FENS 2019, Dublin EFSA's approach in updating the UL of vitamin D for infants, Prof. M. Neuhauser-Berthold

1. EFSA’s approach in
updating the tolerable
upper intake level (UL) of
vitamin D for infants
Monika Neuhäuser-Berthold
Chair of the EFSA working group on Dietary
Reference Values for vitamins
16 October 2019

2. Context of the mandate
The European Commission (EC) requested EFSA in 2017 to update, regarding
infants, its scientific opinion of 2012 on the tolerable upper intake level (UL) for
vitamin D
Delegated Regulation (EU) 2016/127
on infant and follow-on formula
(IF & FoF),
repealing Directive 2006/141/EC in 2020
Directive 2006/141/EC Regulation (EU) 2016/127
Min-Max vit D content (µg/100 kcal)
IF
1-2.5 2-3
FoF
1-3 2-3
 EFSA working group of experts undertook preparatory work to address the
mandate
 Public consultation
 EFSA NDA Panel adopted scientific opinion (2018)
At the time of
the opinion

3. Definition
The tolerable upper intake level (UL) is defined as ….
the maximum level of total chronic daily intake from all
sources (i.e. foods, including supplements) judged to be
unlikely to pose a risk of adverse health effects

4. Conclusions regarding infants:
 There was a paucity of data on infants to set a no- or a lowest observed adverse effect
level
 Narrative description (7 papers) of data on ‘high’ vit D intake and the absence of
retarded growth or hypercalcaemia in infants
 EFSA decided to retain the UL of 25 µg vit D/day previously derived by SCF for
infants
Previous EFSA opinion (2012)
 was already a revision of the
ULs for vit D set by the
Scientific Committee on Food
(SCF, 2003) for all population
groups

5. Methodology for the update (2017-18)
C. INTAKE ASSESSMENTB. HAZARD CHARACTERISATION
D. RISK CHARACTERISATION
TARGET: INFANTS (0-<1 yr), full term, healthy
‘high’ intake of vit D (daily intake above AI of 10 µg/day (EFSA, 2016), D2 or D3, all dietary sources) and:
A. HAZARD IDENTIFICATION
based on previous UL assessments (SCF,
IOM, EFSA) and expert knowledge
 Systematic literature review (SR, 06/2017, 31 studies from 25 papers included)
 trials and observational studies
 full-term healthy infants, breastfed or formula-fed, possibly receiving complementary foods
 Assessment of the risk of bias of the studies
 Assessment of available evidence per outcome/endpoint
 Dose-response relationship between daily vit D intake & study-arm mean achieved S25(OH)D
(meta-regression)
1. Hypercalciuria (& urinary Ca)
2. Hypercalcaemia (& serum Ca)
3. Ectopic calcification e.g. nephrocalcinosis
4. Abnormal growth patterns
 Serum 25(OH)D
o 4 adverse health outcomes
 and 1 surrogate endpoint

6. Data on 4 adverse health outcomes (1)
• HYPERCALCIURIA: inconsistent definition and discrepancy in incidence rate
between studies
• Urinary Ca/Cr: no dose-response; only single spot urines
• HYPERCALCAEMIA: inconsistent definition; no observed clinical symptoms;
no dose-response
• Serum Ca: often only single measurements
• NEPHROCALCINOSIS: scarcity of data
• (RETARDED) GROWTH: secondary endpoint in most of the studies
• Attained length and weight: no dose-response
 Intervention & observational studies included in this SR: daily vit D amounts up to 50 µg
Conclusion:
data on daily
vit D intake and
adverse health
outcomes
could not be
used alone to
set a UL for vit D

7. Dose-response analysis
01 Meta-regression analysis: dose-response relationship between daily supplemental
intake of vit D and study-arm mean achieved serum 25(OH)D
 adjusted for baseline S25(OH)D, age and duration of supplementation
 aggregated data per arm of 6 trials with limited risk of bias
 i.e. 17 arms and 58 time points (baseline, end, intermediate timepoints)
 These trials did not assess the intake of vit D from the diet
02 Simulated distribution of S25(OH)D concentrations that may be achieved by
individuals (original and ln-transformed scales)
03
Estimated % of infants possibly with S25(OH)D above 200 nmol/L calculated for
different vit D intakes
 S25(OH)D ≤ 200 nmol/L is unlikely to pose a risk of adverse health outcomes in
healthy infants.
 Value derived from previous assessments (EFSA & other bodies) and from
data on infants from the systematic review
 Not a cut-off for toxicity but a conservative value from which a UL could be
derived

8. Results and updated ULs
% of infants
exceeding a S25(OH)D
of 200 nmol/L:
o increases with
supplemental vit D
intakes or with
baseline serum
25(OH)D
concentrations
o decreases with age
 Conclusion: updated ULs
 up to 6 mo: available body of evidence supports keeping the previous UL of 25 µg/day
 6 to less than 12 mo: the evidence from the predictions supports a UL of 35 µg/day
Model in original scaleAlso in EFSA opinion:
Results for another
statistical model (ln-
transformed scale)
Vitamin
D
intake
(µg/day)
%infants with achieved serum
25(OH)D concentration exceeding
200 nmol/L
For baseline serum 25(OH)D (nmol/L)
[10, 30) [30,60) [60,100] Any
[5-10) 0 0 0 0
[10-15) 0 0 1 0
[15-20) 0 1 2 1
[20-25) 0 2 4 2
[25-30) 1 3 7 4
[30-35) 3 6 11 7
[35-40) 6 10 16 11
[40-45) 10 15 21 17
[45-50) 15 20 27 22
%infants with achieved serum
25(OH)D concentration exceeding
200 nmol/L
For baseline serum 25(OH)D (nmol/L)
[10, 30) [30,60) [60,100] Any
0 0 0 0
0 0 0 0
0 0 0 0
0 0 1 0
0 1 2 1
1 2 4 2
2 4 8 5
4 7 12 8
7 11 17 12
between 6 and 12 mo of ageup to 6 mo of age

9. Methodology for the update (2017-18)
C. INTAKE ASSESSMENTB. HAZARD CHARACTERISATION
D. RISK CHARACTERISATION
TARGET : INFANTS (0-<1 yr), full term, healthy
‘high’ intake of vit D (daily intake above AI of 10 µg/day (EFSA, 2016), D2 or D3, all dietary sources) and:
A. HAZARD IDENTIFICATION
based on previous UL assessments (SCF,
IOM, EFSA) and expert knowledge
 Systematic literature review (SR, 06/2017, 31 studies from 25 papers included)
 trials and observational studies
 full-term healthy infants, breastfed or formula-fed, possibly receiving complementary foods
 Assessment of the risk of bias of the studies
 Assessment of available evidence per outcome/endpoint
 Dose-response relationship between daily vit D intake & study-arm mean achieved S25(OH)D
(meta-regression)
1. Hypercalciuria (& urinary Ca)
2. Hypercalcaemia (& serum Ca)
3. Ectopic calcification e.g. nephrocalcinosis
4. Abnormal growth patterns
 Serum 25(OH)D
o 4 adverse health outcomes
 and 1 surrogate endpoint

10. Dietary supplements for infants
 In 2017: data on food consumption in infants available in EFSA for 6 countries
(FI, DE, DK, BUL, UK, IT), with limited information on supplements used
and variable percentage of supplements users
 Variability of national supplementation policies on vit D for infants &
variability of compliance
 National supplementation policies: decision of risk managers in Member States.
Supervision by health professionals
 Intake of vit D through consumption of supplements was not taken into
account in this intake assessment

11. Intake assessment for infants up to 4 months

12. Intake of infants up to 4 months: results
Conclusion:
Increased levels of vitamin D in
IF to 3 µg/100 kcal may lead
some younger infants to
consume amounts above the
UL from formulae alone. The
precise percentage of infants
could not be determined from
the data used

13. Intake assessment for infants 4 <12 months

14. Food consumption data
 EFSA European Comprehensive Consumption Database, FoodEx2 classified
 For infants: 6 national food consumption surveys
 Food consumption data for infants, on at least 2 reporting days
 Vitamin D intake estimated based on food consumption without supplements
 Performed by multiplying, for each food category, the average consumption with its vitamin
content, (i) for all infants, (ii) for formula-fed infants and (iii) non formula-fed infants
Country
Number of
subjects
Number of
formula
consumers
Bulgaria 510 220
Denmark 826 598
Finland 500 303
Germany 159 110
Italy 11 6
UK 1,369 1,188
Surveys in infants for which individual data were available to EFSA

15. Intake assessment of infants 4 to <12 months
Calculations
• separately for consumers and non-consumers of voluntarily fortified foods (11 food
categories identified)
• considering consumption of 3 mandatorily fortified foods (IF, FoF, processed cereal-based foods
for infants and young children)
• considering vit D intake via IF and FoF for each with min and max amounts of vit D
• according to both ‘old’ (Directive 2006/141/EC) and ‘new’ regulation (Regulation (EU)
2016/127)
R2016D2006
Min Max Min Max
No voluntary
fortification
Voluntary
fortification
No voluntary
fortification
Voluntary
fortification
No voluntary
fortification
Voluntary
fortification
No voluntary
fortification
Voluntary
fortification
8 intake scenarios assumed to describe situations that may occur on the EU market

16. Intake of infants 4-<12 months: results
Example: 95th percentile, formula consumers only,
R(EU)2016/127 (i.e. 4 of the 8 investigated scenarios (S))
Conclusion:
In older infants, the 95th
percentile of intake does
not exceed the ULs, without
considering vitamin D
supplemental intake

17. Thank you for your attention!
More information?
• www.efsa.europa.eu
• ResearchGate: project ‘Dietary Reference
Values’
• Interactive tool DRV Finder (DRVs incl. ULs)
WG members:
• Mary Fewtrell
• Christel Lamberg-Allardt
• Monika Neuhäuser-Berthold (WG Chair)
• Kristina Pentieva
• Hildegard Przyrembel
• Dominique Turck (NDA Panel chair)
EFSA staff members:
• Davide Arcella
• Céline Dumas
• Lucia Fabiani
• Laura Martino
• Daniela Tomcikova

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