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Suggested Citation:"11 Biotin." Institute of Medicine. 1998. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press. doi: 10.17226/6015.
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11
Biotin

SUMMARY

Biotin functions as a coenzyme in bicarbonate-dependent carboxylation reactions. Values extrapolated from the data for infants and limited estimates of intake are used to set the Adequate Intake (AI) for biotin because of limited data on adult requirements. The AI for adults is 30 µg/day. There are no nationally representative estimates of the intake of biotin from food or from both food and supplements. There are not sufficient data on which to base a Tolerable Upper Intake Level (UL) for biotin.

BACKGROUND INFORMATION

After biotin’s initial discovery in 1927 (Boas, 1927), it took nearly 40 years of research for it to be fully recognized as a vitamin. In mammals this colorless, water-soluble vitamin functions as a cofactor for enzymes that catalyze carboxylation retentions (Dakshinamurti, 1994).

Function

Biotin functions as a required cofactor for four carboxylases found in mammalian species, which each covalently bind the biotin moiety (Bonjour, 1991; McCormick, 1976). Of the four biotin-dependent carboxylases, three are mitochondrial (pyruvate carboxylase, methyl-

Suggested Citation:"11 Biotin." Institute of Medicine. 1998. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press. doi: 10.17226/6015.
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crotonyl-coenzyme A [CoA] carboxylase, and propionyl-CoA carboxylase) whereas the fourth (acetyl-CoA carboxylase) is found in both the mitochondria and the cytosol. An inactive form of acetyl-CoA carboxylase has been postulated to serve as storage for biotin in the mitochondria (Allred and Roman-Lopez, 1988; Allred et al., 1989; Shriver et al., 1993).

Acetyl-CoA carboxylase catalyzes the carboxylation of acetyl CoA to form malonyl CoA. Malonyl CoA then serves as a substrate for fatty acid elongation. The second biotin-dependent carboxylase, pyruvate carboxylase, catalyzes the carboxylation of pyruvate to form oxaloacetate, which serves as an intermediate in the tricarboxylic acid cycle. Oxaloacetate thus formed is converted to glucose in the liver, kidney, and other gluconeogenic tissues.

A third biotin-dependent carboxylase, β-methylcrotonyl-CoA carboxylase, is required for the degradation of leucine, a branch-chained amino acid. Low activity of this enzyme resulting from biotin deficiency leads to the production of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine by an alternate pathway (Mock, 1996). Thus, elevated levels of these abnormal metabolites in urine reflect reduced activity of β-methylcrotonyl-CoA carboxylase, usually resulting from biotin deficiency.

A fourth biotin-dependent carboxylase, propionyl-CoA carboxylase, carboxylates propionyl-CoA to form D-methylmalonyl-CoA, which is racemized to the L-isomer, then undergoes isomerization to succinyl-CoA, and subsequently enters the tricarboxylic acid cycle. Reduction in activity of this carboxylase results in increased excretion of 3-hydroxypropionic acid and 3-methylcitric acid in urine (Mock, 1996).

In the normal breakdown of cellular proteins, these biotin-containing enzymes are degraded to biocytin (ε-N-biotinyl-L-lysine) or short oligopeptides containing biotin-linked lysyl residues (Mock, 1996). Biotinidase (earlier called biocytinase), a hydrolase, releases biotin from this oligopeptide for reuse (Mock, 1996).

Physiology of Absorption, Metabolism, and Excretion

Biotin exists as free biotin and in protein-bound forms in foods. The mechanism of intestinal hydrolysis of protein-bound biotin has not been well characterized, and little is known about factors that affect bioavailability. Although most dietary biotin appears to be protein bound in both meats and cereals, biotin in cereals appears to be less bioavailable (Mock, 1996). Avidin, a protein found in appreciable amounts in raw egg white, has been shown to bind

Suggested Citation:"11 Biotin." Institute of Medicine. 1998. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press. doi: 10.17226/6015.
×

biotin in the small intestine and prevent its absorption (Mock, 1996).

Biotinidase is thought to play a critical role in the release of biotin from covalent binding to protein (Wolf et al., 1984). Doses of free (unbound) biotin in the range of the estimated typical dietary intake (50 to 150 µg/day) given to individuals who have biotinidase deficiency have been shown to prevent the symptoms seen in biotinidase deficiency, indicating that biotinidase deficiency results in a relative biotin deficiency through lack of adequate digestion of protein-bound biotin, inadequate renal reabsorption, or both.

Intestinal Absorption and Microbial Synthesis

A biotin carrier located in the intestinal brush border membrane transports biotin against a sodium ion concentration gradient and is structurally specific, temperature dependent, and electroneutral; at pharmacological concentrations, diffusion predominates (Mock, 1996).

Biotin is synthesized by intestinal microflora (Bonjour, 1991). Although transporter-mediated absorption of biotin is most active in the proximal small intestine of the rat, significant absorption of biotin from the proximal colon occurs, which gives credence to the concept that biotin from microbial synthesis within the colon can contribute to meeting the human requirement. From reports of increased blood concentrations after colonic instillation of biotin, it appears that biotin is absorbed from the human colon (Innis and Allardyce, 1983; Oppel, 1948; Sorrell et al., 1971). However, Kopinski and colleagues (1989a, b) have shown that biotin synthesized by enteric flora may not be present at a location or in a form that contributes importantly to absorbed biotin.

Transport

The mechanism of biotin transport to the liver and other tissues after absorption has not been well established (Mock, 1996). Biotinidase has been identified as possibly serving as a biotin-binding protein in plasma or as a transporter protein to assist biotin’s entry into the cell (Chauhan and Dakshinamurti, 1988; Wolf et al., 1985). Other studies suggest that serum biotin is more than 80 percent unbound (Hu et al., 1994; Mock and Malik, 1992; Schenker et al., 1993). An acid anion carrier with relative specificity for biotin resembling the intestinal carrier appears to mediate uptake by liver cells (Bowers-Komro and McCormick, 1985). Placental uptake of

Suggested Citation:"11 Biotin." Institute of Medicine. 1998. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press. doi: 10.17226/6015.
×

biotin and transport to the fetus have been demonstrated and appear to be specific for biotin (Hu et al., 1994; Karl and Fisher, 1992; Schenker et al., 1993); however, because the fetus does not concentrate biotin, placental transfer appears to be passive.

Metabolism and Excretion

Isolation and chemical identification of more than a dozen metabolites of biotin have established the main features of utilization in microbes and mammals (McCormick, 1976; McCormick and Wright, 1971). About half of the biotin undergoes metabolism to bisnorbiotin and biotin sulfoxide before excretion. Biotin, bisnorbiotin, and biotin sulfoxide are present in molar proportions of approximately 3:2:1 in human urine and plasma (Mock, 1996). Two additional minor metabolites, bisnorbiotin methyl ketone and biotin sulfone, were recently identified in human urine (Zempleni et al., 1997). The urinary excretion and serum concentrations of biotin and its metabolites increase roughly in the same proportion in response to either intravenous or oral administration of large doses of biotin (Mock and Heird, 1997; Zempleni et al., 1997).

Clinical Effects of Inadequate Intake

Signs of biotin deficiency in humans have been demonstrated conclusively in individuals who consume raw egg white over long periods (Baugh et al., 1968) and in total parenteral nutrition (TPN) before biotin supplementation in patients with malabsorption, including short-gut syndrome (Mock et al., 1981). The clinical findings of biotin deficiency include dermatitis, conjunctivitis, alopecia, and central nervous system abnormalities (Mock, 1996).

In adults fed raw egg white or receiving biotin-free TPN for months to years, thinning of hair, frequently with loss of hair color, was reported. Most adults with the deficiency demonstrated a red, scaly, skin rash, frequently around the eyes, nose, and mouth. Most of the adults had neurological symptoms, including depression, lethargy, hallucinations, and paresthesia of the extremities.

In infants on biotin-free TPN, symptoms of biotin deficiency begin to appear within 3 to 6 months after initiation of the TPN regimen, which is earlier than that seen in adults, probably because of the increased biotin requirement related to growth (Mock, 1996). The associated rash appears first around the mouth, eyes, and nose. The rash and the unusual distribution of facial fat observed in these infants together are called biotin deficiency facies. As the rash progresses,

Suggested Citation:"11 Biotin." Institute of Medicine. 1998. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press. doi: 10.17226/6015.
×

the ears and perineal orifices are affected. The resultant rash is similar in appearance to that of cutaneous candidiasis (so termed because Candida can usually be cultured from the lesions) and is quite similar to that seen in zinc deficiency.

Hair loss has been noted in infants after 6 to 9 months of TPN; two infants evaluated had lost all hair, including eyelashes and eyebrows, within 3 to 6 months of the onset of hair loss (Mock, 1996). In biotin-deficient infants, hypotonia, lethargy, and developmental delay, along with a peculiar withdrawn behavior, are all characteristic of a neurological disorder resulting from a lack of biotin; it is thought that the withdrawn behavior may represent the equivalent of depression seen in adults that is due to central nervous system dysfunction.

SELECTION OF INDICATORS FOR ESTIMATING THE REQUIREMENT FOR BIOTIN

The most useful information concerning indicators of the adequacy of biotin intake arises from (1) clinical observations of patients receiving biotin-free intravenous nutrition, individuals with inborn errors of metabolism, and persons who consume large amounts of raw egg white; (2) 2 studies in which biotin deficiency was experimentally induced by feeding raw egg white; and (3) fewer than 10 studies of biotin bioavailability and pharmacokinetics.

Biotin and 3-Hydroxyisovalerate Excretion

The indicators of biotin status that have been validated to the greatest extent are an abnormally decreased urinary excretion of biotin and an abnormally increased urinary excretion of 3-hydroxyisovaleric acid (NI Mock et al., 1997). The urinary excretion of biotin decreased dramatically with time in normal subjects on a raw egg white diet, reaching markedly abnormal values in 9 of 10 subjects by day 20. Bisnorbiotin excretion declined in parallel, providing evidence for regulated catabolism of biotin. By day 14 of egg white feeding, 3-hydroxyisovalerate acid excretion was abnormally increased (greater than 195 µmol/day) in all 10 subjects, providing evidence that biotin depletion decreased the activity of β-methylcrotonyl-coenzyme A (CoA) and altered leucine metabolism relatively early in biotin deficiency (NI Mock et al., 1997). Normal values are 77 to 195 µmol/day (112 ± 38 [standard deviation]); at day 10 the values for the deficient people were 272 ± 92 µmol/day. Abnormally decreased excretion of biotin, abnormally increased excretion

Suggested Citation:"11 Biotin." Institute of Medicine. 1998. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press. doi: 10.17226/6015.
×

of 3-hydroxyisovalerate acid, or both have also been reported in several overt cases of biotin deficiency (Carlson et al., 1995; Gillis et al., 1982; Kien et al., 1981; Lagier et al., 1987; Mock et al., 1981, 1985). Gender differences are not apparent in these two indicators.

Plasma Biotin

A low plasma biotin concentration is not a sensitive indicator of inadequate biotin intake. Abnormally decreased plasma biotin was absent in half the subjects fed raw egg white (NI Mock et al., 1997) and in some overt case reports of biotin deficiency (Carlson et al., 1995; Khalidi et al., 1984; Kien et al., 1981; Matsusue et al., 1985; Mock et al., 1981, 1985).

Odd-Chain Fatty Acid Composition of Plasma Lipids

Odd-chain fatty acid composition in plasma lipids may reflect biotin status (Kramer et al., 1984; Liu et al., 1994; Mock et al., 1988a, b), but the sensitivity and clinical utility of this measurement remains to be determined. The accumulation of odd-chain fatty acids is thought to result from propionyl-CoA carboxylase deficiency.

Methodology

All published studies on biotin nutriture (Zempleni et al., 1997) have used one of three basic types of assays to estimate biotin: bioassays (most studies), avidin-binding assays, or fluorescent derivative assays. Recent modifications of bioassays generally have adequate sensitivity to measure biotin in blood, urine, and foods. For example, the bioassay based on Kloeckera brevis has both excellent sensitivity and metabolite discrimination (Guilarte, 1985). However, the bacterial bioassays (and perhaps the eukaryotic bioassays as well) suffer interference from unrelated substances and variable growth response to biotin metabolites. The acid hydrolysis or protein digestion required to release bound biotin may also release other compounds that support bacterial growth.

There are major discrepancies among the various bioassays and avidin-binding assays concerning the true concentration of biotin in human plasma. Reported mean values range from approximately 0.5 nmol/L to more than 10 nmol/L. The avidin-based radioimmunoassay with high-performance liquid chromatography is among the best current assays (Mock, 1996).

Suggested Citation:"11 Biotin." Institute of Medicine. 1998. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press. doi: 10.17226/6015.
×

FACTORS AFFECTING THE BIOTIN REQUIREMENT

Several factors have been identified that affect the biotin requirement: the ingestion of large quantities of raw eggwhite, which contains a substance (avidin) that binds biotin; biotinidase deficiency (a genetic defect); the use of anticonvulsants that induce biotin catabolism in some individuals; and pregnancy. In the latter two conditions, the ratio of biotin metabolites to biotin in urine is increased (Mock and Dyken, 1997; Mock and Stadler, 1997; DM Mock et al., 1997b). Inherited biotinidase deficiency is particularly relevant to understanding biotin deficiency because the clinical manifestations appear to result largely from a secondary biotin deficiency in the presence of normal dietary intakes.

FINDINGS BY LIFE STAGE AND GENDER GROUP

Infants Ages 0 through 12 Months

Method Used to Set the Adequate Intake

An Adequate Intake (AI) is used as the goal for intake by infants. The AI reflects the observed mean biotin intake of infants fed principally with human milk.

Ages 0 through 6 Months. In early and transitional human milk, the concentration of biotin metabolites is nearly twice the concentration of biotin in samples (DM Mock et al., 1997a). With postpartum maturation of milk production, the biotin concentration increases but the metabolites still account for approximately one-third of total biotin at 5 weeks postpartum. In mature human milk (greater than 21 days postpartum) the concentration of biotin varies substantially (Mock et al., 1992); it exceeds the concentration in serum by one to two orders of magnitude. This suggests that there is an active biotin transport system into milk. According to Hirano and coworkers (1992), estimates of the biotin content of milk are 3.8 ± 1.2 (standard deviation) µg/L as free biotin determined microbiologically and 5.2 ± 2.1 µg/L after acid hydrolysis—slightly higher than earlier estimates of 4.5 µg/L (Salmenpera et al., 1985) and 7 µg/L for total biotin from bioassays (Paul and Southgate, 1978). With greatest weight given to the recent results (Hirano et al., 1992), but with the value within the range of the two other studies (Paul and Southgate, 1978; Salmenpera et al., 1985), the biotin content of human milk was estimated to be 6 µg/L. The adequate intake for biotin for

Suggested Citation:"11 Biotin." Institute of Medicine. 1998. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press. doi: 10.17226/6015.
×

infants ages 0 through 6 months is based on the reported mean volume of milk consumed by this age group (0.78 L/day; see Chapter 2) and the estimate of the biotin concentration in human milk of 6 µg/L (0.78 L × 6 µg/L = 5

Ages 7 through 12 Months. If the reference body weight ratio method described in Chapter 2 to extrapolate up from the AI for biotin for infants ages 0 through 6 months is used, the AI for biotin for the older infants is 6 µg/day after rounding.

Biotin AI Summary, Ages 0 through 12 Months

AI for Infants

0–6 months

5 µg/day of biotin

≈0.7 µg/kg

7–12 months

6 µg/day of biotin

≈0.7 µg/kg

Children and Adolescents Ages 1 through 18 Years

Method Used to Set the AI

Evidence concerning the biotin requirement is minimal and does not justify the setting of an Estimated Average Requirement (EAR). No definitive studies demonstrate evidence of biotin deficiency in normal individuals in any age group resulting from inadequate intakes. In the absence of additional information, including data on needs of adults, AIs for children and adolescents have been extrapolated from values for infants by using the formula

AIchild = (AIyounginfant) (weightchild/weightinfant)0.75.

Biotin AI Summary, Ages 1 through 18 Years

AI for Children

1–3 years

8 µg/day of biotin

4–8 years

12 µg/day of biotin

AI for Boys

9–13 years

20 µg/day of biotin

14–18 years

25 µg/day of biotin

AI for Girls

9–13 years

20 µg/day of biotin

14–18 years

25 µg/day of biotin

Suggested Citation:"11 Biotin." Institute of Medicine. 1998. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press. doi: 10.17226/6015.
×

Adults Ages 19 Years and Older

Method Used to Set the AI

In the absence of data on biotin deficiencies in normal individuals, a reasonable inference would be that the average current dietary intake of biotin should meet the dietary requirement. With this approach, the AI for biotin might be set at either 40 or 60 µg/day depending on the data set used (see “Dietary Intake”). Extrapolation from the AI for infants exclusively fed human milk would be expected to overestimate the requirement for adults because adults require biotin only for maintenance. The result of such an extrapolation using the formula

AIadult = (AIyounginfant) (weightadult/weightinfant)0.75

is 30 µg/day of biotin. Based on this very limited evidence, the AI for adults is set at 30 µg/day of biotin. This value should be adequate for maintaining normal excretion of 3-hydroxyisovaleric acid in adults (NI Mock et al., 1997). Data are not sufficient to set separate values for men and women or for the elderly.

Biotin AI Summary, Ages 19 Years and Older

AI for Men

19–30 years

30 µg/day of biotin

31–50 years

30 µg/day of biotin

51–70 years

30 µg/day of biotin

> 70 years

30 µg/day of biotin

AI for Women

19–30 years

30 µg/day of biotin

31–50 years

30 µg/day of biotin

51–70 years

30 µg/day of biotin

> 70 years

30 µg/day of biotin

Pregnancy

Evidence Considered in Setting the AI

Two recent studies (Mock and Stadler, 1997; DM Mock et al., 1997b) have raised questions, previously expressed (NRC, 1989), about the adequacy of biotin status during pregnancy. Some studies

Suggested Citation:"11 Biotin." Institute of Medicine. 1998. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press. doi: 10.17226/6015.
×

have detected low plasma concentrations of biotin (Bhagavan, 1969; Dostalova, 1984); others have not (Mock and Stadler, 1997). DM Mock and colleagues (1997b) detected increased 3-hydroxyisovaleric acid in more than half of healthy pregnant women by the third trimester, and urinary excretion of biotin was decreased in about 50 percent of the women studied. It is not known whether these changes in values are normal for pregnant women or indicate low biotin intake relative to need. However, these data are not sufficient to justify an increase in the AI to meet the needs of pregnancy except for pregnant adolescents.

Biotin AI Summary, Pregnancy

AI for Pregnancy

14–18 years

30 µg/day of biotin

19–30 years

30 µg/day of biotin

31–50 years

30 µg/day of biotin

Lactation

Method Used to Set the AI

To cover the amount of biotin secreted in milk, the AI is increased by 5 µg/day for lactating adolescents and women. No distinction is made for the stage of lactation or age.

Biotin AI Summary, Lactation

AI for Lactation

14–18 years

35 µg/day of biotin

19–30 years

35 µg/day of biotin

31–50 years

35 µg/day of biotin

Special Considerations

Persons receiving hemodialysis or peritoneal dialysis may have an increased requirement for biotin (Livaniou et al., 1987; Yatzidis et al., 1984) as would persons with genetic biotinidase deficiency (Mock, 1996).

Suggested Citation:"11 Biotin." Institute of Medicine. 1998. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press. doi: 10.17226/6015.
×

INTAKE OF BIOTIN

Food Sources

Biotin contents have been determined for relatively few foods and are not ordinarily included in food composition tables. Although biotin is widely distributed in natural foodstuffs, its concentration varies substantially. For example, liver contains biotin at about 100 µg/100 g whereas fruits and most meats contain only about 1 µg/ 100 g.

Dietary Intake

The U.S. Department of Agriculture Continuing Survey of Food Intakes by Individuals, the Third National Health and Nutrition Examination Survey (NHANES III), and the Boston Nutritional Status Survey do not report biotin intake. Murphy and Calloway (1986), using food intake data from the NHANES II, estimated the mean biotin intake of young women aged 18 to 24 years to be 39.9 ± 26.9 (standard deviation) µg/day. This result is considerably lower than the estimated dietary intake of biotin in a composite Canadian diet (62 µg/day) and an actual analysis of the diet (60 µg/day) (Hoppner et al., 1978). Calculated average intakes of biotin for the British population of adults and children were similar to the U.S. estimate—33 and 35 µg/day (Bull and Buss, 1982; Lewis and Buss, 1988).

Intake from Supplements

According to the 1986 National Health Interview Survey, approximately 17 percent of U.S. adults take a supplement containing biotin (Moss et al., 1989). Specific data on intake from supplements are not available.

TOLERABLE UPPER INTAKE LEVELS

Hazard Identification

No reported adverse effects of biotin in humans or animals were found. Toxicity has not been reported in patients treated with daily doses up to 200 mg orally and up to 20 mg intravenously to treat biotin-responsive inborn errors of metabolism and acquired biotin deficiency (Mock, 1996).

Suggested Citation:"11 Biotin." Institute of Medicine. 1998. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press. doi: 10.17226/6015.
×

Several studies reported that acute doses of biotin (10 mg/100 g body weight) in pregnant rats (at the pre- and postimplantation stages) caused inhibition of fetal and placental growth and resorption of fetuses and placentae (Paul and Duttagupta, 1975, 1976). The dose used was equivalent to a human dose of 7 g for a 70-kg person, which is considerably greater than the recommended intake. These results are not considered useful for deriving a Tolerable Upper Intake Level (UL) for human intakes because of the high doses used, mode and vehicle of administration used (subcutaneous injection administration of 0.1 mol/L of NaOH, which would itself be toxic), and lack of an adequate control group.

Dose-Response Assessment

The data on adverse effects from high biotin intake are not sufficient for a quantitative risk assessment, and a UL cannot be derived. Several studies involving high biotin intakes reported no adverse effects. Koutsikos et al. (1996) found no adverse effects after intravenous administration of 50 mg of biotin to hemodialysis patients. Roth et al. (1982) administered 10 mg/day of biotin during the ninth month of pregnancy and found no adverse effects in the mother or infant. Ramaekers et al. (1993) reported no adverse effects in a 15-year-old boy given 10 mg/day of biotin to treat multiple carboxylase deficiency resulting from an inborn error of metabolism. Colamaria et al. (1989) similarly found no adverse effects in an infant treated with 10 mg/day of biotin to reverse a syndrome consisting of lethargy, sparse scalp hair, autistic-like behavior, myoclonus, and drug-resistant seizures. Taken together, these studies indicate a possible range for intake levels in any future studies of toxic effects of biotin.

Intake Assessment and Risk Characterization

Neither an intake assessment nor a risk characterization is currently possible because national surveys do not provide data on the dietary intake of biotin.

RESEARCH RECOMMENDATIONS FOR BIOTIN

There is a serious lack of data useful for setting Estimated Average Requirements (EARs) for biotin. The understanding of the nutrition of biotin is rudimentary compared with that of some other B vitamins. Although the limited information seems to indicate that

Suggested Citation:"11 Biotin." Institute of Medicine. 1998. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press. doi: 10.17226/6015.
×

there is little cause for concern about the adequacy of biotin intake for healthy people, information on the human requirements, intake, bioavailability, toxicity, and metabolic effects of this compound is needed.

REFERENCES

Allred JB, Roman-Lopez CR. 1988. Enzymatically inactive forms of acetyl-CoA carboxylase in rat liver mitochondria. Biochem J 251:881–885.

Allred JB, Roman-Lopez CR, Jurin RR, McCune SA. 1989. Mitochondrial storage forms of acetyl-CoA carboxylase: Mobilization/activation accounts for increased activity of the enzyme in liver of genetically obese Zucker rats. J Nutr 119:478–483.


Baugh CM, Malone JH, Butterworth CE 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.

Bhagavan HN. 1969. Biotin content of blood during gestation. Int Z Vitaminforsch 39:235–237.

Boas MA. 1927. The effect of desiccation upon the nutritive properties of egg white. Biochem J 21:712–724.

Bonjour J-P. 1991. Biotin. In: Machlin LJ, ed. Handbook of Vitamins. New York: Marcel Dekker. Pp. 393–427.

Bowers-Komro DM, McCormick DB. 1985. Biotin uptake by isolated rat liver hepatocytes. Ann NY Acad Sci 447:350–358.

Bull NL, Buss DH. 1982. Biotin, pantothenic acid and vitamin E in the British household food supply. Hum Nutr Appl Nutr 36:190–196.


Carlson GL, Williams N, Barber D, Shaffer JL, Wales S, Isherwood D, Shenkin A, Irving MH. 1995. Biotin deficiency complicating long-term total parenteral nutrition in an adult patient. Clin Nutr 14:186–190.

Chauhan J, Dakshinamurti K. 1988. Role of human serum biotinidase as biotin-binding protein. Biochem J 256:265–270.

Colamaria V, Burlina AB, Gaburro D, Pajno-Ferrara F, Saudubray JM, Merino RG, Dalla Bernardina B. 1989. Biotin-responsive infantile encephalopathy: EEG-polygraphic study of a case. Epilepsia 30:573–578.


Dakshinamurti K. 1994. Biotin. In: Shils ME, Olson JA, Shike M, eds. Modern Nutrition in Health and Disease. Philadelphia: Lea & Febiger. Pp. 426–431.

Dostalova L. 1984. Vitamin status during puerperium and lactation. Ann Nutr Metab 28:385–408.


Gillis J, Murphy FR, Boxall LB, Pencharz PB. 1982. Biotin deficiency in a child on long-term TPN. J Parenter Enteral Nutr 6:308–310.

Guilarte TR. 1985. Measurement of biotin levels in human plasma using a radiometric-microbiological assay. Nutr Rep Int 31:1155–1163.


Hirano M, Honma K, Daimatsu T, Hayakawa K, Oizumi J, Zaima K, Kanke Y. 1992. Longitudinal variations of biotin content in human milk. Int J Vitam Nutr Res 62:281–282.

Hoppner K, Lampi B, Smith DC. 1978. An appraisal of the daily intakes of vitamin B12, pantothenic acid and biotin from a composite Canadian diet. Can Inst Food Sci Technol J 11:71–74.

Suggested Citation:"11 Biotin." Institute of Medicine. 1998. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press. doi: 10.17226/6015.
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Hu Z-Q, Henderson GI, Mock DM, Schenker S. 1994. Biotin uptake by basolateral membrane vesicles of human placenta: Normal characteristics and role of ethanol. Proc Soc Exp Biol Med 206:404–408.

Innis SM, Allardyce DB. 1983. Possible biotin deficiency in adults receiving long-term total parenteral nutrition. Am J Clin Nutr 37:185–187.


Karl PI, Fisher SE. 1992. Biotin transport in microvillous membrane vesicles, cultured trophoblasts and isolated perfused human placenta. Am J Physiol 262:C302–C308.

Khalidi N, Wesley JR, Thoene JG, Whitehouse WM Jr, Baker WL. 1984. Biotin deficiency in a patient with short bowel syndrome during home parenteral nutrition. J Parenter Enteral Nutr 8:311–314.

Kien CL, Kohler E, Goodman SI, Berlow S, Hong R, Horowitz SP, Baker H. 1981. Biotin-responsive in vivo carboxylase deficiency in two siblings with secretory diarrhea receiving total parenteral nutrition. J Pediatr 99:546–550.

Kopinski JS, Leibholz J, Bryden WL. 1989a. Biotin studies in pigs. 3. Biotin absorption and synthesis. Br J Nutr 62:767–772.

Kopinski JS, Leibholz J, Bryden WL. 1989b. Biotin studies in pigs. 4. Biotin availability in feedstuffs for pigs and chickens. Br J Nutr 62:773–780.

Koutsikos D, Fourtounas C, Kapetanaki A, Agroyannis B, Tzanatos H, Rammos G, Kopelias I, Bosiolis B, Bovoleti O, Darema M, Sallum G. 1996. Oral glucose tolerance test after high-dose i.v. biotin administration in normoglucemic hemodialysis patients. Ren Fail 18:131–137.

Kramer TR, Briske-Anderson M, Johnson SB, Holman RT. 1984. Effects of biotin deficiency on polyunsaturated fatty acid metabolism in rats. J Nutr 114:2047– 2052.


Lagier P, Bimar P, Seriat-Gautier S, Dejode JM, Brun T, Bimar J. 1987. Zinc and biotin deficiency during prolonged parenteral nutrition in infants. Presse Med 16:1795–1797.

Lewis J, Buss DH. 1988. Trace nutrients: Minerals and vitamins in the British household food supply. Br J Nutr 60:413–424.

Liu YY, Shigematsu Y, Bykov I, Nakai A, Kikawa Y, Fukui T, Sudo M. 1994. Abnormal fatty acid composition of lymphocytes of biotin-deficient rats. J Nutr Sci Vitaminol 40:283–288.

Livaniou E, Evangelatos GP, Ithakissios DS, Yatzidis H, Koutsicos DC. 1987. Serum biotin levels in patients undergoing chronic hemodialysis. Nephron 46:331– 332.


Matsusue S, Kashihara S, Takeda H, Koisumi S. 1985. Biotin deficiency during total parenteral nutrition: Its clinical manifestation and plasma nonesterified fatty acid level. J Parenter Enteral Nutr 9:760–763.

McCormick DB. 1976. Biotin. In: Hegsted M, ed. Present Knowledge in Nutrition. Washington, DC: The Nutrition Foundation. Pp. 217–225.

McCormick DB, Wright LD. 1971. The metabolism of biotin and analogues. In: Florkin M, Stotz EH, eds. Comprehensive Biochemistry, Vol. 21. Amsterdam: Elsevier. Pp. 81–110.

Mock DM. 1996. Biotin. In: Ziegler EE, Filer LJ Jr, eds. Present Knowledge in Nutrition, 7th ed. Washington, DC: ILSI Nutrition Foundation. Pp. 220–235.

Mock DM, Dyken ME. 1997. Biotin catabolism is accelerated in adults receiving long-term therapy with anticonvulsants. Neurology 49:1444–1447.

Mock DM, Heird GM. 1997. Urinary biotin analogs increase in humans during chronic supplementation: The analogs are biotin metabolites. Am J Physiol 272:E83–E85.

Suggested Citation:"11 Biotin." Institute of Medicine. 1998. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press. doi: 10.17226/6015.
×

Mock DM, Malik MI. 1992. Distribution of biotin in human plasma: Most of the biotin is not bound to protein. Am J Clin Nutr 56:427–432.

Mock DM, Stadler DD. 1997. Conflicting indicators of biotin status from a cross-sectional study of normal pregnancy. J Am Coll Nutr 16:252–257.

Mock DM, Delorimer AA, Liebman WM, Sweetman L, Baker H. 1981. Biotin deficiency: An unusual complication of parenteral alimentation. N Engl J Med 304:820–823.

Mock DM, Baswell DL, Baker H, Holman RT, Sweetman L. 1985. Biotin deficiency complicating parenteral alimentation: Diagnosis, metabolic repercussions, and treatment. J Pediatr 106:762–769.

Mock DM, Johnson SB, Holman RT. 1988a. Effects of biotin deficiency on serum fatty acid composition: Evidence for abnormalities in humans. J Nutr 118:342– 348.

Mock DM, Mock NI, Johnson SB, Holman RT. 1988b. Effects of biotin deficiency on plasma and tissue fatty acid composition: Evidence for abnormalities in rats. Pediatr Res 24:396–403.

Mock DM, Mock NI, Langbehn SE. 1992. Biotin in human milk: Methods, location, and chemical form. J Nutr 122:535–545.

Mock DM, Mock NI, Stratton SL. 1997a. The concentrations of biotin metabolites in human milk. J Pediatr 131:456–458.

Mock DM, Stadler DD, Stratton SL, Mock NI. 1997b. Biotin status assessed longitudinally in pregnant women. J Nutr 127:710–716.

Mock NI, Malik MI, Stumbo PJ, Bishop WP, Mock DM. 1997. Increased urinary excretion of 3-hydroxyisovaleric acid and decreased urinary excretion of biotin are sensitive early indicators of decreased status in experimental biotin deficiency. Am J Clin Nutr 65:951–958.

Moss AJ, Levy AS, Kim I, Park YK. 1989. Use of Vitamin and Mineral Supplements in the United States: Current Users, Types of Products, and Nutrients. Advance Data, Vital and Health Statistics of the National Center for Health Statistics, No. 174. Hyattsville, MD: National Center for Health Statistics.

Murphy SP, Galloway DH. 1986. Nutrient intake of women in NHANES II, emphasizing trace minerals, fiber, and phytate. J Am Diet Assoc 86:1366–1372.

NRC (National Research Council). 1989. Recommended Dietary Allowances, 10th ed. Washington, DC: National Academy Press.


Oppel TW. 1948. Studies of biotin metabolism in man: 4. Studies of the mechanism of absorption of biotin and the effect of biotin administration on a few cases of seborrhea and other conditions. Am J Med Sci 215:76–83.


Paul AA, Southgate DAT. 1978. McCance and Widdowson’s The Composition of Foods. London: Her Majesty’s Stationery Office.

Paul PK, Duttagupta PN. 1975. The effect of an acute dose of biotin at the pre-implantation stage and its relation with female sex steroids in the rat. J Nutr Sci Vitaminol (Tokyo) 21:89–101.

Paul PK, Duttagupta PN. 1976. The effect of an acute dose of biotin at a post-implantation stage and its relation with female sex steroids in the rat. J Nutr Sci Vitaminol (Tokyo) 22:181–186.


Ramaekers VT, Brab M, Rau G, Heimann G. 1993. Recovery from neurological deficits following biotin treatment in a biotinidase Km variant. Neuropediatrics 24:98–102.

Roth KS, Yang W, Allan L, Saunders M, Gravel RA, Dakshinamurti K. 1982. Prenatal administration of biotin in biotin responsive multiple carboxylase deficiency. Pediatr Res 16:126–129.

Suggested Citation:"11 Biotin." Institute of Medicine. 1998. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press. doi: 10.17226/6015.
×

Salmenpera L, Perheentupa J, Pispa JP, Siimes MA. 1985. Biotin concentrations in maternal plasma and milk during prolonged lactation. Int J Vitam Nutr Res 55:281–285.

Schenker S, Hu Z, Johnson RF, Yang Y, Frosto T, Elliott BD, Henderson GI, Mock DM. 1993. Human placental biotin transport: Normal characteristics and effect of ethanol. Alcohol Clin Exp Res 17:566–575.

Shriver BJ, Roman-Shriver C, Allred JB. 1993. Depletion and repletion of biotinyl enzymes in liver of biotin-deficient rats: Evidence of a biotin storage system. J Nutr 123:1140–1149.

Sorrell MF, Frank O, Thompson AD, Aquino H, Baker H. 1971. Absorption of vitamins from the large intestine in vivo. Nutr Rep Int 3:143–148.


Wolf B, Heard GS, McVoy JR, Raetz HM. 1984. Biotinidase deficiency: The possible role of biotinidase in the processing of dietary protein-bound biotin. J Inherit Metab Dis 7:121–122.

Wolf B, Grier RE, McVoy JR, Heard GS. 1985. Biotinidase deficiency: A novel vitamin recycling defect. J Inherit Metab Dis 8:53–58.


Yatzidis H, Koutsicos D, Agroyannis B, Papastephanidis C, Francos-Plemenos M, Delatola Z. 1984. Biotin in the management of uremic neurologic disorders.


Zempleni J, McCormick DB, Mock DM. 1997. Identification of biotin sulfone, bisnorbiotin methyl ketone, and tetranorbiotin-1-sulfoxide in human urine. Am J Clin Nutr 65:508–511.

Suggested Citation:"11 Biotin." Institute of Medicine. 1998. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press. doi: 10.17226/6015.
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Next: 12 Choline »
Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Get This Book
×

Since 1941, Recommended Dietary Allowances (RDAs) has been recognized as the most authoritative source of information on nutrient levels for healthy people. Since publication of the 10th edition in 1989, there has been rising awareness of the impact of nutrition on chronic disease. In light of new research findings and a growing public focus on nutrition and health, the expert panel responsible for formulation RDAs reviewed and expanded its approach—the result: Dietary Reference Intakes.

This new series of references greatly extends the scope and application of previous nutrient guidelines. For each nutrient the book presents what is known about how the nutrient functions in the human body, what the best method is to determine its requirements, which factors (caffeine or exercise, for example) may affect how it works, and how the nutrient may be related to chronic disease.

This volume of the series presents information about thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline.

Based on analysis of nutrient metabolism in humans and data on intakes in the U.S. population, the committee recommends intakes for each age group—from the first days of life through childhood, sexual maturity, midlife, and the later years. Recommendations for pregnancy and lactation also are made, and the book identifies when intake of a nutrient may be too much. Representing a new paradigm for the nutrition community, Dietary Reference Intakes encompasses:

  • Estimated Average Requirements (EARs). These are used to set Recommended Dietary Allowances.
  • Recommended Dietary Allowances (RDAs). Intakes that meet the RDA are likely to meet the nutrient requirement of nearly all individuals in a life-stage and gender group.
  • Adequate Intakes (AIs). These are used instead of RDAs when an EAR cannot be calculated. Both the RDA and the AI may be used as goals for individual intake.
  • Tolerable Upper Intake Levels (ULs). Intakes below the UL are unlikely to pose risks of adverse health effects in healthy people.

This new framework encompasses both essential nutrients and other food components thought to pay a role in health, such as dietary fiber. It incorporates functional endpoints and examines the relationship between dose and response in determining adequacy and the hazards of excess intake for each nutrient.

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