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Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients (1998)

Chapter: Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients

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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
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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).

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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.

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×

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).

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×

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

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×

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

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×

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

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×

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.

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×

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

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×

(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.

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×

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.

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×

Johnson CM, Wilson DM, O'Fallon WM, Malek RS, Kurland LT. 1979. Renal stone epidemiology: A 25-year study in Rochester, Minn. Kidney Int 16:624–631.

Junor JR, Catto GRD. 1976. Renal biopsy in the milk-alkali syndrome. J Clin Path 29:1074–1076.


Kallmeyer JC, Funston MR. 1983. The milk-alkali syndrome: A case report. S Afr Med J 64:287–288.

Kapsner P, Langsdorf L, Marcus R, Kraemer FB, Hoffman AR. 1986. Milk-alkali syndrome in patients treated with calcium carbonate after cardiac transplantation. Arch Intern Med 146:1965–1968.

Kleinman GE, Rodriquez H, Good MC, Caudle MR. 1991. Hypercalcemic crisis in pregnancy associated with excessive ingestion of calcium carbonate antacid (milk-alkali syndrome): Successful treatment with hemodialysis. Obstet Gynecol 73:496–499.

Kochersberger G, Westlund R, Lyles KW. 1991. The metabolic effects of calcium supplementation in the elderly. J Am Geriatr Soc 39:192–196.


Lemann J Jr, Worcester EM, Gray RW. 1991. Hypercalciuria and stones. Am J Kidney Dis 17:386–391.

Lin S-H, Lin Y-F, Shieh S-D. 1996. Milk-alkali syndrome in an aged patient with osteoporosis and fractures. Nephron 73:496–497.


Malone DNS, Horn DB. 1971. Acute hypercalcemia and renal failure after antacid therapy. Brit Med J 1:709–710.

Massey LK, Roman-Smith H, Sutton RA. 1993. Effect of dietary oxalate and calcium on urinary oxalate and risk of formation of calcium oxalate kidney stones. J Am Diet Assoc 93:901–906.

Matkovic V, Ilich JZ, Andon MB, Hsieh LC, Tzagournis MA, Lagger BJ, Goel PK. 1995. Urinary calcium, sodium, and bone mass of young females. Am J Clin Nutr 62:417–425.

McCarron DA, Morris CD. 1985. Blood pressure response to oral calcium in persons with mild to moderate hypertension: A randomized, double-blind, placebo-controlled, crossover trial. Ann Intern Med 103:825–831.

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 from Vital and Health Statistics, No. 174. Hyattsville, MD: National Center for Health Statistics.

Muldowney WP, Mazbar SA. 1996. Rolaids-yogurt syndrome: A 1990s version of milk-alkali syndrome. Am J Kidney Dis 27:270–272.


Newmark K, Nugent P. 1993. Milk-alkali syndrome: A consequence of chronic antacid abuse. Postgrad Med 93:149–156.

Nusser SM, Carriquiry AL, Dodd KW, Fuller WA. 1996. A semiparametric transformation approach to estimating usual daily intake distributions. J Am Stat Assoc 91:1440–1449.

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
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O'Brien KO, Abrams SA, Stuff JE, Liang LK, Welch TR. 1996. Variables related to urinary calcium excretion in young girls. J Pediatr Gastroenterol Nutr 23:8–12.

Orwoll ES. 1982. The milk-alkali syndrome: Current concepts. Ann Intern Med 97:242–248.


Pak CY. 1988. Medical management of nephrolithiasis in Dallas: Update 1987. J Urol 140:461–467.


Recker RR. 1985. Calcium absorption and aclorhydria. N Engl J Med 313:70–73.

Riggs BL, O'Fallon WM, Muse J, O'Conner MK, Melton LJ III. 1996. Long-term effects of calcium supplementation on serum PTH, bone turnover, and bone loss in elderly women. J Bone Miner Res 11:S118.

Robertson, WG. 1985. Dietary factors important in calcium stone formation. In: Schwille PO, Smith LH, Robertson WG, Vahlensieck W, eds. Urolithiasis and Related Clinical Research. New York: Plenum Press. Pp. 61–68.


Sakhaee K, Baker S, Zerwekh J, Poindexter J, Garcia-Hernandez PA, Pak CY. 1994. Limited risk of kidney stone formation during long-term calcium citrate supplementation in nonstone forming subjects. J Urol 152:324–327.

Saunders D, Sillery J, Chapman R. 1988. Effect of calcium carbonate and aluminum hydroxide on human intestinal function. Dig Dis Sci 33:409–412.

Schiller L, Santa Ana C, Sheikh M, Emmett M, Fordtran J. 1989. Effect of the time of administration of calcium acetate on phosphorus binding. N Engl J Med 320:1110–1113.

Schlesinger L, Arevalo M, Arredondo S, Diaz M, Lonnerdal B, Stekel A. 1992. Effect of a zinc-fortified formula on immunocompetence and growth of malnourished infants. Am J Clin Nutr 56:491–498.

Schuman CA, Jones HW III. 1985. The ''milk-alkali" syndrome: Two case reports with discussion of pathogenesis. Quart J Med (New Series) 55:119–126.

Shils ME. 1994. Magnesium. In: Shils ME, Olson JA, Shike M, eds. Modern Nutrition in Health and Disease. Philadelphia, PA: Lea & Febiger. Pp. 164–184.

Simmer K, Khanum S, Carlsson L, Thompson RP. 1988. Nutritional rehabilitation in Bangladesh—the importance of zinc. Am J Clin Nutr 47:1036–1040.

Slesinski MJ, Subar AF, Kahle LL. 1996. Dietary intake of fat, fiber, and other nutrients is related to the use of vitamin and mineral supplements in the United States: The 1992 National Health Interview Survey. J Nutr 126:3001–3008.

Smith EL, Gilligan C, Smith PE, Sempos CT. 1989. Calcium supplementation and bone loss in middle-aged women. Am J Clin Nutr 50:833–842.

Snedeker SM, Smith SA, Greger JL. 1982. Effect of dietary calcium and phosphorus levels on the utilization of iron, copper, and zinc by adult males. J Nutr 112:136–143.

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×

Sokoll LJ, Dawson-Hughes B. 1992. Calcium supplementation and plasma ferritin concentrations in premenopausal women. Am J Clin Nutr 56:1045–1048.

Spencer H, Menczel J, Lewin I, Samachson J. 1965. Effect of high phosphorus intake on calcium and phosphorus metabolism in man. J Nutr 86:125–132.

Thys-Jacobs S, Ceccarelli S, Bierman A, Weisman H, Cohen M-A, Alvir J. 1989. Calcium supplementation in premenstrual syndrome: A randomized crossover trial. J Gen Intern Med 4:183–189.


Whiting SJ, Wood RJ. 1997. Adverse effects of high-calcium diets in humans. Nutr Rev 55:1–9.

Wood RJ, Zheng JJ. 1990. Milk consumption and zinc retention in postmenopausal women. J Nutr 120:398–403.

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×

B. Folate

Hazard Identification

The potential hazards associated with high intake of folate were reviewed as the first step in developing a Tolerable Upper Intake Level (UL). Careful consideration was given to the metabolic interrelationships between folate and vitamin B12, which include (1) shared participation of the two vitamins in an enzymatic reaction; (2) identical hematological complications resulting from deficiency of either nutrient; (3) amelioration, by folate administration, of the hematologic complications caused by either folate or B12 deficiency; and (4) in B12, deficiency, the occurrence of neurological complications that do not respond to folate administration.

Adverse Effects

No adverse effects have been associated with the consumption of the amounts of folate normally found in unfortified foods (Butterworth and Tamura, 1989). Therefore, this review is limited to evidence concerning intake of supplementary folate. The experimental data in animal studies and in vitro tissue and cell culture studies were considered briefly to determine whether they supported the limited human data.

Neurologic Effects. The risk of neurologic effects described in this section applies to individuals with vitamin B12 deficiency. Vitamin B12 deficiency is often undiagnosed but may affect a substantial percentage of the population, especially older adults. Three types of evidence suggest that excess supplementary folate intake may precipitate or exacerbate the neurologic damage of B12 deficiency. First, numerous human case reports show onset or progression of neurologic complications in vitamin B12-deficient individuals receiving supplemental folate (Table D-3). Second, studies in monkeys (Agamanolis et al., 1976) and fruit bats (van der Westhuyzen and Metz, 1983; van der Westhuyzen et al., 1982) show that vitamin B12-deficient animals receiving supplemental folate develop signs of neuropathology earlier than do controls. The monkey studies used dietary methods to induce vitamin B12 deficiency, whereas the fruit bat studies used a well-described method involving nitrous oxide (Metz and van der Westhuyzen, 1987). Third, a metabolic interaction between folate and vitamin B12 is well documented (Chanarin et al., 1989). Although the association between folate treatment and neurological damage observed in human case reports does not provide proof of causality, the hazard associated with excess supplemental folate cannot be ruled out. The hazard remains plausible given the findings from animal studies and the demonstrated biochemical interaction of

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×

TABLE D-3. Dose and Duration of Oral Folate Administration and the Occurrence of Neurological Manifestations in Patients with Pernicious Anemia

Study

Number of Subjects

Dose (mg/d)

Duration

Occurrence of Neurological Manifestationsa

Crosby, 1960

1

0.35

2 y

1 of 1

Ellison, 1960

1

0.33–1

3 mo

1 of 1

Allen et al., 1990

3

0.4–1

3–18 mo

3 of 3

Baldwin and Dalessio, 1961

1

0.5

16 mo

1 of 1

Ross et al., 1948

4

1.25

9–23 mo

1 of 4

Chodos and Ross, 1951

4

1.25b

3.5–26 mo

3 of 4

Victor and Lear, 1956

2

1.5–2.55

10–39 mo

2 of 2

Conley and Krevans, 1951

1

4.5

3 y

1 of 1

Schwartz et al., 1950

48

5

48 mo

32 of 48

Ross et al., 1948

2

5

20–23 mo

1 of 2

Conley and Krevans, 1951

2

5–8

2–2.5 y

2 of 2

Will et al., 1959

36

5–10

1– y

16 of 36

Bethell and Sturgis, 1948

15

5–20

12 mo

4 of 15

Chodos and Ross, 1951

11

5–30

3–25 mo

7 of 11

Israels and Wilkinson, 1949

20

5–40

35 mo

16 of 20

Wagley, 1948

10

5–600

12 mo

8 of 10

Ellison, 1960

1

5.4–6.4

2 y

1 of 1

Victor and Lear, 1956

1

6.68

2.5 y

1 of 1

Berk et al., 1948

12

10

>17 mo

3 of 12

Best, 1959

1

10

26 mo

1 of 1

Spies and Stone, 1947

1

10

22 d

1 of 1

Ross et al., 1948

6

10–15

12 mo

4 of 6

Hall and Watkins, 1947

14

10–15

2–5 mo

3 of 14

Heinle et al., 1947

16

10–40

12 mo

2 of 16

Jacobson et al., 1948

1

10–65

5 mo

1 of 1

Heinle and Welch, 1947

1

10–100

4 mo

1 of 1

Spies et al., 1948

38

>10

24 mo

28 of 38

Ross et al., 1948

7

15

28–43 moc

3 of 7

Chodos and Ross, 1951

1

15

10.5 moc

1 of 1

Fowler and Hendricks, 1949

2

15–20

4–5 mo

2 of 2

Vilter et al., 1947

21

50–500

10–40 d

4 of 4

NOTE: All studies except Allen et al. (1990) were conducted before folate was added to any foods as a fortificant. In most of the case reports for which hematological status was reported, some degree of hematological improvement occurred. Studies are presented in increasing order by dose. When different doses were reported within a study, there is more than one entry for that study. Case reports that covered hematological rather than neurologic effects were excluded, namely, Alperin (1966), Heinle and Welch (1947), Herbert (1963), Reisner and Weiner (1952), Ritz et al. (1951), Sheehy et al. (1961), and Thirkette et al. (1964). The exception was the study by Allen et al. (1990), in which the subjects were vitamin B12 deficient but did not have pernicious anemia.

a Refers to neurological relapses or progression of preexisting neurological manifestations while on folate therapy.

b In two patients, the neurological progression was characterized as minimal or slight. Neurological progression was also observed when the dose was increased to 15 mg/day in these patients.

c The initial dosage of 1.25 mg/day was increased to 15 mg/day after variable durations of treatment. Neurological progression occurred only at 15 mg/day in these patients.

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×

the two nutrients. The resulting neurological damage may be serious, irreversible, and crippling.

For many years, it has been recognized that excessive intake of folate supplements may obscure or mask and potentially delay the diagnosis of vitamin B12 deficiency. Delayed diagnosis can result in an increased risk of progressive, unrecognized neurological damage.

Evidence from animal as well as in vitro tissue and cell culture (Baxter et al., 1973; Hommes and Obbens, 1972; Kehl et al., 1984; Loots et al., 1982; Olney et al., 1981; Spector, 1972; Weller et al., 1994) studies suggests that folate is neurotoxic and epileptogenic in animals; however, clear evidence of folate-induced neurotoxicity in humans is lacking. Concerns have been raised about the possibility of decreased effectiveness of treatment if individuals treated with anticonvulsant drugs take high doses of folate. However, the UL does not apply to drug-drug interactions or to high doses taken under medical supervision.

General Toxicity. In one nonblinded, uncontrolled trial, oral doses of 15 mg/day of folate for 1 month were associated with mental changes, sleep disturbances, and gastrointestinal effects (Hunter et al., 1970). However, studies using comparable or higher doses, longer durations, or both failed to confirm these findings (Gibberd et al., 1970; Hellstrom, 1971; Richens, 1971; Sheehy, 1973; Suarez et al., 1947).

Reproductive and Developmental Effects. Many studies have evaluated the periconceptional use of supplemental folate (in doses of approximately 0.4 to 5.0 mg) to prevent neural tube defects (see Table D-4). No adverse effects have been demonstrated, but the studies were not specifically designed to assess adverse effects. No reports were found of adverse effects attributable to folate in long-term folate supplement users or in infants born each year to mothers who take supplements, but this has not been investigated systematically. Because it is possible that subtle effects might have been missed, investigations designed to detect adverse effects are needed.

Carcinogenicity. In a large epidemiological study, positive associations were found between supplementary folate intake and the incidence of cancer of the oropharynx and hypopharynx, and total cancer (Selby et al., 1989). However, the authors of this study suggest that these associations might have been related to unmeasured confounding variables such as alcohol and smoking. Additionally, other studies suggest that folate might be anticarcinogenic (Campbell, 1996).

Hypersensitivity. Individual cases of hypersensitivity reactions to oral and parenteral folate administration have been reported (Gotz and Lauper, 1980;

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×

TABLE D-4. Assessing Adverse Reproductive Effects from Studies Involving Supplemental Folate

Reference

Subjects

Duration of Study

Study Design

Laurence et al., 1981

95 women

> 9 wk

Clinical trial: randomized, controlled, double-blinded

Smithells et al., 1981

550 women

110 d (mean duration)

Clinical trial: controlled

Mukherjee et al., 1984

450 pregnant women

> 9 mo

Prospective cohort study

Vergel et al., 1990

81 women

> 3 mo

Clinical trial: controlled

Wald et al., 1991

910 women

A few monthsd

Clinical trial: randomized, double-blinded controlled

Czeizel and Dudas, 1992

4,753 women (<35 y)

3 mo

Clinical trial: randomized, controlled

Holmes-Siedle et al., 1992

100 women

Periconceptional period; 7–10 y follow-up

Observational study

Kirke et al., 1992

354 pregnant women

5 mo

Clinical trial: randomized, controlled

Czeizel et al., 1994

5,502 women

3 mo

Randomized, controlled trial

a NR=not reported. Study was not designed to assess adverse effects.

b Plasma folate was measured at different times in pregnancy, but compliance with prenatal vitamin use was not recorded.

c There was no control of confounding variables making it difficult to interpret the results.

d The average duration of exposure is not indicated in the publication, but was likely a few months.

Mathur, 1966; Mitchell et al., 1949; Sesin and Kirschenbaum, 1979; Sparling and Abela, 1985). Such hypersensitivity is rare, but reactions have occurred at supplemental folate doses as low as 1 mg/day (Sesin and Kirschenbaum, 1979).

Intestinal Zinc Absorption. Although there has been some controversy regarding whether supplemental folate intake adversely affects intestinal zinc absorption (Butterworth and Tamura, 1989), a comprehensive review of the literature reveals that folate supplementation has either no effect on zinc nutriture or an extremely subtle one (Arnaud et al., 1992; Butterworth et al., 1988; Hambidge et al., 1993; Keating et al., 1987; Milne et al., 1984; Tamura,

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×

Reference

Subjects

Folate Dose (mg/d)

Adverse Effects Observed

Method(s) for Assessing Association and Adverse Effects

Laurence et al., 1981

95 women

4

None

NRa

Smithells et al., 1981

550 women

1

None

NR

Mukherjee et al., 1984

450 pregnant women

0.4–1b

Pregnancy complications, fetal distressc

Statistical association between 12 indices of nutrient status and 7 poorly defined categories of complications

Vergel et al., 1990

81 women

5

None

NR

Wald et al., 1991

910 women

4

None

Medical exams performedb

Czeizel and Dudas, 1992

4,753 women (<35 y)

0.8

None

NR

Holmes-Siedle et al., 1992

100 women

1

Frequency of developmental anomalies not greater than expectede

NR

Kirke et al., 1992

354 pregnant women

0.36

None

NR

Czeizel et al., 1994

5,502 women

0.8

13.4% fetal death rate in supplemented group compared with 11.5% fetal death rate on controlsf

Documentation for all pregnancy outcomes was collected. Statistical evaluation based on two-tailed chi-square test.

e The frequency of developmental anomalies was not greater than expected; but parental reports of worries, fearfulness, and fussiness in the children were greater than expected.

f This may be a chance finding resulting from multiple comparisons. It has been reported that prenatal multivitamin supplementation (which includes folate) can reduce preterm deliveries, causing an apparent increase in recognized abortions as the duration of all pregnancies increases (Scholl et al., 1997).

Mukherjee et al. (1984) noted a significant association between the occurrence of fetomaternal complications and the combination of low maternal plasma zinc and high maternal plasma folate concentrations. However, this study may have failed to control for potential confounding factors. Furthermore, these findings are not supported by Tamura and colleagues (1992), who found high serum folate concentrations to be associated with favorable pregnancy outcomes including (1) higher birth weight and Apgar scores of newborns, (2) reduced prevalence of fetal growth retardation, and (3) lower incidence of maternal infection close to the time of delivery.

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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 [1990]) 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.

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×

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

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×

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

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×

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.

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×

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.

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×

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.

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×

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.

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×

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.

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×

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

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×

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.

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×

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.

Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
×
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Suggested Citation:"Appendix D: Case Studies of Application of Risk Assessment Model for Nutrients." Institute of Medicine. 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: The National Academies Press. doi: 10.17226/6432.
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The model for risk assessment of nutrients used to develop tolerable upper intake levels (ULs) is one of the key elements of the developing framework for Dietary Reference Intakes (DRIs). DRIs are dietary reference values for the intake of nutrients and food components by Americans and Canadians. The U.S. National Academy of Sciences recently released two reports in the series (IOM, 1997, 1998). The overall project is a comprehensive effort undertaken by the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes (DRI Committee) of the Food and Nutrition Board (FNB), Institute of Medicine, National Academy of Sciences in the United States, with active involvement of Health Canada. The DRI project is the result of significant discussion from 1991 to 1996 by the FNB regarding how to approach the growing concern that one set of quantitative estimates of recommended intakes, the Recommended Dietary Allowances (RDAs), was scientifically inappropriate to be used as the basis for many of the uses to which it had come to be applied.

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