Dietary reference values for vitamin D
2016; Wiley; Volume: 14; Issue: 10 Linguagem: Inglês
10.2903/j.efsa.2016.4547
ISSN1831-4732
Tópico(s)Vitamin K Research Studies
ResumoEFSA JournalVolume 14, Issue 10 e04547 Scientific OpinionOpen Access Dietary reference values for vitamin D EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA)Search for more papers by this author EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA)Search for more papers by this author First published: 28 October 2016 https://doi.org/10.2903/j.efsa.2016.4547Citations: 123 Correspondence: nda@efsa.europa.eu Requestor: European Commission Question number: EFSA-Q-2011-01230 Panel members: Jean-Louis Bresson, Barbara Burlingame, Tara Dean, Susan Fairweather-Tait, Marina Heinonen, Karen-Ildico Hirsch-Ernst, Inge Mangelsdorf, Harry McArdle, Androniki Naska, Monika Neuhäuser-Berthold, Grażyna Nowicka, Kristina Pentieva, Yolanda Sanz, Alfonso Siani, Anders Sjödin, Martin Stern, Daniel Tomé, Dominique Turck, Henk Van Loveren, Marco Vinceti and Peter Willatts. In line with EFSA's policy on declarations of interest, Panel member Harry McArdle did not participate in the development and adoption of this scientific opinion. Acknowledgements: The Panel wishes to thank the members of the Working Group on dietary reference values for vitamins: Christel Lamberg-Allardt, Monika Neuhäuser-Berthold, Grażyna Nowicka, Kristina Pentieva, Hildegard Przyrembel, Inge Tetens, Daniel Tomé and Dominique Turck for the preparatory work on this scientific opinion and EFSA staff members: Laura Ciccolallo, Céline Dumas, Lucia Fabiani and Laura Martino for the support provided to this scientific opinion. Adopted: 29 June 2016 This publication is linked to the following EFSA Supporting Publications article: http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2016.EN-1078/full AboutSectionsPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) derived dietary reference values (DRVs) for vitamin D. The Panel considers that serum 25(OH)D concentration, which reflects the amount of vitamin D attained from both cutaneous synthesis and dietary sources, can be used as a biomarker of vitamin D status in adult and children populations. The Panel notes that the evidence on the relationship between serum 25(OH)D concentration and musculoskeletal health outcomes in adults, infants and children, and adverse pregnancy-related health outcomes, is widely variable. The Panel considers that Average Requirements and Population Reference Intakes for vitamin D cannot be derived, and therefore defines adequate intakes (AIs), for all population groups. Taking into account the overall evidence and uncertainties, the Panel considers that a serum 25(OH)D concentration of 50 nmol/L is a suitable target value for all population groups, in view of setting the AIs. For adults, an AI for vitamin D is set at 15 μg/day, based on a meta-regression analysis and considering that, at this intake, the majority of the population will achieve a serum 25(OH)D concentration near or above the target of 50 nmol/L. For children aged 1–17 years, an AI for vitamin D is set at 15 μg/day, based on the meta-regression analysis. For infants aged 7–11 months, an AI for vitamin D is set at 10 μg/day, based on trials in infants. For pregnant and lactating women, the Panel sets the same AI as for non-pregnant non-lactating women, i.e. 15 μg/day. The Panel underlines that the meta-regression was done on data collected under conditions of assumed minimal cutaneous vitamin D synthesis. In the presence of cutaneous vitamin D synthesis, the requirement for dietary vitamin D is lower or may even be zero. Summary Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver a Scientific Opinion on dietary reference values (DRV) for the European population, including vitamin D. Vitamin D is the generic term for ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3), which are formed from their respective provitamins, ergosterol and 7-dehydrocholesterol, following a two step-reaction involving ultraviolet-B (UV-B) irradiation and subsequent thermal isomerisation. Vitamin D2 and vitamin D3 are fat-soluble and present in foods and dietary supplements. Vitamin D3 is also synthesised endogenously in the skin following exposure to UV-B irradiation. During summer months, or following exposure to artificial UV-B irradiation, the synthesis of vitamin D3 in the skin may be the main source of vitamin D. Dietary intake of vitamin D is essential in case endogenous synthesis, due to insufficient UV-B exposure, is lacking or insufficient. Factors affecting the synthesis of vitamin D3 in the skin include latitude, season, ozone layer and clouds (absorbing UV-B irradiation), surface characteristics (reflecting UV-B irradiation), time spent outdoors, use of sunscreen, clothing, skin colour and age. The Panel notes that sun exposure may contribute a considerable and varying amount of vitamin D available to the body and therefore considers that the association between vitamin D intake and status, for the purpose of deriving DRVs for vitamin D, should be assessed under conditions of minimal endogenous vitamin D synthesis. Vitamin D from dietary sources is absorbed throughout the small intestine. The Panel considers that the average vitamin D absorption from a usual diet is about 80% and limited data are available on the effect of the food or supplement matrix on absorption of vitamin D (vitamin D2 or vitamin D3). In the body, within hours of ingestion or synthesis in the skin, vitamin D is either converted into its biologically active metabolite 1,25(OH)2D or delivered to the storage tissues (as either vitamin D or its metabolites). The first step of the conversion occurs in the liver, where vitamin D is hydroxylated to 25(OH)D, while the second step occurs primarily in the kidneys, where 25(OH)D is hydroxylated to 1,25(OH)2D. Vitamin D, 1,25(OH)2D and 25(OH)D are transported in the blood bound mainly to the vitamin D-binding protein (DBP). Of the two metabolites of vitamin D, 25(OH)D is the major circulating form, with a longer mean half-life, of about 13–15 days. 25(OH)D is taken up from the blood into many tissues, including in the adipose tissue, muscle and liver for storage. After its release from DBP to tissues, 1,25(OH)2D exerts, in association with the intracellular vitamin D receptor (VDR), important biological functions throughout the body. In the intestine, it binds to VDR to facilitate calcium and phosphorus absorption. In the kidney, it stimulates the parathyroid hormone (PTH)-dependent tubular reabsorption of calcium. In the bone, PTH and 1,25(OH)2D interact to activate the osteoclasts responsible for bone resorption. In addition, 1,25(OH)2D suppresses the PTH gene expression, inhibits proliferation of parathyroid cells, and is involved in cell differentiation and antiproliferative actions in various cell types. Both 25(OH)D and 1,25(OH)2D are catabolised before elimination and the main route of excretion is via the faeces. Vitamin D deficiency leads to impaired mineralisation of bone due to an inefficient absorption of dietary calcium and phosphorus, and is associated with an increase in PTH serum concentration. Clinical symptoms of vitamin D deficiency manifest as rickets in children, and osteomalacia in adults. The Panel reviewed possible biomarkers of vitamin D intake and/or status, namely serum concentration of 25(OH)D, free 25(OH)D, 1,25(OH)2D and PTH concentration, markers of bone formation and bone turnover. In spite of the high variability in 25(OH)D measurements obtained with different analytical methods, the Panel concludes that serum 25(OH)D concentration, which reflects the amount of vitamin D attained from both cutaneous synthesis and dietary sources, can be used as a biomarker of vitamin D status in adult and children populations. Serum 25(OH)D concentration can also be used as a biomarker of vitamin D intake in a population with low exposure to UV-B irradiation. In consideration of the various biological functions of 1,25(OH)2D, the Panel assessed the available evidence on the relationship between serum 25(OH)D concentration and several health outcomes, to evaluate whether they might inform the setting of DRVs for vitamin D. The Panel first considered the available evidence on serum 25(OH)D concentration and musculoskeletal health outcomes, i.e. bone mineral density (BMD)/bone mineral content (BMC) and calcium absorption in adults and infants/children, risk of osteomalacia, fracture risk, risk of falls/falling, muscle strength/muscle function/physical performance in adults, and risk of rickets in infants/children. The Panel then reviewed data on the relationship between maternal serum 25(OH)D concentration and health outcomes in pregnancy (risk of pre-eclampsia, of small for gestational age and of preterm birth, and indicators of bone health in infants) and lactation. The Panel took as a starting point the results of the literature search and the conclusions from the most recent report on DRVs for vitamin D by the Institute of Medicine (IOM) that was based on two systematic reviews. The Panel also considered an update of one of these two systematic reviews, as well as two recent reports from DRV-setting bodies. The Panel undertook a separate literature search to identify primary intervention and prospective observational studies in healthy subjects (infants, children and adults, including free-living older adults) that were published after the IOM report until March 2015. As a second step, the Panel considered available evidence on several other non-musculoskeletal health outcomes (e.g. cancer or cardiovascular diseases), based on the reports and reviews mentioned above without undertaking a specific literature search of primary studies. The Panel considers that the available evidence on serum 25(OH)D concentration and musculoskeletal health outcomes and pregnancy-related health outcomes is suitable to set DRVs for vitamin D for (healthy) adults, infants, children, and pregnant women, respectively. However, the Panel considers that there is no evidence for a relationship between serum 25(OH)D concentration and health outcomes of lactating women that may be used to set a DRV for vitamin D, and that the available evidence on non-musculoskeletal health outcomes is insufficient to be used as criterion for setting DRVs for vitamin D. The Panel notes that data on the relationship between serum 25(OH)D concentration and adverse musculoskeletal or pregnancy-related health outcomes are widely variable. However, taking into account the overall evidence and uncertainties, the Panel considers that, for adults, infants and children, there is evidence for an increased risk of adverse musculoskeletal health outcomes at serum 25(OH)D concentrations below 50 nmol/L. The Panel also considers that there is evidence for an increased risk of adverse pregnancy-related health outcomes at serum 25(OH)D concentrations below 50 nmol/L. The Panel assessed the available evidence on the relationship between vitamin D intake and musculoskeletal health outcomes to evaluate whether they might inform the setting of DRVs for vitamin D. The Panel notes that these studies usually do not provide information on the habitual dietary intake of vitamin D, and the extent to which cutaneous vitamin D synthesis has contributed to the vitamin D supply (and thus may have confounded the relationship between vitamin D intake and the reported health outcomes) is not known. The Panel therefore concludes that these studies are not useful as such for setting DRVs for vitamin D, and may only be used to support the outcome of the characterisation of the vitamin D intake-status relationship undertaken by the Panel under conditions of assumed minimal endogenous vitamin D synthesis. The Panel concludes that a serum 25(OH)D concentration of 50 nmol/L is a suitable target value to set the DRVs for vitamin D, for all age and sex groups (healthy adults, infants, children, pregnant and lactating women). For setting DRVs for vitamin D, the Panel considers the dietary intake of vitamin D necessary to achieve this serum 25(OH)D concentration. As for other nutrients, DRVs for vitamin D are set assuming that intakes of interacting nutrients, such as calcium, are adequate. EFSA undertook a meta-regression analysis of the relationship between serum 25(OH)D concentration and total vitamin D intake (habitual diet, and fortified foods or supplements using vitamin D3). Randomised trials conducted in a period of assumed minimal endogenous vitamin D synthesis were identified through a comprehensive literature search and a review undertaken for EFSA by an external contractor (Brouwer-Brolsma et al., 2016). The analysis was performed using summary data from 83 trial arms (35 studies), of which nine were on children (four trials, age range: 2–17 years) and the other arms were on adults (mean age between 22 and 86 years, excluding pregnant or lactating women). Data were extracted for each arm of the individual trials. The meta-regression analysis resulted in two predictive equations of achieved serum 25(OH)D concentrations: one derived from an unadjusted model (including only the natural log of the total intake) and one derived from a model including the natural log of the total intake and adjusted for a number of relevant factors (baseline serum 25(OH)D concentration, latitude, study start year, type of analytical method applied to assess serum 25(OH)D, assessment of compliance) set at their mean values. The Panel considers that the available evidence does not allow the setting of average requirements (ARs) and population reference intakes (PRIs), and therefore defines adequate intakes (AIs) instead, for all population groups. For adults, the Panel sets an AI for vitamin D at 15 μg/day. This is based on the adjusted model of the meta-regression analysis, and considering that, at this intake, the majority of the adult population will achieve a serum 25(OH)D concentration near or above the target of 50 nmol/L. For children aged 1–17 years, the Panel sets an AI for vitamin D for all children at 15 μg/day. This is based on the adjusted model of the meta-regression analysis on all trials (adults and children) as well as on a stratified analysis by age group (adults versus children). For infants aged 7–11 months, the Panel sets an AI for vitamin D at 10 μg/day, considering four recent trials on the effect of vitamin D supplementation on serum 25(OH)D concentration in (mostly) breastfed infants. For pregnant and lactating women, the Panel considers that the AI is the same as for non-pregnant non-lactating women, i.e. 15 μg/day. The Panel underlines that the meta-regression analysis on adults and children was done on data collected under conditions of assumed minimal cutaneous vitamin D synthesis. In the presence of cutaneous vitamin D synthesis, the requirement for dietary vitamin D is lower or may even be zero. Background as provided by the European Commission The scientific advice on nutrient intakes is important as the basis of Community action in the field of nutrition, for example such advice has in the past been used as the basis of nutrition labelling. The Scientific Committee for Food (SCF) report on nutrient and energy intakes for the European Community dates from 1993. There is a need to review and if necessary to update these earlier recommendations to ensure that the Community action in the area of nutrition is underpinned by the latest scientific advice. In 1993, the SCF adopted an opinion on nutrient and energy intakes for the European Community.1 The report provided Reference Intakes for energy, certain macronutrients and micronutrients, but it did not include certain substances of physiological importance, for example dietary fibre. Since then new scientific data have become available for some of the nutrients, and scientific advisory bodies in many European Union (EU) Member States and in the United States have reported on recommended dietary intakes. For a number of nutrients, these newly established (national) recommendations differ from the reference intakes in the SCF (1993) report. Although there is considerable consensus between these newly derived (national) recommendations, differing opinions remain on some of the recommendations. Therefore, there is a need to review the existing EU Reference Intakes in the light of new scientific evidence, and taking into account the more recently reported national recommendations. There is also a need to include dietary components that were not covered in the SCF opinion of 1993, such as dietary fibre, and to consider whether it might be appropriate to establish reference intakes for other (essential) substances with a physiological effect. In this context, the European Food Safety Authority (EFSA) is requested to consider the existing population reference intakes for energy, micro- and macronutrients and certain other dietary components, to review and complete the SCF recommendations, in the light of new evidence, and in addition advise on a population reference intake for dietary fibre. For communication of nutrition and healthy eating messages to the public, it is generally more appropriate to express recommendations for the intake of individual nutrients or substances in food-based terms. In this context, EFSA is asked to provide assistance on the translation of nutrient based recommendations for a healthy diet into food based recommendations intended for the population as a whole. Terms of Reference as provided by the European Commission In accordance with Article 29 (1)(a) and Article 31 of Regulation (EC) No. 178/20022, the Commission requests EFSA to review the existing advice of the Scientific Committee for Food on population reference intakes for energy, nutrients and other substances with a nutritional or physiological effect in the context of a balanced diet which, when part of an overall healthy lifestyle, contribute to good health through optimal nutrition. In the first instance, EFSA is asked to provide advice on energy, macronutrients and dietary fibre. Specifically advice is requested on the following dietary components: carbohydrates, including sugars; fats, including saturated fatty acids, polyunsaturated fatty acids and monounsaturated fatty acids, trans-fatty acids; protein; dietary fibre. Following on from the first part of the task, EFSA is asked to advise on population reference intakes of micronutrients in the diet and, if considered appropriate, other essential substances with a nutritional or physiological effect in the context of a balanced diet which, when part of an overall healthy lifestyle, contribute to good health through optimal nutrition. Finally, EFSA is asked to provide guidance on the translation of nutrient-based dietary advice into guidance, intended for the European population as a whole, on the contribution of different foods or categories of foods to an overall diet that would help to maintain good health through optimal nutrition (food-based dietary guidelines). Assessment 1 Introduction In 1993, the Scientific Committee for Food (SCF) adopted an opinion on nutrient and energy intakes for the European Community and derived for vitamin D acceptable ranges of intakes for adults aged 18–64 years according to the amount of endogenous synthesis of vitamin D while one single value was set for adults aged ≥ 65 years (SCF, 1993). Acceptable ranges of intakes were also set for infants aged 6–11 months, and children aged 4–10 and 11–17 years, according to the amount of endogenous vitamin D synthesis, while a single reference value for the age range 1–3 years was selected. The same reference value was proposed for pregnancy and for lactation. In the present Opinion, vitamin D intake is expressed in μg and concentrations in blood are expressed in nmol/L.3 2 Definition/category 2.1 Chemistry Vitamin D is the generic term for ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3), which are formed from their respective provitamins ergosterol and 7-dehydrocholesterol (7-DHC) involving ultraviolet-B (UV-B) irradiation that opens the B-ring of the molecules, and subsequent thermal isomerisation (Figure 1). Vitamin D2 differs from vitamin D3 in the side chain where it has a double bond between C22 and C23 and an additional methyl group on C24 (Binkley and Lensmeyer, 2010). The molecular masses of ergocalciferol and cholecalciferol are 396.65 and 384.64 g/mol, respectively. In this assessment, the term vitamin D refers to both vitamin D3 and vitamin D2 unless the specific form is indicated. Analytical methods for the quantification of vitamin D in serum are discussed in Section 2.4.1. Figure 1Open in figure viewerPowerPoint Vitamins D2 (ergocalciferol) and D3 (cholecalciferol) with their respective provitamins. Based on data from Norman (2012) 2.2 Function of vitamin D 2.2.1 Biochemical functions In the body, vitamin D2 and D3 are converted to the main circulating form, 25-hydroxyvitamin D (25(OH)D2 or 25(OH)D3 termed calcidiols). It can be transformed into the biologically active metabolites 1,25-dihydroxy-ergocalciferol (1,25(OH)2D2) or 1,25-dihydroxy-cholecalciferol (1,25(OH)2D3) called calcitriols (Section 2.3.6 and Figure 2). The term 25(OH)D refers to both 25(OH)D2 and 25(OH)D3 and 1,25(OH)2D refers to both 1,25(OH)2D3 and 1,25(OH)2D2 unless the specific form is indicated. Figure 2Open in figure viewerPowerPoint Metabolism of vitamin D. Based on data from Holick (2006) The principal function of the biologically active metabolite 1,25(OH)2D is to maintain calcium and phosphorus homeostasis in the circulation, together with parathyroid hormone (PTH) and fibroblast growth factor (FGF-23) (EFSA NDA Panel, 2012a; Jones, 2013). If the serum ionised calcium concentration falls below a normal concentration of about 1.1–1.4 mmol/L, a cascade of events occurs to restore and maintain it within the range required for normal cellular and tissue functions (Mundy and Guise, 1999; Weaver and Heaney, 2006; Ajibade et al., 2010; EFSA NDA Panel, 2015b). The main target tissues of 1,25(OH)2D are the intestine, the kidneys and the bone (Figure 2, Section 2.3.6). In the intestine, 1,25(OH)2D binds to the vitamin D receptor (VDR) to facilitate calcium and phosphorus absorption by active transport. In the kidneys, 1,25(OH)2D stimulates the tubular reabsorption of calcium dependent on PTH that increases the production of 1,25(OH)2D from 25(OH)D in the proximal tubule (Holt and Wysolmerski, 2011). 1,25(OH)2D also downregulates the activity of the enzyme 1α-hydroxylase (CYP27B1), which is responsible for the conversion of 25(OH)D to 1,25(OH)2D in the kidney. In the bone, PTH and 1,25(OH)2D interact to activate the osteoclasts responsible for bone resorption. Osteoclasts then release hydrochloric acid and hydrolytic enzymes to dissolve the bone matrix and thereby release calcium and phosphorus into the circulation (Holick, 2006, 2007). The metabolite 1,25(OH)2D is also important in other tissues (Bouillon et al., 2008; EFSA NDA Panel, 2012a; Jones, 2014) that have VDRs as well as the 1α-hydroxylase to convert 25(OH)D into 1,25(OH)2D (Holick, 2007). For example, the parathyroid cells express the VDR and the 1α-hydroxylase, which allows the local formation of 1,25(OH)2D. 1,25(OH)2D suppresses the expression of the gene encoding PTH and among other actions, inhibits proliferation of parathyroid cells (Bienaime et al., 2011) (Figure 2). Other functions of 1,25(OH)2D include cell differentiation and antiproliferative actions in various cell types, such as bone marrow (osteoclast precursors and lymphocytes), cells belonging to the immune system, skin, breast and prostate epithelial cells, muscle and intestine (Norman, 2008, 2012; Jones, 2014). 2.2.2 Health consequences of deficiency and excess 2.2.2.1 Deficiency Clinical symptoms of vitamin D deficiency manifest as rickets in children and osteomalacia in adults (Sections 5.1.1, 5.1.2.1.2, 5.1.2.2.2). Both are caused by the impaired mineralisation of bone due to an inefficient absorption of dietary calcium and phosphorus, and both are associated with an increase in serum PTH concentration to prevent hypocalcaemia (Holick, 2006; Holick et al., 2012). Rickets is characterised by a triad of clinical symptoms: skeletal changes (with deformities, craniotabes, growth retardation), radiologic changes (widening of the metaphyseal plates, decreased mineralisation, deformities) and increases in bone alkaline phosphatase (ALP) activity in serum (Wharton and Bishop, 2003). Depending on the severity and duration of vitamin D deficiency, initial hypocalcaemia progresses to normocalcaemia and hypophosphatemia, because of increased PTH secretion and, finally to combined hypocalcaemia and hypophosphatemia when calcium can no longer be released from bone. Osteomalacia is characterised by increased bone resorption and suppression of new bone mineralisation (Lips, 2006), and serum calcium concentration is often normal (2.25–2.6 mmol/L) despite the undermineralisation of bone. The clinical symptoms of vitamin D deficiency in adults are less pronounced than in children, and may include diffuse pain in muscles and bone and specific fractures. Muscle pain and weakness (myopathy) that accompany the skeletal symptoms in older adults may contribute to poor physical performance, increased risk of falls/falling and a higher risk of bone fractures. Prolonged vitamin D insufficiency may lead to low bone mineral density (BMD) and may dispose older subjects, particularly post-menopausal women, for osteoporosis, a situation characterised by a reduction in bone mass, reduced bone quality and an increased risk of bone fracture, predominantly in the forearm, vertebrae, and hip (Heaney et al., 2000; Gaugris et al., 2005; Holick, 2007; Avenell et al., 2014). 2.2.2.2 Excess Following ingestion of pharmacological doses (e.g. 125–1,000 μg/day) of vitamin D over a period of at least 1 month, the concentration of serum 25(OH)D increases, while that of 1,25(OH)2D is unchanged or even reduced (EFSA NDA Panel, 2012a; Jones, 2014). High serum 25(OH)D concentrations (> 220 nmol/L) may lead to hypercalcaemia, which may eventually lead to soft tissue calcification and resultant renal and cardiovascular damage (Vieth, 1999; Zittermann and Koerfer, 2008). In revising the tolerable upper intake Levels (ULs) for vitamin D (EFSA NDA Panel, 2012a), data on possible associations between vitamin D intake or serum 25(OH)D concentration and adverse long-term health outcomes were considered. However, no studies reported on associations between vitamin D intake and increased risk for adverse long-term health outcomes. Studies reporting on an association between serum 25(OH)D concentration and all-cause mortality or cancer were inconsistent. For adults, hypercalcaemia was selected as the indicator of hypervitaminosis D or vitamin D toxicity (EFSA NDA Panel, 2012a). Two studies administered doses between 234 and 275 μg/day vitamin D3 in men without reported hypercalcaemia (Barger-Lux et al., 1998; Heaney et al., 2003b), and a No Observed Adverse Effect Level (NOAEL) of 250 μg/day was established (Hathcock et al., 2007). Taking into account uncertainties associated with these two studies, the UL for adults was set at 100 μg/day. Two studies in pregnant and lactating women, both using doses of vitamin D2 and D3 up to 100 μg/day for several weeks to months, did not report adverse effects for either mothers or their offspring (Hollis and Wagner, 2004a; Hollis et al., 2011). Thus, the UL of 100 μg/day applies to all adults, including pregnant and lactating women (EFSA NDA Panel, 2012a). There is a paucity of data on high vitamin D intakes in children and adolescents. Considering phases of rapid bone formation and growth and the unlikelihood that this age group has a lower tolerance for vitamin D compared to adults, the UL was set at 100 μg/day for ages 11–17 years (EFSA NDA Panel, 2012a). The same consideration applied also to children aged 1–10 years, but taking into account their smaller body size, a UL of 50 μg/day was selected (EFSA NDA Panel, 2012a). For infants, data relating high vitamin D intakes to impaired growth and hypercalcaemia (Jeans and Stearns, 1938; Fomon et al., 1966; Ala-Houhala, 1985; Vervel et al., 1997; Hyppönen et al., 2011) were used as indicators as in the previous risk assessment by the SCF to set the UL at 25 μg/day (SCF, 2002a). The Panel retained the UL of 25 μg/day and noted that no long-term studies on hypercalcaemia were available (EFSA NDA Panel, 2012a). The Panel notes that two randomised controlled trials (RCTs) have been published after the assessment of the UL by the EFSA NDA Panel (2012a). In both RCTs, infants received vitamin D3 supplementation doses ranging between 10 and 40 μg/day, from age 2 weeks to age 3 months (Holmlund-Suila et al., 2012) or from age 1 month to age 12 months (Gallo et al., 2013), with concomitant increases in mean serum 25(OH)D concentrations (Section 5.1.2.2.1). In the shorter term study (Holmlund-Suila et al., 2012), hypercalcaemia or hypercalciuria did not occur at any dose of vitamin D3 supplemented. In the longer term
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