavin interrelates with other B vitamins, notably niacin, which requires FAD for its formation from tryptophan, and vitamin B6, which requires FMN for conversion to the coenzyme pyridoxal 5'-phosphate (McCormick, 1989). These interrelationships are not known to affect the requirement for riboflavin. Energy Intake No studies were found that examined the effect of energy intake on the riboflavin requirement. Some studies provided riboflavin in graded doses that kept the ratio of riboflavin-to-energy constant for subjects with different energy requirements. Others provided total amounts of riboflavin (and sometimes energy) that were the same for all individuals. Five studies using 2- to 3-day complete urine collection (Belko et al., 1983, 1984, 1985; Soares et al., 1993; Winters et al., 1992) reported that the urinary excretion of riboflavin is decreased when physical activity is increased, suggesting higher utilization of riboflavin with increased energy expenditure. Despite the lack of experimental data, the known biochemical function of riboflavin in the utilization of energy suggests at least a small (10 percent) adjustment to reflect differences in the average energy utilization and size of men and women, a small increase in the requirement to cover increased energy use during pregnancy, and a small increase to cover the inefficiencies of milk production. Physical Activity Riboflavin status measurements seem to be affected by physical activity. Some studies have demonstrated a moderate rise in the erythrocyte glutathione reductase activity coefficient (EGRAC) as well as a decrease in urinary riboflavin excretion with an increase in physical activity (Belko et al., 1983, 1984, 1985; Soares et al., 1993; Winters et al., 1992). For example, approximately 20 percent additional riboflavin was required to normalize EGRAC and urinary flavin values of exercising, weight-reducing women (Belko et al., 1985) and older women undergoing exercise training (Winters et al., 1992). Tucker and colleagues (1960) suggest that the decrease in riboflavin after exercise may be related to reduced renal blood

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline flow, but in the studies cited above, all urine was collected over a period of 48 to 72 hours. In a group of East Indian men aged 27 to 47 years with a mean EGRAC of 1.53, short periods of increased physical activity while on a diet providing riboflavin at 0.42 mg/1,000 kcal for 16 days led to an increase in EGRAC. When riboflavin status is marginal, increased physical activity may be more likely to lead to further deterioration as assessed by EGRAC, and values may not return to baseline after the extra exercise segment of the study is completed (Soares et al., 1993). However, the energy cost of the exercise and a measure of mechanical efficiency remained stable throughout. A number of studies have failed to show an improvement in work performance (Powers et al., 1987; Prasad et al., 1990; Tremblay et al., 1984; Weight et al., 1988) and endurance (elderly subjects) (Winters et al., 1992) with riboflavin supplementation even when subjects were described as subclinically deficient (having lower-than-normal ranges of biochemical indices but no clinically observable signs of deficiency). It is possible that the riboflavin requirement is increased for those who are ordinarily very active physically (e.g., athletes or those who carry heavy packs much of the day), but data are not available on which to quantify the adjustment that should be made. Other Factors Although a number of reports indicate that women taking high-dose oral contraceptives have impaired riboflavin status, no difference was seen when dietary riboflavin intake was controlled (Roe et al., 1982). APPROACHES FOR DERIVING THE ESTIMATED AVERAGE REQUIREMENT Primary: Maintenance or Restoration of Riboflavin Status by Using Biochemical Indicators To derive the Estimated Average Requirement (EAR) for adults, more weight was given to experimental studies that included information on response to diets in which the source of riboflavin was food or food plus supplemental riboflavin (Table 5-1). Studies that used more than one indicator were considered most useful, especially if a functional assay (e.g., EGRAC) was conducted along with measurement of erythrocyte or urinary riboflavin. However, the

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Lactation Method Used to Estimate the Average Requirement For lactating women, it is assumed that 0.3 mg of riboflavin is transferred in their milk each day when their daily milk production is 0.78 L (during the first 6 months of lactation; see “Infants Ages 0 through 12 Months”). If the use of riboflavin for milk production by the mother is assumed to be 70 percent efficient (WHO, 1965), values are adjusted upward to 0.4 mg/day for the amount of the vitamin that should be replaced. Women who are breastfeeding older infants who are eating solid foods need slightly less, in proportion to lower volume of milk production. Riboflavin EAR and RDA Summary, Lactation To the EAR of 0.9 mg/day of riboflavin for the nonpregnant and nonlactating woman, 0.4 mg/day is added, giving an EAR of 1.3 mg/day. EAR for Lactation 14–18 years 1.3 mg/day of riboflavin   19–30 years 1.3 mg/day of riboflavin 31–50 years 1.3 mg/day of riboflavin The RDA for riboflavin is set by assuming a coefficient of variation (CV) of 10 percent (see Chapter 1) because information is not available on the standard deviation of the requirement for riboflavin; the RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of the individuals in the group (therefore, for riboflavin the RDA is 120 percent of the EAR). RDA for Lactation 14–18 years 1.6 mg/day of riboflavin   19–30 years 1.6 mg/day of riboflavin 31–50 years 1.6 mg/day of riboflavin Special Considerations As with other B vitamins, persons undergoing hemodialysis or peritoneal dialysis and those with severe malabsorption are likely to require extra riboflavin. Women pregnant with more than one fetus and those breastfeeding more than one infant are also likely to require more riboflavin.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline INTAKE OF RIBOFLAVIN Food Sources Most plant and animal tissues contain at least small amounts of riboflavin. Data obtained from the 1995 Continuing Survey of Food Intakes by Individuals (CSFII) indicate that the greatest contribution to the riboflavin intake of the U.S. adult population comes from milk and milk drinks followed by bread products and fortified cereals (Table 5-2). Other sources of riboflavin are organ meats. Milk is both a rich source of riboflavin and a commonly consumed food. Riboflavin loss occurs if it is exposed to the light, for example, if milk is stored in clear glass under light. Dietary Intake Based on data from CSFII (Appendix G) and the Third National Health and Nutrition Examination Survey (Appendix H), the median intake of riboflavin from food in the United States is approximately 2 mg/day for men and 1.5 mg/day for women. Similarly, a group of healthy residents of rural Georgia was found to have a mean daily intake of riboflavin of 2.1 mg (Roughead and McCormick, 1991). For all life stage and gender groups, fewer than 5 percent of individuals have estimated intakes that are less than the Estimated Average Requirement (EAR) for riboflavin. Dietary riboflavin intake in two Canadian provinces was reported to be similar to U.S. intake (Appendix I). The Boston Nutritional Status Survey (Appendix F) indicates that this relatively advantaged group of people over age 60 had an estimated median riboflavin intake of 1.9 mg/day for men and 1.5 mg/ day for women. Intake from Supplements Information from the Boston Nutritional Status Survey on the use of riboflavin supplements by a free-living elderly population is given in Appendix F. For those taking supplements, the fiftieth percentile of supplemental riboflavin intake was estimated to be 1.9 mg for men and 2.9 mg for women. Approximately 26 percent of all adults took a riboflavin-containing supplement in 1986 (Moss et al., 1989).

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline TABLE 5-2 Food Groups Providing Riboflavin in the Diets of U.S. Men and Women Aged 19 Years and Older, CSFII, 1995a   Contribution to Total Riboflavin Intakeb (%) Foods Within the Group that Provide at Least 0.3 mg of Riboflavinc per Serving Food Group Men Women 0.3–0.7 mg > 0.7 mg Food groups providing at least 5% of total riboflavin intake Milk and milk drinksd 14.5 16.0 Milk and milk products Fortified milk drinks Bread and bread products 10.8 11.2 — — Mixed foodse 9.1 6.7 NAf NA Ready-to-eat cereals 8.7 10.9 Moderately fortified Highly fortified Mixed foods, main ingredient is grain 7.9 6.6 NA NA Riboflavin from other food groups Pasta, rice, and cooked cereals 2.1 2.4 Instant oatmeal — Pork 2.0 1.7 Pork cutlet and spareribs — Finfish 0.7 0.9 Trout — Organ meats 0.7 0.8 — Liver, kidney, and heart Soy-based supplements and meal replacements 0.6 0.2 Soy-based meat replacements — Lamb, veal, game, and other carcass meat 0.3 0.2 Veal chop and venison — a CSFII = Continuing Survey of Food Intakes by Individuals. b Contribution to total intake reflects both the concentration of the nutrient in the food and the amount of the food consumed. It refers to the percentage contribution to the American diet for both men and women based on 1995 CSFII data. c 0.3 mg represents 20% of the Recommended Daily Intake (1.7 mg) of riboflavin—a value set by the Food and Drug Administration. d Includes yogurt. e Includes sandwiches and other foods with meat, poultry, or fish as the main ingredient. f NA = not applicable. Mixed foods were not considered for this table. SOURCE: Unpublished data from the Food Surveys Research Group, Agricultural Research Service, U.S. Department of Agriculture, 1997.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline TOLERABLE UPPER INTAKE LEVELS Hazard Identification No adverse effects associated with riboflavin consumption from food or supplements have been reported. However, studies involving large doses of riboflavin (Schoenen et al., 1994; Stripp, 1965; Zempleni et al., 1996) have not been designed to systematically evaluate adverse effects. The limited evidence from studies involving large intakes of riboflavin is summarized here. No adverse effects were reported in humans after single oral doses of up to 60 mg of supplemental riboflavin and 11.6 mg of riboflavin given intravenously as a single bolus dose (Zempleni et al., 1996). This study is of limited use in setting a Tolerable Upper Intake Level (UL) because it was not designed to assess adverse effects. It is possible that chronic administration of these doses would pose some risk. A study by Schoenen and coworkers (1994) reported no short-term side effects in 49 patients treated with 400 mg/day of riboflavin taken with meals for at least 3 months. Schoenen and coworkers (1994) reported that one patient receiving riboflavin and aspirin withdrew from the study because of gastric upset. This isolated finding may be an anomaly because no side effects were reported in other patients. The apparent lack of harm resulting from high oral doses of riboflavin may be due to its limited solubility and limited capacity for absorption in the human gastrointestinal tract (Levy and Jusko, 1966; Stripp, 1965; Zempleni et al., 1996); its rapid excretion in the urine (McCormick, 1994). Zempleni et al. (1996) showed that the maximal amount of riboflavin that was absorbed from a single oral dose was 27 mg. A study by Stripp (1965) found limited absorption of 50 to 500 mg of riboflavin with no adverse effects. The poor intestinal absorption of riboflavin is well recognized: riboflavin taken by mouth is sometimes used to mark the stool in experimental studies. There are no data from animal studies suggesting that uptake of riboflavin during pregnancy presents a potential hazard for the fetus or newborn. The only evidence of adverse effects associated with riboflavin comes from in vitro studies showing the formation of active oxygen species on intense exposure to visible or ultraviolet light (Ali et al., 1991; Floersheim, 1994; Spector et al., 1995). However, because there are no demonstrated functional or structural adverse effects in humans or animals after excess riboflavin intake, the relevance

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline of this evidence to human health effects in vivo is highly questionable. Nevertheless, it is theoretically plausible that riboflavin increases photosensitivity to ultraviolet irradiation. Additionally, there is a theoretical risk that excess riboflavin will increase the photosensitized oxidations of cellular compounds, such as amino acids and proteins (McCormick, 1977) in infants treated for hyperbilirubinemia, with possible undesirable consequences. Dose-Response Assessment The data on adverse effects from high riboflavin intake are not sufficient for a quantitative risk assessment, and a UL cannot be derived. Special Considerations There is some in vitro evidence that riboflavin may interfere with detoxification of chrome VI by reduction to chrome III (Sugiyama et al., 1992). This may be of concern in people who may be exposed to chrome VI, for example, workers in chrome plating. Infants treated for hyperbilirubinemia may also be sensitive to excess riboflavin, as previously mentioned. Intake Assessment Although no UL can be set for riboflavin, an intake assessment is provided here for possible future use. Data from the Third National Health and Nutrition Examination Survey (see Appendix H) showed that the highest mean intake of riboflavin from diet and supplements for any life stage and gender group reported was for males aged 31 through 50 years: 6.9 mg/day. The highest reported intake at the ninety-fifth percentile was 11 mg/day in females over age 70 years. Risk Characterization No adverse effects have been associated with excess intake of riboflavin from food or supplements. This does not mean that there is no potential for adverse effects resulting from high intakes. Because data on the adverse effects of riboflavin intake are limited, caution may be warranted.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline RESEARCH RECOMMENDATIONS FOR RIBOFLAVIN Priority should be given to studies useful for setting Estimated Average Requirements (EARs) for riboflavin for children, adolescents, pregnant and lactating women, and the elderly. Future studies should be designed specifically around the EAR paradigm, use graded levels of riboflavin intake and clearly defined cutoff values for clinical adequacy and inadequacy, and be conducted for a sufficient duration. Two specific research areas may be productive: development of another functional test for riboflavin status to corroborate and augment the presently used flavin-adenine dinucleotide-dependent erythrocyte glutathione reductase (e.g., a test using a flavin mononucleotide-dependent erythrocyte enzyme such as the pyridoxine [pyridoxamine] 5′-phosphate oxidase) and examination of the effects of physical activity on the requirement for riboflavin. REFERENCES Alexander M, Emanuel G, Golin T, Pinto JT, Rivlin RS. 1984. Relation of riboflavin nutriture in healthy elderly to intake of calcium and vitamin supplements: Evidence against riboflavin supplementation. Am J Clin Nutr 39:540–546. Ali N, Upreti RK, Srivastava LP, Misra RB, Joshi PC, Kidwai AM. 1991. Membrane damaging potential of photosensitized riboflavin. Indian J Exp Biol 29:818–822. Aw TY, Jones DP, McCormick DB. 1983. Uptake of riboflavin by isolated rat liver cells. J Nutr 113:1249–1254. Badart-Smook A, van Houwelingen AC, Al MD, Kester AD, Hornstra G. 1997. Fetal growth is associated positively with maternal intake of riboflavin and negatively with maternal intake of linoleic acid. J Am Diet Assoc 97:867–870. Bamji MS. 1969. Glutathione reductase activity in red blood cells and riboflavin nutritional status in humans. Clin Chim Acta 26:263–269. Bamji MS. 1976. Enzymic evaluation of thiamin, riboflavin and pyridoxine status of parturient women and their newborn infants . Br J Nutr 35:259–265. Bamji MS, Chowdhury N, Ramalakshmi BA, Jacob CM. 1991. Enzymatic evaluation of riboflavin status of infants. Eur J Clin Nutr 45:309–313. Bates CJ. 1987. Human requirements for riboflavin. Am J Clin Nutr 47:122–123. Bates CJ, Prentice AM, Paul AA, Sutcliffe BA, Watkinson M, Whitehead RG. 1981. Riboflavin status in Gambian pregnant and lactating women and its implications for Recommended Dietary Allowances. Am J Clin Nutr 34:928–935. Bates CJ, Powers HJ, Downes R, Brubacher D, Sutcliffe V, Thurnhill A. 1989. Riboflavin status of adolescent vs elderly Gambian subjects before and during supplementation. Am J Clin Nutr 50:825–829. Belko AZ, Obarzanek E, Kalkwarf HJ, Rotter MA, Bogusz S, Miller D, Haas JD, Roe DA. 1983. Effects of exercise on riboflavin requirements of young women. Am J Clin Nutr 37:509–517.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Belko AZ, Obarzanek E, Roach R, Rotter M, Urban G, Weinberg S, Roe DA. 1984. Effects of aerobic exercise and weight loss on riboflavin requirements of moderately obese, marginally deficient young women. Am J Clin Nutr 40:553–561. Belko AZ, Meredith MP, Kalkwarf HJ, Obarzanek E, Weinberg S, Roach R, McKeon G, Roe DA. 1985. Effects of exercise on riboflavin requirements: Biological validation in weight reducing women. Am J Clin Nutr 41:270–277. Bessey OA, Horwitt MK, Love RH. 1956. Dietary deprivation of riboflavin and blood riboflavin levels in man. J Nutr 58:367–383. Blot WJ, Li JY, Taylor PR, Guo W, Dawsey SM, Li B. 1995. The Linxian trials: Mortality rates by vitamin-mineral intervention group. Am J Clin Nutr 62:1424S– 1426S. Boisvert WA, Mendoza I, Castañeda C, De Portocarrero L, Solomons NW, Gershoff SN, Russell RM. 1993. Riboflavin requirement of healthy elderly humans and its relationship to macronutrient composition of the diet. J Nutr 123:915–925. Bowman BB, McCormick DB, Rosenberg IH. 1989. Epithelial transport of watersoluble vitamins. Ann Rev Nutr 9:187–199. Brewer W, Porter T, Ingalls R, Ohlson MA. 1946. The urinary excretion of riboflavin by college women. J Nutr 32:583–596. Brown ML. 1990. Present Knowledge in Nutrition, 6th ed. Washington, DC: International Life Sciences Institute-Nutrition Foundation. Brzezinski A, Bromberg YM, Braun K. 1952. Riboflavin excretion during pregnancy and early lactation. J Lab Clin Med 39:84–90. Burch HB, Bessey OA, Lowry OH. 1948. Fluorometric measurements of riboflavin and its natural derivatives in small quantities of blood serum and cells. J Biol Chem 175:457–470. Chastain JL, McCormick DB. 1987. Flavin catabolites: Identification and quantitation in human urine. Am J Clin Nutr 46:830–834. Chia CP, Addison R, McCormick DB. 1978. Absorption, metabolism, and excretion of 8α-(amino acid) riboflavins in the rat. J Nutr 108:373–381. Cole HS, Lopez R, Cooperman JM. 1976. Riboflavin deficiency in children with diabetes mellitus. Acta Diabetol Lat 13:25–29. Committee on Nutrition. 1985. Composition of human milk: Normative data. In: Pediatric Nutrition Handbook, 2nd ed. Elk Grove Village, IL: American Academy of Pediatrics. Pp. 363–368. Dancis J, Lehanka J, Levitz M. 1988. Placental transport of riboflavin: Differential rates of uptake at the maternal and fetal surfaces of the perfused human placenta. Am J Obstet Gynecol 158:204–210. Daniel H, Wille U, Rehner G. 1983. In vitro kinetics of the intestinal transport of riboflavin in rats. J Nutr 113:636–643. Darby WJ. 1981. Annual Review of Nutrition, Vol. 1. Palo Alto, CA: Annual Reviews. Davis MV, Oldham HG, Roberts LJ. 1946. Riboflavin excretions of young women on diets containing varying levels of the B vitamins. J Nutr 32:143–161. Floersheim GL. 1994. Allopurinol, indomethacin and riboflavin enhance radiation lethality in mice. Radiat Res 139:240–247. Frischer H, Bowman JE, Carson PE, Reickmann KH, Willerson D Jr, Colwell EJ. 1973. Erythrocyte glutathione reductase, glucose-6-phosphate dehydrogenase, and 6-phosphogluconic dehydrogenase deficiencies in populations of the United States, South Vietnam, Iran, and Ethiopia. J Lab Clin Med 81:603–612. Heller S, Salkeld RM, Korner WF. 1974. Riboflavin status in pregnancy. Am J Clin Nutr 27:1225–1230.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Williams RD, Mason HL, Cusick PL, Wilder RM. 1943. Observations on induced riboflavin deficiency and the riboflavin requirement of man. J Nutr 25:361– 377. Wilson JA. 1983. Disorders of vitamins: Deficiency, excess and errors of metabolism. In: Petersdorf RG, Harrison TR, eds. Harrison’s Principles of Internal Medicine, 10th ed. New York: McGraw-Hill. Pp. 461–470. Winters LR, Yoon JS, Kalkwarf HJ, Davies JC, Berkowitz MG, Haas J, Roe DA. 1992. Riboflavin requirements and exercise adaptation in older women. Am J Clin Nutr 56:526–532. Yamada Y, Merrill AH Jr, McCormick DB. 1990. Probable reaction mechanisms of flavokinase and FAD synthetase from rat liver. Arch Biochem Biophys 278:125– 130. Zempleni J, Galloway JR, McCormick DB. 1996. Pharmacokinetics of orally and intravenously administered riboflavin in healthy humans. Am J Clin Nutr 63:54– 66.