National Academies Press: OpenBook
« Previous: Steps in the Development of the Tolerable Upper Intake Level
Suggested Citation:"Derivation of ULs: Summary of Progress to Date." 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.
×
  • 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

Suggested Citation:"Derivation of ULs: Summary of Progress to Date." 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.
×

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

Suggested Citation:"Derivation of ULs: Summary of Progress to Date." 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 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.

Suggested Citation:"Derivation of ULs: Summary of Progress to Date." 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 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

Suggested Citation:"Derivation of ULs: Summary of Progress to Date." 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.
×
Page 20
Suggested Citation:"Derivation of ULs: Summary of Progress to Date." 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.
×
Page 21
Suggested Citation:"Derivation of ULs: Summary of Progress to Date." 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.
×
Page 22
Suggested Citation:"Derivation of ULs: Summary of Progress to Date." 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.
×
Page 23
Next: References »
Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients Get This Book
×
Buy Paperback | $47.00 Buy Ebook | $37.99
MyNAP members save 10% online.
Login or Register to save!
Download Free PDF

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.

  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    Switch between the Original Pages, where you can read the report as it appeared in print, and Text Pages for the web version, where you can highlight and search the text.

    « Back Next »
  6. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  7. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  8. ×

    View our suggested citation for this chapter.

    « Back Next »
  9. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!