Dietary Reference Values for riboflavin

Dietary Reference Values for riboflavin

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 vitamin B2. The Panel considers in this Scientific Opinion that vitamin B2 is riboflavin.

Riboflavin or 7,8-dimethyl-10-ribityl-isoalloxazine, is a water-soluble compound naturally present in food of plant and animal origin as free riboflavin and, mainly, as the biologically active derivatives flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD).

Riboflavin is the integral part of the coenzymes FAD and FMN that act as the cofactors of a variety of flavoprotein enzymes such as glutathione reductase or pyridoxamine phosphate oxidase (PPO). FAD and FMN act as proton carriers in redox reactions involved in energy metabolism, metabolic pathways and formation of some vitamins and coenzymes. In particular, riboflavin is involved in the metabolism of niacin and vitamin B6 and FAD is also required by the methylenetetrahydrofolate reductase (MTHFR) in the folate cycle and thereby is involved in homocysteine metabolism. Signs of riboflavin deficiency are unspecific and include sore throat, hyperaemia and oedema of the pharyngeal and oral mucous membranes, cheilosis, glossitis (magenta tongue), and normochromic normocytic anaemia characterised by erythroid hypoplasia and reticulocytopenia. No tolerable upper intake level has been set for riboflavin.

Dietary riboflavin associated with food protein is hydrolysed to free riboflavin and its absorption mainly takes place in the proximal small intestine through carrier-mediated, saturable transport process. The Panel considers an absorption efficiency of dietary riboflavin of 95%. Free riboflavin transported into enterocytes is subjected to phosphorylation to form FMN, subsequently converted to FAD. From the small intestine, riboflavin enters the plasma, where FAD is reported to be the major form. The uptake of riboflavin into the cells of organs such as the liver is facilitated and may require specific carriers. Absorbed riboflavin appears partly in the plasma, and partly is sequestered by the liver on the first pass through the portal vein from the gut. There is a positive transfer of riboflavin from the pregnant woman to the fetus. Most of the riboflavin in tissues including erythrocytes exists predominantly as FAD and FMN, covalently bound to enzymes. Unbound FAD and FMN are rapidly hydrolysed to free riboflavin that diffuses from cells and is excreted. When riboflavin is absorbed in excess, it is catabolised to numerous metabolites and little is stored in the body tissues. Urine is the main route for elimination of riboflavin.

The Panel reviewed possible biomarkers of riboflavin status and intake, i.e. urinary excretion of riboflavin, erythrocyte glutathione reductase activation coefficient (EGRAC), plasma and erythrocyte riboflavin, FAD and FMN, as well as PPO activity and activation coefficient. The Panel considers that the inflection point in the mean urinary riboflavin excretion curve in relation to riboflavin intake reflects body saturation and can be used to indicate adequate riboflavin status. The Panel also considers that EGRAC is a useful biomarker of riboflavin status and that EGRAC of 1.3 or less indicates adequate riboflavin status in all population groups. However, the Panel considers that the data on the relationship between riboflavin intake and EGRAC cannot be used alone to set DRVs for riboflavin, but can be used in support of data on the inflection in the urinary excretion curve in view of setting DRVs for riboflavin.

The Panel also notes that riboflavin status is modified by physical activity as urinary excretion of riboflavin is (generally) decreased and EGRAC increased when physical activity is increased, suggesting higher utilisation of riboflavin with increased energy expenditure. However, there is a lack of experimental data showing a clear quantitative relationship between riboflavin status biomarkers (urinary excretion of riboflavin and EGRAC) and energy expenditure (or physical activity). In addition, the Panel considers that relationship between riboflavin intake and biomarkers of riboflavin status is also influenced by MTHFR C677T polymorphism, as homozygosity for the T allele can increase the individual requirement for riboflavin, although the extent of this increase cannot be defined. After having reviewed the existing evidence, the Panel concludes that available data on intake of riboflavin and health outcomes cannot be used to derive DRVs for riboflavin.

The Panel notes that new scientific data have become available for adults since the publication of the Scientific Committee for Food (SCF) report in 1993, and considers that updated average requirements (ARs) and population reference intake (PRIs) can be set for adults, children, pregnant and lactating women.

For adults, the Panel considers that an AR of 1.3 mg/day (after rounding) can be determined from the weighted mean of riboflavin intake associated with the inflection point in the mean urinary riboflavin excretion curve in relation to riboflavin intake as reported in four intervention studies in different non-European Union (EU) countries. The Panel considers that the potential effect of physical activity and of MTHFR 677TT genotype on riboflavin requirement is covered by the data presented from the studies considered, thus is accounted for in the assumed the coefficient of variation (CV) applied to set the PRI for riboflavin. A CV of 10% was used to calculate PRIs from the ARs for adults, i.e. 1.6 mg/day after rounding, and the same CV was used for all other population groups. The Panel considers that there is no indication of different riboflavin requirement according to sex or between younger and older adults, and sets the same DRV for men and women (without correction per difference in body weight) of all ages.

For all infants aged 7–11 months, in the absence of sufficient data to set an AR, the Panel sets an AI of 0.4 mg/day based on the estimated intake of riboflavin of exclusively breastfed infants from birth to six months, and upward extrapolation by allometric scaling (on the assumption that riboflavin requirement is related to metabolically active body mass), taking into account the difference in reference body weight.

For children aged 1–17 years, the Panel sets ARs by downward extrapolation from the AR of adults, by allometric scaling (on the assumption that riboflavin requirement is related to metabolically active body mass), applying growth factors and taking into account the differences in reference body weight. The Panel considers unnecessary to set sex-specific ARs and PRIs for boys and girls of all ages. The Panel sets ARs ranging from 0.5 (children aged 1–3 years) to 1.4 mg/day (children aged 15–17 years) and PRIs ranging from 0.6 (children aged 1–3 years) to 1.6 mg/day (children aged 15–17 years).

For pregnant women, the Panel considers that data are insufficient to estimate the additional needs for dietary riboflavin during pregnancy based on fetal uptake and riboflavin accretion in the placenta during pregnancy. The Panel sets an AR of 1.5 mg/day, calculated by allometric scaling from the AR for non-pregnant women, considering the mean gestational increase in body weight of 12 kg, and also sets a PRI of 1.9 mg/day.

For lactating women, an additional riboflavin requirement of 0.31 mg/day is calculated considering the secretion of riboflavin into milk during lactation (0.291 mg/day), the mean milk transfer during the first six months of lactation in exclusively breastfeeding women (0.8 L/day), and an absorption efficiency of 95%. An AR of 1.7 mg/day is calculated by the Panel, considering the additional requirement above the AR of non-lactating women, and a PRI of 2 mg/day is set for lactating women.

Based on data from 13 surveys in nine countries of the EU, riboflavin intake mean estimates ranged across countries from 0.6 to 1.2 mg/day in infants (< 1 year), from 0.9 to 1.4 mg/day in children aged 1 to < 3 years, from 1 to 1.8 mg/day in children aged 3 to < 10 years, and from 1.2 to 2.2 mg/day in children aged 10 to < 18 years. Riboflavin intake mean estimates ranged between 1.4 and 2.2 mg/day in adults.

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