• Experimental animal to human. A UF to account for the uncertainty in extrapolating animal data to humans is generally applied to the NOAEL when animal data are the primary data set available. Larger UFs (close to 10) may be used if it is believed that the animal responses will underpredict average human responses (NRC, 1994).
  • LOAEL to NOAEL. If a NOAEL is not available, a UF may be applied to account for the uncertainty in deriving a UL from the LOAEL. The size of the UF applied involves scientific judgment based on the severity and incidence of the observed effect at the LOAEL and the steepness (slope) of the dose response.
  • Subchronic NOAEL to predict chronic NOAEL. When data are lacking on chronic exposures, scientific judgment is necessary to determine whether chronic exposure is likely to lead to adverse effects at lower intakes than those producing effects after subchronic exposures (exposures of shorter duration).

Characterization of the Estimate and Special Considerations

ULs are derived for various life stage groups using relevant databases, NOAELs and LOAELs, and UFs. In cases where no data exist with regard to NOAELs or LOAELs for the group under consideration, extrapolations from data in other age groups and/or animal data are made on the basis of known differences in body size, physiology, metabolism, absorption, and excretion of the nutrient.

If the data review reveals the existence of subpopulations having distinct and exceptional sensitivities to a nutrient's toxicity, these subpopulations should be explicitly discussed and concerns related to adverse effects noted; however the use of the data is not included in the identification of the NOAEL or LOAEL upon which the UL for the general population is based.

Derivation of ULs: Summary of Progress to Date

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



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--> Experimental animal to human. A UF to account for the uncertainty in extrapolating animal data to humans is generally applied to the NOAEL when animal data are the primary data set available. Larger UFs (close to 10) may be used if it is believed that the animal responses will underpredict average human responses (NRC, 1994). LOAEL to NOAEL. If a NOAEL is not available, a UF may be applied to account for the uncertainty in deriving a UL from the LOAEL. The size of the UF applied involves scientific judgment based on the severity and incidence of the observed effect at the LOAEL and the steepness (slope) of the dose response. Subchronic NOAEL to predict chronic NOAEL. When data are lacking on chronic exposures, scientific judgment is necessary to determine whether chronic exposure is likely to lead to adverse effects at lower intakes than those producing effects after subchronic exposures (exposures of shorter duration). Characterization of the Estimate and Special Considerations ULs are derived for various life stage groups using relevant databases, NOAELs and LOAELs, and UFs. In cases where no data exist with regard to NOAELs or LOAELs for the group under consideration, extrapolations from data in other age groups and/or animal data are made on the basis of known differences in body size, physiology, metabolism, absorption, and excretion of the nutrient. If the data review reveals the existence of subpopulations having distinct and exceptional sensitivities to a nutrient's toxicity, these subpopulations should be explicitly discussed and concerns related to adverse effects noted; however the use of the data is not included in the identification of the NOAEL or LOAEL upon which the UL for the general population is based. Derivation of ULs: Summary of Progress to Date 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

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--> 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. 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

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--> TABLE 1. Dietary Reference Intakes: Tolerable Upper Intake Levels (ULa) for Certain Nutrients and Food Components Life Stage Calcium Phosphorus Magnesium Vitamin D Fluoride Niacin Vitamin B6 Folate Choline Group (g/day) (g/day) (mg/day)b (μg/day) (mg/day) (mg/day)c (mg/day) (μg/day)c (g/day) 0–6 months NDd ND ND 25 0.7 ND ND ND ND 7–12 months ND ND ND 25 0.9 ND ND ND ND 1–3 years 2.5 3 65 50 1.3 10 30 300 1.0 4–8 years 2.5 3 110 50 2.2 15 40 400 1.0 9–13 years 2.5 4 350 50 10 20 60 600 2.0 14–18 years 2.5 4 350 50 10 30 80 800 3.0 19–70 years 2.5 4 350 50 10 35 100 1,000 3.5 > 70 years 2.5 3 350 50 10 35 100 1,000 3.5 Pregnancy ≤ 18 years 2.5 3.5 350 50 10 30 80 800 3.0 19–50 years 2.5 3.5 350 50 10 35 100 1,000 3.5 Lactation ≤ 18 years 2.5 4 350 50 10 30 80 800 3.0 19–50 years 2.5 4 350 50 10 35 100 1,000 3.5 a UL = the maximum level of daily nutrient intake that is likely to pose no risk of adverse effects. Unless otherwise specified, the UL represents total intake from food, water, and supplements. Due to lack of suitable data, ULs could not be established for thiamin, riboflavin, vitamin B12, pantothenic acid, or biotin. In the absence of ULs, extra caution may be warranted in consuming levels above recommended intakes. b The UL for magnesium represents intake from a pharmacological agent only and does not include intake from food and water. c The ULs for niacin and folate apply to synthetic forms obtained from supplements, fortified foods, or a combination of the two. d ND = not determinable due to lack of data of adverse effects in this age group and concern with regard to lack of ability to handle excess amounts. Source of intake should be from food only to prevent high levels of intake.

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--> TABLE 2. UL Critical Adverse Effects Nutrient Adverse Effect Calcium Milk-alkali syndrome Phosphorus Elevated serum Pi Magnesium Osmotic diarrhea Vitamin D Serum calcium > 11 mg/dl Fluoride Children: moderate dental fluorosis Adults: moderate skeletal fluorosis Niacin Flushing Vitamin B6 Sensory neuropathy Folate Neuropathy in B12-deficient individuals Choline Hypotension, fishy body odor 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. 4   In the case of niacin, vitamin B6, folate, and choline, the formula was based on metabolic size: ULchild = (ULadult)(Weightchild/Weight adult)0.75