How Much is Too Much?

Excess Vitamins and Minerals in Food Can Harm Kids’ Health

June 19, 2014

How Much is Too Much? : Appendix D: Tolerable Upper Intake Limits Set in the U.S. and EU

The Tolerable Upper Intake Levels were based on a comprehensive effort by the National Academy of Sciences to define safe and adequate vitamin and mineral intakes. The majority of the research was done in the 1990s, when the broad scientific community came to recognize the risks of over-exposure. In 1994, the Institute of Medicine Food and Nutrition Board organized a symposium titled “Should the Recommended Dietary Allowances Be Revised?”, which pointed to the need to define safe maximum intake levels. In 1998 the Institute followed up by publishing a risk assessment model for determining safe upper limits for vitamins and minerals.

Across the Atlantic, the European Union and the United Kingdom conducted their own risk assessments and published upper intake levels for vitamins and minerals between 2000 and 2005 (EFSA 2006; SCF 2000; UK EVM 2003). The Institute of Medicine and the European agencies used comparable methodologies to assess the risks of excessive intake and arrived at largely similar conclusions. For 4-to-8-year-old children, the EU’s tolerable limit for vitamin A is 20 percent higher than the U.S. level; for zinc, the U.S. limit is 20 percent higher than the EU’s. The Institute of Medicine set a single upper level for all forms of niacin, while the European agencies set two, a lower one for more toxic nicotinic acid and a higher one for much safer niacinamide (see Appendix D for details).

A variety of studies were used for establishing the Tolerable Upper Intake Levels. They include case studies of individuals who had taken large-dose dietary supplements for months or years; small group studies with a few to a few dozen participants taking supplements in a controlled setting for a number of weeks; and large-scale cohort and case-control studies assessing the effects in large populations.

For vitamin A, many individual reports of adults and children ingesting high-dose dietary supplements were published from the 1950s to the 1990s, along with eight large population studies of pregnant women conducted in 1990s. Several small group studies of adults taking zinc supplements were done from 1989 to 2002, as well as a 1976 study of infants ingesting zinc in formula. For niacin, there is one 1938 small group controlled exposure study and at least two known cases of food poisoning from niacin over-fortification of grain-based products (CDC 1983; Sun 2014)

There are still limitations to the data for defining the adequate and safe intake for vitamins and minerals and establishing effective and safe food fortification amounts (Carriquiry and Camaño-Garcia 2006; Zlotkin 2006). The Tolerable Upper Intake Levels set by the Institute of Medicine, however, represent the best science available for preventing excessive and unsafe intakes (Taylor 2012).

Table D1: Risk assessment methodology and Tolerable Upper Intake Limits set by the Institute of Medicine, the European Commission Scientific Committee on Food and the United Kingdom Expert Group on Vitamins and Minerals. Data sources listed below.

Results of risk assessment Vitamin A (preformed)* Zinc Niacin**

U.S. Institute of Medicine (IOM) Upper Level for 4-to-8-year-olds

900 mg/d retinol activity equivalents

12 mg/d

15 mg/d

European Commission Scientific Committee on Food Upper Level for 4-to-8-year-olds

1100 mg/d retinol activity equivalents

10 mg/d

3 mg/d for nicotinic acid; 220 mg/d for nicotinamide (niacinamide)

Studies for deriving IOM Upper Level for adults

Liver toxicity from chronic daily intake of 1,515-30,000 mg/d vitamin A supplement (individual case studies from 1977-1994). 14,000 mg/d chosen as the point of departure for deriving adult UL

Adverse effects of zinc intake on copper status in a 1989 study of 18 women taking daily 50 mg zinc supplements for 10 weeks. 60 mg/d chosen as the point of departure for deriving adult UL (including zinc from supplements and diet)

Short-term flushing effects in a 1938 study of 6 persons taking a daily dose of 30-50 mg nicotinic acid for 13 weeks. 50 mg/d chosen as the Lowest Observed Adverse Effect Level for niacin (all forms)

Uncertainty factor applied to IOM Upper Level for adults

5

1.5

1.5

IOM Upper Level for adults

3000 mg/d (same as the IOM UL for pregnant women)*

40 mg/d

35 mg/d (all forms of niacin)

How IOM Upper Level for children was derived

Scaling down for children’s body weight from adult UL

Scaling up for children’s body weight from a 1976 study of 68 infants that identified 4.5 mg/d as the No Observed Adverse Effect Level

Scaling down for children’s body weight from adult UL

Studies for deriving EU Upper Level for adults

Findings from a 1995 cohort study of 22,748 pregnant women that vitamin A intakes over 3,000 mg/d during pregnancy increase the risk of developmental defects in the fetus

Three studies published in 2000-2001 of men and women (19-25 per group) taking daily zinc supplements for 13-14 weeks. 50 mg/d chosen as the No Observed Adverse Effect Level

Short-term flushing effects in a 1938 study of 6 persons taking a daily dose of 30-50 mg nicotinic acid. 30 mg/d chosen as the Lowest Observed Adverse Effect Level for nicotinic acid. Nicotinamide does not produce a flushing response. No Observed Adverse Effect Level for nicotinamide set at 900 mg/d for adults (not including pregnant women)

Uncertainty factor applied to EU Upper Level for adults

1

2

3 for nicotinic acid;
1 for nicotinamide

EU Upper Level for adults

3,000 mg/d (all adults including pregnant women)

25 mg/d

10 mg/d for nicotinic acid; 900 mg/d for nicotinamide (niacinamide)

How the EU Upper Level for children was derived

Scaling down for children’s body weight from adult UL

Scaling down for children’s body weight from adult UL

Scaling down for children’s body weight from adult UL

UK upper intake levels for adults (UK did not set the Tolerable Upper Intake Levels for children)

1,500 mg/d (defined as “Guidance Level”; did not set “Safe Upper Level”)

25 mg/d (defined as “Safe Upper Level”

“Guidance Levels”: 17 mg/d for nicotinic acid; 500 mg/d for nicotinamide (niacinamide)

How the UK intake level for adults was derived

Identified intakes above 3,000 mg/d as posing a risk of developmental defects during pregnancy; identified 1,500 mg/d as the guidance level for adults based on an increased hip fracture risk in large population studies of post menopausal women.

50 mg/d chosen as the Lowest Observed Adverse Effect Level from controlled intake small group studies conduced in 1984-2000 (same set of studies as used in the EU assessment). Applied an uncertainty factor of 2

For nicotinic acid, identified 50 mg/d as the Lowest Observed Adverse Effect Level for nicotinic acid based on the 1938 study (same as IOM and EU) and applied an uncertainty factor of 3. For niacinamide, identified 560 mg/d as the No Observed Adverse Effect Level for adults (not including pregnant women).

* The Institute of Medicine conducted separate risk assessments of vitamin A toxicity in pregnant women and non-pregnant adults. The risk assessment for adults was based on case studies of adults taking daily vitamin A supplements. The risk assessment for pregnant women was based on multiple cohort and case control studies of fetal developmental effects caused by excessive vitamin A intake. The Institute of Medicine set final Tolerable Upper Intake Levels for pregnant women and for adults generally at 3000 mg/d, same as the European Commission vitamin A UL for all adults, including pregnant women.
** The Institute of Medicine set a single UL for all forms of niacin, while the European Commission  Scientific Committee on Food and the United Kingdom Expert Group on Vitamins and Minerals set two ULs, a low UL for more toxic nicotinic acid and a higher UL for safer nicotinamide (niacinamide). The EU and UK ULs for niacinamide do not apply to pregnant women because there are no data on the safety of niacinamide in pregnancy.

Data sources for Table D1

EFSA (European Food Safety Authority). 2006. Tolerable upper intake levels for vitamins and minerals. Available: http://www.efsa.europa.eu/en/ndatopics/docs/ndatolerableuil.pdf

IOM (Institute of Medicine). 1998b. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. A Report of the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline and Subcommittee on Upper Reference Levels of Nutrients, Food and Nutrition Board, Institute of Medicine. Available: http://www.nap.edu/catalog/6015.html

IOM (Institute of Medicine). 2001. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Panel on Micronutrients, Subcommittees on Upper Reference Levels of Nutrients and of Interpretation and Use of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Available: http://www.nap.edu/catalog/10026.html

SCF (European Commission Scientific Committee on Food). 2000. Guidelines of the Scientific Committee on Food for the development of tolerable upper intake levels for vitamins and minerals (adopted on 19 October 2000). Available: http://ec.europa.eu/food/fs/sc/scf/out80a_en.pdf

SCF (European Commission Scientific Committee on Food). 2002a. Opinion of the Scientific Committee on Food on the Tolerable Intake Levels of Nicotinic Acid and Nicotinamide (Niacin) (expressed on 17 April 2002). Available: http://ec.europa.eu/food/fs/sc/scf/out80j_en.pdf

SCF (European Commission Scientific Committee on Food). 2002b. Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Preformed Vitamin A (retinol and retinyl esters) (expressed on 26 September 2002). Available: http://ec.europa.eu/food/fs/sc/scf/out145_en.pdf

SCF (European Commission Scientific Committee on Food). 2003 Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Zinc (expressed on 5 March 2003). Available: http://ec.europa.eu/food/fs/sc/scf/out177_en.pdf

UK EVM (Expert Group on Vitamins and Minerals). 2003. Safe Upper Levels for Vitamins and Minerals. May 2003. Available: http://cot.food.gov.uk/pdfs/vitmin2003.pdf