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--> Appendix D Case Studies of Application of Risk Assessment Model for Nutrients1 A. Calcium Hazard Identification Calcium is among the most ubiquitous of elements found in the human system. Calcium plays a major role in the metabolism of virtually every cell in the body and interacts with a large number of other nutrients. As a result, disturbances of calcium metabolism give rise to a wide variety of adverse reactions. Disturbances of calcium metabolism, particularly those that are characterized by changes in extracellular ionized calcium concentration, can cause damage in the function and structure of many organs and systems. Currently, the available data on the adverse effects of excess calcium intake in humans primarily concerns calcium intake from nutrient supplements and antacids. Of the many possible adverse effects of excessive calcium intake, the three most widely studied and biologically important are: kidney stone formation (nephrolithiasis), the syndrome of hypercalcemia and renal insufficiency with and without alkalosis (referred to historically as milk-alkali syndrome when associated with a constellation of peptic ulcer treatments), and the interaction of calcium with the absorption of other essential minerals. These are not the only adverse effects associated with excess calcium intake. However, the vast majority of reported effects are related to or result from one of these three conditions. 1 Taken from the two DRI reports published to date: Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride (IOM, 1997), and Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12,f Pantothenic Acid, Biotin, and Choline (IOM, 1998).
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--> Nephrolithiasis Twelve percent of the U.S. population will form a renal stone over their lifetime (Johnson et al., 1979), and it has generally been assumed that nephrolithiasis is, to a large extent, a nutritional disease. Research over the last 40 years has shown that there is a direct relationship between periods of affluence and increased nephrolithiasis (Robertson, 1985). A number of dietary factors seem to play a role in determining the incidence of this disease. In addition to being associated with increased calcium intakes, nephrolithiasis appears to be associated with higher intakes of oxalate, protein, and vegetable fiber (Massey et al., 1993). Goldfarb (1994) argued that dietary calcium plays a minor role in nephrolithiasis because only 6 percent of the overall calcium load appears in the urine of normal individuals. Also, the efficiency of calcium absorption is substantially lower when calcium supplements are consumed (Sakhaee et al., 1994). The issue is made more complex by the association between high sodium intakes and hypercalciuria, since sodium and calcium compete for reabsorption at the same sites in the renal tubules (Goldfarb, 1994). Other minerals, such as phosphorus and magnesium, also are risk factors in stone formation (Pak, 1988). These findings suggest that excess calcium intake may play only a contributing role in the development of nephrolithiasis. Two recent companion prospective epidemiologic studies in men (Curhan et al., 1993) and women (Curhan et al., 1997) with no history of kidney stones found that intakes of dietary calcium greater than 1,050 mg (26.3 mmol)/day in men and greater than 1,098 mg (27.5 mmol)/day in women were associated with a reduced risk of symptomatic kidney stones. This association for dietary calcium was attenuated when the intake of magnesium and phosphorus were included in the model for women (Curhan et al., 1997). This apparent protective effect of dietary calcium is attributed to the binding by calcium in the intestinal lumen of oxalate, which is a critical component of most kidney stones. In contrast, Curhan et al. (1997) found that after adjustment for age, intake of supplemental calcium was associated with an increased risk for kidney stones. After adjustment for potential confounders, the relative risk among women who took supplemental calcium, compared with women who did not, was 1.2. Calcium supplements may be taken without food, which limits opportunity for the beneficial effect of binding oxalate in the intestine. A similar effect of supplemental calcium was observed in men (Curhan et al., 1993), but failed to reach statistical significance. Neither study controlled for the time that calcium supplements were taken (for example, with or without meals); thus, it is possible that the observed significance of the results in women may be due to different usage of calcium supplements by men and women. Clearly, more carefully controlled studies are needed to determine the strength of the causal association between calcium intake vis-à-vis the intake of other nutrients and kidney stones in healthy individuals.
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--> The association between calcium intake and urinary calcium excretion is weaker in children than in adults. However, at observed in adults, increased levels of dietary sodium are significantly associated with increased urinary calcium excretion in children (Matkovic et al., 1995, O'Brien et al., 1996). Hypercalcemia and Renal Insufficiency (Milk-Alkali Syndrome) The syndrome of hypercalcemia and, consequently, renal insufficiency with or without metabolic alkalosis is associated with severe clinical and metabolic derangements affecting virtually every organ system (Orwoll, 1982). Renal failure may be reversible but may also be progressive if the syndrome is unrelieved. Progressive renal failure may result in the deposition of calcium in soft tissues including the kidney (for example, nephrocalcinosis) with a potentially fatal outcome (Junor and Catto, 1976). This syndrome was first termed milk-alkali syndrome (MAS) in the context of the high milk and absorbable antacid intake which derived from the "Sippy diet" regimen for the treatment of peptic ulcer disease. MAS needs to be distinguished from primary hyperparathyroidism, in which primary abnormality of the parathyroid gland results in hypercalcemia, metabolic derangement, and impaired renal calcium resorption. As the treatment of peptic ulcers has changed (for example, systemically absorbed antacids and large quantities of milk are now rarely prescribed), the incidence of this syndrome has decreased (Whiting and Wood, 1997). A review of the literature revealed 26 reported cases of MAS linked to high calcium intake from supplements and food since 1980 without other causes of underlying renal disease (Table D-1). These reports described what appears to be the same syndrome at supplemental calcium intakes of 1.5 to 16.5 g (37.5 to 412.5 mmol)/day for 2 days to 30 years. Estimates of the occurrence of MAS in the North American population may be low since mild cases are often overlooked and the disorder may be confused with a number of other syndromes presenting with hypercalcemia. No reported cases of MAS in children were found in the literature. This was not unexpected since children have very high rates of bone turnover and calcium utilization relative to adults (Abrams et al., 1992). A single case of severe constipation directly linked to daily calcium supplementation of 1,000 mg (25 mmol) or more has been reported in an 8-year-old boy, but this may represent an idiosyncratic reaction of calcium ions exerted locally in the intestine or colon (Frithz et al., 1991). Calcium/Mineral Interactions Calcium interacts with iron, zinc, magnesium, and phosphorus (Clarkson et al., 1967; Hallberg et al., 1992; Schiller et al., 1989; Spencer et al., 1965).
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--> TABLE D-1. Case Reports of Patients with Milk Alkali Syndrome (single dose reported)a Studies Ca Intake (g/day)b Duration Mitigating Factors Hart et al., 1982 10.6c Not stated NaHCO3, 2 g/d Carroll et al., 1983 4.2c 30 years none reported 2d 5 years none reported 3.8c 2 months vitamins A and E 2.8c 10 years NaHCO3, 5 g/d Kallmeyer and Funston, 1983 8c 10 years alkali in antacid Schuman and Jones, 1985 9.8c 20 years none reported 4.8c 6 weeks 10 year history of antacid intake French et al., 1986 8d 2 years none reported 4.2d > 2 years thiazide Kapsner et al., 1986 10c 10 months none reported 6.8c 7 months none reported 4.8d 2 days 10 year history of antacid use Bullimore and Miloszewski, 1987 6.5c 23 years alkali in antacid Gora et al., 1989 4d 2 years thiazide Kleinman et al., 1991 16.5c 2 weeks 10 year history of antacid use Abreo et al., 1993 9.6d > 3 months none reported 3.6d > 2 years none reported 10.8c Not stated none reported Brandwein and Sigman, 1994 2.7d 2 years, 8 months none reported Campbell et al., 1994 5c 3 months none reported Lin et al., 1996 1.5d 4 weeks none reported Muldowney and Mazbar, 1996 1.7d 13 months (52 weeks) none reported Whiting and Wood, 1997 2.4d > 1 year none reported Whiting and Wood, 1997 2.3–4.6d > 1 year none reported Number of Subjects 26 - - Mean 5.9 3 years, 8 months - Median 4.8 13 months - Range 1.5–>16.5 2 days–23 years - a Case reports of patients with renal failure are not included in this table. b Intake estimates provided by Whiting and Wood (1997). c Calcium intake from supplements and diet reported (for example, milk and yogurt consumption). Other dietary sources of calcium not reported are not included. d Calcium intake from supplements reported only. Calcium-mineral interactions are more difficult to quantify than nephrolithiasis and MAS, since in many cases the interaction of calcium with several other
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--> minerals results in changes in the absorption and utilization of each. Thus, it is virtually impossible to determine a dietary level at which calcium intake alone disturbs the absorption or metabolism of other minerals. Nevertheless, calcium clearly inhibits iron absorption in a dose-dependent and dose-saturable fashion (Hallberg et al., 1992). However, the available human data fail to show cases of iron deficiency or even reduced iron stores as a result of calcium intake (Snedeker et al., 1982; Sokoll and Dawson-Hughes, 1992). Similarly, except for a single report of negative zinc balance in the presence of calcium supplementation (Wood and Zheng, 1990), the effects of calcium on zinc absorption have not been shown to be associated with zinc depletion or undernutrition. Neither have interactions of high levels of calcium with magnesium or phosphorus shown evidence of depletion of the affected nutrient (Shils, 1994). Thus, in the absence of clinically or functionally significant depletion of the affected nutrient, calcium interaction with other minerals represents a potential risk rather than an adverse effect, in the sense that nephrolithiasis or hypercalcemia are adverse effects. Still, the potential for increased risk of mineral depletion in vulnerable populations such as those on very low mineral intakes or the elderly needs to be incorporated into the uncertainty factor in deriving a Tolerable Upper Intake Level (UL) for calcium. Furthermore, because of their potential to increase the risk of mineral depletion in vulnerable populations, calcium-mineral interactions should be the subject of additional studies. Dose-Response Assessment Adults: Ages 19 through 70 Years Data Selection. Based on the discussion of adverse effects of excess calcium intake above, the most appropriate data available for identifying a critical endpoint and a no-observed-adverse-effect level (NOAEL) (or lowest-observed-adverse-effect level [LOAEL]) concern the risks of MAS and nephrolithiasis. There are few well-controlled, chronic studies of calcium that show a dose-response relationship. While there are inadequate data on nephrolithiasis to establish a dose-response relationship and to identify a NOAEL (or LOAEL), there are adequate data on MAS that can be used. Identification of a NOAEL (or LOAEL) and Critical Endpoint. Using MAS as the clinically defined critical endpoint, a LOAEL in the range of 4 to 5 grams (100 to 125 mmol)/day can be identified for adults (Table D-1). A review of these reports revealed calcium intakes from supplements (and in some cases from dietary sources as well) in the range of 1.5 to 16.5 g (37.5 to 412.5 mmol)/day. A median intake of 4.8 g (120 mmol)/day resulted in documented cases. Since many of these reports included dietary calcium intake as well as
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--> intake from supplements, an intake in the range of 5 g (125 mmol)/day represents a LOAEL for total calcium intake (for example, from both supplements and food). A solid figure for a NOAEL is not available, but researchers have observed that daily calcium intakes of 1,500 to 2,400 mg (37.5 to 60 mmol) (including supplements), used to treat or prevent osteoporosis, did not result in hypercalcemic syndromes (Kochersberger et al., 1991; McCarron and Morris, 1985; Riggs et al., 1996; Saunders et al., 1988; Smith et al., 1989; Thys-Jacobs et al., 1989). Consideration of hypercalciuria may have additional relevance to the derivation of a UL for adults. Hypercalciuria is observed in approximately 50 percent of patients with calcium oxalate/apatite nephrolithiasis and is an important risk factor for nephrolithiasis (Lemann et al., 1991; Whiting and Wood, 1997). Therefore, it is plausible that high calcium intakes associated with hypercalciuria could produce nephrolithiasis. Burtis et al. (1994) reported a significant positive association between both dietary calcium and sodium intake and hypercalciuria in 282 renal stone patients and derived a regression equation to predict the separate effects of dietary calcium and urinary sodium on urinary calcium excretion. Setting urinary sodium excretion at 150 mmol/day and defining hypercalciuria for men as greater than 300 mg (7.5 mmol) of calcium/day excreted (Burtis et al., 1994), the calcium intake that would be associated with hypercalciuria was 1,685 mg (42.1 mmol)/day. For women, for whom hypercalcemia was defined as greater than 250 mg (6.2 mmol)/day excreted, it would be 866 mg (21.6 mmol)/day. The results of these calculations from the Burtis et al. (1994) equation suggest that calcium intakes lower than the recommended intake levels derived for females (Appendix A) could result in hypercalciuria in susceptible individuals. Although Burtis et al. (1994) identified what could be defined as LOAELs for hypercalciuria, 1,685 mg (42.1 mmol)/day in men and 866 mg (21.6 mmol)/day in women, these values are not considered as appropriate for use as the LOAEL for healthy adults because they were based on patients with renal stones. However, they provide support for the need for conservative estimates of the UL. Uncertainty Assessment. An uncertainty factor (UF) of 2 is recommended to take into account the potential for increased risk due to high calcium intakes based on the following concerns: (1) the 12 percent of the American population with renal stones, (2) the occurrence of hypercalciuria with intakes as low as 1,700 mg (42.5 mmol)/day in male and 870 mg (21.7 mmol)/day in female patients with renal stones (Burtis et al., 1994), and (3) the potential to increase the risk of mineral depletion in vulnerable populations due to the interference of calcium on mineral bioavailability, especially iron and zinc. Derivation of the UL. A UL of 2.5 g (62.5 mmol) of calcium/day is calculated by dividing a LOAEL of 5 g (125 mmol)/day by the UF of 2. The
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--> TABLE D-2. Case Reports of Milk Alkali Syndrome at Higher Dose (multi and increasing doses reported) Ca Intake 1st Dose (g/day) Duration (months) Ca. Intake 2nd Dose (g/day) Duration Malone and Horn, 1971 not reported 13 3a 4.5 weeks Hakim et al., 1979 1a 13 2.5a 3.5 weeks Carroll et al., 1983 2.5 13 3 13 months Schuman and Jones, 1985 not reported 13 4.6 6 weeks Dorsch, 1986 not reported 13 2.1a 6 months Newmark and Nugent, 1993 not reported 13 8.4a < 1 year (recent) Beall and Scofield, 1995 1a 13 2.4a 2 weeks 1 13 4.2 2 weeks 0.3 6 1.8a 1 month Number of Subjects 9 9 Mean (SD) 1.2 (0.8) 12 3.6 (2.0) 16.7 (21) Median 1 13 3 4.5 Range 0.3–2.5 6–13 1.8–8.4 2–53 a Data do not include intake of calcium from dietary sources. data summarized in Table D-2 show that calcium intakes of 0.3 to 2.5 g (7.5 to 62.5 mmol)/day will not cause MAS and provide supportive evidence for a UL of 2,500 mg (62.5 mmol)/day for adults. The estimated UL for calcium in adults is judged to be conservative. For individuals who are particularly susceptible to high calcium intakes, such as those with hypercalcemia and hyperabsorptive hypercalciuria, this level or below should be protective. UL for Adults Ages 19 through 70 years 2,500 mg (62.5 mmol) of calcium/day Infants: Ages 0 through 12 Months The safety of calcium intakes above the levels provided by infant formulas and weaning foods has recently been studied by Dalton et al. (1997). They did not find any effect on iron status of calcium intakes of approximately 1,700 mg (42.5 mmol)/day in infants, which was attained using calcium-fortified infant formula. However, further studies are needed before a UL specific to infants can be established.
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--> UL for Infants Ages 0 through 12 months Not possible to establish; source of intake should be from formula and food only Toddlers, Children, and Adolescents: Ages 1 through 18 years Although the safety of excess calcium intake in children ages 1 through 18 years has not been studied, a UL of 2,500 mg (62.5 mmol)/day is recommended for these life stage groups. Although calcium supplementation in children may appear to pose minimal risk of MAS or hyperabsorptive hypercalciuria, risk of depletion of other minerals associated with high calcium intakes may be greater. With high calcium intake, small children may be especially susceptible to deficiency of iron and zinc (Golden and Golden, 1981; Schlesinger et al., 1992; Simmer et al., 1988). However, no dose-response data exist regarding these interactions or the development of adaptation to chronic high calcium intakes in children. After age 9, rates of calcium absorption and bone formation begin to increase in preparation for pubertal development, but a conservative UL of 2,500 mg (62.5 mmol)/day (from diet and supplements) is recommended for children due to the lack of data. UL for Children Ages 1 through 18 years 2,500 mg (62.5 mmol) of calcium/day Older Adults: Ages > 70 Years Several physiologic differences in older adults need to be considered in setting the UL for people over age 70. Because this population is more likely to have achlorhydria (Recker, 1985), absorption of calcium, except when associated with meals, is likely to be somewhat impaired, which would protect these individuals from the adverse effects of high calcium intakes. Furthermore, there is a decline in calcium absorption associated with age that results from changes in function of the intestine (Ebeling et al., 1994). However, the elderly population is also more likely to have marginal zinc status, which theoretically would make them more susceptible to the negative interactions of calcium and zinc (Wood and Zheng, 1990). This matter deserves more study. These effects serve to increase the UF on the one hand and decrease it on the other, with the final result being to use the same UL for older adults as for younger adults. UL for Older Adults Ages > 70 years 2,500 mg (62.5 mmol) of calcium/day
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--> Pregnancy and Lactation The available data were judged to be inadequate for deriving a UL for pregnant and lactating women that is different from the UL for the nonpregnant and nonlactating female. UL for Pregnancy Ages 14 through 50 years 2,500 mg (62.5 mmol) of calcium/day UL for Lactation Ages 14 through 50 years 2,500 mg (62.5 mmol) of calcium/day Special Considerations Not surprisingly, the ubiquitous nature of calcium results in a population of individuals with a wide range of sensitivities to its toxic effects. Subpopulations known to be particularly susceptible to the toxic effects of calcium include individuals with renal failure, those using thiazide diuretics (Whiting and Wood, 1997), and those with low intakes of minerals that interact with calcium (for example, iron, magnesium, and zinc). For the majority of the general population, intakes of calcium from food substantially above the UL are probably safe. Exposure Assessment The highest median intake of calcium for any age group found in the 1994 CSFII data, adjusted for day-to-day variation (Nusser et al., 1996), was for boys 14 through 18 years of age with a median intake of 1,094 mg (27.4 mmol)/day and a ninety-fifth percentile intake of 2,039 mg (51 mmol)/day. Calcium supplements were used by less than 8 percent of young children, 14 percent of men, and 25 percent of women in the United States (Moss et al., 1989). Daily dosages from supplements at the ninety-fifth percentile were relatively small for children (160 mg [4 mmol]), larger for men (624 mg /[15.6 mmol]), and largest for women (904 mg [22.6 mmol]) according to Moss et al. (1989). Risk Characterization Although the ninety-fifth percentile of daily intake did not exceed the UL for any age group (2,101 mg [52.5 mmol] in males 14 through 18 years of age) in the 1994 CSFII data, persons with a very high caloric intake, especially if intakes of dairy products are also high, may exceed the UL of 2,500 mg (62.5 mmol)/day. Even if the ninety-fifth percentile of intake from foods and the most recently available estimate of the ninety-fifth percentile of supplement use
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--> (Moss et al., 1989) are added together for teenage boys (1,920 + 928 mg/day) or for teenage girls (1,236 + 1,200 mg/day), total intakes are just at or slightly above the UL. Although users of dietary supplements (of any kind) tend to also have higher intakes of calcium from food than nonusers (Slesinski et al., 1996), it is unlikely that the same person would fall at the upper end of both ranges. Furthermore, the prevalence of usual intakes (from foods plus supplements) above the UL is well below 5 percent, even for age groups with relatively high intakes. Nevertheless, an informal survey of food products in supermarkets in the Washington, D.C. metropolitan area between 1994 and 1996 showed that the number of calcium-fortified products doubled in the 2-year period (Y. Park, Food and Drug Administration, February 1997, personal communication). Therefore, it is important to maintain surveillance of calcium-fortified products in the marketplace and monitor their impact on calcium intake. References Abrams SA, Esteban NV, Vieira NE, Sidbury JB, Specker BL, Yergey AL. 1992. Developmental changes in calcium kinetics in children assessed using stable isotopes. J Bone Miner Res 7:287–293. Abreo K, Adlakha A, Kilpatrick S, Flanagan R, Webb R, Shakamuri S . 1993. The milk-alkali syndrome. A reversible form of acute renal failure. Arch Intern Med 153:1005-1010. Beall DP, Scofield RH. 1995. Milk-alkali syndrome associated with calcium carbonate consumption: Report of 7 patients with parathyroid hormone levels and an estimate of prevalence among patients hospitalized with hypercalcemia. Medicine 74:89–96. Brandwein SL, Sigman, KM. 1994. Case report: Milk-alkali syndrome and pancreatitis. Am J Med Sci 308:173–176. Bullimore DW, Miloszewski KJ. 1987. Raised parathyroid hormone levels in the milk-alkali syndrome: An appropriate response? Postgrad Med J 63:789–792. Burtis WJ, Gay L, Insogna KL, Ellison A, Broadus AE. 1994. Dietary hypercalciuria in patients with calcium oxalate kidney stones. Am J Clin Nutr 60:424–429. Campbell SB, MacFarlane DJ, Fleming SJ, Khafagi FA. 1994. Increased skeletal uptake of Tc-99m methylene disphosphonate in milk-alkali syndrome. Clin Nucl Med 19:207–211. Carroll MD, Abraham S, Dresser CM. 1983. Dietary Intake Source Data: United States, 1976–1980. Data from the National Health Survey. Vital and Health Statistics series 11, no. 231. DHHS Publ. No. (PHS) 83–1681. Hyattsville, MD: National Center for Health Statistics, Public Health Service, U.S. Department of Health and Human Services.
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--> Clarkson EM, Warren RL, McDonald SJ, de Wardener HE. 1967. The effect of a high intake of calcium on magnesium metabolism in normal subjects and patients with chronic renal failure. Clin Sci 32:11–18. Curhan GC, Willett WC, Rimm EB, Stampfer MJ. 1993. A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. N Engl J Med 328:833–838. Curhan GC, Willett WC, Speizer FE, Spiegelman D, Stampfer MJ. 1997. Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women. Ann Intern Med 126:497–504. Dalton MA, Sargent JD, O'Connor GT, Olmstead EM, Klein RZ. 1997. Calcium and phosphorus supplementation of iron-fortified infant formula: No effect on iron status of healthy full-term infants. Am J Clin Nutr 65:921–6. Dorsch TR. 1986. The milk-alkali syndrome, vitamin D, and parathyroid hormone. Ann Intern Med 105:800–801. Ebeling PR, Yergey AL, Vieira NE, Burritt MF, O'Fallon WM, Kumar R, Riggs BL. 1994. Influence of age on effects on endogenous 1,25-dihydroxy-vitamin D on calcium absorption in normal women. Calcif Tissue Int 55:330–334. French JK, Koldaway IM, Williams LC. 1986. Milk-alkali syndrome following over-the-counter antacid self-medication. N Zeal Med J 99:322–323. Frithz G, Wictorin B, Ronquist G. 1991. Calcium-induced constipation in a prepubescent boy. Acta Paediatr Scand 80:964–965. Golden BE, Golden MH. 1981. Plasma zinc, rate of weight gain, and the energy cost of tissue deposition in children recovering from severe malnutrition on a cow's milk or soya protein-based diet. Am J Clin Nutr 34:892–899. Goldfarb S. 1994. Diet and nephrolithiasis. Ann Rev Med 45:235–243. Gora ML, Seth SK, Bay WH, Visconti JA. 1989. Milk-alkali syndrome associated with use of chlorothiazide and calcium carbonate. Clin Pharm 8:227–229. Hakim R, Tolis G, Goltzman D, Meltzer S, Friedman R. 1979. Severe hypercalcemia associated with hydrochlorothiazide and calcium carbonate therapy. Can Med Assoc J 21:591–594. Hallberg L, Rossander-Hulten L, Brune M, Gleerup A. 1992. Calcium and iron absorption: Mechanism of action and nutritional importance. Eur J Clin Nutr 46:317–327. Hart M, Windle J, McHale M, Grissom R. 1982. Milk-alkali syndrome and hypercalcemia: A case report. Nebr Med J 67:128–130. IOM (Institute of Medicine). 1997. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academy Press. IOM (Institute of Medicine). 1998. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press.
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--> Summary The weight of the limited, but suggestive evidence that excessive folate intake may precipitate or exacerbate neuropathy in vitamin B12-deficient individuals justifies the selection of this endpoint as the critical endpoint for the development of a UL for folate. Dose-Response Assessment Adults Data Selection. To evaluate a dose-response relationship and derive a UL for folate, case reports were used that involved oral administration of folate in patients with vitamin B12 deficiency who showed development or progression of neurological complications. Because a number of apparently healthy individuals are vitamin B12 deficient (IOM, 1998), these individuals are considered part of the general population in setting a UL. Identification of a NOAEL or LOAEL. The literature was reviewed to find cases in which vitamin B12-deficient patients who were receiving oral doses of folate experienced progression of neurologic disorders. Data were not available on which to set a no-observed-adverse-effect level (NOAEL). A lowest-observed-adverse-effect level (LOAEL) of 5 mg of folate is based on the data presented in Table D-3 and summarized below: At doses of folate of 5 mg/day and above, there were more than 100 reported cases of neurological progression. At doses of less than 5 mg/day of folate (0.33 to 2.5 mg/day), there are only eight well-documented cases. In the majority of cases throughout the dose range, folate supplementation maintained the patients in hematologic remission over a considerable time span. The background intake of folate from food was not specified, but all except for three cases (those reported by Allen and coworkers ) occurred before the fortification of breakfast cereal with added folate. Uncertainty Assessment. An uncertainty factor (UF) of 5 was selected. Compared with the UFs used to date for other nutrients for which there was also a lack of controlled, dose-response data, a UF of 5 is large. The selection of a relatively large UF is based primarily on the severity of the neurological complications observed, but also on the use of a LOAEL rather than a NOAEL to derive the UL. The UF is not larger than 5 on the basis of the uncontrolled observation that millions of people have been exposed to self treatment with about one-tenth of the LOAEL (i.e., 400 μg in vitamin pills) without reported harm.
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--> Derivation of a UL. The LOAEL of 5 mg/day of folate was divided by the UF of 5 to obtain the UL for adults of 1 mg (or 1,000 μg) of folate added to fortified foods or consumed as supplements. A UL of 1,000 μg/day is set for all adults rather than just for the elderly for the following reasons: (1) the devastating and irreversible nature of the neurological consequences, (2) data suggesting that pernicious anemia may develop at a younger age in some racial/ethnic groups (Carmel and Johnson, 1978), and (3) uncertainty about the occurrence of vitamin B12 deficiency in younger age groups. In general, the prevalence of vitamin B12 deficiency in females in the childbearing years is very low, and the consumption of supplementary folate at or above the UL in this subgroup is unlikely to produce adverse effects. Folate UL Summary, Adults UL for Adults Ages 19 years and older 1,000 μg/day of folate added to fortified foods or consumed as supplements Other Life Stage Groups There are no data on other life stage groups that can be used to identify a NOAEL or LOAEL and derive a UL. For infants, the UL was judged not determinable because of lack of data on adverse effects in this age group and concern about the infant's ability to handle excess amounts. To prevent high levels of intake, the only source of intake for infants should be from food, which would include that provided by fortified products. No data were found to suggest that other life stage groups have increased susceptibility to adverse effects of high supplemental folate intake. Therefore, the UL of 1,000 μg/day is also set for adult pregnant and lactating women. The UL of 1,000 μg/day for adults was adjusted for children and adolescents on the basis of relative body weight (see Appendix C). In some cases, values have been rounded down. Life Stage Ages Supplemental Folate UL For Infants 0 through 12 months Not possible to establish for supplemental folate UL for Children 1 through 3 years 300 μg/day 4 through 8 years 400 μg/day 9 through 13 years 600 μg/day 14 through 18 years 800 μg/day
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--> Life Stage Ages Supplemental Folate UL for Pregnancy 14 through 18 years 800 μg/day 19 through 50 years 1,000 μg/day UL for Lactation 14 through 18 years 800 μg/day 19 through 50 years 1,000 μg/day Special Considerations Individuals who are at risk of vitamin B12 deficiency (e.g., those who eat no animal foods [vegans]) may be at increased risk of the precipitation of neurologic disorders if they consume excess folate (IOM, 1998). Intake Assessment It is not possible to use data from the Third National Health and Nutrition Examination Survey (NHANES III) or the Continuing Survey of Food Intake by Individuals (CSFII; USDA 1994–1996) to determine the population's exposure to supplemental folate. Currently available survey data do not distinguish between food folate and synthetic folate (folic acid) added as a fortificant or taken as a supplement. Based on data from NHANES III and excluding pregnant women (for whom folate supplements are often prescribed), the highest reported total folate intake from food and supplements at the ninety-fifth percentile, 983 μg/day, was found in females aged 30 through 50 years. This intake was obtained from food (which probably included fortified, ready-to-eat cereals, a few of which contain as much as 400 μg of folic acid/serving) and supplements. For the same group of women, the reported intake at the ninety-fifth percentile from food alone (which also probably included fortified, ready-to-eat cereal) was 438 μg/day. In Canada, the contribution of ready-to-eat cereals is expected to be lower because the maximum amount of folate that can be added to breakfast cereal is 60 μg of folic acid/100 g (Health Canada, 1996). It would be possible to exceed the UL of 1,000 μg/day of supplemental folate through the ingestion of fortified foods and/or supplements in typical total diets in the U.S. and Canada (IOM, 1998). Risk Characterization The intake of folate is currently higher than indicated by NHANES III because enriched cereal grains in the U.S. food supply, to which no folate was added previously, are now fortified with 140 μg of folic acid/100 g of cereal grain. Using data from the 1987–1988 U.S. Department of Agriculture's Nationwide Food Consumption Survey, the U.S. Food and Drug Administration (FDA) estimated that the ninety-fifth percent percentile of folate intakes for
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--> males aged 11 to 18 years would be 950 μg of total folate at this level of fortification; this value assumes that these young males would also take supplements containing 400 μg of folate (DHHS, 1993). Excluding pregnant women, for whom estimates were not provided, the ninety-fifth percentile for total folate for all other groups would be lower, and folate intake as folic acid would be lower still. Using a different method of analysis, the FDA estimated that those who follow the guidance of the Food Guide Pyramid and consume cereal grains at the upper end of the recommended range would obtain an additional 440 μg of folate as folic acid under the new U.S. fortification regulations (DHHS, 1993). (This estimate assumes 8 servings [16 slices] of bread at 40 μg of folic acid per serving and two ~ 1-cup servings of noodles or pasta at 60 μg of folic acid per serving.) Those who eat other fortified foods (such as cookies, crackers, and donuts) instead of bread might ingest a comparable amount of folic acid. Using either method of analysis and assuming regular use of an over-the-counter supplement that contains folic acid (ordinarily 400 μg per dose), it is unlikely that intake of folate added to foods or as supplements would exceed 1,000 μg on a regular basis for any of the life stage or gender groups. References Agamanolis DP, Chester EM, Victor M, Kark JA, Hines JD, Harris JW. 1976. Neuropathology of experimental vitamin B12 deficiency. Neurology 26:905–914. Allen RH, Stabler SP, Savage DG, Lindenbaum J. 1990. Diagnosis of cobalamin deficiency. I. Usefulness of serum methylmalonic acid and total homocysteine concentrations. Am J Hematol 34:90–98. Alperin JB. 1966. Response to varied doses of folic acid and vitamin B12 in megaloblastic anemia. Clin Res 14:52. Arnaud J, Favier A, Herrmann MA, Pilorget JJ. 1992. Effect of folic acid and folinic acid on zinc absorption. Ann Nutr Metab 36:157–161. Baldwin JN, Dalessio DJ. 1961. Folic acid therapy and spinal-cord degeneration in pernicious anemia. N Engl J Med 264:1339–1342. Baxter MG, Millar AA, Webster RA. 1973. Some studies on the convulsant action of folic acid. Brit J Pharmacol 48:350–351. Berk L, Bauer JL, Castle WB. 1948. A report of 12 patients treated with synthetic pteroylglutamic acid with comments on the pertinent literature. S Afr Med J 22:604–611. Best CN. 1959. Subacute combined degeneration of spinal cord after extensive resection of ileum in Crohn's disease: Report of a case. Brit Med J 2:862–864.
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--> Bethell FH, Sturgis CC. 1948. The relations of therapy in pernicious anemia to changes in the nervous system. Early and late results in a series of cases observed for periods of not less than ten years, and early results of treatment with folic acid. Blood 3:57–67. Butterworth CE, Tamura T. 1989. Folic acid safety and toxicity: A brief review. Am J Clin Nutr 50:353–358. Butterworth CE Jr, Hatch K, Cole P, Sauberlich HE, Tamura T, Cornwell PE, Soong S-J. 1988. Zinc concentration in plasma and erythrocytes of subjects receiving folic acid supplementation. Am J Clin Nutr 47:484–486. Campbell NR. 1996. How safe are folic acid supplements? Arch Intern Med 156:1638–1644. Carmel R, Johnson CS. 1978. Racial patterns in pernicious anemia: Early age at onset and increased frequency of intrinsic-factor antibody in black women. N Engl J Med 298:647–650. Chanarin I, Deacon R, Lumb M, Perry J. 1989. Cobalamin-folate interrelations. Blood Reviews 3:211–215. Chodos RB, Ross JF. 1951. The effects of combined folic acid and liver extract therapy. Blood 6:1213–1233. Conley CL, Krevans JR. 1951. Development of neurologic manifestations of pernicious anemia during multivitamin therapy. N Engl J Med 245:529–531. Crosby WH. 1960. The danger of folic acid in multivitamin preparations. Milit Med 125:233–235. Czeizel AE, Dudas I. 1992. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 327:1832–1835. Czeizel AE, Dudas I, Metneki J. 1994. Pregnancy outcomes in a randomized controlled trial of periconceptional multivitamin supplementation. Final report. Arch Gynecol Obstet 255:131–139. DHHS (U.S. Department of Health and Human Services). 1993. Food and Drug Administration. Folic acid; proposed rules. Fed Registr 21:53293–53294. Ellison ABC. 1960. Pernicious anemia masked by multivitamins containing folic acid. J Am Med Assoc 173:240–243. Fowler WM, Hendricks AB. 1949. Folic acid and the neurologic manifestations of pernicious anemia. Am Pract 3:609–613. Gibberd FB, Nicholls A, Dunne JF, Chaput de Saintonge DM. 1970. Toxicity of folic acid. Lancet 1:360–361. Gotz VP, Lauper RD. 1980. Folic acid hypersensitivity or tartrazine allergy? Am J Hosp Pharm 37:1470–1474. Hall BE, Watkins CH. 1947. Experience with pteroylglutamic (synthetic folic) acid in the treatment of pernicious anemia. J Lab Clin Med 32:622–634. Hambidge M, Hackshaw A, Wald N. 1993. Neural tube defects and serum zinc. Brit J Obstet Gynecol 100:746–749.
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--> Health Canada. 1996. Departmental Consolidation of the Food and Drugs Act and the Food and Drug Regulations with Amendments to December 19, 1996. Ottawa: Canada Communications Group. Heinle RW, Welch AD. 1947. Folic acid in pernicious anemia: Failure to prevent neurologic relapse. J Am Med Assoc 133:739–741. Heinle RW, Dingle JT, Weisberger AS. 1947. Folic acid in the maintenance of pernicious anemia. J Lab Clin Med 32:970–981. Hellstrom L. 1971. Lack of toxicity of folic acid given in pharmacological doses to healthy volunteers. Lancet 1:59–61. Herbert V. 1963. Current concepts in therapy: Megaloblastic anemia. N Engl J Med 268:201–203, 368–371. Holmes-Siedle M, Lindenbaum RH, Galliard A. 1992. Recurrence of neural tube defect in a group of at risk women: A 10 year study of Pregnavite Forte F. J Med Genet 29:134–135. Hommes OR, Obbens EA. 1972. The epileptogenic action of Na-folate in the rat. J Neurol Sci 16:271–281. Hunter R, Barnes J, Oakeley HF, Matthews DM. 1970. Toxicity of folic acid given in pharmacological doses to healthy volunteers. Lancet 1:61–3. IOM (Institute of Medicine). 1998. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press. Israels MC, Wilkinson JF. 1949. Risk of neurological complications in pernicious anemia treated with folic acid. Brit Med J 2:1072–1075. Jacobson SD, Berman L, Axelrod AR, Vonder Heide EC. 1948. Folic acid therapy: Its effect as observed in two patients with pernicious anemia and neurologic symptoms. J Am Med Assoc 137:825–827. Keating JN, Wada L, Stokstad EL, King JC. 1987. Folic acid: Effect of zinc absorption in humans and in the rat. Am J Clin Nutr 46:835–839. Kehl SJ, McLennan H, Collingridge GL. 1984. Effects of folic and kainic acids on synaptic responses of hippocampal neurones. Neuroscience 11:111–124. Kirke PN, Daly LE, Elwood JH. 1992. A randomized trial of low-dose folic acid to prevent neural tube defects. Arch Dis Child 67:1442–1446. Laurence KM, James N, Miller MH, Tennant GB, Campbell H. 1981. Double-blind randomized controlled trial of folate treatment before conception to prevent recurrence of neural tube defects. Brit Med J 282:1509–1511. Loots JM, Kramer S, Brennan MJW. 1982. The effect of folates on the reflex activity in the isolated hemisected frog spinal cord. J Neural Transm 54:239–249. Mathur BP. 1966. Sensitivity of folic acid: A case report. Indian J Med Sci 20:133–134. Metz J, Van der Westhuyzen J. 1987. The fruit bat as an experimental model of the neuropathy of cobalamin deficiency. Comp Biochem Physiol 88A:171–177.
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--> Milne DB, Canfield WK, Mahalko JR, Sandstead HH. 1984. Effect of oral folic acid supplements on zinc, copper, and iron absorption and excretion. Am J Clin Nutr 39:535–539. Mitchell DC, Vilter RW, Vilter CF. 1949. Hypersensivity to folic acid. Ann Intern Med 31:1102–1105. Mukherjee MD, Sandstead HH, Ratnaparkhi MV, Johnson LK, Milne DB, Stelling HP. 1984. Maternal zinc, iron, folic acid and protein nutriture and outcome of human pregnancy. Am J Clin Nutr 40:496–507. Olney JW, Fuller TA, de Gubareff T, Labruyere J. 1981. Intrastriatal folic acid mimics the distant but not local brain damaging properties of kainic acid. Neurosci Lett 25:207–210. Reisner EH Jr, Weiner L. 1952. Studies on mutual effect of suboptimal oral doses of vitamin B12 and folic acid in pernicious anemia. N Engl J Med 247:15–17. Richens A. 1971. Toxicity of folic acid. Lancet 1:912. Ritz ND, Meyer LM, Brahin C, Sawitsky A. 1951. Further observations on the oral treatment of pernicious anemia with subminimal doses of folic acid and vitamin B12. Acta Hematol 5:334–338. Ross JF, Belding H, Paegel BL. 1948. The development and progression of subacute combined degeneration of the spinal cord in patients with pernicious anemia treated with synthetic pteroylglutarnic (folic) acid. Blood 3:68–90. Scholl TO, Hediger ML, Bendich A, Schall JI, Smith WK, Krueger PM. 1997. Use of multivitamin/mineral prenatal supplements: Influence on the outcome of pregnancy. Am J Epidemiol 146:134–141. Schwartz SO, Kaplan SR, Armstrong BE. 1950. The long-term evaluation of folic acid in the treatment of pernicious anemia. J Lab Clin Med 35:894–898. Selby JV, Friedman GD, Fireman BH. 1989. Screening prescription drugs for possible carcinogenicity: Eleven to fifteen years of follow-up. Cancer Res 49:5736–5747. Sesin GP, Kirschenbaum H. 1979. Folic acid hypersensitivity and fever: A case report. Am J Hosp Pharm 36:1565–1567. Sheehy TW. 1973. Folic acid: Lack of toxicity. Lancet 1:37. Sheehy TW, Rubini ME, Perez-Santiago E, Santini R Jr, Haddock J . 1961. The effect of ''minute" and "titrated" amounts of folic acid on the megaloblastic anemia of tropical sprue . Blood 18:623–636. Smithells RW, Sheppard S, Schorah CJ, Seller MJ, Nevin NC, Harris R, Read AP, Fielding DW. 1981. Apparent prevention of neural tube defects by periconceptional vitamin supplementation. Arch Dis Child 56:911–918. Sparling R, Abela M. 1985. Hypersensitivity to folic acid therapy. Clin Lab Hematol 7:184–185. Spector RG. 1972. Influence of folic acid on excitable tissues. Nature 240:247–249.
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--> Spies TD, Stone RE. 1947. Liver extract, folic acid, and thymine in pernicious anemia and subacute combined degeneration. Lancet 1:174–176. Spies TD, Stone RE, Lopez GG, Milanes F, Aramburu T, Toca RL. 1948. The association between gastric achlorhydria and subacute combined degeneration of the spinal cord. Postgrad Med 4:89–95. Suarez RM, Spies TD, Suarez RM Jr. 1947. The use of folic acid in sprue. Ann Intern Med 26:643–677. Tamura T. 1995. Nutrient interaction of folate and zinc. In: Bailey LB, ed. Folate in Health and Disease. New York: Marcel Dekker. Pp. 287–312. Tamura T, Goldenberg RL, Freeberg LE, Cliver SP, Cutter GR, Hoffman HJ. 1992. Maternal serum folate and zinc concentrations and their relationships to pregnancy outcome. Am J Clin Nutr 56:365–370. Thirkette JL, Gough KR, Read AE. 1964. Diagnostic value of small oral doses of folic acid in megaloblastic anemia. Brit Med J 1:1286–1289. van der Westhuyzen J, Metz J. 1983. Tissue S-adenosylmethionine levels in fruit bats with N2O-induced neuropathy. Brit J Nutr 50:325–330. van der Westhuyzen J, Fernandes-Costa F, Metz J. 1982. Cobalamin inactivation by nitrous oxide produces severe neurological impairment in fruit bats: Protection by methionine and aggravation by folates. Life Sci 31:2001–2010. Vergel RG, Sanchez LR, Heredero BL, Rodriguez PL, Martinez AJ. 1990. Primary prevention of neural tube defects with folic acid supplementation: Cuban experience. Prenat Diagn 10:149–152. Victor M, Lear AA. 1956. Subacute combined degeneration of the spinal cord. Current concepts of the disease process. Value of serum vitamin B12 determinations in clarifying some of the common clinical problems. Am J Med 20:896–911. Vilter CF, Vilter RW, Spies TD. 1947. The treatment of pernicious and related anemias with synthetic folic acid. 1. Observations on the maintenance of a normal hematologic status and on the occurrence of combined system disease at the end of one year. J Lab Clin Med 32:262–273. Wagley PF. 1948. Neurologic disturbances with folic acid therapy. N Engl J Med 238:11–15. Wald N, Sneddon J, Densem J, Frost C, Stone R. 1991. Prevention of neural tube defects: Results of the Medical Research Council vitamin study. Lancet 338:131–137. Weller M, Marini AM, Martin B, Paul SM. 1994. The reduced unsubstituted pteroate moiety is required for folate toxicity of cultured cerebellar granule neurons. J Pharmacol Exp Ther 269:393–401. Will JJ, Mueller JF, Brodine C, Kiely CE, Friedman B, Hawkins VR, Dutra J, Vilter RN. 1959. Folic acid and vitamin B12 in pernicious anemia. Studies on patients treated with these substances over a ten-year period. J Lab Clin Med 53:22–38.
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--> C. Riboflavin Hazard Identification No adverse effects associated with riboflavin consumption from food or supplements have been reported. Studies involving large doses of riboflavin (Schoenen et al., 1994; Stripp, 1965; Zempleni et al., 1996) have not been designed to systematically evaluate adverse effects. The limited evidence from studies involving large intakes of riboflavin is summarized here. No adverse effects were reported in humans after single doses of up to 60 mg of supplemental riboflavin together with 11.6 mg of riboflavin given intravenously as a single bolus dose (Zempleni et al., 1996). This study is of limited use in setting a Tolerable Upper Intake Level (UL) because it was not designed to assess adverse effects. It is possible that chronic administration of these doses would pose some risk. In a brief communication, a study by Schoenen and coworkers (1994) stated that no short-term side effects were reported by 48 of 49 patients complaining of migraine headaches and treated with 400 mg/day of riboflavin with or without aspirin (75 mg) taken with meals for at least 3 months. Schoenen and coworkers (1994) reported that one patient receiving riboflavin and aspirin withdrew from the study because of gastric upset. This isolated finding is probably an anomaly since no side effects were reported by other patients. Since no clinical or biochemical assessment was undertaken for possible adverse effects, this study by itself is inadequate to use as a basis for determining a no-observed-adverse-effect level (NOAEL). The apparent lack of harm resulting from high oral doses of riboflavin may be due to its limited solubility, humans' limited capacity to absorb it from the gastrointestinal tract (Levy and Jusko, 1966; Stripp, 1965; Zempleni et al., 1996), and its rapid excretion in the urine (McCormick, 1997). Zempleni et al. (1996) showed that the maximal amount of riboflavin that was absorbed from a single oral dose was 27 mg. A study by Stripp (1965) found limited absorption of 50 to 500 mg of riboflavin with no adverse effects. The poor intestinal absorption of riboflavin is well recognized: riboflavin taken by mouth is sometimes used to mark the stool in experimental studies. There are no data from animal studies suggesting that uptake of riboflavin during pregnancy presents a specific potential hazard for the fetus or infant. The only evidence of adverse effects associated with riboflavin comes from in vitro studies showing the formation of active oxygen species on intense exposure to visible or ultraviolet light (Ali et al., 1991; Floersheim, 1994; Spector et al., 1995). However, given the lack of any demonstrated functional or structural adverse effects in humans or animals following excess riboflavin intake, the relevance of this evidence to human health effects in vivo is highly questionable. Nevertheless, it is theoretically plausible that riboflavin increases photosensitivity to ultraviolet irradiation. Additionally, there is a theoretical risk
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--> that excess riboflavin will increase the photosensitized oxidations of cellular compounds such as amino acids and proteins (McCormick, 1977) in infants treated for hyperbilirubinemia, with possible undesirable consequences. Dose-Response Assessment The data on adverse effects from high riboflavin intake are not sufficient for a quantitative risk assessment to establish a NOAEL (or lowest-observed-adverse-effect level [LOAEL]), and a UL cannot be derived. Special Considerations There is some in vitro evidence that riboflavin may interfere with detoxification of chrome VI by reduction to chrome III (Sugiyama et al., 1992). This may be of concern in people who may be exposed to chrome VI; for example, workers in chrome plating. Infants treated for hyperbilirubinemia may also be sensitive to excess riboflavin. Intake Assessment Although no UL can be set for riboflavin, an intake assessment is provided here for possible future use. Data from the Third National Health and Nutrition and Examination Survey (unpublished data, C.L. Johnson and J.D. Wright, National Center for Health Statistics, Centers for Disease Control and Prevention, 1997) showed that the highest mean intake of riboflavin from diet and supplements for any life stage and gender group reported was for males aged 31 through 50 years: 6.9 mg/day. The highest reported intake at the ninety-fifth percentile was 11 mg/day in females over age 70 years. Risk Characterization No adverse effects have been associated with excess intake of riboflavin from food or supplements. This does not mean that there is no potential for adverse effects resulting from high intakes. Because data on the adverse effects of riboflavin intake are limited, caution may be warranted. References Ali N, Upreti RK, Srivastava LP, Misra RB, Joshi PC, Kidwai AM. 1991. Membrane damaging potential of photosensitized riboflavin. Indian J Exp Biol 29:818–822.
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--> Floersheim GL. 1994. Allopurinol, indomethacin and riboflavin enhance radiation lethality in mice. Pediatrics 139:240–247. Levy G, Jusko WJ. 1966. Factors affecting the absorption of riboflavin in man. J Pharm Sci 55:285–289. McCormick DB. 1977. Interactions of flavins with amino acid residues: Assessments from spectral and photochemical studies. Photochem Photobiol 26:169–182. McCormick DB. 1997. Riboflavin. In: Shils ME, Olson JE, Shike M, Ross AC, eds. Modern Nutrition in Health and Disease. Baltimore, MD: Williams and Wilkins. Schoenen J, Lenaerts M, Bastings E. 1994. Rapid communication: High-dose riboflavin as a prophylactic treatment of migraine: Results of an open pilot study. Cephalalgia 14:328–329. Spector A, Wang GM, Wang RR, Li WC, Kleiman NJ. 1995. A brief photochemically induced oxidative insult causes irreversible lens damage and cataracts. 2. Mechanism of action. Exp Eye Res 60:483–493. Stripp B. 1965. Intestinal absorption of riboflavin by man. Acta Pharmacol Toxicol 22:353–362. Sugiyama M, Tsuzuki K, Lin X, Costa M. 1992. Potentiation of sodium chromate (VI)-induced chromosomal aberrations and mutation by vitamin B2 in Chinese hamster V79 cells. Mutat Res 283:211–214. Zempleni J, Galloway JR, McCormick DB. 1996. Pharmacokinetics of orally and intravenously administered riboflavin in healthy humans. Am J Clin Nutr 63:54–66.
Representative terms from entire chapter: