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Recommended Dietary Allowances: 10th Edition (1989)

Chapter: Water-Soluble Vitamins

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Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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8
Water-Soluble Vitamins

VITAMIN C

Vitamin C (L-ascorbic acid) is a water-soluble antioxidant that can be synthesized by many mammals, but not by humans. In the diet, it is also present to some extent in its oxidized form (dehydroascorbic acid), which also has vitamin C activity (Sabry et al., 1958). Dietary deficiency eventually leads to scurvy, a serious disease characterized by weakening of collagenous structures that results in widespread capillary hemorrhaging (Hornig, 1975; Woodruff, 1975). In the United States, scurvy occurs primarily in infants fed diets consisting exclusively of cow's milk and in aged persons on limited diets.

The best defined biochemical property of vitamin C is its function as a cosubstrate in hydroxylations requiring molecular oxygen, as in the hydroxylation of proline and lysine in the formation of collagen (Barnes, 1975; Myllyla et al., 1978), of dopamine to norepinephrine (Levin et al., 1960), and of tryptophan to 5-hydroxytryptophan (Cooper, 1961). It may also be involved in reactions involving a number of other compounds, including tyrosine (La Du and Zannoni, 1961), folic acid (Stokes et al., 1975), histamine (Clemetson, 1980), corticosteroids (Wilbur and Walter, 1977), neuroendocrine peptides (Glembotski, 1987), and bile acids (Ginter, 1975). Vitamin C can also affect functions of leukocytes (Anderson and Theron, 1979) and macrophages (Anderson and Lukey, 1987), immune responses (Leibovitz and Siegel, 1978), wound healing (Levenson et al., 1971), and allergic reactions (Dawson and West, 1965). Ascorbic acid as such or as present in plant foods increases the absorption of inorganic iron when the two nutrients are ingested together (Hallberg et al., 1987).

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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Absorption, Transport, Storage, and Excretion

L-ascorbic acid is absorbed in the intestine by a sodium-dependent transport process (Stevenson, 1974). At low doses, absorption may be almost complete, but over the range of usual intake in food (30 to 60 mg), 80 to 90% is absorbed (Kallner et al., 1977). Absorbed ascorbic acid is present as the anion in blood plasma, unbound to plasma proteins. As the daily intake of ascorbic acid increases, the plasma concentration rises rapidly and then reaches a plateau of 1.2 to 1.5 mg/dl at an intake of 90 to 150 mg/day (Garry et al., 1987; Sauberlich et al., 1974).

Body stores of ascorbic acid in adult men reach a maximum of approximately 3,000 mg at daily intakes exceeding 200 mg. One half' of this level (1,500 mg) is achieved by much lower daily intakes in the range of 60 to 100 mg. Much of the body stores is normally found within cells, in which the concentrations vary widely but are usually severalfold higher than those in blood plasma. In at least some tissues these concentrations appear to be achieved by a stereoselective transport process (Moser, 1987).

Ascorbic acid and its various metabolites are excreted mainly in the urine. At daily intakes up to 100 mg, oxalate is the major product excreted. When larger amounts are ingested, ascorbic acid is mainly excreted as such (Jaffe, 1984; Kallner et al., 1979). Little ascorbic acid is metabolized to carbon dioxide at ordinary intakes (Baker et al., 1969), but at large doses, degradation within the intestine may be substantial (Kallner et al., 1985).

Dietary Sources and Usual Intakes

Vegetables and fruits contain relatively high concentrations of vitamin C, e.g., green and red peppers, collard greens, broccoli, spinach, tomatoes, potatoes, strawberries, and oranges and other citrus fruits. Meat, fish, poultry, eggs, and dairy products contain smaller amounts, and grains contain none. Ascorbic acid in the U.S. food supply is provided almost entirely by foods of vegetable origin-38% by citrus fruits, 16% by potatoes, and 32%  from other vegetables (Marsten and Raper, 1987). The rest comes from fortified and enriched products and from meat, fish, poultry, eggs, and dairy products. The average amount available per capita in the U.S. food supply increased from 98 mg in 1967-1969 to 114 mg in 1985 (Marsten and Raper, 1987). The average dietary vitamin C intake by adult men in the United States in 1985 was 109 mg (USDA, 1986). The corresponding intakes for adult women and children 1 to 5 years of age were 77 mg and 84 mg, respectively (USDA, 1987).

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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The dietary vitamin C may be considerably lower than the calculated amount in the food ingested, largely because of its destruction by heat and oxygen and its loss in cooking water. On the other hand, the mean total intake of vitamin C may also be considerably higher because (1) supplements of vitamin C are ingested by 35% of a representative U.S. adult population (Stewart et al., 1985), (2) food composition tables used in the U.S. Department of Agriculture surveys provide the L-ascorbic acid content only and do not include the biologically active dehydroascorbate, and (3) ascorbic acid is added to some processed foods because of its antioxidant or other properties (NRC, 1982).

Criteria for Assessing Nutritional Status

Vitamin C status is usually evaluated from signs of clinical deficiency, plasma (or blood) levels, or leukocyte concentrations. It has also been evaluated from isotopic estimates of body stores.

Clinical signs of scurvy, including follicular hyperkeratosis, swollen or bleeding gums, petechial hemorrhages, and joint pain, are associated with plasma (or serum) vitamin C values of less than 0.2 mg/ dl, leukocyte concentrations of less than 2 µg/108 cells, and a body pool size of less than 300 mg (Hodges et al., 1969, 1971; Sauberlich, 1981). To eliminate clinical signs of scurvy in several groups of male subjects, vitamin C intakes ranging from 6.5 to 10 mg/day were required (Baker et al., 1971; Bartley et al., 1953; Hodges et al., 1969, 1971).

Recommended Allowances
Adults

The dietary allowances for vitamin C must be set, somewhat arbitrarily, between the amount necessary to prevent overt symptoms of scurvy (approximately 10 mg/day in adults) and the amount beyond which the bulk of vitamin C is not retained in the body, but rather is excreted as such in the urine (approximately 200 mg/day). Between these limits, body stores vary directly with intake, albeit not linearly. Since vitamin C is poorly retained in the body in the absence of continuous intake, the RDA has traditionally been set at a level that will prevent scorbutic symptoms for several weeks on a diet lacking vitamin C. Observed depletion rates in a small group of well-nourished adult men with a body pool of approximately 1,500 mg were exponential and averaged 3.2% daily (range, 2.2 to 4.1% in nine subjects), which would yield a body pool of vitamin C of 300 mg (the amount below which scorbutic symptoms can occur) in about

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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30 days (Baker et al., 197 1). In 6 of 11 healthy, well-nourished young women  fed ascorbate-free diets, scorbutic symptoms developed within 24 days (bleeding, red, or tender gums) in association with blood levels consistent with body stores below 300 mg (Sauberlich et al., in press). By means of steady state analysis of ascorbate kinetics in men, Kallner et al. (1979) found the turnover time to vary from about 56 days at low intakes (approximately 15 mg/day) to about 14 days at intakes of approximately 80 mg/day. Above 80 mg/day, urinary excretion of unmetabolized ascorbate increased rapidly. Kallner and colleagues reported that a three-pool model was required to fit the observed kinetic data and postulated that one of these pools reflected ascorbate bound within cells. They also failed to observe a clear-cut renal threshold for ascorbate. Since the turnover time varied with tissue stores, Kallner (1987) proposed that the depletion rates observed in earlier studies might be erroneously low. Saturation of tissue binding, and maximal rates of metabolism and renal tubular absorption, seemed to be approached at turnover rates of 60 to 80 mg daily, equivalent to body stores of about 1,500 mg.

The subcommittee has set the RDA for adult men at 60 mg/day, the same as in the previous edition. This amount is based upon (1) the observed variation in depletion rates and turnover rates; (2) the average depletion rates and the steady state turnover rates at a pool size of 1,500 mg; (3) the less than complete absorption of ascorbic acid, estimated at 85% for usual intakes; and (4) the variable loss of ascorbic acid in food preparation. This level of intake will prevent signs of scurvy for at least 4 weeks. Given the development of early scorbutic symptoms in adult women considered to be well nourished after somewhat less than 4 weeks of depletion, the subcommittee recommends the same RDA for adult women as for men.

An intake of 60 mg is easily provided in ordinary mixed diets. In the previous edition of the RDAs, an intake of 45 mg/day for adult men was considered to provide an average pool size of 1,500 mg, and an intake of 60 mg/day was recommended to provide a margin of safety. Higher values, in fact, have been suggested to yield a pool size of 1,500 mg (Kallner, 1987), which would result in a recommended allowance of about 100 mg/day. It was the view of the subcommittee, however, that an allowance of 60 mg/day for both men and women provides an adequate margin of safety.

Persons 65 years and older ingest more vitamin C on the average (90 to 150 mg/day) than the mean intake for all ages (Garry et al., 1982; USDA, 1984). Low plasma concentrations are, however, observed frequently in some groups of elderly persons (Cheng et al., 1985; Newton et al., 1985). Such low levels are believed to reflect

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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inadequate intake in the groups examined. Therefore, no increment in the RDA for the elderly is recommended.

Cigarette smokers have lower concentrations of ascorbic acid in serum (Johnson et al., 1984; Pelletier, 1975; Schectman et al., 1989; Smith and Hodges, 1987) and leukocytes (Brook and Grimshaw, 1968). The lower serum levels are only partially explained by the reduced vitamin C intakes of smokers (Schectman et al., 1989). The metabolic turnover of men who smoked 20 or more cigarettes daily was found to be increased to a level 40% greater than that of nonsmoking men (Kallner et al., 1981). From calculations based on all these observations, the vitamin C requirement of smokers has been estimated to be as much as twice that of nonsmokers. The subcommittee recommends that regular cigarette smokers ingest at least 100 mg of vitamin C daily.

Pregnancy and Lactation 

During pregnancy, the concentration of vitamin C and several other solutes in blood plasma decreases (Morse et al., 1975), probably as a result of the hemodilution that accompanies pregnancy (Hytten, 1980; Rivers and Devine, 1975). Fetal and infant plasma levels of vitamin C are 50% higher than those of the mother (Khattab et al., 1970; Salmenpera, 1984), however, indicative both of active transport across the placenta and of a higher relative pool size in the fetus and infant.

If the requirement for vitamin C per unit body weight is comparable to that of nonpregnant adults, the increment in requirement for the fetus near term would be small (approximately 3 to 4 mg/ day). Requirements are likely to be somewhat higher because the catabolic rate in the fetus is probably greater. To offset losses from the mother's body pool during pregnancy, a 10 mg/day increment in the maternal vitamin C RDA is recommended during pregnancy.

The concentration of vitamin C in human milk varies widely (3 to 10 mg/dl), depending upon the dietary intake of the nutrient as well as other factors (Bates et al., 1983; Byerley and Kirksey, 1985; Salmenpera, 1984; Sneed et al., 1981; Tarjan et al., 1965). Assuming a concentration of 3 mg/dl, and average milk volumes of 750 and 600 ml in the first and second 6 months, respectively, the subcommittee estimates the average maternal losses are 22 and 18 mg/day. Allowing for variation in milk production (2 SDs, or 25%), and an intestinal absorption efficiency of 85%, a daily increment of 35 mg is recommended during the first 6 months of lactation and 30 mg thereafter.

Infants and Children 

Breastfed infants with vitamin C intakes of 7 to 12 mg/day and bottle-fed infants with vitamin C intakes of 7 mg/

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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day have been protected from scurvy (Goldsmith, 1961; Rajalakshmi et al., 1965; Van Eekelan, 1953). There are no other data on which to base an RDA. Accordingly, the subcommittee recommends 30 mg/ day during the first 6 months of life on the basis of the vitamin C content of milk, which should provide an adequate margin of safety. Premature infants may exhibit transient tyrosinemia (Irwin and Hutchins, 1976) and may therefore require a larger amount. The RDA beyond 6 months of age is gradually increased to the adult level.

Other Considerations

Usual daily dietary intakes of vitamin C (25 to 75 mg) can enhance the intestinal absorption of dietary nonheme iron by two- to fourfold (Cook and Monsen, 1977; Rossander et al., 1979). No effect on iron status as assessed from serum ferritin concentration was observed, however, in two studies in which vitamin C supplements were given with meals for several weeks (Cook et al., 1984). In one of these studies (Cook et al., 1984), intestinal adaptation to high intakes was excluded as a cause of apparent lack of change in iron stores. The significance of these observations in omnivorous, meat-eating subjects is unclear (Hallberg et al., 1987), but they do not exclude an effect of vitamin C on iron status in vegetarians or in other individuals with more limited intake of heme iron.

Ascorbic acid may prevent the formation of carcinogenic nitrosamines by reducing nitrites. The ingestion of fruits and vegetables rich in vitamin C has been associated with a reduced incidence of some cancers, but there is no evidence that vitamin C is responsible for any such effects (NRC, 1989).

Pharmacologic Intakes and Toxicity

Daily intakes of ascorbic acid of 1 g or more have been reported to reduce the frequency and severity of symptoms of the common cold and other respiratory illnesses (Pauling, 1971). In controlled, double-blind trials, however, the effect of ascorbic acid was considerably smaller than had previously been reported (Anderson, 1975) or was not reproducible (Coulehan et al., 1976). Several reviewers (Chalmers, 1975; Dykes and Meier, 1975) have concluded that any benefits of large doses of ascorbic acid for these conditions are too small to justify recommending routine intake of large amounts by the entire population.

Large doses of ascorbic acid have also been reported to lower serum cholesterol in some hypercholesterolemic subjects (Ginter et al.,

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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1977), but these observations have not been confirmed by others (Peterson et al., 1975). A number of effects of large doses of ascorbic acid on other medical conditions have been reported, but there is no general agreement about their value.

Many persons habitually ingest 1 g or more of ascorbic acid without developing apparent toxic manifestations. A number of adverse effects have, however, been reported (Barnes, 1975; Hornig and Moser, 1981; Rivers, 1987), and the risk of sustained ingestion of such amounts is unknown. Routine use of large doses of ascorbic acid is therefore not recommended.

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Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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USDA (U.S. Department of Agriculture). 1984. Nationwide Food Consumption Survey. Nutrient Intakes: Individuals in 48 States, Year 1977-78. Report No. 1-2. Consumer Nutrition Division, Human Nutrition Information Service. U.S. Department of Agriculture, Hyattsville, Md. 439 pp.

USDA (U.S. Department of Agriculture). 1986. Nationwide Food Consumption Survey. Continuing Survey of Food Intakes by Individuals: Men 19-50 Years, 1 Day, 1985. Report No. 85-3. Nutrition Monitoring Division, Human Nutrition Information Service. U.S. Department of Agriculture, Hyattsville, Md. 94 pp.

USDA (U.S. Department of Agriculture). 1987. Nationwide Food Consumption Survey. Continuing Survey of Food Intakes of Individuals: Women 19-50 Years and Their Children 1-5 Years, 4 I)ays, 1985. Report No. 85-4. Nutrition Monitoring Division, Human Nutrition Information Service. U.S. Department of Agriculture, Hyattsville, Md. 182 pp.

Van Fekelen, M. 1953. Occurrence of vitamin C in foods. Proc. Nutr. Soc. 12:228232.

Wilbur, V.A., and B.L. Walker. 1977. Dietary ascorbic acid and the time of response of the guinea pig to ACTH administration. Nutr. Rep. Int. 16:789-794.

Woodruff, C.W. 1975. Ascorbic acid¬scurvy. Prog. Food Nutr. Sci. 1:493-506.

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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THIAMIN

Thiamin as thiamin pyrophosphate (TPP) is a coenzyme required for the oxidative decarboxylation of a-keto acids and for the activity of transketolase in the pentose phosphate pathway. At usual levels in the diet, thiamin is rapidly absorbed, largely in the proximal small intestine. It is excreted in the urine, both intact as thiamin acetic acid and as metabolites of its cleavage products-the pyrimidine and thiazolic moieties (Hansen and Munro, 1970; McCormick, 1988; Ziporin et al., 1965).

General Signs of Deficiency

Thiamin deficiency is associated with abnormalities of carbohydrate metabolism related to a decrease in oxidative decarboxylation. During severe deficiencies, plasma and tissue levels of pyruvate are increased. Reduced TPP saturation of erythrocyte transketolase has also been observed in animals and humans fed diets low in thiamin (Sauberlich et al., 1979). Clinical signs of deficiency have been noted when less than 7% (70 µg) of a 1 mg dose of thiamin is excreted in the urine in a dose-retention test (Horwitt et al., 1948).

The clinical condition associated with the prolonged intake of a diet low in thiamin is traditionally called beriberi, whose primary symptoms involve the nervous and cardiovascular systems. The characteristic signs include mental confusion, anorexia, muscular weakness, ataxia, peripheral paralysis, ophthalmoplegia, edema (wet beriberi), muscle wasting (dry beriberi), tachycardia, and enlarged heart (Horwitt et al., 1948; Inouye and Katsura, 1965; Platt, 1967; Williams et al., 1942). In even a moderate deficiency, addition of a glucose load (100 g) can raise the plasma levels of lactic and pyruvic acids above those noted in control subjects (Williams et al., 1943), and may increase liver and heart muscle glycogen (Hawk et al., 1954). Indeed, carbohydrate loading can be an important precipitant of the thiaminresponsive neuropathy characteristic of the Wernicke-Korsakoff syndrome (Watson et al., 1981). Moreover, the development of wet beriberi in both its acute and chronic forms is favored by a high carbohydrate intake and increased physical activity (Burgess, 1958; Platt, 1958), a finding consistent with the fact that addition of even a 1-minute mild exercise period 60 minutes after a glucose load increases the differences in plasma lactic and pyruvic acids between controls and thiamin-depleted subjects (Horwitt et al., 1948). In infants, deficiency symptoms appear more suddenly than they do in adults and are usually more severe, often involving cardiac failure (McCormick, 1988).

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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Thiamin deficiency occurs most frequently in areas where the diet consists mainly of unenriched white rice and white flour, or when low dietary levels of thiamin are associated with consumption of large amounts of raw fish whose intestinal microbes contain thiaminase (Hilker and Somogyi, 1982). In the United States, thiamin deficiency is observed most frequently among alcoholics in whom decreased consumption and absorption and increased requirement all appear to play a role in the development of the deficiency (Leevy and Baker, 1968). Other persons at risk are renal patients undergoing long-term dialysis (Raskin and Fishman, 1976), patients fed intravenously for long periods (Nadel and Burger, 1976), patients with chronic febrile infections (Gilbert et al., 1969), and relatively few people with thiamin-responsive inborn errors of metabolism (McCormick, 1988).

Dietary Sources and Usual Intakes

Dietary sources of thiamin include unrefined cereal grains, brewer's yeast, organ meats (liver, heart, kidney), lean cuts of pork, legumes, and seeds/nuts. Enriched and fortified grains, cereals, and bakery products contribute large amounts of thiamin to the U.S. diet; among different groups of adults, thiamin intake from these sources averaged from 29 to 44% of the RDA according to USDA's 19771978 Nationwide Food Consumption Survey (Cook and Welsh, 1986).

The average thiamin intake of adult men in the United States in 1985 was 1.75 mg (0.68 mg/l,000 kcal) (USDA, 1986). The corresponding intakes for adult women and children 1 to 5 years of age were 1.05 mg (0.69 mg/l,000 kcal) and 1.12 mg (0.79 mg/1,000 kcal), respectively (USDA, 1987).

Recommended Allowances

Allowances for thiamin have been based on assessment of the effects of varying levels of dietary thiamin on the occurrence of clinical signs of deficiency, on the excretion of thiamin or its metabolites, and on erythrocyte transketolase activity.

Adults 

Clinical signs of thiamin deficiency have been observed in adult men and women with intakes of about 0.12 mg/1,000 kcal or less (Elsom et al., 1942; Foltz et al., 1944; Horwitt et al., 1948; Williams et al., 1942, 1943). Various thiamin intakes per 1,000 kcal0.3 mg (Sauberlich et al., 1979), 0.35 mg (Elsom et al., 1942), 0.33 to 0.45 mg (Foltz et al., 1944), 0.41 mg (Glickman et al., 1946), 0.37 to 0.45 mg (Hathaway and Strom, 1946), and 0.5 mg (Williams et al.,

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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1942)-were reported to be consistent with good health during the periods of observation. Anderson et al. (1986) found that thiamin status (as measured by transketolase activity) was better predicted when the dietary intake of thiamin was expressed as mg/day rather than as mg/1,000 kcal. They recommended a minimum thiamin intake of 1.22 mg/day for men and 1.03 mg/day for women.

At low levels of intake, very little thiamin is excreted; excretion increases at higher dietary levels. A critical intake point appears to be approximately 0.2 mg/1,000 kcal, below which urinary excretion is low and clinical signs of thiamin deficiency may appear (Horwitt et al., 1948; Mickelson et al., 1947; Oldham et al., 1946; Pearson, 1962; Williams et al., 1942, 1943). Studies comparing urinary excretion of thiamin at varying levels of intake and measurements of urinary excretion of thiamin in dietary deficiency cases suggest that the minimum requirement is approximately 0.33 to 0.35 mg/l,000 kcal (Bamji, 1970; Melnick, 1942; Ziporin et al., 1965). An intake of more than 0.5 mg/l,000 kcal may be required to ensure tissue saturation (Hathaway and Strom, 1946; Reuter et al., 1967; Williams et al., 1942, 1943), but there is no evidence that so-called tissue saturation is required for good health.

When dietary intake cannot be monitored or urine collected, TPP concentrations in the blood can be measured either directly (Warnock et al., 1978) or indirectly (Berit-Kjosen and Seim, 1977). When healthy subjects were studied under controlled experimental conditions, good correlations of urinary excretions with the erythrocyte transketolase activity and TPP stimulation of transketolase were recorded (Sauberlich et al., 1970, 1979; Wood et al., 1980). Normal red-cell transketolase activities with and without added TPP  have been observed in subjects consuming 0.4 mg/l,000 kcal (Reuter et al., 1967) and 0.5 mg/1,000 kcal (Bamji, 1970; Haro et al., 1966), but 0.6 to 0.8 mg/l,000 kcal of thiamin (Kraut et al., 1966) or 1.1 mg/ 1,000 kcal (Reuter et al., 1967) were necessary to obtain maximum activity. There is no indication, however, that the lower transketolase activity at an intake below 0.4 mg/1,000 kcal was attended by any ill effect.

No evidence that thiamin requirements are increased by aging was observed in a 3-year study of 18 young and 2 1 old male adults (Horwitt et al., 1948). Although blood thiamin levels or transketolase assays have shown low thiamin status in some older adults, Iber et al. (1 982) considered that the thiamin RDA of 0.5 mg/l,000 kcal is sufficient for those over 60 years of age.

On the basis of all these data, a thiamin allowance for adults of 0.5 mg/l,000 kcal, as recommended in the 1980 RDAs, is believed to

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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provide an adequate margin of safety for all adults. A minimum of 1.0 mg/day is recommended, even for those consuming less than 2,000 kcal daily. Although thiamin is essential for the metabolism of carbohydrate and certain amino acids, but not for fat and the remaining protein fraction, it is difficult in practice to separate energy intake into these components; hence, the thiamin recommendation is expressed by convention in terms of total caloric intake.

Pregnancy and Lactation 

Studies of urinary excretion of thiamin, blood thiamin levels, and erythrocyte transketolase activity all indicate that the requirement for thiamin in women increases during pregnancy (Heller et al., 1974; Kaminetzky et al., 1973; Lockhart et al., 1943; Oldham et al., 1950; Toverud, 1940). This increase appears to occur early in pregnancy and to remain constant throughout (Heller et al., 1974; Kaminetzky et al., 1973). On the basis of an increased energy intake of 300 kcal/day during pregnancy and an adult allowance of 0.5 mg of thiamin per 1,000 kcal, an additional 0.4 mg/day is recommended throughout pregnancy to accommodate maternal and fetal growth and increased maternal caloric intake.

Thiamin requirements also increase during lactation. The lactating woman secretes approximately 0.2 mg of thiamin/day in milk (Nail et al., 1980). To account for both the thiamin loss in milk and increased energy consumption during lactation, an increment of 0.5 mg is recommended throughout lactation.

Infants

Information on the thiamin requirements of infants is limited. In one study of the relationship between thiamin intake and excretion, Holt et al. (1949) concluded that the thiamin requirement of seven 1- to 10-month-old infants ranged from 0.14 to 0.20 mg/ day. Studies of the thiamin content of human milk suggest that the minimum daily requirement to protect against deficiency is approximately 0.17 mg/day. This estimate is based on a mean concentration of 0.23 ± 0.03 mg of thiamin/liter of human milk (Nail et al., 1980) and a mean consumption of 750 ml of human milk per day by the infant. Thiamin concentrations were measured in women with unsupplemented (1.26 ± 0.17 mg of thiamin per day) and supplemented (3.33 ± 0.77 mg of thiamin per day) intakes of thiamin. Adequate thiamin status also was documented in both groups of women, i.e., urinary thiamin levels exceeded 0. 1 mg/day. An allowance for thiamin was estimated from the mean thiamin concentration plus 2 SDs in human milk-0.3 mg/liter, or 0.4 mg/1,000 kcal. The American Academy of Pediatrics also estimates the allowance for thiamin for infants at 0.4 mg/1,000 kcal (AAP, 1985).

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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Children and Adolescents

Few studies have been conducted to determine the thiamin requirements of children and adolescents. In one study by Boyden and Erikson (1966), urinary excretion of thiamin and whole blood thiamin levels in a group of preadolescent children indicated that intakes approximating 0.3 mg/1,000 kcal were adequate. In a study of the urinary thiamin excretion of 16- to 18-year-old girls, Hart and Reynolds (1957) concluded that a daily intake of 0.3 mg/1,000 kcal was inadequate. Dick et al. (1958) reported that thiamin excretion of boys 14 to 17 years old fed diets containing 3,582 kcal/day and six different levels of thiamin indicated that their mean daily requirement for thiamin was 0.38 ± 0.059 mg/1,000 kcal. Thus, the mean plus 2 SDs would be 0.50 mg/1,000 kcal. Therefore, the thiamin allowance recommended for children and teenagers, like that for adults, is 0.5 mg/1,000 kcal, which provides for variability in requirements. This appears to provide an adequate margin of safety in the absence of clinical and biochemical evidence of deficiency.

Excessive Intakes and Toxicity

Excess thiamin is easily cleared by the kidneys. Although there is some evidence of toxicity from large doses given parenterally (McCormick, 1988), there is no evidence of thiamin toxicity by oral administration; oral doses of 500 mg taken daily for a month were found to be nontoxic (Hawk et al., 1954).

References

AAP (American Academy of Pediatrics). 1985. Composition of human milk: normative data. Appendix K. Pp. 363-368 in Pediatric Nutrition Handbook, 2nd ed. American Academy of Pediatrics, Elk Grove Village, 1ll.

Anderson, S.H., C.A. Vickery, and A.D. Nicol. 1986. Adult thiamine requirements and the continuing need to fortify processed cereals. Lancet 2:85-89.

Bamji, M.S. 1970. Transketolase activity and urinary excretion of thiamin in the assessment of thiamin-nutrition status of Indians. Am. J. Clin. Nutr. 23:52-58.

Berit-Kjosen, M.S., and S.H. Seim. 1977. The transketolase assay of thiamine in some diseases. Am. J. Clin. Nutr. 30:1591-1596.

Boyden, R.E., and S.E. Erickson. 1966. Metabolic patterns in preadolescent children: thiamine utilization in relation to nitrogen intake. Am. J. Clin. Nutr. 19:398406.

Burgess, R.C. 1958. Beriberi. I. Epidemiology. Fed. Proc. Suppl. 17:3-8.

Cook, D.A., and S.O. Welsh. 1986. The effect of enriched and fortified grain products on nutrient intake. Cereal Foods World 32:191-196.

Dick, E.C., S.D. Chen, M. Bert, and J.M. Smith. 1958. Thiamine requirement of eight adolescent boys, as estimated from urinary thiamine excretion. J. Nutr. 66:173188.

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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Elsom. K.O., J.G. Reinhold, J.T.L. Nicholson, and C. Chornock. 1942. Studies of the B vitamins in the human subject. V. The normal requirement for thiamine; some factors influencing its utilization and excretion. Am. Med. Sci. 203:569-577.

Foltz, E. F., C.J. Barborka, and A.C. Ivy. 1944. The level of vitamin B-complex in the diet at which detectable symptoms of deficiency occur in man. Gastroenterology 2:323-344.

Gilbert, V.E., M.C. Susser, and A. Nolte. 1969. Deficient thiamin  pyrophosphate and blood alpha-ketoglutarate-pyruvate relationships during febrile human infections. Metabolism  18:789-799.

Glickman, N., R.W. Keeton, H.H. Mitchell, M.K. Fahnestock. 1946. The tolerance of man to cold as affected by dietary modifications; high versus low intake of certain water-soluble vitamins. Am. J. Physiol. 146:538-558.

Hansen, R.G., and H.N. Munro, eds. 1970. Proceedings of a Workshop on Problems of Assessment and Alleviation of Malnutrition in the United States. Held at Nashville, Tennessee, January 13-14, 1970. Nutrition and Health Program, Vanderbilt  University, Regional Medical Programs.  Health Services and  Mental Health Administration, Washington, D.C. 186 pp.

Haro, F. N., M. Brin, and W.W. Faloon. 1966. Fasting in obesity. Thiamine depletion as measured by erythrocyte transketolase changes. Arch. Intern. Med. 117:175181.

Hart, M, and  M.S. Reynolds. 1957. Thiamine requirement of adolescent girls. J. Home Econ. 49:35-37.

Hathaway, M.L., and J.E. Strom. 1946. A comparison of thiamine synthesis and excretion in human subjects on synthetic and natural diets. J. Nutr. 32:1-8.

Hawk, P.D., B.L. Oser, and W.H. Summerson, eds. 1954. Vitamins and deficiency diseases. Pp. 1104-1296 in Practical Physiological Chemistry, 13th ed. Blakiston Company, Inc., New York.

Heller, S., R.M. Salkeld, and W.F. Korner.  1974. Vitamin Bl  status in pregnancy. Am. J. Clin. Nutr. 27:1221-1224.

Hilker, D.M., and J.D. Somogyi. 1982. Antithiamins of plant origin: their chemical nature and mode of action. Ann. N.Y. Acad. Sci. 378:137-145.

Holt, L.F., Jr., R.I. Nemir, S.E. Snyderman, A.A. Albanese, K.C. Ketron, L.P. Guy, and R. Carretero. 1949. The thiamine requirement of the normal infant. J. Nutr. 37:53-66.

Horwitt, M.K., E. Liebert, (). Kreisler, and P. Wittman. 1948. Investigations of Human Requirements for B-Complex  Vitamins. Bulletin of the National Research Council No. 116. Report of the Committee on Nutritional Aspects of Ageing, Food and Nutrition Board, Division of Biology and Agriculture. National Academy of Sciences, Washington, D.C. 106 pp.

Iber, F.I., J.P. Blass, MN. Brin, and C.M. Leevy. 1982. Thiamin in the elderly-relation to alcoholism and to neurological degenerative disease. Am. J. Clin. Nutr. 36: 1067-1082.

Inouye, K., and E. Katsura. 1965. Etiology and  pathology of beriberi. Pp. 1-28 in N. Shilazono and E. Katsura. eds. Review of Japanese literature on Beriberi and Thiamine. Vitamin B Research Committee of Japan.  Igaku Shoin, Tokyo.

Kaminetzky. H.A., A. Langer, H. Baker, O. Frank, A.D. Thomson, E.D. Munves, A. Opper, F.C. Behrle, and B. Glista. 1973. The effect of nutrition in teen-age gravidas on pregnancy and status of the neonate. I. A nutritional profile. Am. J. Obstet. Gynecol. 115:639-644.

Kraut,H., L. Wildemann, and M. Bohm. 1966. Untersuchungen zum Thiaminbedarf des Menschen. Int. Z. Vitamininforsch. 36:157-193.

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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Leevy, C.M., and H. Baker. 1968. Vitamins and alcoholism. Am. J. Clin. Nutr. 21:1325-1328.

Lockhart, H.S., S.B. Kirkwood, and R.S. Harris. 1943. The effect of pregnancy and puerperium on the thiamine status of women. Am.  Obstet. Gynecol. 46:358365.

McCormick, D.B. 1988. Thiamin. Pp. 355-361 in M.E. Shils and V.R. Young, eds. Modern Nutrition in Health and Disease, 7th ed. Lea & Febiger, Philadelphia.

Melnick, D. 1942. Vitamin Bl  (thiamin) requirement of man. J. Nutr. 24:139-151.

Mickelsen, O.,W.O. Caster, and A. Keys. 1947. A statistical evaluation of the thiamin and pyramin excretions of normal young  men on controlled intakes of thiamine. J. Biol. Chem. 168:415-431.

Nadel, A.M., and P.C. Burger. 1976. Wernicke encephalopathy following prolonged intravenous therapy. J. Am. Med. Assoc. 235:2403-2431.

Nail, P.A., M.R. Thomas, and B.S. Eakin. 1980. The effect of thiamin and riboflavin supplementation on the level of those vitamins in human breast milk and urine. Am. J. Clin. Nutr. 33: 198-204.

Oldham, H.G., M.V. Davis, and L.J. Roberts. 1946. Thiamine excretions and blood levels of young women on diets containing varying levels of the B vitamins, with some observations on niacin and pantothenic acid. J. Nutr. 32:163-180.

Oldham, H., B.B. Sheft, and T. Porter. 1950. Thiamine and riboflavin intakes and excretions during pregnancy. J. Nutr. 41:231-245.

Pearson, W.N. 1962. Biochemical appraisal of the vitamin nutritional status in man. J. Am. Med. Assoc. 180:49-55.

Platt, B.S. 1958. Beriberi. II. Clinical features of endemic beriberi. Fed. Proc. Suppl. 17:8-20.

Platt, B.S. 1967. Thiamine defciency in human beriberi and in Wernicke's encephalopathy. Pp. 135-143 in G.E.W. Wolstenholme and M. O'Connor, eds. Thiamine Deficiency: Biochemical Lesions and Their Clinical Significance. Ciba Foundation Study Group No. 28. Churchill Livingstone London.

Raskin, N.H., and R.A. Fishman. 1976. Neurologic disorders in renal failure (second of two parts). N. Engl. J. Med. 294:204-210.

Reuter, H.C., B. Gassmann, and M. Bohm. 1967. Thiamine requirement in humans. Int. J. Vit. Res. 37:315-328.

Sauberlich, H.E., Y.F. Herman, and C.0. Stevens. 1970. Thiamin requirement of the adult human. Am. J. Clin. Nutr. 23:671-672.

Sauberlich, H.E., Y.F. Herman, C.O. Stevens, and R.H. Herman. 1979. Thiamin requirement of the adult human. Am. J. Clin. Nutr. 32:2237-2248.

Toverud, K.U. 1940. Excretion of aneurin in pregnant and lactating women  and in infants. Int. Z. Vitaminforsch. 10:255-267.

USI)A (U.S. Department of Agriculture). 1986. Nationwide Food Consumption Survey Continuing Survey of Food Intakes by Individuals: Men 19-50 Years, 1 Day, 1985. Report No. 85-3. Nutrition Monitoring Division, Human Nutrition Information Service. U.S. Department of Agriculture, Hyattsville, Md. 94 pp.

USI)A (U.S. Department of Agriculture). 1987. Nationwide Food Consumption Survey Continuing Survey of Food Intakes by Individuals: Women 19-50 Years and Their Children 1-5 Years, 4 Days, 1985. Report No. 85-4. Nutrition Monitoring Division, Human Nutrition Information Service, U.S. Department of Agriculture, Hyattsville, Md. 182 pp.

Warnock, L.G., C.R. Prudhomme, and C. Wagner. 1978. The determination of thiamin  pyrophosphate in blood and other tissues, and its correlation with erythrocyte transketolase activity. J. Nutr. 108:421-427.

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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Watson, A.J.S., J.F. Walker, G.H. Tomkin, M.M.R. Finn, and J.A.B. Keogh. 1981. Acute Wernicke's encephalopathy precipitated by glucose loading. Isr. J. Med. Sci. 150:301-303.

Williams, R.D., H.L. Mason, B.F. Smith, and R.M. Wilder. 1942. Induced thiamin (vitamin B1) deficiency and the thiamine requirement of man: further observations. Arch. Inter. Med. 69:721-738.

Williams, R.D., H.L. Mason, and R.M. Wilder. 1943. The minimum daily requirement of thiamine of man. J. Nutr. 25:71-97.

Wood, B., A. Gijsbers, A. Goode, S. Davis, J. Mulholland, and K. Breen. 1980. A study of partial thiamin restriction in human volunteers. Am. J. Clin. Nutr. 33:848-861.

Ziporin, Z.Z., W.T. Nunes, R.C. Powell, P.P. Waring, and H.E. Sauberlich. 1965. Thiamine requirement in the adult human as measured by urinary excretion of thiamine metabolites. J. Nutr. 85:297-304.

RIBOFLAVIN

Riboflavin is a water-soluble vitamin that functions primarily as a component of two flavin coenzymes-flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD)-that catalyze many oxidation-reduction reactions. Among the enzymes that require riboflavin is the FMN-dependent oxidase responsible for conversion of phosphorylated pyridoxine to functional coenzyme and the FADdependent hydroxylase involved in the conversion of tryptophan to niacin (McCormick, 1988).

Riboflavin is readily absorbed, largely in the proximal small intestine, and is excreted with its metabolites in the urine. In adults who ingest levels of riboflavin that are about at the RDA, only one-half to two-thirds of urinary flavin is riboflavin; the rest is found in several different oxidation products (Chastain and McCormick, 1987).

Under controlled conditions, riboflavin excreted over a 24-hour period offers the most reliable index of riboflavin nutrition. In men, urinary excretion of less than 10% of riboflavin intake may reflect potential riboflavin deficiency (Horwitt et al., 1950). When urine collections are difficult to obtain, the estimates of the riboflavin present in erythrocytes can provide some indication of riboflavin nutrition (Bates et al., 1981; Bessey et al., 1956).

Erythrocyte glutathione reductase (EGR), an enzyme that requires FAD as a coenzyme, has also been used to assess riboflavin deficiency (Tillotson and Baker, 1972). In erythrocytes from persons consuming a riboflavin-deficient diet, EGR activity increases when FAD is added in vitro, indicating that the apoenzyme is not saturated with the coenzyme. The ratio of EGR activity in erythrocytes with and without added FAD is considered the activity coefficient. Sauberlich et al.

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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(1972) suggested that an EGR activity coefficient above 1.2 may be an indication of riboflavin deficiency.

General Signs of Deficiency

Deficiency symptoms have been reported to include oral-buccal cavity lesions (e.g., cheilosis, angular stomatitis), a generalized seborrheic dermatitis, scrotal and vulval skin changes, and a normocytic anemia. Because riboflavin is essential to the functioning of vitamins B6 and niacin, some symptoms attributed to riboflavin deficiency are actually due to the failure of systems requiring these other nutrients to operate effectively (McCormick, 1988).

Dietary Sources and Usual Intakes

Animal protein sources such as meats, poultry, fish, and, especially, dairy products are good sources of riboflavin. Grain products naturally contain relatively low levels of riboflavin; however, enriched and fortified grains, cereals, and bakery products supply large amounts. Among adults in the United States, riboflavin intake from these plant sources averaged from 20 to 26% of the RDA in 19771978 (Cook and Welsh, 1987). Green vegetables such as broccoli, turnip greens, asparagus, and spinach are good sources.

The USDA found that adult men in the United States consumed an average of 2.08 mg of riboflavin per day in 1985 (USDA, 1986); the intake for adult women was 1.34 mg, and for their children 1 to 5 years of age, 1.57 mg (USDA, 1987).

Recommended Allowances
Adults

Data on which the RDA for riboflavin is based come primarily from several long-term feeding studies in a few humans conducted more than 40 years ago. These studies clearly show that a riboflavin intake of 0.55 mg or less per day results in clinically recognizable signs of riboflavin deficiency (Horwitt et al., 1950; Sebrell et al., 1941). Symptoms appeared after the subjects had been fed the low riboflavin diets for 89 days or longer. In other studies, no signs of deficiency were observed in men receiving 0.31 mg/ 1,000 kcal (Keys et al., 1944) and women receiving 0.35 mg/1,000 kcal (Williams et al., 1943) for periods ranging from 84 days to 288 days. Similarly, only 1 of 22 male subjects receiving from 0.75 to 0.85 mg of riboflavin per day for more than 2 years showed signs of riboflavin deficiency (Horwitt et al., 1950).

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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Subjects fed 0.75 to 0.85 mg of riboflavin per day excreted only marginally more urinary riboflavin than subjects receiving approximately 0.55 mg per day. But riboflavin excretion increased markedly when daily intake was increased from  1.1 to 1.6 mg/day in diets providing 2,200 kcal/day (Horwitt et al., 1950). In women, the proportion of ingested riboflavin excreted was shown to increase markedly at intakes above 1 mg/day in diets providing 1,850 kcal per day (Oldham  et al., 1950). Bessy et al. (1956) found that erythrocyte riboflavin levels were maintained when 1.6 mg/day was consumed by men but were low when 0.55 mg/day was consumed.

The data (summarized above) from controlled, long-term studies in humans fed deficient or low riboflavin intakes suggest that at riboflavin intakes of approximately 1 mg/day (0.5 mg/1,000 kcal), urinary riboflavin is only slightly greater than that observed when riboflavin  deficiency signs are observed. When  riboflavin intakes exceed this level, a higher proportion of consumed riboflavin is excreted via the urine.

These data have led previous RDA committees to consider that consumption of 0.6 mg of ribollavin per 1,000 kcal should supply the needs for essentially all healthy people and therefore to recommend a minimum intake of 1.2 mg/day per adult. The present subcommittee concluded that there are no new data that justify changes in the earlier basic recommendation for riboflavin. In the RDA table, variations in riboflavin intake at various ages are due primarily to changes in recommended caloric intakes at the ages listed.

Several factors are known to change indices of riboflavin status. More riboflavin is retained when nitrogen balance is positive, and more is excreted when nitrogen balance is negative (Pollack and Bookman, 1951; Windmueller et al., 1964). Increased energy expenditure has been related to increased riboflavin requirement. Periods of hard work have been shown to decrease urinary excretion of riboflavin in young men (Tucker et al., 1960), and moderate exercise has been shown to increase the EGR activity ratio and to decrease riboflavin excretion in young women consuming levels of riboflavin at about the RDA (Belko et al., 1983). In the studies of Belko et al. (1983), however, subjects consuming diets containing 1.0 to 1.2 mg of riboflavin per day had urinary riboflavin levels higher than those associated with riboflavin inadequacy, even after exercise. For this reason, the subcommittee has not recommended an increased RDA for riboflavin for people who undertake heavy exercise.

Pregnancy and Lactation 

As pregnancy progresses, women tend to excrete less riboflavin than do nonpregnant women eating similar

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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diets (Brzezinski et al., 1952; Jansen and Jansen, 1954). The EGR activity ratio also tends to increase during pregnancy (Bates et al., 1981; Heller et al., 1974). In view of the increased tissue synthesis for both fetal and maternal development, an additional riboflavin intake of 0.3 mg/day is recommended during pregnancy.

During lactation, the requirement is assumed to increase by an amount at least equal to that excreted in milk (Brzezinski et al., 1952), which has a mean riboflavin content of approximately 35 µg/100 ml (Roderuck et al., 1946; Toverud et al., 1950). At an average milk production of 750 ml/day and 600 ml/day during the first and second 6 months of lactation, riboflavin secretion is 0.26 mg/day and 0.21 mg/day, respectively. Since the utilization of the riboflavin for milk production is assumed to be 70% (WHO, 1965), and the coefficient of variation of milk production is 12.5% , an additional daily intake of 0.5 mg is recommended for the first 6 months of lactation and 0.4 mg thereafter.

Infants and Children 

Although clinical signs of ariboflavinosis are rare, the riboflavin allowance for children is an important consideration, since inadequacy may lead to growth inhibition. Snyderman et al. (1949) noted that an intake of 0.4 mg of riboflavin daily was sufficient for the maintenance of adequate blood and urine levels in infants weighing 5.9 to 9 kg. This corresponds to an intake of 0.53 mg/l,000 kcal for reference infants of these weights whose energy intakes are average. The amount of riboflavin consumed by the average breastfed infant ingesting 750 ml/day is 0.26 mg, or 0.48 mg/ 1,000 kcal. The allowance for the reference infant from birth to 6 months of age is set at 0.6 mg/l,000 kcal. This level allows for a margin of safety and is recommended for children of all ages and for adults.

Excessive Intakes and Toxicity

No cases of toxicity from ingestion of riboflavin have heen reported, since the capacity of the normal human gastrointestinal tract to absorb this modestly soluble vitamin is rather limited (McCormick, 1988).

References

Bates. C.J., A.M. Prentice, A.A. Paul, B.A. Sutcliffe, M. Watkinson, and R.G. Whitehead. 1981. Riboflavin status in Gambian pregnant and lactating women and its implications for Recommended Dietary Allowances. Am. J. Clin. Nutr. 34:928935.

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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Belko, A.Z., E. Obarzanek, H.J. Kalkwarf, M.A. Rotter, S. Bogusz, D. Miller, J.D. Haas, and D.A. Roe. 1983. Effects of exercise on riboflavin requirements of young women. Am. J. Clin. Nutr. 37:509-517.

Bessey, O.A., M.K. Horwitt, and R.H. Love. 1956. Dietary deprivation of riboflavin and blood riboflavin levels in man. J. Nutr. 58:367-383.

Brzezinski, A., Y.M. Bromberg, and K. Braun. 1952. Riboflavin excretion during pregnancy and early lactation. J. Lab. Clin. Med. 39:84-90.

Chastain, J.L., and D.B. McCormick. 1987. Flavin catabolites: identification and quantitation in human urine. Am. J. Clin. Nutr. 46:832-834.

Cook, D.A., and S.O. Welsh. 1987. The effect of enriched and fortified grain products on nutrient intake. Cereal Foods World 32:191-196.

Heller, S., R.M. Salked, and W.F. Korner. 1974. Riboflavin status in pregnancy. Am. J. Clin. Nutr. 27:1225-1230.

Horwitt, M.K., C.C. Harvey, O.W. Hills, and E. Liebert. 1950. Correlation of urinary excretion of riboflavin with dietary intake and symptoms of ariboflavinosis. J. Nutr. 41:247-264.

Jansen, A.P., and B.C. Jansen. 1954. Riboflavin-excretion with urine in pregnancy. Int. Z. Vitaminforsch. 25:193-199.

Keys, A., A.F. Henschel, O. Mickelson, J.M. Brozek, and J.H. Crawford. 1944. Physiological and biochemical functions in normal young men on a diet restricted in riboflavin. J. Nutr. 27:165-178.

McCormick, D.B. 1988. Riboflavin. Pp. 362-369 in M.E. Shils and V.R. Young, eds. Modern Nutrition in Health and Disease. Lea & Febiger, Philadelphia.

Oldham, H., B.B. Shett, and T. Porter. 1950. Thiamin and riboflavin intakes and excretions during pregnancy. J. Nutr. 41:231-245.

Pollack, H., and J.J. Bookman. 1951. Riboflavin excretion as a function of protein metabolism in the normal, catabolic, and diabetic human being. J. Lab. Clin. Med. 38:561-573.

Roderuck, C., N.M. Colrvell, H.H. Williams, and I.G. Macy. 1946. Metabolism of women during reproductive cycle; utilization of riboflavin during lactation. J. Nutr. 32:267-283.

Sauberlich, H.E., J.H. Judd, Jr., G.E. Nichoalds, H.P. Broquist, and W.J. Darby. 1972. Application of the erythrocyte glutathione reductase assay in evaluating riboflavin nutritional status in a high school population. Am. J. Clin. Nutr. 25:756-762.

Sebrell, W.H., Jr., R.E. Butler, J.G. Wooley, and H. Isbell. 1941. Human riboflavin requirement estimated by urinary excretion of subjects on controlled intake. Publ. Health Rep. 56:510-519.

Snyderman, S.E., K.G. Ketron, H.B. Burch, O.H. Lowry, O.A. Bessey, L.P. Guy, and L.E. Holt, Jr. 1949. The minimum riboflavin requirement of the infant. J. Nutr. 39:219-232.

Tillotson, J.A., and E.M. Baker. 1972. An enzymatic measurement of the riboflavin status in man. Am. J. Clin. Nutr. 25:425-431.

Toverud, K.U., G. Stearns, and I.G. Macy. 1950. Maternal Nutrition and Child Health: An Interpretative Review. Bulletin of the National Research Council No. 123. Prepared for the Committee on Maternal and Child Feeding of the Food and Nutrition Board. National Academy of Sciences, Washington, D.C. 174 pp.

Tucker, R.G., O. Mickelson, and A. Keys. 1960. The influence of sleep, work diuresis, heat acute starvation, thiamine intake and bed rest on human riboflavin excretion. J. Nutr. 72:251-261.

USDA (U.S. Department of Agriculture). 1986. Nationwide Food Consumption Survey Continuing Survey of Food Intakes by Individuals: Men 19-50 Years, 1 Day,

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1985. Report No. 85-3. Nutrition Monitoring Division, Human Nutrition Information Service, U.S. Department of Agriculture, Hyattsville, Md. 94 pp.

USDA (U.S. Department of Agriculture). 1987. Nationwide Food Consumption Survey Continuing Survey of Food Intakes by Individuals: Women 19-50 Years and Their Children 1-5 Years, 4 Days, 1985. Report No. 85-4. Nutrition Monitoring Division, Human Nutrition Information Service, U.S. Department of Agriculture, Hyattsville, Md. 182 pp.

WHO (World Health Organization). 1965. Nutrition in Pregnancy and Lactation. Report of a WHO Expert Committee. Technical Report Series No. 302. World Health Organization, Geneva.

Williams, R.D., H.L. Mason, P.L. Cusick, and R.M. Wilder. 1943. Observations on induced riboflavin deficiency and the riboflavin requirement of man. J. Nutr. 25:361-377.

Windmueller, H.G., A.A. Anderson, and O. Mickelsen. 1964. Elevated riboflavin levels in urine of fasting human subjects. Am. J. Clin. Nutr. 15:73-76.

NIACIN

Niacin is a water-soluble vitamin whose requirement by humans and many animal species is normally met in part by the conversion of dietary tryptophan to niacin. The term niacin is used here in the generic sense for both nicotinic acid and nicotinamide (niacinamide). Nicotinamide functions in the body as a component of two coenzymes, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). These coenzymes are present in all cells and participate in many metabolic processes, including glycolysis, fatty acid metabolism, and tissue respiration. Metabolism of nicotinamide nucleotides is regulated at both the cellular (Gholson, 1966) and the systemic levels (Dietrich et al., 1968) by a series of enzyme activations and inhibitions involving the synthesis and degradation of the niacin coenzymes. Determination of the urine levels of two of the many metabolites, N1-methylnicotinamide and its 2pyridone, have proved useful in estimating the nutritional adequacy of the niacin-tryptophan supply in the diet (Lee et al., 1969).

Pellagra is a multiple deficiency disease characterized by dermatitis, diarrhea, inflammation of the mucous membranes, and, in severe cases, dementia (Harris, 1941). It was a widespread problem in the southern United States in the early part of this century and still is in parts of Africa and Asia. This deficiency syndrome has been found to be associated with diets providing only low levels of niacin equivalents and other B vitamins, and flares up when the skin is subjected to strong sunlight. Some cases respond to niacin alone, others only to yeast or mixtures of niacin and other B vitamins (Sebrell and Butler, 1939).

Niacin, which is found in high concentrations in meats, is stable in foods and can withstand reasonable periods of heating, cooking, and

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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storage with little loss. In some foods, however, the bioavailability of the niacin may be low (see  below). Even when tryptophan intake is limited, a portion of it appears to be diverted into the niacin pathway (Brown et al., 1958; Goldsmith et al.. 1961; Horwitt et al., 1956; Nakagawa et al., 1973; Vivian et al., 1958).

Tryptophan to Niacin Interconversion

For calculating the adequacy of a diet as a source of niacin, a factor is needed for estimating the contribution of tryptophan to meeting the need for niacin. In four studies in which niacin status was judged by urinary excretion of niacin metabolites, the quantities of supplementary tryptophan required to give the same response as 1 mg of niacin ranged from 39 to 86 mg Goldsmith et al., 1961; Horwitt et al., 1956; Patterson et al., 1980; Vivian, 1964). The convention is to consider 60 mg of tryptophan as equivalent to 1 mg of niacin, and to regard each to be 1 niacin equivalent (NE) for calculating both dietary contributions and recommended allowances (Horwitt et al., 1981). The extent of conversion is, to some extent, under hormonal control and appears to increase during pregnancy or when contraceptive pills are used.

Dietary Sources and Usual Intakes

Some foods such as milk and eggs contain very little niacin but have sufficient tryptophan to more than offset the lack of niacin. Meat contains high levels of both preformed niacin and tryptophan. Tryptophan intake can be approximated by assuming that proteins contain at least 1.0% tryptophan, i.e., that 60 g of protein provide 600 mg of tryptophan or 10 NEs (Horwitt et al., 1981). If more precision is desired, the following closer approximations of tryptophan content may be used: corn products, 0.6%; other grains, fruits, and vegetables, 1.0%; meats, 1.1%; milk, 1.4%; and eggs, 1.5%  of the protein in each food. In the average U.S. diet, 65% of the protein comes from meat, milk, and eggs.

Some foodstuffs contain niacin in chemical combinations that result in its bioavailability being low (Carter and Carpenter, 1982; Darby et al., 1975; Gopalan and Jaya Rao, 1975; Mason et al., 1973). In mature cereal grains, as much as 70% of the niacin may be biologically unavailable because of the structure of the compounds in which it is bound. In considering cereal-based diets, therefore, it may be necessary to make an allowance for poor bioavailability unless the cereal has been treated with lime, a process that increases niacin availability

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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(Goldsmith et al., 1956). In typical U.S. diets, some 25 to 40% of the preformed niacin comes from grain products (USDA, 1984). If all this is provided by niacin naturally present in the grains, and one allowed for only 30% of this being available, the estimates for total intakes of NEs referred to above would have to be reduced by an average of 5 mg. In practice, much of the niacin comes from fully available, synthetic niacin added to fortify milled grain products. Values in most tables of food composition do not take into account the bioavailability of niacin, nor do they include an estimate of NEs. The latter values must then be calculated from information on the tryptophan content of foods.

Average diets in the United States for women ages 19 to 50 supply 700 mg of tryptophan daily, and for men 19 to 50, 1,000 mg. The corresponding values for preformed niacin are 16 and 24 mg, respectively. Thus, the calculated intakes of total NEs are 27 mg for women and 41 mg for men (USDA, 1984). The most recent estimates for the intakes of low-income women have given essentially the same values as those given above for all women in the earlier survey (USDA, 1987).

Recommended Allowances.
Adults 

There have been only a few studies in which subjects have been fed diets deficient in NEs but otherwise complete. Essentially all the information used in estimating niacin requirements for humans comes from studies conducted more than 30 years ago on adult men and women (Goldsmith et al., 1952, 1955, 1956; Horwitt et al., 1956). In one of these, niacin deficiency was observed in people receiving 4.9 NE/1,000 kcal and as much as 8.8 NE/day (Goldsmith, 1956). When these subjects were fed diets containing approximately 200 mg of tryptophan and varying levels of niacin, there was a significant increase in urinary niacin metabolites whenever they were given 8 to 10 mg of niacin (Goldsmith et al., 1955). These results suggest that a daily intake of 1 1.3 to 13.3 NEs (200 mg of tryptophan + 8 to 10 mg of niacin) is adequate to prevent depletion of body stores of niacin. In another study (Horwitt et al., 1956), no signs of pellagra were observed in 15 subjects receiving 4.4 NE/1,000 kcal or 9.2 to 12.3 NEs daily for 38 to 87 weeks.

Niacin recommendations over the past 20 years have been 6.6 NEs per 1,000 kcal and not less than 13 NEs at caloric intakes of less than 2,000 kcal for adults of all ages. The adequacy of this allowance has recently been confirmed in young men (Jacob et al., 1989). Allowances for adults are therefore unchanged.

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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Pregnancy and Lactation 

The increased conversion of tryptophan to niacin derivatives during pregnancy (Brown et al., 1961; Darby et al., 1953; Wertz et al., 1958) appears to be under hormonal control—a consequence of the increase in estrogen formation during pregnancy (Wolf, 1971). The increase in the urinary excretion of N1methylnicotinamide, also observed in pregnant women (Horwitt et al., 1981), reflects an enchanced capacity for the biosynthesis of nicotinate ribonucleotide from tryptophan. Despite the possible involvement of a biological mechanism that increases the ability of pregnant women to convert tryptophan to niacin derivatives, an increased niacin intake during pregnancy is recommended because of increased energy requirements. The allowance provides for an increase of 2 NEs daily.

The average lactating woman will secrete approximately 1.0 to 1.3 mg of preformed niacin daily (AAP, 1985; USDA, 1976; Wertz et al., 1958) in 750 ml of milk. Taking this into account and the recommended increase in energy expenditure to support lactation, the subcommittee recommends an additional 5 NEs per day throughout lactation.

Infants and Children 

There are no data on the niacin requirements of children from infancy through adolescence. It is known, however, that human milk contains approximately 1.5 mg of niacin and 210 mg of tryptophan per liter (AAP, 1985). This supplies 3.7 NEs per 750 ml of milk, or about 7 NEs per 1,000 kcal. Milk from a well-nourished mother appears to be adequate to meet the niacin needs of the infant. The niacin allowance recommended for formulafed infants up to 6 months of age is 8 NEs per 1,000 kcal.

The niacin allowances for children more than 6 months of age are based on the same standard as for adults, i.e., 6.6 NE/1,000 kcal and are increased in proportion to energy intake. Needs of teenagers are considered to be similar to those of adults. There is no evidence from epidemiological records of pellagra outbreaks that the young are more at risk than adults.

Excessive Intakes and Toxicity

Ingestion of nicotinic acid, but not of the amide, may produce vascular dilatation, or flushing. The ingestion of a pharmacological dose ranging from 3 to 9 g of nicotinic acid daily results in various metabolic effects, including increased utilization of muscle glycogen stores, decreased serum lipids, and decreased mobilization of fatty acids from adipose tissue during exercise (Darby et al., 1975).

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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References

AAP (Amercian Academy of Pediatrics). 1985. Composition of human milk: normative data. Appendix K. Pp. 363-368 in Pediatric Nutrition Handbook, 2nd ed. American Academy of Pediatrics, Elk Grove Village, Ill.

Brown, R.R., V.M. Vivian, M.S. Reynolds, and J.M. Price. 1958. Some aspects of tryptophan metabolism in human subjects. 11. Urinary tryptophan metabolites on low-niacin diet. 1. Nutr. 66:599-606.

Brown, R.R., M.J. Thornton, and J.M. Price. 1961. The effect of vitamin supplementation on urinary excretion of tryptophan metabolites by pregnant women. J. Clin. Invest. 40:617-623.

Carter, E.G.A., and K.J. Carpenter. 1982. The bioavailability for humans of bound niacin from wheat bran. Am. J. Clin. Nutr. 36:855-861.

Darby, W.J., W.J. McGanity, M.P. Martin, E. Bridgforth, P.M. Densen, M.M. Kaser, P.J. Ogle, J.A. Newbill, A. Stockell, M.E. Ferguson, O. Touster, G.S. McClellan, C. Williams, and R.O. Cannon. 1953. The Vanderbilt Cooperative Study of maternal and infant nutrition. IV. Dietary, laboratory and physical findings in 2,129 delivered pregnancies. J. Nutr. 51:565-597.

Darby, W.J., K.W. McNutt, and E.N. Todhunter. 1975. Niacin. Nutr. Rev. 33:289297.

Dietrich, L.S.L. Martinez, and L. Franklin. 1968. Role of the liver in systemic pyridine nucleotide metabolism. Naturwissenschaften 55:231-232.

Gholson, R.D. 1966. The pyridine nucleotide cycle. Nature 212:933-935.

Goldsmith, G.A. 1956. Experimental niacin deficiency. J. Am. Diet. Assoc. 32:312316.

Goldsmith, G.A., H.P. Sarett, U.D. Register, and J. Gibbens. 1952. Studies on niacin requirement in man. 1. Experimental pellagra in subjects on corn diets low in niacin and tryptophan. J. Clin. Invest. 31:533-542.

Goldsmith, G.A., H.L. Rosenthal, J. Gibbens, and W.G. Unglaub. 1955. Studies of niacin requirement in man. II. Requirement on wheat and corn diets low in tryptophan. J. Nutr. 56:371-386.

Goldsmith, G.A., J. Gibbens, W.G. Unglaub, and 0. N. Miller. 1956. Studies on niacin requirement in man. III. Comparative effects of diets containing lime-treated and untreated corn in the production of experimental pellagra. Am. J. Clin. Nutr. 4:151-160.

Goldsmith, G.A., O.N. Miller, and W.G. Unglaub. 1961. Efficiency of tryptophan as a niacin precursor in man. J. Nutr. 73:172-176.

Gopalan, C., and K.S. Jaya Rao. 1975. Pellagra and amino acid imbalance. Vitam. Horm. 33:505-542.

Harris, S. 1941. Clinical Pellagra. Mosby, St. Louis, Mo.

Horwitt, M.K., C.C. Harvey, W.S. Rothwell, J.L. Cutler, and D. Haffron. 1956. Tryptophan-niacin relationships in man: studies with diets deficient in riboflavin and niacin, together with observations on the excretion of nitrogen and niacin metabolites. J. Nutr. 60 Suppl. 1:1-43.

Horwitt, M.K., A.E. Harper, and L.M. Henderson. 1981. Niacin-tryptophan relationships for evaluating niacin equivalents. Am. J. Clin. Nutr. 34:423-427.

Jacob, R.A., M.E. Swendseid, R.W. McKee, C.S. Fu, and R.A. Clemens. 1989. Biochemical markers for assessment of niacin status in young men: urinary and blood levels of niacin metabolites. J. Nutr. 119:591-598.

Lee, Y.C., R.K. Gholson, and N. Raica. 1969. Isolation and identification of two new nicotinamide metabolites. J. Biol. Chem. 244:3277-3282.

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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Mason, J.B., N. Gibson, and E. Kodicek. 1973. The chemical nature of the bound nicotinic acid of wheat bran; studies of nicotinic acid-containing macromolecules. Br. J. Nutr. 30:297-311.

Nakagawa, I., T. Takahashi, A. Sasaki, M. Kajimoto, and T. Suzuki. 1973. Efficiency of conversion of tryptophan to niacin in humans. J. Nutr. 103:1195-1199.

Patterson, J.I., R.R. Brown, H. Linkswiler, and A.E. Harper. 1980. Excretion of tryptophan-niacin metabolites by young men: effects of tryptophan, leucine, and vitamin B6   intakes. Am. J. Clin. Nutr. 33:2157-2167.

Sebrell, W.H., and R.F. Butler. 1939. Riboflavin deficiency in man (ariboflavinosis). Public Health Rep. 54:2121-2131.

USDA (U.S. Department of Agriculture). 1976. Composition of Foods: Dairy and Egg Products, Raw, Processed, Prepared. Agriculture Handbook No. 8-1. U.S. Government Printing Office, Washington, D.C. 144 pp.

USDA (U.S. Department of Agriculture). 1984. Nationwide Food Consumption Survey. Nutrient Intakes: Individuals in 48 States, Year 1977-78. Report No. 1-2. Consumer Nutrition Division, Human Nutrition Information Service. U.S. Department of Agriculture, Hyattsville, Md. 439 pp.

USDA (U.S. Department of Agriculture). 1987. Nationwide Food Consumption Survey. Continuing Survey of Food Intakes of Individuals: Low-income Women 19-50 Years and Their Children 1-5 Years, 1 Day, 1986. Report No. 86-2. Nutrition Monitoring Division, Human Nutrition Information Service. U.S. I)epartment of Agriculture, Hyattsville, Md. 166 pp.

Vivian, V.M. 1964. Relationship between tryptophan-niacin metabolism and changes in nitrogen balance. J. Nutr. 82:395-400.

Vivian, V.M., M.M. Chaloupka, and M.S. Reynolds. 1958. Some aspects of tryptophan metabolism in human subjects. 1. Nitrogen balances, blood pyridine nucleotides and urinary excretion of N1-methylnicotinamide and N1-methyl-2-pryridone-5carboxamide on a low-niacin diet. J. Nutr. 66:587-598.

Wertz, A.W., M.F. Lojkin, B.S. Bouchard, and M.B. Derby. 1958. Tryptophan-niacin relationships in pregnancy. J. Nutr. 64:339-353.

Wolf, H. 1971. Hormonal alterations of efficiency of conversion of tryptophan to urinary metabolites of niacin in man. Am. J. Clin. Nutr. 24:792-799.

VITAMIN B6

Vitamin  B6 comprises three chemically, metabolically, and  functionally related forms-pyridoxine (pyridoxol, PN), pyridoxal (PL), and  pyridoxamine (PM). These forms are converted  in the liver, erythrocytes, and  other  tissues to pyridoxal phosphate (PLP) and pyridoxamine phosphate (PM P), which serve primarily as coenzymes in transamination reactions. PIP also participates in decarboxylation and racemization of A-amino acids, in other metabolic transformations of amino acids, and  in the metabolism of lipids and nucleic acids. In addition, it is the essential coenzyme for glycogen phosphorylase. The phosphoric acid esters of the active forms of vitamin B6 are hydrolyzed before release from cells. Also, PL can be further oxidized to pyridoxic acid and  other  inactive oxidation  products, which are excreted in the urine.

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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The various dietary forms of vitamin B6 are absorbed by intestinal mucosal cells through a nonsaturable process. Cellular B6 is metabolically phosphorylated, and two of the phospho-forms (PNP and PMP) are oxidized to PLP. PLP is largely present in the plasma as a PLP-albumin complex and in erythrocytes in association with hemoglobin.

The requirement for vitamin B6 increases as the intake of protein increases (Baker et al., 1964; Canham et al., 1969; Donald et al., 1971; Linkswiler, 1978; Miller and Linkswiler, 1967; Schultz and Leklem, 1981). This relationship is believed to reflect the major role of PLP in amino acid metabolism.

Vitamin B6 nutritional status can be assessed both clinically and biochemically by a variety of methods. Assessment methods include (1) direct measurements of the vitamer forms of B6 in the blood or urine (e.g., the level of coenzyme PLP in the plasma or the urinary excretion of 4-pyridoxic acid [4-PA], a metabolically inactive end product); (2) load tests (e.g., measurement of urinary tryptophan metabolites such as xanthurenic and kynurenic acids following an oral load of 2-5 g L-tryptophan); and (3) indirect functional tests that measure the activity of several vitamin B6-dependent enzymes (e.g., erythrocyte alanine aminotransferase in plasma or erythrocytes). Vitamin B6 nutriture is best assessed by a combination of these assessment methods (e.g., plasma PLP levels, urinary excretion of 4-PA, and the response of urinary metabolites to a 2-g tryptophan load test) (Leklem and Reynolds, 1981).

General Signs of Deficiency

Vitamin B6 deficiency rarely occurs alone and is most commonly seen in people who are deficient in several B-complex vitamins. Clinical signs of deficiency include epileptiform convulsions, dermatitis, and anemia (McCormick, 1988). Deficiency in infants leads to a variety of neurological symptoms as well as abdominal distress (Bessey et al., 1957; Coursin, 1954; Kirksey and Roepke, 1981). As protein intake increases, the onset of deficiency becomes more rapid.

Dietary Sources and Usual Intakes

The richest sources of vitamin B6 are chicken, fish, kidney, liver, pork, and eggs, each of which provides more than 0.4 mg per 100g serving. Other good sources are unmilled rice, soy beans, oats, whole-wheat products, peanuts, and walnuts. Dairy products and red meats are relatively poor sources. Losses of vitamin B6 through food

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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processing can be considerable. From 15 to 70% is lost in freezing fruits and vegetables, 50 to 70% in processing luncheon meats, and 50 to 90% in milling cereal, but little is lost in processing dairy products (Schroeder, 1971; Tarr et al., 1981).

Data on the vitamin B6 content of foods and its bioavailability are incomplete. Studies in animals and humans have shown, however, that bioavailability varies widely (Gregory and Kirk, 1978; Haskell, 1978; Kabir et al., 1983; Leklem et al., 1980; Nelson et al., 1977).

Approximately 40 drugs (e.g., isonicotinic acid hydrazide and penicillamine) are known to affect the metabolism or bioavailability of vitamin B6 (Bauernfeind and Miller, 1978; Bhagavan, 1985). Oral contraceptives alter tryptophan metabolism, and their use is associated with low plasma PLP values, but it is not clear that these low PLP values are associated with increased risk of vitamin B6 deficiency (Leklem et al., 1975; NRC, 1980).

In 1985, the average vitamin B6 intake of adult men in the United States was 1.87 mg (0.019 mg/g protein) (USDA, 1986). The corresponding intake for adult women was 1.16 mg (0.019 mg/g protein), and, for children 1 to 5 years old, 1.22 mg (0.023 mg/g protein) (USDA, 1987).

Recommended Allowances
Adults

Many studies on adult men have shown that 0.010 to 0.015 mg of vitamin B6 per gram of protein either prevented or eliminated the appearance of biochemical indicators of deficiency when protein intakes ranged from 54 to 165 g/day (Linkswiler, 1978; Miller and Linkswiler, 1967; Park and Linkswiler, 1970). Among women, Brown et al. (1975) reported that subjects needed from 0.8 to 2.0 mg of vitamin B6 per day when protein intake was 78 g (0.010 to 0.016 mg/g). Schultz and Leklem (1981), who measured urinary excretion of 4-PA and vitamin B6 as well as plasma PLP levels in 41 adult females, reported acceptable levels of each indicator at dietary intakes of 1.25 and 1.5 mg (0.0125 and 0.015 mg/g of protein).

A dietary vitamin B6 ratio of 0.016 mg/g protein appears to ensure acceptable values for most indices of nutritional status in adults of both sexes. The RDA is established in relation to the upper boundary of acceptable levels of protein intake, i.e., twice the RDA for protein (NRC, 1989), which is 126 g/day for men and 100 g/day for women. The RDA for vitamin B6 is, accordingly, 2.0 mg/day for men and 1.6 mg/day for women. These allowances are adequate for the reported average protein intakes of approximately 100 g/day for men (USDA, 1986) and 60 g/day for women (USDA, 1987), but may not be suf-

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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ficient for those whose habitual protein intake is at or above the reported 90th percentile of consumers. Because vitamin B6 and protein tend to occur together naturally in foods, vitamin B6 levels are likely to be adequate if protein is consumed at high levels in normal foodstuffs.

The RDA for vitamin B6 in this edition is somewhat lower than in the ninth edition, being based on a figure of 0.016 mg/g protein rather than 0.020 mg/g. The subcommittee concluded the latter figure is higher than can be justified by the requirements studies cited above.

Pregnancy and Lactation

The extra protein allowance for pregnancy should be accompanied by additional vitamin B6. Several investigators have observed that pregnant women have lower levels of both vitamin B6 and PLP in plasma (Cleary et al., 1975; Contractor and Shane, 1970; Hamfelt and Tuvemo, 1972; Roepke and Kirksey, 1979; Schuster et al., 1984) as well as decreased alanine aminotransferase activity and higher activity coefficients (stimulation of enzyme activity by the addition of PLP in vitro) (Lumeng et al., 1976; Schuster et al., 1981) compared to nonpregnant controls. It is uncertain whether these indices of vitamin B6 status reflect inadequate intake or normal physiological changes of pregnancy. In the absence of new data and the lack of any information on the requirements of the fetus, the subcommittee supports the recommendation in the ninth edition of the RDA that pregnant women increase their vitamin B6 intake by 0.6 mg/day.

The concentration of vitamin B6 in human milk is approximately 0.01 to 0.02 mg/liter during the first days of lactation and gradually increases to 0.10 to 0.25 mg/liter (Coursin, 1955; Karlin, 1959; Kirksey and West, 1978; West and Kirksey, 1976). The vitamin B6 content of milk reflects the nutritional status of the mother (Karlin, 1959; Kirksey and West, 1978; Roepke and Kirksey, 1979; Thomas et al., 1979; West and Kirksey, 1976). The ratio of vitamin B6 to protein in human milk averaged 13 µg/g at a consumption of less than 2.5 mg of vitamin B6 per day (Kirksey and West, 1978; West and Kirksey, 1976). In the absence of more recent information, the subcommittee maintains the recommendation in the ninth edition: an additional allowance of 0.5 mg of vitamin B6 per day during lactation.

Infants and Children

The vitamin B6 content and vitamin-to-protein ratio is generally low in milk from nonsupplemented women, and there is evidence of vitamin B6 deficiency symptoms in infants breastfed by women whose intakes are less than 2.0 mg/day and whose

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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milk contains less than 0. 1 mg of vitamin B6 per day (Kirksey et al., 1981; Kirksey and Udipi, 1985; McCoy et al., 1985). In healthy babies, vitamin B6 intakes of 0.3 mg/day protected against abnormal excretion of tryptophan metabolites following a load test (Bessey et al., 1957). General experience with proprietary formulas suggests that metabolic requirements are satisfied if the vitamin is present in amounts of 0.015 mg/g of protein or 0.04 mg/100 kcal (AAP, 1976; McCoy, 1978). The present subcommittee maintains the vitamin B6 recommendations of the ninth edition of the RDA—0.3 mg/day during the first 6 months of infancy and 0.6 mg/day for older infants.

Studies on the nutritional status of children and adolescents in relation to their intake of vitamin B6 are limited. In a study of 35 3to 4-year-old boys and girls, Fries et al. (1981) found 3 subjects whose intakes were less than the RDAs of 0.9 and 1.3 mg and whose blood levels of PLP were indicative of vitamin B6 inadequacy. Lewis and Nunn (1977) reported that 2- to 9-year-old children with an average daily intake of 1.10 mg of vitamin B6 (0.02 mg/g of protein) excreted 48% as 4-PA in their urine, suggesting intakes in excess of need. Kirksey et al. (1978) reported a calculated mean intake of 1.24 ± 0.70 mg for 12- to 14-year-old females. Since there are no new data to justify changes in the vitamin B6 recommendations for children and adolescents, the present subcommittee maintains the RDA of 0.02 mg/g protein from the ninth edition of the RDA. Allowances in the Sumnmary Table for these age groups are based on average protein intakes, as determined by the Nationwide Food Consumption Survey (USDA, 1984).

Excessive Intakes and Toxicity

The acute toxicity of vitamin B6 is low (McCormick, 1988). When taken in gram quantities for months or years (as it might be when self-administered or prescribed by physicians to treat premenstrual syndrome and several types of mental disorders), however, vitamin B6 can cause ataxia and a severe sensory neuropathy (Schaumburg, 1983). Pyridoxine toxicity was the apparent cause of neurological symptoms in 103 women attending a private clinic who took an average of 117 ± 92 mg of this nutrient for more than 6 months to more than 5 years (Dalton and Dalton, 1987). These women recovered completely from their symptoms within 6 months of discontinuing the supplements.

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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References

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Baker, E.M., J.E. Canham, W.T. Nunes, H.E. Sauberlich, and M.E. McDowell. 1964. Vitamin B6 requirement for adult men. Am. J. Clin. Nutr. 15:59-66.

Bauernfeind, J.C., and O.N. Miller. 1978. Vitamin B6: Nutritional and pharmaceutical usage, stability, bioavailability, antagonists, and safety. Pp. 78-110 in Human Vitamin B6 Requirements. Proceedings of a Workshop, June 11-12, 1976. Letterman Army Institute of Research, Presidio of San Francisco, California. A Report of the Committee on Dietary Allowances, Food and Nutrition Board. National Academy of Sciences, Washington, 1).C.

Bessey, ().A., D.J. Adam, and A.E. Hansen. 1957. Intake of vitamin B6 and infantile convulsions: a first approximation of requirements of pyridoxine in infants. Pediatrics 20:33-44.

Bhagavan, H.N. 1985. Interaction between vitamin B6 and drugs. Pp. 401-415 in R.D. Reynolds and J.E. Leklem, eds. Vitamin B6: Its Role in Health and Disease. Alan R. Liss, New York.

Brown, R.R., D.P. Rose, J.E. Leklem, H. Linkswiler, and R. Anand. 1975. Urinary 4-pyridoxic acid, plasma pyridoxal phosphate, and erythrocyte amino-transferase levels in oral contraceptive users receiving controlled intakes of vitamin B6. Am. J. Clin. Nutr. 28:10-19.

Canham, J.E., E.M. Baker, R.S. Harding, H.E. Sauberlich, and I.C. Plough. 1969. Dietary protein-its relationship to vitamin B6 requirements and function. Ann. N.Y. Acad. Sci. 166:16-29.

Cleary, R.E., L. Lumeng, and T.K. Li. 1975. Maternal and fetal plasma levels of pyridoxal phosphate at term: adequacy of vitamin B-6 supplementation during pregnancy. Am. J. Obstet. Gynecol. 121:25-28.

Contractor, S.F., and B. Shane. 1970. Blood and urine levels of vitamin B-6 in mother and fetus before and after loading of mother with vitamin B-6. Am. J. Obstet. Gynecol. 107:635-640.

Coursin, D.B. 1954. Convulsive seizures in infants with pyridoxine-deficient diet. J. Am. Med. Assoc. 154:406-408.

Coursin, D.B. 1955. Symposium on frontiers of human nutrition in relation to milk; vitamin B6 (pyridoxine) in milk. Q. Rev. Pediatr. 10:2-9.

Dalton, K., and M.J.T. Dalton. 1987. Characteristics of pyridoxine overdose neuropathy syndrome. Acta Neurol. Scand. 76:8-11.

Donald, E.A., L.D. McBean, M.H.W. Simpson, M.F. Sun, and H.E. Aly. 1971. Vitamin B6 requirement of young adult women. Am. J. Clin. Nutr. 24:1028-1041.

Fries, M.E., B.M. Chrisley, and J.A. Driskell. 1981. Vitamin B-6 status of a group of preschool children. Am. J. Clin. Nutr. 34:2706-2710.

Gregory, J.F., and J.R. Kirk. 1981. The bioavailability of vitamin B6 in foods. Nutr. Rev. 39:1-8.

Hamfelt, A., and T. Tuvemo. 1972. Pyridoxal phosphate and folic acid concentration in blood and erythrocyte aspartate aminotransferase activity during pregnancy. Clin. Chim. Acta 41:287-298.

Haskell, B.F. 1978. Analysis of vitamin B6. Pp. 61-71 in Human Vitamin B6 Requirements. Proceedings of a Workshop, June 11-12, 1976. Letterman Army Institute of Research, Presidio of San Francisco, California. A Report of the

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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Committee on Dietary Allowances, Food and Nutrition Board. National Academy of Sciences, Washington, D.C.

Kabir, H., J. Leklem, and L.T. Miller. 1983. Measurement of glycosylated vitamin B6 in foods. J. Food Sci. 40:1422-1425.

Karlin, R. 1959. Effect of excess administration of pyridoxine on the vitamin B6 content of human milk. Bull. Soc. Chim. Biol. 41:1085-1091.

Kirksey, A., and J.L.B. Roepke. 1981. Vitamin B-6 nutriture of mothers of three breast-fed neonates with central nervous system disorders. Fed. Proc. 40:864.

Kirksey, A., and S.A. Udipi. 1985. Vitamin B-6 in human pregnancy and lactation. Pp. 57-77 in R.D. Reynolds and .E. Leklem, eds. Vitamin B-6: Its Role in Health and Disease. Alan R. Liss, New York.

Kirksey, A., and K.D. West. 1978. Relationship between vitamin B6 intake and the content of the vitamin in human milk. Pp. 238-251 in Human Vitamin B6 Requirements. Proceedings of a Workshop, June 11-12, 1976. Letterman Army Institute of Research, Presidio of San Francisco, California. A Report of the Committee on Dietary Allowances, Food and Nutrition Board. National Academy of Sciences, Washington, D.C.

Kirksey, A., K. Keaton, R.P. Abernathy, and .L. Greger. 1978. Vitamin B6 nutritional status of a group of female adolescents. Am. J. Clin. Nutr. 31:946-954.

Kirksey, A., J.L.B. Roepke, and L.M. Styslinger. 1981. The vitamin B-6 content in human milk. Pp. 269-288 in J.E. I.eklem and R.D. Reynolds, eds. Methods in Vitamin B-6 Nutrition: Analysis and Status Assessment. Plenum Press, New York.

Leklem, J.E., and R.D. Reynolds. 1981. Recommendations for status assessment of vitamin B-6. Pp. 389-392 in J.E. Leklem and R.D. Reynolds, eds. Methods in Vitamin B-6 Nutrition: Analysis and Status Assessment. Plenum Press, New York.

Leklem, J.E., R.R. Brown, D.P. Rose, and H.M. Iinkswiler. 1975. Vitamin B6 requirements of women using oral contraceptives. Am. J. Clin. Nutr. 28:535-541.

Leklem, J.E., L.T. Miller, A.D. Perera, and D.E. Peffers. 1980. Bioavailability of vitamin B-6 from wheat bread in humans. J. Nutr. 110:1819-1828.

Lewis, J.S., and K.P. Nunn. 1977. Vitamin B6 intakes and 24-hr 4-pyridoxic acid excretions of children. Am. J. Clin. Nutr. 30:2023-2027.

Linkswiler, H.M. 1978. Vitamin B6 requirements of men. Pp. 279-290 in Human Vitamin B6 Requirements. National Academy of Sciences, Washington, D.C.

Lumeng, L., R.E. Cleary, R. Wagner, Y. Pao-Lo, and T.K. Li. 1976. Adequacy of vitamin B-6 supplementation during pregnancy: a prospective study. Am.J. Clin. Nutr. 29:1376-1383.

McCormick, D. 1988. Vitamin B6. Pp. 376-382 in M.E. Shils and V.R. Young, eds. Modern Nutrition in Health and Disease, 7th ed. Lea & Febiger, Philadelphia.

McCoy, E.E. 1978. Vitamin B6 requirements of infants and children. Pp. 257-271 in Human Vitamin B6 Requirements. Proceedings of a Workshop, June 11-12, 1976. Letterman Army Institute of Research, Presidio of San Francisco, California. A Report of the Committee on Dietary Allowances, Food and Nutrition Board. National Academy of Sciences, Washington, D.C.

McCoy, E., K. Strynadka, and K. Brunet. 1985. Vitamin B-6 intake and whole blood levels of breast and formula fed infants. Serial whole blood vitamin B-6 levels in premature infants. Pp. 79-96 in R.D. Reynolds and J.E. Leklem, eds. Vitamin B-6: Its Role in Health and Disease. Alan R. Liss, New York.

Miller, L.T., and H.M. Linkswiler. 1967. Effect of protein intake on the development of abnormal tryptophan metabolism by men during vitamin B6 depletion. 1. Nutr. 93:53-59.

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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Nelson, E.W., C.W. Burgin, and J.J. Cerda. 1977. Characterization of food binding of vitamin B6 in orange juice. J. Nutr. 107:2128-2134.

NRC (National Research Council). 1980. Recommended Dietary Allowances, 9th revised ed. Report of the Committee on Dietary Allowances, Food and Nutrition Board, Division of Biological Sciences, Assembly of Life Sciences. National Academy of Sciences, Washington, D.C. 185 pp.

NRC (National Research Council). 1989. Diet and Health: Implications for Reducing Chronic Disease Risk. Report of the Committee on Diet and Health, Food and Nutrition Board. National Academy Press, Washington, D.C. 750 pp.

Park, Y.K., and H. Linkswiler. 1970. Effect of vitamin B6 depletion in adult man on the excretion of cystathionine and other methionine metabolites. J. Nutr. 100:110-116.

Roepke, J.L.B., and A. Kirksey. 1979. Vitamin B-6 nutriture during pregnancy and lactation. 1. Vitamin B-6 intake, levels of the vitamin in biological fluids, and condition of the infant at birth. Am. J. Clin. Nutr. 32:2249-2256.

Schaumberg, H., J. Kaplan, A. Windebank, N. Vick, S. Ragmus, D. Pleasure, and M.J. Brown. 1983. Sensory neuropathy from pyrisoxine abuse. N. Engl. J. Med. 309:445-448.

Schroeder, H.A. 1971. Losses of vitamins and trace minerals resulting from processing and preservation of foods. Am. J. Clin. Nutr. 24:562-573.

Schultz, T.D., and J.E. Leklem. 1981. Urinary 4-pyridoxic acid, urinary vitamin B6 and plasma pyridoxal phosphate as measures of vitamin B-6 status and dietary intake of adults. Pp. 297-320 in J.E. Leklem and R.D. Reynolds, eds. Methods in Vitamin B-6 Nutrition: Analysis and Status Assessment. Plenum Press, New York.

Schuster, K., L.B. Bailey, and C.S. Mahan. 1981. Vitamin B-6 status of low-income adolescent and adult pregnant women and the condition of their infants at birth. Am. J. Clin. Nutr. 32:1731-1735.

Schuster, K., L.B. Bailey, and C.S. Mahan. 1984. Effect of maternal pyridoxine-HCI supplementation on the vitamin B-6 status of mother and infant on pregnancy outcome. J. Nutr. 114:977-988.

Tarr, J.B., T. Tamura, and E.L.R. Stokstad. 1981. Availability of vitamin B6 and pantothenate in an average American diet in man. Am. J. Clin. Nutr. 34:13281337.

Thomas, M.R., J. Kawamoto, S.M. Sneed, and R. Eaken. 1979. The effects of vitamin C, vitamin B6 and vitamin B12 supplementation on the breast milk and maternal status of well nourished women. Am. J. Clin. Nutr. 32:1679-1685.

USDA (U.S. Department of Agriculture). 1984. Nationwide Food Consumption Survey. Nutrient Intakes: Individuals in 48 States, Year 1977-78. Report No. 1-2. Consumer Nutrition Division, Human Nutrition Information Service. U.S. Department of Agriculture, Hyattsville, Md. 439 pp.

USDA (U.S. Department of Agriculture). 1986. Nationwide Food Consumption Survey. Continuing Survey of Food Intakes by Individuals: Men 19-50 Years, 1 Day, 1985. Report No. 85-3. Nutrition Monitoring Division, Human Nutrition Information Service. U.S. Department of Agriculture, Hyattsville, Md. 94 pp.

USDA (U.S. Department of Agriculture). 1987. Nationwide Food Consumption Survey. Continuing Survey of Food Intakes by Individuals: Women 19-50 Years and Their Children 1-5 Years, 4 Days, 1985. Report No. 85-4. Nutrition Monitoring Division, Human Nutrition Information Service. U.S. Department of Agriculture, Hyattsville, Md. 182 pp.

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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West, K.D., and A. Kirksey. 1976. Influence of vitamin B6 intake on the content of the vitamin in human milk. Am. J. Clin. Nutr. 29:961-969.

FOLATE

Folate and folacin are generic descriptors for compounds that have nutritional properties and chemical structures similar to those of folic acid (pteroylglutamic acid, or PGA). Metabolically active forms of folate have reduced (tetrahydro) pteridine rings and several glutamic acids attached (polyglutamates). Folate activity is measured by microbiological assay and by radioisotope dilution and binding methods.

Folates function metabolically as coenzymes that transport single carbon fragments from one compound to another in amino acid metabolism and nucleic acid synthesis. Deficiency of the vitamin leads to impaired cell division and to alterations of protein synthesiseffects most noticeable in rapidly growing tissues.

Different forms of folate vary in stability under various conditions, but in general, heat, oxidation, and ultraviolet light may cleave the folate molecule, rendering it inactive.

Dietary Sources and Usual Intakes

Folate is widely distributed in foods. Liver, yeast, leafy vegetables, legumes, and some fruits are especially rich sources. As much as 50% of food folate may be destroyed during household preparation, food processing, and storage. Comprehensive data on folate in food are published in the Agriculture Handbooks No. 8 (USDA, 1976-1989). However, food analysis methods present difficulty, and values in these tables may be as much as 20% low due to incomplete recovery (Phillips and Wright, 1983).

Folacin is reported to have been essentially unchanged from 1960 to 1985, averaging 280 to 300 pg in the U.S. food supply per capita per day (USDA, 1988). In Canada, the mean folate intake is reported to be 205  g/day for men and 149 µg/day for women (Health and Welfare Canada, 1977).

Bioavailability

Naturally occurring folates in foods have one or more glutamic acid residues as part of the molecule. Only monoglutamates are absorbed directly from the intestine, but folylpolyglutamate hydrolase enzymes associated with the intestinal mucosa release absorbable monoglutamates from polyglutamates. Approximately three-fourths

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of the folate in a mixed diet is present as polyglutamate (Butterworth et al., 1963). Estimates of the efficiency of absorption of food folates and the availability of polyglutamates relative to monoglutamates are quite variable, depending upon amount and type of test substance and other aspects of methodology (Rodriguez, 1978). Differences in the relative absorption of' folate measurable in different foods may also relate to the presence of folate hydrolase inhibitors, binders, or other unknown factors (Colman et al., 1975a; Tamura and Stokstad, 1973). Efficiency of absorption of folate may also increase when folate status is low (Iyenger and Babu, 1975).

Overall, approximately 90% of folate monoglutamate and 50 to 90% of folate polyglutamate ingested separately from food is absorbed, but this percentage is decreased in the presence of many foods, irrespective of whether the folate was derived from or added to the food (Colman et al., 1975b; Tamura and Stokstad, 1973). Food composition and intestinal absorption data indicate that the bioavailability of folate in the typical U.S. diet is about one-half that of crystalline folic acid, which is efficiently absorbed (Sauberlich et al., 1987).

Assessment of Folate Status

Well-nourished individuals excrete daily up to 40 µg of folate in the urine (Herbert, 1968) and approximately 200 µg in feces (Herbert et al., 1984). The folate content of bile is approximately 5 times that of serum, but enterohepatic recirculation tends to conserve the body pool of folate (Steinberg, 1984). Krumdieck et al. (1978) found that after an equilibration period following an oral dose of radioactive folate, radioactive fecal and urinary losses were approximately equal. Nonradioactive fecal loss greatly exceeds urinary folate excretion, indicating that feces also contain folate synthesized by intestinal bacteria. Fecal folate is therefore not a reliable indicator of turnover, intake, or absorption.

Herbert et al. (1962) estimated the adult male's total folate pool to be 7.5 ± 2.5 mg, a coefficient of variation of 33%. Liver folate is a major part of this total (Chanarin, 1979). Among 370 male and 190 female subjects, distributed among age groups ranging from 1 to more than 80 years old, autopsy data revealed an average hepatic folate concentration of about 7 µg/g liver (range, 3 to 16 µg/g) which did not vary greatly by age or sex (Hoppner and Lampi, 1980). Morphologic evidence of folate deficiency is not manifest until liver levels fall below 1 µg/g (Gailani et al., 1970). Red cell folate reflects liver folate fairly closely (Chanarin, 1979), and average daily dietary

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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folate intake correlates significantly with red cell folate (Bates et al., 1980).

In experimental human folate deficiency, serum and erythrocyte folate levels fall below accepted limits (3 ng/ml and 160 ng/ml, respectively) and evidence of defective DNA synthesis is seen as hypersegmentation of cells and abnormality in the sensitive deoxyuridine (dU) suppression test. Overtly megaloblastic bone marrow and macrocytic anemia are late consequences of deficiency (Herbert and Colman, 1988).

Recommended Allowances

Two general approaches have been used to estimate dietary allowances for folate (Anderson and Talbot, 1981; Rodriguez, 1978). One involves determining a minimum requirement for pure folic acid and increasing this amount to cover bioavailability, individual variation, and the need for adequate reserves. A second approach is evaluation of the average intake of food folate among persons in good folate status.

Adults and Adolescents 

The daily requirement for absorbed folate has been judged to be approximately 50 µg for adults, on the basis of observations that daily parenteral administration of this amount of PGA successfully treats uncomplicated folate deficiency anemia (Zalusky and Herbert, 1961). Dietary intake of about 100 µg/day has been reported to prevent development of folate deficiency (Banerjee et al., 1975; Herbert, 1962). Sauberlich et al. (1987) have concluded that women depleted of folate require 200 to 250 µg/day of dietary folate to maintain stable plasma levels or to restore them toward normal under experimental conditions (including blood sampling). Their graphic portrayal of plasma values indicates that levels were stabilized in four subjects given 80 µg pure PGA plus 20 µg of dietary folate. Forty adult males living in a metabolic ward on a strictly controlled diet containing an average of 200 µg of folate/day (~ 3 µg/ kg body weight) maintained normal serum and red cell folate levels for 6 months (Milne et al., 1983).

The minimum folate requirement can be estimated theoretically from the rate of loss of folate when none is fed. Loss of folate from the liver varies from 35 to 47 µg daily during folate depletion (Gailani et al., 1970). If extrahepatic stores are approximately half those in liver and are lost at the same rate, total daily folate loss in an adult eating essentially no folate would average about 60 µg, or roughly 1 µg/kg body weight.

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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Approximately 85% (range, 50 to 94%) of a 10 to 200 µg oral dose of folic acid is absorbed (Anderson et al., 1960; Jeejeebhoy et al., 1968; Waslien, 1977). Thus, a minimum requirement of approximately 1 µg/kg body weight, adjusted with a conservative estimate of 50% bioavailability of food folate and with a further adjustment for individual variabilty (coefficient of variation approximately 30%), suggests an allowance of approximately 3 µg/kg body weight for adults.

One can also approach the issue of folate allowances from population intakes. The average folate intake of both U.S. and Canadian populations is roughly 3 µg/kg body weight. Approximately 10% of people from these populations are reported to have low folate stores but no signs of deficiency (Senti and Pilch, 1984). Therefore, the average dietary intakes must provide about 90% of the adult population with sufficient absorbable folate for daily metabolic needs and also for substantial folate storage.

The elderly are considered in the same category as other adults with respect to folate needs (Rosenberg et al., 1982). On diets estimated to contain 135 µg folate per day, all of 21 elderly men and women living at home sustained erythrocyte folate greater than 100 ng/ml and were hematologically normal; 9 had levels less than 150 ng/ml (Bates et al., 1980).

The RDA for folate is accepted to be approximately 3 µg/kg body weight for men, nonpregnant, nonlactating women, and adolescents. The RDA is 200 µg for adult males and 180 µg for adult females. This allowance should provide for liver storage adequate to protect against development of a folate deficiency during short periods of inadequate intake.

Pregnancy and Lactation

Pregnancy increases the incidence of folate deficiency among populations with low or marginal intakes of the vitamin (Colman et al., 1975c; Giles, 1966; Lawrence and Klipstein, 1967). Even for populations consuming nutritionally sound diets, folic acid supplements ranging from 100 to 1,000 µg/day have been recommended by different investigators (Chanarin et al., 1968; Colman et al., 1974, 1975b). Baumslag et al. (1970) reported a reduced incidence of premature births in women given supplementary folic acid; an oral PGA supplement of 500 µg/day was associated with a 50% reduction in the incidence of small-for-date births among 134 pregnant women in India (Iyengar and Rajalakshmi, 1975).

A daily oral supplement of 100 µg of PGA prevented any fall in the mean erythrocyte folate of British women during pregnancy (Chanarin et al., 1968). The dietary folate content in the United

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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Kingdom was subsequently reported to be about 190 µg/day (Bates et al., 1982). Thus, in women who started pregnancy with moderate folate stores, folate deficiency probably was prevented by the equivalent of 200 µg of PGA per day (100 µg supplement plus 50% of the average population intake of dietary folate). In women with poor folate stores and whose diet was essentially devoid of folate, the progression of folate deficiency was as effectively prevented by administering a supplement of 300 µg of PGA daily in maize meal (a food that reduced availability by 44%, i.e., the effective dose was 168 µg of PGA) as it was by higher doses of more efficient vehicles (Colman et al., 1975b).

On the basis of a 50% food folate absorption, the RDA for folate is set at 400 µg/day during pregnancy to build or maintain maternal folate stores and to keep pace with the increased folate need to support rapidly growing tissue. This level can be met by a well-selected diet without food fortification or oral supplementation.

In the past, the demand of lactation on maternal folate reserves was estimated to be 20 µg/day, varying with the folate content and volume of milk (Matoth et al., 1965). This estimate was based on daily production of 850 ml of milk with an average folate content of 50 µg per liter. Ek (1983) reported that supplementation was unnecessary to maintain folate status in women in the socioeconomic middle class in Sweden. On the basis of daily production of 750 ml of milk, a coefficient of variation of 12.5%, and 50% absorption of food folate, the allowance for folate during lactation is set at the RDA of 180 µg plus 100 µg/day, a total of 280 µg/day during the first 6 months. The increment during the second 6 months, based on average milk production of 600 ml/day and the same adjustments, is 80 µg/day, a total of 260 µg/day.

Infants and Children 

Although serum folate in infants at birth is 3 times maternal folate, body stores at birth are small and are rapidly depleted by the requirements for growth, especially in premature infants. Full-term infants have higher liver stores of folate (Salmi, 1963). By 2 weeks of age, serum and erythrocyte folate fall below adult values and remain there during the entire first year of life (WHO, 1968). In a study of 20 infants aged 2 to 11 months, Asfour et al. (1977) demonstrated the nutritional adequacy of diets providing 3.6 µg of folate per kilogram of body weight per day over 6- to 9-month periods. Waslien (1977) concluded that 3.5 µg of folate per kilogram of body weight per day appeared adequate for infants up to 2 years of age.

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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Human and cow milk both contain about 50 µg of folate per liter; the concentration of folate in human colostrum and early milk is much lower. The needs of infants are adequately met by milk from humans or cows, but not by goat milk, which contains only 10 µg/ liter (Herbert, 1981).

Milk contains a factor that is essentially unaffected by pasteurization and that facilitates folate uptake by gut cells (Colman et al., 1981 a, 1981 b). Presumably, this factor facilitates both absorption of dietary folate and reabsorption of bile folate. Boiling, or the preparation of evaporated milk, destroys an average of 50% of the folate in cow's milk, so that infants receiving boiled formulas prepared from pasteurized, sterilized, or powdered cow's milk should be given additional folate to ensure an adequate intake (Ghitis, 1966). If the diet consists of goat's milk, folic acid supplementation should be given in any case.

Megaloblastic anemia due to dietary folate deficiency is rare in children. Those who drink vegetable or fruit juice or eat fresh uncooked fruits or vegetables each day maintain adequate folate status; deficiency has been observed among children whose entire diet consists of fine-particulate foods cooked for a long time (Herbert, 1981).

On the basis of the above considerations, the allowance for folate is set at 3.6 µg/kg per day for healthy infants from birth to age 1 year. This value should provide an adequate margin of safety and is comparable to the folate content of human milk. The folate RDA for healthy children between 1 and 10 years of age is interpolated from the allowances for infants and adolescents.

Excessive Intakes and Toxicity

Folic acid and the anticonvulsant drug phenytoin inhibit uptake of each other at the gut cell membrane and possibly at the brain cell membrane (Chanarin, 1979; Colman and Herbert, 1979). Very large doses of folic acid (100 or more times the RDA) may precipitate convulsions in persons whose epilepsy is in continuous control by phenytoin (Colman and Herbert, 1979). In laboratory animals, very large doses of folic acid given parenterally may precipitate in the kidneys, producing kidney damage and hypertrophy (Colman and Herbert, 1979). No untoward effects have been reported in women given 10 mg/day of folic acid continuously for 4 months (Butterworth et al., 1988). However, without evidence of benefit and with some potential for toxicity, excessive intakes of supplemental folate are not recommended.

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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Changes in Folate Allowances Compared to Ninth Edition

Recognition that diets containing about half as much folate as the previous RDA maintain adequate folate status (including liver stores greater than 3 µg/g) provides the basis for lowering the folate RDA in the present edition. The new  RDA  is consistent with the safe level of folate intake recommended by the FAO (1988).

References

Anderson, S.A., and J.M.Talbot. 1981. A Review of Folate Intake, Methodology, and Status. Life Sciences Research Office. Federation of American Societies for Experimental Biology, Bethesda, Md.

Anderson, B.E.H. Belcher, I. Chanarin, and D.L,. Mollin. 1960. The urinary and faecal excretion of radioactivity after oral doses of 3H-folic acid. Br. J. Haematol. 6:439-455.

Asfour, R., N. Wahbea, C. Waslien, S. Guindi, and W.J. Darby, Jr. 1977. Folacin requirements of children. III. Normal infants. Am. J. Clin. Nutr. 30:1098-1105.

Banerjee, D.K., A. Maitra, A.K. Basu, and J.B. Chatterjea. 1975. Minimal daily requirement of folic acid in normal Indian subjects. Indian J. Med. Res. 63:4553.

Bates, C.J., M. Fleming, A.A. Paul, A.E. Black, and A.R. Mandal. 1980. Folate status and its relation to vitamin C in healthy elderly men and women. Age Ageing 9:241-248.

Bates, C.J., A.E. Black, D.R. Phillips, A.J. Wright, and D.A. Southgate. 1982. The discrepancy between normal folate intakes and the folate RDA. Human  Nutr. Appl. Nutr. 36:422-429.

Baumslag, N., T. Edelstein, and J. Metz. 1970. Reduction of incidence of prematurity by folic acid supplementation in pregnancy. Br.  Med. J. 1:16-17.

Butterworth, C.E., Jr. R. Santini, Jr. and W.B. Frommeyer, Jr. 1963. The pteroylglutamate composition of American diets as determined by chromatographic fractionation. J. Clin. Invest. 42:1929-1939.

Butterworth, C.E.. K. Hatch, P. Cole, H.E. Sauberlich, T. Tamura, P.E. Cornwell, and S.J. Soong. 1988. Zinc concentration in plasma and erythrocytes of subjects receiving folic acid supplementation. Am. J. Clin. Nutr. 47:484-486.

Chanarin, I. 1979. The Megaloblastic Anaemias, 2nd ed. Blackwell, Oxford.

Chanarin, I., D. Rothman, A. Ward, and J. Perry. 1968. Folate status and requirement in pregnancy. Br. Med. J. 2:390-394.

Colnan, N., and V. Herbert. 1979. Dietary assessments with special emphasis on prevention of folate deficiency. Pp. 23-33 in M.I. Botez and E.H. Reynolds, eds. Folic Acid in Neurology, Psychiatry, and Internal Medicine. Raven Press, New York.

Colman, N., M. Barker, R. Green, and J. Metz. 1974. Prevention of folate deficiency in pregnancy by food fortification. Am. J. Clin. Nutr. 27:339-344.

Colnan, N., R. Green, and J. Metz. 1975a. Prevention of folate deficiency by food fortification. II. Absorption of folic acid from fortified staple foods. Am. J. Clin. Nutr. 28:459-464.

Colman, N., J.V. Larsen, M. Barker, F.A. Barker, R. Green, and J. Metz. 1975b. Prevention of folate deficiency by food fortification. II. Effect in pregnant subjects of varying amounts of added folic acid. Am. J. Clin. Nutr. 28:465-470.

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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Colman, N., E.A. Barker, M. Barker, R. Green, and J. Metz. 1975c. Prevention of folate deficiency by food fortification. IV. Identification of target groups in addition to pregnant women in an adult rural population. Am. J. Clin. Nutr. 28:471-476.

Colman, N., N. Hettiarachchy, and V. Herbert. 1981a. Detection of a milk factor that facilitates folate uptake by intestinal cells. Science 211:1427-1429.

Colman, N., J.-F. Chen, W. Gavin, and V. Herbert. 1981b. Factors affecting enhancement by milk of folate uptake into intestinal cells. Blood 58 Suppl. 1:26a.

Ek, J. 1983. Plasma, red cell, and breast milk folacin concentrations in lactating women. Am. J. Clin. Nutr. 38:929-935.

FAO (Food and Agriculture Organization). 1988. Requirements of Vitamin A, Iron, Folate and Vitamin B 12. Report of a Joint FAO/WHO Expert Consultation. FAO Food and Nutrition Series No. 23. Food and Agriculture Organization, Rome. 107 pp.

Gailani, S.D., R.W. Carey, J.F. Holland, and J.A. O'Malley. 1970. Studies of folate deficiency in patients with neoplastic diseases. Cancer Res. 30:327-333.

Ghitis, J. 1966. The labile folate of milk. Am. J. Clin. Nutr. 18:452-457.

Giles, C. 1966. An account of 335 cases of megaloblastic anemia of pregnancy and the puerperium. J. Clin. Pathol. 19: 1-11.

Health and Welfare Canada. 1977. Food Consumption Patterns. Bureau of Nutritional Sciences, Department of National Health and Welfare. Canadian Government Publishing Centre, Ottawa.

Herbert, V. 1962. Experimental nutritional folate deficiency in man. Trans. Assoc. Am. Physicians 75:307-320.

Herbert, V., N. Cuneen, L. Jaskiell, and C. Kapff. 1962. Minimal daily adult folate requirement. Arch. Intern. Med. 110:649-652.

Herbert, V. 1968. Nutritional requirements for vitamin B12 and folic acid. Am. J. Clin. Nutr. 21:743-752.

Herbert, V. 1981. Nutritional anemias of childhood-Folate, B12: the megaloblastic anemias. Pp. 133-144 in R.M. Suskind, ed. Textbook of Pediatric Nutrition. Raven Press, New York.

Herbert, V., and N. Colman. 1988. Folic acid and vitamin B12. Pp. 388-416 in M. E. Shils and V. Young, eds. Modern Nutrition in Health and Disease, 7th ed. Lea & Febiger, Philadelphia.

Herbert, V., G. Drivas, C. Manusselis, B. Mackler, J. Eng, and E. Schwartz. 1984. Are colon bacteria a major source of cobalamin analogues in human tissues? 24-h human stool contains only about 5 µg cobalamin but about 100 µg apparent analogue (and 200 µg folate). Trans. Assoc. Am. Physicians 97:161-171.

Hoppner, K., and B. Lampi. 1980. Folate levels in human liver from autopsies in Canada. Am. J. Clin. Nutr. 33:862-864.

Iyengar, L., and S. Babu. 1975. Folic acid absorption in pregnancy. Br. J. Obstet. Gynaecol. 82:20-23.

Iyengar, L., and K. Rajalakshmi. 1975. Effect of folic acid supplement on birth weights of infants. Am. J. Obstet. Gynecol. 122:332-336.

Jeejeebhoy, K.N., H.G. Desai, A.V. Borkar, V. Deshpande, and S.M. Pathare. 1968. Tropical malabsorption syndrome in West India. Am. J. Clin. Nutr. 21:9941006.

Krumdieck, C.I., K. Fukushima, T. Fukushima, T. Shiota, and C.E. Butterworth, Jr. 1978. A long-term study of the excretion of folate and pterins in a human subject after ingestion of 14C folic acid, with observations on the effect of diphenylhydantoin administration. Am. J. Clin. Nutr. 31:88-93.

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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awrence, C., and F.A. Klipstein. 1967. Megaloblastic anemia of pregnancy in New York City. Ann. Intern. Med. 66:25-34.

Matoth, Y., A. Pinkas, and C. Sroka. 1965. Studies on folic acid in infancy. III. Folates in breast fed infants and their mothers. Am. J. Clin. Nutr. 16:356-359.

Milne, D. B., L.K. Johnson, J.R. Mahalko, and H.H. Sandstead. 1983. Folate status of adult males living in a metabolic unit: possible relationships with iron nutriture. Am. J. Clin. Nutr. 37:768-773.

Phillips, D.R., and A.J.A. Wright. 1983. Studies on the response of Lactobacillus casei to folate vitamin in foods. Br. J. Nutr. 49: 181-186.

Rodriguez, M .S. 1978. A conspectus of research on folacin requirements of man. J. Nutr. 108:1983-2103.

Rosenberg,  I.H., B.B. Bowman, B.A. Cooper, C.H. Halsted, and  J. Lindenbaum. 1982. Folate nutrition in the elderly. Am. J. Clin. Nutr. 36:1060-1066.

Salmi, H.A. 1963.  Comparative studies on vitamin Bl2 in developing organisms and placenta.  Human and animal investigations with reference to the effects of low vitamin B12 diet on tissue vitamin B12 concentrations in rat. Ann. Acad. Sci. Fenn. 103: 1-91.

Sauberlich, H.E., M.J.. Kretsch, J.H. Skala, H.L. Johnson, and P.C. Taylor. 1987. Folate requirement and metabolism in nonpregnant women. Am. J. Clin. Nutr. 46:1016-1028.

Senti, F.R., and S.M. Pilch, eds. 1984. Assessment of the Folate Nutritional Status of the  U.S. Population Based on Data Collected in the Second National Health and Nutrition Fxamination Survey, 1976-1980. Life Sciences Research Office. Federation of American Societies for Experimental Biology, Bethesda, Md. 96 pp.

Steinberg, S.E. 1984. Mechanisms of folate homeostasis. Am. J. Physiol. 246:G319G324.

Tamura, T. and E.L.R. Stokstad. 1973. The availability of food folate in man. Br. J. Haematol. 25:513-532.

USDA (U.S. Department of Agriculture). 1976-1989. USI)A Agricultural Handbook Series 8. Composition of Foods-Raw, Processed, and Prepared. Nutrient Data Research, Human Nutrition Information Service. U.S. Department of Agriculture, Hyattsville, Md. (various pagings)

USDA (U.S. Department of Agriculture). 1988. The Nutrient Content of the U.S. Food Supply. Tables of Nutrients and Food Provided by the U.S. Food Supply. Human Nutrition Information Service Report No. 299-21. U.S. Department of Agriculture.  Hyattsville, Md. 72 pp.

Waslien, C.I. 1977. Folacin requirements of infants. Pp. 232-246 in Folic Acid: Biochemistry and Physiology in Relation to the Human Nutrition Requirement. Report of the Food and Nutrition Board, National Research Council. National Academy of Sciences, Washington, D.D.

WHO (World Health Organization). 1968. Nutritional Anaemias. Report of a Scientific Group.  WHO Technical Report Series No. 405. World Health Organizatin.  Geneva.

Zaluky, R. and V. Herbert. 1961. Megaloblastic anemia in scurvy with response to 50 micrograms of folic acid daily. N. Engl. J. Med. 265:1033-1038.

VITAMIN B12

The terms vitamin  B12 and  cobalamin  refer to all members of a group of large cobalt-containing corrinoids that can be converted to methylcobalamin or 5'-deoxyadenosylcobalamin, the two cobalamin

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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coenzymes active in human metabolism. Cyanocobalamin is the commercially available form of vitamin B12 used in vitamin pills and pharmaceuticals. This form is water soluble and heat stable and, when given either orally or parenterally, is converted by the removal of cyanide to the forms that are metabolically active in humans. In plasma and tissue, the predominant forms are methylcobalamin, adenosylcobalamin, and hydroxocobalamin (Dolphin, 1982). Animal products are the primary dietary source of the vitamin. The dominant forms in meat are adenosyl- and hydroxocobalamin, whereas dairy products, including human milk, contain mainly methyl- and hydroxocobalamin (Gimsing and Nex, 1983).

Dietary Sources and Usual Intakes

Bacteria, fungi, and algae can synthesize vitamin B12, but yeasts, higher plants, and animals cannot. In the human diet, vitamin B12 is supplied primarily by animal products, where it has accumulated from bacterial synthesis. Plant foods are essentially devoid of vitamin B12 except for adventitious inclusion of microbially formed B, in soil or water.

The average dietary vitamin B12 intake of adult men in the United States was 7.84 µg/day in 1985 (USDA, 1986). The corresponding intakes for adult women and their children 1 to 5 years of age were 4.85 µg and 3.80 µg/day, respectively. About 5 to 30% of the reported vitamin B12 in foods may be microbiologically active noncobalamin corrinoids rather than true vitamin B12 (Herbert et al., 1984).

An additional nondietary source of small amounts of absorbable vitamin B12 may be bacteria in the small intestine of humans (Albert et al., 1980). A 24-hour human stool contains approximately 5 µg of cobalamin and about 100 µg of non-B12 analogs, produced in part by bacteria in the colon (Herbert et al., 1984). Cobalamin does not, however, appear to be absorbed from the colon (Dolphin, 1982).

General Signs of Deficiency

Vitamin B,, deficiency results in macrocytic, megaloblastic anemia, in neurological symptoms due to demyelination of the spinal cord and brain and the optic and peripheral nerves, and in other less specific symptoms (e.g., sore tongue, weakness). Neuropsychiatric manifestations of vitamin B,, deficiency are seen in the absence of anemia, particularly in the elderly (Lindenbaum et al., 1988). Dietary deficiency of vitamin B12 is rare; more than 95% of the vitamin B12

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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deficiency seen in the United States is due to inadequate absorption (Herbert, 1984).

The coenzyme methylcobalamin catalyzes a transmethylation from a folic acid cofactor to homocysteine to form methionine. This reaction releases the unmethylated folate cofactor for other single carbon transfer reactions important to nucleic acid synthesis. This reaction is a site of B12-folate interaction and may relate to the similarity in B,2 and folate deficiency signs (Herbert and Colman, 1988). The other cobalamin coenzyme, deoxyadenosylcobalamin, catalyzes the conversion of methylmalonyl-coenzyme A to succinyl-coenzyme A, a reaction in the pathway for the degradation of certain amino acids and odd-chain fatty acids. Blockage of this reaction in B12 deficiency leads to the characteristic increased urinary excretion of methylmalonic acid.

Metabolism

The intestinal absorption of vitamin B12 takes place at receptor sites in the ileum, mediated by a highly specific binding glycoprotein (Castle's intrinsic factor), which is secreted in the stomach. In crossing the intestinal mucosa, vitamin B12 is transferred to the plasma transport protein transcobalamin II, which delivers the vitamin to cells. Absorption may also occur by simple diffusion, a process that probably accounts for the absorption of only 1 to 3% of the vitamin consumed in ordinary diets. This mechanism becomes biologically important when pharmacologic amounts (30 µg or more) of the free vitamin are ingested (Herbert and Colman, 1988).

At intakes of 0.5 µg or less, approximately 70% of the available vitamin is absorbed (Heyssel et al., 1966). The percentage absorbed decreases as the intake of vitamin B12increases, although the absolute amount of B12 absorbed increases. A maximum of about 1.5 µg is absorbed from single oral doses ranging from 5 to 50 µg (Chanarin, 1979). Intrinsic factor-mediated B12 absorption appears to be a saturable process, but absorption of 1.5 µg in one meal does not preclude absorption of normal amounts of the vitamin some hours later (FAO, 1988).

An effective enterohepatic circulation recycles the vitamin from bile and other intestinal secretions, accounting in part for its long biological half-life. In pernicious anemia, vitamin B12 is not absorbed from the diet or reabsorbed from the bile due to lack of intrinsic factor activity. The importance of reabsorption of cobalamin excreted in the bile is illustrated by the fact that vegetarians who eat no animal products (but may receive small amounts from bacterial sources and

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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contaminants) develop vitamin B12 deficiency only after 20 to 30 years, but in pernicious anemia or with other absorptive defects, vitamin B12 deficiency may develop in as short a time as 2 to 3 years (Chanarin, 1979; Herbert, 1984).

Pool Size and Turnover

Adams (1962) estimated total body vitamin B12 content to be 2.2 mg, based on analysis of tissues obtained at autopsy. This pool size (2 to 2.5 mg) was confirmed by Hall (1964) and Linnell et al. (1974). Reizenstein et al. (1966) calculated the body pool to be 3.0 mg as measured by radioisotope dilution.

The daily loss of vitamin B12 is approximately 0.1% (range, 0.05 to 0.2%) of the body pool, regardless of pool size (Heyssel et al., 1966). Using a whole-body counting technique, Heinrich (1964) found the half-life of a tracer dose to be 1,360 days and estimated the daily loss to be 2.55 µg, and Reizenstein et al. (1966) calculated a daily loss of 1.2 µg from two healthy subjects. Hall (1964) reported half-life to range from 480 to 1,284 days and the average daily loss of radiolabeled vitamin B12 to be 1.3 µg, almost equally divided between urine and feces.

Basis for Establishing Allowances

In patients with pernicious anemia, daily injections of 0.1 µg of cyanocobalamin are reported to produce suboptimal hematologic responses (Sullivan and Herbert, 1965), whereas doses of 0.5 to 1.0 µg/ day have maintained patients with pernicious anemia in complete hematologic and neurologic remission (Herbert, 1968). Patients with pernicious anemia or those who have undergone total gastrectomy are not, however, good models for determining normal dietary requirements, because they are unable to reabsorb the B12 excreted in the bile. Nonetheless, they do provide information on the gross requirement for absorbed B12.

Other evidence derives from studies of persons whose diets are low or deficient in vitamin B12. Deficiency can be, but rarely is, produced by a strict vegetarian (i.e., vegan) diet devoid of meat, eggs, and dairy products. An Indian woman resident of London developed deficiency with a diet containing 0.5 µg of vitamin B12 per day (Stewart et al., 1970). Intakes in four other deficiency cases ranged from 0.07 to 0.25 µg/day (Baker and Mathin, 1981). Only 21 of 431 Australian vegetarians had unacceptable blood levels of B12 at an average intake of 0.26 ± 0.23 µg/day (mean ± SD), and none of these developed

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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deficiency symptoms over a 1-year period of evaluation (Armstrong et al., 1974). An intake of 0.3 to 0.65 µg/day in food produced satisfactory hematologic responses in vitamin B12-deficient Indian patients (Baker and Mathin, 1981). Although serum concentrations of vitamin B,, remained below normal in these cases, bone marrow became normoblastic, and there was no anemia.

These findings suggest that the adult requirement for vitamin B12 is approximately 0.5 µg/day for persons with low serum B12 concentrations and whose pool size is presumed to be small. The evidence of the long lag period before symptoms of deficiency appear when absorption is impaired suggests that the usual pool size of omnivores (2 to 3 mg) exceeds daily needs by perhaps three orders of magnitude. To maintain the usual pool size with turnover rates as reported above (half-life of 480 to 1,360 days) would require 1 to 3 µg/day. Estimates of requirement are necessarily dependent on a judgment as to desirable pool size.

Recommended Allowances
Adults 

A dietary intake of 1 µg daily can be expected to sustain average normal adults. To allow for biological variation and the maintenance of normal serum concentrations and substantial body stores, the vitamin B2 RDA for adults is set at 2.0 µg. The subcommittee has concluded that a substantial body store is desirabe in view of the increasing prevalence of achlorhydria and pernicious anemia beyond age 60 (Chanarin, 1979). Dietary intake will frequently exceed the RDA, but this is not considered a justification for either raising the allowance or modifying the diet.

The results of various surveys have indicated that although serum vitamin B12 levels decline in the elderly (Carmel and Karnaze, 1985), they tend to remain in the normal range (Garry et al., 1984). The evidence reported by Herbert (1985) suggests that the decline in the mean serum Bl2 level is due to the gradual appearance among the elderly of B12 malabsorption. Such malabsorption would require injection of vitamin B12, rather than an increase in the RDA for B12 in the elderly. Measurement of cobalamin in serum among the elderly will identify those who require medical intervention (Herbert, 1985; Herzlich et al., 1985).

Pregnancy and Lactation 

From analysis of the vitamin B12 content of stillborn infants from normally nourished mothers, FAO (1988) estimated that fetal demands are approximately 0.1 to 0.2 µg/day. The placenta concentrates vitamin B12, and the serum B12 levels of

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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newborns are double that of their mothers (Giugliani et al., 1985). Normally, maternal body stores are sufficient to meet the needs of pregnancy, and it is unlikely that any increment in vitamin B12 intake is needed. An additional allowance of 0.2 µg/day can, however, be justified.

Vitamin B12 in human milk parallels the concentration in serum. At 6 months postpartum, 0.6 µg/liter was found in the milk of wellnourished women in the United States (Thomas et al., 1980). This would mean a loss of 0.45 µg in 750 ml of human milk, or 0.56 µg/ day at the upper level of production. An additional allowance of 0.6 µg/day is recommended for lactating women.

Symptoms of vitamin B12 deficiency have been observed in some breastfed infants of women who are strict vegetarians (Higginbottom et al., 1978; Specker et al., 1988). Pregnant and lactating women adhering to diets devoid of animal-source foods should be advised to take supplementary vitamin B12 at RDA levels (i.e., 2.2 and 2.6 µg/ day, respectively).

Infants and Children 

Since overt vitamin B12 deficiency does not occur in infants breastfed by women with adequate serum vitamin B12 levels (Lampkin et al., 1966), and vitamin B12-deficient infants of B12-deficient vegetarian mothers show a full therapeutic response to oral doses of 0.1 µg/day (Jadhav et al., 1962), the RDA for the young infant has been set at 0.3 µg/day (i.e., 0.05 µg/kg body weight) to allow a substantial margin for storage. The RDAs for older infants and preadolescent children have been based on progressive increases with increasing body size (at 0.05 µg/kg body weight) until the RDA for adults (2 µg) is reached.

Excessive Intakes and Toxicity

No clear toxicity has been reported from daily oral ingestion of up to 100 µg. Similarly, no benefit has been reported in nondeficient people from such large quantities.

Changes in Vitamin B12 Allowances Compared to Ninth Edition

The present RDAs for vitamin B12 are one-third to one-half lower than those given in the ninth edition. They are, however, approximately double the safe level of intake of vitamin B12 established by the FAO (1988). The difference in recommendations based on the same body of evidence reflects the present subcommittee's conserv-

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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ative stance on the desirability of maintaining a substantial body pool of vitamin B12.

References

Adams, J.F. 1962. The measurement of the total assayable vitamin Bl2 in the body. P. 397 in C. Heinrich, ed. Vitamin B12 und Intrinsic Faktor. Ferdinand Enke, Stuttgart, Federal Republic of Germany.

Albert, M.J., V.I. Mathan, and S.J. Baker. 1980. Vitamin B12 synthesis by human small intestinal bacteria. Nature 283:781-782.

Armstrong, B.K., R.E. Davis, D.J. Nicol, A.J. van Merwyk, and C.J. Larwood. 1974. Hematological, vitamin B12, and folate studies on Seventh-Day Adventist vegetarians. Am. J. Clin. Nutr. 27:712-718.

Baker, S.J., and V.I. Mathan. 1981. Evidence regarding the minimal daily requirement of dietary vitamin B12. Am. J. Clin. Nutr. 34:2423-2433.

Carmel, R., and D.S. Karnaze. 1985. The deoxyuridine suppression test identifies subtle cobalamin deficiency in patients without typical megaloblastic anemia. J. Am. Med. Assoc. 253:1284-1287.

Chanarin, 1. 1979. The Megaloblastic Anaemias, 2nd ed. Blackwell, Oxford.

Dolphin, D., ed. 1982. B12 Vol. 2. Biochemistry and Medicine. John Wiley & Sons, New York. 505 pp.

FAO (Food and Agriculture Organization). 1988. Requirements of Vitamin A, Iron, Folate, and Vitamin B12. Report of a Joint FAO/WHO Expert Consultation. FAO Food and Nutrition Series No. 23. Food and Agriculture Organization, Rome. 107 pp.

Garry, P.J., J.S. Goodwin, and W.C. Hunt. 1984. Folate and vitamin B12 status in a healthy elderly population. J. Am. Geriatr. Soc. 32:719-726.

Gimsing, P., and E. Nex. 1983. The forms of cobalamin in biological materials. Pp. 7-30 in C.A. Hall, ed. The Cobalamins. Churchill Livingstone, Edinburgh.

Giugliani, E.R.J., S.M. Jorge, and A.L. Gonçalves. 1985. Serum vitamin B12levels in parturients, in the intervillous space of the placenta and in full-term newborns and their interrelationships with folate levels. Am. J. Clin. Nutr. 41:330-335.

Hall, C.A., 1964. Long term excretion of Co57-vitamin B12 and turnover within plasma. Am. J.  Clin. Nutr. 14:156-162.

Heinrich, H.C . 1964. Metabolic basis of the diagnosis and therapy of vitamin B12 deficiency. Semin. Hematol. 1:199-249.

Herbert, V. 1968. Nutritional requirements for vitamin B12 and folic acid. Am. J. Clin. Nutr. 21:743-752.

Herbert, V. 1984. Vitamin B12. Pp. 347-364 in Nutrition Reviews' Present Knowledge in Nutrition, 5th ed. The Nutrition Foundation, Washington, D.C.

Herbert, V. 1985. Biology of disease: megaloblastic anemias. Lab. Invest. 52:3-19.

Herbert, V.D., and N. Colman. 1988. Folic acid and vitamin B12. Pp. 388-416 in M.E. Shils and V.R. Young, eds. Modern Nutrition in Health and Disease, 7th ed. Lea & Febiger, Philadelphia.

Herbert, V., G. Drivas, C. Manusselis, M. Mackler, J. Eng, and E. Schwartz. 1984. Are colon bacteria a major source of cobalamin analogues in human tissues? 24h human stool contains only about 5 µg of cobalamin but about 100 µg of apparent analogue (and 200 µg folate). Trans. Assoc. Amer. Phys. 97:161-171.

Herzlich, B., G. Drivas, and V. Herbert. 1985. A new serum test which may reliably diagnose vitamin B12 deficiency: total desaturation of serum transcobalamin II (TC II). Clin. Res. 33:605A.

Suggested Citation:"Water-Soluble Vitamins." National Research Council. 1989. Recommended Dietary Allowances: 10th Edition. Washington, DC: The National Academies Press. doi: 10.17226/1349.
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Heyssel, R.M., R.C. Bozian, W.J. Darby, and M.C. Bell. 1966. Vitamin B12 turnover in man. The assimilation of vitamin B12 from natural foodstuff by man and estimates of minimal dietary requirements. Am. J. Clin. Nutr. 18:176-184.

Higginbottom, M.C., L. Sweetman, and W.L. Nuhan, 1978. A syndrome of methylmalonic aciduria, homocystinuria, megaloblastic anemia and neurologic abnormalities in a vitamin B12-deficient breast-fed infant of a strict vegetarian. N. Eng. J. Med. 299:317-323.

Jadhav, M., J.K.G. Webb, S. Vaishnava, and S.J. Baker. 1962. Vitamin B12 deficiency in Indian infants: a clinical syndrome. Lancet 2:903-907.

Lampkin, B.D., N.A. Shore, and D. Chadwick. 1966. Megaloblastic anemia of infancy secondary to maternal pernicious anemia. N. Engl. J. Med. 274:1168-1171.

Lindenbaum, J., E.B. Healton, D.G. Savage, J.C.M. Brust, T.J. Garrett, E.R. Podell, P.D. Marcell, S.P. Stabler, and R.H. Allen. 1988. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N. Engl. J. Med. 318:1720-1728.

Linnell, J.C., A.V. Hoffbrand, H.A.A. Hussein, I.J. Wise, and D.M. Matthews. 1974. Tissue distribution of coenzyme and other forms of vitamin B12 in control subjects and patients with pernicious anemia. Clin. Sci. Mol. Med. 46:163-172.

Reizenstein, P.C., G. Ek, and C.M.E. Matthews. 1966. Vitamin B12 kinetics in man. Implications of total-body B 12 determinations, human requirements, and normal and pathological cellular B12 uptake. Phys. Med. Biol. 2:295-306.

Specker, B.L., D. Miller, E.J. Norman, H. Greene, and K.C. Hayes. 1988. Increased urinary methylmalonic acid excretion in breast-fed infants of vegetarian mothers and identification of an acceptable dietary source of vitamin B12. Am. J. Clin. Nutr. 47:89-92.

Stewart, J.S., P.D. Roberts, and A.V. Hoffbrand. 1970. Response of dietary vitaminB12 deficiency to physiological oral doses of cyanocobalamin. Lancet 2:542-545.

Sullivan, L.W., and V. Herbert. 1965. Studies on the minimum daily requirements for vitamin B12 Hematopoietic responses to 0.1 microgram of cyanocobalamin or coenzyme B12 and comparison of their relative potency. N. Engl. J. Med. 272:340-346.

Thomas, M.R., S.M. Sneed, C. Wei, P.A. Nail, M. Wilson, and E.E. Sprinkle I11. 1980. The effects of vitamin C, vitamin B6, vitamin B12, folic acid, riboflavin, and thiamin on the breast milk and maternal status of well-nourished women at 6 months postpartum. Am. J. Clin. Nutr. 33:2151-2156.

USDA (U.S. Department of Agriculture). 1986. Nationwide Food Consumption Survey Continuing Survey of Food Intakes by Individuals: Men 19-50 Years, 1 Day, 1985. Report No. 85-3. Nutrition Monitoring Division, Human Nutrition Information Service. U.S. Department of Agriculture, Hyattsville, Md. 94 pp.

USDA (U.S. Department of Agriculture). 1987. Nationwide Food Consumption Survey Continuing Survey of Food Intakes by Individuals: Women 19-50 Years and Their Children 1-5 Years, 4 Days, 1985. Report No. 85-4. Nutrition Monitoring Division, Human Nutrition Information Service. U.S. Department of Agriculture, Hyattsville, Md. 182 pp.

BIOTIN

Biotin is a sulfur-containing vitamin essential for several species, including humans. It is a component of various foods and is synthesized in the lower gastrointestinal tract by microorganisms and some

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fungi. The chemically related compounds oxybiotin and biocytin are also biologically active for some species. (For a more detailed discussion of the role of biotin in human nutrition, see Bonjour, 1985.)

Biotin is an integral part of enzymes that transport carboxyl units and fix carbon dioxide in animal tissue. The conversion of biotin to the active coenzyme is dependent on magnesium and adenosine triphosphate (ATP) (Bonjour, 1984). Two biotin enzymes, pyruvate carboxylase and acetyl-coenzyme A (CoA) carboxylase, play essential roles in gluconeogenesis and fatty acid synthesis, respectively. Extensive fatty infiltration of the liver and kidney, hypoglycemia, and depressed gluconeogenesis in the liver of biotin-deficient chicks provide further evidence of the importance of biotin in carbohydrate and lipid metabolism (Bannister, 1976). Two other biotin enzymes, propionyl-CoA carboxylase and 3-methylcrotonyl CoA carboxylase, are required for propionate metabolism and the catabolism of branchedchain amino acids. Low activity of biotin enzymes results in the urinary excretion of organic acids (the nature of which is determined by the metabolic step that is blocked), skin rash, and hair loss. Multiple carboxylase deficiencies are usually due to defective holocarboxylase synthetase, which is required for the conversion of inactive apocarboxylase to form active carboxylases through the addition of biotin (Sweetman, 1981). This inborn error of metabolism can be overcome by large doses (10 to 40 mg) of biotin (Wolf and Feldman, 1982). Another genetic defect results in a deficiency of biotinidase, an enzyme that releases protein-bound  biotin and cleaves biocytin so that the biotin can be rectcled (Wolf and Feldman, 1982).

General Signs of Deficiency

In adult humans ad most animals, biotin deficiency can be produced by the ingestion of large amounts of avidin—the biotin-binding glycoprotein found only in raw egg white (Baugh et al., 1968). Biotin deficiency is characterized by anorexia, nausea, vomiting, glossitis, pallor, mental depression, alopecia and a dry scaly dermatitis, and an increase in serum cholesterol and bile pigments. Symptoms of hair loss have been observed in two adults on long-term total parenteral nutrition (TPN) without added biotin following extensive gut resection, which decreases the amount produced by intestinal biosynthesis (Innis and Allardyce, 1983), and in children on TPN (McClain, 1983). Symptoms were alleviated with 200 to 300 µg of biotin per day. Hair loss in an infant on TPN for 5 months was reversed by administering 10 mg of biotin (Mock et al., 1981). Evidence indicates that the seborrheic dermatitis of infants under 6 months of age is due to nu-

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tritional biotin deficiency. In such cases, blood levels and urinary excretion of the vitamin are depressed. Prompt improvement occurs with therapeutic doses of the vitamin-approximately 5 mg/day (Bonjour, 1985).

Dietary Sources and Usual Intakes

The best sources of biotin are liver (100 to 200 µg/100 g), egg yolk (16 µg/100 g), soy flour (60 to 70 µg/100 g), cereals (3 to 30 µg/100 g), and yeast (100 to 200 µg/100  g). Fruit and meat are poor sources, each containing from 0.6 to 2.3 µg of biotin per 100 g (Guilarte, 1985; Hoppner and Lampi, 1983; Paul and Southgate, 1978). The bioavailability of biotin varies considerably, depending on whether it is present in the biologically available unbound form as it is in most foods or in the unavailable bound form in wheat.

Information on the biotin content of food provided in tables of food composition is not complete. As a result, intake of biotin is seldom considered in nutrient consumption studies. In a study by Marshall et al. (1985), biochemical analyses of duplicate samples of U.S. diets indicated that biotin intakes were 28 to 42 µg/day. Dietary biotin consumed in Western Europe is estimated to range from 50 to 100 µg/day (Bonjour, 1985).

Intestinal Synthesis

Biotin is synthesized by intestinal microorganisms, but the extent of its availability for absorption is not established. The combined urinary and fecal excretion of biotin can exceed the dietary intake. Thus, fecal excretion apparently comprises biotin synthesized in the gut as well as unabsorbed dietary biotin. The urine contains biotin absorbed from the diet, from body stores, and, possibly, from intestinal synthesis. Urinary values range from less than 6 to 50 µg/day (Baker, 1985; Marshall et al., 1985).

Information on blood levels is so variable that it is of little diagnostic value. Men whose diets contained 28 to 42 µg/day had serum biotin levels ranging from 627 to 737 pg/ml (Marshall et al., 1985). Serum, urinary, and dietary biotin were correlated.

Estimated Safe and Adequate Daily Dietary Intakes
Adults 

The lack of definitive studies of biotin requirements make it difficult to estimate an allowance. A daily dose of 60 µg has maintained adults on total parenteral nutrition symptom-free for 6

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months in the absence of meaningful intestinal synthesis (Innis and Allardyne, 1983).

Diets supplying 28 to 42 µg of biotin per day were associated with urinary excretion of 20 to 24 µg/day in volunteers. There was no indication of inadequate status in the subjects. In view of the incomplete knowledge of the bioavailability of biotin in foods and of the uncertain contribution of intestinal synthesis to the total intake, a range of 30 to 100 µg is provisionally recommended for adults. This range is lower than that recommended in the previous edition of the RDA, because improved analytical methods for biotin have reduced the estimates of daily intakes compatible with good health.

Pregnancy and Lactation

Blood biotin levels are significantly lower in pregnant than in nonpregnant women and fall progressively throughout gestation. However, low blood biotin levels are not associated with low birth weight infants (Bonjour, 1984). Thus, no increment for pregnancy is recommended. Data are not sufficient for a recommendation to be made for lactation.

Infants and Children 

The biotin content of human milk, all in the free, available form, has been variously reported as 3 to 4.7 (Goldsmith et al., 1982), 7 (Paul and Southgate, 1978), and 20 µg/ liter (Heard et al., 1987). Ifa daily milk consumption is assumed to be 750 ml, the intake of infants would range from 2 to 15 µg/day, depending on which analysis is accepted. An intake of 10 and 15 µg/ day is tentatively recommended for formula-fed infants during the first and second 6 months, respectively, in agreement with the recommendations of the American Academy of Pediatrics for biotin in infant formulas (AAP, 1976). Recommended intakes for children and adolescents are gradually increased to adult levels above age 11.

Excessive Intakes and Toxicity

There have been no reports of toxicity associated with intakes as high as 10 mg daily (LSRO, 1978).

References

AAP (American Academy of Pediatrics). 1976. Commentary on breast feeding and infant formulas, including proposed standards for formulas. Pediatrics 57:278285.

Baker, H. 1985. Assessment of biotin status: clinical implications. Ann. N.Y. Acad. Sci. 447:129-132.

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Bannister, D.W. 1976. The biochemistry of fatty liver and kidney syndrome. Biochem. J. 156:167-173.

Baugh, C.M.,J.W. Malone, and C.E. Butterworth, Jr. 1968. Human biotin deficiency. A case history of biotin deficiency induced by raw egg consumption in a cirrhotic patient. Am.J. Clin. Nutr. 21:173-182.

Bonjour, J.-P. 1984. Biotin. Pp. 403-435 in L.J. Machlin, ed. Handbook of Vitamins: Nutritional, Biochemical and Clinical Aspects. Marcel Dekker, New York.

Bonjour, J.-P. 1985. Biotin in human nutrition. Ann. N.Y. Acad. Sci. 447:97-104.

Goldsmith, S.J., R.R. Eitenmiller, R.M. Feeley, H.M. Barnhart, and F.C. Maddox. 1982. Biotin content of human milk during early lactational states. Nutr. Res. 2:579-583.

Guilarte, T.R. 1985. Analysis of biotin levels in selected foods using a radiometricmicrobiological method. Nutr. Rep. Int. 32:837-845.

Heard, G.S., J.B. Redmond, and B. Wolf. 1987. Distribution and bioavailability of biotin in human milk. Fed. Proc. 46:897.

Hoppner, K., and B. Lampi. 1983. The biotin content of breakfast cereals. Nutr. Rep. Int. 28:793-798.

Innis, S.M., and D.B. Allardyce. 1983. Possible biotin deficiency in adults receiving long-term total parenteral nutrition. Am. J. Clin. Nutr. 37:185-187.

LSRO (Life Sciences Research Office). 1978. Evaluation of the Health Aspects of Biotin as a Food Ingredient. SCOGS 92. Federation of American Societies for Experimental Biology, Bethesda, Md. 16 pp.

Marshall, M.W., J.T. Judd, and H. Baker. 1985. Effects of low and high-fat diets varying in ratio of polyunsaturated to saturated fatty acids on biotin intakes and biotin in serum, red cells and urine of adult men. Nutr. Res. 5:801-814.

McClain, C.J. 1983. Biotin deficiency complicating parenteral alimentation. J. Am. Med. Assoc. 250:1028.

Mock, D.M., A.A. deLorimer, W.M. Liebman, L. Sweetman, and H. Baker. 1981. Biotin deficiency: an unusual complication of parenteral alimentation. N. Engl. J. Med. 304:820-823.

Paul, A.A., and D.A.T. Southgate. 1978. The Composition of Foods. Her Majesty's Stationery Office, London.

Sweetman, L. 1981. Two forms of biotin-responsive multiple carboxylase deficiency. J. Inherited Metab. Dis. 4:53-54.

Wolf, B., and G.L. Feldman. 1982. The biotin-dependent carboxylase deficiencies. Am. J. Hum. Genet. 34:699-716.

PANTOTHENIC ACID

Pantothenic acid, a B-complex vitamin, plays its primary physiological roles as a component of the coenzyme A molecule and within the 4'-phosphopantetheine moiety of the acyl carrier protein of fatty acid synthetase, which serves in acyl-group activation and transfer reactions (McCormick, 1988). These reactions are important in the release of energy from carbohydrates; in gluconeogenesis; in the synthesis and degradation of fatty acids; in the synthesis of such vital compounds as sterols and steroid hormones, porphyrins, and acetylcholine; and in acylation reactions in general (Abiko, 1975; Goldman and Vagelos, 1964).

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General Signs of Deficiency

Dietary deficiency of pantothenic acid in animals results in a broad spectrum of biochemical defects. These manifest themselves in a variety of abnormalities: retarded growth rates in young animals; infertility, abortion, and frequent neonatal deaths; abnormalities of skin, hair, pigmentation, and feathers; neuromuscular disorder; gastrointestinal malfunction; adrenal cortical failure; and sudden death (Novelli, 1953).

Evidence of dietary deficiency has not been clinically recognized in humans, but deficiency symptoms have been produced by administering a metabolic antagonist, w-methylpantothenic acid (Hodges et al., 1959), and more recently by feeding subjects a semisynthetic diet virtually free of pantothenic acid for 9 weeks (Fry et al., 1976). The young adult males studied by Fry and colleagues appeared listless and complained of fatigue after 9 weeks on the pantothenic acidfree diet; blood and urinary levels of this nutrient were significantly lower compared to controls. Naturally occurring pantothenic acid deficiencies have not been reliably documented. However, they have been implicated in the ''burning feet" syndrome observed among prisoners of war and among malnourished individuals in the Far East, since the symptoms appeared to respond to pantothenic acid preparations and not to other members of the vitamin B complex (Glusman, 1947).

Dietary Sources and Usual Intakes

Pantothenic acid is widely distributed among foods. It is especially abundant in animal tissues, whole grain cereals, and legumes. Smaller amounts are found in milk, vegetables, and fruits. Synthesis of pantothenic acid by intestinal microflora has been suspected, but the amount produced and the availability of the vitamin from this source are unknown. The apparent absence of pantothenic acid deficiency in the human population may therefore be attributed both to its ubiquity in foods and to possible additional contributions front intestinal flora.

The usual intake of pantothenic acid in the United States has been reported to range from 5 to 10 mg/day (Fox and Linkswiler, 1961; Fry et al., 1976). In two more recent studies, investigators reported average intakes of approximately 6 mg/day (Srinivasan et al., 198l; Tarr et al., 1981). Srinivasan and colleagues conducted a study in an elderly population, and showed no difference in intakes between institutionalized and noninstitutionalized subjects. In another study,

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Johnson and Nitzke (1975) found that diets consumed by a group of low-income women provided about 4 mg of pantothenic acid per day. In a group of 7- to 9-year-old children, diets that met the recommended allowances for all other nutrients provided 4 to 5 mg of pantothenic acid daily (Pace et al., 1961). In a small group of pregnant, postpartum, and nonpregnant teenagers, the calculated dietary intakes were lower, ranging from 1.1 to 7.2 mg/day (Cohenour and Calloway, 1972).

Estimated Safe and Adequate Daily Dietary Intakes
Adults 

Urinary excretion generally correlates with dietary intake of pantothenic acid, although individual variation is large. Adults who consume 5 to 7 mg of pantothenic acid daily excrete 2 to 7 mg/ day in the urine and 1 to 2 mg/day in the feces (Fox and Linkswiler, 1961). In experimental diets, 100  mg/day has generally been selected for supplementation. At this level, subjects were found to excrete 5 to 7 mg/day in the urine (Fry et al., 1976). This evidence suggests that an intake of 4 to 7 mg/day should be safe and adequate for adults. The subcommittee concluded that there is insufficient evidence to set an RDA for pantothenic acid.

Pregnancy and Lactation 

The amounts of pantothenic acid secreted in milk can represent a large fraction of the usual dietary intake. Nonetheless, the absence of reports of pantothenic acid deficiency either in pregnant or lactating women indicates that present levels of consumption from the diet (e.g., more than 5 mg/day), possibly supplemented by intestinal microfloral synthesis, is adequate to cover the needs of pregnancy and lactation. Thus, the suggested intake for nonpregnant adults would appear to be adequate for this group.

Infants, Children, and Adolescents 

Reports of the mean pantothenic acid content of human milk have varied from 1 mg/day (Deodhar and Ramakrishnan, 1960) to 5 mg/day (Johnston et al., 1981), based on an average daily milk production of 750 ml. Song et al. (1984) reported a mean pantothenic acid content at 2 and 12 weeks postpartum of 2.57 mg/liter and 2.55 mg/liter, respectively, for mothers of full-term infants. These values are equivalent to approximately 1.9 mg/day in 750 ml of milk. The differences in the various reports may represent differences in maternal intakes or in analytical techniques. There are no reports of pantothenic acid deficiency in infants, suggesting that intake is adequate. The provisional recommended

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allowance is set at 2 to 3 mg/day for infants. Recommended intakes for children and adolescents are gradually increased to adult levels by age 11.

Excessive Intakes and Toxicity

Evidence suggests that pantothenic acid is relatively nontoxic. As much as 10 g of calcium pantothenate per day was given to young men for 6 weeks with no toxic symptoms reported (Ralli and Dumm, 1953). Other studies indicate that daily doses of 10 to 20 g may result in occasional diarrhea and water retention (Sebrell and Harris, 1954).

References

Abiko, Y. 1975. Metabolism of coenzyme A. Pp. 1-25 in D.M. Greenberg, ed. Metabolism of Sulfur Compounds, Vol. 7. Metabolic Pathways. Academic Press, New York.

Cohenour, S.H., and D.H. Calloway. 1972. Blood, urine and dietary panthothenic acid levels of pregnant teenagers. Am. J. Clin. Nutr. 25:512-517.

Deodhar, A.D., and C.V. Ramakrishnan. 1960. Studies on human lactation (relation between the dietary intake of lactating women and the chemical composition of milk with regard to vitamin content). J. Trop. Pediatr. 6:44-47.

Fox, H.M., and H. Linkswiler. 1961. Pantothenic acid excretion on three levels of intake. J. Nutr. 75:45:1-454.

Fry, P.C., H.M. Fox, and H.G. Tao. 1976. Metabolic reponse to a pantothenic acid deficient diet in humans. J. Nutr. Sci. Vitaminol. 22:339-346.

Glusman, M. 1947. Syndrome of "burning feet" (nutritional melalgia) as manifestation of nutritional deficiency. Am. J. Med. 3:211-223.

Goldman, P., and P.R. Vagelos. 1964. Acyl-transfer reactions (CoA-structure, function). Pp. 71-92 in M. Florkin and E. H. Stotz, eds. Comprehensive Biochemistry, Vol. 15. Group-Transfer Reactions. Elsevier, Amsterdam.

Hodges, R.E., W.B. Bean, M.A. Ohison, and B. Bleiler. 1959. Human pantothenic acid deficiency produced by omega-methylpantothenic acid. J. Clin. Invest. 38:1421-1425.

Johnson, N.E., and S. Nitzke. 1975. Nutritional adequacy of diets of a selected group of low-income women: identification of some related factors. Home Econ. Res. J. 3:241-246.

Johnston, L., L.. Vaughan, and H.M. Fox. 1981. Pantothenic acid content of human milk. Am. J. Clin. Nutr. 34:2205-2209.

McCormick, D.B. 1988. Pantothenic acid. Pp. 383-387 in M.E. Shils and V.R. Young, eds. Modern Nutrition in Health and Disease, 7th ed. Lea & Febiger, Philadelphia.

Novelli, G.D. 1953. Metabolic significance of B-vitamins: Symposium; Metabolic functions of pantothenic acid. Physiol. Rev. 33:525-543.

Pace, J.K., L.B. Stier, D.D. Taylor, and P.S. Goodman. 1961. Metabolic patterns in preadolescent children. V. Intake and urinary excretion of pantothenic acid and of folic acid. J. Nutr. 74:345-351.

Ralli, E.P., and M.E. Dumm. 1953. Relation of pantothenic acid to adrenal cortical function. Vitam. Horm. 11:133-158.

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Sebrell, W.H., Jr., and R.S. Harris, eds. 1954. Pantothenic acid. Pp. 591-694 in The Vitamins: Chemistry, Physiology, Pathology, Vol. 2. Academic Press, New York.

Srinivasan, V., N. Christensen, B.W. Wyse, and R.G. Hansen. 1981. Pantothenic acid nutritional status in the elderly-institutionalized and noninstitutionalized. Am. J. Clin. Nutr. 34:1736-1742.

Song, W.O., G.M. Chan, B.W. Wyse, and R.G. Hansen. 1984. Effect of pantothenic acid status on the content of the vitamin in human milk. Am. J. Clin. Nutr. 40:317-324.

Tarr, J.B., T. Tamura, and E.L.R. Stokstad. 1981. Availability of vitamin B6 and pantothenate in an average American diet in man. Am. J. Clin. Nutr. 34:13281337.

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Since its introduction in 1943 Recommended Dietary Allowances has become the accepted source of nutrient allowances for healthy people.

These Recommended Dietary Allowances (RDAs) are used throughout the food and health fields. Additionally, RDAs serve as the basis for the U.S. Recommended Daily Allowances, the Food and Drug Administration's standards for nutrition labeling of foods.

The 10th Edition includes research results and expert interpretations from years of progress in nutrition research since the previous edition and provides not only RDAs but also "Estimated Safe and Adequate Daily Dietary Intakes"--provisional values for nutrients where data were insufficient to set an RDA.

Organized by nutrient for ready reference, the volume reviews the function of each nutrient in the human body, sources of supply, effects of deficiencies and excessive intakes, relevant study results, and more.

The volume concludes with the invaluable "Summary Table of Recommended Dietary Allowances," a convenient and practical summary of the recommendations.

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