Scientific Opinion on Dietary Reference Values for folate

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Article
Panel on Dietetic Products, Nutrition and Allergies
EFSA Journal
EFSA Journal 2014;12(11):3893 [59 pp.].
doi
10.2903/j.efsa.2014.3893
Panel members at the time of adoption
Carlo Agostoni, Roberto Berni Canani, Susan Fairweather-Tait, Marina Heinonen, Hannu Korhonen, Sébastien La Vieille, Rosangela Marchelli, Ambroise Martin, Androniki Naska, Monika Neuhäuser-Berthold, Grażyna Nowicka, Yolanda Sanz, Alfonso Siani, Anders Sjödin, Martin Stern, Sean (J.J.) Strain, Inge Tetens, Daniel Tomé, Dominique Turck and Hans Verhagen.
Acknowledgements

The Panel wishes to thank the members of the Working Group on Dietary Reference Values for vitamins: Monika Neuhäuser-Berthold, Grażyna Nowicka, Kristina Pentieva, Hildegard Przyrembel, Sean (J.J.) Strain, Inge Tetens, Daniel Tomé and Dominique Turck for the preparatory work on this scientific opinion and EFSA staff: Anja Brönstrup for the support provided to this scientific opinion.

Contact
Type
Opinion of the Scientific Committee/Scientific Panel
On request from
European Commission
Question Number
EFSA-Q-2011-01212
Adopted
30 October 2014
Published
20 November 2014
Last Updated
6 February 2015. This version replaces the previous one/s.
Affiliation
European Food Safety Authority (EFSA), Parma, Italy
Note
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Abstract

Following a request from the European Commission, the Panel on Dietetic Products, Nutrition and Allergies (NDA) derived Dietary Reference Values (DRVs) for folate. The Panel concludes that an Average Requirement (AR), as well as a Population Reference Intake (PRI) assuming a coefficient of variation (CV) of 15 % to account for the additional variability associated with the higher requirement for folate in individuals with the methylene-tetrahydrofolate reductase (MTHFR) 677TT genotype, can be derived from biomarkers of folate status. Several health outcomes possibly associated with folate intake/status were also considered, but data were found to be insufficient to establish DRVs. For adults, the AR is determined from the folate intake required to maintain folate adequacy characterised by serum and red blood cell folate concentrations of ≥ 10 and 340 nmol/L, respectively. An AR of 250 µg dietary folate equivalents (DFE)/day and a PRI of 330 µg DFE/day are derived. For infants aged 7–11 months, an Adequate Intake (AI) of 80 µg DFE/day is derived by extrapolating upwards from the estimated folate intake in exclusively breast-fed infants. For children, ARs are extrapolated from the AR for adults using allometric scaling and growth factors and considering differences in reference weights. PRIs ranging from 120 µg DFE/day for 1–3 year-old children to 330 µg DFE/day for boys and girls aged 15–17 years are derived. For pregnant women, an AI of 600 µg DFE/day is derived based on a study on maintenance of serum and red blood cell folate concentrations in pregnancy. For lactating women, an additional intake of 130 µg DFE/day is considered to cover folate losses via breast milk; this figure is added to the AR for non-lactating women and a PRI of 500 µg DFE/day is derived.

Summary

Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver a scientific opinion on Dietary Reference Values (DRVs) for the European population, including folate.

Folate is a generic term used for a family of compounds which belong to the group of B-vitamins. Naturally occurring food folates are a mixture of reduced mono- and polyglutamates, and their chemical structure makes them unstable. In contrast, the synthetic folic acid, which arises in the diet only through ingesting fortified foods or food supplements, is a fully oxidised monoglutamate and the most chemically stable form. Upon ingestion, polyglutamated folate forms are hydrolysed to monoglutamates and actively absorbed by a pH-dependent saturable mechanism in the duodenum and upper jejunum, or by passive diffusion in the ileum if consumed in supraphysiological amounts. Natural food folates have a lower bioavailability than folic acid. In order to take into account these differences, dietary folate equivalents (DFE) have been introduced and defined as 1 µg DFE = 1 µg food folate = 0.6 µg folic acid from fortified food or as a supplement consumed with food = 0.5 µg of a folic acid supplement taken on an empty stomach.

Folates function as cofactors for enzymes involved in one-carbon metabolism. Folate provides one-carbon units for the formation of nucleotides necessary for the synthesis of RNA and DNA. Folate is also fundamental for the normal functioning of the methionine cycle, which is responsible for both the conversion of homocysteine to methionine and the production of the universal methyl donor S-adenosylmethionine (SAM). SAM donates its methyl group to more than 100 methyltransferases for a wide range of substrates such as DNA, hormones, proteins, neurotransmitters and membrane phospholipids, all of which are regulators of important physiological processes. Folate deficiency impairs DNA replication and cell division, which adversely affects rapidly proliferating tissues such as bone marrow and results in the production of unusually large macrocytic cells with poorly differentiated nuclei. The predominant feature of folate deficiency is megaloblastic anaemia.

Serum and red blood cell folate concentrations are sensitive biomarkers of folate intake and status, and the Panel considers that these are suitable primary criteria for deriving DRVs for folate. Although plasma total homocysteine on its own is not suitable for use as a biomarker of folate status, the Panel notes that its relationship with folate can be used to define the blood folate concentrations necessary for plasma total homocysteine to level off. The Panel considers that the previously defined cut-offs for folate adequacy (serum folate of ≥ 10 nmol/L and red blood cell folate of ≥ 340 nmol/L), based on the inverse and non-linear association of plasma total homocysteine with serum and red blood cell folate concentrations, are suitable criteria for determining the requirement for folate. Homozygosity for the T allele of the methylene-tetrahydrofolate reductase (MTHFR) 677C→T polymorphism, which has a prevalence of up to 24 % in some European countries, is associated with low folate status and mostly unfavourable health effects. The Panel considers that this polymorphism should be taken into account when determining the requirement for folate. The Panel has also considered several health outcomes that are possibly associated with folate intake and status, but data are insufficient to establish DRVs.

For healthy adult men and women, an Average Requirement (AR) of 250 µg DFE/day is proposed based on results of one controlled study showing that an intake of 205–257 µg DFE/day for seven weeks after a depletion phase maintains serum folate concentrations above the cut-off for folate adequacy in at least half of the group. These findings are in close agreement with those of two other controlled studies showing that folate intakes of around 200–300 µg/day may be sufficient to maintain serum and red blood cell folate concentrations of ≥ 10 and ≥ 340 nmol/L, respectively. A Population Reference Intake (PRI) of 330 µg DFE/day is derived assuming a coefficient of variation (CV) of 15 % to account for the additional variability associated with the higher requirement for folate in individuals with the MTHFR 677TT genotype.

For infants aged 7–11 months, an Adequate Intake (AI) of 80 µg DFE/day is derived by extrapolating upwards from the estimated folate intake from breast milk of exclusively breast-fed infants for which folate deficiency has not been observed.

For children and adolescents, the ARs for folate are extrapolated from the AR for adults by allometric scaling and the use of growth factors. The PRIs are derived by assuming a CV of 15 % and range from 120 µg DFE/day for 1–3 year-old children to 330 µg DFE/day for both boys and girls aged 15–17 years.

In pregnancy, intakes of 630–680 µg DFE/day administered in a controlled study to pregnant women during their second and third trimesters resulted in concentrations of biomarkers of folate status well above cut-offs for folate adequacy as established in non-pregnant adults. Acknowledging that the database is weaker than that for non-pregnant adults, an AI of 600 µg DFE/day for folate is proposed for pregnancy.

For lactating women, an additional requirement of 130 µg DFE/day is derived to compensate for folate losses through breast milk. By adding this additional requirement to account for losses to the AR for non-lactating women, an AR of 380 µg DFE/day is obtained. Assuming a CV of 15 %, a PRI of 500 µg DFE/day is established.

Keywords
folate, folic acid, Average Requirement, Dietary Reference Value, health outcomes
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Number of Pages
59