Derivation of ULs: Summary of Progress to Date

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Derivation of UFs

The model described in this document has been applied to two groups of nutrients and food components as part of the continuing DRI process. The selection of a UF of approximately 1.0 for fluoride and magnesium is primarily based on the very mild (and in the case of magnesium, reversible) nature of the adverse effects observed. A slightly larger UF (1.2) was selected for vitamin D intake in adults and in other life stage groups except infants as the short duration of the study used (Narang et al., 1984) and the small sample size supports the selection of a slightly larger UF. For vitamin D in infants, a larger UF (1.8) was selected due to the insensitivity of the critical endpoint, the small sample sizes of the studies, and the limited data about the sensitivity at the tails of the distribution. A UF of 2 was selected for calcium to account for the potential increased susceptibility to high calcium intake by individuals who form renal stones and the potential to increase the risk of mineral depletion due to the interference of calcium on mineral bioavailability, especially iron and zinc. The UF for phosphorus is based on the lack of information concerning potential adverse effects of serum inorganic phosphate values in the range between normal serum phosphate levels and levels associated with ectopic mineralization. The selection of a UF of 2.5 for phosphorus was due to the relative lack of human data describing adverse effects of excess phosphorus intakes.

With regard to the B vitamins and choline, because of lack of suitable data that met the requirements of the model, NOAELs (and LOAELs) could not be determined for thiamin, riboflavin, vitamin B12, pantothenic acid, or biotin. The UF for folate added to food or as a supplement was 5, 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. For niacin as a supplement or food fortificant, the UF selected was 1.5, based on the transient nature of the adverse effect of flushing, and the consideration that it was applied to a LOAEL and not a NOAEL. The UF for both vitamin B6 and choline was 2. In the case of vitamin B6, there were less data available involving responses to pyridoxine doses under 500 mg/day, and thus more limited information upon which to base a UL. The UF of 2 for choline was selected because of the limited data regarding hypotension and the magnitude of the interindividual variation in response to cholinergic effects.

Derivation of a UL

UL values have been established for broad age groups for nutrients for which adequate data are available (see Table 1). Values are set at levels that are unlikely to pose risk to the most sensitive members of the general population. They cannot be used to assess the prevalence of the population at risk for adverse effects as a result of excess intakes. The UL for magnesium is from supplement intake only, and for niacin and folate from fortified food and supplement intake only. In all three cases, the nutrient naturally found in foods is excluded from concern. The adverse effect or critical endpoint used for each nutrient is given in Table 2. Three case studies (calcium, folate, and riboflavin) are described in Appendix D.

TABLE 1. Dietary Reference Intakes: Tolerable Upper Intake Levels (UL) for Certain Nutrients and Food Components.


Dietary Reference Intakes: Tolerable Upper Intake Levels (UL) for Certain Nutrients and Food Components.

TABLE 2. UL Critical Adverse Effects.


UL Critical Adverse Effects.

Derivation of a UL for Other Groups

The UL is derived by dividing the NOAEL (or LOAEL) by a single UF that incorporates all relevant uncertainties for the life stage category for which the data are available (see Table 1). The derivation of a UL involves the use of scientific judgment to select the appropriate NOAEL (or LOAEL) and UF. The risk assessment requires explicit consideration and discussion of all choices made, both regarding the data used and the uncertainties accounted for.

For infants, ULs were not determined for any of the B vitamins, choline, magnesium, phosphorus, or calcium because of the lack of data on adverse effects in this age group and concern regarding infants' possible lack of ability to handle excess amounts. Thus, caution is warranted; food should be the source of intake of these nutrients by infants. For vitamin D and fluoride, due to the significant information on effects from various levels of intake by infants for these nutrients, ULs were developed.

When data were not available on children or adolescents, ULs were determined by extrapolating from the UL for adults based on body weight differences using the formula:4

ULchild = (ULadult)(Weightchild/Weightadult).

The reference weight for males aged 19 through 30 years (see Appendix C) was used for adults and the reference weights for female children and adolescents were used in the formula above to obtain the UL for each age group. The use of these reference weights yields a conservative UL to protect the sensitive individuals in each age group.



In the case of niacin, vitamin B6, folate, and choline, the formula was based on metabolic size: ULchild = (ULadult)(Weightchild/Weight adult)0.75