European Food Safety Authority

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1 TECHNICAL REPORT APPROVED: 3 August 2016 Outcome of a public consultation on the Draft Scientific Opinion of the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) on Dietary Reference Values for vitamin D Abstract European Food Safety Authority The European Food Safety Authority (EFSA) carried out a public consultation to receive input from the scientific community and all interested parties on the draft Scientific Opinion on Dietary Reference Values (DRVs) for vitamin D, prepared by the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA Panel) and endorsed by the Panel for public consultation at its Plenary meeting on 2 February The written public consultation for this document was open from 21 March 2016 to 16 May EFSA received comments from 67 interested parties. EFSA and its NDA Panel wish to thank all stakeholders for their contributions. The current report summarises the outcome of the public consultation, and includes a brief summary of the comments received and how the comments were addressed. The NDA Panel prepared an updated version of the Scientific Opinion on Dietary Reference Values for vitamin D taking into account the comments received. The Scientific Opinion was discussed and adopted at the NDA Plenary meeting on 29 June 2016, and is published in the EFSA Journal. European Food Safety Authority, 2016 Key words: vitamin D, 25(OH)D, UV-B irradiation, musculoskeletal health outcomes, metaregression, Adequate Intake, Dietary Reference Value, public consultation Requestor: EFSA Question number: EFSA-Q Correspondence: nda@efsa.europa.eu EFSA Supporting publication 2016:EN-1078

2 Acknowledgements: EFSA 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 and EFSA staff members: Laura Ciccolallo, Céline Dumas, Lucia Fabiani and Laura Martino for the preparatory work on this scientific output. Suggested citation: EFSA (European Food Safety Authority), Outcome of a public consultation on the Draft Scientific Opinion of the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) on Dietary Reference Values for vitamin D. EFSA supporting publication 2016:EN pp. European Food Safety Authority, 2016 Reproduction is authorised provided the source is acknowledged. Reproduction of the images/figures listed in this report is prohibited and permission must be sought from the copyright holder. 2 EFSA Supporting publication 2016:EN-1078

3 Table of contents Abstract Introduction Background Terms of Reference Consideration Screening and evaluation of comments received Comments received Nature of specific comments Editorial suggestions Generic comments Definition/category and biochemical functions Excess Cutaneous synthesis of vitamin D Transport in blood Biomarkers of vitamin D Effect of genotype Dietary sources and intake Overview of Dietary Reference Values and recommendations Musculoskeletal health outcomes Non-musculoskeletal health outcomes Setting of DRVs for vitamin D Vitamin D intake and serum 25(OH)D concentration Recommendations for research References Abbreviations Appendix A Explanatory text for the public consultation on the draft Scientific Opinion on Dietary Reference Values for vitamin D Appendix B Full list of comments submitted by means of the electronic form on the EFSA website Appendix C Full list of comments submitted by means of Appendix D Additional sensitivity analyses EFSA Supporting publication 2016:EN-1078

4 1. Introduction 1.1. Background 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 report on nutrient and energy intakes for the European Community dates from In 2005, the European Commission (EC) asked the European Food Safety Authority (EFSA) to review and if necessary update such advice to ensure that Community action in the area of nutrition is underpinned by the latest scientific advice. To this end, EFSA has been requested to consider the existing Population Reference Intakes (PRIs) for nutrients and certain other dietary components. The Scientific Opinion on general principles for deriving and applying Dietary Reference Values (DRVs), and the Scientific Opinions on DRVs for water, for fats and for carbohydrates and dietary fibre were published in The Scientific Opinions on DRVs for protein and for energy were published in 2012 and 2013, respectively. The work on Opinions on DRVs for micronutrients is ongoing Terms of Reference In line with EFSA s policy on openness and transparency, and in order for EFSA to receive comments from the scientific community and stakeholders, EFSA shall release the Draft Scientific Opinion on DRVs for vitamin D for public consultation. The comments resulting from the public consultation shall be published in a technical report. Before its adoption by the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA Panel), the Draft Scientific Opinion on DRVs for vitamin D needs to be revised, taking into account the comments received during the public consultation Consideration Upon request from the European Commission and following previously published Scientific Opinions on DRVs for macronutrients, energy, water, and several micronutrients, the EFSA NDA Panel developed a Draft Scientific Opinion on DRVs for vitamin D. In line with EFSA s policy on openness and transparency, and in order for EFSA to receive comments on its work from the scientific community and stakeholders, EFSA engages in public consultations on key issues. Accordingly, the draft Scientific Opinion was published on EFSA s website for comments (21 March to 16 May 2016) (see Appendix A). The NDA Panel prepared an updated version of the Scientific Opinion, taking into account the comments received. The updated Scientific Opinion was discussed and adopted at the NDA Plenary meeting on 29 June 2016, and is published in the EFSA Journal (EFSA NDA Panel, 2016a). EFSA is committed to publishing the comments received during the public consultation, as well as a short report on the outcome of the public consultation. 2. Screening and evaluation of comments received 2.1. Comments received EFSA received 116 different submissions, of which 105 were submitted electronically (Appendix B) and 11 were submitted by (one being an update of a previously submitted one, Appendix C). Comments were received from 13 interested parties (Table 1), including one non-governmental organisation, three industry associations, three national scientific advisory bodies, one national competent authority, two national institutes, 4 individuals (academia from three Universities) including three in a common comment, and comments were received from 54 other individuals. Some interested parties submitted comments through the electronic tool and also submitted the comments (either the same or expanded comments) via s. 4 EFSA Supporting publication 2016:EN-1078

5 Submissions usually addressed more than one specific item so the numbering below does not match the number of submissions received. Comments related to policy or risk management aspects were considered to be outside the scope of the consultation, and are not covered in this report. Table 1: List of organisations submitting comments Organisation Alliance for Natural Health International Federation of European Specialty Food Ingredients Industries (ELC) Food Supplements Europe Health Council of the Netherlands Health Food Manufacturer's Association National Institute for Public Health and Environment, The Netherlands National Nutrition Council Finland Northern Ireland Centre for Food & Health, Ulster University Swedish National Food Agency Swiss Federal Commission for Nutrition University College Cork, Ireland, and University of Copenhagen, Denmark University of Aberdeen, United Kingdom 2.2. Nature of specific comments Editorial suggestions Comments received: 1. In the summary of the Scientific Opinion, the Panel was asked to specifically reference the external contractor (Brouwer-Brolsma et al., 2016) mentioned in particular in Section of the Scientific Opinion and who undertook the comprehensive literature search and review. 2. In Figure 3 of the Scientific Opinion, it was asked to remove the peculiar visual effect, with the green and yellow shooting up, at the left end of the plot. Panel consideration of comments received: Ad1. The external contractor (Brouwer-Brolsma et al., 2016) was indeed identified in Section The Panel agreed to add this reference to the Summary of the Scientific Opinion. Ad2. This peculiar visual effect was due to a technical software issue, which is solved in the published opinion Generic comments Comments received: 3. Concern was expressed by a number of individuals that the setting of Adequate Intakes (AIs) at 15 μg/day will limit access to, or cause other bodies to restrict the availability of, vitamin D supplements or medical prescriptions at higher doses, in particular in relation to supplementation of individuals with medical conditions (e.g. autoimmune diseases, immune dysregulation, Crohn s disease, rheumatoid arthritis, multiple sclerosis), or of individuals living at certain latitudes or with specific diets (e.g. vegan diet). It was stated that high doses of vitamin D are an alternative free of side effect and cost-effective compared to medication and that an interested organisation recommends 125 μg to prevent disease. Concern was also expressed numerous times that possible limitation of daily vitamin D intake to 15 µg/day was a violation of the human right to nourishment and would deny individuals the right and liberty to choose to consume what they consider adequate amounts of vitamin D. 5 EFSA Supporting publication 2016:EN-1078

6 Individuals reported taking doses ranging from 25 to 2,750 µg/day (1, ,000 IU/day 1 ) (adults or children), with marked improvements in their conditions and/or marked changes in test results for blood 25-hydroxy-vitamin D (25(OH)D) with normal calciuria and parathyroid hormone (PTH) concentrations and/or no experience of toxicity. One individual pointed out that they cannot work without 250 μg/day of vitamin D, and that daily supplementation is necessary all year round. A number of individuals reported the vitamin D doses they consume for 2 3 days at the onset of illness, such as a common cold. It was noted that many studies (no reference provided) have shown that vitamin D deficiency is linked to risk of multiple sclerosis, dementia and cancers, such as breast cancer, or other health problems, e.g. migraine, high blood pressure, depression, anxiety, hormonal problems. It was stated that the dose needed to treat individuals deficient in vitamin D should be a therapeutic dose higher than that of the proposed AI. 4. It was stated that EFSA does not appear to have consulted acknowledged vitamin D experts, as their views are not reflected in the draft Opinion. The Panel was asked to formally request input from these experts. The Panel was invited to view a link from the website of an interested organisation indicating in particular a list of experts. Panel consideration of comments received: Ad3. The setting of maximum amounts in dietary supplements 2 is not within the Terms of Reference of this Scientific Opinion, as it is a risk management decision 3 under the responsibility of the European Union (EU) Risk Managers (e.g. the EC together with Member States). As indicated in Section 2.1. of this technical report, comments related to policy or risk management aspects are considered to be outside the scope of the consultation. In addition, pharmaceutical products are regulated at European level differently from food, including dietary supplements, and the scientific assessment of pharmaceutical products is not in the remit of EFSA. DRVs are set for healthy people (EFSA NDA Panel, 2010a). Following the Terms of Reference as provided by the EC, EFSA reviewed existing DRVs on vitamin D in the light of new scientific evidence (see list of references of the Scientific Opinion). This review of the scientific evidence and a statistical data analysis (meta-regression) specifically done for this Scientific Opinion led the Panel to set the following AIs for vitamin D for the healthy general population: 15 µg/day for all adults and children aged 1 17 years, and 10 µg/day for infants aged 7 11 months. Anecdotal evidence or individual experience of use of high doses of vitamin D for therapeutic use cannot be used for deriving DRVs for the (healthy) population. A review of data on vitamin D intake/status and treatment of diseases was not within the scope of this Scientific Opinion. It is not within the scope of this Opinion to provide special reference values for people with various gastrointestinal or metabolic disorders that may impact vitamin D status. Likewise, DRVs cannot provide therapeutic concepts for individual disease conditions. Such conditions should be treated under the supervision and responsibility of health care professionals with individually tailored measures. Ad4. EFSA considered and discussed relevant scientific publications from vitamin D experts including some from those referred to by the commenter, and invited interested parties to comment during the public consultation on the draft Scientific Opinion. The Panel considered that no change in the Scientific Opinion was needed in relation to these comments. 1 For conversion between µg and International Units (IU) of vitamin D intake: 1 µg = 40 IU and µg = 1 IU. For conversion between nmol/l and ng/ml for serum 25(OH)D concentration: 2.5 nmol/l = 1 ng/ml. 2 As outlined in Directive 2002/46/EC of the European Parliament and of the Council of 10 June 2002 on the approximation of the laws of the Member States relating to food supplements. OJ L 183, , p EFSA Supporting publication 2016:EN-1078

7 Definition/category and biochemical functions Comments received: 5. For Section 2.1. of the Scientific Opinion, it was pointed out that, despite its name, vitamin D is not actually a vitamin, but a precursor to calcitriol (1,25-dihydroxy-vitamin D (1,25(OH) 2 D)). To support this, a number of reviews were mentioned as (Bikle 2014, Feldman et al. 2014, Carlberg 2014) (without full citation/identification). It was stated that the single sentence describing vitamin D as a prohormone in Section of the Scientific Opinion was an inadequate explanation of this function. Panel consideration of comments received: Ad5. Section of the Scientific Opinion explains that vitamin D is converted to the main circulating form 25(OH)D that is transformed into the biologically active metabolite 1,25(OH) 2 D. These two steps of conversion are explained in further details in Section on metabolism and related Figure 2. Cross-reference to this Section and this Figure has been clarified in Section 2.1. The sentence referring to the term prohormone has been deleted. The fatsolubility of vitamin D 2 and D 3 is now mentioned in Section 3 of the Scientific Opinion (instead of Section 2.1.) and the summary has been revised accordingly Excess 6. It was stated that the upper daily intake level recommendation should remain at 100 μg/day in adults and 50 μg/day in children aged 1 11 years. Another comment stated that the Tolerable Upper Intake Level (UL) (EFSA NDA Panel, 2012) is excessively and unnecessarily cautious, and the Panel was invited to refer to Hathcock et al. (2007) and Verkerk and Hickey (2010). In another comment, it was stated that a UL of 25 μg/day was not adequate for maintaining a strong immune system and optimum health. Panel consideration of comments received: Ad6. The Panel was requested by the EC to derive DRVs, which are reference values for dietary nutrient intakes (EFSA NDA Panel, 2010a). It was not in the Terms of Reference of this Scientific Opinion to revise ULs previously set for vitamin D (EFSA NDA Panel, 2012). The difference between the DRVs covered by the Terms of Reference as received from the EC and the ULs is described elsewhere (SCF, 2000; EFSA NDA Panel, 2010a). The following ULs were set in 2012, as indicated in Section of the Scientific Opinion: 100 μg/day for all adults (and not 25 µg/day as suggested in a comment received), including pregnant and lactating women, 100 μg/day for children aged 11 to 17 years, 50 µg/day for children aged 1 to 10 years, and 25 µg/day for infants. Section of the Scientific Opinion discusses the several functions of the biologically active metabolite of vitamin D, i.e. 1,25(OH) 2 D, including its involvement in cell differentiation and antiproliferative actions in various cell types, such as cells belonging to the immune system. Also, the Panel reviewed the data on vitamin D status in relation to markers of immune function available in systematic reviews and reports in particular by the Institute of Medicine (IOM, 2011), by Newberry et al. (2014) and by the Scientific Advisory Committee on Nutrition (SACN, 2016) (Section of the Scientific Opinion). The Panel came to the same conclusion, i.e. that there is a lack of consistent results and that the evidence for a cause and effect relationship between vitamin D intake/status and immune function was insufficient for setting DRVs for vitamin D. The Panel considered that no change in the Scientific Opinion was needed in relation to these comments Cutaneous synthesis of vitamin D Comments received: 7 EFSA Supporting publication 2016:EN-1078

8 7. It was stated that an intake of 250 μg/day is safe as it is equivalent to the vitamin D amount synthesised during 20 minutes of sun exposure of the body. Another similar comment stated that whole body exposure to the sun for 30 minutes would provide 250 to 500 µg, which are values above the proposed AI. No supporting reference was given in these comments. In another comment, with regard to Section of the Scientific Opinion, it was stated that Webb et al show a saturation level after prolonged exposure of ~12% provitamin D converted to previtamin-d and that Holick et al estimated the provitamin D abundance in Caucasian human leg skin to be 10,000 µg/m 2 (no full citations were provided in the comment received and the Panel assumed these references to be: (Holick et al., 1980; Webb et al., 1989)). Then, it was reasoned that the full body of an adult (2 m 2 skin) exposed to saturation of the photosynthesis process would result in the synthesis of 12% of [2 m 2 ] x 10,000 [µg/m 2 ] = 2,400 µg of vitamin D. Then, if the saturation process reported by Webb et al. is an explanation of why cutaneous vitamin D photosynthesis is not toxic, the Panel was asked to explain why the current upper intake level is set to 100 µg/day, only about 4% of the safe ultraviolet (UV) production. It was noted that the dose that is required to achieve the 12% conversion is not physiological and therefore saturation will not be a relevant process. However, referring to Holick, it was stated that full-body exposure to 1 minimal erythema dose (MED), which is a regular, physiological dose, results in the synthesis of 400 μg, i.e. four times the current upper intake limit as mentioned in the comment received. 8. It was suggested that the Panel considers that the association between vitamin D intake and status for the purpose of deriving DRVs for vitamin D should be assessed for all status values thought to be low, rather than under conditions of minimal endogenous vitamin D synthesis as mentioned e.g. in Section of the Scientific Opinion. The Panel was also asked to quantify what is meant by low exposure to UV-B irradiation from sunlight in several sections of the Scientific Opinion, e.g. for the setting of DRVs (conclusion of Section , introduction of Section ) or for the use of serum 25(OH)D as a biomarker of vitamin D intake (Section ). As exposure to UV-B irradiation from sunlight is an important confounder in assessing the effect of supplemental intakes, the Panel was asked to address UV-B irradiation in more detail. 9. For Section , where the length of the vitamin D winter is discussed for different latitudes and parts of the year, it was noted that, in Amsterdam, the sun is higher in April than in September, therefore it was suggested to consider the period October through March for 52.5 N (instead of October to April). The Panel was referred to Tsiaras and Weinstock (2011) and Engelsen et al. (2005) for further information. It was also noted that Kiely and Cashman (2015) have previously addressed the issue of UV-B irradiation from sunlight. In another comment, modelled UV-B dose data for European regions arising from an on-going research project were commented upon, to underline that for countries residing in the latitude of N there can be significant UV-B availability sufficient for cutaneous synthesis of pre-vitamin D 3 during some winter months. In another comment, it was stated that a prerequisite for vitamin D production in skin is that the UV-B light has an intensity of at least 18 mj/cm², and that in the northern hemisphere at latitudes greater than around 40 N (North of Madrid), sunlight is not strong enough to trigger synthesis of vitamin D in the skin from October to March (Spiro and Buttriss, 2014). Panel consideration of comments received: Ad7. The Panel was requested by the EC to derive DRVs, which are reference values for dietary nutrient intakes (EFSA NDA Panel, 2010a). The Panel acknowledges the importance of skin synthesis for vitamin D status, but considers that vitamin D synthesis by exposure of the skin to 8 EFSA Supporting publication 2016:EN-1078

9 the sun cannot be used to derive DRVs. In addition, it was not in the Terms of Reference of this Scientific Opinion to revise ULs for vitamin D (EFSA NDA Panel, 2012) mentioned in the comments received (see Ad6.). The Scientific Opinion (Section ) outlines that previtamin D 3 and vitamin D 3 are photodegraded in the skin to biologically inert isomers following UV-B exposure, thus preventing vitamin D toxicity due to prolonged sun exposure. The Panel considered that no change in the Scientific Opinion was needed in relation to these comments. Ad8. The Panel acknowledges the suggestion of assessing vitamin D dietary intake and synthesis in the skin through sun exposure in a large sample of subjects with low vitamin D status. However, to date, such data are lacking. The Panel was requested by the EC to derive DRVs, which are reference values for dietary nutrient intakes (EFSA NDA Panel, 2010a) (see Ad7.). The Panel is aware that sun exposure contributes to the relationship between vitamin D intake and status, and therefore derives DRVs for vitamin D from data collected under conditions of assumed minimal endogenous vitamin D synthesis. The Panel stresses that available studies on vitamin D intake-status relationship often do not measure and report quantitatively on the amount of sun exposure or related parameters/factors (e.g. amount of time spent outdoors). The available studies more often report only on latitude and months of the year at/during which the studies were undertaken (see Section of the Scientific Opinion for further information on the several factors affecting vitamin D synthesis in the skin). The Panel is also aware of experimental data obtained under controlled conditions aiming to quantify the amount of vitamin D synthesised in the skin, and of mathematical integrated models aiming to predict serum 25(OH)D concentration in relation to both local UV-B irradiation and vitamin D dietary intake in specific populations (e.g. in an Irish study population (Cashman et al., 2015)). However, the Panel considers that the formulation of recommendations for dietary vitamin D intake according to UV-B irradiation at national/regional/local level in the EU according to specific characteristics (e.g. latitude, atmospheric and climatological conditions, or recommendations for skin protection, as possibly assessed/monitored by national bodies/authorities) is a risk management decision, and therefore outside the remit of this Scientific Opinion. The Panel considered that no change in the Scientific Opinion was needed in relation to these comments. Ad9. The Panel was requested to derive DRVs, which are reference values for dietary nutrient intakes (EFSA NDA Panel, 2010a) (see Ad7.). The Scientific Opinion outlines the steps and influencing factors of cutaneous synthesis of vitamin D (Section ). The Panel confirms the adequate reporting of months of insufficient cutaneous vitamin D synthesis as per the papers cited in Section 2.3.1, and mentioned in the comment received (Engelsen et al., 2005; Tsiaras and Weinstock, 2011). Section was clarified with regard to the reporting of the following references: (Engelsen et al., 2005; Webb, 2006; Webb and Engelsen, 2006; Tsiaras and Weinstock, 2011). The results from an on-going research project discussed in a comment received suggest that modelled average monthly UV-B doses are above 1,000 J/m 2 in Thessaloniki (Greece, N) for all months except December and January. This UV-B dose is considered by the commenter as a guide to where UV-B irradiation is sufficient to synthesise pre-vitamin D in the skin. Some other data also indicate that during wintertime in latitudes greater than 38, the angle of the sun is too oblique for UV-B rays to pass through ozone, so little or no vitamin D is dermally synthesised (Kiely and Cashman, 2015) and that in the northern hemisphere at latitudes greater than around 40 N [ ], sunlight is not strong enough to trigger synthesis of vitamin D in the skin from October to March (Spiro and Buttriss, 2014). 9 EFSA Supporting publication 2016:EN-1078

10 The Panel notes that the available data at European level on the length of the vitamin D winter at different latitudes are inconsistent. The Panel supports further research on the extent of vitamin D synthesis in the skin in relation to UV-B irradiation in Europe. Apart from the rephrasing mentioned above, the Panel considered that no change in the Scientific Opinion was needed in relation to these comments Transport in blood Comment received: 10. Regarding Section of the Scientific Opinion, it was noted that a plasma/serum 25(OH)D half-life of up to 50 days has been reported. The Panel was asked to refer to the vitamin D chapter in the Nordic Nutrition Recommendations (NNR) 2012 report (Nordic Council of Ministers, 2014). Panel consideration of comment received: Ad10. The Panel is aware of the study by Clements et al. (1987) referred to in the NNR 2012 (Nordic Council of Ministers, 2014). This study was undertaken on seven patients with primary hyperparathyroidism subjected to an injection of 3 H-25(OH)D, and it assessed the elimination half-life of 3 H-25(OH)D in plasma before and after parathyroidectomy. The Panel slightly revised Sections and of the Scientific Opinion, using the reference of Jones et al. (2014) instead of Jones et al. (2012) (and the Summary was aligned). The Panel used values from this study on 36 healthy subjects receiving orally 25(OH)D, which showed a mean half-life of 13.9 days for 25(OH)D 2 and of 15.1 days for 25(OH)D 3 (Jones et al., 2014) Biomarkers of vitamin D Comments received: 11. Support was expressed for the Panel conclusion 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. However, in other comments, the flaws in using serum 25(OH)D concentrations as a marker of vitamin D status was pointed out. It was added that analytical method is not the only source of between-laboratory discrepancy, also sample preparation, duration of sample storage and method of sample collection. In addition, it was pointed out that older data may be affected by the lack of an international standard. 12. It was noted that individuals who are vitamin D deficient will have a proportionally greater increase in serum 25(OH)D concentration after consumption of a given amount of vitamin D than individuals with a higher serum 25(OH)D concentration, potentially putting the latter individuals at risk. Panel consideration of comments received: Ad11. The Panel concluded that serum 25(OH)D concentration can be used as a biomarker of vitamin D status with precaution (precaution in relation to analytical measurements, as explained in further detail in the Opinion, Sections and ). The Panel noted the lack of a common standard for the measurement of 25(OH)D in serum in Section of the Scientific Opinion. The Panel slightly revised Section to clarify that formerly, all methods suffered from the lack of an international common standard, this lack contributing to the variability of results of serum 25(OH)D measurements. This Section also discusses the concerns about differences between methods both within and between laboratories, the recent introduction of a standard reference material, and the on-going efforts to develop protocols for standardising procedures of 25(OH)D measurement. This covers, for example, sample preparation, duration of sample storage and method of sample collection EFSA Supporting publication 2016:EN-1078

11 The Panel also notes that analytical issues were taken into account in Section and related Appendices C and D of the Scientific Opinion, as study start year (as a proxy to the temporal trends in assay method use) and the assay methods were used as covariates in the adjusted model of the meta-regression analysis. Ad12. The Panel is aware of the influence of baseline serum 25(OH)D concentration on the response of serum 25(OH)D concentration to vitamin D supplementation, as indicated in the introduction of Section 5.3. of the Scientific Opinion. In its meta-regression analysis (Section ), the Panel also considered mean baseline serum 25(OH)D concentration among the covariates included in the adjusted model. The Panel considered that no change in the Scientific Opinion was needed in relation to this comment Effect of genotype Comments received: 13. Regarding Section 2.5. of the Scientific Opinion, it was noted that, although current data are probably insufficient to tailor DRVs to specific genotypes, there is a considerable number of polymorphisms in the group-specific component gene (GC gene) related to 25(OH)D concentration, in particular in relation to ethnic or population differences. The Panel was invited to view HuGe Navigator as an example. In another comment, the Panel was asked to include information on the polymorphisms of the vitamin D receptor (VDR) Fok1 T>C, VDR Bsm1 C>T and VDR Taq1 C>T (Huang et al., 2015; Lee and Gyu Song, 2015; Mun et al., 2015; Tizaoui and Hamzaoui, 2015). Panel consideration of comments received: Ad13. The Panel described the polymorphisms of genes related to vitamin D status, vitamin D synthesis, transport and metabolism in Section 2.5. of the Scientific Opinion (including variants in the GC gene mentioned in the comment received). Thus, the Panel did not report on data on VDR polymorphisms Fok1, Bsm1 and Taq1 in relation to risk of several health outcomes (e.g. risk of tuberculosis, of melanoma, of cancer or of rheumatoid arthritis as in the references cited in a comment). The Panel recognizes in Section 2.5. a potential impact of genotype on vitamin D synthesis, transport and metabolism, and considers that, at present, data on the effect of genotypes on vitamin D metabolism are insufficient to be used for deriving the requirements for vitamin D according to genotype variants. The Panel considered that no change in the Scientific Opinion was needed in relation to these references. The conclusion of Section 2.5. of the Scientific Opinion was, however, clarified as follows: The Panel considers that data on the effect of genotype on vitamin D synthesis, transport and metabolism are insufficient for use in deriving the requirements for vitamin D according to genotype variants Dietary sources and intake Comment received: 14. The importance of exogenous sources of vitamin D to achieve the DRV was pointed out, and the Panel was invited to consider the inclusion of a recently validated vitamin D food frequency questionnaire (FFQ) (Weir et al., 2016) as a reference for future research wishing to quantify the contribution of dietary and supplemental vitamin D intake. 15. It was noted that dietary supply of vitamin D is limited to marine fish and fish liver oil, and to foods like meat and eggs that provide small amounts of vitamin D. It was added that, besides Norway, where fish and fish oil consumption is a regular part of the diet, vitamin D intake across Europe is very low (Spiro and Buttriss, 2014). Panel consideration of comment received: Ad14. The reference cited in the comment received deals with the validation of a new FFQ (based on foods known to contribute to dietary vitamin D intake) against a four-day weighed food record 11 EFSA Supporting publication 2016:EN-1078

12 and biomarker data (25(OH)D) in a group of 49 apparently healthy adults at the end of winter. The Panel is aware of the uncertainties of dietary intake estimation and welcomes research to improve this estimation. However, the Panel considers that it is outside the Terms of Reference of this Scientific Opinion to review methodologies for dietary intake estimation. Ad15. The Panel considers that this comment does not contradict what is already discussed in detail in Section 3 of the Scientific Opinion. The Panel considered that no change in the Scientific Opinion was needed in relation to these comments Overview of Dietary Reference Values and recommendations Comments received: 16. The Panel was asked to add to the paragraph describing the DRVs set by the Health Council of the Netherlands in Section 4 of the Scientific Opinion that, in the Netherlands, the average yearly vitamin D production in the skin is estimated to be 7 μg/day. 17. The Panel was asked to explain the difference in the conclusions of the report by SACN (draft published for public consultation in 2015) that proposed a Reference Nutrient Intake (RNI) of 10 μg/day (SACN, 2016) and of the Panel that proposed an AI of 15 μg/day while the evidence considered is similar. It was repeatedly indicated that this report indicated that 28 μg/day of vitamin D is required for the 97.5% percentile of the population to achieve a serum 25(OH)D concentration of 50 nmol/l. It was suggested that the Panel view the SACN report on vitamin D and dietary requirements for adults aged years estimated during winter (SACN, 2016). The work of Cashman et al. (2008; 2009) in Ireland was also highlighted as demonstrating that 20 μg/day of vitamin D is needed to achieve a serum 25(OH)D concentration of 50 nmol/l in 90 95% of the population. Panel consideration of comments received: Ad16. The Panel agreed to include the following information in Section 4.1. of the Scientific Opinion, in the paragraph on the report of the Health Council of the Netherlands (2012): It was roughly estimated that sunlight exposure in the Netherlands leads to the production, on average over the whole year, of 6 to 7 µg/day vitamin D, with significantly higher amounts during summer and a decline to nearly zero during winter (Signaleringscommissie Kanker van KWF Kankerbestrijding, 2010). Ad17. The overview of DRVs set by other bodies/authorities is provided in Section 4 of the Scientific Opinion, including those set by SACN (2016). Both EFSA s NDA Panel and SACN (2016) concluded that serum concentration of 25(OH)D continues to be the best indicator of vitamin D intake and status, and therefore both have used this parameter to derive DRVs for vitamin D. Both the Panel and SACN considered the scientific evidence on the relationship between intake and status, and between status and various health outcomes, and both focused on musculoskeletal health outcomes in view of setting DRVs for vitamin D. However, the approaches taken and the evidence used were not exactly the same. SACN (2016) focused on health outcomes such as rickets and osteomalacia in the first instance, and secondly on muscle strength and function, and explained that the serum concentration of 25 nmol/l was considered to represent a population protective level ; i.e., the concentration that individuals in the UK should be above, throughout the year, in terms of protecting musculoskeletal health. The Panel considered changes in bone mineral density (BMD)/bone mineral content (BMC) and fracture risk as additional health outcomes in its assessment, and set a target serum 25(OH)D concentration of 50 nmol/l. See also Ad EFSA Supporting publication 2016:EN-1078

13 SACN proposed an RNI of 10 µg/day for the UK population (aged four years and more) based on individual data on serum 25(OH)D concentrations and vitamin D status from studies conducted at UK latitudes (51 60 N). The assessment by EFSA s NDA Panel was based on mean values (meta-regression) from more studies covering broader latitudes (around 40 and above) to propose DRVs for the European population. Individual data were largely not available in the studies considered by EFSA. See also Ad32., for the use of the prediction interval in the context of the meta-regression. Of importance is that EFSA s NDA Panel and SACN considered different types of DRVs: EFSA derived an AI for all age groups while SACN derived an RNI for population groups of 4 years and older and a safe intake (SI) 4 for children aged under four years. For vitamin D, the Panel considered that the available data did not allow the setting of Average Requirements (ARs) upon which PRIs at European level could be based (See also Ad32. and Ad33., for the uncertainties/limitations of the available data and for the interpretation of an AI). The Panel therefore established an AI value at which the majority of the adult population will achieve the target serum 25(OH)D concentrations when exposure to sun is minimal. EFSA highlights that in the presence of endogenous vitamin D synthesis, e.g. by exposure to sun, the requirement for dietary vitamin D is lower or may even be zero. Thus, the DRVs for vitamin D derived by EFSA and SACN are not directly comparable. Their interpretation needs to be considered taking into account their respective and different Terms of Reference and the specifics of the respective approaches used that are detailed in the Scientific Opinion of the EFSA NDA Panel on Dietary Reference Values for vitamin D and the report on Vitamin D and Health by SACN. The Panel considered that no change in the Scientific Opinion was needed in relation to this comment Musculoskeletal health outcomes 18. Regarding the introduction of Section of the Scientific Opinion, it was stated that there was inadequate discussion on the relevance of the various outcomes related to musculoskeletal health, in particular the relationship between calcium absorption and risk of rickets and fractures. Panel consideration of comments received: Ad18. The relationship between vitamin D status and calcium absorption is addressed in Sections (adults) and (children) of the Scientific Opinion. The relationship between vitamin D status and the risk of rickets is discussed in Section of the Scientific Opinion, as well as the limitation of the available data (in particular, the lack of information on the calcium intake of the subjects). Moreover, clinical symptoms of vitamin D deficiency (rickets in children, and osteomalacia in adults) are discussed in Section of the Scientific Opinion, in particular the fact that both are caused by the impaired mineralisation of bone due to an inefficient absorption of dietary calcium and phosphorus. This Section also contains a discussion on the fact that prolonged vitamin D insufficiency may dispose older subjects to, for example, an increased risk of bone fracture. Section is referred to in the introduction of Section of the Scientific Opinion. The Panel has restructured the introduction of this Section following this comment, and clarified the cross-references to previous Sections (Sections 2.2.1, and ) in which vitamin D deficiency and/or calcium absorption are discussed. 4 Defined as a value judged to be a level or range of intake at which there is no risk of deficiency, and below a level where the there is a risk of undesirable effects EFSA Supporting publication 2016:EN-1078

14 Bone mineral density (BMD)/bone mineral content (BMC) in adults Comments received: 19. The Panel was asked to clarify the results of the randomised controlled trial (RCT) by Macdonald et al. (2013) in relation to BMD in adults in Section of the Scientific Opinion. 20. In the same Section, it was noted that, in some of the RCTs, supplements of calcium were given and that, therefore, conclusions cannot be made for vitamin D alone as calcium is vitamin D-sparing. 21. It was noted that the conclusions of the Panel that there is some evidence that the risk of increased BMD/BMC loss in free-living adults is higher with a serum 25(OH)D concentration below 50 nmol/l is derived from observational data, which are confounded. More generally (whatever the health outcomes considered), it was stated that it was important to explain the limitations of using observational data to link serum 25(OH)D concentration and health outcomes to set an AI. It was suggested that the Panel s consideration that there is some evidence that the risk of increased BMD/BMC loss in free-living adults is higher with a serum 25(OH)D concentration below 50 nmol/l should be amended (Section and of the Scientific Opinion): adults should be changed to free-living postmenopausal women and older men to reflect the data on which the statement is based. Panel consideration of comments received: Ad19. The Panel amended the text in order to clarify the results of this study. The new text reads as follows: Neither at baseline nor at the final visit were significant associations between serum 25(OH)D and mean total hip BMD or lumbar spine BMD found. The Panel notes that raising mean 25(OH)D concentration from about 34 to 65 and 76 nmol/l, respectively, by supplemental doses of 10 or 25 μg/day of vitamin D for one year in these postmenopausal women did not result in corresponding dose-dependent effects on BMD. This suggests that other factors may confound the relationship between vitamin D intake, serum 25(OH)D and BMD, and that 25(OH)D concentrations above 34 nmol/l were not associated with BMD in this study. Ad20. As for other nutrients, DRVs for vitamin D are set assuming that intakes of interacting nutrients, such as calcium (EFSA NDA Panel, 2015), are adequate (Section 6 of the Scientific Opinion). The Panel acknowledges that most of the RCTs included in the Scientific Opinion either measured calcium intake or used a calcium supplement ensuring that calcium intake was sufficient. Also, there was no evidence of a vitamin D sparing effect of high calcium intake in a winter-based double-blind RCT in adults on vitamin D 3 supplementation (20 µg/day) versus placebo, that showed similar changes in serum 25(OH)D concentration in analyses stratified according to calcium intake (Cashman et al., 2014). The Panel considered that no change in the Scientific Opinion was needed in relation to this comment. Ad21. In consideration of this comment, the Panel rephrased the conclusion of Section as follows: Taking into account the conclusions of IOM (2011) and the studies published thereafter, the Panel considers that there is some evidence, mostly from observational studies in mainly older adults, that the risk of increased BMD/BMC loss in free-living adults is higher with a serum 25(OH)D concentration below 50 nmol/l. With regard to the confounding of observational data mentioned in the comment, the Panel focused its literature search on intervention studies and prospective observational studies in healthy subjects. The Panel acknowledged on several occasions in the Scientific Opinion (e.g. Section ) that, in observational studies, positive, inverse, or lack of associations between 25(OH)D concentrations and musculoskeletal health outcomes might be biased because of 14 EFSA Supporting publication 2016:EN-1078

15 uncertainties in the methodology for measuring serum 25(OH)D concentrations, or confounded by factors that have not been properly addressed. The Panel considered that no change to the Scientific Opinion was needed in relation to this comment. See also Ad23. Osteomalacia Comments received: 22. The Panel conclusion that the risk of vitamin D-deficiency osteomalacia appears to be small with serum 25(OH)D concentrations at or above 50 nmol/l was acknowledged. It was noted that this implies that the risk of osteomalacia may increase below 50 nmol/l, and that this may be equally true below 25 nmol/l. It was pointed out that the study by Priemel et al. (2010) has methodological issues mentioned in the Scientific Opinion in Section and that studies reviewed by SACN were not considered in the final conclusion on serum 25(OH)D concentration related to osteomalacia. It was suggested that a clearer conclusion could include a statement summarizing the small risk of vitamin D-deficiency osteomalacia related to a mean serum 25(OH)D concentration greater than 20 nmol/l, and that one post-mortem study observed a small risk with a mean serum 25(OH)D concentration greater than 50 nmol/l. Panel consideration of comments received: Ad22. For its literature search on musculoskeletal health outcomes, the Panel focused on intervention studies and prospective observational studies on healthy subjects, and cross-sectional studies in the specific case of osteomalacia, and did not consider case reports in patients (Section of the Scientific Opinion). As for other musculoskeletal health outcomes, the Panel has however mentioned the findings on osteomalacia by other systematic reviews and reports in Section of the Scientific Opinion, including the report mentioned in the comment received. Therefore, the Panel considered that no change in this Section was needed in relation to this comment. The Panel considers that the risk of vitamin D-deficiency osteomalacia appears to be small with serum 25(OH)D concentrations at or above 50 nmol/l, notes that mean concentrations were below about 20 nmol/l in patients with osteomalacia (Section ), and that there are not enough data to estimate the risk of osteomalacia between these two concentrations. The summary of conclusions on serum 25(OH)D concentration as an indicator of musculoskeletal health in adults (Section ) was amended to clarify this point: The Panel concludes that, regarding the relationship between serum 25(OH)D concentration and [ ] osteomalacia, overt osteomalacia has been reported in studies on patients at mean serum 25(OH)D concentration below about 20 nmol/l, while there is some evidence that the risk of vitamin D-deficiency osteomalacia is small with serum 25(OH)D concentrations at or above 50 nmol/l. Fracture risk in adults Comments received: 23. With regard to Section of the Scientific Opinion, it was noted that the conclusions on fracture risk in adults appear to have focused on observational studies, which are confounded. It was added that linking the serum 25(OH)D concentrations from observation data to a target concentration is considered flawed, and appears inconsistent with the conclusion of the NNR 2012 that intervention with vitamin D alone is not proven as effective against fractures. 24. For Section of the Scientific Opinion in relation to fracture risk in adults, the Panel was asked if there was any evidence as to the sufficiency of calcium status in the studies included in the meta-analyses used to inform their conclusion. It was pointed out that data on vitamin D 15 EFSA Supporting publication 2016:EN-1078

16 and calcium intake and lowered fracture risk could be considered as a basis to conclude on a DRV for vitamin D for adults with adequate calcium intakes. In addition, for the same Section, it was pointed out that calcium and vitamin D may also have an effect in non-institutionalised older adults; to support this, the results of a subgroup analysis by residential status in the systematic review by Avenell et al. (2014) were mentioned, where a non-significant reduction in hip fractures in the community-dwelling group was pointed out. Panel consideration of comments received: Ad23. With regard to the type of studies considered, the Panel focused its literature search on intervention studies and prospective observational studies in healthy subjects (Section of the Scientific Opinion). While the possible relationship between serum 25(OH)D concentration and health outcomes is discussed in Section 5.1. (in particular Section for fracture risk), data on vitamin D intake and health outcomes are discussed in Section 5.2. (in particular for fracture risk, in particular with data on RCTs). Potential confounding of observational studies is addressed in several sections (e.g. in Sections , or ). The Panel considers, however, that observational studies and in particular long-term prospective observational studies can provide important information and should not be disregarded a priori. The limitations and uncertainties from the available studies are reflected in the conclusion on fracture risk in Section See also Ad21. With regard to NNR 2012, the Panel rephrased the sentence on Lamberg-Allardt et al. (2013) as follows: The overall conclusion in the NNR 2012 is that intervention with vitamin D alone has not been proven effective in preventing fractures in older adults. Moreover, Lamberg-Allardt et al. (2013) concluded that, although a threshold for serum 25(OH)D concentration of 74 nmol/l was considered to show a reduction in total fracture incidence, the variability in analytical methods and the fact that serum 25(OH)D was assayed only in subsamples, made this threshold unreliable. Ad24. For all outcomes discussed in the Scientific Opinion, the Panel took as a starting point the results of the literature search and conclusions from the report by IOM (2011). For its literature search on musculoskeletal health outcomes, the Panel focused on intervention studies and prospective observational studies in healthy subjects published after the IOM report until March 2015 (Section of the Scientific Opinion). The Panel also considered an update of one of the two systematic reviews used by IOM (2011), as well as two recent reports from DRV-setting bodies. The meta-analyses referred to in the comment received are mentioned in the Scientific Opinion in the context of describing the conclusions of these other DRV-setting bodies (Section ). These meta-analyses included studies with or without calcium supplementation, without specific information on calcium status. As indicated previously, as for other nutrients, DRVs for vitamin D are set assuming that intakes of interacting nutrients, such as calcium (EFSA NDA Panel, 2015) (Section 6 of the Scientific Opinion), are adequate (see Ad19.). The meta-analyses referred to in the comment received included studies on institutionalised as well as non-institutionalised (i.e. free-living) subjects (Section ), while the Panel, in view of setting DRVs for vitamin D for healthy adults, focused in its literature search on free-living adults (as indicated, for example, in the introduction of Section and ). It is also explained in Section that the evidence from available studies does not indicate that vitamin D supplementation up to 20 µg/day has a significant positive effect on fracture risk in community-dwelling adults with adequate calcium intakes. Taking into consideration the comments received, the Panel added the following sentence in Section : The systematic review by Avenell et al. (2014) included a subgroup analysis on community-dwelling subjects receiving vitamin D plus calcium (versus placebo or no treatment), 16 EFSA Supporting publication 2016:EN-1078

17 indicating that hip fracture incidence was not significantly reduced with vitamin D supplementation of 10 to 20 µg/day. In addition, the Summary of the Opinion and the introduction of Section 5.2. were modified to clarify that, for adults, the Panel focused its literature search on free-living adults. Calcium absorption Comments received: 25. It was noted that calcium absorption in adults is not compromised below the target serum 25(OH)D concentration of 50 nmol/l, but rather at 25(OH)D < 10 nmol/l. Panel consideration of comments received: Ad25. This is already stated in the Scientific Opinion, in Section on calcium absorption. The Panel considered that no change in the Scientific Opinion was needed in relation to this comment. Muscle strength Comments received: 26. The Panel was invited to view a recently published RCT on vitamin D and muscle strength and physical performance (Todd et al., 2016). It was noted that this study also provides new data on the supplementation during winter months of vitamin D using an oral spray presented as bypassing intestinal absorption. In another comment welcoming the recommendation for further research on musculoskeletalrelated health outcomes, the Panel was invited to consider a recently published paper that supports a role for vitamin D in the muscle function of adolescents (Carson et al., 2015). Panel consideration of comments received: Ad26. For its literature search related to musculoskeletal health outcomes, the Panel considered pertinent primary studies (intervention and prospective observational studies), i.e. excluding for example cross-sectional studies (except for osteomalacia), published from 2010 (after the IOM report) onwards until March 2015 (Section of the Scientific Opinion). The Summary of the Opinion was modified to clarify this point. The paper by Carson et al. (2015) cited in the comment received was on a cross-sectional study, thus not corresponding to the selection criteria of the literature search. The Panel, however, added to the Scientific Opinion a reference on BMD, falls and muscle strength that matched the selection criteria and time frame of this search (Uusi-Rasi et al., 2015). The other paper cited in the comments received was published in March 2016 (Todd et al., 2016). This paper was about a randomised placebo-controlled trial in 42 footballers, 22 and 50% of them with serum 25(OH)D concentration below 30 and in the range nmol/l, respectively. This RCT investigated the effect of 75 µg/day vitamin D 3 supplementation via an oral spray solution compared with placebo, for twelve weeks, on the maximal volume of oxygen utilised (primary outcome) and skeletal muscle function and physical performance (left and right handgrip strength and vertical jump test) and lung function. There was no correlation between total 25(OH)D concentration and measures of muscle function and physical performance at either time point. Vitamin D supplementation did not increase significantly vertical jump height or handgrip strength compared to placebo. The Panel considers that this study does not provide data that would change the Panel s conclusion regarding vitamin D intake or status and muscle strength/function and physical performance. The Panel considered that no change in the Scientific Opinion was needed in relation to these two references (Carson et al., 2015; Todd et al., 2016) EFSA Supporting publication 2016:EN-1078

18 Infants and children Comments received: 27. For Sections and , it was pointed out that IOM (2011) had concluded that risk of rickets was minimal when serum 25(OH)D concentration ranges between 30 and 50 nmol/l. It was therefore suggested that the Panel conclusion that there is no risk of vitamin D-deficiency rickets with serum 25(OH)D concentrations at or above 50 nmol/l and adequate calcium intake serum seems too strong. 28. For Section , it was stated that the range of serum 25(OH)D concentrations required for optimal BMD/BMC, rickets prevention and optimal calcium absorption ranges from 30 to 60 nmol/l in children. It was therefore suggested to emphasize the uncertainty in selecting a target value for serum 25(OH)D concentration in children in comparison to adults. Panel consideration of comments received: Ad27. The conclusion by IOM (2011) is already mentioned in Section of the Scientific Opinion. The Panel considered that no change in Section was needed in relation to this comment. However, in Section on Summary of conclusions on serum 25(OH)D concentration as indicator of musculoskeletal health in infants and children, the statement on rickets was rephrased as follows: In spite of the large variation in the results [ ], the Panel concludes that, regarding the relationship between serum 25(OH)D concentration and [ ] rickets, there is evidence of overt rickets at mean serum 25(OH)D concentrations below 30 nmol/l with adequate calcium intake, but no risk of vitamin D-deficiency rickets with serum 25(OH)D concentrations at or above 50 nmol/l and adequate calcium intake. Ad28. In the summary of conclusions on serum 25(OH)D concentration as an indicator of musculoskeletal health in infants and children (Section ), the Panel concluded that, regarding the relationship between serum 25(OH)D concentration and BMD/BMC in infants and children, there is some evidence that increasing mean serum 25(OH)D from about nmol/l to higher values is not associated with further benefit on BMC/BMD. The statement on rickets in this Section was modified as indicated above (see Ad27.). Also, the Panel does not refer to optimal calcium absorption for children but rather concludes that there is no relationship between fractional calcium absorption in children and serum 25(OH)D concentration above about nmol/l. This is in line with the further conclusion that the Panel considers that the evidence on associations between serum 25(OH)D and musculoskeletal health outcomes is not adequate to set a different target value for serum 25(OH)D concentration in children compared to adults. The limitations of these data have been described (Sections , and to ). The Panel considered that no change in the Scientific Opinion was needed in relation to this comment Non-musculoskeletal health outcomes Comments received: 29. It was stated that there are many studies that confirm the link between vitamin D, PTH and autoimmune diseases. It was repeatedly stated that oral vitamin D reduces a wide range of conditions including various cancers (e.g. breast, colon, kidney, pancreatic), coronary heart disease, hypertension, diabetes, osteoporosis and bone fractures, as well as stimulates general immunity. It was also stated that vitamin D supplementation at higher doses reduces inflammation, dermatitis, allergies, chronic sinusitis, common colds, influenza and human parainfluenza viruses occurrence in individuals. It was noted that although early vitamin D work focused on musculoskeletal health, it has become apparent that vitamin D impacts many other aspects of health, regulating approximately 300 genes and affecting virtually all body tissues. It was added that observational and intervention studies have shown that vitamin D affects heart and vascular, brain and nervous tissue, eye, skin and gastro-intestinal tract health, as well as the immune system EFSA Supporting publication 2016:EN-1078

19 It was stated that non-musculoskeletal health outcomes were not adequately addressed in the Scientific Opinion (in particular in Section ). The following references were suggested for cancer (Garland et al., 2009; Lin et al., 2015; McDonnell et al., 2016), multiple sclerosis or neuroprotection (Sundstrom and Salzer, 2015; Mowry et al., 2016), respiratory health (Zittermann et al., 2016), immune health (Zhang et al., 2013; Azizieh et al., 2016) and cardiovascular health (Perez-Hernandez et al., 2016). A link from a website of an interested organization was suggested, as well as the following reference (Coimbra and Junqueira, 2003). The Panel was also asked to refer to the systematic review by Autier et al. (2014) on the nonmusculoskeletal benefits of vitamin D. Panel consideration of comments received: Ad29. The Panel is aware of the relationship between vitamin D and PTH. In Section of the Scientific Opinion, it is discussed why PTH cannot be used as a biomarker of vitamin D intake or status. In Section of the Scientific Opinion, the Panel reviewed the data on vitamin D status or vitamin D intake in relation to risk of/changes in non-musculoskeletal health outcomes available in systematic reviews and reports, in particular by IOM (2011) (that, for outcomes other than bone health, was based on the large systematic review of intervention and observational studies by Chung et al. (2009)), Newberry et al. (2014) (that is an update of Chung et al. (2009)) and SACN (2016) (see also Ad6.). The Panel came to the same conclusion, i.e. that at present the available evidence on these non-musculoskeletal health outcomes is insufficient to be used as criteria for setting DRVs for vitamin D. The data in the comment received comprise a website, a reference on riboflavin, a number of references of various nature including an open letter, RCTs (including some trials with subjects receiving atorvastatin or vitamin D in doses above the UL), a cross-sectional study on serum 25(OH)D concentration and factors (e.g. C-reactive protein, proinflammatory and antiinflammatory cytokines) that are not specific to the effect of vitamin D in the body, narrative reviews, and a systematic review of two cohort and seven nested case control studies. Taking into account one comment received, a reference to the large systematic review of prospective cohort studies (290) and randomised trials (172) by Autier et al. (2014) was added to Section of the Scientific Opinion, as follows: The Panel also noted the systematic review of prospective cohort studies and randomised trials by Autier et al. (2014) whose conclusions are in line with those from IOM (2011), Newberry et al. (2014) and SACN (2016), in that many prospective studies have shown associations between low 25(OH)D concentrations and a wide range of health disorders, but that a similar number of RCTs did not provide evidence for a causal relationship between serum 25(OH)D concentrations and the occurrence or the course of such disorders Setting of DRVs for vitamin D Target serum 25(OH)D concentration, musculoskeletal health outcomes and vitamin D intake Comments received: 30. The Panel was asked to consider a serum 25(OH)D concentration of at least 75 nmol/l (30 ng/ml) as a suitable target for musculoskeletal health outcomes. It was stated that this target was as recommended by the US Endocrine Society (Holick et al., 2011), the International Osteoporosis Foundation (Dawson-Hughes et al., 2010), the Canadian Osteoporosis Society (Hanley et al., 2010b; Hanley et al., 2010a) and a number of other papers (Bischoff-Ferrari et al., 2005; Bischoff-Ferrari et al., 2009a; Souberbielle et al., 2010). It was added that the authors of these references recommended μg/day supplemental vitamin D. In another comment, it was pointed out that in the meta-analyses by Bischoff-Ferrari et al. (2005; 2009a) a serum 25(OH)D concentration of 75 nmol/l (30 ng/ml) was associated with a 19 EFSA Supporting publication 2016:EN-1078

20 reduced risk of fractures, and that supplementation with μg/day vitamin D 3 was required to reach this concentration in individuals aged 60 years or more. Higher supplementation doses in relation to this target 25(OH)D concentration in all adults or older adults have been proposed (Dawson-Hughes et al., 2010; Holick et al., 2011). 31. It was stated that the target serum 25(OH)D concentration should be nmol/l (40-60 ng/ml), and links to the websites of interested organisations were given as support. In another comment, it was stated that experienced clinicians recognise that supplemental vitamin D of μg are required for optimal vitamin D status defined as nmol/l. In another comment, the range of serum 25(OH)D concentration of nmol/l was considered as normal. In another comment, support was expressed for the target of 50 nmol/l proposed by the Panel. The Panel was repeatedly asked to consider the reference ranges of an interested organisation for serum 25(OH)D concentration: deficient nmol/l (0 40 ng/ml), sufficient nmol/l (40 80 ng/ml), high-normal nmol/l ( ng/ml), undesirable > 250 nmol/l (> 100 ng/ml), toxic > 375 nmol/l (> 150 ng/ml). It was stated repeatedly that the serum 25(OH)D concentration of 50 nmol/l is not a sufficient target as based only on musculoskeletal health outcomes, and that 125 nmol/l (50 ng/l) should be used instead. A position statement was also indicated as supportive (a link to a website was provided, which contained the text of the reference by Pludowski et al. (2013), see also question 35). It was stated that, above a serum 25(OH)D concentration of 50 nmol/l, vitamin D had benefits for a wide range of diseases. In support of the reference ranges of an interested organisation mentioned above, the following reasons were given: a. It was stated that the human genome was selected with abundance of vitamin D, and that humans evolved near the equator with the ability for considerable cutaneous vitamin D synthesis. It was further stated that lifeguards, equatorial farmers and huntergatherers maintain blood concentrations of nmol/l (40 80 ng/ml) (Haddad and Chyu, 1971; Vieth, 2005; Luxwolda et al., 2012). b. Maternal breast milk 25(OH)D concentration of 45 ng/ml or greater has been shown to prevent rickets in offspring and should be considered as a biomarker for optimal vitamin D status (Wagner et al., 2006). c. Maximal suppression of PTH at 100 nmol/l (40 ng/ml) or higher should be considered as a biomarker for optimal vitamin D status (Vieth et al., 2003; Vieth, 2005). d. It was stated that the UL should be set at a concentration of 250 nmol/l (100 ng/ml) as cutaneous synthesis of vitamin D alone has not been shown to achieve higher concentrations (Vieth, 2005). In addition, no studies have shown any beneficial effect at concentrations above 100 ng/ml. It was stated that vitamin D toxicity manifests as hypercalciuria and hypercalcemia and that serum calcium levels are not related to 25(OH)D concentrations of nmol/l (257 ng/ml) or below (Bischoff-Ferrari et al., 2010). It was added that cases of toxicity have been reported at a 25(OH)D concentration of 485 nmol/l (194 ng/ml) (Jacobsen et al., 2011) and therefore a conservative threshold of 375 nmol/l (150 ng/ml) should be considered as the lower limit of toxicity. In another comment, it was stated that the target of a serum 25(OH)D concentration of 50 nmol/l proposed by the Panel does not provide a safety margin, and that there is a risk that a large portion of the population will have insufficient vitamin D status. Further to this, it was noted that vitamin D insufficiency, defined as less than 50 nmol/l, is common in Europe (Hilger et al., 2013) due to insufficient sunlight for cutaneous production in the winter months and a limited dietary intake of marine fish and fish liver oil. It was therefore suggested that the Panel consider a target of a serum 25(OH)D concentration of 75 nmol/l as recommended by the International Osteoporosis Society (2010). It was additionally noted that an even higher target of a serum 25(OH)D concentration of 95 nmol/l, which is still below the safety threshold of 250 nmol/l, has also been advocated. To support this concentration of 95 nmol/l, an online news article was mentioned (referred to as Kleuser 2015 in a comment received) EFSA Supporting publication 2016:EN-1078

21 Panel consideration of comments received: Ad30. One of the references cited in the comments received (Souberbielle et al., 2010) provided recommendations for clinical practice in relation to adult patients with or at risk for fractures, falls, cardiovascular or autoimmune diseases and cancer. Recommendations for clinical practice are outside the scope of this Scientific Opinion, which aims to set DRVs for the general healthy population. For its literature search related to musculoskeletal health outcomes, the Panel considered pertinent primary studies (intervention and prospective observational studies) published from 2010 (after the IOM report) onwards until March 2015, as stated in Section (see Ad26.). Several of the papers cited in the comments received are position statements (Dawson-Hughes et al., 2010; Hanley et al., 2010b; Hanley et al., 2010a; Holick et al., 2011). Thus, these references do not match the selection criteria mentioned above. These position statements refer to studies with vitamin D intake higher than the UL and/or already discussed in the report by IOM (2011) whose literature review was used as a starting point by the Panel (Section of the Scientific Opinion). They also refer to serum PTH concentration, for which data showed that it cannot be used as a biomarker of vitamin D intake (as serum PTH is also influenced by, for example, serum calcium and phosphate concentrations and other factors) or vitamin D status (Section of the Scientific Opinion). Some of the position statements also refer to a number of systematic reviews to support their conclusion on the vitamin D intake needed for older adults to reach a serum 25(OH)D concentration of 75 nmol/l (with regard to risk of fractures and falls). The Panel is aware of these systematic reviews, undertaken in a small sample of studies that analysed together ambulatory community-dwelling and institutionalised subjects, while the Panel, in view of setting DRVs for vitamin D for healthy adults, focused its literature search on primary studies on free-living adults (see Ad24.). Also, several individual studies are in common between these meta-analyses and the larger literature review by other meta-analyses/reports (Avenell et al., 2009; IOM, 2011). With regard specifically to the risk of fractures mentioned in a comment received, by taking into consideration the overall evidence, the majority of studies indicate an increased fracture risk associated with 25(OH)D concentrations of < 18 nmol/l to < 50 nmol/l in free-living adults (Section of the Scientific Opinion). Considering several musculoskeletal health outcomes, overall the Panel concluded that a serum 25(OH)D concentration of 50 nmol/l is a suitable target value, in view of setting DRVs for vitamin D for healthy adults (including freeliving older adults), as well as healthy infants, children and pregnant women (Sections and 6. of the Scientific Opinion). The Panel considered that no change in the Scientific Opinion was needed in relation to these comments. Ad31. The Panel selected the criteria for the establishment of vitamin D adequacy in relation to vitamin D status. The Panel was informed by reviewing primary studies on musculoskeletal health outcomes, together with the report by IOM (2011) and other reviews or reports from DRV-setting bodies with regard to musculoskeletal and non-musculoskeletal health outcomes (Section 5.1. of the Scientific Opinion). The Panel concluded that a serum 25(OH)D concentration of 50 nmol/l is a suitable target value for setting DRVs for vitamin D for all age and sex groups. The Panel did not consider establishing reference categories for serum 25(OH)D concentrations such as insufficient/sufficient. Rather, the Panel used the studies identified in Sections 5.1. of the Scientific Opinion to obtain a suitable target value for the criterion chosen (serum 25(OH)D concentration) in relation to the selected musculoskeletal health outcomes. Taking into account the overall evidence and uncertainties, the Panel considered that, for adults, infants and 21 EFSA Supporting publication 2016:EN-1078

22 children, there is evidence for an increased risk of adverse musculoskeletal health outcomes at serum 25(OH)D concentrations below 50 nmol/l, and evidence for an increased risk of adverse pregnancy-related health outcomes below the same concentration. See also Ad29., with regard to non-musculoskeletal health outcomes, and Ad30., with regard to a target 25(OH)D serum concentration different from 50 nmol/l. With regard to point a), the Panel is aware of studies reporting on lifeguards, equatorial farmers and hunter-gatherers having serum 25(OH)D concentrations of nmol/l (Haddad and Chyu, 1971; Vieth, 2005; Luxwolda et al., 2012), but also notes that these studies were not on the relationship between serum 25(OH)D concentration and health outcomes. With regard to point b), the Panel considers that the derivation of a DRV for vitamin D for lactating women based on the compensation of vitamin D secretion in breast milk is not justified, and that the derivation of a DRV for vitamin D for infants in the second half of the first year of life by extrapolation from the vitamin D intake of breast-fed infants is not possible (as explained in further detail in Sections , , 6.2. and 6.5. of the Scientific Opinion). With regard to point c), the Panel considers that serum PTH concentration in healthy subjects is not a biomarker of vitamin D intake nor a useful biomarker of vitamin D status (Section of the Scientific Opinion) (see Ad29.). With regard to point d), the Panel was requested by the EC to derive DRVs (EFSA NDA Panel, 2010a), and it was not in the Terms of Reference of this Scientific Opinion to revise ULs for vitamin D (EFSA NDA Panel, 2012) (see Ad6.). A comment received mentioned an online news article (referred to as Kleuser, 2015 ), which was not from a peer-reviewed journal. With regard to prevalence of serum 25(OH)D concentration below 30 or below 50 nmol/l in Europe discussed in a comment received, the Panel refers to a paper cited in the Scientific Opinion (Section ) that provides data from a re-analysis, using the protocols of the Vitamin D Standardization Program, of serum 25(OH)D concentrations from 14 European studies in children and adult populations (Cashman et al., 2016). The Panel considered that no change in the Scientific Opinion was needed in relation to these comments. Type of DRV and value derived 32. Concern was expressed for the proposed AI of 15 μg/day, and it was suggested that the AI for adults including older adults should be set at 20 μg/day of vitamin D in line with Linseisen et al. (2011). In support of an AI of 20 μg/day, it was stated that this dose has been shown: to decrease risk of musculoskeletal impairment, falls, fractures, and premature death; to achieve a serum 25(OH)D concentration of 50 nmol/l or greater in 90 95% of the population; not to have any noteworthy side effects or risks and to be below the UL (EFSA NDA Panel, 2012); to be in line with approved health claims on vitamin D and musculoskeletal health (EFSA NDA Panel, 2010b, 2011). In another comment, concern was expressed that the AI proposed by the Panel is too low and only reflects a threshold related to musculoskeletal health. Therefore, the Panel was asked to reconsider the value. In other comments, it was stated that, based on the evidence, the serum 25(OH)D concentration of 50 nmol/l and AI of 15 μg seemed too high. It was pointed out that, in Section of the Scientific Opinion, the Panel stated that the setting and analyses of the available studies do not allow a conclusion to be drawn as to whether this concentration should be achieved by about half of or most subjects in the population. It was also pointed out that, in Section 6.1., the Panel states that it used information obtained from characterising the intake-status relationship for vitamin D to derive the vitamin D intake to achieve a target serum 25(OH)D concentration of 50 nmol/l for the 22 EFSA Supporting publication 2016:EN-1078

23 majority of the population. The Panel was asked to give an explanation as to why it selected to target most of the population as opposed to half of the population. It was noted that if the Panel proposed a serum 25(OH)D concentration of 50 nmol/l that needs to be achieved by half of the population, the AI would be 10 μg/day for adults. The same comments were given in relation to the setting of an AI at 10 µg/day (instead of 15 µg/day) for children in Section 6.3., with the additional remark that there is considerable uncertainty in the data supporting a target of 50 nmol/l serum 25(OH)D concentration (Section ). 33. The Panel was asked to demonstrate the scientific basis for the statement, repeated, for example, in Section 6 and Conclusions of the Scientific Opinion, that in the presence of endogenous cutaneous vitamin D synthesis, the requirement for dietary vitamin D is lower or may even be zero. In addition, given the range of latitudes in Europe, it was asked that the Panel either provides a quantitative indication of the amount of sunlight exposure necessary for endogenous cutaneous production of vitamin D to a level at which no dietary vitamin D would be necessary (or how much the requirement would be reduced in relation to sunlight), or states that such a quantitative relationship cannot be established. It was also added that, although younger adults may be expected to have greater cutaneous synthesis than older adults, this is not always the case, mainly due to seasonal, cultural, religious or lifestyle reasons. The Panel was also asked to give advice on how to apply an AI that expects no UV-B induced cutaneous synthesis. Support was expressed for the Panel consideration that ARs and PRIs cannot be derived for adults, infants and children, and that AIs are defined for all population groups. However, in another comment, it was pointed out that there are serious long-term impacts for public health by adopting an AI, considered in the comment as a technically inferior indicator with limited usefulness in the public health context. The AR is a superior indicator for evaluating adequacy of intakes in population groups, which is a core application of the DRV framework. The AI should only be used in the absence of adequate data, and the commenter advocates that such adequate data exist (i.e. individual data from RCTs, see question 48). 34. The interaction between vitamin D, and, for example, calcium or vitamin A with regard to bone health was highlighted, and the importance of the Panel s specification that DRVs for vitamins are set assuming that intakes of interacting nutrients, such as calcium, are adequate was underlined. Panel consideration of comments received: Ad32. The overview of DRVs and recommendations set by other bodies (including the Germanspeaking countries referred to in one comment) is given in Section 4. The Panel also underlines that its literature search covers a period up to March 2015, i.e. after the date of publication of the reference mentioned in one comment. See also Ad36., with reference to health claims. Most evidence on the relationship between serum 25(OH)D concentration and health outcomes is related to musculoskeletal health outcomes (Section 5.1.) (although data on nonmusculoskeletal health outcomes have also been assessed by the Panel). The evidence from intervention and prospective observational studies on a possible threshold value for serum 25(OH)D concentration with regard to adverse musculoskeletal or pregnancyrelated health outcomes, that may be used to inform the setting of DRVs for vitamin D, shows a wide variability of results (Sections to ). Some RCTs discussed in the Scientific Opinion report that vitamin D supplementation (with or without calcium) that led to an increase in mean 25(OH)D concentration between baseline and end of intervention was associated with, for example, a significantly higher increase in BMD compared to the control group. Others did not report such results. Some observational studies reported an increased risk below a certain serum 25(OH)D concentration in analyses by, for example, quartiles, quintiles, or based on a pre-defined cut-off, and others did not report such a result EFSA Supporting publication 2016:EN-1078

24 Several factors contribute to this wide variability of results, as discussed in the Scientific Opinion, e.g.: heterogeneity of study designs, populations and skeletal sites investigated, confounding by a variety of factors (e.g. PTH, genetic factors, sex steroids, body composition, age, sex, calcium intake, life-style factors, baseline values, season of assessment, and possible other yet unknown factors), large variation in the results from different laboratories and assays used for measuring serum 25(OH)D concentrations. Furthermore, observational studies mostly used single measurements of 25(OH)D concentration, thus possible long-term changes in 25(OH)D concentration were not considered in the analyses of the relationship with health outcomes. Taking into account the overall evidence and uncertainties (summarised above) for healthy infants, children and free-living adults, the Panel considers that there is sufficient evidence for an increased risk of adverse musculoskeletal health outcomes at 25(OH)D concentrations below 50 nmol/l. Taking into account the overall evidence and uncertainties for pregnancy, the Panel considers that there is also evidence for an increased risk of adverse pregnancy-related health outcomes at serum 25(OH)D concentrations below 50 nmol/l. After careful consideration of the available evidence, the Panel concludes that this concentration can be used as a target value to derive a DRV for vitamin D intake for adults, infants, children and pregnant and lactating women. In relation to the wide variability of results and the uncertainties/limitations (summarised above), the setting and analyses of the available studies do not allow a conclusion to be drawn as to whether this concentration should be achieved by about half of or most subjects in the population. With regard to the mention, in a comment received, of the effect of vitamin D supplementation dose on a number of health outcomes, the Panel concluded that data on vitamin D intake (mostly as supplements) and some musculoskeletal health outcomes in children and free-living adults, in pregnancy and in lactation are not useful as such for setting DRVs for vitamin D, for a number of limitations described in Section In this Section, the Panel concluded that these data may only be used to support the outcome of the characterisation of the vitamin D intakestatus relationship undertaken by the Panel under conditions of assumed minimal endogenous vitamin D synthesis. With regard to the dose response intake-status relationship (Sections and 6 of the Scientific Opinion and related Appendices) mentioned in a comment received, the Panel supports the use of the 95% prediction interval (and not only the 95% confidence interval) in the context of the meta-regression analysis. The confidence interval illustrates the uncertainty about the position of the regression line (across-study conditional means) while the prediction interval illustrates the uncertainty about the true mean effect that would be predicted in a future study. The 95% prediction interval constitutes an approximation of the interval that would include 95% of all individual responses from the populations of interest. The extent of this approximation could not be quantified at that stage 5 (see Section 6.1. for further detail). In the adjusted model proposed by the Panel, the total intake estimated to achieve a serum 25(OH)D concentration of 50 nmol/l, as identified by the lower limit of the 95% prediction interval, is 16.1 µg/day; equally, at a vitamin D intake of 15 µg/day, the predicted 25(OH)D value at the lower limit of the 95% prediction interval is 49 nmol/l. The Panel thus sets an AI for vitamin D for adults at 15 µg/day, considering that, at this intake, the majority of the adult population (without possible further quantification) will achieve the target serum 25(OH)D concentration near or above 50 nmol/l. A precautionary approach was taken that the target value should be reached by the majority of the population. This precautionary approach was supported by the fact that, in the unadjusted model, which can be 5 Preliminary results of simulations, based on an assumption of normal (Gaussian) distribution of serum 25(OH)D concentration applied as a first simplified exploratory approach, suggest that about 15% of individuals might be outside the lower and upper limits of the 95% prediction interval of the unadjusted model of the meta-regression. However, these are very preliminary results that need to be confirmed, also testing different assumptions of the distribution of serum 25(OH)D concentration in the European population (e.g. Cashman et al. 2016) EFSA Supporting publication 2016:EN-1078

25 also taken into account as it encompasses the whole heterogeneity across trials, at a vitamin D intake of 15 µg/day, the predicted value at the lower limit of the 95% PI is 34 nmol/l. This concentration is above those that have been observed in relation to overt adverse health outcomes. The same AI of 15 µg/day was set for children aged 1 17 years, as the meta-regression analysis was undertaken on data on adults and children, and the stratified analysis on the few data on children (nine arms from four trials), of which the limitations have been described in the Scientific Opinion, did not show contradictory results. This meta-regression analysis was done by the Panel on data collected under conditions of assumed minimal cutaneous vitamin D synthesis. With regard to the type of DRV set, the Panel considered that the available data do not allow the setting of ARs and PRIs (Section 6. of the Scientific Opinion). This is based on the uncertainties/limitations summarised above and described in detail in Section 5.1. (serum 25(OH)D concentration and health outcomes), Section (vitamin D intake and health outcomes) and Section (characterisation of the intake-status relationship). An AI, as proposed by the Panel for vitamin D, is estimated when a PRI cannot be established because an average requirement (AR) cannot be determined (EFSA NDA Panel, 2010a). This previous Scientific Opinion explains that an AI can be derived from the average (median) daily level of intake based on observed intakes in a group (or groups) of apparently healthy people, and that is assumed to be adequate. An AI can also be derived from a level of intake based on experimentally determined approximations or estimates of nutrient intake, by a group (or groups) of apparently healthy people, that is assumed to be adequate. This previous Opinion also explains that the practical implication of an AI is similar to that of a PRI, i.e. to describe the level of intake that is considered adequate for health reasons and that the terminological distinction relates to the different way in which these values are derived and to the resultant difference in the firmness of the basis for this value. In view of these definitions and characteristics, the Panel considered that the setting of an AI was more appropriate than a PRI in the case of vitamin D. The Panel considered that no change in the Scientific Opinion was needed in relation to these comments. Ad33. The Panel set AIs for vitamin D based on a meta-regression analysis done on data collected under conditions of assumed minimal endogenous vitamin D synthesis. In the presence of endogenous cutaneous vitamin D synthesis, which may depend on many factors (e.g. latitude, season, ozone layer, clouds, surface type such as snow, time spent outdoors, sunscreen, clothing, skin type, age, see Section ), the requirement for dietary vitamin D is lower and may even be zero. The aim of this Scientific Opinion is to set DRVs for vitamin D for the general healthy population at various age groups. The derivation of reference values for specific population subgroups (in relation to, for example, the influencing factors mentioned above) is considered by the Panel to be a risk management decision. The quantification of the amount of sunlight exposure, necessary for endogenous cutaneous production of vitamin D to a level at which no dietary vitamin D would be necessary at the population level, is outside the Terms of Reference of this Scientific Opinion. The Panel agrees that the setting of an AR and a PRI provide more certainty for the various applications and technical uses of such values, as described in detail in Section 6. of a previous Scientific Opinion, in particular with regard to the assessment of the risk of inadequacy of nutrient intake in populations and in individuals (EFSA NDA Panel, 2010a). However, in the case of vitamin D, the available data do not allow the setting of ARs and PRIs (Sections 5.1.6, , and 6. of the Scientific Opinion, See Ad32). Discussion of applications of DRVs for vitamin D was not within the scope of this Scientific Opinion, and decisions on this issue are under the responsibility of the EU risk managers (i.e. the EC together with Member States). The Panel considered that no change in the Scientific Opinion was needed in relation to this comment. See also Ad48., with regard to the use of individual data from RCTs EFSA Supporting publication 2016:EN-1078

26 Ad34. The Panel considers that this comment does not contradict Section of the Scientific Opinion, which outlines the metabolic links between vitamin D and other nutrients, e.g. calcium, phosphorus, potassium, vitamin A and vitamin K. The introduction of Section 6. indicates that, as for other nutrients, DRVs for vitamin D are set assuming that intakes of interacting nutrients, such as calcium (EFSA NDA Panel, 2015) (Section ), are adequate. The Panel considered that no change in the Scientific Opinion was needed in relation to this comment. Other proposed DRVs or recommendations 35. It was noted that guidelines indicating higher requirements in infants, children and adults, including pregnant and lactating women and older adults, have been published in Central Europe and Belgium (Pludowski et al., 2013; Conseil Supérieur de la Santé, 2015). Consequently, the Panel was asked to reconsider the proposed DRVs. Panel consideration of comments received: Ad35. The reference by Pludowski et al. (2013) mentioned in the comment is a position statement that considered several health outcomes, including non-musculoskeletal health outcomes (i.e. breast and colorectal cancer, cardiovascular disease, diabetes, cognitive impairment/decline, hip fracture, mortality, respiratory infections), to recommend a serum 25(OH)D above 75 nmol/l (see Ad31.) and formulate recommendations for the level and period of vitamin D supplementation. The conclusions on non-musculoskeletal health outcomes in this position statement are in contrast with other large systematic reviews and reports (IOM, 2011; Newberry et al., 2014; SACN, 2016) (Section of the Scientific Opinion). In addition, the formulation of recommendations for level and period of vitamin D supplementation is a different purpose than that of this Scientific Opinion, which was the setting of DRVs for vitamin D. The other reference mentioned in the comment received (Conseil Supérieur de la Santé, 2015) explains that the values set for vitamin D in this reference refer to dietary supplementation independently of the amount provided by the diet, and with regard to public health considerations and local characteristics in Belgium (e.g. frequent low vitamin D status of pregnant women in this country, low exposure to the sun, low frequency of food fortified with vitamin D, cases of tetany observed the whole year in the country, for example in older adults in nursing homes). The Panel notes that this reference seems in agreement with the Panel s conclusion regarding the interpretation of serum 25(OH)D concentration above 50 nmol/l. The Panel considered that no change in the Scientific Opinion was needed in relation to these comments. DRV for older adults 36. The Panel was asked to consider a DRV for vitamin D of at least 20 μg/day for older adults (defined as aged 50 years and older, 60 years and older or 65 years and older, depending on the comments) to prevent falls and fractures. It was also mentioned that there is an age-dependent decrease in the endogenous synthesis of vitamin D, frequently exacerbated by reduced mobility and thus reduced sun exposure. It was stated that it is not clear how much vitamin D is needed to reach the 75 nmol/l threshold presented in the comment as needed for an effective fall and fracture prevention (Bischoff-Ferrari et al., 2010), but it was suggested that this threshold may be reached in 93% of older adults with a daily vitamin D intake of 50 µg/day (Bischoff-Ferrari et al., 2009b). It was stated that RCTs show that oral vitamin D supplementation reduces both falls and non-vertebral fractures, including hip fractures, and that µg/day vitamin D (700-1,000 IU/day) are required to assure both fall and fracture prevention in older adults (Bischoff-Ferrari et al., 2009b; Bischoff- Ferrari et al., 2009a). For optimal fall and fracture reduction, a serum 25(OH)D concentration of at least 75 nmol/l is required (Bischoff-Ferrari et al., 2010). This threshold may be reached with 20 to 25 µg/day (800 to 1,000 IU) vitamin D in 50% of adults, whereas higher doses of vitamin D would be required to shift all adults to this threshold EFSA Supporting publication 2016:EN-1078

27 The following references were given to support these comments: (Bischoff-Ferrari et al., 2005; Bischoff-Ferrari et al., 2009b; Bischoff-Ferrari et al., 2009a; Bischoff-Ferrari et al., 2010; Dawson-Hughes et al., 2010; Hanley et al., 2010a; Holick et al., 2011; Federal Commission for Nutrition, 2012; Dachverband Osteologie e V, 2014; Cashman, 2015). In addition, although there is no reduction in the absorption of vitamin D with age, it was noted that the authorized health claims, which target women aged 50 years and older and adults aged 60 years and older, correspond to 20 μg/day vitamin D (EFSA NDA Panel, 2010b, 2011) (see question 32). The Panel was therefore asked to consider setting a separate AI of 20 μg/day for older adults. Panel consideration of comments received: Ad36. For all outcomes discussed in the Scientific Opinion, the Panel took a starting point in the results of the literature search and conclusions from the report by IOM (2011). For its literature search on musculoskeletal health outcomes, the Panel focused on intervention studies and prospective observational studies in healthy subjects published after the IOM report until March 2015 (Section of the Scientific Opinion). The Panel also considered an update by Newberry et al. (2014) of one of the two systematic reviews used by IOM (2011), as well as two recent reports from DRV-setting bodies. DRVs are set for the general healthy population (EFSA NDA Panel, 2010a). Thus, in its literature search, with regard to data on adults, the Panel focused on free-living adults. The Panel is aware that older adults in institutions may be at higher risk of having an inadequate vitamin D status, possibly because of reduced mobility and reduced sun exposure. The assessment as to whether older adults living in institutions such as geriatric wards, special care or nursing homes may require higher vitamin D intakes possibly due to comorbidities or diseases, is considered by the Panel as outside the scope of this Scientific Opinion. The majority of studies published until 2015 and reviewed in this Scientific Opinion indicate an increased fracture risk associated with serum 25(OH)D concentrations of < 18 nmol/l to < 50 nmol/l in free-living adults (Section ). Available evidence also does not indicate that, in community-dwelling adults with adequate calcium intakes, vitamin D supplementation up to 20 μg/day has a significant positive effect on fracture risk (Section ). With regard to falls, the Panel concluded that no target value for serum 25(OH)D concentration can be derived (Section ). Although the Panel acknowledges that there is some evidence for an effect on the risk of falls with daily μg vitamin D supplementation in community-dwelling older adults, the results among studies in older adults are inconsistent and considered insufficient for the setting of DRVs for vitamin D (Section ). For a number of limitations described in Section , the Panel concluded that data on vitamin D intake (mostly as supplements, with or without calcium) and some musculoskeletal health outcomes in children and free-living adults, in pregnancy and in lactation 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. The Panel set AIs for vitamin D based on a meta-regression done on data collected under conditions of assumed minimal endogenous vitamin D synthesis (Section 6.). The Panel decided not to set specific AIs for younger or older adults, because there was no evidence of a significant difference in absorption capacity of vitamin D between younger and older healthy adults (Section 2), and because the majority of the studies used to set the target value for 25(OH)D concentration were carried out in older free-living healthy adults (Section 5.). For the reference by Cashman (2015) mentioned in the comment received, see Ad48. on the use of individual RCTs or a meta-regression approach. One of the health claims mentioned in the comments received refers to the cause and effect relationship between the intake of calcium (either alone or with vitamin D), and reducing the loss of BMD, which may contribute to a reduction in the risk of bone fracture. The Scientific Opinion on another health claim on vitamin D (with calcium, compared to calcium alone) and the reduction in the risk of falling indicates that the available data do not provide information about the lowest effective dose of vitamin D needed to obtain the claimed effect. The Panel also wishes to clarify that the 27 EFSA Supporting publication 2016:EN-1078

28 scientific substantiation of claims is not linked to the concept of DRVs (EFSA NDA Panel, 2016b). Finally, the Panel is aware of the systematic reviews on fall or fracture risk cited among the references mentioned in the comment received, undertaken in a small sample of studies that analysed together ambulatory community-dwelling and institutionalised subjects, while the Panel, in view of setting DRVs for vitamin D for healthy adults, focused in its literature search on primary studies on free-living adults (see Ad24.). Also, several individual studies are in common between these meta-analyses and the larger literature review by other metaanalyses/reports, in particular the report by IOM (2011). See also Ad30. The Panel considered that no change in the Scientific Opinion was needed in relation to these comments. DRVs for infants and children 37. In relation to the AI for infants, it was noted that the four studies used by the Panel (Ala- Houhala et al., 1986; Holmlund-Suila et al., 2012; Atas et al., 2013; Gallo et al., 2013) were mostly on breastfed infants and do not accurately reflect the typical intake of infants aged 7 11 months. It was added that the vitamin D sources for this age group are usually from fortified formula, supplements and complementary foods as infants are usually only partly breastfed. In another comment, higher DRVs for children were mentioned (see question 35.). In another comment, support for the DRVs proposed by the Panel for infants and children was expressed. Panel consideration of comments received: Ad37. There are few data, mostly in breastfed infants, on the relationship between 25(OH)D concentration or vitamin D intake and musculoskeletal health outcomes available in infants (Sections , and 6.2. and Appendix B of the Scientific Opinion). There is also a lack of data on vitamin D and musculoskeletal health outcomes in infants fed infant or follow-on formulas. The data on vitamin D intake and status in infants in situations of assumed minimal endogenous vitamin D synthesis were too limited (two studies) for a dose-response analysis. This lack of data is acknowledged in the Scientific Opinion. However, in line with IOM (2011) which based its conclusion on a number of studies (Section 4.2. and Appendix B of the Scientific Opinion), the Panel noted, in view of setting a DRV for vitamin D for infants aged 7 11 months, that supplementation with 10 µg/day vitamin D in (mostly) breastfed infants was sufficient to reach a plasma/serum 25(OH)D concentration of at least 50 nmol/l in almost all subjects in the four studies mentioned in the comment received. The Panel considered that no change in the Scientific Opinion was needed in relation to this comment. See also Ad35., as well as Ad54., for an additional recommendation for research. DRVs for pregnant or lactating women 38. The AI for pregnant women was questioned. It was stated that the DRV for pregnant and lactating women should be at least 20 μg/day (see question 35). The Panel was also referred to a multicentre double-blind, randomised, placebo-controlled trial with pregnant women receiving either 25 µg/day of vitamin D or placebo, in which only 83% of those receiving supplementation achieved a serum 25(OH)D concentration of 50 nmol/l (Cooper et al., 2016). Panel consideration of comments received: Ad38. For its literature search related to health outcomes in pregnancy, the Panel considered pertinent primary studies (intervention and prospective observational studies), published from 2010 (after the IOM report) onwards until March 2015, as stated in Section (see Ad24.). In the multi-center double-blind randomised placebo-controlled trial referred to in the comment received (Cooper et al., 2016), 569 pregnant women (with serum 25(OH)D concentration at weeks gestation in the range nmol/l) were randomised to either 25 µg/day or placebo from 14 weeks of gestation (or at least before 17 weeks of gestation) and until delivery. Power calculation was undertaken based on neonatal whole-body BMC (assessed within two weeks of birth) as the primary outcome. However, fewer dual-energy X-ray absorptiometry scans of neonates were available compared to the numbers derived from the 28 EFSA Supporting publication 2016:EN-1078

29 power calculation. Mean serum 25(OH)D concentrations of the mothers at baseline were 45.9 (placebo group) and 46.7 (intervention group) nmol/l. The study did not show any significant difference in neonatal whole body BMC (primary outcome) between the two groups. The study also showed that, at 34 weeks of gestation, 64% (placebo group) and 17% (intervention group) of mothers had 25(OH)D concentration below 50 nmol/l, while mean concentrations in each group were 43.3 and 67.8 nmol/l, respectively. This study was published outside the timeframe of the literature search undertaken by the external contractor (Brouwer-Brolsma et al., 2016) that was used as a basis for the characterisation of the intake-status relationship by the Panel (Section ). This characterisation was undertaken on a set of trials after exclusion in particular of the two arms from studies on pregnant women (as this population represents particular physiological conditions and the number of arms was low, Section ). The Panel also considers that the study by Cooper et al. (2016) does not provide data that would change the Panel s conclusion on maternal serum 25(OH)D concentration or vitamin D intake in pregnancy and indicators of bone health in the child at birth. This conclusion was, in particular, that there are no data to suggest a different target value for 25(OH)D concentration for pregnant women compared to non-pregnant women. The Panel considered that no change in the Scientific Opinion was needed in relation to the study by Cooper et al. (2016). However, the Panel added more information in Sections and of the Scientific Opinion on changes in maternal serum 25(OH)D and 1,25(OH) 2 D during pregnancy. See also Ad35. for discussion on other references on pregnancy Vitamin D intake and serum 25(OH)D concentration Meta-regression Comments received: 39. It was acknowledged that serum 25(OH)D measurement is useful to understand metabolism and for monitoring patients in clearly defined cases, however it was argued that too much focus on the relationship between vitamin D intake and serum 25(OH)D concentrations is not advisable. It was added that given the issues around measurement (e.g. lack of international common standard, variability, influence of time of storage, see question 11) of serum 25(OH)D, meta-regression approaches should not be used. Concern was expressed that due to the methodological aspects of vitamin D blood analysis (see question 11) and other issues (e.g. lack of association between the marker and health outcomes, influence of ethnicity), a biomarker-driven approach is not suitable for the setting of DRVs. It was suggested to examine the relationship between vitamin D intake, rather than serum 25(OH)D concentrations, and health outcomes, thus avoiding the variability arising from analysis. It was added that serum 25(OH)D concentration could be used as a marker of compliance or confounding in studies investigating intake and health. 40. It was stated that the Panel, like IOM (2011), appear to be erroneous in their ability to determine the vitamin D intake required to achieve the target serum 25(OH)D concentration in 97.5% of the population. It was pointed out that the statistical error in the IOM s calculation is highlighted in Veugelers et al. (2015). It was added that this analysis determined that a mean intake of 73 μg/day of vitamin D is needed to achieve a serum 25(OH)D concentration of 50 nmol/l in 97.5% of individuals. In addition, contrary to the analysis carried out by the Panel, the analysis showed that mean intake required to reach this threshold increases with increasing body mass index (BMI). It was also stated that there was a statistical error in the calculations of the IOM and a supporting reference was provided (Veugelers and Ekwaru, 2014) EFSA Supporting publication 2016:EN-1078

30 41. It was noted that there is a discrepancy between values in Figure 3 (Section ) and Table 11 (Appendix D.B.) of the Scientific Opinion, the Panel was therefore asked to correct all final status values of the cases for drift in the controls. It was also pointed out that, in Figure 3, the data points are displayed in pairs (initial and final samples), and the Panel was asked to make this clear visually. 42. It was observed that in Figure 3, intakes of 3 5 μg/day corresponded to a serum 25(OH)D concentration between nmol/l. 43. It was suggested to plot the meta-regression model in Figure 3 alongside other models. An example of such a figure is given in Appendix C of this Technical Report, with the models of a number of references, i.e. IOM (2011) and others for which the full citations are not provided. The Panel assumes that these refer to the following references: (Garland et al., 2011; Holick et al., 2011; McKenna and Murray, 2013). 44. It was stated that the linear relationship between vitamin D intake and serum 25(OH)D concentrations was not adequately addressed in the draft opinion. It was added that, although the Panel focused on data during a period of minimal endogenous vitamin D synthesis, serum 25(OH)D concentrations at the start of the period (November) are likely higher than those at the end of the period (March). It was noted that there are no data on long-term storage of vitamin D. 45. It was suggested that the Panel should have investigated the dose-response relationship for target serum 25(OH)D concentrations of 50, 100 and 150 nmol/l. 46. It was stated that, in determining the dose-response relationship, a cut-off of 100 μg/day for total vitamin D intake (from foods and supplements) should not be used (Section 5.3. and Appendices C and D of the Scientific Opinion). It was suggested that the cut-off of 50 μg/day as supplemental dose (i.e. 100 µg/day as total vitamin D intake) was chosen to reflect the UL previously set by the Panel (EFSA NDA Panel, 2012). Dissatisfaction was expressed at the exclusion of data from studies with supplementation doses at or greater than the UL. It was stated that this limitation, and the elimination of the clinical evidence other than on bone/musculoskeletal health that shows the level of supplementation needed for presumably optimum vitamin D status, distort the true nature of the dose-response relationship between vitamin D intake and serum 25(OH)D concentration. In another comment, it was stated that the inclusion in the meta-regression model of studies with high doses of vitamin D, such as about 60 µg/day, in the meta-analysis are not relevant for the setting of DRVs. 47. The Panel was asked to justify the exclusion of studies using interventions with vitamin D 2, such as Ala-Houhala et al. (1988). 48. It was stated that the approach taken by the Panel has resulted in an underestimation of the vitamin D intake necessary to achieve the target of 50 nmol/l for serum 25(OH)D concentration. A comprehensive supporting document was submitted ( 9, Appendix C of this Technical Report). a. The main recommendations are to: - limit the inclusion criteria to studies conducted at latitudes above 50 N, as it was pointed out that there is evidence that cutaneous synthesis is possible in some winter months at latitudes between N. - reconsider including the four high-dose vitamin D supplementation arms in the modeling, on the basis that intakes achieved are outside that normally seen in the 97.5 percentile of European populations (EFSA NDA Panel, 2012). - consider using individual data from available RCTs to calculate reliable estimates of the AR and PRI. It was noted that the authors can make the raw data of these RCTs available. Characteristics of the two approaches (meta EFSA Supporting publication 2016:EN-1078

31 regression or use of individual data) were discussed and compared in detail, also referring to available literature (Riley et al., 2011; Vale et al., 2015). b. It was noted in the supporting documentation that analysis of individual data from six winter-based vitamin D RCTs (n = 854 for the six RCTs, two of them unpublished when the comments were submitted, (Cashman et al., 2008; Cashman et al., 2009; Cashman et al., 2011; Cashman et al., 2014)) at locations greater than 50 N using the same methodology to assess dietary intake and with accredited serum 25(OH)D analysis, as well as ensuring high compliance, showed that dietary requirement estimates based on individual data are at least twice those based on meta-regression in the draft Scientific Opinion, even when adjusted meta-regression models are used. Panel consideration of comments received: Ad39. The Panel considered all the different aspects mentioned in the comments, in particular data on vitamin D intake and health outcomes (Section 5.2. of the Scientific Opinion). The conclusion of the Panel is that, due to a number of limitations described in the Scientific Opinion, these data on vitamin D intake and health outcomes are not useful as such for setting DRVs for vitamin D, but may only be used to support the outcome of the characterisation of the vitamin D intakestatus relationship undertaken under conditions of assumed minimal endogenous vitamin D synthesis (Section 5.2.). The Panel considered data on a possible relationship between serum 25(OH)D concentration and health outcomes (Section 5.1. of the Scientific Opinion) and decided to use a meta-regression approach to characterize the dose-response vitamin D intake/status relationship (Section 5.3.). The Panel discussed the variation in the results of serum 25(OH)D measurement from different laboratories and assays on several occasions in the Scientific Opinion (e.g. Sections and ). The analytical issues of serum 25(OH)D measurement were taken into account in the meta-regression undertaken by the Panel, as study start year (as a proxy to the temporal trends in assay method use) and the assay methods were used as covariates in the adjusted model of the meta-regression analysis (Section of the Scientific Opinion and related Appendices) (see also Ad11.). A number of other factors potentially influencing the doseresponse vitamin D intake/status relationship were investigated (Section and related Appendices), in order to select factors to be included in the final model to characterise the high heterogeneity of results across individual trials. These included ethnicity, as a proxy for skin pigmentation, possible effects of genotypes and some lifestyle habits (Sections and 2.5.) that were usually not reported in the included trials. In particular for ethnicity, the data were missing for almost half of the studies, as this information was not reported in the papers (Appendix C). Thus ethnicity could not be used as a covariate in the adjusted model of the meta-regression analysis proposed by the Panel. The uncertainties in total vitamin D intake estimates used in the meta-regression are also described (Section ). The Panel considered that no change in the Scientific Opinion was needed in relation to this comment. Ad40. The Panel is aware of the publication by Veugelers and Ekwaru (2014) criticising the approach by IOM (2011). The approach described in Section of the Scientific Opinion differs from that followed by IOM (2011), in that the Panel used and interpreted the 95% prediction interval (in addition to the 95% confidence interval). The publication by Veugelers et al. (2015) contains a first analysis of vitamin D supplementation and 25(OH)D in aggregated studies and a second analysis of individual data from a different source. In both analyses, vitamin D supplementation doses much higher than the UL were considered. The first analysis on aggregated data (AD) is based on 36 published studies (summary statistics) and 108 doses, and is characterised by a large range of achieved mean serum 25(OH)D concentrations ( nmol/l), a large range of standard deviations of achieved means ( nmol/l), a large range of vitamin D supplementation doses (0-175 µg/day), and no assumption of minimal endogenous synthesis. The second analysis on individual data yielded the derivation of different vitamin D intake values for normal weight, overweight and 31 EFSA Supporting publication 2016:EN-1078

32 obese subjects mentioned in the comment received. Thus, the publication by Veugelers et al. (2015) describes two statistical approaches that are different from that applied by the Panel to which they cannot be directly compared (see Section and related Appendix C of the Scientific Opinion, for the extensive description of the Panel s approach). The inverse relationship between BMI/body fat and serum 25(OH)D concentrations is discussed in Section of the Scientific Opinion (see Ad53.). Section and related Appendices C and D explain that the role of BMI in the meta-regression was tested and was not included in the final adjusted model as covariate, both because it did not further explain heterogeneity and because of potential ecological fallacy. The discussion on BMI in Section was expanded to clarify this point. In Appendix C of the Scientific Opinion, it is also stated that overweight and obese subgroups from the study populations showed on average higher achieved means when compared to the normal weight group (Appendix D.C, Figure 13) but lower values once adjusted for all other covariates. The Panel considered that no change in the Scientific Opinion was needed in relation to this comment. Ad41. Figure 3 in Section of the Scientific Opinion was not interpreted correctly: circles represent mean achieved 25(OH)D in all included arms, either control or intervention arms. The only pairing that can be identified is related to control and intervention groups that come from the same trial. Mean achieved values are modelled against total vitamin D intake and adjusted in the multivariable approach by mean baseline values. Mean differences were not modelled, although they were meta-analysed, where possible, as a check for result consistency. A legend to Figure 3 (and Figure 19 in Appendix D.F.) was added to facilitate its interpretation (see also Ad42., Ad49. and Ad50.): Circles represent mean achieved 25(OH)D in all included arms, either control or intervention arms. Mean achieved values are modelled against total vitamin D intake and adjusted in the multivariable approach by mean baseline values, latitude, study start year, analytical method for measuring serum 25(OH)D and compliance. The confidence interval (CI) illustrates the uncertainty about the position of the regression line. The prediction interval (PI) illustrates the uncertainty about the true mean effect that would be predicted in a future study. Ad42. This comment derives from reading Figure 3 (Section ). In this Figure, circles represent mean achieved 25(OH)D concentration in serum in all included arms (see Ad41., Ad49. and Ad50.). The Panel considers that it is inappropriate to rely only on a few observed data points (circles), and underlines the need to interpret the meta-regression analysis considering in particular the 95% confidence and prediction intervals (Section of the Scientific Opinion). The Panel considered that no change in this Section was needed in relation to this comment. Ad43. In the comment received, it is proposed to derive conclusions based on a comparison between different dose-response relationships, but it is not explained what the objectives of such a comparison would be. The study by Garland et al. (2011) cited in the comment received provides a statistical analysis using individual data from a cohort (about 3,600 subjects) with self-reported supplemental doses over a large range from zero to above 250 µg/day (10,000 IU/day) vitamin D and use of a blood spot 25(OH)D test kit. The study by McKenna and Murray (2013) cited in the comment received is not a meta-regression, as underlined by the authors themselves. The authors selected studies from reports and systematic reviews (Cranney et al., 2007; Chung et al., 2009; IOM, 2011), with inclusion criteria of daily oral dose of 50 µg/day (2,000 IU/day) vitamin D 2 or D 3, duration of at least three months, and results of both baseline and final 25(OH)D concentration. The expected 25(OH)D concentration in these studies was calculated by the authors based on 1) the equation of the meta-regression by IOM (2011) (curvilinear relationship, using total intake), 2) the equation 32 EFSA Supporting publication 2016:EN-1078

33 obtained considering the individual data and the dose administered in a specific study (curvilinear relationship), 3) the rate constant i.e. a linea relationship as proposed by Holick et al. (2011) (i.e. expected serum 25(OH)D increase by 2.5 nmol/l for each 2.5 µg/day of ingested vitamin D), 4) another rate constant (i.e. 5 nmol/l for each 2.5 µg/day). The studies mentioned in the comment received applied different selection criteria and approaches from those applied by the Panel (Section and related Appendices C and D of the Scientific Opinion for full detail). The Panel considered that no change in the Scientific Opinion was needed in relation to this comment. Ad44. In its meta-regression analysis (Section ), the Panel also considered mean baseline serum 25(OH)D concentration (as a continuous variable) among the covariates included in the adjusted model (see Ad12.). As explained in Section (and related Appendices C and D of the Scientific Opinion), a number of factors potentially influencing the dose-response relationship between vitamin D intake and status were investigated, including also study duration ( three months versus > three months; or three months, versus three to six months versus one to two years), but this parameter was not included in the final adjusted model as covariate, because it did not further explain heterogeneity. The possible shape of the dose-response relationship between vitamin D intake and status (i.e. linear or not) is discussed in Sections and Storage of vitamin D in the body is discussed in Section The Panel considered that no change in the Scientific Opinion was needed in relation to this comment. Ad45. The available evidence does not provide support for a target serum 25(OH)D concentration higher than 50 nmol/l for the general healthy population (see Ad30., Ad31. and Ad36.). The analysis as proposed in the comment received may be of interest in view of revising the ULs, which was not in the Terms of Reference of this Scientific Opinion (see Ad6). The Panel considered that no change in the Scientific Opinion was needed in relation to this comment. Ad46. On the issue of the cut-off applied for total vitamin D intake in the meta-regression analysis (Section of the Scientific Opinion), it is important to note that the mere availability of observations in a specific total intake range is not a sufficient criterion to consider inclusion in the model. The inclusion of the two additional observations at high doses (i.e. 100 µg/day, (Vieth et al., 2001; Forman et al., 2013)) in the model derived by the Panel cannot guarantee the non-distortion of the dose-response relationship, as a sufficient number of points is necessary to adequately characterise the curve in the range of interest. Table 8 (Appendix D.A. of the Scientific Opinion) indicates in particular the few arms (seven) that were excluded as the total vitamin D intake investigated was above the UL (supplemental doses up to 1,250 µg/day), with two of them using a supplemental dose of 100 µg/day (Vieth et al., 2001; Forman et al., 2013). The Panel undertook a sensitivity analysis comparing the full data set of 83 trials used in the meta-regression in the Scientific Opinion with the same data with the addition of the two arms with total vitamin D intake slightly above 100 µg/day. This sensitivity analysis showed no important impact of the exclusion of these two arms on the predicted serum 25(OH)D concentration at selected values of total vitamin D intake or on the estimated vitamin D intake at selected serum 25(OH)D values (Appendix D of this Technical Report), compared with those of the Scientific Opinion (Tables 6 and 7 in Appendix C of the Scientific Opinion). See also Ad48. with regard to the inclusion in the model (Table 11 of Appendix D.B. of the Scientific Opinion) of studies with total vitamin D intake in the range of µg/day. The Panel considered that no change in the Scientific Opinion was needed in relation to this comment. Ad47. Most of the vitamin D naturally present in foods in Europe is vitamin D 3, while both vitamin D 2 and D 3 may be used for food fortification and supplements in Europe (Section 3 of the Scientific Opinion). The Panel noted the conflicting results regarding the potential differences in the 33 EFSA Supporting publication 2016:EN-1078

34 biological potencies and catabolism of vitamin D 2 and D 3 (Section of the Scientific Opinion). As indicated in Section , based on these data and in view of the low number of arms using vitamin D 2 in the data collected (six arms, Table 8 in Appendix D.A. of the Scientific Opinion), the Panel considered that exclusion of arms in which vitamin D 2 was administered was appropriate, for the characterisation of the intake-status relationship. The Panel considered that no change in the Scientific Opinion was needed in relation to this comment. Ad48. Following this extensive comment received ( 9, Appendix C of this Technical Report), the Panel notes the following points: Regarding the latitude In the dose-response analysis undertaken by the Panel, most of the trials (8 out of 10) in the lower latitudes group (40 49 o N) were carried out in North America (Table 9 in Appendix D.B of the Scientific Opinion). The modelled UV-B dose data for European regions arising from the on-going research project mentioned in the comment received are relevant to European countries; they might not be as relevant to US regions. The Panel has carried out a stratified analysis by latitude (< 50 o N; o N; 55 o N) that showed that modelled response in o N trials is lower than in o N trials when only intake is taken into account (i.e. unadjusted model), and only slightly higher than in o N trials once adjusted for all covariates from the final model. Another sensitivity analysis in which latitude was considered as a dichotomous variable (< 50 o N vs. 50 o N) did not show substantial differences in results (Appendix D of the Technical Report). The latitude range in the meta-regression analysis provided by the Panel can be seen as a trade-off between the need for minimal endogenous vitamin D synthesis and representativeness in terms of European populations. The Panel is aware of the uncertainties related to the selection of studies performed in a period of assumed minimal endogenous vitamin D synthesis, which implies that UV-B irradiation is probably not completely absent. The Panel is also aware of the numerous factors in addition to latitude and season that affects vitamin D synthesis in the skin of humans (e.g. ozone layer, clouds, surface, time spent outdoors, use of sunscreen, clothing, skin type, etc.). The Panel underlines that a number of sensitivity analyses were also carried out to evaluate whether the findings were robust to assumptions made in the systematic review protocol and the analyses (Section and Appendices C and D of the Scientific Opinion). In particular, a sensitivity analysis was undertaken on characteristics of participants (e.g. exclusion of trials that did not explicitly exclude supplement users, persons using sunbeds/artificial UV-B sources or going on sunny holidays, Table 16 of Appendix D.H. of the Scientific Opinion). None of these sensitivity analyses raised serious concerns about the robustness of the overall analysis. As indicated in Section of the Scientific Opinion, additional further selections were also proposed (Brouwer-Brolsma et al., 2016), based on the UV-index (UV-index < 3) or a simulation model (Webb, 2006; Webb and Engelsen, 2006) (Section ); neither were applied, as it would have led to a substantial reduction in the number of arms (53% and 86% of the 83 arms would have been excluded respectively). In terms of modelling, it is not clear how the exclusions of the four high-dose vitamin D supplementation arms suggested by the commenter (i.e. those with total vitamin D intake in the range of µg/day, Table 11 of Appendix D.B. of the Scientific Opinion) can be consistent with the modelling approach proposed by the authors, in which estimated intakes would only be extrapolated if the higher doses are not taken into account (see also related comment below). Regarding the six winter-based RCTs using vitamin D 3 referred to in the comment received: The commenter states that because of their design, which focussed on addressing vitamin D DRVs, these 6 RCTs meet and exceeded EFSA's stated inclusion criteria for RCT and as such pooling data from these RCTs did not require several of the adjustments EFSA required in 34 EFSA Supporting publication 2016:EN-1078

35 relation to their selected more heterogeneous mix of RCTs (such as latitude, study start year, type of analytical method applied to assess serum 25(OH)D, assessment of compliance). These studies were undertaken in a restricted area (latitudes between 51 and 60 N) in specific populations. In the meta-regression analysis provided by the Panel, it was of interest to characterise the high heterogeneity across trials that represent different target European populations. In this received comment, Individual Participant Data (IPD) analysis is discussed as compared to AD analysis. It seems from the description that the authors have carried out an IPD analysis using first a one-stage approach (i.e. the individual participant data from all studies are modelled simultaneously) and then a meta-regression approach on the same data but modelling their aggregated version (i.e. summary statistics) to mimic the meta-regression approach proposed by the Panel. It is clear, from how the trials were selected, that they are not representative of the same evidence base considered in the Panel s analysis. The subset of RCTs proposed by the commenter (six RCTs) does not include all eligible trials. While the six RCTs are certainly identified by meeting clear eligibility criteria (like that of minimal endogenous synthesis, plus other criteria that are partially in line with those applied by the Panel), an IPD meta-analysis in the context of a systematic approach would require the identification of all eligible trials. For an adequate comparison of both types of analysis (IPD and AD), individual and AD from the 35 studies included in the meta-regression analysis of the Scientific opinion would be needed. Individual Participant Data level-based analyses: In the comment received ( 9, Appendix C of this Technical Report), there is no mentioning of the account for clustering of participants within studies in the statistical analysis; failing to account for it may introduce bias and/or artificially precise estimates. The commenter states that The curvilinear model (setting 0 nmol/l as intercept) was achieved serum 25(OH)D = 22.7*Ln(Total vitamin D intake [in μg/d]). Interestingly, this is very similar to the prediction equation of the EFSA unadjusted model (y = 23.2*Ln(Total vitamin D intake)). The commenter states that predictions of the vitamin D intakes required to keep 97.5% of individuals over serum 25(OH)D thresholds were generated from these two models. It is not specified how such predictions were generated (e.g. using the prediction equations applied on the 95% prediction limits). According to the ranges of supplemental doses (0 20 μg/day) and dietary vitamin D ( μg/day) as reported in Table 1 of 9 (Appendix C of this Technical Report) - and consistently with the authors choice of a total vitamin D intake < 35 μg/day - the estimated values (28.5, 38.7 μg/day) of vitamin D intake required to keep 97.5% of individuals over the serum 25(OH)D threshold of 50 nmol/l (Table 1) from both the linear and curvilinear models are extrapolated. Apart from the higher uncertainty that affects extrapolated values, it is not clear why the authors propose to cap the meta-regression model of the Panel to 35 μg/day (and exclude the four arms with doses of 50 μg/day), while in order to achieve the threshold of 50 nmol/l their individual-data models suggest intakes in ranges that are not adequately covered by the actual dose ranges in their selected trials. The commenter states to have adjusted for age (mean), and separately, baseline serum 25(OH)D (mean), and in a further model for both age and baseline serum 25(OH)D (means). It is not clear why, having individual data available on age and baseline serum concentrations, the commenter has opted for their mean values instead, since one of the advantages of IPD analysis is to be able to model treatment-covariates effects as analysed within studies, overcoming the ecological fallacy issue. Weighted linear meta-regression analysis approach The commenter does not specify whether a fixed-effect or a random-effects model has been assumed, although the high heterogeneity in the data shown (I 2 = 86%) and the fact that the commenter has likely estimated the 95% prediction limits should imply the second choice EFSA Supporting publication 2016:EN-1078

36 In this second analysis, the commenter has possibly tried to compare an IPD analysis with an AD approach (meta-regression) using the same data. It is surprising that results from the one-stage IPD models are so different from the meta-regression ones, especially when considering the unadjusted models. Usually discrepancies between IPD and AD meta-analyses arise when the data included are not the same (e.g. reinstatement of originally excluded participants); alternatively they can be due to the fact that IPD can better investigate individual-level effect modifiers. Lack of ability of the meta-regression approach to recover between-individual variability (e.g. variability in intakes) can be a plausible explanation for differences, although there could also be methodological issues playing a role (e.g. no account for clustering, as mentioned above). In the exercise carried out by the commenter, the estimates based on individual data are at least twice those based on meta-regression. This cannot be immediately generalised to all IPD/AD comparisons. It is not clear from the conclusions of the commenter how individual data should be used to integrate the current meta-regression approach proposed by the Panel. It is well documented that meta-regression can analyse across-study effects (i.e. quantify how particular factors modify the treatment effect across studies) that are meaningful at the population level and, in ideal conditions, such effects will reflect within-study interactions (i.e. those meaningful to individuals). In most actual cases, though, across-study effects have low power, and even in case of adequate power (i.e. when there is large between-study variation in the mean factor value) are prone to ecological bias and confounding. The reference by Vale et al. (2015), mentioned in the comment received, was on the use of systematic reviews and meta-analyses, based on individual participant data, in clinical practice guidelines; the Panel notes that the setting of such guidelines was not the task of the Panel. This reference indicates that a relevant IPD meta-analysis should always contribute to clinical guidelines if available, unless it is determined to be of poor methodological quality, based on limited data or superseded by a more recent aggregate data meta-analysis that includes several new trials. The Panel considered that no change in the Scientific Opinion was needed in relation to this comment. Appendix D of the Scientific Opinion Comments received: 49. The Panel was asked to clarify how to interpret the prediction interval in Figure 19 (Appendix D.F., also shown as Figure 3 in Section of the Scientific Opinion). It was stated that the confidence interval gave the impression that 10 μg/day vitamin D would be sufficient. 50. The Panel was asked to clarify whether the data from older studies in Figure 19 (Appendix D.F., also shown as Figure 3 in Section ) were adjusted for the method of analysis, as it was stated that radioimmunoassays underestimate the serum concentration of 25(OH)D. 51. The Panel was asked to clarify if the effect of supplementation vehicle, discussed in Section of the Scientific Opinion, was considered in the meta-regression model. 52. It was pointed out that, in Table 11 (Appendix D.B.), the status values for Heaney (2008) (initial: 74, 73, 67, 73 nmol/l and final: 71, 60, 52, 39) for supplementation arms (15, 10, 5, 0 µg/day respectively), are comparable to, but not identical to, what is reported in the original paper (initial: 75.9, 72.2, 60.0, 65.7; and final: 69.0, 60.0, 49.7, 37.4). 53. The Panel was asked to exclude the study by Rich-Edwards et al. (2011) on Mongolian schoolchildren with a BMI of less than 17 kg/m 2. Panel consideration of comments received: Ad49. A legend to Figure 3 (in Section ), as well as Figures 18 and 19 (Appendix D.F.), was added to clarify the meaning of the confidence and prediction intervals (See Ad41., Ad42. and Ad50.). The confidence interval illustrates the uncertainty about the position of the regression line. The prediction interval illustrates the uncertainty about the true mean effect that would be predicted in a future study. As explained in Sections and 6., the Panel supports the use 36 EFSA Supporting publication 2016:EN-1078

37 of the prediction interval (and not only the confidence interval) in the context of the metaregression analysis. A sentence was added to Section 6.1. to underline this further. Ad50. The model was adjusted for the 25(OH)D measurement issue mentioned in the comment received, by including both the assay method and the study start year as independent covariates (Appendices C and D and Section of the Scientific Opinion), based on data on variability in results of different assay methods and temporal trends in assay method use (Section of the Scientific Opinion). A legend to Figure 3 (in Section ) and Figure 19 (Appendix D.F.) was added to clarify the list of covariates considered in the adjusted model (See Ad41., Ad42., and Ad49.). Ad51. Section indicates that limited data are available on the effect of the food or supplement matrix on absorption of vitamin D, and that the effect is unclear. In addition, with regard to a possible matrix effect (food matrix versus supplement), a sensitivity analysis on fortified food vs. supplements was carried out (Appendix D of this Technical Report). This was based on 70 arms on non-fortified food trials (i.e. trials using supplements) versus the full data set of 83 trials used in the meta-regression in the Scientific Opinion. This sensitivity analysis showed no important impact of the exclusion of studies using fortified foods on the adjusted model coefficients. The Panel considered that no change in the Scientific Opinion was needed in relation to this comment. Ad52. Heaney et al. (2003) was included in the meta-regression, not Heaney et al (no full reference provided in the comment received). The baseline and final values mentioned in the comment seem to be those from the study by Cashman et al. (2008). Original summary measures of the studies included in the meta-regression undertaken by the Panel are not always reported or reported in the same way in all trials. The slight difference between values indicated in Table 11 (Appendix D.B. of the Scientific Opinion) and those published is due (as for the case of other trials included in the meta-regression) to the fact that original summary measures (i.e. numbers of subjects, as well as location measures like means and variability measures like standard deviations) have been statistically treated to get comparable estimates to be used in the meta-regression. Although different choices can be made in order to achieve this, such an approach is standard methodology and a necessary step towards metaanalytic modelling. The Panel considered that no change in the Scientific Opinion was needed in relation to this comment. Ad53. The inverse relationship between BMI/body fat and serum 25(OH)D concentrations is discussed in Section of the Scientific Opinion, and Section and related Appendices C and D explain that the role of BMI in the meta-regression was tested and was not included in the final model as covariate (see also Ad40.). More specifically for children, out of the four children trials included, two do not provide BMI data. In the study by O'Connor et al. (2010), children have an average BMI of 18.1 kg/m 2, which is not substantially divergent from the BMI reported in the comment received for Rich- Edwards et al. (2011). Outliers have been identified by evaluating standardised residual values and other types of consistencies: for Rich-Edwards et al. (2011), one arm was excluded on this basis (i.e. fortified milk arm, as indicated in Table 8 of Appendix D.A of the Scientific Opinion), but the others were retained. Excluding these arms would make the children analyses, the limitations of which have been described (Section , Tables 14 and 15 of Appendix D.G of the Scientific Opinion), even less informative. The Panel also notes that the data on BMI of the children (aged 9 11 years) of the study by Rich-Edwards et al. (2011) correspond to World Health Organization (WHO) growth standards for similar ages (WHO Multicentre Growth Reference Study Group, 2006). The Panel considered that no change in the Scientific Opinion was needed in relation to this comment EFSA Supporting publication 2016:EN-1078

38 Recommendations for research Comments received: 54. It was stated that there is urgent need for studies that assess the different diets of infants, in particular those consuming formula fortified with vitamin D in addition to vitamin D supplements. For setting dietary guidelines, it was also indicated that a safe range of intakes, including a UL, should be identified. 55. It was stated that prospective studies on vitamin D that follow children into adulthood are needed. 56. It was suggested to add a recommendation to study the influence of sunlight exposure on serum 25(OH)D concentrations in order to determine the corresponding percentage reduction in dietary vitamin D requirements and the conditions under which the requirement is zero. It was noted that research on how to optimize vitamin D status over the whole year utilizing cutaneous synthesis of vitamin D without increasing skin cancer risk or the need for fortified foods or supplements would be useful. The Panel was invited to view Kiely and Cashman (2015) for further information. 57. In addition to data on total vitamin D concentration in foods as already mentioned as Recommendations for research in the Scientific Opinion, it was stated that data was especially needed with respect to total vitamin D in fortified foods and supplements. It was added that further research was needed on how to accurately assess the potencies of intake of vitamin D 2, D 3 and 25(OH)D with respect to serum 25(OH)D concentration; the notion of D equivalents was suggested. For further information on these topics, the Panel was invited to view Le Blanc et al and Cashman et al., 2012, that the Panel assumes to be LeBlanc et al. (2013) and Cashman et al. (2012). 58. The recommendation for research on the role of vitamin D status in non-musculoskeletal health was also welcomed, in particular with regard to pregnancy, lactation, cancers and autoimmune diseases. Panel consideration of comments received: Ad54. The Panel acknowledges that the suggested research objective is important. The Section on Recommendations for research of the Scientific Opinion was amended as follows: There is a need for studies that assess the different diets of infants, in particular those consuming infant or follow-on formulas and processed cereal-based foods fortified with vitamin D in addition to vitamin D supplements. With regards to the UL, see Ad6. Ad55. Without further information, the Panel considered the purpose of such studies to be unclear. The Panel considered that no change in the Scientific Opinion was needed in relation to this comment. Ad56. The Panel acknowledges that the suggested research objective is important. The Section on Recommendations for research of the Scientific Opinion was amended as follows: There is a need for further research to study the respective impact of vitamin D dietary intake and sunlight exposure on serum 25(OH)D concentrations. Future studies should investigate food-based strategies to ensure adequate vitamin D intakes accounting for latitude, sunlight exposure and diet. Ad57. The Panel acknowledges that the suggested research objectives are important. The Section on Recommendations for research of the Scientific Opinion was amended as follows: More precise data on total vitamin D concentration in foods would also be useful. Studies investigating the effect of 25(OH)D naturally occurring in foods on serum 25(OH)D concentration are also suggested. Ad58. The Panel considers that this is already covered in the Section on Recommendations for research of the Scientific Opinion, therefore no change in the Scientific Opinion was needed in relation to this comment. However, in view of the additional recommendations for research added, the Panel reorganised this Section EFSA Supporting publication 2016:EN-1078

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41 Regulation (EC) No 1924/2006. EFSA Journal 2010; 8(5):1609, 10 pp. doi: /j.efsa EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies), Scientific Opinion on the substantiation of a health claim related to vitamin D and risk of falling pursuant to Article 14 of Regulation (EC) No1924/2006. EFSA Journal 2011;9(9):2382, 18 pp. doi: /j.efsa EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies), Scientific Opinion on the Tolerable Upper Intake Level of vitamin D. EFSA Journal 2012;10(7):2813, 45 pp. doi: /j.efsa EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies), Scientific Opinion on Dietary Reference Values for calcium. EFSA Journal 2015;13(5):4101, 82 pp. doi: /j.efsa EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies), 2016a. Scientific Opinion on Dietary Reference Values for vitamin D. EFSA Journal 2016;14(10):4547. doi: /j.efsa EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies), 2016b. General scientific guidance for stakeholders on health claim applications. EFSA Journal 2016;14(1):4367, 38 pp. doi: /j.efsa Engelsen O, Brustad M, Aksnes L and Lund E, Daily duration of vitamin D synthesis in human skin with relation to latitude, total ozone, altitude, ground cover, aerosols and cloud thickness. Photochemistry and Photobiology, 81, Federal Commission for Nutrition, Vitamin D deficiency: Evidence, safety, and recommendations for the Swiss Population. Federal Office for Public Health, Zurich, 95 pp. Forman JP, Scott JB, Ng K, Drake BF, Suarez E, Hayden DL, Bennett GG, Chandler PD, Hollis BW, Emmons KM, Giovannucci EL, Fuchs CS and Chan AT, Effect of vitamin D supplementation on blood pressure in blacks. Hypertension, 61, Gallo S, Comeau K, Vanstone C, Agellon S, Sharma A, Jones G, L'Abbe M, Khamessan A, Rodd C and Weiler H, Effect of different dosages of oral vitamin D supplementation on vitamin D status in healthy, breastfed infants: a randomized trial. JAMA, 309, Garland CF, Grant WB, Boucher BJ, Cross HS, Garland FC, Gillie O, Gorham ED, Heaney RP, Holick MF, Hollis BW, Moan JE, Peterlik M, Reichrath J and Zittermann A, Open letter to IARC Director Christopher P. Wild-Re: IARC Working Group Report 5: Vitamin D and Cancer. Dermatoendocrinology, 1, Garland CF, French CB, Baggerly LL and Heaney RP, Vitamin D supplement doses and serum 25-hydroxyvitamin D in the range associated with cancer prevention. Anticancer Research, 31, Haddad JG and Chyu KJ, Competitive protein-binding radioassay for 25-hydroxycholecalciferol. Journal of Clinical Endocrinology and Metabolism, 33, Hanley DA, Cranney A, Jones G, Whiting SJ, Leslie WD and Guidelines Committee of the Scientific Advisory Council of Osteoporosis Canada, 2010a. Vitamin D in adult health and disease: a review and guideline statement from Osteoporosis Canada (summary). Canadian Medical Association Journal, 182, Hanley DA, Cranney A, Jones G, Whiting SJ, Leslie WD, Cole DE, Atkinson SA, Josse RG, Feldman S, Kline GA, Rosen C and Guidelines Committee of the Scientific Advisory Council of Osteoporosis Canada, 2010b. Vitamin D in adult health and disease: a review and guideline statement from Osteoporosis Canada. Canadian Medical Association Journal, 182, E Hathcock JN, Shao A, Vieth R and Heaney R, Risk assessment for vitamin D. American Journal of Clinical Nutrition, 85, Health Council of the Netherlands, Evaluation of dietary reference values for vitamin D. No 2012/15E, 138 pp EFSA Supporting publication 2016:EN-1078

42 Heaney RP, Davies KM, Chen TC, Holick MF and Barger-Lux MJ, Human serum 25- hydroxycholecalciferol response to extended oral dosing with cholecalciferol. American Journal of Clinical Nutrition, 77, Hilger J, Friedel A, Herr R, Rausch T, Roos F, Wahl DA, Pierroz DD, Weber P and Hoffman K, A systematic review of vitamin D status in populations worldwide. British Journal of Nutrition, 111, Holick MF, MacLaughlin JA, Clark MB, Holick SA, Potts JT, Jr., Anderson RR, Blank IH, Parrish JA and Elias P, Photosynthesis of previtamin D3 in human skin and the physiologic consequences. Science, 210, Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM and Endocrine Society, Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism, 96, Holmlund-Suila E, Viljakainen H, Hytinantti T, Lamberg-Allardt C, Andersson S and Makitie O, High-dose vitamin d intervention in infants--effects on vitamin d status, calcium homeostasis, and bone strength. Journal of Clinical Endocrinology and Metabolism, 97, Huang L, Liu C, Liao G, Yang X, Tang X and Chen J, Vitamin D receptor gene FokI polymorphism contributes to increasing the risk of tuberculosis: an update meta-analysis. Medicine (Baltimore),, 94, e2256. IOM (Institute of Medicine), Dietary Reference Intakes for Calcium and Vitamin D. National Academies Press, Washington, DC, USA, 1115 pp. Jacobsen RB, Hronek BW, Schmidt GA and Schilling ML, Hypervitaminosis D associated with a vitamin D dispensing error. Annals of Pharmacotherapy, 45, e52. Jones KS, Schoenmakers I, Bluck LJ, Ding S and Prentice A, Plasma appearance and disappearance of an oral dose of 25-hydroxyvitamin D2 in healthy adults. British Journal of Nutrition, 107, Jones KS, Assar S, Harnpanich D, Bouillon R, Lambrechts D, Prentice A and Schoenmakers I, (OH)D2 half-life is shorter than 25(OH)D3 half-life and is influenced by DBP concentration and genotype. Journal of Clinical Endocrinology and Metabolism, 99, Kiely M and Cashman KD, on behalf of the ODIN Consortium, The ODIN project: Development of food-based approaches for prevention of vitamin D deficiency throughout life. Nutrition Bulletin, 40, Lamberg-Allardt C, Brustad M, Meyer HE and Steingrimsdottir L, Vitamin D - a systematic literature review for the 5th edition of the Nordic Nutrition Recommendations. Food & Nutrition Research, 57. LeBlanc ES, Perrin N, Johnson JD, Jr., Ballatore A and Hillier T, Over-the-counter and compounded vitamin D: is potency what we expect? JAMA Internal Medicine, 173, Lee YH and Gyu Song G, Vitamin D receptor FokI, BsmI, TaqI, ApaI, and EcoRV polymorphisms and susceptibility to melanoma: a meta-analysis. Journal of the Balkan Union of Oncology, 20, Lin G, Ning L, Gu D, Li S, Yu Z, Long Q, Hou LN and Tan WL, Examining the association of circulating 25-hydroxyvitamin D with kidney cancer risk: a meta-analysis. International Journal of Clinical and Experimental Medicine, 8, Linseisen J, Bechthold A, Bischoff-Ferrari HA, Hintzpeter B, Leschik-Bonnet E, Reichrath J, Stehle P, Volkert D, Wolfram G and Zittermann A, Stellungnahme. Vitamin D und Prävention ausgewählter chronischer Krankheiten. Deutschen Gesellschaft für Ernährung e. V. (DGE), 47 pp. Luxwolda MF, Kuipers RS, Kema IP, Dijck-Brouwer DA and Muskiet FA, Traditionally living populations in East Africa have a mean serum 25-hydroxyvitamin D concentration of 115 nmol/l. British Journal of Nutrition, 108, EFSA Supporting publication 2016:EN-1078

43 Macdonald HM, Wood AD, Aucott LS, Black AJ, Fraser WD, Mavroeidi A, Reid DM, Secombes KR, Simpson WG and Thies F, Hip bone loss is attenuated with 1000 IU but not 400 IU daily vitamin D3: a 1-year double-blind RCT in postmenopausal women. Journal of Bone and Mineral Research, 28, McDonnell SL, Baggerly C, French CB, Baggerly LL, Garland CF, Gorham ED, Lappe JM and Heaney RP, Serum 25-hydroxyvitamin D concentrations >/=40 ng/ml are associated with >65% lower cancer risk: pooled analysis of randomized trial and prospective cohort study. PLoS ONE, 11, e McKenna MJ and Murray BF, Vitamin D dose response is underestimated by Endocrine Society's Clinical Practice Guideline. Endocrine Connections, 2, Mowry EM, Pelletier D, Gao Z, Howell MD, Zamvil SS and Waubant E, Vitamin D in clinically isolated syndrome: evidence for possible neuroprotection. European Journal of Neurology, 23, Mun MJ, Kim TH, Hwang JY and Jang WC, Vitamin D receptor gene polymorphisms and the risk for female reproductive cancers: A meta-analysis. Maturitas, 81, Newberry SJ, Chung M, Shekelle PG, Booth MS, Liu JL, Maher AR, Motala A, Cui M, Perry T, Shanman R and Balk EM, Vitamin D and calcium: a systematic review of health outcomes (update). Evidence Report/Technology Assessment No Prepared by the Southern California Evidencebased Practice Center under Contract No I. AHRQ Publication No. 14-E004-EF. Agency for Healthcare Research and Quality. Rockville, USA, 929 pp. Nordic Council of Ministers, Nordic Nutrition Recommendations Integrating nutrition and physical activity. Nordic Council of Ministers, Copenhagen, Denmark, 627 pp. O'Connor E, Molgaard C, Michaelsen KF, Jakobsen J and Cashman KD, Vitamin D-vitamin K interaction: effect of vitamin D supplementation on serum percentage undercarboxylated osteocalcin, a sensitive measure of vitamin K status, in Danish girls. British Journal of Nutrition, 104, Perez-Hernandez N, Aptilon-Duque G, Nostroza-Hernandez MC, Vargas-Alarcon G, Rodriguez-Perez JM and Blachman-Braun R, Vitamin D and its effects on cardiovascular diseases: a comprehensive review. Korean Journal of Internal Medicine, Apr 27. doi: /kjim [Epub ahead of print]. Pludowski P, Karczmarewicz E, Bayer M, Carter G, Chlebna-Sokol D, Czech-Kowalska J, Debski R, Decsi T, Dobrzanska A, Franek E, Gluszko P, Grant WB, Holick MF, Yankovskaya L, Konstantynowicz J, Ksiazyk JB, Ksiezopolska-Orlowska K, Lewinski A, Litwin M, Lohner S, Lorenc RS, Lukaszkiewicz J, Marcinowska-Suchowierska E, Milewicz A, Misiorowski W, Nowicki M, Povoroznyuk V, Rozentryt P, Rudenka E, Shoenfeld Y, Socha P, Solnica B, Szalecki M, Talalaj M, Varbiro S and Zmijewski MA, Practical guidelines for the supplementation of vitamin D and the treatment of deficits in Central Europe - recommended vitamin D intakes in the general population and groups at risk of vitamin D deficiency. Endokrynologia Polska, 64, Priemel M, von Domarus C, Klatte TO, Kessler S, Schlie J, Meier S, Proksch N, Pastor F, Netter C, Streichert T, Puschel K and Amling M, Bone mineralization defects and vitamin D deficiency: histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675 patients. Journal of Bone and Mineral Research, 25, Rich-Edwards JW, Ganmaa D, Kleinman K, Sumberzul N, Holick MF, Lkhagvasuren T, Dulguun B, Burke A and Frazier AL, Randomized trial of fortified milk and supplements to raise 25- hydroxyvitamin D concentrations in schoolchildren in Mongolia. American Journal of Clinical Nutrition, 94, Riley RD, Higgins JP and Deeks JJ, Interpretation of random effects meta-analyses. British Medical Journal, 342, d549. SACN (Scientific Advisory Committee on Nutrition), Vitamin D and Health report. 304 pp EFSA Supporting publication 2016:EN-1078

44 SCF (Scientific Committee on Food), Guidelines of the Scientific Committee on Food for the development of Tolerable Upper Intake Levels for vitamins and minerals. 6 pp. Signaleringscommissie Kanker van KWF Kankerbestrijding, De relatie tussen kanker, zonnestraling en vitamine D. pp Smith SM, Gardner KK, Locke J and Zwart SR, Vitamin D supplementation during Antarctic winter. American Journal of Clinical Nutrition, 89, Souberbielle JC, Body JJ, Lappe JM, Plebani M, Shoenfeld Y, Wang TJ, Bischoff-Ferrari HA, Cavalier E, Ebeling PR, Fardellone P, Gandini S, Gruson D, Guerin AP, Heickendorff L, Hollis BW, Ish-Shalom S, Jean G, von Landenberg P, Largura A, Olsson T, Pierrot-Deseilligny C, Pilz S, Tincani A, Valcour A and Zittermann A, Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: Recommendations for clinical practice. Autoimmunity Reviews, 9, Spiro A and Buttriss JL, Vitamin D: An overview of vitamin D status and intake in Europe. Nutrition Bulletin, 39, Sundstrom P and Salzer J, Vitamin D and multiple sclerosis-from epidemiology to prevention. Acta Neurologica Scandinavica, 132, Tizaoui K and Hamzaoui K, Association between VDR polymorphisms and rheumatoid arthritis disease: Systematic review and updated meta-analysis of case-control studies. Immunobiology, 220, Todd JJ, McSorley EM, Pourshahidi LK, Madigan SM, Laird E, Healy M and Magee PJ, Vitamin D supplementation using an oral spray solution resolves deficiency but has no effect on VO max in Gaelic footballers: results from a randomised, double-blind, placebo-controlled trial. European Journal of Nutrition, Mar 25. doi: /s [Epub ahead of print]. Tsiaras WG and Weinstock MA, Factors influencing vitamin D status. Acta Dermato- Venereologica, 91, Uusi-Rasi K, Patil R, Karinkanta S, Kannus P, Tokola K, Lamberg-Allardt C and Sievanen H, Exercise and vitamin D in fall prevention among older women: a randomized clinical trial. JAMA Internal Medicine, 175, Vale CL, Rydzewska LH, Rovers MM, Emberson JR, Gueyffier F, Stewart LA and Cochrane IPDM-aMG, Uptake of systematic reviews and meta-analyses based on individual participant data in clinical practice guidelines: descriptive study. British Medical Journal, 350, h1088. Verkerk RH and Hickey S, A critique of prevailing approaches to nutrient risk analysis pertaining to food supplements with specific reference to the European Union. Toxicology, 278, Veugelers PJ and Ekwaru JP, A statistical error in the estimation of the recommended dietary allowance for vitamin D. Nutrients, 6, Veugelers PJ, Pham TM and Ekwaru JP, Optimal vitamin D supplementation doses that minimize the risk for both low and high serum 25-hydroxyvitamin D concentrations in the general population. Nutrients, 7, Vieth R, Chan PCR and MacFarlane GD, Efficacy and safety of vitamin D3 intake exceeding the lowest observed adverse effect level. American Journal of Clinical Nutrition, 73, Vieth R, Ladak Y and Walfish PG, Age-related changes in the 25-hydroxyvitamin D versus parathyroid hormone relationship suggest a different reason why older adults require more vitamin D. Journal of Clinical Endocrinology and Metabolism, 88, Vieth R, The pharmacology of vitamin D, including fortification strategies. In: Vitamin D. Eds Feldman D, Pike JW and Gloreieux FH. Elsevier Academic Press, Wagner CL, Hulsey TC, Fanning D, Ebeling M and Hollis BW, High-dose vitamin D3 supplementation in a cohort of breastfeeding mothers and their infants: a 6-month follow-up pilot study. Breastfeeding Medicine, 1, EFSA Supporting publication 2016:EN-1078

45 Webb AR, DeCosta BR and Holick MF, Sunlight regulates the cutaneous production of vitamin D3 by causing its photodegradation. Journal of Clinical Endocrinology and Metabolism, 68, Webb AR and Engelsen O, Calculated ultraviolet exposure levels for a healthy vitamin D status. Photochemistry and Photobiology, 82, Webb AR, Who, what, where and when-influences on cutaneous vitamin D synthesis. Progress in Biophysics and Molecular Biology, 92, Weir RR, Carson EL, Mulhern MS, Laird E, Healy M and Pourshahidi LK, Validation of a food frequency questionnaire to determine vitamin D intakes using the method of triads. Journal of Human Nutrition and Dietetics, 29, WHO Multicentre Growth Reference Study Group (World Health Organization), WHO (World Health Organization) Child Growth Standards: Length/height-for-age, weight-for-age, weight-forlength, weight-for-height and body mass index-for-age: Methods and development. 312 pp. Zhang H, Shih DQ and Zhang X, Mechanisms underlying effects of 1,25-Dihydroxyvitamin D3 on the Th17 cells. European Journal of Microbiology and Immunology, 3, Zittermann A, Pilz S, Hoffmann H and Marz W, Vitamin D and airway infections: a European perspective. European Journal of Medical Research, 21, EFSA Supporting publication 2016:EN-1078

46 Abbreviations 1,25(OH)2D 1,25-dihydroxy-vitamin D 25(OH)D 25-hydroxy-vitamin D AD Aggregated data AI Adequate intake AR Average Requirement BMC bone mineral content BMD bone mineral density BMI body mass index CI confidence interval CPBA competitive protein binding assay DRV Dietary Reference Value EC European Commission ELISA enzyme-linked immunosorbent assay FFQ food frequency questionnaire GC group specific component gene HPLC high-performance liquid chromatography IOM U.S. Institute of Medicine of the National Academy of Sciences IPD individual participant data IU international unit LC-MS liquid chromatography-mass spectrometry MED minimal erythema dose NNR Nordic Nutrition Recommendations nr not reported PRI Population Reference Intake PTH parathyroid hormone RCT randomised controlled trial RIA radioimmunoassay RNI Reference Nutrient Intake SACN Scientific Advisory Committee on Nutrition SE standard error SI Safe intake UK United Kingdom UL Tolerable Upper Intake Level US United States UV ultraviolet VDR vitamin D receptor 46 EFSA Supporting publication 2016:EN-1078

47 Vitamin D 2 Vitamin D 3 WHO ergocalciferol cholecalciferol World Health Organization 47 EFSA Supporting publication 2016:EN-1078

48 Appendix A Explanatory text for the public consultation on the draft Scientific Opinion on Dietary Reference Values for vitamin D EFSA has launched an open consultation on its draft scientific opinion on dietary reference values for vitamin D. This document proposes dietary reference values for vitamin D for adults, infants and children, pregnant and lactating women. In line with EFSA s policy on openness and transparency and in order for EFSA to receive comments from the scientific community and stakeholders, EFSA has launched a public consultation on the draft document developed by the NDA Panel of EFSA. Interested parties are invited to submit written comments by 16 May Please use the electronic template provided to submit comments and refer to the line and page numbers. Please note that after 2 hours your working session will expire and comments submitted after that time will not be recorded and transmitted. If you would like to submit additional data to support your comments or files send an to:nda.publicconsult.66@efsa.europa.eu. Please note that comments will not be considered if they: are submitted after the closing date of the public consultation; are not related to the contents of the document; contain complaints against institutions, personal accusations, irrelevant or offensive statements or material; are related to policy or risk management aspects, which are out of the scope of EFSA's activity. EFSA will assess all comments from interested parties which are submitted in line with the criteria above. The comments will be further considered by the relevant EFSA Panel and taken into consideration if found to be relevant EFSA Supporting publication 2016:EN-1078

49 Appendix B Full list of comments submitted by means of the electronic form on the EFSA website Organisation Chapter text Comment text National Institute for Public Health and Environment 1. Introduction P4, line 126: For quality purposes and to keep maximal transparency we would advise to disclose the identity of this so-called external contractor. In other words, refer here directly to the report of Brouwer-Brolsma 2016 if that is the correct reference. Anonymous Anonymous Anonymous Anonymous Anonymous 2.2. Function of vitamin D 2.2. Function of vitamin D 2.2. Function of vitamin D 2.2. Function of vitamin D Health consequences of deficiency and excess P9, line323: We think it is important to emphasize directly on the fact that despite its name, vitamin D is not really a vitamin. As detailed in many recent reviews, it is the precursor to the potent steroid hormone calcitriol, which mediates numerous actions in many tissues of the body (Bikle 2014, Feldman et al. 2014, Carlberg 2014). The single remark on p10, line 369 about vitamin D being a prohormone is only scratching the surface. high doses of vitamin D are able to solve my immunitary problems and i can avoid the Metatrexate theraphy that is very dangerous for his collateral effects on the health. Affetta da sclerosi multipla da 20 anni. Assumo da circa un mese la vit D con dosi giornaliere di unità. Ho progressivi miglioramenti dull equilibrio la gorza e la spasticità. Per favore nn limitate la prescrizione della vit D funzionaaaa. Sono affetta da fibromialgia ed avevo livelli bassissimi di vitamina D (21). Attualmente prendo U.i. Al giorno di vit.d e sto benissimo!! Quindi l'apporto massiccio di vitamina D funziona!!! È una vitamina importante, forse la più importante!! reminder to EFSA that oral Vitamin D is a proven supplement that is highly cost effective and reduces the risk of a wide range of conditions including various cancers, heart attack, hypertension, diabetes, osteoporosis and bone fractures Indicate the daily amount you have taken or currently take (e.g. 100 mcg = 4000 IU/day, which is nearly seven times greater than the amount proposed for the adult dietary reference intake for adults) Specify if you have had blood tests for vitamin D and what levels you have attained Propose that the target levels for circulating 25-hydroxyvitamin D for adults should be set at 125 mmol/l (50 ng/ml), in line with the recommendations of the Vitamin D Council and an extensive Polish study Suggest that EFSA should follow the reference ranges for circulating 25- hydroxyvitamin D given by the Vitamin D Council, which are as follows: Deficient: nmol/l (0-40 ng/ml) Sufficient: nmol/l (40-80 ng/ml) High Normal: nmol/l ( ng/ml) Undesirable: > 250 nmol/l (> 100 ng/ml) Toxic: > 375 nmol/l (> 150 ng/ml) It is also my belief that what supplementation I desire is my own personal decision not that of people who will not live with the consequences. I am a UK registered General medical Practitioner and I am writing to say that the EFSA needs to revise its current thinking on vitamin D levels. The UK is currently experiencing an epidemic of vitamin D deficiency - and this is in terms of the levels set that are supposed to stop people's getting rickets. When the EFSA is setting what it regards as 'normal' levels - it must to 49 EFSA Supporting publication 2016:EN-1078

50 Organisation Chapter text Comment text more that set a level just above that which would give a child rickets or an adult osteomalacia, the levels need top be set at levels which actually promote health - far higher. the target levels for circulating 25-hydroxyvitamin D for adults should be set at 125 mmol/l (50 ng/ml), in line with the recommendations of the Vitamin D Council and the extensive Polish study The levels should be set at the reference ranges for circulating 25- hydroxyvitamin D given by the Vitamin D Council: Deficient: nmol/l (0-40 ng/ml) Sufficient: nmol/l (40-80 ng/ml) High Normal: nmol/l ( ng/ml) and not toxic until above 375 nmol/l (150 ng/ml) The strengths that are available over the counter without prescription shouild not be reduced. Capsules and preparations 25mcg (1000iu) should remain available to the general public, in order to improve their health and be less of a burden on the scarce resources we have in the NHS Anonymous Anonymous Health consequences of deficiency and excess Health consequences of deficiency and excess studies show that vitamin D deficiency is linked to risk of MS (Scotland), dementia and cancers particularly breast. Lots of studies out there! reminder to EFSA that oral Vitamin D is a proven supplement that is highly cost effective and reduces the risk of a wide range of conditions including various cancers, heart attack, hypertension, diabetes, osteoporosis and bone fractures Indicate the daily amount you have taken or currently take (e.g. 100 mcg = 4000 IU/day, which is nearly seven times greater than the amount proposed for the adult dietary reference intake for adults) Specify if you have had blood tests for vitamin D and what levels you have attained Propose that the target levels for circulating 25-hydroxyvitamin D for adults should be set at 125 mmol/l (50 ng/ml), in line with the recommendations of the Vitamin D Council and an extensive Polish study Suggest that EFSA should follow the reference ranges for circulating 25- hydroxyvitamin D given by the Vitamin D Council, which are as follows: Deficient: nmol/l (0-40 ng/ml) Sufficient: nmol/l (40-80 ng/ml) High Normal: nmol/l ( ng/ml) Undesirable: > 250 nmol/l (> 100 ng/ml) Toxic: > 375 nmol/l (> 150 ng/ml) It is also my belief that what supplementation I desire is my own personal decision not that of people who will not live with the consequences. Anonymous Deficiency As a nutritional therapist I am seeing on a weekly basis clients who are deficient in Vitamin D. These people have health problems such as migraines, high blood pressure, depression, anxiety, hormonal problems - all of which scientific studies have linked to Vitamin D deficiency. Most of them have had months of expensive tests and treatment from their GP and local hospitals before coming to see me. A few have already been tested for Vitamin D deficiency but have then been given a ridiculously low dose ( iu dialy) which has had little effect on their deficiency. (Or they have been told that their level is normal when it is 51nmol/l). I am sure that you are aware that oral Vitamin D is a proven supplement that is highly cost effective and reduces the risk of a wide range of conditions including various cancers, heart attack, hypertension, diabetes, osteoporosis and bone fractures. However when someone is deficient it needs to be taken at a therapeutic 50 EFSA Supporting publication 2016:EN-1078

51 Organisation Chapter text Comment text dose. When a client is below 50nmol/l (and often they are around 20nmol/l) I will recommend a dose of 9000iu per day for 8 weeks. This is guaranteed to raise their level to one which is or is closer to optimum ( ). However this dose is many times greater than the amount proposed for the adult dietary reference intake. I propose that the target levels for circulating 25-hydroxyvitamin D for adults should be set at 125 mmol/l (50 ng/ml), in line with the recommendations of the Vitamin D Council and an extensive Polish study. Also I suggest that the EFSA should follow the reference ranges for circulating 25-hydroxyvitamin D given by the Vitamin D Council, which are as follows: Deficient: nmol/l (0-40 ng/ml) Sufficient: nmol/l (40-80 ng/ml) High Normal: nmol/l ( ng/ml) Undesirable: > 250 nmol/l (> 100 ng/ml) Toxic: > 375 nmol/l (> 150 ng/ml) I believe that this can save the NHS many thousands of pounds in unnecessary treatment for health problems which are easily remedied or prevented with adequate nutrition. Anonymous Deficiency Vitamin D deficiency does not only lead to rickets in children and osteomalacia in adults, but in addition to a variety of other problems. The problem in this draft is that the levels for deficiency are considered too low. 20ng/ml may be considered as the "osteomalacia level", but anti-inflammatory, anticancer, anti-dementia levels etc. must me set to at least 40 ng/ml. With a personal serum level of 41ng/ml after a daily intake of 4000IE of vitamin D for now 4 years, I have not had any common cold, or influenca, or parainfluenca. As a subject suffering from chronic sinusitis with the need to take antibiotics > 3 times a year due to exacerbations in the past, I did not have any exacerbation within the last 3 years. EFSA should reconsider its opinion on "deficiency levels", and should take current published data into account. EFSA should set the "deficiency level" to at least 40 ng/ml. Following this, the EFSA should remain with its upper daily intake level recommendation, i.e IE for adults and children > 11 yrs, and 2000 IE for children > 1 yrs. With this recommendations, adequate levels with serum vitamin D levels of 40ng/ml or higher can be achieved without any risk of Vitamin D overdose. Anonymous Excess line 396 : I myself (male 69 years old) takes 6000 IU/day (150 mcg/day) vitamin D3 with circulating 25-hydroxyvitamin D level of 70 ng/ml (175 nmol/l). In case of first symptoms of a disease : à IU/day for 2 to 3 days (i.e. common cold, ) gives healing within 3 days with no negative effects. Anonymous Excess line 396 : I myself (female 68 years old) takes 5000 IU/day (125 mcg/day) vitamin D3 with circulating 25-hydroxyvita.min D level of 60 ng/ml (150 nmol/l). In case of first symptoms of a disease : à IU/day for 2 to 3 days (i.e. common cold, ) gives healing within 3 days with no negative effects. Swedish National Food Agency Individual (academia), University of Aberdeen Transport in blood Page 14, line nr 527. Longer half-life for 25(OH)D has also been reported (up to about 50 days). See e.g. vitamin D chapter in NNR Elimination Although 25OHD is currently the best marker for vitamin D status it is not ideal as noted by the Panel (lines ). It is well recognised that this marker is flawed on many counts. Although a sensitivity analysis was done, this was on type of measurement technique only. The method of analysis is not the only source of discrepancies between different laboratories, but critically how the sample is prepared prior to analysis; how long it has been stored for, prior to analysis; and method of sample 51 EFSA Supporting publication 2016:EN-1078

52 Organisation Chapter text Comment text collection. In addition, older data in particular are affected by the lack of an international standard. Whereas 25OHD measurement is useful as a research tool in helping our understanding vitamin D metabolism, and for testing/ monitoring patients in clearly defined cases, I would argue that placing too much focus on the relationship between intakes and 25OHD is not the best approach for deriving dietary reference values. Although the approach was used by others specifically for the IOM recommendations, a sensible starting point at that time, it is important not to continue the practice and especially not to promote meta regression approaches in light of current understanding the issue around 25OHD measurements. There will be different opinions on how this should be done, likely coming up with slightly different conclusions. The focus on the marker may lead to unnecessary testing. (1) lack of a linear relationship between vitamin D intakes and 25OHD, which was somewhat glossed over in the document. The lower the starting 25OHD, the greater the increase in 25OHD will be. Although the focus was on periods of limited light exposure, 25OHD measurements carried out in Northern Europe in November will be much higher than those done in March and we still do not have data on long-term storage of the vitamin. It is important to note that those who are vitamin D deficient will have a proportionally greater increase in 25OHD for a small amount of vitamin D than those starting with higher 25OHD. It is this group of the population who are at risk of vitamin D deficiency that DRVs need to protect. If one ignores that the approach is flawed, the metaregression figure (page 81) illustrates the non linear relationship. One can observe that even at daily vitamin D intakes between 3ug and 5 ug all points show that the corresponding 25OHD value is between nmol/l (with one or two studies up to 60nmol/L). (2) lack of association between the marker and health outcomes. Recent evaluations by IOM, SACN and EFSA all agree that this can only be done for musculoskeletal outcomes. There will be racial differences. Black African Americans have low 25OHD but have better BMD compared to Whites. It would have been preferable to link vitamin D intakes (supplements or oral intake) directly to health outcomes rather than tie it to a marker which can vary between different studies simply because of laboratory techniques. Perhaps, depending on the study, 25OHD could be viewed simply as a marker of compliance, or indication of confounding, but not as a primary focus. (3) other dietary factors, for example dietary calcium and vitamin A (and other nutrients) that will work with vitamin D in maintaining bone health. It is understood that calcium is 'vitamin D sparing' and this is particular important during growth. Vitamin D will not work alone in maintaining optimum musculoskeletal health. The panel specify in their conclusions that they assume that intakes of other nutrients such as calcium are adequate (line 3639). The use of observational data was required to link health to 25OHD which is confounded. Although only an adequate intake was proposed, it is important to clarify what this means. On the evidence 50 nmol/l 25OHD and 15 ug vit d appears too high. Anonymous 2.4. Biomarkers I would like to propose that the target levels for circulating 25- hydroxyvitamin D for adults should be set at 125 mmol/l (50 ng/ml), in line with the recommendations of the Vitamin D Council. I m currently taking UI that is much more higher of the dietary reference value indicate in the report, I m following the Coimbra Protocol for autoimmune diseases under the supervision of a prepared doctor and with due dietary restrictions. My last blood test attests a Vitamin D level of 160 ng/ml and PTH 31 pg/ml EFSA Supporting publication 2016:EN-1078

53 Organisation Chapter text Comment text Oral vitamin D as a food supplement at daily dosages of at least 50 mcg (2000 IU) and preferably double this amount is one of the most costeffective solutions to reducing the risk of a wide range of health problems or diseases. These not only include various cancers (e.g. breast, pancreas, kidney), but also heart attack, type 1 diabetes, hypertension, osteoporosis and bone fractures, many autoimmune diseases. I suggest that EFSA should follow the reference ranges for circulating 25- hydroxyvitamin D given by the Vitamin D Council, which are as follows: Deficient: nmol/l (0-40 ng/ml) Sufficient: nmol/l (40-80 ng/ml) High Normal: nmol/l ( ng/ml) Undesirable: > 250 nmol/l (> 100 ng/ml) Toxic: > 375 nmol/l (> 150 ng/ml). My atopic dermatitis and allergye improves dramatically that i'm not using any cortisone cream. I hope you consider my comment. It's so important for me like all other patients with autoimmune diseases or immune disregulation. ELC - Federation of European Specialty Food Ingredients Industries National Institute for Public Health and Environment Alliance for Natural Health International 2.4. Biomarkers Lines 7-9: 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 biomarker of vitamin D status in adult and children populations. - ELC agrees with this conclusion Biomarkers P18, line 693 and others like 3408 (minimal endogenous vitamin D synthesis): low dose exposure to UV-B is frequently referred to in various paragraphs, but is not at all quantified to any extent. Because it is a general known confounding factor in the estimation of plasma 25(OH)D levels and/or the underlying dose-response relations with supplemental intakes, it should be addressed more thoroughly like for example in the Kiely & Cashman paper 2014 (doi : /nbu.12159). see also our related comment on p86, line 3748 P21, line 837: Although probably still insufficient to tailor genotype assisted DRV s there is considerable more information about polymorphisms in GC in relation to 25(OH)D levels especially with regard to ethnic/population differences (see HuGE Navigator for example) Conclusions on biomarkers The serum 25(OH)D level of 50 nmol/l has been selected primarily on the basis of bone/calcium metabolism data. When taking into account other health benefits, it is clear that higher levels are optimum and reduce the risk of a wide range of other diseases given the diverse range of biological activities of circulating vitamin D. Accordingly, vitamin D experts have proposed the following ranges: The Vitamin D Council recommends maintaining serum levels of 125 nmol/l (50 ng/ml), with the following reference ranges: Deficient: nmol/l (0-40 ng/ml) Sufficient: nmol/l (40-80 ng/ml) High Normal: nmol/l ( ng/ml) Undesirable: > 250 nmol/l (> 100 ng/ml) Toxic: > 375 nmol/l (> 150 ng/ml) See: The Vitamin D Council makes a recommendation of 50 ng/ml and defines the above reference ranges for the following reasons: The human genome was selected with abundance of vitamin D. Humans evolved in the sun near the equator, synthesizing robust quantities of vitamin D in the skin. Research has shown that lifeguards, 53 EFSA Supporting publication 2016:EN-1078

54 Organisation Chapter text Comment text farmers near the equator, and sun dwelling hunter gatherers maintain blood levels between ng/ml on sun exposure alone [1,2,3]. The Vitamin D Council believes that the maternal 25(OH)D status necessary to provide antirachitic activity for offspring should be considered a biomarker for optimal vitamin D status in humans. Research shows that antirachitic activity in breast milk occurs at 45 ng/ml or higher, but not at 38.4 ng/ml or lower [4]. Research has generally shown that parathyroid hormone is maximally suppressed at 40 ng/ml or higher, another finding that the Vitamin D Council considers a biomarker for optimal vitamin D status [5,3]. The human body is usually unable to achieve 25(OH)D levels above 100 ng/ml on UVB exposure alone3. There are no studies to date to suggest that 25(OH)D levels over 100 ng/ml are beneficial, so the Vitamin D Council believes that the upper limit should be set at 100 ng/ml. Vitamin D toxicity manifests itself by hypercalcuria and hypercalcemia. Research has shown that serum calcium levels are not related to 25(OH)D levels up to 257 ng/ml6, but cases of toxicity have been reported at levels as low as 194 ng/ml7. The Vitamin D Council believes that a conservative threshold of 150 ng/ml should be considered the lower limit of toxicity. The Vitamin D Council recognizes that there are not enough controlled trials at this time to either support these recommendation or oppose these recommendations. Alliance for Natural Health International 2.5. Effects of genotypes References: See 17 references provided as justification at: Omission of data on effect of specific genotypes on vitamin D status: There are emerging data on the effects of a range of single nucleotide polymorphisms that affect vitamin D status. It is inappropriate to simply ignore these on the basis that data are considered 'insufficient". Data on the following SNPs/variants that were not even mentioned, include VDR Fok1 T>C, VDR BSM1 C>T and VDR Taq1 C>T. Recent meta-analyses include: Huang L, Liu C, Liao G, Yang X, Tang X, Chen J. Vitamin D Receptor Gene FokI Polymorphism Contributes to Increasing the Risk of Tuberculosis: An Update Meta-Analysis. Medicine (Baltimore) Dec;94(51):e2256. Mun MJ, Kim TH, Hwang JY, Jang WC. Vitamin D receptor gene polymorphisms and the risk for female reproductive cancers: A metaanalysis. Maturitas Jun;81(2): Lee YH, Gyu Song G.Vitamin D receptor FokI, BsmI, TaqI, ApaI, and EcoRV polymorphisms and susceptibility to melanoma: a metaanalysis. J BUON Jan-Feb;20(1): Review. Tizaoui K, Hamzaoui K. Association between VDR polymorphisms and rheumatoid arthritis disease: Systematic review and updated metaanalysis of case-control studies. Immunobiology Jun;220(6): EFSA Supporting publication 2016:EN-1078

55 Organisation Chapter text Comment text NICHE, Ulster 3. Dietary sources Response on behalf of Vitamin D Researchers from the Northern Ireland University and intake data Centre for Food and Health (NICHE), Ulster University. Anonymous 4. Overview of Dietary Reference Values and recommendations We would like to draw the committee s attention to a recently validated vitamin D food frequency questionnaire (Weir et al. J Hum Nutr Diet Apr;29(2): doi: /jhn.12328) which may be useful for future research wishing to determine the contribution of natural dietary sources, fortified foods as well as supplements to total vitamin D intake and status. This is of growing importance in vitamin D research given the reliance on such exogenous sources that will be required to achieve the revised RNI/Safe Intake, and we hope the committee will find it useful for inclusion within the report. oral Vitamin D is a proven supplement that is highly cost effective and reduces the risk of a wide range of conditions including various cancers, heart attack, hypertension, diabetes, osteoporosis and bone fractures I have taken doses of 10,000IU/day, which is considerably greater than the amount proposed for the adult dietary reference intake for adults). I have had no adverse effects from this. I propose that the target levels for circulating 25-hydroxyvitamin D for adults should be set at 125 mmol/l (50 ng/ml), in line with the recommendations of the Vitamin D Council and an extensive Polish study. I would hope that EFSA should follow the reference ranges for circulating 25-hydroxyvitamin D given by the Vitamin D Council, which are as follows: Deficient: nmol/l (0-40 ng/ml) Sufficient: nmol/l (40-80 ng/ml) High Normal: nmol/l ( ng/ml) Undesirable: > 250 nmol/l (> 100 ng/ml) Toxic: > 375 nmol/l (> 150 ng/ml) Anonymous 4.1. Adults line 907 : Based on my personal observations of myself (circulating 25- hydroxyvitamin D level of 70 ng/ml (175 nmol/l) ) in correspondence with my intake of vitamin D3 of 6000 IU and my family (every family member at least intake of 1500 IU/day) is a EFSA reference level of 20 ng/ml (50 nmol/l) absolutely to low and forms a basis for a failing immune system. A UL of 1000 IU is inadequate for maintaining a strong immune system and keeping good health. Anonymous 4.1. Adults line 907 : Based on my personal observations of myself (circulating 25- hydroxyvitamin D level of 60 ng/ml (150 nmol/l) ) and my family (every family member at least intake of 1500 IU/day) is a EFSA reference level of 20 ng/ml (50 nmol/l) absolutely to low and forms a basis for a failing immune system. A UL of 1000 IU is inadequate for maintaining a strong immune system and keeping good health. Anonymous 4.1. Adults it is recommended by practitioners to have 1000 iu per 25kg body weight. I take this and no toxicity. Anonymous 4.1. Adults Please do not reduce the dietary refernce values. Vitamin D at a good level, reduces the risk of breast cancer and alzeimers and many other illnessess. I take 5000iu and it helps my arthritic knees. Please ensure I will be able to keep taking 5000iu if I wish as that is the dose recommended by the vitamin D council to prevent a miriad of illnesses not just rickets. Anonymous 4.1. Adults Line 1 I am very concerned at the proposal to set a low optimal limit for vitamin D. As someone diagnosed with MS I was very grateful to discover the work of Australian medical professor George Jelinek and his overcoming 55 EFSA Supporting publication 2016:EN-1078

56 Organisation Chapter text Comment text MS charity. His extensive review of research on vitamin d shows an optimum level of 10,000 supplement a day - particularly as we live in a place with limited sun! I have been following this for some while and believe it is limiting the effects of MS a and have achieved blood level of 150 on this dose, as people with ms are usually very deficient in vitamin d. Please look at the extensive work of George jelinek in his book for more information and don't limit this vital supplement for so many thousands of people with ms. Health Council of the Netherlands Anonymous Anonymous Alliance for Natural Health International 4.1. Adults Lines Line 946: please add that the average yearly vitamin D production in the skin estimate is 7 micrograms per day in the Netherlands Serum 25(OH)D concentrations and muscuskeletal health Line 1272 The document lacks a discussion of the relevance of the various outcome measures to bone health. Is calcium absorption for instance directly related to bone health in terms of risk of rickets or fractures? Line and line : the data concern postmenopausal women and older men instead of adults. Please change into noninstitutionalized postmenopausal women and older men. Line and line : The conclusion about the concentration of serum 25(OH)D protective of osteomalacia seems rather strong, considering the evidence. The study of Priemel at al is the only one that provides evidence for a cut off of >50 nmol/l, but suffers from considerable methodological issues, as it is unclear whether postmortem 25(OH)D measurements are valid, as described in lines The studies described by SACN provide evidence that mean concentrations were below about 20 nmol/l in all studies considered. However, this does not seem to be taken into account in the conclusion. A conclusion that better reflects the evidence would be more appropriate: e.g. the risk of vitamin D-deficiency osteomalacia appears to be small with mean serum 25(OH)D concentrations above 20 nmol/l; in one post mortem study the risk was small with serum concentrations above 50 nmol/l Infants and children 4.2. Infants and children 5. Criteria (endpoints) on which to base Dietary Reference Values line 1050 : In the family children 6 and 4 years of age take daily 1000 IU/day of vitamin D3 and in case of first symptoms of a disease : 3000 IU/day for 2 to 3 days (i.e. common cold, ) which gives fast healing within 3 days with no negative effects. For the past years they were practically not sick or no more than 1 to 2 days. line 1050 : In the family children 6 and 4 years of age take daily 1000 IU/day of vitamin D3 and in case of first symptoms of a disease : 3000 IU/day for 2 to 3 days (i.e. common cold, ) which gives fast healing within 3 days with no negative effects. For the past years they were practically not sick or no more than 1 to 2 days. End-points are excessively limited and do not reflect intake requirements for other health benefits. The panel has focused its work on end-points relating to serum 25(OH)D levels in relation to musculoskeletal health outcomes, these relating to bone and calcium metabolism in particular. While these outcomes are supported by a wealth of, albeit very heterogeneous, data, there is no attempt to establish whether the serum 25(OH)D levels for these outcomes are appropriate for other known very important benefits, such as those linked to decreased risk of particular diseases. These include: 1. Cancer, see: McDonnell SL, Baggerly C, French CB, Baggerly LL, Garland CF, Gorham ED, Lappe JM, Heaney RP. Serum 25-Hydroxyvitamin D Concentrations 56 EFSA Supporting publication 2016:EN-1078

57 Organisation Chapter text Comment text 40 ng/ml Are Associated with >65% Lower Cancer Risk: Pooled Analysis of Randomized Trial and Prospective Cohort Study. PLoS One Apr 6;11(4):e doi: /journal.pone ecollection Also, refer to Open letter to IARC Director Christopher P. Wild Re: IARC Working Group Report 5: Vitamin D and Cancer (2009): 2. Multiple sclerosis, see review: Sundström P, Salzer J. Vitamin D and multiple sclerosis from epidemiology to prevention. Acta Neurol Scand. 2015;132(199): doi: /ane Respiratory health, see: Zittermann A, et al. Vitamin D and airway infections: a European perspective. Eur J Med Res Mar 24;21:14. doi: /s y. 4. Immune health, see Azizieh F, et al. Association between levels of vitamin D and inflammatory markers in healthy women. J Inflamm Res Apr 27;9:51-7. doi: /JIR.S Health Council of the Netherlands Food Supplements Europe 5.1. Serum 25(OH)D concentration and health outcomes Serum 25(OH)D concentration and musculoskeletal health outcomes 5. Cardiovascular health, see review: Pérez-Hernández N, et al. Vitamin D and its effects on cardiovascular diseases: a comprehensive review. Korean J Intern Med Apr 27. doi: /kjim Overall conclusions Line : The Panel states explicitly that the available studies do not allow a conclusion to be drawn as to whether the 25(OH)D concentration of 50 nmol/l should be achieved by half of or most subjects in the population. However, in section 6.1 (line ), the AI for adults is based on the assumption that most subjects should achieve the level of 50 nmol/l. Please add an explanation why a target value that should be achieved by most instead of half of the population was selected.. There are a number of arguments that warrant that EFSA would reconsider the proposed DRVs. 1. EFSA considers that serum 25(OH)D concentration of 50 nmol/l is a suitable target value for musculo-skeletal health outcomes. This is not the view of many authors on this topic that propose a serum 25(OH)D concentration of at least 30 ng/ml (75 nmol/l) as optimal/preferable level for musculoskeletal health benefits. A meta analysis from 2005 and the most up to date one from 2009, which focused on the anti-fracture effect from high quality double blind RCTs, confirmed that the anti-fracture efficacy started at 25(OH)D levels of at least 30 ng/ml (75 nmol/l). This level was reached only in trials that provided IU/day ( µg/day) vitamin D3 to persons 60/65 years. (Bischoff Ferrari HA. et al. Fracture Prevention With Vitamin D Supplementation, A Meta analysis of Randomized Controlled Trials, JAMA 2005) (Bischoff Ferrari HA. et al. Prevention of Nonvertebral Fractures With Oral Vitamin D and Dose Dependency, A Meta analysis of Randomized Controlled Trials, Arch.Intern. Med. 2009) The US Endocrine Society recommended in 2011 that to maximize vitamin D s effect on calcium, bone, and muscle metabolism, the 25(OH)D blood level should be above 30 ng/ml (75 nmol/l). In adults 19 years and over, to raise the blood level of 25(OH)D above 30 ng/ml may require at least IU/day ( µg/day) of supplemental vitamin D EFSA Supporting publication 2016:EN-1078

58 Organisation Chapter text Comment text (Holick MF et al. Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab, July 2011, 96(7): ) Also the International Osteoporosis Foundation confirmed in 2010 that 75 nmol/l (30 ng/ml) is the appropriate target level of serum 25OHD for older individuals ( 65 years) for musculoskeletal health benefits. The estimated average vitamin D requirement for older adults to reach a serum 25OHD level of 75 nmol/l (30 ng/ml) is 20 to 25 μg/day (800 to 1,000 IU/day). (Dawson Hughes B. et al. IOF position statement: vitamin D recommendations for older adults, Osteoporos. Int An Expert Panel, in 2010 published Recommendation for clinical practice and confirmed that a 25(OH)D level of 30 to 44 ng/ml (75 to110 nmol/l) provides optimal benefits for outcomes in musculoskeletal and cardiovascular health. Fracture reduction was only achieved in trials that achieved 25(OH)D levels of at least 30 to 40 ng/ml (75 to 100 nmol/l). At least 24 ng/ml (60 nmol/l), i.e. doses of supplemental vitamin D > 700 IU/day (17.5 µg/day) is needed for anti-fall efficacy in individuals 65 years. (Souberbielle JC. et al. Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: Recommendations for clinical practice, Autoimmun.Rev.2010). Health Council of the Netherlands Health Council of the Netherlands Alliance for Natural Health International The Canadian Osteoporosis Society, in 2010, stated that the optimal level of serum 25(OH)D for musculoskeletal benefits is at least 75 nmol/l. This indicates that medical evidence from clinical trials and Vitamin D expert panels all define a serum 25(OH)D concentration of at least 30 ng/ml (75 nmol/l) as optimal/preferable level for musculoskeletal health benefits Rickets and : In 2007 Cranney et al concluded that in the presence of adequate calcium intake, risk of rachitis increases at serum 25(OH)D concentrations below 30 nmol/l and especially below 20 nmol/l. SACN indicates that in the majority of case studies of rickets mean serum 25(OH)D concentrations were < 25 mmol/l and that information on calcium intake was missing in most of these studies. The IOM s conclusion of minimal risk at concentrations between nmol/l in the presence of adequate calcium intake seems therefore to better reflect the study findings that EFSA s conclusion of no risk at concentrations > 50 nmol/l in the presence of adequate calcium intake. The latter conclusion seems too strong given the evidence Summary of conclusions on serum 25(OH)D concentration as indicator of musculoskeletal health in infants and children Serum 25(OH)D concentration and nonmusculoskeletal health outcomes : The range of serum 25(OH)D concentrations required for optimal BMD/BMC, rickets prevention (please, see our other comments) and optimal calcium absorption ranges from 30 to 60 nmol/l in children. This indicates that there is considerable uncertainty in selecting a target value for children. Perhaps it would be suitable to emphasize this uncertainty when concluding that there is not adequate evidence to set a different target value for 25(OH)D in children compared to adults. The threshold of 50 nmol/l for serum 25(OH)D is too low as it reflects only a threshold for bone metabolism and not for other benefits. The modelling of dose-response should have been conducted using at least three different target levels for serum 25(OH)D e.g. 50, 100 and 150 nmol/l. A useful review pointing to benefits other than those relating to musculoskeletal health is: Autier P, et al. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol Jan;2(1): doi: /S (13) EFSA Supporting publication 2016:EN-1078

59 Organisation Chapter text Comment text Alliance for Natural Health International Anonymous Anonymous Anonymous Health Council of the Netherlands Overall conclusions on serum 25(OH)D concentration and various health outcomes, in relation to the setting of DRVs for vitamin D Overall conclusions on serum 25(OH)D concentration and various health outcomes, in relation to the setting of DRVs for vitamin D Overall conclusions on serum 25(OH)D concentration and various health outcomes, in relation to the setting of DRVs for vitamin D Overall conclusions on serum 25(OH)D concentration and various health outcomes, in relation to the setting of DRVs for vitamin D Fracture risk in adults the models used by EFSA, like those, used by the IoM, appear to be erroneous in terms of their ability to determine the intake requirements required to meet a serum 25(OH)D level in 97.5% of the population This point is very clearly demonstrated by a recent analysis performed at the School of Public Health, University of Alberta (Veugelers PJ, Pham TM, Ekwaru JP. Optimal Vitamin D Supplementation Doses that Minimize the Risk for Both Low and High Serum 25-Hydroxyvitamin D Concentrations in the General Population. Nutrients Dec 4; 7(12): ). This paper reveals a statistical error in IoM s calculation of the reference intake. The study shows that a mean intake of 73 mcg/d (2909 IU) of vitamin D is needed to achieve serum 25(OH)D concentrations of 50 nmol/l or more in 97.5% of healthy individuals. More importantly, the research shows that for normal weight, overweight and obese subjects require intakes of 77 mcg/d (3094 IU/d), 111 mcg/d (4450 IU/d) and 181 mcg/d (7248 IU/d) respectively to achieve this threshold. The finding that significantly higher intake levels are required in overweight and obese individuals is consistent with clinical experience. Given that the opposite tendency was shown in the models used by EFSA, this suggests a failure in the models used by EFSA. line 2945 and line 3002 : With my intake of vitamin D IU/day for at least the last 10 years I have an excellent health with no major illnesses. My personal conclusion is that vitamin D3 is the major component for a strong immune system and heart vascular health. line 2945 and line 3002 : With my intake of vitamin D IU/day for at least the last 10 years I have an excellent health with no major illnesses. My personal conclusion is that vitamin D3 is the major component for a strong immune system and heart vascular health. I'm following Coimbra Protocol with high dose of vitamin D for multiple sclerosis, Coimbra developped the protocol almost 13 years ago, many researches and studies confirm the link between vitamin D level, PTH and autoimmune diseases. Line The focus of this chapter is on the effect of vitamin D supplementation on fracture risk. The Panel concludes is that the available evidence does not indicate that, in community-dwelling adults with adequate calcium intakes, vitamin D-supplementation up to 20 mcg/d has a significant effect on fracture risk. However it is unclear whether calcium intake was sufficient in the studies summarized in the meta-analyses. A way to obtain a sufficient calcium intake is to provide both vitamin D plus calcium. As vitamin D plus calcium does lower fracture risk, one could consider using this finding as an outcome on which to base ad DRV for vitamin D in the presence of an adequate calcium intake. Whether the effect of vitamin D and calcium is restricted to institutionalized elderly is subject of discussion: the effect might be stronger in institutionalized elderly than in independently living elderly, but it cannot be ruled out that there is still a small effect in the latter 59 EFSA Supporting publication 2016:EN-1078

60 Organisation Chapter text Comment text group. Avenell et al 2014 for instance conclude the following: the subgroup analysis by residential status (institution versus community: see Analysis 4.2) there was evidence that hip fracture incidence was reduced in institutional residents with a RR of 0.75, 95% CI 0.62 to 0.92 (two trials, 3853 participants); it was also reduced in the community dwelling group but this was a non-significant finding (RR of 0.91, 95% CI 0.77 to 1.09, seven trials, 46,000 participants; see Analysis 4.2). The test for subgroup differences was not significant (P value 0.15). A similar pattern was seen for any fracture. Anonymous Individual (academia), University College Cork Muscle strength/function and physical performance in adults 5.3. Vitamin D intake and serum 25(OH)D concentration I just want to say that I cannot work without 250 mcg of vitamin D every day. Supplementation is necessary every day all year. This submission to the public consultation on the EFSA draft scientific opinion on dietary reference values for vitamin D focuses on a single substantive issue, that of the intake-status modeling (Chap 5, Sections and associated Conclusions), including 1) selection of randomised trials (RCTs) included in the meta-regression analyses; 2) the approaches taken to the dose-response modeling itself and 3) the adoption of an Adequate Intake (AI) value for vitamin D, instead of the preferable indicators of Average Requirement (AR) and Population Reference Intervals (PRI) [EFSA Journal 2010; 8(3):1458]. We have ed a supporting document, which provides comprehensive evidence based on analysis of RCT data that two fundamental areas within the process and associated modeling, namely the criteria for selection of RCTs included in the modeling and the modeling of vitamin D intake-status itself, have resulted in substantial errors in the estimates for vitamin D requirements. As such, these estimates will not offer the population protective effects vitamin D DRV should provide for European individuals. In this document, we have addressed each issue in turn, with supporting data that show clearly that the approach taken by the Panel has generated lower vitamin D recommendations than are required to meet the Panel s specified indicator of 50 nmol/l of 25-hydroxyvitamin D (25(OH)D). Based on the evidence presented in the supporting document, we propose the following recommendations: 1. Limit the meta-regression to those RCTs conducted at latitudes >50oN on the basis of evidence proved by us that at latitudes between 40-50oN, dermal production of vitamin D is possible in some winter months within the EFSA specified October through April period. This will ensure the assumption of minimal endogenous vitamin D synthesis will be more likely to be met within the overall modeling. 2. Reconsider including the 4 high-dose vitamin D supplementation arms in the modeling on the basis that the intakes achieved are outside that normally seen in the 97.5 percentile of European populations. A recent state of the art paper series from Cochrane has highlighted a number of key publications outlining the challenges and benefits of using individual participant data-based approaches where possible, and highlights their use by guideline developers could lead to improved guidelines ensuring that routine patient care is based on the most reliable evidence available. (Vale et al. BMJ. 2015;350:h1088) On the basis of analysis of individual data from 6 winter-based vitamin D RCTs (n=854) at locations >50oN using the same methodology to assess 60 EFSA Supporting publication 2016:EN-1078

61 Organisation Chapter text Comment text dietary intake and with accredited serum 25(OH)D analysis, as well as ensuring high compliance, we have shown in the supporting documentation that dietary requirement estimates based on individual data are at least twice those based on meta-regression, even when adjusted meta-regression models are used. 3. The EFSA panel is urged to consider using individual data from available RCTs (we are making the raw data available). Use of the individual data will permit reliable estimates of the AR and PRI. National Institute for Public Health and Environment 5.3. Vitamin D intake and serum 25(OH)D concentration 4. Based on the outcomes of these supporting data, we propose that the Panel reconsider its decision to set an AI as opposed to an AR and PRI, as there are serious long-term ramifications for public health to adopting a technically inferior indicator with limited usefulness in the public health context. The AR is a superior indicator for evaluating adequacy of intakes in population groups, which is a core application of the DRV framework. The AI should only be used in the absence of adequate data, which we have clearly demonstrated is present for vitamin D. P77 t/m p86, various lines These important paragraph s explain and demonstrate the final calculation of the dose-response between intake of vitamin D and 25(OH)D concentration in serum. P12, line 450: In April, the Amsterdam sun is even higher than in September. Therefore, I would suggest March instead of April for N and check the other data from Tsirias and Weinstock 2011 and Engelse et al P13, line 480: Webb et al show a saturation level after prolonged exposure of ~12% provitamin-d converted to previtamin-d. Holick et al (1980) estimated the provitamin-d abundance in Caucasian human leg skin to be µg/m2. An adult has about two m2 of skin. Full body (2 m2) exposure to saturation of the photosynthesis process would thus give 12% of [2 m2] x [µg /m2] = 2400 µg of vitamin-d. If you really think that the saturation process reported by Webb et al is a reasonable explanation why cutaneous vitamin-d photosynthesis is not toxic, then please explain why the current upper intake level is set to 100 µg /d, only about 4% of the safe UV-production. The dose that is required to achieve the 12% conversion is not physiological and therefore saturation will not be a relevant process. Still, according to Holick s rule, full-body exposure to 1 MED, which is a regular, physiological dose, gives 400 IU, four times the current upper intake limit. Could you please address this issue? P13, line 484: I would think that it is better to estimate the required supplementary intake for all status values that are thought to be too low, and not only for zero UV-exposure, see also previous comment on minimal endogenous vitamin D synthesis. P81, line 3557: Figure 3: The samples shown here come in twins: initial and final status from the same supplementation arm, but this pairing of the samples is not visually made clear. Please find a way to show the pairs as pairs. Figure 3: please leave out the peculiar visual effect at the left end of the plot with the green and yellow band shooting up. In your Table 11, you give the status values for the controls, but in Figure 3, you still show the raw final status values for the cases. For the Cashman study, this gives peculiar effects, since even the highest supplementation arm, 15 µg /d, had a negative status change. Please correct all final status values of the cases for drift in the controls. Figure 3: Other studies report different dose-effect relations. Some of them are already used by other authorities to derive intake suggestions. Would it be an idea to plot your relation along with some of the competing relations, as in the figure below (where the non-adjusted EFSA model is shown and where the Garland relation is dashed to show that is 61 EFSA Supporting publication 2016:EN-1078

62 Organisation Chapter text Comment text only an extrapolation of their model for higher status)? P86, line 3748: as outlined before and because of its consequences towards the calculated AI of 15 µg/day a much better definition of under conditions of minimal cutaneous vitamin D synthesis including geographical differences across Europe (North of Finland- South of Spain) should be included to our opinion, see also our comment on line 450. Alliance for Natural Health International Anonymous Anonymous Alliance for Natural Health International 5.3. Vitamin D intake and serum 25(OH)D concentration 5.3. Vitamin D intake and serum 25(OH)D concentration 5.3. Vitamin D intake and serum 25(OH)D concentration 6. Data on which to base Dietary Reference Values P153, line 6325: Table 11: The status values for Heaney (2008) (initial: 74, 73, 67, 73) nmol/l and (final: 71, 60, 52, 39) for supplementation arms (15, 10, 5, 0) µg/d respectively, are comparable to but not identical to what we found in that paper: (initial: 75.9, 72.2, 60.0, 65.7) and (final: 69.0, 60.0, 49.7, 37.4). Table 11: Please, do not use the study by Rich-Edwards (2011) on Mongolian schoolchildren with a BMI of less than 17. NOTE TO EFSA: I had submitted previously today a comment which included an incorrect cut-off for intake data, namely 50 rather than 100 mcg/day. Therefore the comment should be deleted and replaced with the following: Selection criteria in determination of dose responses should not use a 100 mcg/d intake cut-off This 50 mcg/d level was been chosen because it reflects EFSA s UL. However, in understanding the kinetics relating to the effects of vitamin D intake on serum 25(OH)D levels, the failure to take into account intakes in trials greater than 100 mcg/d could result in skews or distortions in the true dose-response relationship. The EFSA UL itself reflects an excessively and unnecessarily cautious approach (see Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. Am J Clin Nutr Jan; 85(1): 6-18, and; Verkerk RH, Hickey S. A critique of prevailing approaches to nutrient risk analysis pertaining to food supplements with specific reference to the European Union. Toxicology Nov 28; 278(1): ) 5.3 Vit D intake I do NOT want the advised amount of Vit D supplementation lowered. This will only make people ill. There is no reason to alter the status quo. Dear sirs and madams, i use vitamin D3 integrator daily 2000 ui, my arthrithis reumatoidis has became really less agrressive and finally I can say that i do not need cortison anymore. But if the dosage will be lower for one pill it will cause only my disage to have to buy more quantity, pay more and produce more waste, also to intake more gelatin or other substances that are used to make a pill.there are a lot of recent studies revealing innoquicy and importance of vitamin D3. Please, stop eccessive burocracy where it is not neccessary. Selection criteria in determination of dose responses should not use a 50 mcg/d intake cut-off. This cut-off has been chosen because it reflects EFSA s UL. However, in understanding the kinetics relating to the effects of vitamin D intake on serum 25(OH)D levels, the failure to take into account intakes in trials greater than 50 mcg/d could result in skews or distortions in the true dose-response relationship. The EFSA UL itself reflects an excessively and unnecessarily cautious 62 EFSA Supporting publication 2016:EN-1078

63 Organisation Chapter text Comment text approach (see Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. Am J Clin Nutr Jan; 85(1): 6-18, and; Verkerk RH, Hickey S. A critique of prevailing approaches to nutrient risk analysis pertaining to food supplements with specific reference to the European Union. Toxicology Nov 28; 278(1): ) HFMA (Health Food Manufacturer's Association) HFMA (Health Food Manufacturer's Association) 6.1. Adults Line 3679 Appreciating that the proposed DRVs relate to conditions of minimal cutaneous synthesis of vitamin D, nevertheless it would be helpful if there is any scientific basis to quantify further the statement that in the presence of of endogenous cutaneous vitamin D synthesis (section 2.3.1), the requirement for dietary vitamin D is lower or may even be zero. Given that Europe spans a range of latitudes with different sunlight exposures from Northern to Southern Member States, it would be helpful to have a more quantitative indication of how much sunlight exposure is needed for zero dietary requirements, and some indication of what % lower requirement relates to what level of sunlight exposure. If this is not possible from the available data, a statement to this effect could usefully be added to the end of section 6.1. The same comment also applies to sections 6.3 (line 3729), 6.4 (line 3737), 6.5 (line 3750) and 6.6 (line 3776) Adults Line 3666 Despite there being no difference in absorption capacity for older adults (i.e. no reduction with age), nevertheless as there are 3 EU authorised disease risk reduction health claims targeted at older adults (women aged 50+ and older adults aged 60+ years) that require a daily intake of 20mcg vitamin D, consideration should be given to setting a separate AI for older adults at 20 mcg per day, based on the scientific evidence that substantiates these health claims. Anonymous 6.1. Adults line 3645 : Based on my personal observations of myself (circulating 25- hydroxyvitamin D level of 70 ng/ml (175 nmol/l) ) and my family (every family member at least intake of 1500 IU/day) is a EFSA reference level of 20 ng/ml (50 nmol/l) absolutely to low and forms a basis for a failing immune system in the stress conditions of the European environment. I propose that the target levels for circulating 25-hydroxyvitamin D for adults should be set at 125 mmol/l (50 ng/ml), in line with the recommendations of the Vitamin D Council and an extensive Polish study Anonymous 6.1. Adults line 3645 : Based on my personal observations of myself (circulating 25- hydroxyvitamin D level of 60 ng/ml (150 nmol/l) ) and my family (every family member at least intake of 1500 IU/day) is a EFSA reference level of 20 ng/ml (50 nmol/l) absolutely to low and forms a basis for a failing immune system in the stress conditions of the European environment. I propose that the target levels for circulating 25-hydroxyvitamin D for adults should be set at 125 mmol/l (50 ng/ml), in line with the recommendations of the Vitamin D Council and an extensive Polish study Food Supplements Europe 6.1. Adults Many authors also do not share the view that the AI value for Adults (600 IU vitamin D/day 15 µg/day) is-also valid for the Elderly The International Osteoporosis Foundation, in 2010, stated that supplementation in amounts of 700 1,000 IU vitamin D/day (20-25 Mg/day) lowered risk of falling by 20% in older individuals (( 65 years) independent of their calcium intake level. (Dawson Hughes B. et al. IOF position statement: vitamin D recommendations for older adults, Osteoporos. Int. 2010). The German Osteoporosis Society in 2014 recommended intake of IU vitamin D/day (20-25 µg/day) for prevention of falls and fractures in elderly persons 60 years. (Dachverband Osteologie e.v. (DVO), DVO Leitlinie Osteoporose 2014 Kurz und Langfassung - German Osteoporosis Confederation Guideline 63 EFSA Supporting publication 2016:EN-1078

64 Organisation Chapter text Comment text on Osteoporosis 2014 Short and Long Version - osteologie.org/uploads/leitlinie%202014/dvo- Leitlinie%20Osteoporose%202014%20Kurzfassung%20und%20Langfass ung%20version%201a%2012%2001% pdf) Health Council of the Netherlands The US Endocrine Society in 2011 stressed that the importance of the intake level of supplemental vitamin D for minimizing risk of falls was confirmed by a multidose double-blind RCT and by a 2009 meta-analysis. Participants 65 years, receiving 800 IU/day (20 µg/day) had a 72% lower rate of falls than those taking placebo or a lower dose of vitamin D. (Hollick MF et al. Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab, July 2011, 96(7): ) A 2009 meta-analysis on fall prevention showed that supplemental vitamin D in at an intake level of IU/day ( µg/day) reduced the risk of falling among older individuals ( 65 years) by 19%. (Bischoff Ferrari HA. et al. Fall prevention with supplemental and active forms of Vitamin D: a metaanalysis of randomised controlled trials, BMJ 2009) The Canadian Osteoporosis Society in 2010 recommended supplementation with at least µg ( IU) of vitamin D 3 daily to achieve optimal vitamin D status (> 75 nmol/l) in adults over 50 years. (Hanley DA. et al. Vitamin D in adult health and disease: a review and guideline statement from Osteoporosis Canada (summary), CMAJ 2010). Two meta-analysis, from 2005 and 2009 on fracture prevention found that a daily intake level of IU vitamin D ( µg) provides prevention against fractures in individuals 60/65 years. (Bischoff Ferrari HA. et al. Fracture Prevention With Vitamin D Supplementation, A Meta analysis of Randomized Controlled Trials, JAMA 2005) (Bischoff Ferrari HA. et al. Prevention of nonvertebral Fractures With Oral Vitamin D and Dose Dependency, A Meta analysis of Randomized Controlled Trials, Arch.Intern. Med. 2009) Very recently, in 2015, Cashman et al indicated that 20 µg vitamin D/day is needed in adults > 50 yrs. to achieve at least a serum 25(OH)D concentration of 50 nmol/l. With 15 µg vitamin D/day 10% of adults > 64 yrs. had serum 25(OH)D levels < 50 nmol/l. (Cashman KD. Vitamin D: dietary requirements and food fortification as a means of helping achieveadequate vitamin D status, J.Steroid. Biochem. & Mol.Biol. 2015) This indicates that it is confirmed by clinical evidence and supported by Vitamin D Expert Panels that elderly persons 50/60 yrs. need at least 20 µg vitamin D/day (800 IU/day) for anti-fall and -fracture efficacy Adults Line The panel does not explain why it chose a 25(OH)D concentration of at least 50 nmol/l for most subjects in the population (see our earlier remark on 5.1.6, lines ). If it accepts that a 25(OH)D concentration of 50 nmol/l needs to be achieved by half of the population and not the whole population, an Adequate Intake of 10 mcg/d could be set. Anonymous 6.3. Children line 3706 : In the family children 6 and 4 years of age take daily 1000 IU/day of vitamin D3 and in case of first symptoms of a disease : 3000 IU/day for 2 to 3 days (i.e. common cold, ) which gives healing within 3 days with no negative effects. For the past years they were practically not sick or no more than 1 to EFSA Supporting publication 2016:EN-1078

65 Organisation Chapter text Comment text days. Anonymous 6.3. Children line 3706 : In the family children 6 and 4 years of age take daily 1000 IU/day of vitamin D3 and in case of first symptoms of a disease : 3000 IU/day for 2 to 3 days (i.e. common cold, ) which gives healing within 3 days with no negative effects. For the past years they were practically not sick or no more than 1 to 2 days. Health Council of the Netherlands Food Supplements Europe 6.3. Children Line The panel does not explain why it chose a 25(OH)D concentration of at least 50 nmol/l for most children in the population. From lines it appears that there is considerable uncertainty in the target value of 25(OH)D in children. In addition, there is no clear evidence that 50 nmol/l should be achieved by half of or most subjects in the population. Taking these considerations into account, the AI could also be set at 10 mcg/d, if one decides that 50 nmol/l should be achieved by half of the population Pregnancy Authors also confirm that the AI value for Adults (600 IU vitamin D/day) is not valid for pregnant women In 2016, Cooper found, in a multicentre, double blind, randomised, placebo controlled trial with 1134 pregnant women receiving either 25 µg Vit. D per day or placebo, that 83% in the Vitamin D group achieved sufficient 25(OH)D level ( 50 nmol/l) compared to only 36% in the placebo group. The authors concluded that 25 µg Vit. D is needed during pregnancy to achieve maintenance of Vitamin D repletion. (Cooper C. et al., Maternal gestational vitamin D supplementation an offspring bone health (MAVIDOS): a multicenter, double blind, randomised placebo controlled trial, Lancet Diab. & Endocrinol. 2016) Anonymous 7. Conclusions line 3762 : I suggest that EFSA should follow the reference ranges for circulating 25- hydroxyvitamin D given by the Vitamin D Council, which are as follows: o Deficient: nmol/l (0-40 ng/ml) o Sufficient: nmol/l (40-80 ng/ml) o High Normal: nmol/l ( ng/ml) o Undesirable: > 250 nmol/l (> 100 ng/ml) Toxic: > 375 nmol/l (> 150 ng/ml) Anonymous 7. Conclusions line 3762 : I suggest that EFSA should follow the reference ranges for circulating 25- hydroxyvitamin D given by the Vitamin D Council, which are as follows: National Nutrition Council Finland o Deficient: nmol/l (0-40 ng/ml) o Sufficient: nmol/l (40-80 ng/ml) o High Normal: nmol/l ( ng/ml) o Undesirable: > 250 nmol/l (> 100 ng/ml) Toxic: > 375 nmol/l (> 150 ng/ml) 7. Conclusions Conclusions: Row 3769: For infants aged 7 11 months, the Panel sets an AI for vitamin D at 10 μg/day, based on four recent trials on the effect of vitamin D supplementation on serum 25(OH)D concentration in (mostly) breastfed infants. We would like to point out that any of the 4 trials used as reference do not take into account the most typical situation in feeding infants of 7-11 months. The sources of vitamin D in the diet of infants of this age are vitamin D fortified formula, vitamin D supplements and complementary foods and they are only partially breast fed. In conclusion, there is an urgent need for studies that take into account 65 EFSA Supporting publication 2016:EN-1078

66 Organisation Chapter text Comment text the different schemes of feeding infants, in particular infants fed fortified formulae in addition to vitamin D supplements. For dietary guidelines we need in addition to the AI the safe range of intake including the UL. Also studies where children have been followed up until adulthood are needed. Food Supplements Europe 7. Conclusions It is noted that also opinions of other Expert Panels confirm the higher needs of Vitamin D: Practical guidelines for the supplementation of vitamin D in Central Europe: Recommended intake in general population: Infants (0-12 mo): 400 IU Vitamin D/d (10 µg/day) Children & adolescents (1-18 y): IU Vitamin D/day (15-25 µg/d) Adults (>18 y): IU Vitamin D/day (20-50 µg/d) Pregnant, lactating women: IU Vitamin D /day ( µg/d) (Pludowski P. et al. Practical guidelines for the supplementation of vitamin D and the treatment of deficits in Central Europe recommended vitamin D intakes in the general population and groups at risk of vitamin D deficiency, Endokrynol. Polska 2013) BE Health Council report 2015: Recommended intake: Pregnant, lactating women: 800 IU Vitamin D/d (20 µg/day) Elderly >70 yrs.: 800 IU Vitamin D/d (20 µg/day) (Conseil Supérieur de la Santé : Recommandations nutritionnelles pour la Belgique Partim I: vitamines et oligoéléments, juin 2015, CSS n 9164 & 9174) In the light of these findings, we would like to request EFSA to reconsider the proposed DRVs for Vitamin D Anonymous 7. Conclusions Line 1 I am very concerned at the proposal to set a low optimal limit for vitamin D. As someone diagnosed with MS I was very grateful to discover the work of Australian medical professor George Jelinek and his overcoming MS charity. His extensive review of research on vitamin d shows an optimum level of 10,000 supplement a day - particularly as we live in a place with limited sun! I have been following this for some while and believe it is limiting the effects of MS a and have achieved blood level of 150 on this dose, as people with ms are usually very deficient in vitamin d. Please look at the extensive work of George jelinek in his book for more information and don't limit this vital supplement for so many thousands of people with ms. ELC - Federation of European Specialty Food Ingredients Industries ELC - Federation of European Specialty Food 7. Conclusions Lines 9-11 & : 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. ELC Comment: Early work on vitamin D has focused on musculoskeletal health due to the finding that vitamin D prevents rickets and osteomalacia. The health impact of vitamin D, however, goes far beyond musculoskeletal health. During recent years, it has become evident that vitamin D regulates approximately 300 genes and has an impact on virtually all body tissues. Observational and interventions studies have shown that vitamin D affects heart & vascular health, brain & nervous system health, eye health, skin health, gastro-intestinal health, and the immune system. 7. Conclusions Lines & : 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 EFSA Supporting publication 2016:EN-1078

67 Organisation Chapter text Comment text Ingredients Industries - ELC agrees with this conclusion. ELC - Federation of European Specialty Food Ingredients Industries 7. Conclusions Lines & : 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. ELC Comment: A serum 25(OH)D concentration of 50 nmol/l is the lower limit of what is considered normal ( nmol/l). ELC does not agree with the Panel in setting the borderline value of 50 nmol/l as suitable target for all population groups. The suitable target should be higher to provide a safety margin. If DRVs, particularly acceptable intakes (AIs) for the general healthy population are set to achieve just borderline serum concentrations, the risk of having a large part of the population reaching only insufficient levels is high. Therefore ELC would respectfully propose serum 25(OH)D concentration of 75 nmol/l as suitable target, which is the level considered optimal for bone health and recommended by the International Osteoporosis Society (2010). Some experts advocate even higher levels of 95 nmol/l as the optimum for disease prevention (Kleuser B et al, 2015). This is still far below the safety threshold of 250 nmol/l. Vitamin D insufficiency (< 50 nmol/l) is very common in Europe (see meta-analysis by Hilger J et al, 2014) for the following reasons: light has an intensity of at least 18 mj/cm². In the northern hemisphere at latitudes greater than around 40 N (north of Madrid), sunlight is not strong enough to trigger synthesis of vitamin D in the skin from October to March (Spiro A et al, 2014) ELC - Federation of European Specialty Food Ingredients Industries liver oil (which are the only good sources), and to foods like meat and eggs, which provide small amounts of vitamin D. Beside Norway, where fish and fish oil consumption is regular part of the diet, the vitamin D intake across Europe is very low (see table from Spiro A et al, 2014). (Tables will be sent by emial.) 7. Conclusions Lines & & & : For adults, an AI for vitamin D is set at 15 μg/day, based on a metaregression analysis and considering that, at this intake, most of the population will achieve a serum 25(OH)D concentration near or above the target of 50 nmol/l. ELC Comments: ELC does not agree with this recommendation of the Panel. We recommend to set an AI for adults of at least 20 μg/day, in line with the conclusions of vitamin D experts (Linseisen J et al, 2011): o Elderly people ( 65 years old) should be recommended daily intake of at least 20 μg vitamin D, Because this dosage lowered in intervention studies with convincing evidence the risk of musculoskeletal impairment, falls, fractures, and premature death Because with this dosage approximately 90-95% of the population can achieve 25(OH)D levels 50 nmol/l Because this dosage is not associated with any noteworthy risks or side effects (Upper Level set by IOM in 2011 is 100 μg vitamin D per day; Upper Level set by EFSA in 2006 is 50 μg per day). EFSA opinions on claims published in 2010 on calcium and vitamin D and the reduction of the risk of osteoporotic fractures by reducing bone loss which was linked to a daily intake of 1200 mg calcium and 800 IU (20 µg) vitamin D and in 2011 on vitamin D and risk of falling with again 20 µg/d vitamin D for men and women above 60. o Although younger adults are expected to have more UVB exposure, this is still not sufficient for adequate vitamin D supply. Particularly during 67 EFSA Supporting publication 2016:EN-1078

68 Organisation Chapter text Comment text wintertime, or if women are shielded (cultural / religious reasons), or if sun exposure is avoided (lifestyle reasons). In order to maintain 50 nmol/l plasma 25(OH)D levels in winter when the endogenous vitamin D production ceased, more than 28 µg/day vitamin D are needed for healthy European adults (20-40 years old) to reach the 97.5 percentile (SCAN report on vitamin D and health, open for public consultation in 2015, please see table 3 Estimated dietary requirements for vitamin D at selected percentiles in men and women aged years (n=215) to maintain serum 25(OH)D above selected concentrations during winter o For determining, which amount of vitamin D is necessary to reach a serum 25(OH)D concentration of at least 50 nmol/l, the data from Cashman et al. (2008, 2009) provide valuable insights: in the Irish population, 10 μg of daily vitamin D intake lead in 50 % of the population to > 50 nmol/l serum 25(OH)D concentrations, while 20 μg of daily vitamin D intake lead in % to this target value. If μg would be consumed, a serum 25(OH)D concentration of > 75 nmol/l could be achieved, which is the level recommended by the International Osteoporosis Society. ELC - Federation of European Specialty Food Ingredients Industries ELC - Federation of European Specialty Food Ingredients Industries HFMA (Health Food Manufacturer's Association) National Institute for Public Health and Environment NICHE, Ulster University 7. Conclusions Lines & & : 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. ELC is in agreement with this recommendation due to lack sufficient intervention studies. 7. Conclusions Lines & & : For pregnant and lactating women, the Panel sets the same AI as for non-pregnant non-lactating women, i.e. 15 μg/day. 8. Recommendations for research 8. Recommendations for research 8. Recommendations for research ELC does not agree with this recommendation of the Panel. We recommend to set an AI for pregnant and lactating women of at least 20 μg/day, as for non-pregnant women. We strongly ask for reconsideration of the AIs proposed by the Panel based on the arguments and data provided in ELC's input. Line 3781 Within this section, the EFSA panel could add a recommendation to study the influence of sunlight exposure on serum 25(OH)D concentrations in order to determine the percentage reduction in dietary vitamin D requirements and the conditions under which the requirement is zero. P87, line 3781: In addition to the More precise data on total vitamin D concentration in foods would also be useful., which we fully support both with respect to fortified foods and supplements (Le Blanc et al. 2013), a proper way to address the different potencies of D2, D3 and 25(OH)D to raise 25(OH)D levels in serum should be considered too (D equivalents?), see also Cashman et al for differences in potency between vitamin D3 and 25(OH)D3 supplementation. Finally, better real life scenario s (over the whole year) for the combination of UVB exposure levels enabling subcutaneous vitamin D synthesis without skin cancer risk and fortification/supplementation should be developed. Many practical suggestions including this topic are currently addressed within the ODIN Consortium, see Kiely & Cashman Response on behalf of Vitamin D Researchers from the Northern Ireland Centre for Food and Health (NICHE), Ulster University. We welcome the committee s recommendation for future research into the role of vitamin D in musculoskeletal related health outcomes and would like to draw the committee s attention to a recently published peer reviewed paper which supports the role for vitamin D in muscle function in adolscents (Carson et al., J Clin Endocrinol Metab EFSA Supporting publication 2016:EN-1078

69 Organisation Chapter text Comment text Dec;100(12): doi: /jc ) Alliance for Natural Health International Alliance for Natural Health International Alliance for Natural Health International Swedish National Food Agency HFMA (Health Food Manufacturer's Association) Swiss Federal Commission for Nutrition Anonymous Appendix B. Summary of the evidence considered by the IOM to set DRVs for vitamin D Appendix C. Dose-response analysis undertaken by EFSA of serum 25(OH)D to total vitamin D intake: methods and key results Appendix C. Dose-response analysis undertaken by EFSA of serum 25(OH)D to total vitamin D intake: methods and key results Appendix D. Dose-response analysis undertaken by EFSA of serum 25(OH)D to total vitamin D intake: methods and key results: appendices GENERIC COMMENTS GENERIC COMMENTS GENERIC COMMENTS See statistical error in IoM calculation of reference intake: Veugelers PJ, Ekwaru JP. A statistical error in the estimation of the recommended dietary allowance for vitamin D. Nutrients Oct 20;6(10): doi: /nu The models do not adequately reflect the nature of the dose response as they deal primarily with one set of relationships, namely those pertaining to bone metabolism/musculoskeletal health outcomes, and ignore others. By eliminating these other outcomes and placing a ceiling on intake of 100 mcg/d from arms of studies, the true nature of the dose-response relationship has been distorted and cannot be validated against clinical experience (which often warrants dosages of mcg/d ( ,000 IU/d) to yield optimum vitamin D status, i.e. 125 mmol/l. The model only predicts 25(OH)D levels up to 100 mcg/d intake because this reflects the maximum intake of data from trials. This is noonsensical when there is copious clinical evidence that levels between mcg/d are routine required to elevate 25(OH)D status to optimum levels, which exceed the 50 nmol/l threshold used by EFSA, which reflects only data for bone/calcium metabolism. Page 168, line nr 6405, figure 19. To facilitate the interpretation of the figure please clarify. How to interpret the prediction interval? When we interpret the CI in the figure we interpret that 10 µg/d is sufficient. Page 168, line nr 6405, figure 19. Are results from older studies adjusted? In some of these studies older assays were used, e.g. RIA assays that underestimated the concentration of 25(OH)D. Please clarify if the results are adjusted or not. The effect of different supplements could differ and therefore it may be an underestimation of the effect from some supplements, due to vehicle. It is written about it in section 2.3.2, but is this considered in the metaregression model? This comment is to acknowledge the impressive amount of work the panel has undertaken to draft this opinion, which contains a wealth of information, interpretation and analysis. In formulating the proposed DRVs it is evident that the panel has followed a thorough approach to assess and interpret the evidence. Dear all, As we do not have a specific comment on each line. We will send you an to submitt our comments. Generally we think that it would be interesting to add eldery as a group and to put a higher AI (20ug) comparing to the aldults. Kind regards Line number 391 et seq. I had a blood test to check my vitamin D levels as I was experiencing an apparent exacerbation of multiple sclerosis symptoms i.e. pain, weakness, fatigue and mobility problems. My vitamin D levels were almost zero. I have since then, approx 2 years, been taking by oral supplement 5000iu of vit D3 per day. Because of my condition and the latitude of where I live it is nearly impossible to get enough vitamin D through sunlight. Since I started taking the supplements I have suffered no ill effects at all 69 EFSA Supporting publication 2016:EN-1078

70 Organisation Chapter text Comment text and the problems I was experiencing have greatly reduced allowing me to resume a near normal lifestyle. Research already shows a link between vitamin D levels and incidence of MS. As there is no cure but high dose vitamin D is beneficial to many sufferers surely it is inhumane to limit the amount that people can obtain. National Institute for Public Health and Environment GENERIC COMMENTS P4, line 126: For quality purposes and to keep maximal transparency we would advise to disclose the identity of this so-called external contractor. In other words, refer here directly to the report of Brouwer-Brolsma 2016 if that is the correct reference. Alliance for Natural Health International Alliance for Natural Health International GENERIC COMMENTS GENERIC COMMENTS P9, line323: We think it is important to emphasize directly on the fact that despite its name, vitamin D is not really a vitamin. As detailed in many recent reviews, it is the precursor to the potent steroid hormone calcitriol, which mediates numerous actions in many tissues of the body (Bikle 2014, Feldman et al. 2014, Carlberg 2014). The single remark on p10, line 369 about vitamin D being a prohormone is only scratching the surface. The EFSA panel, in the development of its draft opinion, does no appear to have consulted with acknowledged vitamin D experts, all of which have expressed views that do not reflect those within the draft opinion. It is strongly recommended that the EFSA panel formally requests input from these experts, who in turn derive their expertise from their own and others' research, as well as clinical experience, and have assembled in a call for D* Action, see: The vitamin D experts are as follows: (list of names published in: on_ pdf) ISSUE 1: the models used by EFSA, like those, used by the IoM, appear to be erroneous in terms of their ability to determine the intake requirements required to meet a serum 25(OH)D level in 97.5% of the population. ISSUE 2: The threshold of 50 nmol/l for serum 25(OH)D is too low as it reflects only a threshold for bone metabolism and not for other benefits. ISSUE 3: End-points are limited and do not reflect intake requirements for other health benefits ISSUE 4: Selection criteria in determination of dose responses should not use a 100 mcg/d intake cut-off. ISSUE 5: Omission of data on effect of specific genotypes on vitamin D status. ISSUE 6: the EFSA panel, in the development of its draft opinion, does no appear to have consulted with acknowledged vitamin D experts, all of which have expressed views that do not reflect those within the draft opinion. It is widely recognised by clinicians with many years of experience at prescribing vitamin D, that supplemental intakes of vitamin D3 of mcg/d are required to induce optimal vitamin D status (in the range nmol/l). The above issues are discussed in greater detail in relation to the individual sections of the draft opinion EFSA Supporting publication 2016:EN-1078

71 Organisation Chapter text Comment text Swedish National Food Agency GENERIC COMMENTS Scientific evidence Concerning the selection of studies in the meta-regression model for intake of vitamin D and plasma 25(OH)D, we do not think that studies with high doses of vitamin D (some of them include intake of vitamin D up to about 60 µg/day) are relevant when setting DRV for vitamin D. Why is Alahouhala s study with vitamin D2 excluded? We think that studies with vitamin D2 also are relevant. NICHE, Ulster University Interpretation of AR How to apply an AR that expects no sun-induced production of vitamin D, i.e. a stay in a room/environment without sun exposure? A number of active vitamin D researchers from the Northern Ireland Centre for Food & Health (NICHE), Ulster University recently met to review this consultation document. Northern Ireland Centre for Food & Health, Ulster university Food Supplements Europe GENERIC COMMENTS GENERIC COMMENTS Firstly, we would like to thank the committee for preparing this review of the data on vitamin D and bringing together the extensive evidence in order to review the dietary reference values for vitamin D. This was particularly timely given the significant amount of new research that was available since the 1993 update and we welcome this report, including its recommendations, to act as a future resource (for research and teaching purposes) and to help inform future research in the area. As a group we are actively involved in ongoing vitamin D research across a broad range of disciplines, involving healthy adults as well as various patient groups. Specifically, we particularly welcome the committee s recommendations for need for future research into the role of vitamin D in the following non-musculoskeletal health outcomes and (which align with our ongoing research within NICHE): Pregnancy & lactation Cancers (e.g. prostate cancer) Autoimmune disease (e.g. systemic lupus erythematosus) Dear EFSA, Our research group have recently published a new RCT on vitamin D and fitness/muscle strength: Full citation: Todd JJ, McSorley EM, Pourshahidi LK, Madigan SM, Laird E, Healy M & Magee PJ (2016) Vitamin D3 supplementation using an oral spray solution resolves deficiency but has no effect on VO2 max in Gaelic footballers: results from a randomised, double-blind, placebo-controlled trial. European Journal of Nutrition doi: /s This study also provides new data on the effect of vitamin D supplementation on wintertime 25(OH)D concentrations using a different method of delivery (oral spray rather than capsule) which bypasses intestinal absorption. Please feel free to incorporate within your report as you see fit. Kind regards Food Supplements Europe welcomes the EFSA draft opinion on dietary reference values for Vitamin D. We would offer the following comments on the draft opinion: General comments: There seems to be an inconsistency between the EFSA draft vitamin D DRVs scientific opinion and the scientific opinions EFSA published in 71 EFSA Supporting publication 2016:EN-1078

72 Organisation Chapter text Comment text relation to health claims for vitamin D on bone health (2010) and the reduction of the risk of falls (2011). In the draft opinion EFSA recommends the vitamin D adequate intake (AI) to be set at 15 μg/day for adults. At this level of intake, the panel believes that most of the population will achieve a plasma 25(OH)D concentration near or above the target of 50 nmol/l. However, this is not consistent with the two vitamin D health claims opinions published earlier. - In 2010, EFSA published a scientific opinion on a health claim for calcium and vitamin D and the reduction of the risk of osteoporotic fractures by reducing bone loss. The panel proposed together with 1200 mg calcium 80 0 IU (20 μg/day) of vitamin D to be consumed daily. In 2011, the EFSA panel published a scientific opinion on the substantiation of a health claim for vitamin D and the reduction of the risk of falling. The panel concluded that a cause and effect relationship has been established between the intake of vitamin D and a reduction in the risk of falling. In order to obtain the claimed effect, 800 IU (20 µg) of vitamin D from all sources should be consumed daily. The target population was men and women of 60 years of age and older. We believe that the new vitamin D DRVs in the present scientific opinion are not consistent with theses previous opinions in which 20 μg/day was recommended. We also would doubt that an intake level of 15 μg/day is sufficient to maintain 50 nmol/l plasma 25(OH)D levels in the winter months, which is the time of year particularly relevant in the context of vitamin D deficiency, since during these months the endogenous vitamin D production is decreased or even ceased. To maintain 50 nmol/l plasma levels in healthy European adults during winter time, more than 28 μg/day of vitamin D are needed to reach the targeted 97.5% percentile, as confirmed by a SACN, UK, vitamin D and health report, 2015, that is under public consultation, Table 3. ( Anonymous GENERIC COMMENTS We provide further and additional arguments to support this in the relevant sections of the draft opinion. The whole document show that your scientists do not know much about Vitamin D. That is typical for Medical Doctors. Vitamin D is SAFE!. Instead of spending time on restricting harmless vitamins that has KILLED NO- ONE! Why not concentrate on restricting all the harmful medicine coming from BIG PHARMA THAT REALLY KILL PEOPLE? It is NOT ACCEPTABLE that you plan to take away my ability to take responsibility for my own health. By limit natural nutrients and vitamins like Vitamin D you do! Shame on you! My son is diagnosed with Chrons. By taking 5000 IU Vitamin D daily and get a vitamin D level of about 150 nanomol/liter, he is off medication costing about 1500 Euro a month for the Norwegian Government. He have no bad side effects like he had with medication like depression. He do not have any symptoms of Chrons anymore, he has no trouble with the decease. Now you want to put him back on medication costing a "ton of money" and giving him a lot of side effects? Shame on you! A healthy and good level is 120 to 150 nanomol. That is the same level as black people in Africa have and also what other primates have. It is the level that reduces a lot of illnesses. Even if you don t think it is enough evidence, what gives you the right to take away a nutrient that 72 EFSA Supporting publication 2016:EN-1078

73 Organisation Chapter text Comment text harms no-one? What is the purpose with this silly limitation? And you are wrong about Vitamin D is not reducing healtproblems. There is more than enough evidence that higher vitamin D levels give fewer illnesses, you just have to use high enough doses. And it is absolutely not dangerous. Why do you want to restrict it? Is it to keep people sick so that Big Pharma can make their extra money? Which side are you on? The People of Europe or Big Pharma? Anonymous Anonymous Anonymous Anonymous GENERIC COMMENTS GENERIC COMMENTS GENERIC COMMENTS GENERIC COMMENTS There is only one way to handle this! KEEP YOURE HANDS OFF! LET PEOPLE TAKE RESPONSIBILITY FOR THEIR OWN HEALTH and LET PEOPLE EAT THE VITAMINS THEY WANT! I would like to propose that the target levels for circulating 25- hydroxyvitamin D for adults should be set at 125 mmol/l (50 ng/ml), in line with the recommendations of the Vitamin D Council. I m currently taking UI, that is much more higher of the dietary reference value indicate in the report, I m following the Coimbra Protocol for autoimmune diseases under the supervision of a prepared doctor and with due dietary restrictions. My last blood test attests a Vitamin D level of 650 (OH)D Oral vitamin D as a food supplement at daily dosages of at least 50 mcg (2000 IU) and preferably double this amount is one of the most costeffective solutions to reducing the risk of a wide range of health problems or diseases. These not only include various cancers (e.g. breast, pancreas, kidney), but also heart attack, type 1 diabetes, hypertension, osteoporosis and bone fractures, many autoimmune diseases. I suggest that EFSA should follow the reference ranges for circulating 25- hydroxyvitamin D given by the Vitamin D Council, which are as follows: Deficient: nmol/l (0-40 ng/ml) Sufficient: nmol/l (40-80 ng/ml) High Normal: nmol/l ( ng/ml) Undesirable: > 250 nmol/l (> 100 ng/ml) Toxic: > 375 nmol/l (> 150 ng/ml) I take 60,000 IU per day of vitamin D for 1 year for arthritis and I feel better. All my test are normal. For Vitamin D council the sufficient range of 25(OH)D is ng/ml ( For GrassrootsHealth (Dr. Holick) the recommended range of 25(OH)D is ng/ml ( For this reasons and in accord to a lot of studies, the serum level of 25(OH)D should be fixed at least at ng/ml. Recommending a lower level means ignoring all recent studies that demonstrate a wide variety of decrease of health problems (osteoporosis, various types of cancer, diabetes, hypertension, heart attack, atopic dermatitis, psoriasis, etc...). The cost of Vitamin D is low and so the rapport between cost and benefits is very high and it will reduce sanitary costs. I made various times 25(OH)D serum level test and I reached 60 ng/ml after months of oral intake of UI/day. I think it will be a huge mistake recommending a lower intake per day, because as you can see I reached a sufficient range of Vitamin D with this intake and it will be quite the same for a lot of other people. An oral intake of UI/day is safe because a exposing the body to the sun for 20 minutes will produce this quantity of Vitamin D. I would like to propose that the target levels for circulating 25- hydroxyvitamin D for adults should be set at 125 mmol/l (50 ng/ml), in line with the recommendations of the Vitamin D Council. I m currently taking IU that is much more higher of the dietary reference value 73 EFSA Supporting publication 2016:EN-1078

74 Organisation Chapter text Comment text indicate in the report, for RCU disease. My first last blood test attests a Vitamin D level of 13 ng/ml. Oral vitamin D as a food supplement at daily dosages of at least 50 mcg (2000 IU) and preferably double this amount is one of the most cost-effective solutions to reducing the risk of a wide range of health problems or diseases. These not only include various cancers (e.g. breast, pancreas, kidney), but also heart attack, type 1 diabetes, hypertension, osteoporosis and bone fractures, many autoimmune diseases. I suggest that EFSA should follow the reference ranges for circulating 25-hydroxyvitamin D given by the Vitamin D Council, which are as follows: Deficient: nmol/l (0-40 ng/ml) Sufficient: nmol/l (40-80 ng/ml) High Normal: nmol/l ( ng/ml) Undesirable: > 250 nmol/l (> 100 ng/ml) Toxic: > 375 nmol/l (> 150 ng/ml) Anonymous GENERIC COMMENTS I would like to propose that the target levels for circulating 25- hydroxyvitamin D for adults should be set at 125 mmol/l (50 ng/ml), in line with the recommendations of the Vitamin D Council. I m currently taking UI that is much more higher of the dietary reference value indicate in the report, I m following the Coimbra Protocol for autoimmune diseases under the supervision of a prepared doctor and with due dietary restrictions. My last blood test attests a Vitamin D level of 700ng/ml. Anonymous Anonymous GENERIC COMMENTS GENERIC COMMENTS Oral vitamin D as a food supplement at daily dosages of at least 50 mcg (2000 IU) and preferably double this amount is one of the most costeffective solutions to reducing the risk of a wide range of health problems or diseases. These not only include various cancers (e.g. breast, pancreas, kidney), but also heart attack, type 1 diabetes, hypertension, osteoporosis and bone fractures, many autoimmune diseases. I suggest that EFSA should follow the reference ranges for circulating 25- hydroxyvitamin D given by the Vitamin D Council, which are as follows: Deficient: nmol/l (0-40 ng/ml) Sufficient: nmol/l (40-80 ng/ml) High Normal: nmol/l ( ng/ml) Undesirable: > 250 nmol/l (> 100 ng/ml) Toxic: > 375 nmol/l (> 150 ng/ml) I would like to propose that the target levels for circulating 25- hydroxyvitamin D for adults should be set at 125 mmol/l (50 ng/ml), in line with the recommendations of the Vitamin D Council. I m currently taking UI that is much more higher of the dietary reference value indicate in the report, I m following the Coimbra Protocol for autoimmune diseases under the supervision of a prepared doctor and with due dietary restrictions. My last blood test attests a Vitamin D level of 410 ng/ml Oral vitamin D as a food supplement at daily dosages of at least 50 mcg (2000 IU) and preferably double this amount is one of the most costeffective solutions to reducing the risk of a wide range of health problems or diseases. These not only include various cancers (e.g. breast, pancreas, kidney), but also heart attack, type 1 diabetes, hypertension, osteoporosis and bone fractures, many autoimmune diseases. I suggest that EFSA should follow the reference ranges for circulating 25- hydroxyvitamin D given by the Vitamin D Council, which are as follows: Deficient: nmol/l (0-40 ng/ml) Sufficient: nmol/l (40-80 ng/ml) High Normal: nmol/l ( ng/ml) Undesirable: > 250 nmol/l (> 100 ng/ml) Toxic: > 375 nmol/l (> 150 ng/ml) I would like to propose that the target levels for circulating 25- hydroxyvitamin D for adults should be set at 125 mmol/l (50 ng/ml), in line with the recommendations of the Vitamin D Council EFSA Supporting publication 2016:EN-1078

75 Organisation Chapter text Comment text i m currently taking UI that is much more higher of the dietary reference value indicate in the report, I m following the Coimbra Protocol for autoimmune diseases under the supervision of a prepared doctor and with due dietary restrictions. My last blood test attests a Vitamin D level of 1.050,1 ng/ml. Oral vitamin D as a food supplement at daily dosages of at least 50 mcg (2000 IU) and preferably double this amount is one of the most costeffective solutions to reducing the risk of a wide range of health problems or diseases. These not only include various cancers (e.g. breast, pancreas, kidney), but also heart attack, type 1 diabetes, hypertension, osteoporosis and bone fractures, many autoimmune diseases. I suggest that EFSA should follow the reference ranges for circulating 25- hydroxyvitamin D given by the Vitamin D Council, which are as follows: Deficient: nmol/l (0-40 ng/ml) Sufficient: nmol/l (40-80 ng/ml) High Normal: nmol/l ( ng/ml) Undesirable: > 250 nmol/l (> 100 ng/ml) Toxic: > 375 nmol/l (> 150 ng/ml) Anonymous GENERIC COMMENTS I would like to propose that the target levels for circulating 25- hydroxyvitamin D for adults should be set at 125 mmol/l (50 ng/ml), in line with the recommendations of the Vitamin D Council. i m currently taking IU/daily that is much more higher of the dietary reference value indicate in the report, I m following the Coimbra Protocol for autoimmune diseases under the supervision of a prepared doctor and with due dietary restrictions. My last blood test attests a Vitamin D level of 258,3 ng/ml. Oral vitamin D as a food supplement at daily dosages of at least 50 mcg (2000 IU) and preferably double this amount is one of the most costeffective solutions to reducing the risk of a wide range of health problems or diseases. These not only include various cancers (e.g. breast, pancreas, kidney), but also heart attack, type 1 diabetes, hypertension, osteoporosis and bone fractures, many autoimmune diseases. I suggest that EFSA should follow the reference ranges for circulating 25- hydroxyvitamin D given by the Vitamin D Council, which are as follows: Deficient: nmol/l (0-40 ng/ml) Sufficient: nmol/l (40-80 ng/ml) High Normal: nmol/l ( ng/ml) Undesirable: > 250 nmol/l (> 100 ng/ml) Toxic: > 375 nmol/l (> 150 ng/ml) Anonymous GENERIC COMMENTS Thanks for your attention to this matter I would like to propose that the target levels for circulating 25- hydroxyvitamin D for adults should be set at 125 mmol/l (50 ng/ml), in line with the recommendations of the Vitamin D Council. i m currently taking IU/daily that is much more higher of the dietary reference value indicate in the report, I m following the suggestions of prof. Cicero Galli Coimbra under the supervision of a prepared doctor. My last blood test attests a Vitamin D level of 54,2 ng/ml. Oral vitamin D as a food supplement at daily dosages of at least 50 mcg (2000 IU) and preferably double this amount is one of the most costeffective solutions to reducing the risk of a wide range of health problems or diseases. These not only include various cancers (e.g. breast, pancreas, kidney), but also heart attack, type 1 diabetes, hypertension, osteoporosis and bone fractures, many autoimmune diseases. I suggest that EFSA should follow the reference ranges for circulating 25- hydroxyvitamin D given by the Vitamin D Council, which are as follows: Deficient: nmol/l (0-40 ng/ml) Sufficient: nmol/l (40-80 ng/ml) High Normal: nmol/l ( ng/ml) 75 EFSA Supporting publication 2016:EN-1078

76 Organisation Chapter text Comment text Undesirable: > 250 nmol/l (> 100 ng/ml) Toxic: > 375 nmol/l (> 150 ng/ml) Anonymous Anonymous Anonymous Anonymous GENERIC COMMENTS GENERIC COMMENTS GENERIC COMMENTS GENERIC COMMENTS Thanks for your attention to this matter I would like to propose that the target levels for circulating 25- hydroxyvitamin D for adults should be set at 125 mmol/l (50 ng/ml), in line with the recommendations of the Vitamin D Council. i m currently taking UI daily that is much more higher of the dietary reference value indicate in the report, I m following the Coimbra Protocol for autoimmune diseases under the supervision of a prepared doctor and with due dietary restrictions. I suggest that EFSA should follow the reference ranges for circulating 25- hydroxyvitamin D given by the Vitamin D Council, which are as follows: Deficient: nmol/l (0-40 ng/ml) Sufficient: nmol/l (40-80 ng/ml) High Normal: nmol/l ( ng/ml) Undesirable: > 250 nmol/l (> 100 ng/ml) Toxic: > 375 nmol/l (> 150 ng/ml I would like to propose that the target levels for circulating 25- hydroxyvitamin D for adults should be set at 125 mmol/l (50 ng/ml), in line with the recommendations of the Vitamin D Council. i m currently taking UI that is much more higher of the dietary reference value indicate in the report, I m following the Coimbra Protocol for autoimmune diseases under the supervision of a prepared doctor and with due dietary restrictions. My last blood test attests a Vitamin D level of 150 ng/ml, calciuria perfectly in the range and PTH too. Oral vitamin D as a food supplement at daily dosages of at least 50 mcg (2000 IU) and preferably double this amount is one of the most costeffective solutions to reducing the risk of a wide range of health problems or diseases. These not only include various cancers (e.g. breast, pancreas, kidney), but also heart attack, type 1 diabetes, hypertension, osteoporosis and bone fractures, many autoimmune diseases. I suggest that EFSA should follow the reference ranges for circulating 25- hydroxyvitamin D given by the Vitamin D Council, which are as follows: Deficient: nmol/l (0-40 ng/ml) Sufficient: nmol/l (40-80 ng/ml) High Normal: nmol/l ( ng/ml) Undesirable: > 250 nmol/l (> 100 ng/ml) Toxic: > 375 nmol/l (> 150 ng/ml) In my opinion it is unbelievable that the the intake of vitamin D will be limited to such a small amount/capsule. You ignore completely recent and cutting edge studies about the effect of higher levels of circulating vitamin D on autoimmune diseases of on cancer development: just a very small amount of examples: and so on... Your initiative is just another way of restricting the liberty of citizens in EU I am a multiple sclerosis patient. I'm following the Coimbra protocol with UI of D3 per day. Currently, the only therapy that blocks the disease without side effects (~95% success rate) EFSA Supporting publication 2016:EN-1078

77 Organisation Chapter text Comment text Your new proposal of restrictions are absurd. Most of the people of the civilized world have vitamin D deficiency. You know, the scientific literature on this topic is vast. Regardless of your decision, I will continue to take my high doses of vitamin D. Anonymous Anonymous Anonymous Anonymous GENERIC COMMENTS GENERIC COMMENTS GENERIC COMMENTS GENERIC COMMENTS A special wish to your children, may they can live with good levels of vitamin D. I do not give consent to restricting D-vitamin intake to proposed values. Dear EFSA, With the cost of healthcare skyrocketing, it boggles my mind that you would recommend reducing the target levels for circulating 25- hydroxyvitamin D levels. Vitamin D3 supplements are a very inexpensive way to prevent a wide variety of health conditions, including breast, colon, lung, kidney and pancreatic cancer, heart attacks, high blood pressure, diabetes, osteoporosis and bone fractures. I personally take 5000 iu of Vitamin D3 daily and my 25-hydroxyvitamin D levels range between ng/ml. You must agree that if an individual can take an inexpensive Vitamin D3 supplement in order to prevent chronic illness and catastrophic illness(cancer), that action not only benefits the individual's personal health, but it also benefits the financial health of a country by reducing the massive costs of caring for the chronically ill and the catastrophically ill persons in that country. I suggest that you follow the reference ranges for circulating 25- hydroxyvitamin D outlined by The Vitamin D Council. They are as follows: Deficient: nmol/l(0-40 ng/ml) Sufficient: nmol/l( ng/ml) High Normal: nmol/l ( ng/ml) Undesirable: >250 nmol/l (100ng/ml) Toxic: >375 nmol/l (> 150 ng/ml) oral Vitamin D is a proven supplement that is highly cost effective and reduces the risk of a wide range of conditions including various cancers, heart attack, hypertension, diabetes, osteoporosis and bone fractures I currently take (e.g. 100 mcg = 4000 IU/day, which is nearly seven times greater than the amount proposed for the adult dietary reference intake for adults). I Propose that the target levels for circulating 25-hydroxyvitamin D for adults should be set at 125 mmol/l (50 ng/ml), in line with the recommendations of the Vitamin D Council and an extensive Polish study I believe you should follow the reference ranges for circulating 25- hydroxyvitamin D given by the Vitamin D Council, which are as follows: Deficient: nmol/l (0-40 ng/ml) Sufficient: nmol/l (40-80 ng/ml) High Normal: nmol/l ( ng/ml) Undesirable: > 250 nmol/l (> 100 ng/ml) Toxic: > 375 nmol/l (> 150 ng/ml) Hello, My husband and I recently took place in a study at the University of Chester - we had our vitamin D blood levels tested and completed a food diary. Our vitamin D levels were grossly different! Mine came back as nmol/l and his were nmol/l. We have a vegan diet and we supplement with vitamin b12. My son (4) we give a 1000iu daily dose of vitamin D and he is thriving. My husband takes algae oil (vegan version of cod liver oil) daily. I have since started 77 EFSA Supporting publication 2016:EN-1078

78 Organisation Chapter text Comment text taking a 3000iu daily spray of vitamin D supplement and will continue to do so as I feel vastly better. We have since had a retest done and so I will of course, update you with these results. He, however, is a highly active, very healthy 27 year old with none of the symptoms of apparent vitamin D toxicity which you would associate (according to the internet) with such high levels of vitamin D. Anonymous Anonymous GENERIC COMMENTS GENERIC COMMENTS I hope this is helpful :) Line 14 - I take a strong interest in my health and vitamin D levels. I use the Vitamin D Council reference ranges to guide supplementation. Their reference range for Sufficient levels of circulating Vitamin D is nmol/l. This is somewhat higher than your suggested target value of 50 nmol/l. I believe that the target range should be set at 125 nmol/l, in line with the Vitamin D Council recommendations and that of the 2013 Polish Study. May I remind you that oral Vitamin D is a proven supplement that is highly cost effective and reduces the risk of a wide range of conditions including various cancers, heart attack, hypertension, diabetes, osteoporosis and bone fractures. Line 15 - I currently take 4000 IU (100 mcg) vitamin D3 daily and blood tests (Birmingham City Hospital) show about 120 nmol/l of circulating 25- hydroxyvitamin D. Therefore, your recommendation of supplementing at 15mcg per day is extremely low and, if implemented, would leave me deficient. I urge to to reconsider your suggested reference intake. reminder to EFSA that oral Vitamin D is a proven supplement that is highly cost effective and reduces the risk of a wide range of conditions including various cancers, heart attack, hypertension, diabetes, osteoporosis and bone fractures Indicate the daily amount you have taken or currently take (e.g. 100 mcg = 4000 IU/day, which is nearly seven times greater than the amount proposed for the adult dietary reference intake for adults) Specify if you have had blood tests for vitamin D and what levels you have attained Propose that the target levels for circulating 25-hydroxyvitamin D for adults should be set at 125 mmol/l (50 ng/ml), in line with the recommendations of the Vitamin D Council and an extensive Polish study Suggest that EFSA should follow the reference ranges for circulating 25- hydroxyvitamin D given by the Vitamin D Council, which are as follows: Deficient: nmol/l (0-40 ng/ml) Sufficient: nmol/l (40-80 ng/ml) High Normal: nmol/l ( ng/ml) Undesirable: > 250 nmol/l (> 100 ng/ml) Toxic: > 375 nmol/l (> 150 ng/ml) It is also my belief that what supplementation I desire is my own personal decision not that of people who will not live with the consequences EFSA Supporting publication 2016:EN-1078

79 Appendix C Full list of comments submitted by means of Organisation Anonymous (01) Anonymous (02) Anonymous (03) Comment text Dear Sirs I have the following comments to offer on the "Scientific Opinion on Dietary Reference Values for vitamin D" Draft Scientific Opinion. Whilst I am glad to see the EFSA focusing on the serum level of vitamin D, I do not understand how the paper has come to the conclusions it has about the recommended supplementation doses for this vitamin. I can only imagine that the data to support this have been drawn highly selectively, as I am aware of sources (which I would consider to be authoritative and reliable) which recommend much higher levels. One example would be: Because of the EFSA's policy on only using what it considers to be 'generally accepted data', the definition of which I believe is vastly too narrow, a large amount of useful and important recent data as well as years of clinical experience of doctors and other medical practitioners is not taken into account. This data shows clear links between low vitamin D levels and a number of diseases, which thus do not form part of the EFSA's paper. I believe this to be a serious omission and to distort the conclusions. Again, there are many sources to support this view. The following are three specific examples: I am concerned that, if the EFSA keeps the dietary reference intakes currently suggested, other bodies may seek to restrict the availability of doses higher than this. I have benefited from oral doses of vitamin D that are much higher than those suggested in your paper and would not wish to see this freedom of choice restricted. I believe that vitamin D supplementation at doses significantly higher than those you are proposing provides a low cost, simple and effective tool to improve the health of many people. I ask that you take a closer look at the full range of data available and revise your paper to reflect this. I also ask that you act in the best interests of people in general. Yours faithfully Dear Sir or Madam Re: Vit D3 Guidance EFSA I write to challenge this report for the following reasons: Vit D3 is a proven highly cost effective oral supplement in the effective preventative treatment of various diseases, among them are: cancer, heart attack, hypertension, diabetes, osteoporosis & bone fractures. I take, and have done for 15 months, 5000IU's daily without ill effect or intolerance of any kind. My latest blood test results show I have a serum level of 133nrnol/L. I propose that the target levels for circulating 25-hydroxyvitamin D for adults should be set at 125 mmol/l (50 ng/ml), in line with the recommendations of the Vitamin D Council and an extensive Polish study. I suggest that EFSA should follow the reference ranges for circulating 25- hydroxyvitamin D given by the Vitamin D Council, which are as follows: Deficient: nmo1/1 (0-40 ng/ml) Sufficient: nmo1/1 (40-80 ng/ml) High Normal: nnno1/1 ( ng/ml) Undesirable: > 250 nmo1/1(> 100 ng/ml) Toxic: > 375 nnno1/1(> 150 ng/nnl). Thank you. I and my partner take iu of vitamin D supplements throughout the winter and around iu during the summer. we have noticed nothing but beneficial effects. Vitamin D is a proven supplement that is highly cost effective and reduces the risk of a wide range of conditions including various cancers, heart attack, hypertension, diabetes, osteoporosis and bone fractures. the net benefits to EU health provision costs are obvious. The target levels for circulating 25-hydroxyvitamin D for adults should be set at 125 mmol/l (50 ng/ml), in line with the recommendations of the Vitamin D Council and evidenced in the recent extensive Polish study. EFSA should follow the reference ranges for circulating 25-hydroxyvitamin D given by the Vitamin D 79 EFSA Supporting publication 2016:EN-1078

80 Organisation Anonymous (04) Federation of European Specialty Food Ingredients Industries (ELC) (05) Federation of European Specialty Food Ingredients Industries (ELC) (05) Comment text Council, which are as follows: Deficient: nmo1/1 (0-40 ng/ml) Sufficient: nmo1/1 (40-80 ng/ml) High Normal: nmo1/1 ( ng/ml) Undesirable: > 250 nmo1/1 (> 100 ng/ml) Toxic: > 375 nmo1/1 (> 150 ng/ml) Best regards Dear SIr/ madam. I send you in attached the blood analysis of vitamind and PTH. I 'm here for any problem, Best regards, [Attachment refers to personal results of blood tests; personal data are not disclosed] Dear Sir, Dear Madam, Please find attached the ELC comments on the EFSA draft Scientific Opinion on dietary reference values for vitamin D which include tables and references mentioned in the ELC comments submitted to EFSA via the electronic template. Many thanks indeed in advance for consideration of our input. Best regards, ELC Comments on the EFSA draft opinion on DRV for vitamin D Lines 7-9: 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 biomarker of vitamin D status in adult and children populations. > ELC agrees with this conclusion. Lines 9-11 & : 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. > Early work on vitamin D has focused on musculoskeletal health due to the finding that vitamin D prevents rickets and osteomalacia. The health impact of vitamin D, however, goes far beyond musculoskeletal health. During recent years, it has become evident that vitamin D regulates approximately 300 genes and has an impact on virtually all body tissues. Observational and interventions studies have shown that vitamin D affects heart & vascular health, brain & nervous system health, eye health, skin health, gastro-intestinal health, and the immune system. Lines & : 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. > ELC agrees with this conclusion. Lines & : Taking into account the overall evidence and uncertainties, the Panel considers 80 EFSA Supporting publication 2016:EN-1078

81 Organisation Comment text 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. > A serum 25(OH)D concentration of 50 nmol/l is the lower limit of what is considered normal ( nmol/l). ELC does not agree with the Panel in setting the borderline value of 50 nmol/l as suitable target for all population groups. The suitable target should be higher to provide a safety margin. If DRVs, particularly acceptable intakes (AIs) for the general healthy population are set to achieve just borderline serum concentrations, the risk of having a large part of the population reaching only insufficient levels is high. Therefore ELC would respectfully propose serum 25(OH)D concentration of 75 nmol/l as suitable target, which is the level considered optimal for bone health and recommended by the International Osteoporosis Society (2010). Some experts advocate even higher levels of 95 nmol/l as the optimum for disease prevention (Kleuser B et al, 2015). This is still far below the safety threshold of 250 nmol/l. Vitamin D insufficiency (< 50 nmol/l) is very common in Europe (see metaanalysis by Hilger J et al, 2014) for the following reasons: > Skin: A prerequisite for vitamin D production in skin is that the UVB light has an intensity of at least 18 mj/cm 2. In the northern hemisphere at latitudes greater than around 40 N (north of Madrid), sunlight is not strong enough to trigger synthesis of vitamin D in the skin from October to March (Spiro A et al, 2014) > Diet: Dietary supply with vitamin D is limited to marine fish and fish liver oil (which are the only good sources), and to foods like meat and eggs, which provide small amounts of vitamin D. Beside Norway, where fish and fish oil consumption is regular part of the diet, the vitamin D intake across Europe is very low (see table from Spiro A et al, 2014). Dietary vitamin D intake in Europe: [Note: refers to Table 10 extracted from reference cited below. Owing to copyright issues, it is not disclosed] (Source: Spiro A et al, 2014) Prevalence of vitamin D insufficiency in Europe: [Note: refers to Figure 2 extracted from reference cited below. Owing to copyright issues, it is not disclosed] (Source: Hilger J et al, 2014; selected data) Lines & & & : 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, most of the population will achieve a serum 25(OH)D concentration near or above the target of 50 nmol/l. > ELC does not agree with this recommendation of the Panel. We recommend to set an AI for adults of at least 20 μg/day, in line with the conclusions of vitamin D experts (Linseisen J et al, 2011): o Elderly people ( 65 years old) should be recommended daily intake 81 EFSA Supporting publication 2016:EN-1078

82 Organisation Comment text of at least 20 μg vitamin D, Because this dosage lowered in intervention studies with convincing evidence the risk of musculoskeletal impairment, falls, fractures, and premature death Because with this dosage approximately 90-95% of the population can achieve 25(OH)D levels 50 nmol/l Because this dosage is not associated with any noteworthy risks or side effects (Upper Level set by IOM in 2011 is 100 μg vitamin D per day; Upper Level set by EFSA in 2006 is 50 μg per day). o o A daily intake at 20 µg vitamin D would be in line with the previous EFSA opinions on claims published in 2010 on calcium and vitamin D and the reduction of the risk of osteoporotic fractures by reducing bone loss which was linked to a daily intake of 1200 mg calcium and 800 IU (20 µg) vitamin D and in 2011 on vitamin D and risk of falling with again 20 µg/d vitamin D for men and women above 60. Although younger adults are expected to have more UVB exposure, this is still not sufficient for adequate vitamin D supply. Particularly during wintertime, or if women are shielded (cultural / religious reasons), or if sun exposure is avoided (lifestyle reasons). In order to maintain 50 nmol/l plasma 25(OH)D levels in winter when the endogenous vitamin D production ceased, more than 28 µg/day vitamin D are needed for healthy European adults (20-40 years old) to reach the 97.5 percentile (SCAN report on vitamin D and health, open for public consultation in 2015, please see table 3 Estimated dietary requirements for vitamin D at selected percentiles in men and women aged years (n=215) to maintain serum 25(OH)D above selected concentrations during For determining, which amount of vitamin D is necessary to reach a serum 25(OH)D concentration of at least 50 nmol/l, the data from Cashman et al. (2008, 2009) provide valuable insights: in the Irish population, 10 μg of daily vitamin D intake lead in 50 % of the population to > 50 nmol/l serum 25(OH)D concentrations, while 20 μg of daily vitamin D intake lead in % to this target value. If μg would be consumed, a serum 25(OH)D concentration of > 75 nmol/l could be achieved, which is the level recommended by the International Osteoporosis Society. Lines & & : 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. > We are in agreement with this recommendation due to lack sufficient intervention studies EFSA Supporting publication 2016:EN-1078

83 Organisation Comment text Lines & & : For pregnant and lactating women, the Panel sets the same AI as for non-pregnant non-lactating women, i.e. 15 μg/day. > ELC does not agree with this recommendation of the Panel. We recommend to set an AI for pregnant and lactating women of at least 20 μg/day, as for nonpregnant women. We strongly ask for reconsideration of the AIs proposed by the Panel based on the arguments and data provided above. References: Hilger J et al, A systematic review of vitamin D status in populations worldwide; British Journal of Nutrition Vol. 111, Issue 1, pp , 2014 (Review) Kleuser B, VitaminD: Mehr als gesunde Knochen, Pharmazeutische Zeitung Online, (GERMAN) Linseisen J et al: DGE STellungnahme: Vitamin D und Prävention ausgewählter chronischer Krankheiten, Spiro A et al, Vitamin D: An overview of vitamin D status and intake in Europe; Nutrition Bulletin, 39, 4, , 2014 (Review) Anonymous (06) I consider the proposal of the EFSA to restrict the daily intake of Vitamin D to 1000 International Units(IU) to be wholly unnecessary, hazardous to good health, contrary to decades of high dose experience and a violation of human rights to consume adequate nourishment from food i.a.w. the 1948 Universal of Human Rights Act(Article 25). Denying people the right to consume what they consider to be adequate levels of Vitamin D is to impose malnutrition on those who wish to take Vitamin D supplements. I have taken 10,000 IU of Vitamin D3 daily for the past four years and my wife 20,000 IU daily. This is 10 and 20 times respectively the amount now being proposed by the EFSA. There is a huge amount of evidence of individuals taking up to 100,000 IU daily for years and in some cases even larger amounts, but with only beneficial outcomes. The complete absurdity of the EFSA proposal is exemplified by the fact that whole body exposure to the Sun for 30 minutes gives the body 10,000 to 20,000IUs, once again 10 to 20 times the proposed EFSA limit. In addition different coloured skinned peoples and whether they live in the South(e.g. Malta) or in Northern climes(e.g. Scotland) will all have different requirements for Vitamin D intake for optimum health. But apparently this is being ignored by the EFSA. It is difficult to think of a more unnecessary and harmful to health proposal. This leads me to the only possible conclusion that this proposal has nothing whatsoever to do with health and everything to do with the profits of drug manufacturers. They make no money from healthy people(like me) an incontrovertible fact! I would remind the EFSA that the "drugs" Delso, Deltalin and Drisdol were nothing more than 50,000 IU of Vitamin D2 and a filler. They proved very effective as would be expected. There are no recorded deaths or serious health issues with Vitamin D supplements. The same cannot be said however for over-the-counter drugs which are responsible for thousands of deaths every year, or the tens of thousands of deaths from correctly prescribed drugs given by the medical professionals! For these reasons this ill conceived proposal should be abandoned forthwith as it is clearly nothing more than a further attempt to micro manage the lives of EU citizens for the benefit of drug manufacturers. 12 May 2016 References: Alliance for Natural Health- International Miraculous Results of Extremely High Doses of Vitamin D3 by Jeff T Bowles Commision fédérale de l alimentation (COFA) (07) Dear all Please find our comments to the consultation related to the scientific opinion on dietary reference values for vitamin D. We attached as well the Vitamin D expert report of our commission and the summary, that 83 EFSA Supporting publication 2016:EN-1078

84 Organisation Commision fédérale de l alimentation (COFA) (07) Comment text may be useful for you. Do not hesitate to contact us for more information if needed. Best regards Consultation on the Scientific Opinion on Dietary Reference Values for vitamin D The Swiss Federal Commission for Nutrition (FCN) would like to take part of this consultation on Vitamin D. The Swiss Federal Commission for Nutrition (FCN) is an extra-parliamentary commission that acts in an advisory capacity. It prepares scientifically based opinions and expert reports in the area of nutrition or on the effect of nutrition on health for the Federal Council and for the Federal Food Safety and Veterinary Office (FSVO). The commission is a body supporting the federal government and providing expertise in various areas concerned with nutrition. The members of the commission include representatives from education and research in the area of nutritional sciences and food sciences, nutritional medicine, the food industry and food trade, the cantonal enforcement authorities and consumer organizations. In 2012 has the FCN wrote a report about Vitamin D deficiency" for the FSVO (previously the Federal Office of Public Health FOPH) to update recommendations on Vitamin D intake in Switzerland for different population groups: pregnant women, children and adolescents, adults and elderly. This report was chaired by Prof. Dr. Heike Bischoff-Ferrari, an internationally recognized expert in the field of vitamin D ((FCN), 2012). We will focus our comments more on the last population group namely the elderly. After reading the draft of the Scientific Opinion on Dietary Reference Values for vitamin D, the FCN would encourage the inclusion of specific recommendations for the elderly (> 60 years old) The rational is the age-dependent decrease of the endogenous synthesis of vitamin D, frequently exacerbated by a reduced mobility and thus sun exposure and with the age skin production of vitamin D is reduce. Furthermore, a higher intake of vitamin D has beneficial effects, in particular in fall prevention. As presented in the FCN report randomized-controlled trials show that an oral vitamin D supplementation reduces both falls and non-vertebral fractures, including hip fractures. However, this benefit is dose-dependent and a dose of IU vitamin D per day is required to assure both fall and fracture prevention in older adults (Bischoff-Ferrari, Dawson- Hughes, et al., 2009; Bischoff-Ferrari, Willett, et al., 2009). For optimal fall and fracture reduction a serum 25-hydroxyvitamin D concentration of at least 75 nmo1/1 is required. (Bischoff-Ferrari et al., 2010) This threshold may be reached with 800 to 1000 IU vitamin D in 50% of adults, whereas higher doses of vitamin D would be required to shift all adults to this threshold. As regards the recommended intake for the general population, the authors of the FCN report largely support the 2010 recommendations of the Institute of Medicine (IOM) with the aim to reduce vitamin D deficiency in all subgroups of the population (IOM, 2010). However, the panel recommends a daily vitamin D intake of 800 IU (20 pg) starting at age 60 rather than 70, as suggested by the IOM to reflect the data from RCTs on fracture and fall prevention (Bischoff-Ferrari et al., 2010). The goal of these recommendations for the general population is to ensure that 25(OH)D concentrations of at least 50 nmol/l are attained in most individuals, so as to improve bone health. With a daily vitamin D intake of IU in children and adolescents, and IU in adults, more than 97% of individuals will reach a threshold of 50 nmol/l, including pregnant and breastfeeding women, and about 50% will reach a concentration of 75 nmol/l. It is not clear how much vitamin D is needed to reach the 75 nmol/l threshold needed for an effective fall and fracture prevention (Bischoff-Ferrari et al., 2010). However, based on a recent trial in Swiss hip fracture patients, this threshold may be reached in 93% of older adults with a daily vitamin D intake of 2000 IU (Bischoff-Ferrari, Dawson-Hughes, et al., 2009) References (FCN), F. C. f. N. (2012). Vitamin D deficiency: Evidence, safety, and recommendations for the Swiss population Bern Retrieved from NHzLpZeg7t,lnp6I0NTU042l2Z6ln1ad1IZn4Z2qZpnO2Yuq2Z6gpJCFfYB9f2ym162ep Ybg2c JjKbNoKSn6A-- Bischoff-Ferrari, H. A., Dawson-Hughes, B., Staehelin, H. B., Orav, J. E., Stuck, A. E., 84 EFSA Supporting publication 2016:EN-1078

85 Organisation Commision fédérale de l alimentation (COFA) (07) Comment text Theiler, R.,... Henschkowski, J. (2009). Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ, 339, b3692. doi: /bmj.b3692 Bischoff-Ferrari, H. A., Shao, A., Dawson-Hughes, B., Hathcock, J., Giovannucci, E., & Willett, W. C. (2010). Benefit-risk assessment of vitamin D supplementation. Osteoporos Int, 21(7), doi: /s Bischoff-Ferrari, H. A., Willett, W. C., Wong, J. B., Stuck, A. E., Staehelin, H. B., Orav, E. J.,... Henschkowski, J. (2009). Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch Intern Med, 169(6), doi: /archinternmed IOM. (2010). Dietary Reference Intakes for Calcium and Vitamin D [attachments comprised the following document: Vitamin D deficiency: Evidence, safety, and recommendations for the Swiss population. Report written by a group of experts on behalf of the Federal Commission for Nutrition (FCN) 2012, available at the following link: LpZeg7t,lnp6I0NTU042l2Z6ln1ad1IZn4Z2qZpnO2Yuq2Z6gpJCFfYB9f2ym162epYbg2c_JjKbNo KSn6A-- ] Commision fédérale de l alimentation (COFA) (07) [attachments comprised the following document: Vitamin D deficiency: Evidence, safety and recommendations for the Swiss population. Swiss recommendations on vitamin D intake available at the following link: LpZeg7t,lnp6I0NTU042l2Z6ln1ad1IZn4Z2qZpnO2Yuq2Z6gpJCFfYB9f2ym162epYbg2c_JjKbNo KSn6A-- ] Individual (academia), University of Aberdeen (08) The literature review was well done with clear conclusions (although I may not agree with the premise). It was helpful pulling the studies together. I could concur with all the points made with regard to markers, starting lines 756, 778, 795, 810, 855. With regard to 25OHD 814, particularly lines 817 to 818, I would certainly agree with this statement, but this appears not to have been followed through. Line 1033, using the same evidence it states that an RNI has been set at 10 ug to cover 97.5% of the populations needs (based on 25 nmol/l 25OHD). It would be helpful to understand the differences in conclusions and how one should reconcile this with an adequate intake of 15ug a day. Lines concerns the recent RCTs. Some of these interventions also gave calcium supplements so conclusions cannot be made on vitamin D / 25OHD only, especially as calcium is vitamin D-sparing. Lines concludes, after considering the RCTs, prospective studies and IOM (2011) report, that there is some evidence of higher bone loss with 25OHD > 50 nmol/l. It is difficult to support as this conclusion appears to have come from the observational data, which is confounded. Lines Although the statement with regard to increased osteomalacia risk may be true, it could equally be true if 25OHD<25nmol/L. Line 1409 Macdonald JBMR The conclusion was that BMD loss was not different between groups, whereas we gave the following conclusions below. There was a lack of dose response with 25OHD as indicated (line 1298). In conclusion, we found a small effect of vitamin D on BMD change in healthy postmenopausal women >5 years past menopause, in which 1000 IU but not 400 IU vitamin D appeared 85 EFSA Supporting publication 2016:EN-1078

86 Organisation Comment text to attenuate bone loss over 1 year. There was a dose response effect on PTH and serum calcium, albeit small, but not on any of the other measured markers including 1,25(OH)2D and bone turnover markers. Lines The opinion on fracture risk appears to have focused only on observational studies only which are confounded; and in linking to 25OHD measurements (which is noted to be flawed) to obtain a 25OHD cut off of 50 nmol/l. Yet lines concluded that vitamin D alone has not proven effective in reducing fractures. With regard to other outcomes I would agree with conclusions on muscular strength and function (Lines ) and falls (line ) and non musculoskeletal outcomes (lines ), in that the evidence is insufficient to set DRVs on vitamin D. With regard to calcium absorption in adults, the conclusion is that it is compromised only at 25OHD < 10 nmol/l, which is a much lower threshold than has been proposed. Lines The conclusions with regard to supplements and health outcomes are that benefits of vitamin D could depend on calcium intake. It was concluded that 10ug a day vitamin D has a benefit on some musculoskeletal outcomes. However the RCT data was considered confounded and not suitable for derivation of DRVs (line 3256). I have concerns with relating vitamin D intake and 25OHD for section 5.3. The biomarker has issues acknowledged earlier in the report (lines 817-8) and therefore the suggestion that meta regression approach is used to set DRVs is disappointing (line 3403). DRVs should be set with health outcomes as the focus, not biomarkers which has been indicated earlier are not ideal. Accepting this premise however, using 15 ug vitamin D a day the adjusted model was considered appropriate in adults and predicted a mean serum concentration is 63 nmol/l (CI nmol/l) (line 3652), which does seem higher than would be required for most people, given the evidence reviewed in the rest of the document. In particular, on line 3677 the Panel underlines that the meta-regression was done on data collected under conditions of minimal cutaneous vitamin D synthesis, and in the presence of endogenous cutaneous synthesis the requirement for vitamin is lower or may be zero. Individual (academia), University College Cork (09) Although there are no safety concerns and the unadjusted model predicted lower and upper limits (34 nmol/ L and 91 nmol/l, respectively) are within physiological ranges (line 3676), again this is without sunlight exposure, which does apply to most of the population who will obtain most of their vitamin D from the latter source. Importantly it also means that levels of food fortification strategies might be difficult to achieve in order to meet these intakes. Dear Sir or Madam, Please find attached the supporting document with key new data as referenced in (and in support of) our online submission through the EFSA portal in relation to the EFSA draft scientific opinion on dietary reference values for vitamin D (Re: Supporting documentation for response submitted by [xxx. Names provided]) Kind regards, Individuals (academia), University College Cork and University of Copenhagen (09) Public consultation on the draft scientific opinion on dietary reference values for vitamin D This submission to the public consultation focuses on a single substantive issue, relating to Section 5.3 of the draft opinion: Vitamin D intake and serum 25(OH)D concentration. The document provides evidence that two fundamental areas within the process and associated modeling, namely some of the criteria for selection of RCTs included in the modeling as well as the modeling of vitamin D intake-status itself have resulted in substantial errors in the estimates for vitamin D requirements. The conditions imposed by the modeling approach taken by the Panel and its unfounded conclusion that the data were inadequate to set DRVs based on PRI and AR, has, we believe, produced an unfavorable and retrograde proposal of an Al for vitamin D, which, if adopted, will have long-term consequences for public health nutrition in the European context EFSA Supporting publication 2016:EN-1078

87 Organisation Comment text We have provided this analysis of data to address these issues and based on the evidence presented propose the following recommendations: 1) Limit the meta-regression to those RCTs implemented at latitudes >50 N. This will ensure that the assumption of minimal endogenous vitamin D synthesis is more likely to be met, and would also be consistent with the IOM's use of RCTs in the zone of >49.5 N in preference to those between N. 2) Reconsider including the 4 high-dose vitamin D supplementation arms (>50 µg/d) in the modeling, irrespective of which model is used. 3) As the estimates based on individual data are at least twice those based on metaregression, even when adjusted meta-regression models are used, the EFSA panel is urged to consider using individual data from available RCTs (we are making the raw data available as required). In further support of this request, the EAR estimates based on individual data are of a similar magnitude to the meta-regression based estimates, suggesting the EFSA proposed values will only ensure adequacy for 50% of the population. 4) We propose that Panel reconsider the retrograde step of setting Als, which will have longterm adverse consequences for public health. The AR is a superior indicator for evaluating adequacy of intakes in population groups, which is a core application of the DRV framework. In this respect, the Al is a much weaker alternative and should only be used in the absence of adequate data, which we have clearly demonstrated is present for vitamin D. As we have demonstrated below, use of the individual data analysis in particular allows reliable estimates of the AR as well as the PRI. Context: Key summary points as outlined in the draft Opinion [2016] of the Panel's process The EFSA 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 (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. The Panel 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 controlled trials (RCTs) conducted in a period of assumed minimal endogenous vitamin D synthesis were identified through a comprehensive literature search and a review was undertaken by an external contractor. 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 (excluding pregnant or lactating women). Data were extracted for each arm of the individual trials. The Panel underlines that the meta-regression was done on data collected under conditions of minimal cutaneous vitamin D synthesis. Note: RCTs were identified which were performed in a period of assumed minimal endogenous vitamin D synthesis, i.e. at latitudes above 40 N from October through April (or below 40 S from April through October). The weighted 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 logarithm (Ln) of the total intake) and one derived from a model including the Ln of the total intake and adjusted for a number of relevant factors (baseline 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. Note: the non-linear (Ln) model was used to accommodate inclusion of results from trials using higher supplemental doses (i.e up to 50 µg/day) and which recognized that a blunting of serum 25(OH)D response to increasing vitamin D intake occurs around 35 µg/d. The Ln model was the chosen model and basis for derivation of their Al estimates. 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 (Als) instead, for all population groups. The Panel set Al for vitamin D at 15 µg/day, based on a meta-regression analysis and considering that, at this intake, most of the population will achieve a serum 25(OH)D 87 EFSA Supporting publication 2016:EN-1078

88 Organisation Comment text concentration near or above the target of 50 nmol/l. For children aged 1-17 years, an Al for vitamin D is set at 15 µg/day, based on the meta-regression analysis. For infants aged 7-11 months, an Al for vitamin D is set at 10 µg/day, based on trials in infants. For pregnant and lactating women, the Panel sets the same Al as for non-pregnant nonlactating women, i.e. 15 µg/day. Evidence presented for the Panel's consideration 1. Rationale for inclusion of some of the RCT data in the modeling, specifically (1A) those performed at latitudes between 40 and 49.5 o N, and (18) high-dose vitamin D arms from 4 RCTs. 1A. A fundamental underpinning element of the meta-regression analysis is that is based on an analysis of RCTs conducted in a period of assumed minimal endogenous vitamin D synthesis. To achieve this, RCTs that were performed in a period at latitudes above 40 N from October through April (or below 40 S from April through October) were identified, screened and those considered appropriate included in modeling. Of the 35 studies identified and accepted for inclusion, 10 RCTs were in a latitude band of N (8 RCTs in fact were in the latitude zone of N). Modeled UVB dose data (spectrally weighted to reflect that effective for synthesis of previtamin D in skin) for European regions [arising from our EC-funded ODIN project (www. ODIN-VITD.eu)] shows that for countries residing in the N, there can be significant UVB availability (sufficient for cutaneous synthesis of pre-vitamin D3) during some winter months. As seen in Figure 1 below showing exemplar regions in Europe that are in the N zone, UVB availability is evident in October and also March and April. Note: the line inserted at 1000 Jm-2 in the Figure is a guide to where UVB is capable of synthesizing previtamin D in the skin. Countries close to 40 N have UVB availability in all but December and January, while those closer to N, have UVB availability in April and even part of March and October (as bars in graph reflect mean UVB dose for that month). One or two countries at latitudes >.50 N have UVB availability in April, while not in Nov through to March (see below). Thus, almost one-third of the 35 studies chosen for the meta-regression analysis may have had contribution to vitamin D status from skin synthesis, and violate the inclusion criterion of minimal endogenous vitamin D synthesis. This refers to (Barger-Lux et al. 1998; Bischoff et al. 2003; Forman et al. 2013; Goussous et al. 2005; Harris & Dawson-Hughes, 2002a; Harris & Dawson-Hughes, 2002b; Heaney 2003; Holick et al. 2008; Rich-Edwards et al. 2011; Vieth et al. 2001), bringing the number of studies that met the minimal endogenous vitamin D synthesis criterion from 35 down to 25. Our recommendation: Limit the meta-regression to those RCTs implemented at latitudes >50 o N. This will ensure the assumption of minimal endogenous vitamin D synthesis will be more likely to be met, and would also be consistent with the IOM's use of RCTs in the zone of >49.5oN in preference to those between oN. Figure 1. Average monthly UVB doses effective for pre-vitamin D synthesis in Europe between 2003 and 2012, based on modeled UVB data generated in the ODIN project EFSA Supporting publication 2016:EN-1078

89 Organisation Comment text 1B. EFSA chose to implement the non-linear [i.e., Ln(total vitamin D intake) v. achieved serum 25(OH)D] model to accommodate inclusion of results from trials using higher supplemental doses (i.e up to 50 µg/day), recognizing that a blunting of the response of serum 25(OH)D to increasing vitamin D intake occurs around 35 g/d. Furthermore, the Ln model was the chosen as the model of preference over the linear model. Of the 83 RCT arms, four RCT arms had intakes in excess of 35 g/d (in fact total vitamin D intakes were in excess of 50 μg/d). The remainder of the RCT arms had total vitamin D intakes below 35 μg/d. The rationale behind selection of the range of vitamin D intakes within the RCT arms should ideally be such that they are reflective of that in the European population for which the DRV are being developed. In this regard, data from the EFSA 2012 Scientific Opinion on UL for Vitamin D (based on dietary intake data on 14 countries) suggests the highest 97.5th percentile of total vitamin D intake (diet plus supplement use) reported was 29.3 µg/day (older adults in Ireland). Thus, limiting the RCT arms to those with total vitamin D intakes below 35 μg/d would be representative of European population intakes. Also in terms of modeling and its impact on DRV estimates (see below) this intake range would be below the intakes where the dose-response blunting occurs which may influence the vitamin D intake-status relation, irrespective of whether linear or non-linear (curvilinear) model applied. Our recommendation: Reconsider including the 4 high-dose vitamin D supplementation arms in the modeling, irrespective of which model is used. 2. Impact of the model/approach used in DRV estimates for vitamin D The underpinning dose-response analysis for derivation of the DRV estimates is of critical importance to the process, and the pros and cons are well versed within the draft opinion. EFSA chose the meta-regression approach and considered unadjusted and adjusted models. However, the EFSA panel has also suggested that 'Attempts have been made to augment the meta-analytic approach by using individual data from vitamin D RCTs (Cashman et al., 2011b). However, in this case the panel states that it did not have access to a sufficiently large and representative sample of individual data from a study considered relevant for the aim of setting DRVs at the European level (Chap 5, Section 5.3.1). Two of the authors [NB: initials provided] provided written input to the EFSA secretariat, following an informal meeting at FENS in Oct These inputs made EFSA aware of two new vitamin D RCTs designed to provide individual data on which to base data analysis for setting DRVs. The raw data for these and previous existing studies that were designed 89 EFSA Supporting publication 2016:EN-1078

90 Organisation Comment text similarly in different life stage groups, with the specific purpose of addressing vitamin D DRVs, was offered to EFSA, if of use. Since then, we have used these data to generate models of relevance to this draft opinion and in particular to the dietary requirement estimates based on the meta-regression analysis. This is in addition, and beyond, points 1A and 1B above. Briefly, we have data from 6 relatively recent winter-based vitamin D3 RCTs, all of which had the same design, performed in locations above 50oN, winter-based, had same validated dietary assessment methodology for vitamin D and CDC-accredited analytical method for serum 25(OH)D, and which all included only data where high subject compliance was assured (see Appendix I). It is also worth noting that because of their design, which focussed on addressing vitamin D DRVs, these 6 RCTs meet and exceeded EFSA's stated inclusion criteria for RCT and as such pooling data from these RCTs did not require several of the adjustments EFSA required in relation to their selected more heterogeneous mix of RCTs (such as latitude, study start year, type of analytical method applied to assess serum 25(OH)D, assessment of compliance). For example the 12 and T2 for these 6 RCTs in metaanalysis, as per EFSA, were 86% and 48.4, respectively. The RCTs included young children, adolescents, adults and older adults and thus captured a wide age-range. These 6 RCTs yielded a total n of 855 providing significant power [of note also, of the 855 individuals, only one achieved a total vitamin D intake >35 μg/d; and this subject was excluded from our modelling for reasons outlined in 1B above]. We used the data from these RCTs to perform analysis on the individual data from these 854 participants (Individual Participant Data levelbased analysis) but also extracted the data on the basis of RCT arm, as per EFSA (and 1OM), yielding 21 separate RCT data points (Meta-regression analysis). Individual Participant Data level-based analyses: We used the 854 paired data points (total vitamin D intake and achieved serum 25(OH)D) and fit a simple linear model (total vitamin D intake versus achieved serum 25(OH)D) and in addition, as per EFSA, a Ln[total vitamin D intake] versus achieved serum 25(OH)D (in which the intercept was forced through 0 nmol/l). This was the simplest model and intended as an initial exemplar. More complex models were, and can, be run adjusting for covariates (see below): Figure 2. Simple unadjusted Linear model and Curvilinear model (based on individual data from the 6 RCTs, n=854). The linear model (r 2 =0.435) yielded: Achieved serum 25(OH)D = 1.667*(Total vitamin D intake [in μg/d]) The curvilinear model (setting 0 nmol/l as intercept) was Achieved serum 25(OH)D = 22.7*Ln(Total vitamin D intake [in μg/d]) EFSA Supporting publication 2016:EN-1078

91 Organisation Comment text Table 1. Predictions of vitamin D intake required to keep 97.5% of individuals over serum 25(OH)D thresholds using both models and based on individual data from 6 RCTs (n 854): We again used the two models above, but adjusted for two covariates as exemplars. As the data comes from individuals of differing age (children, teens, adults and older adults) we adjusted for age (mean), and separately, baseline serum 25(OH)D (mean), and in a further model for both age and baseline serum 25(OH)D (means). The impact of these adjustments in the modeling on the resulting PRI estimates at a serum 25(OH)D threshold of 50 nmol/l, as suggested by EFSA, are shown in Table 2 below: Table 2. Predictions of vitamin D intake required to keep 97.5% of individuals over serum 25(OH)D thresholds using adjusted models and based on individual data from 6 RCTs (n 854): Point to note: The estimates from the EFSA curvilinear (Ln) adopted model provide higher estimates because the blunting of response with this model occurs at intakes closer to μg/d rather than the 35 μg/d. There are other non-linear models available. Weighted linear Meta-regression analysis approach: We again used the simplest linear model and curvilinear models (i.e., total vitamin D intake v. achieved 25(OH)D and Ln[total vitamin D intake] v achieved 25(OH)D, respectively), as above, but with mean data from each of the 21 arms from the 6 RCT (same RCTs as above). Figure 3. Simple unadjusted 'Linear model' and 'Curvilinear model' (based on RCT arms [n=21]) means from the 6 same RCTs used above) 91 EFSA Supporting publication 2016:EN-1078

92 Organisation Comment text Predictions of the vitamin D intakes required to keep 97.5% of individuals over serum 25(OH)D thresholds were generated from these two models, see Table 3. Table 3. Predictions of vitamin D intake required to keep 97.5% of individuals over serum 25(OH)D thresholds using both Meta-regression models: The impact of the adjustments for age, baseline serum 25(OH)D, and both combined, (as used above with the Individual Participant Data-level analyses) in the Meta-regression modeling on the resulting PRI estimates at a serum 25(OH)D threshold of 50 nmol/l, as suggested by EFSA, are shown in the Table 4 below: Table 4. Predictions of vitamin D intake required to keep 97.5% of individuals over serum 25(OH)D thresholds using both Meta-regression models, but adjusted for covariates: Point to note: The estimates from the EFSA curvilinear (Ln) and linear meta-regression models are similar at 50 nmol/l; but both very dissimilar (about half) to those based on individual data. Note: We also performed this analysis with just kids (as per EFSA's model in 2-17 y olds), the same trends were evident in this subset (individual data n = 361; RCT arms = 9) [data not shown]. Our conclusions: Vitamin D dietary requirement estimates arising from Meta-regression models (linear or curvilinear) appear to be about half those from equivalent models with the individual participant data even though both based on data from the same set of RCTs EFSA Supporting publication 2016:EN-1078