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Scientific Opinion on the Tolerable Upper Intake Level of vitamin D

EFSA Journal 2012;10(7):2813 [45 pp.]. doi:10.2903/j.efsa.2012.2813
  EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) Panel Members Carlo Agostoni, Jean-Louis Bresson, Susan Fairweather-Tait, Albert Flynn, Ines Golly, Hannu Korhonen, Pagona Lagiou, Martinus Løvik, Rosangela Marchelli, Ambroise Martin, Bevan Moseley, Monika Neuhäuser-Berthold, Hildegard Przyrembel, Seppo Salminen, Yolanda Sanz, Sean (J.J.) Strain, Stephan Strobel, Inge Tetens, Daniel Tomé, Hendrik van Loveren and Hans Verhagen Acknowledgment The Panel wishes to thank the members of the Working Group on Upper Levels: Albert Flynn, Ambroise Martin, Hildegard Przyrembel and Sean (J.J.) Strain for the preparatory work on this scientific opinion and EFSA staff: Anja Brönstrup for the support provided to this scientific opinion. Contact nda@efsa.europa.eu
Type: Opinion of the Scientific Committee/Scientific Panel On request from: European Commission Question number: EFSA-Q-2011-00955 Adopted: 26 June 2012 Published: 27 July 2012 Affiliation: European Food Safety Authority (EFSA), Parma, Italy
Abstract

Following a request from the European Commission, the Panel on Dietetic Products, Nutrition and Allergies was asked to re-evaluate the safety in use of vitamin D and to provide, if necessary, revised Tolerable Upper Intake Levels (ULs) of vitamin D for all relevant population groups. The ULs for adults including pregnant and lactating women, children and adolescents were revised. For adults, hypercalcaemia was selected as the indicator of toxicity. In two studies in men, intakes between 234 and 275 µg/day were not associated with hypercalcaemia, and a no observed adverse effect level (NOAEL) of 250 µg/day was established. Taking into account uncertainties associated with these studies, the UL for adults including pregnant and lactating women was set at 100 µg/day. Despite a continuing paucity of data for high vitamin D intakes in children and adolescents, the UL was adapted to 100 µg/day for ages 11-17 years, considering that owing to phases of rapid bone formation and growth this age group is unlikely to have a lower tolerance for vitamin D compared to adults. The same applies also to children aged 1-10 years, but taking into account their smaller body size, a UL of 50 µg/day is proposed. For infants, the UL of 25 µg/day based on previously available data relating high vitamin D intakes to impaired growth and hypercalcaemia was retained as limited additional evidence has emerged since the previous risk assessment. Data on vitamin D intakes from surveys in 14 European countries indicate that intakes in high consumers are below the revised ULs for vitamin D for all population groups.

© European Food Safety Authority, 2012

Summary

Following a request from the European Commission, the Panel on Dietetic Products, Nutrition and Allergies was asked to re-evaluate the safety in use of vitamin D and to provide, if necessary, revised Tolerable Upper Intake Levels (ULs) of vitamin D for all relevant population groups.

Vitamin D derives from the diet but can also be synthesised in the skin under the influence of UV‑B radiation. Serum 25(OH)D concentration is a good marker of vitamin D status, but can only be used as a biomarker of vitamin D intake in people with low exposure to sunlight. Following ingestion of large doses of vitamin D, the concentration of 25(OH)D in serum increases, while that of the active metabolite 1,25(OH)2D is unchanged or even reduced. Very high serum 25(OH)D concentrations may lead to hypercalcaemia, which is considered the critical effect of excess intake of vitamin D. Hypercalciuria can be associated with hypercalcaemia, but it can also occur without.

For the derivation of the UL, the occurrence of hypercalcaemia and hypercalciuria has been assessed in studies using daily or weekly supplementation of vitamin D for several weeks to months. The shorter-term studies were generally performed in seasons of low sun exposure. Study populations were not generally vitamin D-deficient, and two studies were conducted in subjects with a high vitamin D status at baseline. Study populations included whites, African Americans, young men, pre- and postmenopausal women, elderly nursing home residents, and overweight and obese adults. It was concluded that vitamin D at doses up to 275 µg/day does not lead to persisting hypercalcaemia or hypercalciuria in adults.

Long-term health outcomes (all-cause mortality, cardiovascular disease, cancer, fractures and kidney stones) were also considered, but no studies reported an association between vitamin D intake and increased risk for adverse long-term health outcomes. Studies reporting on an association between 25(OH)D concentration and all-cause mortality or cancer were inconsistent. When 25(OH)D concentrations were associated with an increased risk for adverse long-term health outcomes in some studies, there was a wide variation in 25(OH)D concentrations associated with the adverse effect. It was considered that 25(OH)D concentrations cannot be used to characterise the risk for adverse long-term health outcomes.

In adults, a daily vitamin D dose of 250 µg/day (range 234-275 µg/day) was considered to reflect a no observed adverse effect level (NOAEL). This value was based on only two studies of short duration (up to five months) in small samples of healthy young men with minimal sun exposure. To take into account the uncertainties associated with this value, an uncertainty factor of 2.5 was chosen, and the UL was established at 100 µg/day. It was considered that the UL of 100 µg/day for adults also applies to pregnant and lactating women. This UL is supported by two studies in pregnant and lactating women, both using doses of vitamin D2 or D3 up to 100 µg/day for several weeks to months, which did not report adverse events for either the mothers or their offspring.

For infants, there is historical evidence on retarded growth from a study in which infants received various regimens of vitamin D exceeding 45 µg/day up to one year of age, although another small study using doses up to 54 µg vitamin D/day until about five months of age did not show such an effect. More recent intervention studies using doses up to 25 µg vitamin D/day (plus the amount ingested via fortified infant formula) for up to five months after birth did not indicate that these intakes are associated with hypercalcaemia in infants. As new data from intervention studies in healthy infants have not become available since the previous risk assessment by the SCF (2003), it was decided that the UL of 25 µg vitamin D/day previously derived for infants from 0 to 12 months of age should be retained.

For children and adolescents aged 10-17 years, there is limited evidence from two studies showing that vitamin D intakes at doses up to 50 µg/day do not lead to hypercalcaemia. While there are no studies at higher intakes, it was considered that there is no reason to believe that adolescents in the phase of rapid bone formation and growth have a lower tolerance for vitamin D compared to adults, and a UL of 100 µg/day for adolescents aged 11-17 years was proposed.

For children aged 1-10 years, no new data from intervention studies have emerged since the previous risk assessment. It was considered that there is no reason to believe that children aged 1-10 years in the phase of rapid bone formation and growth have a lower tolerance for vitamin D compared to adults, and, by taking into account their smaller body size, a UL for vitamin D of 50 µg/day was proposed.

Data from European populations indicate that vitamin D intakes from all sources in high consumers are below the UL for all population subgroups (i.e., about 25 %, 75 %, 30 % and 8 % of the UL for adults, infants, children and adolescents, respectively).

Keywords

Vitamin D, supplements, hypercalcaemia, UL, safety