Draft Vitamin D and Health report Scientific consultation: 22 July to 23 September 2015 Contents Page 1. Introduction 3 2. Biology and metabolism 5 3. Photobiology of vitamin D 16 4. Measuring vitamin D exposure (from diet and sunlight) 24 5. Relationship between vitamin D exposure and serum (25(OH)D concentration 29 6. Vitamin D and health outcomes 35 Musculoskeletal outcomes 37 Rickets 39 Osteomalacia 41 Pregnancy and lactation 42 Infants (up to 12 months) 44 Children (1-3y) 45 Children (4-8y) 45 Adults < 50 years 47 Adults > 50 years 50 Conclusions – vitamin D & musculoskeletal health outcomes 59 Non-musculoskeletal health outcomes 61 Pregnancy & lactation – non-musculoskeletal health outcomes 61 Cancers 67 Cardiovascular disease & hypertension 70 All-cause mortality 74 Autoimmune disease 76 Infectious disease 81 Neuropsychological functioning 85 Oral health 88 Age-related macular degeneration 90 Conclusions – non-musculoskeletal health outcomes 92 Selection of health outcomes to inform the setting of DRVs for vitamin D 93 7. Potential adverse effects of high vitamin D intakes/high serum 25(OH)D 95 concentration 8. Dietary vitamin D intakes and serum/plasma 25(OH)D concentrations of the UK 102 population 9. Review of DRVs 109 10. Overall summary & conclusions 121 11. Recommendations 130 12. References 131 2 1. Introduction Background 1. Vitamin D is synthesised in the skin by the action of sunlight. Skin synthesis is the main source of vitamin D for most people; dietary sources are essential when exposure to sunlight containing the appropriate wavelength is limited. The Committee on Medical Aspects of Food and Nutrition Policy (COMA), which set Dietary Reference Values (DRVs) for vitamin D in 1991 (DH1, 1991), did not set a Reference Nutrient Intake (RNI2) for groups in the population considered to receive adequate sunlight exposure. It was assumed that, for most people, the amount of vitamin D produced by exposure to summer sunlight would produce enough vitamin D for their needs during winter. 2. Current UK government advice is that no dietary intake of vitamin D is necessary for individuals living a ‘normal lifestyle’. Only certain groups of the population, who are at risk of vitamin D deficiency, are advised to take a daily supplement: pregnant and breastfeeding women (10 µg), infants and children aged under 4 years (7-8.5 µg); adults over 65 years (10 µg); those with limited exposure to the sun (e.g., if they cover their skin for cultural reasons or are housebound) (10 µg) and people of Asian origin (10 µg). The DRVs for vitamin D were reviewed and endorsed by COMA in 1998. 3. Although the current recommendations for vitamin D are based on bone health, it is suggested that vitamin D may have a role in other health outcomes including reducing the risk of cancer, cardiovascular disease (CVD), infectious diseases and autoimmune diseases. 4. The evidence on vitamin D and health was previously considered by the Scientific Advisory Committee on Nutrition (SACN) in 2007 in its position statement ‘Update on Vitamin D’. At that time, SACN concluded that there was insufficient evidence to reconsider the existing COMA DRVs for vitamin D and that the evidence on the relationship between vitamin D status and chronic disease, other than the metabolic bone diseases rickets and osteomalacia, was insufficient to draw conclusions. 5. In October 2010, SACN agreed to review the data on vitamin D because a significant amount of new evidence had accumulated since its previous considerations including: results from research commissioned by the Food Standards Agency (FSA); a detailed report published by the Institute of Medicine (IOM) in the United States (US) on Dietary Reference Intakes for Calcium and Vitamin D (2011); and numerous studies on vitamin D and various health outcomes. Terms of Reference 6. The SACN Working Group on Vitamin D was established in 2011 to consider whether the current DRVs for vitamin D intake set by COMA in 1991 were still appropriate to ensure vitamin D adequacy of the UK population in the context of current lifestyles and public health advice (e.g., to stay out of sun and to wear sunscreen). 7. The terms of reference of the SACN Working Group on Vitamin D were: to review the Dietary Reference Values for vitamin D and make recommendations. 8. This required a risk assessment of the vitamin D status of the UK population and consideration of the: . biochemical indicators of vitamin D status and the validity of the values used to assess risk of deficiency and excess; . association between vitamin D status and various health outcomes at different life stages and in different population groups and the effects of biological modifiers; 1 Department of Health 2 The amount of a nutrient that is sufficient to meet the needs of 97.5% of the population. 3 . contribution of cutaneous vitamin D synthesis to vitamin D status in the UK taking account of the effects of modifiers of skin exposure to sunlight; the risks of skin damage and other adverse health outcomes associated with sunlight exposure; . potential adverse effects of high vitamin D intakes; . relative contributions made by dietary vitamin D intake (from natural food sources, fortified foods and supplements) and cutaneous vitamin D synthesis to the vitamin D status of the UK population. Methodology 9. In considering the evidence on vitamin D and health outcomes, the preference was for randomised controlled trials (RCTs) and then prospective cohort studies. Other types of human studies (e.g., case- control, cross-sectional, case-reports) were considered when RCTs or prospective cohort studies were not available. Where possible, any dietary recommendations were based on data from RCTs. 10. Data from the National Diet and Nutrition Survey, the Health Survey for England, the Low Income Diet and Nutrition Survey, the UK Diet and Nutrition Survey of Infants and Young Children and the Scottish Health Survey were used to assess the vitamin D status of the UK population. 11. The IOM report on Dietary Reference Intakes for Calcium and Vitamin D (2011) provided an important and comprehensive database and a useful reference resource for consideration of the evidence on vitamin D and health outcomes. The IOM report was informed by two systematic reviews of the evidence (Cranney et al, 2007; Chung et al, 2009) which were conducted by the Agency for Healthcare Research and Quality (AHRQ). Prior to its considerations, the SACN vitamin D working group (WG) updated the evidence base to include studies published since the IOM report. It subsequently considered findings from studies identified in an AHRQ update of the evidence (Newberry et al, 2014). 12. While the WG considered the evidence on vitamin D relating to nutritional aspects, additional expertise on ultraviolet radiation exposure was provided by Dr John O’Hagan (PHE). Advice on adverse effects of high vitamin D intakes was provided by the Committee on Toxicity (COT). Information on the photobiology of vitamin D and on the effect of sunlight on endogenous vitamin D synthesis was provided by Professor Antony Young (King’s College, London) and Professor Ann Webb (University of Manchester) respectively. 4 2. Biology and metabolism 13. Vitamin D plays an important role in the regulation of calcium and phosphorus metabolism and, therefore, in bone health (Jones, 1998). 14. Vitamin D is synthesised in the skin by the action of sunlight containing ultraviolet B (UVB) radiation. It can also be obtained from the diet. When skin is regularly exposed to sunlight, cutaneous production is, quantitatively, a more important source of vitamin D than diet (Holick et al, 1980). Dietary vitamin D supply becomes essentiaI if there is insufficient cutaneous synthesis (generally caused by limited solar exposure during the summer and lack of UVB containing sunlight during the winter). 15. The two major forms of vitamin D are vitamin D3 (also referred to as cholecalciferol) and vitamin D2 (also referred to as ergocalciferol). In this report, the term vitamin D refers to both vitamin D2 and D3 unless the specific form is indicated. Chemistry 16. Vitamin D is classified as a secosteroid. Vitamin D2 (C28H44O) differs from vitamin D3 (C27H44O) in the side chain attached to the secosteroid skeleton, which contains an additional methyl group on carbon atom 24 and a double bond between carbon atoms 22 and 23 (Norman, 2008) (see Figure 1). This difference means that the molecular mass of vitamin D2 (396.65 g/mol) is 3.1% higher than that of vitamin D3 (384.64 g/mol). FIGURE 1 Molecular structure of vitamins D2 and D3 Vitamin D2 Vitamin D3 Units of measurement 17. Vitamin D intake is expressed in International Units (IU) or in micrograms (µg). IUs are based on antirachitic activity3 measured in bioassays using rats. One IU of vitamin D is defined by the World Health Organization (WHO) (1950) as the activity produced by 0.025 µg of crystalline vitamin D3 (1 µg = 40 IU). Although this definition is based on vitamin D3 activity, the conversion continues to be generalised to both forms of the vitamin regardless of the difference in their molecular mass. 18. Serum concentrations of circulating vitamin D and its metabolites are expressed as nanomoles per litre (nmol/L) or nanograms per millilitre (ng/ml); 2.5 nmol/L is equivalent to 1 ng/ml. However due to the differences in molecular mass, there is not absolute correspondence in the conversion of ng to nmol for vitamin D2 and D3 and their metabolites. The inconsistencies relating to the measurement of the two forms of vitamin D need to be considered in the interpretation of studies comparing vitamin D2 and D3. 19. Units of measurement used in this report are µg (intakes) and nmol/L (serum concentration); the corresponding amounts in IU (intakes) and ng/ml (serum concentration) are also provided in parentheses.