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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline 4 Thiamin SUMMARY Thiamin functions as a coenzyme in the metabolism of carbohydrates and branched-chain amino acids. The method used to estimate the Recommended Dietary Allowance (RDA) for thiamin combines erythrocyte transketolase activity, urinary thiamin excretion, and other findings. The RDA for adults is 1.2 mg/day for men and 1.1 mg/day for women. Recently, the median intake of thiamin from food in the United States was approximately 2 mg/ day, and the ninety-fifth percentile of intake from both food and supplements was approximately 6.1 mg. Intakes in two Canadian populations were slightly lower. Data concerning adverse effects are not sufficient to set a Tolerable Upper Intake Level (UL) for thiamin. BACKGROUND INFORMATION Thiamin (also known as vitamin B1 and aneurin) was the first B vitamin identified. Lack of thiamin causes the deficiency disease called beriberi, which has been known since antiquity. More recently, at least in industrialized nations, thiamin deficiency has been mainly found in association with chronic alcoholism, where it presents as the Wernicke-Korsakoff syndrome. Chemically, thiamin consists of substituted pyrimidine and thiazole rings linked by a methylene bridge. It exists mainly in various interconvertible phosphorylated forms, chiefly thiamin pyrophosphate

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline (TPP). TPP, the coenzymatic form of thiamin, is involved in two main types of metabolic reactions: decarboxylation of α-ketoacids (e.g., pyruvate, α-ketoglutarate, and branched-chain keto acids) and transketolation (e.g., among hexose and pentose phosphates). Physiology of Absorption, Metabolism, and Excretion Following ingestion, absorption of thiamin occurs mainly in the jejunum, at lower concentrations as an active, carrier-mediated system involving phosphorylation and at higher concentrations by passive diffusion. Thiamin is transported in blood both in erythrocytes and plasma. Only a small percentage of a high dose of thiamin is absorbed, and elevated serum values result in active urinary excretion of the vitamin (Davis et al., 1984). After an oral dose of thiamin, peak excretion occurs in about 2 hours, and excretion is nearly complete after 4 hours (Levy and Hewitt, 1971; Morrison and Campbell, 1960). In a study by Davis and colleagues (1984), a 10-mg oral dose of thiamin was given in water, and the mean serum thiamin peaked at 24 nmol/L (7.2 µg/L) —42 percent above baseline. Within 6 hours the serum thiamin concentration had returned to baseline, 17 nmol/L (5.2 µg/L). Prompt urinary excretion of thiamin was also reported by Najjar and Holt (1940) and McAlpine and Hills (1941). With higher pharmacological levels, namely repetitive 250-mg amounts taken orally and 500 mg given intramuscularly, nearly 1 week was required for steady state plasma concentrations to be reached; a mean elimination half-life of 1.8 days was estimated (Royer-Morrot et al., 1992). Total thiamin content of the adult human has been estimated to be approximately 30 mg, and the biological half-life of the vitamin is probably in the range of 9 to 18 days (Ariaey-Nejad et al., 1970). Clinical Effects of Inadequate Intake Early stages of thiamin deficiency may be accompanied by non-specific symptoms that may be overlooked or easily misinterpreted (Lonsdale and Shamberger, 1980). The clinical signs of deficiency include anorexia; weight loss; mental changes such as apathy, decrease in short-term memory, confusion, and irritability; muscle weakness; and cardiovascular effects such as an enlarged heart (Horwitt et al., 1948; Inouye and Katsura, 1965; Platt, 1967; Williams et al., 1942; Wilson, 1983). In wet beriberi, edema occurs; in dry

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline beriberi, muscle wasting is obvious. In infants, cardiac failure may occur rather suddenly (McCormick and Greene, 1994). Severe thiamin deficiency in industrialized countries is likely to be related to heavy alcohol consumption with limited food consumption, as was noted for at least four of five Welsh cases reported by Anderson and colleagues (1985). In those cases renal and cardiovascular complications were life threatening. SELECTION OF INDICATORS FOR ESTIMATING THE REQUIREMENT FOR THIAMIN Biochemical changes in thiamin status occur well before the appearance of overt signs of deficiency. Thiamin status can be assessed by determining erythrocyte transketolase activity, by measuring the concentration of thiamin and its phosphorylated esters in blood or serum components using high-performance liquid chromatography, or by measuring urinary thiamin excretion under basal conditions or after thiamin loading. Commonly used reference values indicating marginal deficiency for these indicators are given in Table 4-1. Other methods have also been reported and are covered briefly below. No currently available indicator, by itself, provides an adequate basis on which to estimate the thiamin requirement. Urinary Thiamin Excretion The urinary excretion of thiamin is the indicator that has been used most widely in metabolic studies of thiamin requirements and TABLE 4-1 Reference Values for the Primary Measures of Thiamin Status Indicator Marginal Deficiency Deficiency Erythrocyte transketolase activitya 1.20–1.25 > 1.25 Erythrocyte thiamin (nmol/L)a 70–90 < 70 Thiamin pyrophosphate effect (%)b 15–24 ≥ 25 Urinary thiamina     (nmol [µg]/g creatinine) 90–220 (27–66) < 27 (nmol [µg]/d) 133–333 (40–100) < 40 a Schrijver (1991). b Stimulated value, expressed as a multiple of the basal value. Also termed the activity coefficient. Brin (1970).

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline was thus given careful consideration in deriving the Estimated Average Requirement (EAR). Urinary thiamin excretion decreases markedly as thiamin status declines and is also affected by recent dietary intake. Bayliss and coworkers (1984) reported a correlation of 0.86 between the oral dose of thiamin and urinary thiamin excretion. However, in doses of up to 1.05 mg there was overlap with baseline values. The use of a load test, in which thiamin excretion is measured before and after a test load of thiamin, helps differentiate between extremes of vitamin status (McCormick and Greene, 1994). Erythrocyte Transketolase Activity Erythrocyte transketolase activity has also been widely used and is generally regarded as the best functional test of thiamin status (McCormick and Greene, 1994), but it has some limitations for deriving the EAR and should be evaluated along with other indicators. In this test, erythrocytes are lysed and the transketolase activity is measured before and after stimulation by the addition of thiamin pyrophosphate (TPP); the basal level and the stimulated value (typically expressed as a multiple of the basal level, termed the activity coefficient or TPP effect) are measured. In thiamin-depleted individuals, basal erythrocyte transketolase typically is low and the incremental response after TPP addition is enhanced. Although the test has long been used in assessing thiamin status, in one recent study (Bailey et al., 1994) it correlated poorly with dietary thiamin intake in English adolescents. Similarly, in a study population of 179 adult men, Gans and Harper (1991) found a wide range of TPP effect values (0 to 95 percent) associated with thiamin intakes that were all above 1.5 mg/day over a 3-day period. Similarly, they also found a TPP effect of 0 percent associated with a wide range of intakes (approximately 0.75 to 6.0 mg/day). Schrijver (1991) reported that the activity coefficient may appear normal after prolonged deficiency, making identification of the deficiency more problematic. From studies of the elderly, Pekkarinen and colleagues (1974) concluded that evaluation of thiamin status should consider other indicators along with erythrocyte transketolase activity. Factors other than thiamin status, such as genetic defects, may influence the enzyme activity and thus the test results. Individuals and tissues both differ in their sensitivity to thiamin deficiency. This observation may be explained by the pronounced lag in the formation of active holoenzyme and the interindividual and cell type variation in the lag during thiamin deficiency (Singleton et al., 1995).

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Erythrocyte Thiamin As thiamin status declines, the concentration of TPP in erythrocytes decreases at approximately the same rate as occurs in other tissues (Brin, 1964; McCormick and Greene, 1994). The TPP effect may be noted within 2 weeks after the initiation of a thiamin-restricted diet (Brin, 1962). Baines and Davies (1988) provided evidence that, compared with erythrocyte transketolase activity, erythrocyte TPP is more stable in frozen erythrocytes, easier to standardize, and less susceptible to factors that influence enzyme activity. Other Measurements Because of the wide variety of signs and symptoms characteristic of thiamin deficiency, numerous other indicators of thiamin status have been reported. These include blood pyruvic acid values after exercise (Foltz et al., 1944); both pyruvic acid and lactic acid values after administration of glucose (Bueding et al., 1941; Williams et al., 1943); various indicators of work performance (e.g., maximum work test to exhaustion) (Wood et al., 1980); aerobic power, respiratory exchange ratio, and ventilatory equivalent (van der Beek et al., 1994); work output over time (Foltz et al., 1944); gross behavior changes (Williams et al., 1942); neurological changes (Wood et al., 1980); psychological changes (Wood et al., 1980); and quality of life (Wilkinson et al., 1997). None of these was judged to be a dependable criterion of thiamin status. FACTORS AFFECTING THE THIAMIN REQUIREMENT Bioavailability Data on the bioavailability of thiamin in humans are extremely limited. Levy and Hewitt (1971) reported that absorption of thiamin supplements taken with breakfast does not differ from that taken on an empty stomach. No adjustments for bioavailability were judged necessary for deriving the Estimated Average Requirement (EAR). Energy Intake No studies were found that examined the effect of energy intake on the thiamin requirement. Some studies provided thiamin in

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline graded doses that kept the ratio of thiamin to energy constant for those studied who had different energy requirements. Other studies provided total amounts of thiamin (and sometimes energy) that were the same for all individuals. Sauberlich and colleagues (1979) adjusted activity levels rather than energy intake to maintain weight in their subjects. Several investigators examined their data to assess whether it would be better to express thiamin as an absolute value or in relation to energy. For example, Dick and colleagues (1958) reported that the coefficient of variation of the estimated thiamin requirement for adolescent boys was 14.2 percent/person, 15.5 percent/1,000 kcal, 27.5 percent/kg body weight, 19.5 percent/m2 surface area, and 19.2 percent/mg of creatinine excretion. Elsom and coworkers (1942) noted that they could not distinguish whether it was better to express thiamin in absolute values or per 1,000 kcal but that thiamin intake expressed per body weight did not discriminate between those who were deficient and those who were not. Anderson and colleagues (1986) presented evidence that expressing the thiamin requirements in absolute terms is more useful for predicting biochemical thiamin status than expressing it in relation to energy intake, and data from individuals presented by Henshaw and coworkers (1970) appear supportive. Despite the lack of direct experimental data, the known biochemical function of thiamin as thiamin pyrophosphate (TPP) in the metabolism of carbohydrate suggests that at least a small (10 percent) adjustment to the estimated requirement to reflect differences in the average energy utilization and size of men and women, a 10 percent increase in the requirement to cover increased energy utilization during pregnancy, and a small increase to cover the energy cost of milk production during lactation may be necessary. It has been observed that during periods of starvation such as in war, larger individuals present signs of beriberi more rapidly than do those with smaller body builds, indicating their greater needs for thiamin and other energy-related nutrients (Burgess, 1946). Many studies report thiamin intake per 1,000 kcal; others report total intake. Thus, the evidence below is presented as it was done in the studies and not because the ratio is considered important. Physical Activity Heavy exercise under certain conditions may increase the requirement for thiamin as well as other vitamins, but the observations on the effects of physical activity on the thiamin requirement have been inconsistent, the effects small, and the experimental conditions

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline highly variable. For example, one 14-week, double-blind, 2 × 2 × 2 complete factorial experiment examined the effects of restriction of three vitamins—thiamin, riboflavin, and vitamin B6—on physical performance in 24 healthy Dutch males (van der Beek et al., 1994). In the thiamin-restricted group, thiamin intake was 0.43 mg/day (analyzed mean value). Thiamin concentration, erythrocyte transketolase activity, and urinary thiamin decreased significantly over the 11-week experimental period, and α-erythrocyte transketolase activity (or activation coefficient) increased. The decrease in thiamin status was accompanied by small but significant decrements in performance as measured during single short bouts of intense exercise, but these could not be attributed to any one of the three vitamins studied. In another double-blind study, 12 mg of thiamin (15 mg of thiamin nitrate) along with riboflavin and pyridoxine were provided to all 22 subjects in the experimental group for 5 weeks. Although the activation coefficients for transketolase (and other enzymes) decreased in the supplemented group, no change in blood lactate was found after exercise (Fogelholm et al., 1993). An observational study (Folgeholm et al., 1992) that found comparable erythrocyte transketolase activation coefficients in skiers and nonskiers provided little useful information on the effect of energy expenditure on thiamin requirements. Compared with the nonskiers, the skiers had much higher energy intakes and expenditures along with much higher intakes of all reported nutrients. For both males and females, mean thiamin intakes were 0.8 mg/1,000 kcal for the skiers and 0.7 mg/1,000 kcal for the control subjects. It was thus concluded that under normal conditions, physical activity does not appear to influence thiamin requirements to a substantial degree. However, those who are engaged in physically demanding occupations or who spend much time training for active sports may require additional thiamin. Gender Studies were not found that directly compare the thiamin requirements of males and females. A small (10 percent) difference in the average thiamin requirements of men and women is assumed on the basis of mean differences in body size and energy utilization.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline 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. Ages 0 through 6 Months. The AI reflects the observed mean thiamin intake of infants consuming human milk. Thus, the thiamin AI for young infants is based on mean intake data from infants fed human milk exclusively during their first 6 months and uses the thiamin concentration of milk produced by well-nourished mothers. There are no reports of full-term infants who were exclusively fed milk from U.S. or Canadian mothers who manifested any signs of thiamin deficiency; however, infants breastfed by mothers with beriberi have been reported to develop beriberi themselves by age 3 to 4 weeks (Hytten and Thomason, 1961). The thiamin content of human milk was similar for well-nourished mothers who received vitamin supplements and for those who did not (Nail et al., 1980; Pratt and Hamil, 1951). The thiamin concentration is low in colostrum (approximately 0.01 µg/L). The mean concentration of thiamin in mature human milk is 0.21 ± 0.04 mg/L (mean ± standard deviation) (Committee on Nutrition, 1985). Using the mean volume for intake of human milk of 0.78 L/day (see Chapter 2) and the average thiamin content of 0.21 mg/L, the AI for thiamin is 0.16 mg/day for infants ages 0 through 6 months, which is rounded to 0.2 mg. For the reference infant weight of 7 kg, this corresponds to 0.03 mg/kg/ day. Blood concentration of total thiamin (phosphorylated and nonphosphorylated) has been shown to decrease with age: in a cross-sectional study of well-nourished individuals, blood thiamin concentrations in infants less than 3 months of age (n = 64) averaged 258 ± 63 nmol/L (75 ± 23 µg/L) (mean ± standard deviation), infants 3 to 12 months of age (n = 100) averaged 214 ± 44 nmol/L (64 ± 13 µg/L), while in children and young adults (n = 159) the value decreased to 187 ± 39 µmol/L (56 ± 12 µg/L) (Wyatt et al., 1991). Because total thiamin concentrations in whole blood and cerebrospinal fluid decrease in the first 12 to 18 months of life, age-specific norms should be used for determining thiamin status in infancy.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Ages 7 through 12 Months. If the reference body weight ratio method described in Chapter 2 to extrapolate from the AI for thiamin for infants ages 0 through 6 months is used, the AI for thiamin for the older infants would be 0.2 mg/day after rounding. The second method (see Chapter 2), extrapolating from the Estimated Average Requirement (EAR) for adults and adjusting for the expected variance to estimate a recommended intake, gives an AI of 0.3 mg of thiamin, a value higher than that obtained from the first method. Alternatively, the AI for thiamin for infants ages 7 through 12 months could be calculated by using the estimated thiamin content of 0.6 L of human milk, the average volume consumed by this age group (thiamin content equals 0.13 mg), and adding the amount of thiamin provided by solid foods (0.5 mg), as estimated by Montalto et al. (1985) (see Chapter 2). The result equals approximately 0.6 mg/day. This value was judged to be unreasonably high because it is two to three times the extrapolated values given above. Thus the AI for thiamin is 0.3 mg/day for infants ages 7 through 12 months— the value extrapolated from estimates of adult requirements. Thiamin AI Summary, Ages 0 through 12 Months AI for Infants 0–6 months 0.2 mg/day of thiamin ≈0.03 mg/kg 7–12 months 0.3 mg/day of thiamin ≈0.03 mg/kg Children Ages 1 through 8 Years Method Used to Estimate the Average Requirement No direct data were found on which to base an EAR for children ages 1 through 8 years. In the absence of additional information, EARs and Recommended Dietary Allowances (RDAs) for these age groups have been extrapolated from adult values by using the method described in Chapter 2. Thiamin EAR and RDA Summary, Ages 1 through 8 Years EAR for Children 1–3 years 0.4 mg/day of thiamin   4–8 years 0.5 mg/day of thiamin The RDA for thiamin is set by assuming a coefficient of variation (CV) of 10 percent (see Chapter 1) because information is not available on the standard deviation of the requirement for thiamin; the

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of the individuals in the group (therefore, for thiamin the RDA is 120 percent of the EAR). RDA for Children 1–3 years 0.5 mg/day of thiamin   4–8 years 0.6 mg/day of thiamin Children and Adolescents Ages 9 through 18 Years Evidence Considered in Estimating the Average Requirement Five studies were found for this age group, none of which involved children younger than 13 years. In an observational study of 19 boys and 35 girls aged 13 or 14 years, thiamin intake was calculated from 7-day food records and was also analyzed by high-performance liquid chromatography from duplicate portions (Bailey et al., 1994). The correlations of the results from the food records and the analyses of duplicate portions were significant but moderate (r = 0.59 for boys and 0.43 for girls). However, the indicators of thiamin status (erythrocyte transketolase, erythrocyte transketolase activity coefficient, and total erythrocyte thiamin concentration) were not correlated with each other. Moreover, none of them was correlated with thiamin intake as estimated from the food records or measured in the duplicate portions. A substantial percentage of the subjects (girls, 12 percent; boys, 17 percent) had activity coefficients that indicated a high risk of thiamin deficiency according to Brin’s criterion for adults (Brin, 1970) even though estimated intakes were above 0.4 mg/1,000 kcal. A controlled-diet, dose-response experiment was conducted with nine girls aged 16 to 18 years to examine the thiamin requirement (Hart and Reynolds, 1957). In this study, the girls were given 0.29 mg of thiamin/1,000 kcal/day (0.63 mg/day total) for the first 16-day period and 0.6 mg/1,000 kcal/day (1.3 mg/day) for the second 16-day period. The adequacy of intake was assessed by measuring total daily thiamin excretion, the percentage of consumed thiamin that was excreted, the ratio of thiamin to creatinine in the urine, and the percentage of excretion of a 5-mg oral test dose of thiamin hydrochloride. Using a modification of the thiochrome method for thiamin determination, the investigators were unable to obtain reliable measurements of the amount of thiamin excreted on the low-thiamin diet. The authors noted that the subjects became irritable and uncooperative and lost the ability to concentrate when fed the low-thiamin diet—symptoms also noted by others in the early stage

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline of thiamin deficiency. On the diet that provided 1.3 mg/day of thiamin, 24-hour thiamin excretion ranged between 0.27 and 0.44 µmol (81 and 133 µg). These data suggest that the average thiamin requirement is less than 1.3 mg/day, especially considering the short period of repletion and the use of a generous cutoff point for urinary thiamin excretion, but they do not allow further refinement of the estimate. In a study of eight boys aged 14 to 17 years, Dick and colleagues (1958) calculated thiamin requirements from a regression of excretion on intake at five levels of thiamin that ranged from 0.6 to 2.7 mg/day. By taking the abscissa of the intersection of two straight lines fitted to the observations on each subject, a mean requirement of 1.41 mg/day was computed. However, at this level of intake, mean urinary excretion averaged 0.618 µmol/day (186 µg/day) —a value far in excess of usual cutoffs. In the absence of additional definitive information about requirements, EARs and RDAs for thiamin for these age groups were extrapolated from the adult values by using the method described in Chapter 2. Because only urinary excretion of thiamin was measured, the results reported by Hart and Reynolds (1957) are not considered strong enough to warrant adjustment of results from the extrapolation method. Thiamin EAR and RDA Summary, Ages 9 through 18 Years EAR for Boys 9–13 years 0.7 mg/day of thiamin   14–18 years 1.0 mg/day of thiamin EAR for Girls 9–13 years 0.7 mg/day of thiamin   14–18 years 0.9 mg/day of thiamin The RDA for thiamin is set by assuming a coefficient of variation (CV) of 10 percent (see Chapter 1) because information is not available on the standard deviation of the requirement for thiamin; the RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of the individuals in the group (therefore, for thiamin the RDA is 120 percent of the EAR). RDA for Boys 9–13 years 0.9 mg/day of thiamin   14–18 years 1.2 mg/day of thiamin RDA for Girls 9–13 years 0.9 mg/day of thiamin   14–18 years 1.0 mg/day of thiamin

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline EAR for Men 51–70 years 1.0 mg/day of thiamin   > 70 years 1.0 mg/day of thiamin EAR for Women 51–70 years 0.9 mg/day of thiamin   > 70 years 0.9 mg/day of thiamin The RDA for thiamin is set by assuming a coefficient of variation (CV) of 10 percent (see Chapter 1) because information is not available on the standard deviation of the requirement for thiamin; the RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of the individuals in the group (therefore, for thiamin the RDA is 120 percent of the EAR). RDA for Men 51–70 years 1.2 mg/day of thiamin   > 70 years 1.2 mg/day of thiamin RDA for Women 51–70 years 1.1 mg/day of thiamin   > 70 years 1.1 mg/day of thiamin Pregnancy Method Used to Estimate the Average Requirement The few studies of the thiamin need of pregnant women focus mainly on single indicators of status, usually without reference to dietary intake. For example, one measurement of transketolase activity was made in each of 556 pregnant German women at various stages of gestation (Heller et al., 1974). The mean activation coefficient was 1.13 whereas that of a reference group of 300 blood donors was 1.05; the cutoff value of normal activation coefficients, derived from data on nonpregnant adults, was 1.20. Twenty-six percent of the women with uncomplicated pregnancies and 21 percent of those with complications had activation coefficients above the cutoff and were classified as abnormal. Regardless of the nutritional status of the mother, erythrocyte transketolase activity was higher in cord blood than in maternal blood (Tripathy, 1968). Similarly, the free thiamin concentration was higher in cord blood (Slobody et al., 1949). Transketolase activity in cord blood tended to be proportional to that in maternal blood and higher in the blood of pregnant than of nonpregnant women (Tripathy, 1968). In 103 pregnant Malaysian women whose staple diet was rice, 36 percent had a TPP effect greater than 25

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline percent—a larger percentage than was found for males and nonpregnant women (Chong and Ho, 1970). Oldham and coworkers (1950) found a very strong correlation (r = 0.98) between total thiamin intake and excretion but no consistent decrease in thiamin excretion or in the percentage of a test dose excreted over the course of pregnancy. These investigators compared their results with those from studies of nonpregnant women of comparable ages (Daum et al., 1948; Hathaway and Strom, 1946; Oldham et al., 1946) and found that the pregnant women excreted two to three times as much thiamin as did the nonpregnant women on similar intakes (estimated at less than 1 mg) whereas their excretion of a test dose was similar. In contrast, Toverud (1940) observed no or minimal excretion of thiamin in the urine normally or after a load test in 46 percent of 114 pregnant women. Lockhart and coworkers (1943) reported that approximately three times as much thiamin, as obtained from both supplements and diet, was needed by 16 pregnant women to achieve the urinary excretion peak in the tenth lunar month as was needed by a group of nonpregnant women. Thiamin EAR and RDA Summary, Pregnancy For pregnancy the requirement is increased by about 30 percent based on increased growth in maternal and fetal compartments (approximately 20 percent) and a small increase in energy utilization (about 10 percent). This results in an additional requirement for pregnancy of 0.27 ≅ 0.3 mg/day of thiamin. Data from the studies cited above are equivocal about the effects of pregnancy on thiamin requirements and thus are not useful in refining this estimate. Adding 0.3 to the EAR of 0.9 mg for nonpregnant, nonlactating women gives an EAR for the second and third trimesters of pregnancy of 1.2 mg. No adjustment is made for the woman’s age. EAR for Pregnancy 14–18 years 1.2 mg/day of thiamin 19–30 years 1.2 mg/day of thiamin 31–50 years 1.2 mg/day of thiamin The RDA for thiamin is set by assuming a coefficient of variation (CV) of 10 percent (see Chapter 1) because information is not available on the standard deviation of the requirement for thiamin; the RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of the individuals in the group (therefore, for thiamin the RDA is 120 percent of the EAR).

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline RDA for Pregnancy 14–18 years 1.4 mg/day of thiamin 19–30 years 1.4 mg/day of thiamin 31–50 years 1.4 mg/day of thiamin Lactation Method Used to Estimate the Average Requirement For lactating women it is assumed that 0.16 mg of thiamin is transferred in their milk each day when daily milk production is 0.78 L (see “Ages 0 through 6 Months”). To estimate the average thiamin requirement of lactating women, an additional 0.1 mg of thiamin is added to the EAR (0.9 mg/day) for the nonpregnant, nonlactating woman to cover the energy cost of milk production. Thus, the EAR for thiamin for the lactating woman is 0.9 + 0.16 + 0.1 = 1.16 ≅ 1.2 mg/day of thiamin. Women who are breastfeeding older infants who are eating solid foods might need slightly less thiamin because of a lower volume of milk production. Thiamin EAR and RDA Summary, Lactation EAR for Lactation 14–18 years 1.2 mg/day of thiamin 19–30 years 1.2 mg/day of thiamin 31–50 years 1.2 mg/day of thiamin The RDA for thiamin is set by assuming a coefficient of variation (CV) of 10 percent (see Chapter 1) because information is not available on the standard deviation of the requirement for thiamin; the RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of the individuals in the group (therefore, for thiamin the RDA is 120 percent of the EAR). RDA for Lactation 14–18 years 1.4 mg/day of thiamin 19–30 years 1.4 mg/day of thiamin 31–50 years 1.4 mg/day of thiamin

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Special Considerations Persons who may have increased needs for thiamin include those being treated with hemodialysis or peritoneal dialysis, individuals with malabsorption syndrome, women carrying more than one fetus, and lactating women who are nursing more than one infant. INTAKE OF THIAMIN Food Sources Data obtained from the 1995 Continuing Survey of Food Intakes by Individuals indicate that the greatest contribution to thiamin intake of the U.S. adult population comes from the following enriched, fortified, or whole-grain products: bread and bread products, mixed foods whose main ingredient is grain, and ready-to-eat cereals (Table 4-3). Small differences are seen in the contributions of various foods to the overall thiamin intake of men and women. Other sources include pork and ham products and cereals and meat substitutes fortified with vitamins. Dietary Intake Data from nationally representative surveys during the past decade (Appendixes G and H) indicate that the median daily intake of thiamin in the United States by young men was approximately 2 mg and the median intake by young women was approximately 1.2 mg daily. For all life stage and gender groups except lactating females, fewer than 5 percent of the individuals had intakes that were lower than the Estimated Average Requirement (EAR). Five to 10 percent of lactating females had intakes lower than the EAR. Results from Canadian surveys indicate that thiamin intakes in two Canadian provinces were slightly lower than U.S. intakes for both men and women (Appendix I). The Boston Nutritional Status Survey (Appendix F) indicates that this relatively advantaged group of people over age 60 had a median thiamin intake of 1.4 mg/day for men and 1.1 mg/day for women. Intake from Supplements Information from the Boston Nutritional Status Survey conducted on the use of thiamin supplements by a free-living elderly population is given in Appendix F. For those taking supplements, the fifti-

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline TABLE 4-3 Food Groups Providing Thiamin in the Diets of U.S. Men and Women Aged 19 Years and Older, CSFII, 1995a   Contribution to Total Thiamin Intakeb (%) Foods Within the Group that Provide at Least 0.3 mg of Thiaminc per Serving Food Group Men Women 0.3–0.6 mg > 0.6 mg Food groups providing at least 5% of total thiamin intake Bread and bread products 17.1 17.7 — — Mixed foods, main ingredient is grain 9.6 8.1 NAd NA Ready-to-eat cereals 9.3 11.8 Moderately fortified Highly fortified Mixed foodse 9.1 6.5 NA NA Pasta, rice, and cooked cereals 6.7 7.2 Egg noodles, spinach noodles Fortified oatmeal Processed meatsf 5.8 4.1 Pork sausage — Pork 5.6 4.9 — Pork and ham Thiamin from other food groups Finfish 0.9 1.5 Pompano, fresh tuna, catfish, and trout — Soy-based supplements and meal replacements 0.7 0.2 Soy milk Soy-based meat substitutes Seeds 0.1 0.3 Sunflower seeds — NOTE: Most of the grain products are enriched, whole grain, or fortified. a CSFII = Continuing Survey of Food Intakes by Individuals. b Contribution to total intake reflects both the concentration of the nutrient in the food and the amount of the food consumed. It refers to the percentage contribution to the American diet for both men and women, based on 1995 CSFII data. c 0.3 mg = 20% of the Recommended Daily Intake (1.5 mg) of thiamin—a value set by the Food and Drug Administration. d NA = not applicable. Mixed foods were not considered for this table. e Includes sandwiches and other foods with meat, poultry, or fish as the main ingredient. f Includes frankfurters, sausages, lunch meats, and meat spreads. SOURCE: Unpublished data from the Food Surveys Research Group, Agricultural Research Service, U.S. Department of Agriculture, 1997.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline eth percentile of supplemental thiamin intake was 2.4 mg for men and 3.2 mg for women. Approximately 27 percent of adults surveyed took a thiamin-containing supplement in 1986 (Moss et al., 1989). TOLERABLE UPPER INTAKE LEVELS Hazard Identification Adverse Effects There are no reports available of adverse effects from consumption of excess thiamin by ingestion of food and supplements. Because the data are inadequate for a quantitative risk assessment, no Tolerable Upper Intake Level (UL) can be derived for thiamin. Supplements that contain up to 50 mg/day of thiamin are widely available without prescription, but the possible occurrence of adverse effects resulting from this level or more of intake appears not to have been studied systematically. The limited evidence of adverse effects after large intakes of thiamin is summarized here. Anaphylaxis. There have been occasional reports of serious and even fatal responses to the parenteral administration of thiamin (Stephen et al., 1992). The clinical characteristics have strongly suggested an anaphylactic reaction. Symptoms associated with thiamin-induced anaphylaxis include anxiety, pruritus, respiratory distress, nausea, abdominal pain, and shock, sometimes progressing to death (Laws, 1941; Leitner, 1943; Reingold and Webb, 1946; Schiff, 1941; Stein and Morgenstern, 1944; Stiles, 1941). Allergic Sensitivity and Pruritus. Royer-Morrot and colleagues (1992) reported one case of pruritus after an intake of 500 mg/day of thiamin intramuscularly. Another study (Wrenn et al., 1989), which involved intravenous administration of 100 mg of thiamin hydrochloride to 989 patients, reported a burning effect at the injection site in 11 patients and pruritus in 1 patient. No reports of pruritus after thiamin ingestion were found. Because pruritus was only observed with parenteral administration and at a dosage well above the maximum that can be absorbed, it is irrelevant for setting a UL. The finding of Wrenn and coworkers (1989) supports the conclusion that even intravenous administration of high doses of thiamin is relatively safe. The apparent lack of toxicity of supplemental thiamin may be

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline explained by the rapid decline in absorption that occurs at intakes above 5 mg (Hayes and Hegsted, 1973; SCOGS/LSRO, 1978) and the rapid urinary excretion of thiamin (Davis et al., 1984; McAlpine and Hills, 1941; Najjar and Holt, 1940). Dose-Response Assessment In the absence of known toxic effects by ingestion, a lowest-observedadverse-effect level (LOAEL) and an associated no-observed-adverseeffect level (NOAEL) cannot be determined. Supplements that contain up to 50 mg/day of thiamin are widely available without prescription, but effects of this level or more of intake do not appear to have been studied systematically. Intake Assessment Although no UL can be set for thiamin, an exposure assessment is provided here for possible future use. Based on data from the Third National Health and Nutrition Examination Survey, the highest mean intake of thiamin from diet and supplements for any life stage or gender group was reported for men aged 31 through 50 years: 6.7 mg/day. The highest reported intake at the ninety-fifth percentile was 11.0 mg/day in women aged 51 years and older (see Appendix H). Risk Characterization Although no adverse effects have been associated with excess intake of thiamin from food or supplements, this does not mean that there is no potential for adverse effects resulting from high intakes. Because data on the adverse effects of thiamin intake are extremely limited, caution may be warranted. RESEARCH RECOMMENDATIONS FOR THIAMIN Priority should be given to studies useful for setting Estimated Average Requirements (EARs) for thiamin for children, adolescents, pregnant and lactating women, and the elderly. Future studies should be designed around the EAR paradigm, use graded levels of thiamin intake with clearly defined cutoff values for clinical adequacy and inadequacy, and be conducted for a sufficient duration. To do this, close attention should be given to the identification of indicators on which to base thiamin requirements.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline If studies are designed to test high doses of thiamin for possible beneficial effects, the design should also provide for the careful investigation of possible adverse effects. REFERENCES Anderson SH, Charles TJ, Nicol AD. 1985. Thiamine deficiency at a district general hospital: Report of five cases. Q J Med 55:15–32. Anderson SH, Vickery CA, Nicol AD. 1986. Adult thiamine requirements and the continuing need to fortify processed cereals. Lancet 2:85–89. Ariaey-Nejad MR, Balaghi M, Baker EM, Sauberlich HE. 1970. Thiamin metabolism in man. Am J Clin Nutr 23:764–778. Bailey AL, Finglas PM, Wright AJ, Southon S. 1994. Thiamin intake, erythrocyte transketolase (EC 2.2.1.1) activity and total erythrocyte thiamin in adolescents. Br J Nutr 72:111–125. Baines M, Davies G. 1988. The evaluation of erythrocyte thiamin diphosphate as an indicator of thiamin status in man, and its comparison with erythrocyte transketolase activity measurements. Ann Clin Biochem 25:698–705. Bamji MS. 1970. Transketolase activity and urinary excretion of thiamin in the assessment of thiamin-nutrition status of Indians. Am J Clin Nutr 23:52–58. Bayliss RM, Brookes R, McCulloch J, Kuyl JM, Metz J. 1984. Urinary thiamine excretion after oral physiological doses of the vitamin. Int J Vitam Nutr Res 54:161–164. Brin M. 1962. Erythrocyte transketolase in early thiamine deficiency. Ann NY Acad Sci 98:528–541. Brin M. 1964. Erythrocyte as a biopsy tissue for functional evaluation of thiamine adequacy. J Am Med Assoc 187:762–766. Brin M. 1970. Transketolase (sedoheptulose-7-phosphate: D-glyceral-dehyde-3-phosphate dihydroxyacetonetransferase, EC 2.2.1.1) and the TPP effect in assessing thiamine adequacy. In: McCormick DB, Wright LD, eds. Methods in Enzymology, Vol. 18, Part A. London: Academic Press. Pp. 125–133. Bueding E, Stein MH, Wortis H. 1941. Blood pyruvate curves following glucose ingestion in normal and thiamine-deficient subjects. J Biol Chem 140:697–703. Burgess RC. 1946. Deficiency diseases in prisoners-of-war at Changi, Singapore, February 1942 to August 1945. Lancet 2:411–418. Chong YH, Ho GS. 1970. Erythrocyte transketolase activity. Am J Clin Nutr 23:261– 266. Committee on Nutrition. 1985. Composition of human milk: Normative data. In: Pediatric Nutrition Handbook, 2nd ed. Elk Grove Village, IL: American Academy of Pediatrics. Pp. 363–368. Daum K, Tuttle WW, Wilson M, Rhoads H. 1948. Influence of various levels of thiamine intake on physiologic response. 2. Urinary excretion of thiamine. J Am Diet Assoc 24:1049. Davis RE, Icke GC, Thom J, Riley WJ. 1984. Intestinal absorption of thiamin in man compared with folate and pyridoxal and its subsequent urinary excretion. J Nutr Sci Vitaminol (Tokyo) 30:475–482. Dick EC, Chen SD, Bert M, Smith JM. 1958. Thiamine requirement of eight adolescent boys, as estimated from urinary thiamine excretion. J Nutr 66:173–188.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Elsom KO, Reinhold JG, Nicholson JT, Chornock C. 1942. Studies of the B vitamins in the human subject. 5. The normal requirement for thiamine; some factors influencing its utilization and excretion. Am J Med Sci 203:569–577. Fogelholm M, Rehunen S, Gref CG, Laakso JT, Lehto J, Ruokonen I, Himberg JJ. 1992. Dietary intake and thiamin, iron, and zinc status in elite Nordic skiers during different training periods. Int J Sport Nutr 2:351–365. Fogelholm M, Ruokonen I, Laakso JT, Vuorimaa T, Himberg JJ. 1993. Lack of association between indices of vitamin B1, B2, and B6 status and exercise-induced blood lactate in young adults. Int J Sport Nutr 3:165–176. Foltz EE, Barborka CJ, Ivy AC. 1944. The level of vitamin B-complex in the diet at which detectable symptoms of deficiency occur in man. Gastroenterology 2:323– 344. Gans DA, Harper AE. 1991. Thiamin status of incarcerated and nonincarcerated adolescent males: Dietary intake and thiamin pyrophosphate response. Am J Clin Nutr 53:1471–1475. Hart M, Reynolds MS. 1957. Thiamine requirement of adolescent girls. J Home Econ 49:35–37. Hathaway ML, Strom JE. 1946. A comparison of thiamine synthesis and excretion in human subjects on synthetic and natural diets. J Nutr 32:1. Hayes KC, Hegsted DM. 1973. Toxicity of the vitamins. In: Toxicants Occurring Naturally in Foods. Washington, DC: National Academy Press. Pp. 235–253. Heller S, Salkeld RM, Korner WF. 1974. Vitamin B1 status in pregnancy. Am J Clin Nutr 27:1221–1224. Henshaw JL, Noakes G, Morris SO, Bennion M, Gubler CJ. 1970. Method for evaluating thiamine adequacy in college women. J Am Diet Assoc 57:436–441. Hoorn RK, Flikweert JP, Westerink D. 1975. Vitamin B1, B2 and B6 deficiencies in geriatric patients, measured by coenzyme stimulation of enzyme activities. Clin Chim Acta 61:151–162. Horwitt MK, Liebert E, Kreisler O, Wittman P. 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. Washington, DC: National Academy of Sciences. Hytten FE, Thomason AM. 1961. Nutrition of the lactating women. In: Kon SK, Cowie AT, eds. Milk: The Mammary Gland and Its Secretion. New York: Academic Press. Pp. 3–46. Inouye K, Katsura E. 1965. Etiology and pathology of beriberi. In: Shimazono N, Katsura E, eds. Review of Japanese Literature on Beriberi and Thiamine. Igaku Shoin, Tokyo: Vitamin B Research Committee of Japan. Pp. 1–28. Kraut H, Wildemann L, Böhm M. 1966. Human thiamine requirements. Int Z Vitaminforsch 36:157–193. Laws CL. 1941. Sensitization to thiamine hydrochloride. J Am Med Assoc 117:146. Leitner ZA. 1943. Untoward effects of vitamin B1. Lancet 2:474–475. Levy G, Hewitt RR. 1971. Evidence in man for different specialized intestinal transport mechanisms for riboflavin and thiamin. Am J Clin Nutr 24:401–404. Lockhart HS, Kirkwood S, Harris RS. 1943. The effect of pregnancy and puerperium on the thiamine status of women. Am J Obstet Gynecol 46:358–365. Lonsdale D, Shamberger RJ. 1980. Red cell transketolase as an indicator of nutritional deficiency. Am J Clin Nutr 33:205–211. McAlpine D, Hills GM. 1941. The clinical value of the thiochrome test for aneurin (vitamin B1) in urine. Q J Med 34:31–39.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline McCormick DB, Greene HL. 1994. Vitamins. In: Burtis CA, Ashwood ER, eds. Tietz Textbook of Clinical Chemistry. Philadelphia: Saunders. Pp. 1275–1316. Montalto MB, Benson JD, Martinez GA. 1985. Nutrient intake of formula-fed infants and infants fed cow’s milk. Pediatrics 75:343–351. Morrison AB, Campbell JA. 1960. Vitamin absorption studies. 1. Factors influencing the excretion of oral test doses of thiamine and riboflavin by human subjects. J Nutr 72:435–440. 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. Nail PA, Thomas MR, Eakin R. 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. Najjar VA, Holt LE Jr. 1940. Studies in thiamin excretion. Bull Johns Hopkins Hosp 67:107–124. Nichols HK, Basu TK. 1994. Thiamin status of the elderly: Dietary intake and thiamin pyrophosphate response. J Am Coll Nutr 13:57–61. O’Rourke NP, Bunker VW, Thomas AJ, Finglas PM, Bailey AL, Clayton BE. 1990. Thiamine status of healthy and institutionalized elderly subjects: Analysis of dietary intake and biochemical indices. Age Ageing 19:325–329. Oldham H. 1962. Thiamine requirements of women. Ann NY Acad Sci 98:542–549. Oldham HG, Davis MV, Roberts LJ. 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, Sheft BB, Porter T. 1950. Thiamine and riboflavin intakes and excretions during pregnancy. J Nutr 41:231–245. Pekkarinen M, Koivula L, Rissanen A. 1974. Thiamine intake and evaluation of thiamine status among aged people in Finland. Int J Vitam Nutr Res 44:435– 442. Platt BS. 1967. Thiamine deficiency in human beriberi and in Wernicke’s encephalopathy. In: Wolstenholme GEW, O’Connor M, eds. Thiamine Deficiency: Biochemical Lesions and their Clinical Significance. Ciba Foundation Study Group No. 28. London: Churchill Livingstone. Pp. 135–143. Pratt JB, Hamil BM. 1951. Metabolism of women during the reproductive cycle. 18. The effect of multivitamin supplements on the secretion of B vitamins in human milk. J Nutr 44:141–157. Reingold IM, Webb FR. 1946. Sudden death following intravenous administration of thiamine hydrochloride. J Am Med Assoc 130:491–492. Reuter H, Gassmann B, Erhardt V. 1967. Contribution to the question of the human thiamine requirement. Int Z Vitaminforsch 37:315–328. Royer-Morrot MJ, Zhiri A, Paille F, Royer RJ. 1992. Plasma thiamine concentrations after intramuscular and oral multiple dosage regimens in healthy men. Eur J Clin Pharmacol 42:219–222. Sauberlich HE, Herman YF, Stevens CO, Herman RH. 1979. Thiamin requirement of the adult human. Am J Clin Nutr 32:2237–2248. Schiff L. 1941. Collapse following parenteral administration of solution of thiamine hydrochloride. J Am Med Assoc 117:609. Schrijver J. 1991. Biochemical markers for micronutrient status and their interpretation. In: Pietrzik K, ed. Modern Lifestyles, Lower Energy Intake and Micronutrient Status. London: Springer-Verlag. Pp. 55–85.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline SCOGS/LSRO (Select Committee on GRAS Substances, Life Sciences Research Office). 1978. Evaluation of the Health Aspects of Thiamin Hydrochloride and Thiamin Mononitrate as Food Ingredients. Bethesda, MD: LSRO/FASEB. Singleton CK, Pekovich SR, McCool BA, Martin, PR. 1995. The thiamine-dependent hysteretic behavior of human transketolase: Implications for thiamine deficiency. J Nutr 125:189–194. Slobody LB, Willner MM, Mestern J. 1949. Comparison of vitamin B1 levels in mothers and their newborn infants. Am J Dis Child 77:736. Stein W, Morgenstern M. 1944. Sensitization to thiamine hydrochloride: Report of a case. Ann Intern Med 70:826–828. Stephen JM, Grant R, Yeh CS. 1992. Anaphylaxis from administration of intravenous thiamine. Am J Emerg Med 10:61–63. Stiles MH. 1941. Hypersensitivity to thiamine chloride, with a note on sensitivity to pyridoxine hydrochloride. J Allergy 12:507–509. Toverud KU. 1940. The excretion of aneurin in pregnant and lactating women and infants. Z Vitaminforsch 10:255–267. Tripathy K. 1968. Erythrocyte transketolase activity and thiamine transfer across human placenta. Am J Clin Nutr 21:739–742. van der Beek EJ, van Dokkum W, Wedel M, Schrijver J, van den Berg H. 1994. Thiamin, riboflavin and vitamin B6: Impact of restricted intake on physical performance in man. J Am Coll Nutr 13:629–640. Wilkinson TJ, Hanger HC, Elmslie J, George PM, Sainsbury R. 1997. The response to treatment of subclinical thiamine deficiency in the elderly. Am J Clin Nutr 66:925–928. Williams RD, Mason HL, Smith BF, Wilder RM. 1942. Induced thiamin (vitamin B1) deficiency and the thiamine requirement of man: Further observations. Arch Intern Med 69:721–738. Williams RD, Mason HL, Wilder RM. 1943. The minimum daily requirement of thiamine in man. J Nutr 25:71–97. Wilson JA. 1983. Disorders of vitamins: Deficiency, excess and errors of metabolism. In: Petersdorf RG, Harrison TR, eds. Harrison’s Principles of Internal Medicine, 10th ed. New York: McGraw-Hill. Pp. 461–470. Wood B, Gijsbers A, Goode A, Davis S, Mulholland J, Breen K. 1980. A study of partial thiamin restriction in human volunteers. Am J Clin Nutr 33:848–861. Wrenn KD, Murphy F, Slovis CM. 1989. A toxicity study of parenteral thiamine hydrochloride. Ann Emerg Med 18:867–870. Wyatt DT, Nelson D, Hillman RE. 1991. Age-dependent changes in thiamin concentrations in whole blood and cerebrospinal fluid in infants and children. Am J Clin Nutr 53:530–536. Ziporin ZZ, Nunes WT, Powell RC, Waring PP, Sauberlich HE. 1965. Thiamine requirement in the adult human as measured by urinary excretion of thiamine metabolites. J Nutr 85:297–304.